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CloseFluconazole: Pediatric drug informationFluconazole: Pediatric drug information(For additional information see "Fluconazole: Drug information" and see "Fluconazole: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USDiflucanBrand Names: CanadaACT Fluconazole;APO-Fluconazole;Diflucan;Fluconazole SDZ;MYLAN-Fluconazole;PMS-Fluconazole;PRO-Fluconazole;TARO-Fluconazole;TEVA-FluconazoleTherapeutic CategoryAntifungal Agent, SystemicDosing: NeonatalGeneral dosing, susceptible infection (Ref):Prophylaxis: IV, Oral: 3 to 6 mg/kg/dose twice weekly.Treatment: IV, Oral: Initial: 25 mg/kg on day 1, followed by 12 mg/kg/dose once daily.Candidiasis, prophylaxis for NICUs with high rates (>10%) of invasive candidiasis: Birth weight <1 kg: IV, Oral: 3 to 6 mg/kg/dose twice weekly for up to 6 weeks or until IV access is no longer required; initiate within 48 to 72 hours of birth (Ref); NICU-specific Candida sp. susceptibility patterns/minimum inhibitory concentration (MIC) distributions may be considered when selecting the dose; pharmaco*kinetic simulations suggest that the lower dose (3 mg/kg) provides adequate coverage when MICs ≤2 mcg/mL and a higher dose (6 mg/kg) is necessary when MIC >2 mcg/mL (Ref); when MICs are low within a NICU, 3 mg/kg is likely as efficacious as 6 mg/kg (Ref). Note: Prophylaxis may also be used in NICUs with lower rates of infection for patients who have risk factors (eg, central venous catheters, third-generation cephalosporins, carbapenems) for invasive candidiasis (Ref).Candidiasis, systemic (including Candidemia and invasive candidiasis), treatment: Note: Alternative treatment for patients who have not received fluconazole prophylaxis.IV, Oral: 12 mg/kg/dose once daily (Ref). Based on pharmaco*kinetic studies, a loading dose of 25 mg/kg, followed by 12 mg/kg/dose once daily achieves the desired AUC within 24 hours (Ref). Some experts have suggested 12 mg/kg/dose every 24 to 48 hours for extremely preterm infants PNA <8 days (Ref).Candidiasis, CNS infection, step-down therapy: IV, Oral: 12 mg/kg/dose once daily until all signs, symptoms, and CSF and radiological abnormalities have resolved (Ref).Candidiasis, esophageal; treatment (Ref): Note: Minimum duration of therapy is 3 weeks and for at least 2 weeks following resolution of symptoms:GA 26 to 29 weeks: IV, Oral:PNA ≤14 days: 6 mg/kg/dose every 72 hours; change to every 24 hours once beyond the first 2 weeks of life. Dose up to 12 mg/kg/dose may be used based on clinical response.PNA >14 days: 6 mg/kg/dose once daily; doses up to 12 mg/kg/dose may be used based on clinical response.GA >29 weeks: IV, Oral: 6 mg/kg/dose once daily; doses up to 12 mg/kg/dose may be used based on clinical response.Candidiasis, oropharyngeal (thrush); treatment (Ref):GA 26 to 29 weeks: IV, Oral:PNA ≤14 days: Initial: 6 mg/kg on day 1, followed by 3 to 6 mg/kg/dose every 72 hours; change to every 24 hours once beyond the first 2 weeks of life.PNA >14 days: Initial: 6 mg/kg on day 1, followed by 3 to 6 mg/kg/dose once daily for at least 2 weeks.GA >29 weeks: IV, Oral: Initial: 6 mg/kg on day 1, followed by 3 to 6 mg/kg/dose once daily for at least 2 weeks.Candidiasis, extracorporeal membrane oxygenation (ECMO) patients: Limited data available; dosing based on a pharmaco*kinetic study of pediatric patients (including neonates):Term neonates:Prophylaxis: IV: 12 mg/kg on day 1, followed by 6 mg/kg/dose once daily (Ref).Treatment: IV: 35 mg/kg on day 1, followed by 12 mg/kg/dose once daily (Ref).Coccidioidomycosis, empiric therapy: IV, Oral: 6 to 12 mg/kg/dose once daily until diagnosis is ruled out (Ref).Cryptococcal, CNS disease (meningitis):Acute treatment: Limited data in neonates, other agents preferred: Neonates ≥30 weeks: IV, Oral: 12 mg/kg/dose on day 1, followed by 6 to 12 mg/kg/day for 10 to 12 weeks after CSF culture becomes negative.Consolidation therapy (after treatment with amphotericin B and flucytosine): IV, Oral: 12 mg/kg/dose on day 1, then 10 to 12 mg/kg/dose daily for a minimum of 8 weeks (Ref).Prevention of relapse (HIV-infected patients): IV, Oral: 6 mg/kg/dose once daily (Ref).Dosing adjustment in renal impairment: There are no specific neonatal dosage adjustments provided in the manufacturer's labeling; some experts have suggested the following indication-specific dosing based on pharmaco*kinetic studies (Ref):Candidiasis, prophylaxis: IV, Oral: PNA ≥3 days: Scr ≥1.3 mg/dL: 6 mg/kg/dose once weekly; resume 6 mg/kg/dose twice weekly when Scr is ≤1 mg/dL.Dosing: PediatricGeneral dosing, susceptible infection: Infants, Children, and Adolescents: IV, Oral: Initial: 6 to 12 mg/kg/dose on day 1, followed by 3 to 12 mg/kg/dose once daily; duration and dosage depends on severity of infection; the manufacturer suggests limiting dose to 600 mg/dose; however, higher maximum doses have been used; see specific indications.Candida infections, prophylaxisCandida infections, prophylaxis:Oncology patients at high risk of invasive candidiasis (eg, AML, recurrent ALL, myelodysplastic syndrome [MDS], HSCT recipients): Limited data available: Infants, Children, and Adolescents: IV, Oral: 6 to 12 mg/kg/dose once daily; maximum dose: 400 mg/dose; duration dependent upon type of transplant and/or chemotherapy, consult institution-specific protocols (Ref).Surgical prophylaxis, high-risk patients undergoing liver, pancreas, kidney, or pancreas-kidney transplantation: Infants, Children, and Adolescents: IV: 6 mg/kg as a single dose 60 minutes before procedure; maximum dose: 400 mg/dose; time of initiation and duration varies with transplant type, consult institution-specific protocols (Ref).Candidiasis, systemic, treatmentCandidiasis, systemic (including Candidemia and invasive candidiasis), treatment: Infants, Children, and Adolescents: IV, Oral: 12 mg/kg/dose once daily; maximum dose: 800 mg/dose; continue treatment for ≥14 days after documented clearance, resolution of symptoms, and resolution of neutropenia if present (Ref). An initial loading dose of 25 mg/kg has also been suggested (Ref).Candidiasis, CNS candidiasis, step-down therapyCandidiasis, CNS candidiasis, step-down therapy: Infants, Children, and Adolescents: Oral, IV: 12 mg/kg/dose once daily following initial therapy with liposomal amphotericin B (with or without flucytosine); maximum dose: 800 mg/dose; treatment should continue until all signs, symptoms, and CSF and radiological abnormalities have resolved (Ref).Candidiasis, endophthalmitis, treatmentCandidiasis, endophthalmitis, treatment: Infants, Children, and Adolescents: Oral, IV: 12 mg/kg/dose once daily for at least 4 to 6 weeks until examination indicates resolution; maximum dose: 800 mg/dose. Note: Use in combination with intravitreal injection of voriconazole or amphotericin B deoxycholate when vitritis or macular involvement is present (Ref). An initial loading dose of 25 mg/kg has also been suggested (Ref).Candidiasis, esophagealCandidiasis, esophageal:Treatment: Infants and Children: Oral, IV: 6 to 12 mg/kg/dose once daily for 14 to 21 days (Ref); maximum dose: 600 mg/dose (Ref). Note: An initial loading dose of 25 mg/kg has also been suggested (Ref).Adolescents: Oral, IV: 6 to 12 mg/kg/dose once daily for 14 to 21 days (Ref); usual adult dose: 400 mg/dose (Ref). Note: An initial loading dose of 25 mg/kg has also been suggested (Ref).Suppressive therapy (secondary prophylaxis): Patients with HIV: Note: Not typically recommended, but can be considered if experiencing frequent severe recurrent infection (Ref).Infants and Children: Oral: 6 to 12 mg/kg/dose three times weekly; maximum dose: 600 mg/dose. If daily administration is required, maximum dose is 200 mg/dose (Ref).Adolescents: Oral: 100 to 200 mg once daily (Ref).Candidiasis, oropharyngealCandidiasis, oropharyngeal:Treatment:Infants and Children: Oral: 6 to 12 mg/kg/dose once daily for 7 to 14 days (Ref); maximum dose: 400 mg/dose (Ref).Adolescents: Oral: 6 mg/kg/dose once daily for 7 to 14 days (Ref); usual adult dose: 100 to 200 mg/dose (Ref).Suppressive therapy (secondary prophylaxis): Patients with HIV: Note: Not typically recommended, but can be considered if experiencing frequent severe recurrent infection (Ref).Infants and Children: Oral: 6 to 12 mg/kg/dose three times weekly; maximum dose: 600 mg/dose. If daily administration is required, maximum dose is 200 mg/dose (Ref).Adolescents: Oral: 100 to 200 mg once daily or three times weekly (Ref).Candidiasis, peritoneal dialysis-related infectionsCandidiasis, peritoneal dialysis-related infections (Ref):Peritonitis: Infants, Children, and Adolescents:Treatment: Intraperitoneal, IV, Oral: 6 to 12 mg/kg/dose every 24 to 48 hours; maximum dose: 400 mg/dose.Prophylaxis for high-risk situations (eg, during antibiotic therapy or PEG placement): IV, Oral: 3 to 6 mg/kg/dose every 24 to 48 hours; maximum dose: 200 mg/dose.Exit-site or tunnel infection, treatment: Infants, Children, and Adolescents: Oral: 6 mg/kg/dose every 24 to 48 hours; maximum dose: 400 mg/dose.Candidiasis, vulvovagin*l infectionCandidiasis, vulvovagin*l infection:Uncomplicated infections, treatment (independent of HIV status): Adolescents: Oral: 150 mg as a single dose (Ref).Severe infections, treatment:Non-HIV-exposed/-infected: Adolescents: Oral: 150 mg every 72 hours for 2 to 3 doses (Ref).HIV-exposed/-infected: Adolescents: Oral: 100 to 200 mg once daily for ≥7 days; may follow with chronic suppressive therapy of 150 mg once weekly (Ref).Recurrent infection, treatment:Non HIV-exposed/-infected: Adolescents: Oral: Initial: 100 to 200 mg every 72 hours for 3 doses; followed by maintenance of 100 to 200 mg once weekly for 6 months (Ref).HIV-exposed/-infected: Adolescents: Oral: 100 to 200 mg once daily for ≥ 7 days; may follow with chronic suppressive therapy of 150 mg once weekly (Ref).Coccidioidomycosis, HIV-exposed/-infectedCoccidioidomycosis, HIV-exposed/-infected (Ref):Mild to moderate non-meningeal infection (eg, focal pneumonia): Infants and Children: IV, Oral: 6 to 12 mg/kg/dose once daily; maximum dose: 400 mg/dose.Adolescents: Oral: 400 mg once daily for ≥6 months.Severe illness (diffuse pulmonary or disseminated non-meningitic disease) initial therapy if unable to use amphotericin or as step-down therapy: Infants and Children: IV, Oral: 12 mg/kg/dose once daily; maximum dose: 800 mg/dose for a total of 1 year of treatment followed by secondary prophylaxis.Meningeal infection:Infants and Children: IV, Oral: 12 mg/kg/dose once daily; maximum dose: 800 mg/dose, followed by lifelong secondary prophylaxis.Adolescents: IV, Oral: 400 to 800 mg once daily, followed by lifelong suppressive therapy.Secondary prophylaxis/chromic suppressive therapy: Infants, Children, and Adolescents: Oral: 6 mg/kg/dose once daily; maximum dose: 400 mg/dose.Cryptococcal infectionCryptococcal infection:Mild to moderate localized infection including pneumonia (not CNS), treatment:Non HIV-exposed/-infected: Infants, Children, and Adolescents: Oral: 6 to 12 mg/kg/dose once daily for 6 to 12 months. Usual adult dose is 400 mg/dose (Ref).HIV-exposed/-infected: Infants and Children: IV, Oral: 12 mg/kg on day 1, then 6 to 12 mg/kg/dose once daily; maximum dose: 600 mg/dose; duration depends on severity and clinical response (Ref).Adolescents: Oral: 400 mg daily for 12 months (Ref).CNS, severe pulmonary or disseminate infection, treatment:Induction therapy: HIV-exposed/-infected (not first-line therapy):Infants and Children: IV: 12 mg/kg on day 1, then 10 to 12 mg/kg/dose once daily in combination with amphotericin B or flucytosine for ≥14 days; maximum dose: 800 mg/dose (Ref).Adolescents: IV, Oral: 400 to 800 mg once daily in combination with flucytosine for ≥14 days or 800 mg once daily in combination with amphotericin for ≥14 days or 1,200 mg once daily as monotherapy for at least 2 weeks (Ref).Consolidation:Non-HIV-exposed/-infected: Infants, Children, and Adolescents: IV, Oral: 10 to 12 mg/kg/day once daily or in divided doses twice daily for 8 weeks; maximum dose: 800 mg/dose (Ref).HIV-exposed/-infected:Infants and Children: IV, Oral: 12 mg/kg on day 1, then 10 to 12 mg/kg/day once daily for ≥8 weeks; maximum daily dose: 800 mg/dose (Ref).Adolescents: IV, Oral: 400 mg once daily for ≥8 weeks (Ref).Secondary prophylaxis/chronic suppressive maintenance therapy: Non-HIV-exposed/-infected: Infants, Children, and Adolescents: Oral: 6 mg/kg/dose once daily for 6 to 12 months; maximum dose: 200 mg/dose (Ref).HIV-exposed/-infected: Infants, Children, and Adolescents: Oral: 6 mg/kg/dose once daily for ≥12 months; maximum dose: 200 mg/dose (Ref).HistoplasmosisHistoplasmosis: HIV-exposed/-infected patients, alternative therapy (Ref):Pulmonary, acute primary disease: Infants and Children: Oral: 3 to 6 mg/kg/dose once daily; maximum dose: 200 mg/dose.Disseminated disease, mild to moderate:Infants and Children: IV, Oral: 5 to 6 mg/kg/dose twice daily for 12 months; maximum dose: 300 mg/dose.Adolescents: Oral: 800 mg once daily.Secondary prophylaxis/chronic suppressive therapy:Infants and Children: Oral: 3 to 6 mg/kg/dose once daily for ≥12 months; maximum dose: 200 mg/dose.Adolescents: Oral: 400 mg once daily for ≥12 months.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricNote: Dosing is based on pharmaco*kinetic parameters, limited pediatric studies, adult studies, and expert opinion (Ref).Altered kidney function:Infants, Children, and Adolescents (Ref): Note: In critically ill patients with altered kidney function, consider monitoring serum concentrations if available (Ref).CrCl ≥50 mL/minute/1.73 m2: IV, Oral: Administer the usual indication-specific dose every 24 hours.CrCl <50 mL/minute/1.73 m2: IV, Oral: Administer the usual indication-specific dose every 48 hours or administer 100% of the usual indication-specific dose or loading dose initially, followed by 50% of the usual indication-specific dose every 24 hours.Note: No dosage adjustment necessary for single-dose therapy for vagin*l candidiasis (Ref).Hemodialysis, intermittent:Note: Based on adult information, fluconazole is dialyzable (33% to 38% with low-flux dialyzers (Ref) or approximately 50% after a 3-hour session (Ref).Infants, Children, and Adolescents: IV/Oral:Dialysis days: Administer the usual indication-specific dose after each dialysis session (Ref). Note: The manufacturer's labeling recommends that in addition to 100% of the dose given after dialysis on dialysis days, patients should also receive a reduced dose according to their creatinine clearance on nondialysis days; however, based on adult data, this appears unnecessary, as fluconazole concentrations decrease only minimally during the interdialytic period (Ref).Peritoneal dialysis:Infants, Children, and Adolescents: IV, Oral: Administer 50% of the usual indication-specific dose every 24 to 48 hours (Ref).CRRT:Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Flow rates vary widely in pediatric patients. Appropriate dosing requires consideration of drug penetration to site of infection, severity of illness, and consideration of loading dose. Close monitoring of response and adverse reactions due to drug accumulation is important. Due to limited data and patient variability, monitor serum concentrations if available (target AUC24/MIC 50 to 100 or trough concentrations 10 to 15 mg/L [for MICs up to 4 mg/L] in critical illness) (Ref)­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­.CVVH/CVVHD/CVVHDF: Children and Adolescents: IV, Oral: Loading dose: 6 to 12 mg/kg once, followed by 6 to 12 mg/kg/dose (as appropriate for patient-specific indication) every 24 hours; maximum dose: 800 mg/dose. For some indications, a higher initial loading dose may be appropriate (Ref).Note: Fluconazole undergoes substantial tubular reabsorption in patients with normal kidney function. Because this reabsorption is absent in anuric patients receiving renal replacement therapy, total fluconazole clearance in adults receiving CRRT with rates of 1,500 to 3,000 mL/hour is 1.5 to 2.3 times that reported in healthy volunteers (Ref). In one case report in an adolescent receiving CVVH with a high flow rate (4,090 mL/hour), the patient required double the initial dosage (to 20 mg/kg/day) to achieve pharmacodynamic targets (Ref).Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in manufacturer's labeling; use with caution.Dosing: Adult(For additional information see "Fluconazole: Drug information")BlastomycosisBlastomycosis (off-label use):CNS disease (alternative agent): Step-down therapy: Oral: 800 mg once daily for ≥12 months and until resolution of cerebrospinal (CSF) abnormalities (Ref).Pulmonary disease (alternative agent if unable to tolerate itraconazole): Oral: 400 to 800 mg once daily for 6 to 12 months (Ref).Candidiasis, treatmentCandidiasis, treatment: Note: Consider weight-based dosing for patients <50 kg or >90 kg (Ref). A maximum dose has not been established, but based on a small number of patients, doses up to 1.6 g/day appear to be well tolerated (Ref).Candidemia (neutropenic and non-neutropenic patients):Initial therapy (alternative agent):Note: For use in non-neutropenic patients that are not critically ill and not at high risk of fluconazole-resistant isolate. For use in neutropenic patients that are not critically ill and have had no prior azole exposure (Ref); some experts reserve for neutropenic patients who cannot be treated with other agents and whose ANC is >500 and increasing (Ref).IV, Oral: Loading dose of 800 mg (or 12 mg/kg) on day 1, then 400 mg (or 6 mg/kg) once daily; if fluconazole-susceptible Candida glabrata isolated, transition to 800 mg (or 12 mg/kg) once daily (Ref).Step-down therapy:Isolates other than C. glabrata: Oral: 400 mg (or 6 mg/kg) once daily (Ref).Isolates of C. glabrata (if fluconazole-susceptible or susceptible dose-dependent): Oral: 800 mg (or 12 mg/kg) once daily (Ref).Duration: Continue for ≥14 days after first negative blood culture and resolution of signs/symptoms (longer duration required in patients with metastatic complications); step-down therapy to oral fluconazole (eg, after initial therapy with an echinocandin) is recommended after 5 to 7 days in stable patients with negative repeat cultures and fluconazole-susceptible isolates (Ref).Cardiac device infection (eg, implantable cardiac defibrillator, pacemaker, ventricular assist device [VAD]): Step-down therapy: IV, Oral: 400 to 800 mg (or 6 to 12 mg/kg) once daily for 4 to 6 weeks after device removal (4 weeks for infections limited to generator pockets and ≥6 weeks for infections involving wires). Note: If VAD cannot be removed, chronic suppressive therapy with fluconazole 400 to 800 mg (or 6 to 12 mg/kg) once daily should be used (Ref).Chronic, disseminated (hepatosplenic): Step-down therapy: Oral: 400 mg (or 6 mg/kg) once daily; continue until lesion resolution (usually several months) and through periods of immunosuppression (Ref).CNS: Step-down therapy (fluconazole-susceptible isolates): IV, Oral: 400 to 800 mg (or 6 to 12 mg/kg) once daily; continue until signs/symptoms and CSF/radiologic abnormalities have resolved (Ref).Endocarditis, native or prosthetic valve: Step-down therapy (fluconazole-susceptible isolates): IV, Oral: 400 to 800 mg (or 6 to 12 mg/kg) once daily for ≥6 weeks after valve replacement surgery (longer durations recommended in patients with perivalvular abscesses or other complications). Note: In patients who cannot undergo valve replacement surgery or with prosthetic valve endocarditis, chronic suppressive therapy with fluconazole 400 to 800 mg (or 6 to 12 mg/kg) once daily should be used (Ref).Endophthalmitis, endogenous (with or without vitritis) (fluconazole-susceptible isolates): IV, Oral: Loading dose of 800 mg (or 12 mg/kg) on day 1, then 400 to 800 mg (or 6 to 12 mg/kg) once daily for ≥4 to 6 weeks and until examination indicates resolution (longer duration may be needed for patients with vitritis); for patients with vitritis or macular involvement, intravitreal antifungal therapy is also recommended (Ref).Esophageal, treatment: IV, Oral: 400 mg (or 6 mg/kg) on day 1, then 200 to 400 mg (or 3 to 6 mg/kg) once daily for 14 to 21 days (Ref). Some experts increase to 800 mg once daily for those with C. albicans infection who do not respond after 1 week (Ref).Esophageal, chronic suppression for recurrent infection:Note: Suppressive therapy is usually unnecessary. Reserve for immunocompromised patients (eg, with HIV and low CD4 count) who have multiple recurrent infections (Ref).Oral: 100 to 200 mg once daily (Ref). Some experts suggest 100 to 200 mg 3 times weekly (Ref); however, resistance may be a potential concern (Ref). May discontinue once immune reconstitution occurs (Ref).Intertrigo, refractory to topical therapy (off-label use): Oral: 150 mg once weekly for 4 weeks (Ref).Intra-abdominal infection, acute, including peritonitis and/or abscess (alternative agent):Note: For empiric therapy, reserve as an alternative to an echinocandin if no previous azole exposure, noncritically ill, and not at high risk of fluconazole-resistant isolate (Ref). Step-down therapy (after patient has responded to initial therapy [eg, echinocandin]) with fluconazole is recommended in stable patients with a fluconazole-susceptible isolate (Ref).IV, Oral: 800 mg (or 12 mg/kg) on day 1, then 400 mg (or 6 mg/kg) once daily. Total antifungal duration is ≥14 days based on source control and clinical response (Ref).Oropharyngeal: Note: Reserve use for moderate to severe disease, poor response to topical treatment, or recurrent infection (Ref).IV, Oral: 200 mg on day 1, then 100 to 200 mg once daily for 7 to 14 days (Ref); some experts increase to 400 mg once daily for those who do not initially respond (Ref).Oropharyngeal, chronic suppression for recurrent infection: Note: Suppressive therapy is usually unnecessary. Reserve for immunocompromised patients (eg, with HIV and low CD4 count) who have multiple recurrent infections (Ref).Oral: 100 mg once daily (Ref). Some experts suggest 100 mg 3 times weekly (Ref); however, resistance may be a potential concern (Ref). May discontinue once immune reconstitution occurs (Ref).Osteoarticular (osteomyelitis or septic arthritis) (fluconazole-susceptible isolates): Initial or step-down therapy: IV, Oral: 400 mg (or 6 mg/kg) once daily. Duration for osteomyelitis is 6 to 12 months and for septic arthritis is 6 weeks. Course may include 2 weeks of initial treatment with a lipid formulation of amphotericin B or an echinocandin. For prosthetic joints that cannot be removed, chronic suppressive therapy with fluconazole 400 mg (or 6 mg/kg) once daily is recommended (Ref).Peritonitis, associated with peritoneal dialysis: Note: Use for empiric treatment if no prior azole exposure or for directed therapy against fluconazole-susceptible isolates (Ref):IV, Oral: 200 mg on day 1, then 100 to 200 mg once daily for 2 to 4 weeks (Ref).Thrombophlebitis, suppurative: Initial or step-down therapy: IV, Oral: 400 to 800 mg (or 6 to 12 mg/kg) once daily for ≥2 weeks after candidemia (if present) has cleared (Ref).Urinary tract infection:Candiduria (asymptomatic):Patients with neutropenia: Treat as if patient has candidemia (Ref).Patients undergoing a urologic procedure: Oral: 400 mg (or 6 mg/kg) once daily several days before and after the procedure (Ref).Cystitis (symptomatic): Oral: 200 mg (or 3 mg/kg) once daily for 2 weeks (Ref).Pyelonephritis: Oral: 200 to 400 mg (or 3 to 6 mg/kg) once daily for 2 weeks (Ref).Urinary tract infection associated with fungus balls: Oral: 200 to 400 mg (or 3 to 6 mg/kg) once daily; concomitant amphotericin B deoxycholate irrigation via nephrostomy tubes, if present, is also recommended, along with surgical management (Ref).Vulvovagin*l: Note: Not recommended for infection due to C. glabrata or C. krusei (Ref).Mild or moderate infection in immunocompetent patient: Oral: 150 mg as a single dose (Ref).Severe infection or infection in immunocompromised patient: Oral: 150 mg every 72 hours for 2 or 3 doses (Ref).Recurrent infection:Fluconazole monotherapy: Oral: 150 mg every 72 hours for 10 to 14 days, followed by 150 mg once weekly for 6 months (Ref) or 100 mg, 150 mg, or 200 mg every 72 hours for 3 doses, then 100 mg, 150 mg, or 200 mg once weekly for 6 months (Ref).Combination therapy with oteseconazole: Oral:Days 1 to 7: Fluconazole 150 mg as a single dose on days 1, 4, and 7 (Ref).Days 14 to 20: Oteseconazole 150 mg once daily (Ref).Starting on day 28: Oteseconazole 150 once weekly for 11 weeks (Ref).Candidiasis, prophylaxisCandidiasis, prophylaxis:Hematologic malignancy patients (off-label use) or hematopoietic cell transplant (HCT) recipients who do not warrant mold-active prophylaxis (off-label use): Oral: 400 mg once daily. Duration is at least until resolution of neutropenia and/or through day 75 in allogeneic HCT recipients (Ref).ICU patients (high risk) in units with a high rate (>5%) of invasive candidiasis (off-label use): Oral, IV: Loading dose of 800 mg (or 12 mg/kg) once on day 1, then 400 mg (or 6 mg/kg) once daily (Ref).Peritoneal dialysis-associated infection (concurrently treated with antibacterials), prevention of secondary fungal infection: Oral: 200 mg every other day or 100 mg once daily (Ref).Solid organ transplant recipients (selected patients at high-risk for Candida infection) (off-label use): Oral, IV: 400 mg (or 6 mg/kg) given perioperatively and continued once daily postoperatively; indications and duration vary among transplant centers (Ref).Coccidioidomycosis, treatmentCoccidioidomycosis, treatment (off-label use):Bone and/or joint infection: Initial or step-down therapy: Oral: 800 mg once daily for ≥3 years; in some cases, lifelong treatment is needed; duration depends on severity and host immunocompetence (Ref).Meningitis: Oral: 400 mg to 1.2 g once daily, depending on severity (Ref); some experts favor a starting dose of ≥800 mg once daily (Ref). Continue lifelong as there is a high relapse rate when the dose is decreased or treatment is discontinued (Ref).Pneumonia, primary infection: Note: Only for patients with significantly debilitating illness, extensive pulmonary involvement, concurrent diabetes, frailty due to age or comorbidities, or HIV (Ref):Oral: Usual dose: 400 mg once daily; IDSA guidelines state that some experts recommend 800 mg once daily. Duration of therapy is 3 to 6 months for immunocompetent patients; immunocompromised patients require a longer duration of therapy (sometimes lifelong) (Ref).Pneumonia, symptomatic chronic cavitary and/or cavitary disease in immunocompromised patients: Oral: 400 mg once daily for ≥12 months. In patients with ruptured cavities, the duration may be shorter, but depends upon the postoperative course (Ref).Soft tissue infection (not associated with bone infection): Oral: 400 mg once daily; some experts give up to 800 mg once daily; duration is for ≥6 to 12 months (Ref).Coccidioidomycosis, prophylaxisCoccidioidomycosis, prophylaxis (off-label use):Patients with HIV: Note: Primary prophylaxis is not recommended; yearly or twice-yearly serologic testing should be performed in patients living in endemic areas.Patients with a CD4 count <250 cells/mm3 who have a new positive serology: Oral: 400 mg once daily until antiretroviral therapy has fully suppressed HIV replication and the CD4 count is ≥250 cells/mm3 (Ref).Solid organ transplant recipients:Seronegative patients in endemic areas (regardless of clinical history of coccidioidomycosis): Oral: 200 mg once daily for 6 to 12 months following transplantation (Ref); some experts favor 400 mg once daily (Ref).Seropositive patients in endemic areas: Oral: 400 mg once daily for 6 to 12 months following transplantation (Ref); some experts favor 400 mg once daily for 12 months posttransplantation followed by 200 mg once daily for the duration of immunosuppressive therapy (Ref).Cryptococcal meningitisCryptococcal meningitis:Patients with HIV:Induction: Note: Induction therapy should be continued beyond the durations listed below if clinical improvement is not observed and/or if CSF cultures remain positive (Ref).Resource-rich settings, alternative regimens:If flucytosine is unavailable or not tolerated: Oral: 800 mg to 1.2 g once daily in combination with amphotericin B (lipid formulation preferred) for ≥2 weeks (Ref).If amphotericin B is unavailable or not tolerated: Oral: 800 mg to 1.2 g once daily in combination with flucytosine for ≥2 weeks (Ref).If flucytosine and amphotericin B are unavailable or not tolerated: Oral: 1.2 g once daily as monotherapy for ≥2 weeks (Ref).Resource-limited settings:Oral: 1.2 g once daily for 2 weeks in combination with flucytosine and a single dose of liposomal amphotericin B (preferred regimen) (Ref).If liposomal amphotericin B is not available: Oral: 1.2 g once daily for 1 week, started after completion of 1 week of amphotericin B deoxycholate in combination with flucytosine (Ref).If no amphotericin B formulation is available: Oral: 1.2 g once daily in combination with flucytosine for 2 weeks (Ref).If flucytosine is unavailable: Oral: 1.2 g once daily in combination with liposomal amphotericin B or amphotericin B deoxycholate for 2 weeks (Ref).Consolidation: Oral: 800 mg once daily for ≥8 weeks; may consider reducing dose to 400 mg once daily in patients who are treated with amphotericin B and flucytosine induction regimen, have negative CSF cultures after 2 weeks of induction therapy, and are initiated on antiretroviral therapy (Ref).Maintenance (suppression): Oral: 200 mg once daily for ≥12 months; may discontinue if completed induction, consolidation, and ≥12 months of maintenance therapy, patient remains asymptomatic, and CD4 count has been ≥100 cells/mm3 for ≥3 months and HIV RNA is suppressed in response to effective antiretroviral therapy (Ref).HIV-uninfected patients:Induction (alternative regimens):If flucytosine is unavailable or not tolerated: Oral: 800 mg once daily in combination with amphotericin B for 2 weeks (Ref).If amphotericin B is unavailable or not tolerated: Oral: 800 mg to 1.2 g once daily in combination with flucytosine for 2 to 10 weeks, depending on severity and response to therapy (Ref).If amphotericin B and flucytosine are unavailable or not tolerated: Oral: 1.2 g once daily as monotherapy for ≥10 weeks (Ref).Consolidation: Oral: 400 to 800 mg once daily for 8 weeks (some experts prefer 800 mg once daily for patients who receive a 2-week induction course) (Ref).Maintenance (suppression): Oral: 200 to 400 mg once daily for 6 to 12 months (Ref). A longer duration may be warranted for patients receiving very high doses of immunosuppression (eg, high-dose steroids or biologic agents [eg, alemtuzumab]) or with radiographic evidence of cryptococcoma (Ref).Cryptococcosis, pulmonary infectionCryptococcosis, pulmonary infection (off-label use):Mild to moderate symptoms (if severe pneumonia, treat like CNS infection): Immunocompetent or immunocompromised patients without diffuse pulmonary infiltrates or disseminated infection: Oral: 400 mg once daily for 6 to 12 months (Ref); for patients with HIV, some experts recommend 400 to 800 mg once daily for 10 weeks, followed by 200 mg once daily for a total of 6 months in combination with effective antiretroviral therapy (Ref). Chronic suppressive therapy may be warranted for patients with ongoing immunosuppression (Ref).OnychomycosisOnychomycosis (alternative agent) (off-label use):Note: For patients unable to use preferred agents (Ref).Oral: 150 to 450 mg once weekly. Usual duration of therapy: 3 months (fingernail) or 6 to 12 months (toenail) (Ref).Tinea infectionsTinea infections (alternative agent) (off-label use): Note: For disease that is extensive or refractory to topical therapy (Ref).Tinea corporis/tinea cruris: Oral: 150 to 200 mg once weekly for 2 to 4 weeks (Ref).Tinea pedis/tinea manuum: Oral: 150 mg once weekly for 2 to 6 weeks (Ref).Tinea versicolor: Oral: 300 mg once weekly for 2 weeks (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Altered kidney function: Note: Renal function estimated using the co*ckcroft-Gault formula.No adjustment for vagin*l candidiasis single-dose therapy.For multiple dosing, administer 100% of the indication-specific loading/initial dose recommended in the adult dosing section, then adjust daily doses as follows: IV, Oral (Ref):CrCl >50 mL/minute: No dosage adjustment necessary.CrCl ≤50 mL/minute: Reduce dose by 50%.Hemodialysis, intermittent (thrice weekly): IV, Oral: Dialyzable (33% to 38% with low-flux dialyzers (Ref):Three-times-weekly (postdialysis) dosing: No dosage adjustment necessary for indication-specific loading/initial or maintenance dose recommended in the adult dosing section; however, only administer maintenance doses 3 times/week (on dialysis days) after the dialysis session (Ref).Note: The manufacturer's labeling recommends that in addition to 100% of the dose given after dialysis on dialysis days, patients should also receive a reduced dose according to their creatinine clearance on nondialysis days; however, this appears unnecessary, as fluconazole concentrations decrease only minimally during the interdialytic period (Ref).Once-daily dosing (may be considered when a more convenient dosing regimen is preferred [eg, hospitalized patients]): Administer 100% of the indication-specific loading/initial dose recommended in the adult dosing section, then reduce maintenance dose by 50% and administer once daily; when scheduled dose falls on a dialysis day, administer after dialysis (Ref).Peritoneal dialysis:IV, Oral: Initial: Administer 100% of the indication-specific loading/initial dose recommended in the adult dosing section; reduce maintenance doses by 50% (Ref).CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour), unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.CVVH/CVVHD/CVVHDF: IV, Oral:If the usual recommended dose is 200 mg once daily, administer 400 mg once daily (Ref) (see note regarding increased clearance in patients receiving renal replacement therapy below).If the usual recommended dose is 400 mg once daily, administer an 800 mg loading dose, followed by maintenance doses of 800 mg/day in 1 to 2 divided doses (Ref).If the usual recommended dose is 800 mg once daily, administer a 1.2 g loading dose, followed by maintenance doses of 1.2 g/day in 1 to 2 divided doses (Ref) (see note regarding increased clearance in patients receiving renal replacement therapy below).Note: Fluconazole undergoes substantial tubular reabsorption in patients with normal kidney function. Because this reabsorption is absent in anuric patients receiving renal replacement therapy, total fluconazole clearance during CRRT with rates of 1,500 to 3,000 mL/hour is 1.5 to 2.3 times that reported in healthy volunteers (Ref).PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.PIRRT (effluent flow rate 4 to 5 L/hour, 8- to 10-hour session given every day):IV, Oral:Loading dose:Administer 100% of the recommended indication-specific loading dose recommended in the adult dosing section.Maintenance dose: Note: Optimal dose not well established. Select dose based on pathogen, minimum inhibitory concentration, immunocompromised state, and disease severity.400 mg once (Ref) or twice daily (Ref).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling; use with caution.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Intravenous: Generic: 200 mg (100 mL); 200 mg/100 mL in NaCl 0.9% (100 mL); 400 mg (200 mL)Solution, Intravenous [preservative free]: Generic: 100 mg/50 mL in NaCl 0.9% (50 mL); 200 mg (100 mL [DSC]); 200 mg/100 mL in NaCl 0.9% (100 mL); 400 mg (200 mL); 400 mg/200 mL in NaCl 0.9% (200 mL)Suspension Reconstituted, Oral: Diflucan: 10 mg/mL (35 mL); 40 mg/mL (35 mL) [orange flavor]Generic: 10 mg/mL (35 mL); 40 mg/mL (35 mL)Tablet, Oral: Diflucan: 50 mg [DSC], 100 mg, 150 mg, 200 mg [contains fd&c red #40(allura red ac)aluminum lake]Generic: 50 mg, 100 mg, 150 mg, 200 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution, Intravenous: Diflucan: 2-0.9 MG/ML-% (100 mL)Generic: 2-0.9 MG/ML-% (100 mL)Suspension Reconstituted, Oral: Diflucan: 10 mg/mL (35 mL) [contains sodium benzoate]Tablet, Oral: Generic: 50 mg, 100 mg, 200 mgAdministration: PediatricOral: Administer without regard to meals; shake suspension well before use.Parenteral: Do not use if cloudy or precipitated. Administered by IV infusion over approximately 1 to 2 hours at a rate not to exceed 200 mg/hour. The following infusion times were described in pediatric clinical trials:Neonatal: Loading doses (25 mg/kg) have been infused over 2 hours (Ref); doses ranging from 3 to 12 mg/kg/dose have been infused over 1 to 2 hours including extremely low birth weight neonates (Ref).Pediatric: Doses up to 8 to 10 mg/kg were infused over 2 hours (Ref).Administration: AdultIV: Do not use if cloudy or precipitated. Infuse over ~1 to 2 hours; do not exceed 200 mg/hour.Oral: May be administered without regard to meals.Hazardous Drugs Handling ConsiderationsHazardous agent (NIOSH 2016 [group 3]).Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.NIOSH recommends single gloving for administration of intact tablets or capsules. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration. For IV compounding, double gloves, a protective gown, ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator), and closed system transfer devices (CSTDs) are recommended. Double gloving and a gown are required during IV administration (NIOSH 2016). Premixed solutions may be excluded from some hazardous drug handling requirements. Assess risk to determine appropriate containment strategy (USP-NF 2017).Storage/StabilityTablet: Store at <30°C (86°F).Powder for oral suspension: Store dry powder at <30°C (86°F). Following reconstitution, store at 5°C to 30°C (41°F to 86°F). Discard unused portion after 2 weeks. Do not freeze. Injection: Store injection in glass at 5°C to 30°C (41°F to 86°F). Store injection in plastic flexible containers with overwrap at 20°C to 25°C (68°F to 77°F). Do not freeze. Do not unwrap unit until ready for use.UseTreatment of candidiasis (vagin*l, oropharyngeal, esophageal, urinary tract infections, peritonitis, pneumonia, and systemic infections); cryptococcal meningitis; antifungal prophylaxis in allogeneic bone marrow transplant recipients (All indications: FDA approved in all ages); has also been used as prophylaxis and treatment of peritonitis and treatment of exit-site and tunnel infections in patients with peritoneal dialysis catheters.Medication Safety IssuesSound-alike/look-alike issues: Fluconazole may be confused with flecainide, FLUoxetine, furosemide, itraconazole, voriconazoleDiflucan may be confused with diclofenac, Diprivan, disulfiramInternational issues:Canesten (oral capsules) [Great Britain] may be confused with Canesten brand name for clotrimazole (various dosage forms) [multiple international markets]; Cenestin brand name estrogens (conjugated A/synthetic) [US, Canada] Adverse Reactions (Significant): ConsiderationsCardiovascular effectsDysrhythmias: Azole antifungals, including fluconazole, have been associated with prolonged QT interval on ECG, which may lead to torsades de pointes (TdP) or polymorphic ventricular arrhythmias. Numerous probable cases of TdP have been reported with fluconazole in patients with additional risk factors (Ref). Drug-drug interactions commonly play a role in risk related to cardiac effects with fluconazole either by an additive pharmacodynamic effect, reducing the clearance of fluconazole, or by lowering potassium and/or magnesium concentrations (Ref).Vascular: Another rare cardiac effect with fluconazole is hypersensitivity coronary syndrome (ie, allergic angina or Kounis syndrome) (Ref).Mechanism:Dysrhythmias: One proposed mechanism is that azole antifungals may block the IKr channel (Ref). Another possible mechanism is depression of rapidly activating delayed rectifier potassium channels (Ref).Vascular: Kounis syndrome is thought to be caused by an allergen mediated-IgE and mast cell activation and degranulation causing histamine release (Ref).Onset:Dysrhythmias: Rapid; QT prolongation occurred within the first 24 hours to a couple of days after initiation, dependent on drug-drug interactions (Ref).Vascular: Kounis syndrome may occur immediately after the first dose (Ref).Risk factors:Drug-induced QTc prolongation/TdP (in general):• Females (Ref)• Age >65 years (Ref)• Structural heart disease (eg, history of myocardial infarction or heart failure with reduced ejection fraction) (Ref)• Genetic defects of cardiac ion channels (Ref)• History of drug-induced TdP (Ref)• Congenital long QT syndrome (Ref)• Longer baseline QTc interval (eg, >450 msec) or lengthening of the QTc by ≥60 msec (Ref)• Electrolyte disturbances (eg, hypocalcemia, hypokalemia, hypomagnesemia) (Ref)• Bradycardia (Ref)• Hepatic impairment (Ref)• Kidney impairment (Ref)• Diuretic use (Ref)• Sepsis (Ref)• Concurrent administration of multiple medications (≥2) that prolong the QT interval or medications with drug interactions that increase serum concentrations of QT-prolonging medications (Ref)Dermatologic reactionsDermatologic reactions are usually mild and include maculopapular skin rash (Ref), fixed drug eruption (FDE) (Ref), alopecia (Ref) and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) (Ref). Rare reports of severe cutaneous adverse reactions (SCARs) include Stevens-Johnson syndrome (SJS) (Ref), toxic epidermal necrolysis (TEN) (Ref), drug reaction with eosinophilia and systemic symptoms (DRESS) (Ref), and acute generalized exanthematous pustulosis (AGEP) (Ref). Other cutaneous reactions include Sweet’s syndrome (Ref).Mechanism: Non–dose-related; immunologic. Maculopapular eruptions, FDE, SDRIFE, and SCARs are T-cell-mediated (Ref).Onset: Delayed hypersensitivity reactions: Varied. Maculopapular rash usually occurs 5 to 21 days after start of therapy (Ref), although can occur after 1 dose, especially in previously sensitized patients (Ref). FDE lesions can develop within 15 minutes to 2 days after drug administration (Ref). SCARs usually occur 1 to 8 weeks after initiation (Ref); reexposure may lead to more rapid onset (usually within 1 to 4 days) (Ref).Risk factors:• Cross-reactivity: Cross-reactivity among oral azole antifungals has not been consistently reported. Possible cross-reactivity between fluconazole and itraconazole has been suggested (Ref). However, lack of cross-reactivity has been documented between fluconazole and itraconazole, as well as between fluconazole and ketoconazole (Ref). In addition, no cross-reactivity was noted between fluconazole and voriconazole (Ref).HepatotoxicityAzole antifungals, including fluconazole, may cause hepatotoxicity (ranging from mild and asymptomatic liver abnormalities to hepatic failure) (Ref). From a 2010 meta-analysis, fluconazole users had increased serum transaminases that did not require discontinuation (Ref). Hepatotoxicity may also occur as part of drug rash eosinophilia with systemic symptoms (DRESS) (Ref). Fluconazole liver injury is usually hepatocellular hepatitis, but may present as cholestatic hepatitis or hepatitis (mixed) (Ref). Most cases of hepatotoxicity are self-limited; although, recovery may take up to 3 to 4 months (Ref).Mechanism: Not well known; possible mechanisms include mitochondrial dysfunction, idiosyncratic, and immunologic (Ref).Onset: Varied; most cases occur within 1 to 2 months of initiation (Ref).Risk factors:• Fluconazole-induced liver injury has been reported as both dose- and non–dose-dependent (Ref)• Preexisting liver disease (Ref)• Concurrent hepatotoxic agents and drug interactions (Ref)• Kidney impairment (Ref)• HIV (Ref)• Cross-reactivity among oral azole antifungals has not been consistently reported in patients with histories of hepatotoxicity (Ref)• Acute liver injury is less common with fluconazole than other azoles (voriconazole, posaconazole) (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%: Nervous system: Headache (adults: 2% to 13%)1% to 10%:Dermatologic: Skin rash (adults: 2%)Gastrointestinal: Abdominal pain (2% to 6%), diarrhea (2% to 3%), dysgeusia (adults: 1%), dyspepsia (adults: 1%), nausea (adults: 4% to 7%; children and adolescents: 2%), vomiting (2% to 5%)Nervous system: Dizziness (adults: 1%)Frequency not defined: Hepatic: Increased serum alkaline phosphatasePostmarketing:Cardiovascular: Prolonged QT interval on ECG, torsades de pointes (Poluzzi 2010)Dermatologic: Acute generalized exanthematous pustulosis (Alsadhan 2002; Di Lernia 2015), alopecia (Pappas 1995), diaphoresis, exfoliative dermatitis, Stevens-Johnson syndrome (Craythorne 2009, Monastirli 2008), Sweet’s syndrome (Adler 2018), toxic epidermal necrolysis (George 2012, Islam 2014)Endocrine & metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemiaGastrointestinal: XerostomiaHematologic & oncologic: Agranulocytosis (Murakami 1992), leukopenia, neutropenia, thrombocytopenia (Murakami 1992)Hepatic: Cholestatic hepatitis (Joseph 2019), hepatic failure (Gayam 2018), hepatitis (mixed) (Joseph 2019), hepatocellular hepatitis (Joseph 2019), hepatotoxicity (Kyriakidis 2017, Song 2005), increased serum transaminases (Wang 2010)Hypersensitivity: Anaphylaxis (Neuhaus 1991), angioedema, fixed drug eruption (Nakai 2013, Quint 2019)Immunologic: Drug reaction with eosinophilia and systemic symptoms (Benjamin Lash 2016, Su 2003)Nervous system: Drowsiness, fatigue, insomnia, malaise, paresthesia, seizure, vertigoNeuromuscular & skeletal: Asthenia, myalgia, tremorMiscellaneous: FeverContraindicationsHypersensitivity to fluconazole or any component of the formulation (cross-reaction with other azole antifungal agents may occur, but has not been established; use caution); coadministration with CYP3A4 substrates, which may lead to QTc prolongation (eg, erythromycin, pimozide, quinidine).Warnings/PrecautionsConcerns related to adverse effects:• CNS effects: May occasionally cause dizziness or seizures; use caution driving or operating machinery.Disease-related concerns:• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be necessary.Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.• Sucrose: Oral suspension contains sucrose; avoid use in patients with fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency.Metabolism/Transport EffectsInhibits CYP2C19 (strong), CYP2C9 (moderate), CYP3A4 (moderate)Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAbemaciclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib.Management: Monitor for increased abemaciclib toxicities if combined with moderate CYP3A4 inhibitors. Consider reducing the abemaciclib dose in 50 mg decrements if necessary. Risk C: Monitor therapyAbrocitinib: Fluconazole may increase the serum concentration of Abrocitinib.Risk X: Avoid combinationAcalabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Acalabrutinib.Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use. Risk D: Consider therapy modificationAlfentanil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Alfentanil.Management: If use of alfentanil and moderate CYP3A4 inhibitors is necessary, consider dosage reduction of alfentanil until stable drug effects are achieved. Frequently monitor patients for respiratory depression and sedation when these agents are combined. Risk D: Consider therapy modificationAlfuzosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Alfuzosin.Risk C: Monitor therapyAlitretinoin (Systemic): CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Alitretinoin (Systemic).Management: Consider reducing the alitretinoin dose to 10 mg when used together with moderate CYP2C9 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a moderate CYP2C9 inhibitor. Risk D: Consider therapy modificationALPRAZolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ALPRAZolam.Management: Consider alternatives to this combination when possible. If combined, consider an alprazolam dose reduction and monitor for increased alprazolam effects and toxicities (eg, sedation, lethargy). Risk D: Consider therapy modificationAmiodarone: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Amiodarone. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Amiodarone.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationAmisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapyAmitriptyline: May enhance the QTc-prolonging effect of Fluconazole. Fluconazole may increase the serum concentration of Amitriptyline. Risk C: Monitor therapyAmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine.Risk C: Monitor therapyAmphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B.Risk C: Monitor therapyApixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban.Risk C: Monitor therapyAprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant.Risk X: Avoid combinationARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole.Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy, indication, or dosage form. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapyARIPiprazole Lauroxil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole Lauroxil.Risk C: Monitor therapyAstemizole: Fluconazole may enhance the QTc-prolonging effect of Astemizole. Fluconazole may increase the serum concentration of Astemizole.Risk X: Avoid combinationAsunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir.Risk X: Avoid combinationAtazanavir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Atazanavir.Risk C: Monitor therapyAtogepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Atogepant.Risk C: Monitor therapyAtorvastatin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Atorvastatin.Risk C: Monitor therapyAvacopan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avacopan.Risk C: Monitor therapyAvanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.Management: The maximum avanafil dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects (eg, hypotension, syncope, priapism). Risk D: Consider therapy modificationAvapritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avapritinib.Management: Avoid use of moderate CYP3A4 inhibitors with avapritinib. If this combination cannot be avoided, reduce the avapritinib dose to 100 mg daily for the treatment of GIST or to 50 mg daily for the treatment of advanced systemic mastocytosis. Risk D: Consider therapy modificationAvatrombopag: Fluconazole may increase the serum concentration of Avatrombopag.Management: For chronic immune thrombocytopenia, reduce initial avatrombopag dose to 20 mg 3 times per week. No dosage reduction needed for patients with chronic liver disease-associated thrombocytopenia using altrombopag prior to a procedure. Risk D: Consider therapy modificationAxitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Axitinib.Risk C: Monitor therapyBarnidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Barnidipine.Risk C: Monitor therapyBelzutifan: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Belzutifan.Risk C: Monitor therapyBenidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benidipine.Risk C: Monitor therapyBenzhydrocodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased.Risk C: Monitor therapyBlonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin.Risk C: Monitor therapyBortezomib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bortezomib.Risk C: Monitor therapyBosentan: Fluconazole may increase the serum concentration of Bosentan.Risk X: Avoid combinationBosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib.Risk X: Avoid combinationBrexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole.Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Risk C: Monitor therapyBrigatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brigatinib.Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inhibitors when possible. If such a combination cannot be avoided, reduce the dose of brigatinib by approximately 40% (ie, from 180 mg to 120 mg, from 120 mg to 90 mg, or from 90 mg to 60 mg). Risk D: Consider therapy modificationBrivaracetam: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Brivaracetam.Risk C: Monitor therapyBromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine.Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Risk D: Consider therapy modificationBudesonide (Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Oral Inhalation).Risk C: Monitor therapyBudesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic).Management: Avoid the concomitant use of CYP3A4 inhibitors and oral budesonide. If patients receive both budesonide and CYP3A4 inhibitors, they should be closely monitored for signs and symptoms of corticosteroid excess. Risk D: Consider therapy modificationBudesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical).Risk X: Avoid combinationBuprenorphine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Buprenorphine.Risk C: Monitor therapyBusPIRone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of BusPIRone.Risk C: Monitor therapyCabozantinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cabozantinib.Risk C: Monitor therapyCannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased.Risk C: Monitor therapyCannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased.Risk C: Monitor therapyCarBAMazepine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of CarBAMazepine.Risk C: Monitor therapyCariprazine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Cariprazine. Specifically, concentrations of didesmethylcariprazine (DDCAR), the primary active metabolite of cariprazine, may increase. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cariprazine.Risk C: Monitor therapyCarisoprodol: CYP2C19 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Carisoprodol. CYP2C19 Inhibitors (Strong) may increase the serum concentration of Carisoprodol.Risk C: Monitor therapyCarvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased.Risk C: Monitor therapyCelecoxib: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Celecoxib.Risk C: Monitor therapyCeritinib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Ceritinib. Ceritinib may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ceritinib.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyCilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol.Management: Decrease the dose of cilostazol to 50 mg twice daily when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationCisapride: Fluconazole may enhance the QTc-prolonging effect of Cisapride. Fluconazole may increase the serum concentration of Cisapride.Risk X: Avoid combinationCitalopram: Fluconazole may enhance the QTc-prolonging effect of Citalopram. Fluconazole may increase the serum concentration of Citalopram.Management: Limit citalopram dose to a maximum of 20 mg/day if used with fluconazole, which is a strong CYP2C19 inhibitor. Patients using this combination should be monitored closely for citalopram toxicities, including serotonin syndrome and QT prolongation. Risk D: Consider therapy modificationClindamycin (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Clindamycin (Systemic).Risk C: Monitor therapyCloBAZam: CYP2C19 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Strong) may increase the serum concentration of CloBAZam.Risk C: Monitor therapyClopidogrel: CYP2C19 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Clopidogrel.Management: Consider alternatives to this combination whenever possible. If such a combination must be used, monitor patients closely for evidence of a diminished response to clopidogrel. Risk D: Consider therapy modificationCobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib.Management: Avoid this combination when possible. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose from 60 mg to 20 mg daily. Avoid concomitant use in patients already receiving reduced cobimetinib doses. Risk D: Consider therapy modificationCodeine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Codeine.Risk C: Monitor therapyColchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine.Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. See interaction monograph for details. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: Consider therapy modificationConivaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Conivaptan.Risk C: Monitor therapyCopanlisib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Copanlisib.Risk C: Monitor therapyCrizotinib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Crizotinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Crizotinib.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyCyclophosphamide: Fluconazole may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, serum bilirubin and serum creatinine may be increased. Fluconazole may increase the serum concentration of Cyclophosphamide.Risk C: Monitor therapyCycloSPORINE (Systemic): Fluconazole may increase the serum concentration of CycloSPORINE (Systemic).Risk C: Monitor therapyDabigatran Etexilate: Fluconazole may enhance the anticoagulant effect of Dabigatran Etexilate.Risk C: Monitor therapyDabrafenib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Dabrafenib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dabrafenib.Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and dabrafenib adverse effects when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyDapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine.Management: The dose of dapoxetine should be limited to 30 mg per day when used together with a moderate inhibitor of CYP3A4. Risk D: Consider therapy modificationDaridorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Daridorexant.Management: Limit the daridorexant dose to 25 mg, no more than once per night, when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationDarifenacin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Darifenacin.Risk C: Monitor therapyDeflazacort: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deflazacort.Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Risk D: Consider therapy modificationDexAMETHasone (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DexAMETHasone (Systemic).Risk C: Monitor therapyDexlansoprazole: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Dexlansoprazole.Risk C: Monitor therapyDiazePAM: CYP2C19 Inhibitors (Strong) may increase the serum concentration of DiazePAM.Risk C: Monitor therapyDichlorphenamide: Antifungal Agents (Azole Derivatives, Systemic) may enhance the hypokalemic effect of Dichlorphenamide.Risk C: Monitor therapyDiclofenac (Systemic): CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Diclofenac (Systemic).Risk C: Monitor therapyDilTIAZem: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DilTIAZem.Risk C: Monitor therapyDOCEtaxel: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOCEtaxel.Risk C: Monitor therapyDomperidone: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Domperidone. Risk X: Avoid combinationDOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional).Risk X: Avoid combinationDronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol.Risk C: Monitor therapyDronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol.Risk C: Monitor therapyDronedarone: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Dronedarone. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dronedarone.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationEbastine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ebastine.Risk C: Monitor therapyElbasvir and Grazoprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Elbasvir and Grazoprevir.Risk C: Monitor therapyEletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan.Risk X: Avoid combinationElexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor.Management: When combined with moderate CYP3A4 inhibitors, twoelexacaftor/tezacaftor/ivacaftor (100 mg/50 mg/75 mg) tablets should be given in the morning, every other day. Ivacaftor (150 mg) should be given in the morning, every other day on alternate days. Risk D: Consider therapy modificationEliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat.Management: Reduce eliglustat dose to 84 mg daily in CYP2D6 EMs when used with moderate CYP3A4 inhibitors. Avoid use of moderate CYP3A4 inhibitors in CYP2D6 IMs or PMs. Use in CYP2D6 EMs or IMs also taking strong or moderate CYP2D6 inhibitors is contraindicated. Risk D: Consider therapy modificationEncorafenib: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Encorafenib. Management: Avoid use of encorafenib and moderate CYP3A4 inhibitors when possible. If combined, decrease encorafenib dose from 450 mg to 225 mg; 300 mg to 150 mg; and 225 mg or 150 mg to 75 mg. Monitor closely for QT interval prolongation. Risk D: Consider therapy modificationEntrectinib: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Entrectinib. Risk X: Avoid combinationEplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone.Management: If coadministered with moderate CYP3A4 inhibitors, the max dose of eplerenone is 25 mg daily if used for heart failure; if used for hypertension initiate eplerenone 25 mg daily, titrate to max 25 mg twice daily. Risk D: Consider therapy modificationErdafitinib: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Erdafitinib.Management: Avoid concomitant use of erdafitinib and moderate CYP2C9 inhibitors when possible. If combined, monitor closely for erdafitinib adverse reactions and consider dose modifications accordingly. Risk D: Consider therapy modificationErgot Derivatives (Vasoconstrictive CYP3A4 Substrates): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates).Risk C: Monitor therapyErlotinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Erlotinib.Risk C: Monitor therapyErythromycin (Systemic): Fluconazole may enhance the QTc-prolonging effect of Erythromycin (Systemic). Fluconazole may increase the serum concentration of Erythromycin (Systemic).Risk X: Avoid combinationEscitalopram: May enhance the QTc-prolonging effect of Fluconazole. Fluconazole may increase the serum concentration of Escitalopram. Risk C: Monitor therapyEszopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eszopiclone.Risk C: Monitor therapyEtizolam: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Etizolam.Risk C: Monitor therapyEtravirine: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Etravirine.Risk C: Monitor therapyEverolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus.Risk C: Monitor therapyFedratinib: Fluconazole may increase the serum concentration of Fedratinib.Risk X: Avoid combinationFelodipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Felodipine.Risk C: Monitor therapyFentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL.Management: Consider fentanyl dose reductions when combined with a moderate CYP3A4 inhibitor. Monitor for respiratory depression and sedation. Upon discontinuation of a CYP3A4 inhibitor, consider a fentanyl dose increase; monitor for signs and symptoms of withdrawal. Risk D: Consider therapy modificationFexinidazole: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Fexinidazole. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may decrease serum concentrations of the active metabolite(s) of Fexinidazole.Management: Consider alternatives to this combination. If combined, monitor for QT interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QT prolongation may be at even higher risk. Also monitor for reduced fexinidazole efficacy. Risk D: Consider therapy modificationFinerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Finerenone.Risk C: Monitor therapyFlibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin.Management: Use of flibanserin with moderate CYP3A4 inhibitors is contraindicated. If starting flibanserin, start 2 weeks after the last dose of the CYP3A4 inhibitor. If starting a CYP3A4 inhibitor, start 2 days after the last dose of flibanserin. Risk X: Avoid combinationFluorouracil Products: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Fluorouracil Products.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyFlurbiprofen (Systemic): CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Flurbiprofen (Systemic).Risk C: Monitor therapyFluticasone (Nasal): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fluticasone (Nasal).Risk C: Monitor therapyFluticasone (Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fluticasone (Oral Inhalation).Risk C: Monitor therapyFluvastatin: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Fluvastatin.Management: Fluvastatin should be used at the lowest effective dose and should not exceed 20 mg twice daily when combined with moderate CYP2C9 inhibitors. Monitor patients closely for increased fluvastatin toxicities when combined. Risk D: Consider therapy modificationFosamprenavir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosamprenavir.Risk C: Monitor therapyFosaprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosaprepitant.Risk X: Avoid combinationFosphenytoin-Phenytoin: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Fosphenytoin-Phenytoin.Risk C: Monitor therapyGlasdegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Glasdegib.Risk C: Monitor therapyGuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE.Management: Reduce the extended-release guanfacine dose 50% when combined with a moderate CYP3A4 inhibitor. Monitor for increased guanfacine toxicities when these agents are combined. Risk D: Consider therapy modificationHaloperidol: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyHYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone.Risk C: Monitor therapyIbrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib.Management: When treating B-cell malignancies, decrease ibrutinib to 280 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Risk D: Consider therapy modificationIbuprofen: Fluconazole may increase the serum concentration of Ibuprofen.Risk C: Monitor therapyIfosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide.Risk C: Monitor therapyIloperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Iloperidone.Risk C: Monitor therapyInfigratinib: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Infigratinib.Risk X: Avoid combinationIrinotecan Products: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, the serum concentration of SN-38 may be increased. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Irinotecan Products.Risk C: Monitor therapyIsavuconazonium Sulfate: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Moderate) may increase isavuconazole serum concentrations.Risk C: Monitor therapyIsradipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Isradipine.Risk C: Monitor therapyItraconazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Itraconazole.Risk C: Monitor therapyIvabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine.Risk X: Avoid combinationIvacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor.Management: Ivacaftor dose reductions may be required; consult full drug interaction monograph content for age- and weight-specific dosage recommendations. Risk D: Consider therapy modificationIvosidenib: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ivosidenib. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationIxabepilone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ixabepilone.Risk C: Monitor therapyLansoprazole: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Lansoprazole.Risk C: Monitor therapyLapatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lapatinib.Risk C: Monitor therapyLarotrectinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Larotrectinib.Risk C: Monitor therapyLefamulin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lefamulin.Management: Monitor for lefamulin adverse effects during coadministration of lefamulin tablets with moderate CYP3A4 inhibitors. Risk C: Monitor therapyLemborexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lemborexant.Risk X: Avoid combinationLercanidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lercanidipine.Risk C: Monitor therapyLesinurad: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Lesinurad.Risk C: Monitor therapyLevamlodipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levamlodipine.Risk C: Monitor therapyLevoketoconazole: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Levoketoconazole. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Levoketoconazole.Risk X: Avoid combinationLevoketoconazole: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Levoketoconazole.Risk X: Avoid combinationLevomethadone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levomethadone.Risk C: Monitor therapyLevomilnacipran: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levomilnacipran.Risk C: Monitor therapyLidocaine (Systemic): CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Lidocaine (Systemic). Specifically, concentrations of monoethylglycinexylidide (MEGX) may be increased. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lidocaine (Systemic).Risk C: Monitor therapyLomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide.Risk X: Avoid combinationLonafarnib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lonafarnib.Risk X: Avoid combinationLopinavir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lopinavir.Risk C: Monitor therapyLorlatinib: Fluconazole may increase the serum concentration of Lorlatinib.Management: Avoid use of lorlatinib with fluconazole whenever possible. If the combination cannot be avoided, reduce the lorlatinib dose from 100 mg once daily to 75 mg once daily. Risk D: Consider therapy modificationLornoxicam: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Lornoxicam.Risk C: Monitor therapyLosartan: CYP2C9 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Losartan. CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Losartan.Risk C: Monitor therapyLovastatin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lovastatin.Risk C: Monitor therapyLumateperone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lumateperone.Management: Limit the lumateperone dose to 21 mg once daily when used with a moderate CYP3A4 inhibitor. Risk D: Consider therapy modificationLurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone.Management: US labeling recommends reducing lurasidone dose by 50% with a moderate CYP3A4 inhibitor and initiating 20 mg/day, max 80 mg/day. Some non-US labels recommend initiating lurasidone 20 mg/day, max 40 mg/day. Avoid concurrent use of grapefruit products. Risk D: Consider therapy modificationLurbinectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurbinectedin.Management: Avoid concomitant use of lurbinectedin and moderate CYP3A4 inhibitors when possible. If combined, consider a lurbinectedin dose reduction as clinically indicated. Risk D: Consider therapy modificationMacitentan: Fluconazole may increase the serum concentration of Macitentan.Risk X: Avoid combinationManidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Manidipine.Risk C: Monitor therapyMaraviroc: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Maraviroc.Risk C: Monitor therapyMavacamten: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Mavacamten.Risk X: Avoid combinationMeloxicam: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Meloxicam.Risk C: Monitor therapyMeperidine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Meperidine.Risk C: Monitor therapyMethadone: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for increased methadone toxicities (eg, respiratory depression, QTc interval prolongation). Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationMethylPREDNISolone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of MethylPREDNISolone.Risk C: Monitor therapyMethysergide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Methysergide.Risk X: Avoid combinationMidazolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Midazolam.Management: Avoid concomitant use of nasal midazolam and moderate CYP3A4 inhibitors. Consider alternatives to use with oral midazolam whenever possible and consider using lower midazolam doses. Monitor patients for sedation and respiratory depression if combined. Risk D: Consider therapy modificationMiFEPRIStone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of MiFEPRIStone.Risk C: Monitor therapyMirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil.Risk C: Monitor therapyMitapivat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mitapivat.Management: When coadministered with moderate CYP3A4 inhibitors, doses of mitapivat should not exceed 20 mg twice daily. Additionally, patients should be monitored for changes in hemoglobin response and increased mitapivat adverse effects. Risk D: Consider therapy modificationMizolastine: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Mizolastine.Risk X: Avoid combinationMobocertinib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Mobocertinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase serum concentrations of the active metabolite(s) of Mobocertinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Mobocertinib.Management: Avoid use of QT prolonging moderate CYP3A4 inhibitors with mobocertinib when possible. If combined, the mobocertinib dose should be reduced by approximately 50% (ie, from 160 mg to 80 mg, 120 mg to 40 mg, or 80 mg to 40 mg). Monitor QTc interval closely. Risk D: Consider therapy modificationMoclobemide: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Moclobemide.Risk C: Monitor therapyNaldemedine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naldemedine.Risk C: Monitor therapyNalfurafine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nalfurafine.Risk C: Monitor therapyNaloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol.Management: The use of naloxegol and moderate CYP3A4 inhibitors should be avoided. If concurrent use is unavoidable, reduce naloxegol dose to 12.5 mg once daily and monitor for signs of opiate withdrawal (eg, hyperhidrosis, chills, diarrhea, anxiety, irritability). Risk D: Consider therapy modificationNateglinide: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Nateglinide.Risk C: Monitor therapyNelfinavir: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Nelfinavir.Risk C: Monitor therapyNeratinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Neratinib.Risk C: Monitor therapyNevirapine: Fluconazole may increase the serum concentration of Nevirapine.Risk C: Monitor therapyNIFEdipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NIFEdipine.Risk C: Monitor therapyNiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine.Risk C: Monitor therapyNisoldipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nisoldipine.Risk X: Avoid combinationNitrendipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nitrendipine.Risk C: Monitor therapyOlaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib.Management: Avoid use of moderate CYP3A4 inhibitors with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib tablets should be reduced to 150 mg twice daily and the dose of olaparib capsules should be reduced to 200 mg twice daily. Risk D: Consider therapy modificationOliceridine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Oliceridine.Risk C: Monitor therapyOlmutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olmutinib.Risk C: Monitor therapyOmeprazole: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Omeprazole.Risk C: Monitor therapyOndansetron: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyOrelabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Orelabrutinib.Risk X: Avoid combinationOspemifene: Fluconazole may increase the serum concentration of Ospemifene.Risk X: Avoid combinationOxyCODONE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased.Risk C: Monitor therapyPAcl*taxel (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PAcl*taxel (Conventional).Risk C: Monitor therapyPAcl*taxel (Protein Bound): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PAcl*taxel (Protein Bound).Risk C: Monitor therapyPacritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pacritinib.Risk X: Avoid combinationPalbociclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Palbociclib.Risk C: Monitor therapyPalovarotene: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Palovarotene.Risk C: Monitor therapyPanobinostat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Panobinostat.Risk C: Monitor therapyParecoxib: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Parecoxib. Specifically, serum concentrations of the active moiety valdecoxib may be increased.Management: Use the lowest effective dose of parecoxib and consider a dose reduction in patients taking moderate CYP2C9 inhibitors. Risk D: Consider therapy modificationPAZOPanib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of PAZOPanib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of PAZOPanib.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPemigatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pemigatinib.Management: If combined use cannot be avoided, reduce the pemigatinib dose from 13.5 mg daily to 9 mg daily, or from 9 mg daily to 4.5 mg daily. Resume prior pemigatinib dose after stopping the moderate inhibitor once 3 half-lives of the inhibitor has passed. Risk D: Consider therapy modificationPentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPexidartinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pexidartinib.Management: Avoid use of pexidartinib with moderate CYP3A4 inhibitors if possible. If combined, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg per day to 200 mg once daily. Risk D: Consider therapy modificationPimavanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimavanserin.Risk C: Monitor therapyPimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus.Risk C: Monitor therapyPimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combinationPONATinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PONATinib.Risk C: Monitor therapyPrazepam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Prazepam.Risk C: Monitor therapyPraziquantel: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Praziquantel.Risk C: Monitor therapyProguanil: CYP2C19 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Proguanil. CYP2C19 Inhibitors (Strong) may increase the serum concentration of Proguanil.Risk C: Monitor therapyQT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Risk C: Monitor therapyQT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class IA Antiarrhythmics (Highest Risk): Fluconazole may enhance the QTc-prolonging effect of QT-prolonging Class IA Antiarrhythmics (Highest Risk).Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Kinase Inhibitors (Moderate Risk): QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Moderate Risk).Risk C: Monitor therapyQT-prolonging Miscellaneous Agents (Highest Risk): Fluconazole may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluconazole.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): Fluconazole may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Fluconazole. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Fluconazole may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQUEtiapine: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QUEtiapine. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QUEtiapine.Management: Monitor for increased quetiapine toxicities including QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQuiNIDine: Fluconazole may enhance the QTc-prolonging effect of QuiNIDine. Fluconazole may increase the serum concentration of QuiNIDine.Risk X: Avoid combinationQuinidine (Non-Therapeutic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Quinidine (Non-Therapeutic).Risk C: Monitor therapyRamelteon: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Ramelteon.Risk C: Monitor therapyRanolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine.Management: Limit the ranolazine dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors. Monitor for increased ranolazine effects and toxicities during concomitant use. Risk D: Consider therapy modificationRed Yeast Rice: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Red Yeast Rice.Risk C: Monitor therapyRegorafenib: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Regorafenib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Regorafenib.Risk C: Monitor therapyRifabutin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rifabutin.Risk C: Monitor therapyRifAMPin: May decrease the serum concentration of Fluconazole. Fluconazole may increase the serum concentration of RifAMPin. Management: Consider increasing the dose of fluconazole when used concurrently with rifampin. When combined, monitor for both reduced clinical efficacy of fluconazole and increased rifampin toxicities. Risk D: Consider therapy modificationRifapentine: May decrease the serum concentration of Fluconazole. Risk C: Monitor therapyRimegepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rimegepant.Management: If taking rimegepant for the acute treatment of migraine, avoid a second dose of rimegepant within 48 hours when used concomitantly with moderate CYP3A4 inhibitors. No dose adjustment needed if using rimegepant for prevention of episodic migraine. Risk D: Consider therapy modificationRisperiDONE: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of RisperiDONE.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyRitonavir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ritonavir.Risk C: Monitor therapyRivaroxaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rivaroxaban. This warning is more specifically for drugs that are inhibitors of both CYP3A4 and P-glycoprotein.For erythromycin, refer to more specific erythromycin-rivaroxaban monograph recommendations.Risk C: Monitor therapyRoflumilast-Containing Products: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Roflumilast-Containing Products.Risk C: Monitor therapyRupatadine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rupatadine.Risk C: Monitor therapyRuxolitinib (Systemic): Fluconazole may increase the serum concentration of Ruxolitinib (Systemic).Management: Avoid fluconazole doses over 200 mg/day in combination with ruxolitinib. Dose adjustments are required in some circ*mstances. See full interaction monograph for details. Risk D: Consider therapy modificationSaccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii.Risk X: Avoid combinationSalmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol.Risk C: Monitor therapySAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin.Risk C: Monitor therapySelpercatinib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Selpercatinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Selpercatinib.Management: Avoid combination if possible. If use is necessary, reduce selpercatinib dose as follows: from 120mg twice/day to 80mg twice/day, or from 160mg twice/day to 120mg twice/day. Monitor QT interval more closely for QTc interval prolongation and arrhythmias. Risk D: Consider therapy modificationSelumetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Selumetinib.Management: Avoid concomitant use when possible. If combined, selumetinib dose reductions are recommended and vary based on body surface area and selumetinib dose. For details, see the full drug interaction monograph or selumetinib prescribing information. Risk D: Consider therapy modificationSertindole: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Sertindole. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Sertindole.Risk X: Avoid combinationSildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil.Risk C: Monitor therapySilodosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Silodosin.Risk C: Monitor therapySimeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir.Risk X: Avoid combinationSimvastatin: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simvastatin.Risk C: Monitor therapySiponimod: Fluconazole may increase the serum concentration of Siponimod.Risk X: Avoid combinationSirolimus (Conventional): Fluconazole may increase the serum concentration of Sirolimus (Conventional).Management: Monitor for increased serum concentrations of sirolimus if combined with fluconazole. Lower initial sirolimus doses or sirolimus dose reductions will likely be required. Risk D: Consider therapy modificationSirolimus (Protein Bound): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sirolimus (Protein Bound).Management: Reduce the dose of protein bound sirolimus to 56 mg/m2 when used concomitantly with a moderate CYP3A4 inhibitor. Risk D: Consider therapy modificationSolifenacin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Solifenacin.Risk C: Monitor therapySonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib.Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible.When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Risk D: Consider therapy modificationSulfonylureas: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Sulfonylureas.Risk C: Monitor therapySUNItinib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of SUNItinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of SUNItinib.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapySuvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant.Management: The recommended dose of suvorexant is 5 mg daily in patients receiving a moderate CYP3A4 inhibitor. The dose can be increased to 10 mg daily (maximum dose) if necessary for efficacy. Risk D: Consider therapy modificationTacrolimus (Systemic): Fluconazole may increase the serum concentration of Tacrolimus (Systemic).Management: Monitor tacrolimus concentrations closely and adjust oral tacrolimus dose as necessary when concomitantly administered with fluconazole. Reduced doses of tacrolimus will likely be required. Risk D: Consider therapy modificationTadalafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tadalafil.Risk C: Monitor therapyTamsulosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin.Risk C: Monitor therapyTazemetostat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tazemetostat.Management: Avoid when possible. If combined, reduce tazemetostat dose from 800 mg twice daily to 400 mg twice daily, from 600 mg twice daily to 400 mg in AM and 200 mg in PM, or from 400 mg twice daily to 200 mg twice daily. Risk D: Consider therapy modificationTelithromycin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Telithromycin.Risk C: Monitor therapyTemsirolimus: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, concentrations of sirolimus may be increased.Risk C: Monitor therapyTerfenadine: Fluconazole may enhance the QTc-prolonging effect of Terfenadine. Fluconazole may increase the serum concentration of Terfenadine.Management: Concomitant use of fluconazole at doses of 400 mg/day or greater and terfenadine is contraindicated and should be avoided. If lower doses of fluconazole and terfenadine are combined, monitor patients for QT-prolongation. Risk D: Consider therapy modificationTetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol.Risk C: Monitor therapyTetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol.Risk C: Monitor therapyTetrahydrocannabinol and Cannabidiol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol. Specifically, concentrations of tetrahydrocannabinol may be increased.Risk C: Monitor therapyTetrahydrocannabinol and Cannabidiol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol.Risk C: Monitor therapyTezacaftor and Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tezacaftor and Ivacaftor.Management: If combined with moderate CYP3A4 inhibitors, give tezacaftor/ivacaftor in the morning, every other day; give ivacaftor in the morning, every other day on alternate days. Tezacaftor/ivacaftor dose depends on age and weight; see full Lexi-Interact monograph Risk D: Consider therapy modificationTheophylline Derivatives: Fluconazole may increase the serum concentration of Theophylline Derivatives.Risk C: Monitor therapyThiotepa: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Thiotepa.Risk C: Monitor therapyTicagrelor: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor.Risk C: Monitor therapyTipranavir: Fluconazole may increase the serum concentration of Tipranavir.Management: Limit fluconazole adult maximum dose to 200 mg/day in patients treated with tipranavir. Risk D: Consider therapy modificationTofacitinib: Fluconazole may increase the serum concentration of Tofacitinib.Management: Tofacitinib dose reductions are recommended when combined with fluconazole. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full Lexi Interact monograph for details. Risk D: Consider therapy modificationTolterodine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolterodine.Risk C: Monitor therapyTolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan.Management: Avoid this combination with Samsca brand of tolvaptan. Reduce dose for Jynarque brand: 90 mg AM and 30 mg PM, reduce to 45 mg AM and 15 mg PM; 60 mg AM and 30 mg PM, reduce to 30 mg AM and 15 mg PM; 45 mg AM and 15 mg PM, reduce to 15 mg AM and PM. Risk D: Consider therapy modificationTorsemide: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Torsemide.Risk C: Monitor therapyTrabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin.Risk C: Monitor therapyTraMADol: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of TraMADol. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of TraMADol.Risk C: Monitor therapyTraZODone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of TraZODone.Risk C: Monitor therapyTretinoin (Systemic): Fluconazole may increase the serum concentration of Tretinoin (Systemic).Risk C: Monitor therapyTriazolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Triazolam.Management: Consider triazolam dose reduction in patients receiving concomitant moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationUbrogepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ubrogepant.Management: Use an initial ubrogepant dose of 50 mg and avoid a second dose for 24 hours when used with moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationUdenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil.Risk C: Monitor therapyUlipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal.Risk C: Monitor therapyValbenazine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Valbenazine.Risk C: Monitor therapyVardenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vardenafil.Management: Limit Levitra (vardenafil) dose to a single 5 mg dose within a 24-hour period if combined with moderate CYP3A4 inhibitors. Avoid concomitant use of Staxyn (vardenafil) and moderate CYP3A4 inhibitors. Combined use is contraindicated outside of the US. Risk D: Consider therapy modificationVenetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax.Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with moderate CYP3A4 inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationVerapamil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Verapamil.Risk C: Monitor therapyVilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone.Risk C: Monitor therapyVinBLAStine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of VinBLAStine.Risk C: Monitor therapyVinCRIStine: Fluconazole may increase the serum concentration of VinCRIStine.Risk C: Monitor therapyVinCRIStine (Liposomal): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of VinCRIStine (Liposomal).Risk C: Monitor therapyVindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine.Risk C: Monitor therapyVinflunine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Vinflunine. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vinflunine.Risk C: Monitor therapyVitamin K Antagonists (eg, warfarin): Fluconazole may increase the serum concentration of Vitamin K Antagonists.Management: Consider alternatives when possible. If combined, consider reducing the vitamin K antagonist dose by 10% to 20% if combined with fluconazole. Monitor for increased anticoagulant effects (ie, increased INR, bleeding) to guide further dose adjustments. Risk D: Consider therapy modificationVoclosporin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Voclosporin.Management: Decrease the voclosporin dose to 15.8 mg in the morning and 7.9 mg in the evening when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationVorapaxar: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vorapaxar.Risk C: Monitor therapyVoriconazole: Fluconazole may enhance the QTc-prolonging effect of Voriconazole. Fluconazole may increase the serum concentration of Voriconazole.Risk X: Avoid combinationZanubrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zanubrutinib.Management: Decrease the zanubrutinib dose to 80 mg twice daily during coadministration with a moderate CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details. Risk D: Consider therapy modificationZopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone.Risk C: Monitor therapyReproductive ConsiderationsBased on human data, in utero exposure to high doses of fluconazole may cause fetal harm. According to the manufacturer, patients who may become pregnant and who are taking higher doses (≥400 mg/day) should use effective contraception during therapy and for ~1 week after the final fluconazole dose.Pregnancy ConsiderationsBased on human data, in utero exposure to high doses of fluconazole may cause fetal harm. Following exposure during the first trimester, malformations have been noted in humans when maternal fluconazole was used in higher doses (≥400 mg/day). Abnormalities reported include brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. Fetal outcomes following exposure to lower doses is less clear and additional study is needed to confirm an association between maternal use of low dose fluconazole and an increased risk of birth defects. However, epidemiological studies of fluconazole ≤150 mg as a single dose or repeated doses in the first trimester suggest a potential risk of spontaneous abortion and malformations (Budani 2021; Diflucan [fluconazole oral] prescribing information).Oral fluconazole for the treatment of vagin*l candidiasis is not recommended during pregnancy. Topical therapy for oral or vagin*l candidiasis is recommended in pregnant patients (HHS [OI adult 2020]; Workowski [CDC 2021]). Secondary prophylaxis or chronic maintenance therapy using oral or IV fluconazole should not be initiated during pregnancy for esophageal, oropharyngeal, or vagin*l candidiasis; fluconazole should be discontinued if pregnancy occurs during therapy (HHS [OI adult 2020]). Fluconazole is not the treatment of choice for invasive candidiasis in pregnant patients (IDSA [Pappas 2016]). Fluconazole may be used for the treatment of cryptococcosis or coccidioidomycosis after the first trimester if otherwise appropriate (HHS [OI adult 2020]; IDSA [Galgiani 2016]; Pastick 2020).Monitoring ParametersPeriodic liver function (AST, ALT, alkaline phosphatase), renal function tests, serum potassium, CBC with differential and platelet count; conjugated bilirubin in neonates (Egunsola 2013)Mechanism of ActionInterferes with fungal cytochrome P450 activity (lanosterol 14-α-demethylase), decreasing ergosterol synthesis (principal sterol in fungal cell membrane) and inhibiting cell membrane formationPharmaco*kinetics (Adult data unless noted)Absorption: Oral: Well absorbed; food does not affect extent of absorptionDistribution: Vd: ~0.6 L/kg; widely throughout body with good penetration into CSF, eye, peritoneal fluid, sputum, skin, and urineRelative diffusion blood into CSF: Adequate with or without inflammation (exceeds usual MICs)CSF:blood level ratio: Normal meninges: 50% to 90%; Inflamed meninges: ~80%Protein binding, plasma: 11% to 12%Bioavailability: Oral: >90%Half-life elimination: Normal renal function: ~30 hours (range: 20 to 50 hours); Elderly: 46.2 hours; Neonates (gestational age 26 to 29 weeks): 73.6 to 46.6 hours (decreases with increasing postnatal age); Pediatric patients 9 months to 15 years: 19.5 to 25 hoursTime to peak, serum: Oral: 1 to 2 hours Excretion: Urine (80% as unchanged drug)Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: Pharmaco*kinetics are markedly affected; there is an inverse relationship between half-life and creatinine clearance.Additional InformationDosing equivalency suggested by the manufacturer's labeling: Pediatric patients 3 mg/kg = Adults 100 mg Pediatric patients 6 mg/kg = Adults 200 mg Pediatric patients 12 mg/kg = Adults 400 mg Pricing: USSolution (Fluconazole in Sodium Chloride Intravenous)100 mg/50 mL 0.9% (per mL): $0.12200 mg/100 mL 0.9% (per mL): $0.05 - $0.58400 mg/200 mL 0.9% (per mL): $0.03 - $0.42Suspension (reconstituted) (Diflucan Oral)10 mg/mL (per mL): $0.5840 mg/mL (per mL): $0.96Suspension (reconstituted) (Fluconazole Oral)10 mg/mL (per mL): $0.99 - $1.0340 mg/mL (per mL): $3.59 - $3.73Tablets (Diflucan Oral)50 mg (per each): $1.36100 mg (per each): $1.36150 mg (per each): $73.05200 mg (per each): $75.11Tablets (Fluconazole Oral)50 mg (per each): $0.49 - $5.60100 mg (per each): $8.75 - $8.80150 mg (per each): $1.29 - $14.01200 mg (per each): $14.32 - $14.40Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAfungil (CR, DO, GT, HN, MX, NI, PA, SV);Apicon (BD);Asperlican (VN);Avezol (MY);Baten (DO, EC, GT, HN, PA, SV);Beagyne (FR);Biozole (MY);Burnax (EC);Canazole (BD);Candid (BD);Candifix (ES);Candinil (LK);Candivast (BH);Canesoral (AU);Canesten Oral (GB);Cryptal (ID);Damicol (AR);Diflazole (IE);Diflazon (UA, VN);Diflucan (AT, AU, BB, BE, BF, BG, BH, BJ, BM, BS, BZ, CH, CI, CL, CN, CR, CZ, DE, DK, DO, EE, EG, ES, ET, FI, GB, GH, GM, GN, GT, GY, HK, HN, HR, HU, ID, IE, IS, IT, JM, JO, JP, KE, KR, KW, LB, LR, LT, LU, LV, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NI, NL, NO, NZ, PA, PE, PH, PL, PT, QA, RO, RU, SA, SC, SD, SE, SI, SK, SL, SN, SR, SV, TH, TN, TR, TT, TW, TZ, UG, VE, ZA, ZM);Difluvid (MY, PH);Difluzol (UA);Difluzole (KR);Difnazol (KR);Dimycon (HR);Dizole (AU);Dofil (CR, DO, GT, HN, NI, PA, SV);Duflucan (UA);Dyzolor (PH);Eapacon (ET);Exomax (BH, HK, ZA);FCZ Infusion (ID);Flocan (KR);FLU-D (TW);Flucan (TR);Flucand (BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);Flucanol (IL, ZW);Flucazol (AE, BR, CH, CY, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);Flucazole (NZ);Flucogus (TW);Flucol (IE);Flucon (KR, MY);Flucona (KR);Flucona-Denk (TZ);Fluconal (BD);Fluconaz (PH);Flucoral (BH, ID);Flucoran (NZ);Flucoxan (MX);Flucozal (BR, LK, MT, PK);Flucozol (MY);Fludicon (HK);Fludizol (TH);Fluken (ZW);Flumax (KR);Flumyc (ZW);Flunazol (CY);Flunazole (TW);Flunco (TH);Fluxar (ID);Fluzin (KR);Fluzole (AU, LK);Fluzoral (TH);Forcan (CZ, IN, LV, VN);f*ckole (MY, PH);Fumay (TW);Funa (TH);Funazol (KR);Funex (CO);Fungata (DE);Fungicon (ZW);Fungostatin (GR);Fungoz (ID);Funzela (PH);Funzol (JO, LB, QA, SA);Fuzolan (ID);Fuzolsel (VN);Glonaz (PH);Insep (ZA);Jenfunga (EG);Klevaflu (VN);Kyrin (TH);Medoflucon (CN, SG);Mutum (AR, PE);Mycocyst (BM, BS, BZ, GY, JM, SR, TT, UA);Mycomox (LV);Mycorest (SG);Mycosyst (HU);Mycozole (PH);Neoconal (KR);Nobzol-1 (CO);Nobzol-2 (CO);Odaft (MY, PH);Omastin (SG);Onecan (LK);Oneflu (KR);Oramax (AE, ET, KW, LB, QA, SA);Oxifungol (MX);Oxole (AU);Reforce (PT);Sixanol (PY, UY);Solona (SE);Spirolac (PY);Stabilanol (ET, IL);Stalene (TH);Syscan (ET, IN);Tavor (EC);Tinazole (KR);Treflucan (AE, CY, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);Triconal (EG);Triflucan (FR, IL, TR);Trigal (BD);Uzol (TW);Zemyc (ID);Zocol (MY);Zoldicam (MX);Zoleshot (PH);Zolmed (VN)For country code abbreviations (show table)<800> Hazardous Drugs—Handling in Healthcare Settings. 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Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/Adult_OI.pdf. Updated June 11, 2021. Accessed January 31, 2022.Valtonen M, Tiula E, Neuvonen PJ. Effect of continuous venovenous haemofiltration and haemodiafiltration on the elimination of fluconazole in patients with acute renal failure. J Antimicrob Chemother. 1997;40(5):695-700. [PubMed 9421318]Van Daele R, Wauters J, Lagrou K, et al. Pharmaco*kinetic variability and target attainment of fluconazole in critically ill patients. Microorganisms. 2021;9(10):2068. doi:10.3390/microorganisms9102068 [PubMed 34683388]van der Elst KC, Pereboom M, van den Heuvel ER, Kosterink JG, Schölvinck EH, Alffenaar JW. Insufficient fluconazole exposure in pediatric cancer patients and the need for therapeutic drug monitoring in critically ill children. Clin Infect Dis. 2014;59(11):1527-1533. doi:10.1093/cid/ciu657 [PubMed 25148892]Vas S, Oreopoulos DG. Infections in patients undergoing peritoneal dialysis. Infect Dis Clin North Am. 2001;15(3):743-774. [PubMed 11570140]Vazquez JA. Management of candidemia and invasive candidiasis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed July 27, 2022.Veltri MA, Neu AM, Fivush BA, Parekh RS, Furth SL. Drug dosing during intermittent hemodialysis and continuous renal replacement therapy: special considerations in pediatric patients. Paediatr Drugs. 2004;6(1):45-65. [PubMed 14969569]Vivjoa (oteseconazole) [prescribing information]. Durham, NC: Mycovia Pharmaceuticals Inc; April 2022.Wade KC, Benjamin DK Jr, Kaufman DA, et al. Fluconazole Dosing for the Prevention or Treatment of Invasive Candidiasis in Young Infants. Pediatr Infect Dis J. 2009;28(8):717-723. [PubMed 19593252]Wang AY, Yu AW, Li PK, Leung CB, Lai KN, Lui SE. Factors predicting outcome of fungal peritonitis in peritoneal dialysis: analysis of a 9-year experience of fungal peritonitis in a single center. Am J Kidney Dis. 2000;36(6):1183-1192. doi:10.1053/ajkd.2000.19833 [PubMed 11096043]Wang JL, Chang CH, Young-Xu Y, Chan KA. Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection. Antimicrob Agents Chemother. 2010;54(6):2409-2419. doi:10.1128/AAC.01657-09 [PubMed 20308378]Warady BA, Bakkaloglu S, Newland J, et al. Consensus guideline for the prevention and treatment of catheter-related infections and peritonitis in pediatric patients receiving peritoneal dialysis: 2012. Peritoneal Dialysis International. 2012;32:s32-86. [PubMed 22851742]Wassmann S, Nickenig G, Bohm M. Long QT syndrome and torsade de pointes in a patient receiving fluconazole. Ann Inter Med. 1999;131(10):797. [PubMed 10577320]Watt KM, Benjamin DK Jr, Cheifetz IM, et al. Pharmaco*kinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J. 2012;31(10):1042-1047. [PubMed 22627870]Watt KM, Cohen-Wolkowiez M, Barrett JS, et al. Physiologically based pharmaco*kinetic approach to determine dosing on extracorporeal life support: fluconazole in children on ECMO. CPT Pharmacometrics Syst Pharmacol. 2018;7(10):629-637. doi:10.1002/psp4.12338 [PubMed 30033691]Watt KM, Gonzalez D, Benjamin DK Jr, et al. Fluconazole population pharmaco*kinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation. Antimicrob Agents Chemother. 2015;59(7):3935-3943. doi:10.1128/AAC.00102-15 [PubMed 25896706]Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45(7):807-825. [PubMed 17806045]Wingard JR. Prophylaxis of invasive fungal infection in adults with hematologic malignancies. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 9, 2019.Winston DJ, Busuttil RW. Randomized controlled trial of oral itraconazole solution versus intravenous/oral fluconazole for prevention of fungal infections in liver transplant recipients. Transplantation. 2002;74(5):688-695. doi: 10.1097/01.TP.0000019727.88291.F5. [PubMed 12352887]Wong SF, Leung MP, Chan MY. Pharmaco*kinetics of fluconazole in children requiring peritoneal dialysis. Clin Ther. 1997;19(5):1039-1047. doi:10.1016/s0149-2918(97)80056-2 [PubMed 9385491]World Health Organization (WHO). Breastfeeding and maternal medication, recommendations for drugs in the Eleventh WHO Model List of Essential Drugs. http://www.who.int/maternal_child_adolescent/documents/55732/en/. Published 2002.World Health Organization (WHO). Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. https://www.who.int/publications/i/item/9789240052178. Published June 27, 2022. Accessed October 16, 2022.Workowski KA, Bachmann LH, Chan PA, et al; Centers for Disease Control and Prevention (CDC). Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. doi:10.15585/mmwr.rr7004a1 [PubMed 34292926]Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015 [published correction appears in MMWR Recomm Rep. 2015;64(33):924]. MMWR Recomm Rep. 2015;64(RR-03):1-137. [PubMed 26042815]Zeuli JD, Wilson JW, Estes LL. Effect of combined fluoroquinolone and azole use on QT prolongation in hematology patients. Antimicrob Agents Chemother. 2013;57(3):1121-1127. doi:10.1128/AAC.00958-12 [PubMed 23229485]Topic 13303 Version 628.0

CloseOndansetron: Drug informationOndansetron: Drug information(For additional information see "Ondansetron: Patient drug information" and see "Ondansetron: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USZofran;Zuplenz [DSC]Brand Names: CanadaACCEL-Ondansetron;APO-Ondansetron;ATHENA-Ondansetron ODT;AURO-Ondansetron;Auro-Ondansetron ODT;CCP-Ondansetron;JAMP Ondansetron;JAMP-Ondansetron;Mar-Ondansetron;MAR-Ondansetron ODT;MINT-Ondansetron;MINT-Ondansetron ODT;MYLAN-Ondansetron;NAT-Ondansetron;Ondansetron ODT;Ondissolve ODF;PMS-Ondansetron;PMS-Ondansetron ODT;SANDOZ Ondansetron;TEVA Ondansetron;VAN-Ondansetron [DSC];Zofran;Zofran ODTPharmacologic CategoryAntiemetic;Selective 5-HT3 Receptor AntagonistDosing: AdultNote: Zuplenz has been discontinued in the United States for >1 year. Single IV doses >16 mg are no longer recommended due to the potential for QT prolongation (Ref). Avoid use in patients with congenital long-QT syndrome.Carcinoid syndrome-associated diarrhea, severe, refractoryCarcinoid syndrome-associated diarrhea, severe, refractory (alternative agent) (off-label use): Based on limited data (case reports):Oral: 8 mg 3 times daily (Wymenga 1998) or 8 mg twice daily for 3 days, followed by a maintenance dose of 4 to 8 mg/day for 4 to 12 weeks (Ref).IV: 4 to 8 mg every 8 hours (Ref).Chemotherapy-induced nausea and vomiting, preventionChemotherapy-induced nausea and vomiting, prevention:Single-day IV chemotherapy regimens:Highly emetogenic chemotherapy (>90% risk of emesis [eg, cisplatin, breast cancer regimens that include an anthracycline combined with cyclophosphamide]):Day of chemotherapy: Administer prior to chemotherapy and in combination with a neurokinin 1 (NK1) receptor antagonist, dexamethasone, and olanzapine (Ref).IV: 8 mg or 0.15 mg/kg as a single dose (Ref). Maximum: 16 mg/dose (Ref).Oral:Tablet formulations and oral solution: 8 mg twice daily for 2 doses with the first dose administered prior to chemotherapy administration (Ref) or 24 mg as a single dose (Ref).Oral soluble film: 24 mg (three 8 mg doses given together) as a single dose (Ref).Post–chemotherapy days: 5-HT3 receptor antagonist use is not necessary (other components of the antiemetic regimen are administered) (Ref).Moderately emetogenic chemotherapy (30% to 90% risk of emesis): Carboplatin-based regimens:Day of chemotherapy: Administer prior to chemotherapy and in combination with an NK1 receptor antagonist and dexamethasone (Ref).IV: 8 mg or 0.15 mg/kg as a single dose (Ref). Maximum: 16 mg/dose (Ref).Oral: 8 mg twice daily for 2 doses with the first dose administered prior to chemotherapy administration (Ref).Post–chemotherapy days: 5-HT3 receptor antagonist use is not necessary (other components of the antiemetic regimen may be administered) (Ref).Moderately emetogenic chemotherapy (30% to 90% risk of emesis): Non-carboplatin-based regimens (alternative agent): Note: ASCO guidelines and MASCC/ESMO guidelines do not state a preference for which 5-HT3 receptor antagonist should be used in this setting; however, palonosetron may be preferred (Ref).Day of chemotherapy: Administer prior to chemotherapy and in combination with dexamethasone (Ref).IV: 8 mg or 0.15 mg/kg as a single dose (Ref). Maximum: 16 mg/dose (Ref).Oral: 8 mg twice daily for 2 doses with the first dose administered prior to chemotherapy administration (Ref).Post–chemotherapy days: 5-HT3 receptor antagonist use is not necessary (other components of the antiemetic regimen may be administered) (Ref); however, if a first-generation 5-HT3 receptor antagonist (eg, ondansetron, granisetron) was used on day 1 of chemotherapy rather than palonosetron, the first-generation 5-HT3 receptor antagonist may be continued for postchemotherapy emetic prophylaxis on days 2 and 3 (Ref).Low emetogenic risk (10% to 30% risk of emesis):Note: Single-agent ondansetron is an option for prophylaxis (Ref).Day of chemotherapy: IV: 8 mg as a single dose prior to chemotherapy (Ref).Oral (off-label): 8 mg as a single dose prior to chemotherapy (Ref).Post–chemotherapy days: Prophylaxis is not necessary on subsequent days (Ref).Minimal emetogenic risk (<10% risk of emesis): Routine antiemetic prophylaxis is not generally necessary (Ref).High-dose chemotherapy with stem or bone marrow transplant: Day of chemotherapy: Administer prior to chemotherapy and in combination with a neurokinin 1 (NK1) receptor antagonist, dexamethasone, with or without olanzapine (Ref).IV: 8 mg or 0.15 mg/kg as a single dose (Ref). Maximum: 16 mg/dose (Ref).Oral: 24 mg as a single dose (Ref).Oral chemotherapy agents:High/moderate emetogenic risk oral agent (≥30% risk of emesis): Oral: 8 to 16 mg/day administered before chemotherapy and continued daily (Ref).Low/minimal emetogenic risk oral agent (<30% risk of emesis): Oral: 8 to 16 mg/day on an as-needed basis only (Ref).Gastroparesis, symptomatic treatment of nausea and vomitingGastroparesis, symptomatic treatment of nausea and vomiting (alternative agent) (off-label use): Note: For patients with persistent symptoms refractory to prokinetic therapy. No data available; recommendations for use and dose are based on expert opinion.Oral: 4 to 8 mg 3 times daily (Ref).Nausea and/or vomiting, acute, severeNausea and/or vomiting, acute, severe (off-label use): Note: Use has primarily been evaluated in patients with undifferentiated nausea/vomiting presenting to the emergency department; however, may also use for nausea/vomiting due to viral gastroenteritis, acute mountain sickness, and a variety of other medical conditions associated with severe, self-limiting acute nausea/vomiting (Ref).Oral, IV, IM: 4 mg as a single dose (Ref). Note: For parenteral therapy, IV administration is preferred over IM when possible (Ref).Prevention of vomiting (and associated increase in intraocular pressure) in patients with eye trauma: IV: 4 to 8 mg as a single dose (Ref).Postoperative nausea and vomiting, preventionPostoperative nausea and vomiting, prevention:Moderate- to high-risk patients: Note: In patients at moderate risk, may combine ondansetron with other prophylactic interventions (eg, another antiemetic agent from a different pharmacologic class, modification of anesthetic technique, acupuncture); in patients at high risk, combine 3 or more interventions (Ref).Usual dose: IV: 4 mg as a single dose at the end of surgery (Ref).Alternative strategy: Oral (oral disintegrating tablet or oral soluble film): 8 mg as a single dose given 30 to 60 minutes prior to surgery (Ref).Low-risk patients:Although prophylaxis is not always indicated in low-risk patients, consensus guidelines acknowledge that some experts may administer an antiemetic in these patients; however, clinicians are also advised that this strategy comes with the potentially unnecessary risk of rare adverse effects (Ref). If ondansetron is given, the dosing is the same as for moderate- to high-risk patients.Postdischarge management in high-risk patients: Limited data available; dosage regimen studied in a single clinical trial: Oral (oral disintegrating tablet or oral soluble film): 8 mg to be taken on discharge and in the morning of postoperative days 1 and 2 (Ref).Postoperative nausea and vomiting, treatment or rescue therapyPostoperative nausea and vomiting, treatment or rescue therapy (off-label use): IV: 4 mg as a single dose when a prophylactic agent was not utilized (treatment) or following failure of an agent utilized as prophylaxis (rescue therapy) (Ref). Note: Rescue therapy should always include an antiemetic from a different class than the one used for prophylaxis, unless a potentially inadequate dose was initially administered or the effect of the first drug has worn off (>6 hours since initial dose for most 5-HT3 receptor antagonists) (Ref). However, some experts do not recommend repeat administration of a 5-HT3 antagonist unless triple therapy has been used for prophylaxis and no alternatives are available for rescue that were not used for prophylaxis (Ref).Pregnancy-associated nausea and vomiting, severe or refractoryPregnancy-associated nausea and vomiting, severe or refractory (off-label use): Note: May be considered for adjunctive treatment of nausea and vomiting when symptoms persist following initial pharmacologic therapy (Ref).Patients without hypovolemia:Oral, IV (bolus): 4 mg every 8 hours, as needed, added to current treatment regimen (Ref). If necessary, some experts increase to a maximum of 8 mg/dose (Ref).Patients with hypovolemia:Note: For patients with persistent symptoms despite intravenous fluid replacement:IV: 8 mg administered over 15 minutes every 12 hours, added to current treatment regimen (Ref). Some experts use 4 to 8 mg administered as an IV bolus every 8 hours until stabilization (Ref).Radiation therapy-associated nausea and vomiting, preventionRadiation therapy-associated nausea and vomiting, prevention: High-emetogenic risk radiation therapy (total body irradiation): Radiation day(s):IV (off-label): 8 mg or 0.15 mg/kg (maximum: 16 mg/dose [manufacturer’s labeling]) once daily or twice daily prior to each fraction of radiation; administer in combination with dexamethasone (Ref).Oral: 8 mg once daily or twice daily administered 1 to 2 hours prior to each fraction of radiation; administer in combination with dexamethasone (Ref) or, in one clinical trial of 4 days of hyperfractionated total body irradiation, 8 mg (without dexamethasone) was administered 1.5 hours prior to every fraction of radiation (3 times daily for the first 3 days and twice daily on day 4) (Ref).Post–radiation days: IV (off-label), Oral: The appropriate duration of therapy following radiotherapy days is not well defined; ASCO guidelines recommend continuing ondansetron once daily or twice daily on the day after each day of radiation (Ref).Moderate-emetogenic risk radiation therapy (upper abdomen, craniospinal irradiation) (off-label use): Radiation day(s):IV (off-label): 8 mg or 0.15 mg/kg (maximum: 16 mg/dose [manufacturer’s labeling]) once daily or twice daily prior to each fraction of radiation; may administer with or without dexamethasone before the first 5 fractions (Ref).Oral: 8 mg once daily or twice daily administered 1 to 2 hours prior to each fraction of radiation; may administer with or without dexamethasone before the first 5 fractions (Ref) or, in clinical trials involving upper abdomen radiation (high-dose single exposure or multiple-day fractionated course), 8 mg 3 times daily (without dexamethasone) has been given; doses were administered 1 to 2 hours prior to radiation therapy (Ref).Low- (brain, head and neck, thorax, pelvis) to minimal- (extremities, breast) emetogenic risk radiation therapy:Routine prophylaxis not recommended; however, may use as rescue therapy using the following dosing with consideration of using prophylactically for the remainder of radiation therapy (Ref).IV: 8 mg or 0.15 mg/kg (Ref) (maximum: 16 mg/dose (Ref)).Oral: 8 mg (Ref).Vertigo-associated nausea and vomitingVertigo-associated nausea and vomiting (alternative agent) (off-label use):IV (preferred), IM: 4 to 8 mg once for acute symptoms (Ref).Oral: 4 mg every 8 to 12 hours as needed (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Altered kidney function: IV, Oral: No dose adjustments likely to be necessary, as clearance by the kidney accounts for only 5% of total clearance (Roila 1995; manufacturer’s labeling). Unlikely to be significantly dialyzed due to relatively high volume of distribution and plasma protein binding (Ref).Dosing: Hepatic Impairment: AdultMild to moderate impairment: No dosage adjustment necessary.Severe impairment (Child-Pugh class C):IV: Day 1: Maximum daily dose: 8 mg; however, according to the manufacturer, there is no experience beyond first-day administration (has not been studied beyond day 1)Oral: Maximum daily dose: 8 mgDosing: Pediatric(For additional information see "Ondansetron: Pediatric drug information")Note: Zuplenz oral film has been discontinued in the United States for >1 year.Chemotherapy-induced nausea and vomiting, preventionChemotherapy-induced nausea and vomiting, prevention: Note: Use in combination with or without dexamethasone and aprepitant or fosaprepitant depending upon patient age, chemotherapy emetogenic potential, and drug-interaction profile (refer to specific protocols or guidelines) (Ref).Guideline dosing:Highly emetogenic chemotherapy: Infants, Children, and Adolescents: IV, Oral: 0.15 mg/kg/dose (5 mg/m2/dose); administer first dose before the start of chemotherapy and then every 8 hours (Ref); usual reported maximum dose: 8 mg/dose (Ref).Moderately emetogenic chemotherapy: Infants, Children, and Adolescents: IV, Oral: 0.15 mg/kg/dose (5 mg/m2/dose); maximum dose: 8 mg/dose; administer first dose before the start of chemotherapy with subsequent doses every 12 hours (Ref).Low emetogenic chemotherapy: Infants, Children, and Adolescents: IV, Oral: 0.3 mg/kg/dose once (10 mg/m2/dose); maximum dose: 16 mg/dose; administered 30 minutes before the start of chemotherapy (Ref).Manufacturer's labeling:IV: Emetogenic chemotherapy: Infants, Children, and Adolescents (limited data available for infants <6 months): IV: 0.15 mg/kg/dose every 4 hours for a total of 3 doses beginning 30 minutes before the start of chemotherapy (manufacturer's labeling); maximum daily dose: 32 mg/day (Ref).Oral: Moderately emetogenic antineoplastic therapy:Children 4 to 11 years: Oral: 4 mg beginning 30 minutes before chemotherapy; repeat 4 and 8 hours after initial dose, then 4 mg every 8 hours for 1 to 2 days after chemotherapy completed (Ref).Children ≥12 years and Adolescents: Oral: 8 mg beginning 30 minutes before chemotherapy; repeat dose 8 hours after initial dose, then 8 mg every 12 hours for 1 to 2 days after chemotherapy completed (Ref).Single-dose regimen (low, moderate, or highly emetogenic potential): Limited data available; efficacy results variable:Infants, Children, and Adolescents: IV: 0.3 mg/kg/dose once daily; maximum dose: 16 mg/dose (Ref); dosing based on a randomized controlled study comparing a single daily IV dose of 0.3 mg/kg to standard therapy administered every 8 hours in 194 patients ages 0 to 18 years; the single daily dose was shown to be as effective as the multidose regimen in patients ≥7 years of age; however, in patients <7 years of age the every-8-hour dosing provided better control of nausea symptoms (Ref).Cyclic vomiting syndrome; treatment of acute attackCyclic vomiting syndrome (CVS); treatment of acute attack Limited data available; dosing based on case reports and clinical experience:Children >2 years and Adolescents:Low dose: IV: 0.15 mg/kg every 4 hours as needed for up to 3 doses; maximum dose: 16 mg/dose (Ref).High dose: IV: 0.3 to 0.4 mg/kg/dose every 4 to 6 hours; maximum dose: 16 mg/dose (Ref); per manufacturer labeling, should not exceed 3 doses in a 24-hour period.Gastroenteritis, acute; treatmentGastroenteritis, acute; treatment: Note: Routine use of ondansetron is not recommended in most cases of acute gastroenteritis (Ref).IV: Infants and Children: IV: 0.15 or 0.3 mg/kg/dose once; maximum dose: 16 mg/dose (Ref).Oral: Infants ≥6 months and Children ≤10 years, weighing ≥8 kg (Ref):8 to 15 kg: Oral: 2 mg/dose once.>15 to 30 kg: Oral: 4 mg/dose once.>30 kg: Oral: 8 mg/dose once.Postoperative nausea and vomiting; preventionPostoperative nausea and vomiting; prevention: Administer immediately before or following induction of anesthesia, or postoperatively if the patient is symptomatic. Repeat doses given in response to inadequate control of nausea/vomiting from preoperative doses are generally ineffective.Infants and Children:≤40 kg: IV: 0.1 mg/kg/dose as a single dose; maximum dose: 4 mg/dose.>40 kg: IV: 4 mg/dose as a single dose.Adolescents: IM, IV: 4 mg/dose as a single dose.Radiation-induced nausea and vomiting, preventionRadiation-induced nausea and vomiting, prevention: Limited data available:Weight-directed dosing: Infants ≥5 months, Children, and Adolescents: Oral: 0.2 mg/kg/dose (maximum dose: 8 mg/dose) administered every 8 hours throughout total body irradiation (TBI) prior to hematopoietic stem cell transplant (HSCT) (n=68; mean age: 6.7 years; range: 5 months to 20 years); doses were generally rounded to 4 mg/dose in children 4 to 11 years and 8 mg/dose in children ≥12 years and adolescents (Ref).Alternate weight-based dosing: Children and Adolescents: Oral: 0.15 mg/kg/dose administered 3 to 4 times daily throughout TBI (n=33; mean age: 9 years; range: 13 months to 16 years) (Ref).Fixed dose: Note: Derived from rounding weight-based (0.2 mg/kg/dose) doses (Ref).Children 4 to 11 years: Oral: 4 mg every 8 hours throughout TBI prior to HSCT.Children ≥12 years and Adolescents: Oral: 8 mg every 8 hours throughout TBI prior to HSCT.Alternate fixed-dosing: Children ≥9 years and Adolescents: Oral: 8 mg every 12 hours on days of TBI prior to bone marrow transplantation (age range: 9 to 67 years; median age range: 39 to 49 years). Note: Administered in combination with dexamethasone (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricIV: No dosage adjustment is necessary.Oral: No dosage adjustment is necessary; however, there is no experience for oral ondansetron in renal impairment beyond first-day administration (has not been studied beyond day 1)Dosing: Hepatic Impairment: PediatricThere are no pediatric-specific recommendations; based on experience in adult patients, no adjustment may be necessary for mild to moderate hepatic impairment; for severe impairment, dosing adjustment suggested.Dosing: Older AdultOral: No dosing adjustment required; refer to adult dosing.IV: Single IV doses >16 mg are no longer recommended due to the potential for QT prolongation (Ref). In patients ≥75 years, Canadian recommendations place additional restrictions to limit initial IV doses to ≤8 mg due to this risk (Ref).Dosing: Adjustment for Toxicity: AdultHypersensitivity: Discontinue ondansetron; manage as clinically indicated.Serotonin syndrome: Discontinue ondansetron and initiate supportive management.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productFilm, Oral: Zuplenz: 4 mg (30 ea [DSC]); 8 mg (30 ea [DSC])Solution, Injection, as hydrochloride [strength expressed as base]: Generic: 4 mg/2 mL (2 mL); 40 mg/20 mL (20 mL)Solution, Injection, as hydrochloride [strength expressed as base, preservative free]: Generic: 4 mg/2 mL (2 mL)Solution, Oral, as hydrochloride [strength expressed as base]: Zofran: 4 mg/5 mL (50 mL [DSC])Generic: 4 mg/5 mL (5 mL, 50 mL)Solution Prefilled Syringe, Injection, as hydrochloride: Generic: 4 mg/2 mL (2 mL)Tablet, Oral, as hydrochloride [strength expressed as base]: Zofran: 4 mg, 8 mg [DSC]Generic: 4 mg, 8 mg, 24 mgTablet Disintegrating, Oral: Generic: 4 mg, 8 mgGeneric Equivalent Available: USMay be product dependentDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Film, Oral: Ondissolve ODF: 4 mg (6 ea, 10 ea, 50 ea); 8 mg (6 ea, 10 ea, 50 ea) [contains levomenthol, polyethylene glycol (macrogol), polysorbate 80]Solution, Intravenous: Zofran: 2 mg/mL (2 mL, 4 mL, 20 mL)Generic: 2 mg/mL (2 mL, 4 mL, 5 mL, 20 mL)Solution, Oral, as hydrochloride [strength expressed as base]: Zofran: 4 mg/5 mL (50 mL) [contains alcohol, usp, sodium benzoate]Generic: 4 mg/5 mL (50 mL)Tablet, Oral, as hydrochloride [strength expressed as base]: Zofran: 4 mg, 8 mgGeneric: 4 mg, 8 mgTablet Disintegrating, Oral: Zofran ODT: 4 mg, 8 mg [contains aspartame, methylparaben sodium, propylparaben sodium]Generic: 4 mg, 8 mgProduct AvailabilityZuplenz has been discontinued in the United States for >1 year.Administration: AdultOral: Oral dosage forms should be administered 30 minutes prior to chemotherapy; 1 to 2 hours before radiation; 30 to 60 minutes prior to surgery or induction of anesthesiaOrally disintegrating tablets: Do not remove from blister until needed. Peel backing off the blister, do not attempt to push tablet through the foil. Using dry hands, place tablet on tongue and allow to dissolve. Swallow with saliva (no need to administer with liquids).Oral soluble film: Do not remove from pouch until immediately before use. Using dry hands, place film on top of tongue and allow to dissolve (4 to 20 seconds). Swallow with or without liquid. If using more than one film, each film should be allowed to dissolve completely before administering the next film.IM: Should be administered undiluted.IV:IVPB: Infuse diluted solution over 15 minutesChemotherapy-induced nausea and vomiting: Give first dose 30 minutes prior to beginning chemotherapy.IV push: Prevention of postoperative nausea and vomiting: Single doses may be administered IV injection as undiluted solution over at least 30 seconds but preferably over 2 to 5 minutesAdministration: PediatricOral (all dosage forms): May administer without regard to meals. Administer 30 minutes prior to chemotherapy, 1 to 2 hours prior to radiotherapy, and 1 hour prior to induction of anesthesia.Orally disintegrating tablet (Zofran ODT): Do not remove from blister until needed. Peel backing off the blister; do not push tablet through foil backing. Using dry hands, place tablet on tongue and allow to dissolve; swallow with saliva (no need to administer with liquids).Soluble film (Zuplenz): Do not remove from pouch until immediately before use. Using dry hands, place film on top of tongue and allow to dissolve (4 to 20 seconds). Swallow with or without liquid. If using more than one film, allow each film to dissolve completely before administering the next film.Parenteral:IV:IVPB infusion:Prevention of chemotherapy-induced nausea and vomiting: Infuse over 15 minutes.Cyclic vomiting syndrome: Infuse over 15 to 30 minutes (Ref).IV push: May be administered undiluted IV over 2 to 5 minutes for prevention of PONV.IM: Administer as undiluted injection.Use: Labeled IndicationsCancer chemotherapy-induced nausea and vomiting: IV: Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy (including high-dose cisplatin).Oral:Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy (including cisplatin ≥50 mg/m2).Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.Postoperative nausea and/or vomiting: IV, IM, Oral: Prevention of postoperative nausea and/or vomiting (PONV). If nausea/vomiting occur in a patient who had not received prophylactic ondansetron, IV ondansetron may be administered to prevent further episodes.Limitations of use: Routine prophylaxis for PONV in patients with minimal expectation of nausea and/or vomiting is not recommended, although use is recommended in patients when nausea and vomiting must be avoided in the postoperative period, even if the incidence of PONV is low.Radiotherapy-associated nausea and vomiting: Oral: Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen.Use: Off-Label: AdultCarcinoid syndrome-associated diarrhea, severe, refractory; Gastroparesis, symptomatic treatment of nausea and vomiting (alternative agent in patients with persistent symptoms refractory to prokinetic therapy); Nausea and/or vomiting, acute, severe; Postoperative nausea and vomiting, treatment or rescue therapy; Pregnancy-associated nausea and vomiting, severe or refractory; Vertigo-associated nausea and vomitingMedication Safety IssuesSound-alike/look-alike issues: Ondansetron may be confused with dolasetron, granisetron, palonosetron Zofran may be confused with Zantac, ZosynAdverse Reactions (Significant): ConsiderationsConstipationOndansetron may commonly cause constipation (Ref). Rare cases of intestinal obstruction have also been reported (Ref).Mechanism: Likely due to blockade of 5-HT3 gut receptors which results in decreased motility (Ref). May also occur as a result of decreased colonic transit time (Ref) and inhibition of postprandial increase in tone (Ref).Onset: Varied; one reported case of constipation occurred the same day as oral ondansetron administration; intestinal obstruction resulted approximately 2 weeks after continuous twice daily dosing (Ref).Risk factors:• Preexisting liver disease (Ref)HeadacheHeadache is the most reported adverse reaction with ondansetron (Ref). Additional doses and movement (with or without postural changes) have been associated with worsening (Ref). Severe headache has led to discontinuation in reported cases (Ref).Onset: Rapid; severe headache reported to occur within minutes of administration, often lasting minutes to hours. There have been multiple case reports of children experiencing throbbing headaches for several days following ondansetron and chemotherapy (Ref). One patient reported onset of severe headache occurring within 2 hours of the first dose and continued to occur every 12 hours following repeated administration (Ref).Risk factors:• Personal or family history of migraine (Ref)• Concurrent use of propofol and/or fentanyl (Ref)• Higher doses (potential risk factor) (Ref)Hypersensitivity (immediate)Immediate hypersensitivity reactions may occur with ondansetron, including urticaria, angioedema, hypotension, bronchospasm, dyspnea, and anaphylaxis (Ref). Some patients may only present with hypotension, without any accompanying symptoms (Ref). Patients may have more severe reactions on subsequent exposure (Ref).Mechanism: Non-dose-related; immunologic; likely IgE-mediated (Ref); may be the result of direct mast cell stimulation (in some patients without previous exposure) (Ref).Onset: Rapid; immediate hypersensitivity reactions generally occur within 1 hour of administration, but may occur up to 6 hours after exposure (Ref). Reactions usually occur after the first dose during the second or third course of chemotherapy (Ref).Risk factors:• Adults with cancer (Ref); however, a few isolated cases have been reported in children (Ref)• IV route of administration; however, anaphylaxis following sublingual administration has been reported (Ref)• Cross-reaction between serotonin 5-HT3 antagonists has been described in limited case reports (Ref)QT prolongationIncreases in ECG intervals (eg, PR, QRS duration, JT); prolonged QT interval on ECG; and bradycardia have been observed with ondansetron (Ref). Cases of ventricular arrhythmias and torsades de pointes have also been reported. Rare cases of fatalities have occurred even at low doses (Ref).Mechanism: QT prolongation may occur due to HERG K+ channel-blockade (Ref). Suppression of autonomic reflexes may contribute to bradycardia, hypotension, and tachyarrhythmias (Ref).Onset: Rapid; usually occurs 1 to 2 hours after administration (Ref); however, QT prolongation peaks have been observed within ~5 to 15 minutes following administration (Ref). QTc intervals >500 ms have been recorded within 15 minutes after administration (Ref). May persist >2 hours from administered dose (Ref).Risk factors:• IV route of administration (Ref)• Single doses >16 mg IV (Ref); however, risk should be considered even with low IV doses (Ref)• Concomitant medications that prolong the QT interval (Ref)• Females (Ref)• Hypothermia (Ref)• Concomitant volatile anesthetics or cumulative high-dose anthracycline therapy (Ref)• Underlying heart disease including heart failure or acute coronary syndromes (Ref)• Electrolyte abnormalities (eg, hypokalemia, hypomagnesemia) (Ref)• History of QT prolongation, bradycardia, tachycardia, or cardiac rhythm disorders (especially ventricular arrhythmia) (Ref)• Patients receiving ondansetron following anesthesia, while in the intensive care unit, or during hospital admission (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidence reported in adult patients unless otherwise specified.>10%:Gastrointestinal: Constipation (9% to 11%)Ondansetron: Adverse Reaction: ConstipationDrug (Ondansetron)Placebo DoseDosage FormIndicationNumber of Patients (Ondansetron)Number of Patients (Placebo)9%0.4%8 mg twice dailyOralChemotherapy-induced nausea and vomiting24226211%N/AN/AInjectionN/AN/AN/ANervous system: Fatigue (oral: ≤13%), headache (9% to 24%), malaise (oral: ≤13%)Ondansetron: Adverse Reaction: HeadacheDrug (Ondansetron)Comparator (Metoclopramide)Placebo DoseDosage FormIndicationNumber of Patients (Ondansetron)Number of Patients (Metoclopramide)Number of Patients (Placebo)24%N/A13%8 mg twice dailyOralChemotherapy-induced nausea and vomiting242N/A26217%7%15%0.15 mg/kg x 3InjectionChemotherapy-induced nausea and vomiting4191563417%N/A14%4 mg single doseIVPostoperative nausea and vomiting547N/A5479%N/A5%16 mg single doseOralPostoperative nausea and vomiting550N/A5311% to 10%:Dermatologic: Pruritus (2% to 5%), skin rash (1%)Gastrointestinal: Diarrhea (oral: 6%; IV: children 1 to 24 months of age: 2%)Genitourinary: Gynecologic disease (oral: 7%), urinary retention (oral: 5%)Hepatic: Increased serum alanine aminotransferase (>2 times ULN: 1% to 5%; transient), increased serum aspartate aminotransferase (>2 times ULN: 1% to 5%; transient)Hypersensitivity: Anaphylaxis (<2%) (Fernando 2009)Local: Injection site reaction (4%; includes burning sensation at injection site, erythema at injection site, injection site pain)Nervous system: Agitation (oral: ≤6%), anxiety (oral: ≤6%), dizziness (7%), drowsiness (IV: ≤8%), paresthesia (IV: 2%), sedated state (IV: ≤8%), sensation of cold (IV: 2%)Respiratory: Bronchospasm (<2%), hypoxia (oral: 9%)Miscellaneous: Fever (2% to 8%)<1%:Cardiovascular: HypotensionNervous system: Extrapyramidal reaction (Ritter 2003; Sprung 2003)Frequency not defined:Cardiovascular: Angina pectoris, peripheral vascular disease, tachycardiaEndocrine & metabolic: HypokalemiaNervous system: Tonic clonic epilepsyPostmarketing:Cardiovascular: Atrial fibrillation (Havrilla 2009), bradycardia (Afonso 2009; Rapp 2015), depression of ST segment on ECG, flushing, ischemic heart disease (most commonly due to coronary artery spasm and may occur with oral or IV [predominantly IV]; occurred immediately after IV administration and resolved with treatment), palpitations, prolonged QT interval on ECG (Ganjare 2013; Moffett 2016), second degree atrioventricular block, supraventricular tachycardia, syncope, torsades de pointes (Lee 2017; Patel 2019), ventricular premature contractions, ventricular tachycardiaDermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis (Saraogi 2012), urticaria (Bousquet 2005)Gastrointestinal: Hiccups, intestinal obstruction (Cohen 2014)Hematologic & oncologic: Positive lymphocyte transformation testHepatic: Hepatic failureHypersensitivity: Angioedema, fixed drug eruption (Maitra 2017), hypersensitivity reaction (Garcia Nunez 2015; Leung 2013), nonimmune anaphylaxisNervous system: Dystonic reaction (Diaz-Parlet 2015), serotonin syndrome (George 2008)Neuromuscular & skeletal: LaryngospasmOphthalmic: Accommodation disturbance, oculogyric crisis (Macachor 2014), transient blindness (lasted ≤48 hours) (Cherian 2005), transient blurred vision (following infusion)Respiratory: Dyspnea, laryngeal edema, stridorContraindicationsHypersensitivity to ondansetron or any component of the formulation; concomitant use with apomorphineWarnings/PrecautionsConcerns related to adverse effects:• Serotonin syndrome: Serotonin syndrome (SS) has been reported with 5-HT3 receptor antagonists, predominantly when used in combination with other serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and/or methylene blue). Some of the cases have been fatal. The majority of serotonin syndrome reports due to 5-HT3 receptor antagonist have occurred in a postanesthesia setting or in an infusion center. SS has also been reported following overdose of ondansetron. Signs/symptoms of SS include mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile BP, diaphoresis, dizziness, flushing, hyperthermia); neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures.Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.• Phenylalanine: Orally disintegrating tablets contain phenylalanine.Other warnings/precautions:• Chemotherapy-associated emesis: Antiemetics are most effective when used prophylactically (MASCC/ESMO [Roila 2016]). If emesis occurs despite optimal antiemetic prophylaxis, re-evaluate emetic risk, disease status, concurrent morbidities and current medications to assure antiemetic regimen is optimized (ASCO [Hesketh 2020]).Metabolism/Transport EffectsSubstrate of CYP1A2 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Amiodarone: May enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationAmisulpride (Oral): May enhance the QTc-prolonging effect of Ondansetron. Risk C: Monitor therapyApomorphine: Antiemetics (5HT3 Antagonists) may enhance the hypotensive effect of Apomorphine.Risk X: Avoid combinationCYP3A4 Inducers (Strong): May decrease the serum concentration of Ondansetron. Risk C: Monitor therapyDabrafenib: Ondansetron may enhance the QTc-prolonging effect of Dabrafenib.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyDomperidone: May enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationFluorouracil Products: Ondansetron may enhance the QTc-prolonging effect of Fluorouracil Products.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyHaloperidol: Ondansetron may enhance the QTc-prolonging effect of Haloperidol.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyMetFORMIN: Ondansetron may increase the serum concentration of MetFORMIN.Risk C: Monitor therapyPanobinostat: Ondansetron may enhance the arrhythmogenic effect of Panobinostat.Risk C: Monitor therapyPentamidine (Systemic): May enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPimozide: May enhance the QTc-prolonging effect of Ondansetron. Risk X: Avoid combinationQT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Antidepressants (Moderate Risk): Ondansetron may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Ondansetron may enhance the serotonergic effect of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome.Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome when these agents are combined. Patients with additional risk factors for QTc prolongation or serotonin syndrome may be at even higher risk. Risk C: Monitor therapyQT-prolonging Antipsychotics (Moderate Risk): Ondansetron may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk).Management: Monitor for QTc interval prolongation, ventricular arrhythmias, including torsades de pointes, when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-Prolonging Inhalational Anesthetics (Moderate Risk): Ondansetron may enhance the QTc-prolonging effect of QT-Prolonging Inhalational Anesthetics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Kinase Inhibitors (Moderate Risk): Ondansetron may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): Ondansetron may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Quinolone Antibiotics (Moderate Risk): Ondansetron may enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapySerotonergic Agents (High Risk): Ondansetron may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyTapentadol: Ondansetron may diminish the analgesic effect of Tapentadol.Risk C: Monitor therapyTraMADol: Ondansetron may enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. Ondansetron may diminish the therapeutic effect of TraMADol.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and diminished tramadol efficacy when these agents are combined. Risk C: Monitor therapyFood InteractionsTablet: Food slightly increases the extent of absorption. Management: Administer without regard to meals.Pregnancy ConsiderationsOndansetron crosses the placenta (Elkomy 2014; Siu 2006).Ondansetron can be detected in fetal tissue (Siu 2006). The risk of developing a major congenital malformation following first trimester exposure is under study. Risks related to specific birth defects (eg, cardiac anomalies, oral clefts) requires confirmation; available human data are conflicting (ACOG 2018; Dormuth 2021; Kaplan 2019; Lemon 2020; Lavecchia 2018; Picot 2020). Clearance is decreased immediately after birth in neonates exposed to ondansetron in utero (Elkomy 2014).Due to pregnancy-induced physiologic changes, clearance of ondansetron may increase as pregnancy progresses (Lemon 2016). Dose adjustment is not needed when administered for the prevention of nausea and vomiting associated with cesarean delivery (Elkomy 2014).Ondansetron may be considered for the treatment of severe or refractory nausea and vomiting of pregnancy (NVP) when preferred agents have failed (ACOG 2018; Campbell 2016). Until additional information related to fetal safety is available, current guidelines suggest use prior to 10 weeks gestation be individualized (ACOG 2018). Dose-dependent QT-interval prolongation can occur with use; therefore, ECG monitoring is recommended in patients with risk factors for arrhythmia (ACOG 2018); this may include patients with electrolyte abnormalities associated with some cases of NVP (Koren 2012).Ondansetron may be considered as part of a multimodal approach to prevent nausea and vomiting associated with cesarean delivery. A combination of ≥2 antiemetics with different mechanisms of action is recommended to treat intraoperative and postoperative nausea and vomiting (Bollag 2021; Griffiths 2012; Habib 2013; Jetling 2017; Macones 2019; Zhou 2018).An international consensus panel recommends that 5-HT3 antagonists (including ondansetron) can be used when necessary in pregnant patients receiving chemotherapy for the treatment of gynecologic cancers (Amant 2019).Breastfeeding ConsiderationsIt is not known if ondansetron is present in breast milk.According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the patient.Dietary ConsiderationsSome products may contain phenylalanine.Monitoring ParametersECG if applicable (eg, high-risk or elderly patients, concurrent use of other medications known to prolong QT interval, electrolyte abnormalities [hypokalemia or hypomagnesemia], heart failure, bradyarrhythmias, and cumulative high-dose anthracycline therapy); serum potassium and magnesium levels. Monitor for signs/symptoms of serotonin syndrome and hypersensitivity; monitor for decreased bowel activity (particularly in patients at risk for bowel obstruction). Monitor for signs/symptoms of myocardial ischemia.Mechanism of ActionOndansetron is a selective 5-HT3-receptor antagonist which blocks serotonin, both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zonePharmaco*kineticsOnset of action: ~30 minutesAbsorption: Oral: 100%; nonlinear absorption occurs with increasing oral doses; Zofran ODT tablets are bioequivalent to Zofran tablets; absorption does not occur via oral mucosad*stribution: Vd:Infants and Children: Surgical patients:1 to 4 months: 3.5 L/kg5 to 24 months: 2.3 L/kg3 to 12 years: 1.65 L/kgChildren and Adolescents: Cancer patients: 4 to 18 years: 1.9 L/kgAdults: 1.9 L/kgProtein binding, plasma: 70% to 76%Metabolism: Extensively hepatic via hydroxylation, followed by glucuronide or sulfate conjugation; CYP1A2, CYP2D6, and CYP3A4 substrate; some demethylation occursBioavailability: Oral: 50% to 70% due to some first-pass metabolism; in cancer patients (adults), 85% to 87% bioavailability possibly related to changes in metabolismHalf-life elimination:Children: Cancer patients: Children and Adolescents: 4 to 18 years: 2.8 hours; Surgical patients: Infants 1 to 4 months: 6.7 hours; Infants and Children 5 months to 12 years: 2.9 hoursAdults: 3 to 6 hours; Mild-to-moderate hepatic impairment (Child-Pugh classes A and B): 12 hours; Severe hepatic impairment (Child-Pugh class C): 20 hoursTime to peak: Oral: ~2 hours; Oral soluble film: ~1 hourExcretion: Urine (44% to 60% as metabolites, ~5% as unchanged drug); feces (~25%)Clearance:Cancer patients: Children and Adolescents 4 to 18 years: 0.599 L/kg/hourSurgical patients: Infants and Children: 1 to 4 months: 0.401 L/kg/hour; 5 to 24 months: 0.581 L/kg/hour; 3 to 12 years: 0.439 L/kg/hourAdult (normal): 19 to 40 years: 0.381 L/kg/hour; 61 to 74 years: 0.319 L/kg/hour; >75 years: 0.262 L/kg/hourPharmaco*kinetics: Additional ConsiderationsAltered kidney function: Mean plasma clearance is reduced by 41% (IV) and 50% (oral) in patients with severe renal impairment (CrCl <30 mL/minute).Hepatic function impairment: In patients with mild to moderate impairment, clearance is reduced 2-fold and the mean half-life is increased to 11.6 hours (compared to 5.7 hours in subjects with normal hepatic function). Clearance is reduced 2- to 3-fold and the apparent Vd is increased, and the half-life is increased to 20 hours in patients with severe hepatic impairment (Child-Pugh class C).Older adult: In elderly patients >75 years of age, there is a reduction in clearance and an increase in elimination half-life.Sex: The extent and rate of absorption is greater in women than in men. There is slower clearance, a smaller volume of distribution, and higher bioavailability in women.Pricing: USSolution (Ondansetron HCl Injection)4 mg/2 mL (per mL): $0.28 - $1.3540 mg/20 mL (per mL): $0.30 - $1.25Solution (Ondansetron HCl Oral)4 mg/5 mL (per mL): $4.78 - $6.00Solution Prefilled Syringe (Ondansetron HCl Injection)4 mg/2 mL (per mL): $1.11Tablet, orally-disintegrating (Ondansetron Oral)4 mg (per each): $22.25 - $23.118 mg (per each): $36.66 - $38.50Tablets (Ondansetron HCl Oral)4 mg (per each): $0.54 - $24.898 mg (per each): $0.64 - $41.5324 mg (per each): $106.51Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAntivon (CR, DO, GT, HN, NI, PA, SV);Apulset (BD);Avessa (LU);Avessaron (BE);Cedantron (ID);Cetron (AR);Danac (MX);Danset (EG);Dantron (TH, ZA);Emeset (IN, LK, RO);Emeton (UA);Emetron (HU);Emiset (BD);Emistop (ZA, ZW);Emizof (IE);Emodan (PH);Enset (PH);Finaber (PY);Frazon (ID);Glotron (ID);Invomit (ID);Izofran (CL, UY);Krindor (CR, DO, GT, HN, NI, PA, SV);Lartron (MX);Mefoz (ID);Modifical (CO, EC);Nalisen (CR, DO, GT, HN, NI, PA, SV);Narfoz (ID);Nausedron (BR);Odnatron (IL);Ofran (LK);Ondak (CO);Ondan (EG);Ondanaccord (NZ);Ondant (KR);Ondantor (HR);Ondavell (ID, MY, PH, SG, TH);Ondawi (LK);Ondran (IE);Onetic (ID);Onrex (NZ);Onsat (BD);Onset-8 (PH);Onsetron (KR);Onsett (TZ, ZW);Onsia (TH);Onzet (PH);Onzod (TW);Osetron (AU, BD, RO);Periset (BD);Setofilm (ES, GB);Setron (BH);Setronax (HK, MY, SG, VN);Trondamet (HK);Vomceran (ID);Vometron (ID);Vomiof (IN);Vomiz (TW);Yatrox (ES);Zetron (TH);Zilfujim (AU);Zofer (ZA);Zofran (AE, AR, AT, AU, BB, BE, BF, BG, BH, BJ, BM, BR, BS, BZ, CH, CI, CN, CY, CZ, DE, DK, EC, EE, EG, ES, ET, FI, GB, GH, GM, GN, GY, HK, HR, HU, ID, IE, IL, IQ, IR, IS, IT, JM, JO, JP, KE, KR, KW, LB, LR, LT, LU, LV, LY, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NL, NO, OM, PE, PH, PK, PL, PT, PY, QA, RU, SA, SC, SD, SE, SI, SK, SL, SN, SR, SY, TN, TR, TT, TW, TZ, UA, UG, VE, VN, YE, ZA, ZM, ZW);Zofran Melt (AE, BH, KW, QA, SA);Zofran ODT (BB);Zofran Zydis (KR);Zofron (GR);Zofsetron (BE);Zondaron (RO);Zophren (FR)For country code abbreviations (show table)Abas MN, Tan PC, Azmi N, Omar SZ. 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[PubMed 21691464]Phillips RS, Gopaul S, Gibson F, et al, "Antiemetic Medication for Prevention and Treatment of Chemotherapy Induced Nausea and Vomiting in Childhood," Cochrane Database Syst Rev, 2010, (9):CD007786. [PubMed 20824866]Piche T, Vanbiervliet G, Cherikh F, et al. Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study. Gut. 2005;54(8):1169-1173. doi:10.1136/gut.2004.055251 [PubMed 16009690]Picot C, Berard A, Grenet G, Ripoche E, Cucherat M, Cottin J. Risk of malformation after ondansetron in pregnancy: An updated systematic review and meta-analysis. Birth Defects Res. Published online 2020. doi:10.1002/bdr2.1705 [PubMed 32420702]Pinkerton CR, Williams D, Wootton C, et al, “5-HT3 Antagonist Ondansetron - An Effective Outpatient Antiemetic in Cancer Treatment,” Arch Dis Child, 1990, 65(8):822-5. [PubMed 2144721]Platt AJ, Heddle RM, Rake MO, et al. Ondansetron in carcinoid syndrome. Lancet. 1992;339(8806):1416. [PubMed 1375972]Popovic M, Warr DG, Deangelis C, et al. Efficacy and safety of palonosetron for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a systematic review and meta-analysis of randomized controlled trials. Support Care Cancer. 2014;22(6):1685-1697. doi: 10.1007/s00520-014-2175-6. [PubMed 24590374]Priestman TJ, Roberts JT, Lucraft H, et al. Results of a randomized, double-blind comparative study of ondansetron and metoclopramide in the prevention of nausea and vomiting following high-dose upper abdominal irradiation. Clin Oncol (R Coll Radiol). 1990;2(2):71-75. [PubMed 1702012]Priestman TJ, Roberts JT, Upadhyaya BK. A prospective randomized double-blind trial comparing ondansetron versus prochlorperazine for the prevention of nausea and vomiting in patients undergoing fractionated radiotherapy. Clin Oncol (R Coll Radiol). 1993;5(6):358-363. [PubMed 8305355]Rapp JH, Yuen M, Abraham T. Bradycardia after intravenous ondansetron with asystole on rechallenge: a case report. Hosp Pharm. 2015;50(10):918-921. doi:10.1310/hpj5010-918 [PubMed 27729680]Refer to manufacturer's labeling.Rice GP, Ebers GC. Ondansetron for intractable vertigo complicating acute brainstem disorders. Lancet. 1995;345(8958):1182-1183. [PubMed 7723573]Ritter MJ, Goodman BP, Sprung J, Wijdicks EF. Ondansetron-induced multifocal encephalopathy. Mayo Clin Proc. 2003;78(9):1150-1152. doi:10.4065/78.9.1150 [PubMed 12962170]Roila F, Del Favero A. Ondansetron clinical pharmaco*kinetics. Clin Pharmaco*kinet. 1995;29(2):95-109. doi:10.2165/00003088-199529020-00004 [PubMed 7586904]Roila F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27(suppl 5):v119-v133. [PubMed 27664248]Ruff P, Paska W, Goedhals L, et al. Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a multicentre double-blind, randomised, parallel-group study. The Ondansetron and Granisetron Emesis Study Group [published correction appears in Oncology. 1994;51(3):243]. Oncology. 1994;51(1):113-118. doi:10.1159/000227321 [PubMed 8265095]Ruktrirong J, Traivaree C, Monsereenusorn C, Photia A, Lertvivatpong N, Rujkijyanont P. Single daily dosing versus divided dosing intravenous ondansetron to prevent chemotherapy-induced nausea and vomiting among children: A comparative randomized double-blind controlled trial. Pediatr Blood Cancer. Published online March 23, 2021. doi:10.1002/pbc.29002 [PubMed 33754455]Saberi A, Pourshafie SH, Kazemnejad-Leili E, Nemati S, Sutohian S, Sayad-Fathi S. Ondansetron or promethazine: which one is better for the treatment of acute peripheral vertigo? 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Br J Clin Pharmacol. 2002;54(1):11-20. doi:10.1046/j.1365-2125.2002.01612.x [PubMed 12100220]Spitzer TR, Friedman CJ, Bushnell W, Frankel SR, Raschko J. Double-blind, randomized, parallel-group study on the efficacy and safety of oral granisetron and oral ondansetron in the prophylaxis of nausea and vomiting in patients receiving hyperfractionated total body irradiation. Bone Marrow Transplant. 2000;26(2):203-210. [PubMed 10918432]Sprung J, Choudhry FM, Hall BA. Extrapyramidal reactions to ondansetron: cross-reactivity between ondansetron and prochlorperazine?. Anesth Analg. 2003;96(5):1374-1376. doi:10.1213/01.ane.0000058845.72102.f2 [PubMed 12707136]Svanberg A, Birgegård G. Addition of aprepitant (Emend) to standard antiemetic regimen continued for 7 days after chemotherapy for stem cell transplantation provides significant reduction of vomiting. Oncology. 2015;89(1):31-36. doi: 10.1159/000371523. [PubMed 25659986]Talley NJ, Phillips SF, Haddad A, et al. 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Pediatr Crit Care Med. 2016;17(7):e317-e323. doi:10.1097/PCC.0000000000000776 [PubMed 27387786]Veneziano M, Framarino Dei Malatesta M, Bandiera AF, Fiorelli C, Galati M, Paolucci A. Ondansetron-induced headache. Our experience in gynecological cancer. Eur J Gynaecol Oncol. 1995;16(3):203-207. [PubMed 7664768]Weiss KS. Anaphylactic reaction to ondansetron. Arch Intern Med. 2001;161(18):2263. doi:10.1001/archinte.161.18.2263 [PubMed 11575988]White L, Daly SA, McKenna CJ, et al. A comparison of oral ondansetron syrup or intravenous ondansetron loading dose regimens given in combination with dexamethasone for the prevention of nausea and emesis in pediatric and adolescent patients receiving moderately/highly emetogenic chemotherapy. Pediatr Hematol Oncol. 2000;17(6):445-455. doi:10.1080/08880010050120791 [PubMed 10989464]WHO Pharmaceuticals Newsletter. Ondansetron and serotonin syndrome. 2012; 3:16-21.Wymenga AN, de Vries EG, Leijsma MK, Kema IP, Kleibeuker JH. Effects of ondansetron on gastrointestinal symptoms in carcinoid syndrome. Eur J Cancer. 1998;34(8):1293-1294. [PubMed 9849494]Zhou C, Zhu Y, Bao Z, Wang X, Liu Q. Efficacy of ondansetron for spinal anesthesia during cesarean section: a meta-analysis of randomized trials. J Int Med Res. 2018;46(2):654-662. doi:10.1177/0300060517716502 [PubMed 28856920]Zofran injection (ondansetron) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals; April 2021.Zofran tablets and oral solution and Zofran ODT orally disintegrating tablets (ondansetron) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals; October 2021.Zuplenz (ondansetron) [prescribing information]. Warren, NJ: Aquestive Therapeutics; August 2021.Topic 9719 Version 635.0

CloseAzithromycin (systemic): Pediatric drug informationAzithromycin (systemic): Pediatric drug information(For additional information see "Azithromycin (systemic): Drug information" and see "Azithromycin (systemic): Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USZithromax;Zithromax Tri-Pak;Zithromax Z-PakBrand Names: CanadaACT Azithromycin [DSC];AG-Azithromycin;APO-Azithromycin Z;AURO-Azithromycin;DOM-Azithromycin;GD-Azithromycin [DSC];GEN-Azithromycin;JAMP-Azithromycin;M-Azithromycin;Mar-Azithromycin;NRA-Azithromycin;PMS-Azithromycin;PRO-Azithromycin;RATIO-Azithromycin;RIVA-Azithromycin;SANDOZ Azithromycin;TEVA-Azithromycin;ZithromaxTherapeutic CategoryAntibiotic, MacrolideDosing: NeonatalNote: With oral therapy, monitor for infantile hypertrophic pyloric stenosis (IHPS).General dosing, susceptible infection (Ref): Oral, IV: 10 mg/kg once daily.Chlamydia trachomatis congenital infection, treatmentChlamydia trachomatis congenital infection (conjunctivitis or pneumonia), treatment (alternative): Limited data available: Oral: 20 mg/kg/dose once daily for 3 days (Ref).Pertussis, treatment or postexposure prophylaxisPertussis, treatment or postexposure prophylaxis: Oral, IV: 10 mg/kg/dose once daily for 5 days (Ref).Ureaplasma spp., respiratory eradication in extremely low gestation newbornsUreaplasma spp., respiratory eradication in extremely low gestation newborns: Limited data available: GA 24 to <29 weeks, PNA <72 hours: IV: 20 mg/kg/dose every 24 hours for 3 doses; dosing based on a prospective, multicenter pilot study of preterm neonates randomized to receive azithromycin or placebo (total n=121; azithromycin group n=60); all patients were cultured for Ureaplasma prior to the first dose of azithromycin; Ureaplasma-positive patients (n=44; azithromycin group n=19) receiving azithromycin had a significantly higher rate of Ureaplasma-free survival, defined as survival to NICU discharge with 3 negative cultures post-treatment, compared to Ureaplasma-positive patients receiving placebo (84% vs 12%); overall survival and bronchopulmonary dysplasia-free survival were similar between groups but not powered to determine a difference (Ref).Dosing: PediatricGeneral dosing, susceptible infection (Ref): Infants, Children, and Adolescents:Oral: 5 to 12 mg/kg/dose; typically administered as 10 to 12 mg/kg/dose on day 1 (usual maximum dose: 500 mg/dose) followed by 5 to 6 mg/kg once daily (usual maximum dose: 250 mg/dose) for remainder of treatment duration.IV: 10 mg/kg once daily; maximum dose: 500 mg/dose.BabesiosisBabesiosis: Limited data available: Infants, Children, and Adolescents: Oral: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose), then 5 mg/kg/dose once daily (maximum dose: 250 mg/dose) in combination with atovaquone for a total duration of 7 to 10 days; longer duration may be necessary in some patients with severe or persistent symptoms until parasitemia is cleared; in immunocompromised patients, higher doses (eg, adults: 600 to 1,000 mg daily) have been used (Ref).Cat scratch diseaseCat scratch disease (Bartonella henselae) (lymphadenitis) (Ref): Limited data available:Infants, Children, and Adolescents weighing ≤45 kg: Oral: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose), then 5 mg/kg/dose once daily for 4 additional days (maximum dose: 250 mg/dose).Children and Adolescents weighing >45 kg: Oral: 500 mg as a single dose on day 1, then 250 mg once daily for 4 additional days.Cervicitis or urethritis, empiric treatmentCervicitis or urethritis, empiric treatment: Limited data available:Infants and Children <45 kg: Optimal dose uncertain: Oral: 60 mg/kg as a single dose in combination with ceftriaxone; maximum dose: 1,000 mg/dose (Ref).Children ≥45 kg and Adolescents: Oral: 1,000 mg as a single dose in combination with ceftriaxone (Ref).ChancroidChancroid (Haemophilus ducreyi) (Ref): Limited data available:Infants and Children <45 kg: Oral: 20 mg/kg as a single dose; maximum dose: 1,000 mg/dose.Children ≥45 kg and Adolescents: Oral: 1,000 mg as a single dose.Chlamydia trachomatis infectionChlamydia trachomatis infection:Urogenital/anogenital tract or oropharyngeal infection (eg, cervicitis, urethritis): Children <8 years weighing ≥45 kg or Children ≥8 years and Adolescents: Oral: 1,000 mg as a single dose (Ref).Pneumonia, congenital: Infants: Oral, IV: 20 mg/kg/dose once daily for 3 days (Ref).Cholera, treatmentCholera (Vibrio cholerae), treatment: Limited data available: Infants, Children, and Adolescents: Oral: 20 mg/kg as a single dose in combination with hydration; maximum dose: 1,000 mg/dose (Ref).Cystic fibrosis; chronic lung maintenanceCystic fibrosis; chronic lung maintenance: Limited data available; dosing regimen variable: Note: Recommended for use in patients with a history of Pseudomonas aeruginosa; may also be considered in patients without Pseudomonas who experience frequent exacerbations (Ref). Patients should be screened for nontuberculous mycobacterial infection prior to treatment (if able) and azithromycin should not be used if present (Ref).Weight-directed dosing:Infants ≥6 months, Children, and Adolescents: Oral: 10 mg/kg/dose 3 times weekly; maximum dose: 500 mg/dose (Ref).Fixed dosing:Children ≥6 years and Adolescents (Ref):18 to <36 kg: Oral: 250 mg 3 times weekly (Monday, Wednesday, Friday).≥36 kg: Oral: 500 mg 3 times weekly (Monday, Wednesday, Friday).Diarrhea, infectiousDiarrhea, infectious:Campylobacter infection:Non-HIV-exposed/-infected: Infants, Children, and Adolescents: Oral: 10 mg/kg/dose once daily for 3 days (Ref); maximum dose: 500 mg/dose (Ref).HIV-exposed/-infected: Adolescents: Oral: 500 mg once daily for 5 days (Ref).Shigellosis:Non-HIV-exposed/-infected: Infants, Children, and Adolescents:5-day regimen: Oral: 12 mg/kg once on day 1 (maximum dose: 500 mg/dose), followed by 5 mg/kg/dose once daily on days 2 to 5 (maximum dose: 250 mg/dose) (Ref).3-day regimen: Oral: 10 mg/kg/dose once daily for 3 days; maximum dose: 500 mg/dose (Ref).HIV-exposed/-infected: Adolescents: Oral: 500 mg once daily for 5 days (Ref).Endocarditis; prophylaxisEndocarditis; prophylaxis: Infants, Children, and Adolescents: Oral: 15 mg/kg/dose 30 to 60 minutes before procedure; maximum dose: 500 mg/dose (Ref).Gonococcal infectionGonococcal infection: Limited data available:Uncomplicated gonococcal infections of the cervix, urethra, or rectum (alternative agent in severe cephalosporin allergy): Children >45 kg and Adolescents: Oral: 2,000 mg as a single dose in combination with IM gentamicin (Ref). Note: For treatment failure, consult an infectious diseases specialist and report to the CDC through state and local health departments within 24 hours of diagnosis (Ref).Disseminated gonococcal infection (arthritis, arthritis-dermatitis, meningitis, endocarditis): Children >45 kg and Adolescents: Oral: 1,000 mg as a single dose in combination with daily ceftriaxone (Ref).Gonococcal conjunctivitis: Children >45 kg and Adolescents: Oral: 1,000 mg as a single dose in combination with ceftriaxone (Ref).Lyme disease, erythema migransLyme disease (Borrelia spp. infection), erythema migrans (alternative agent): Limited data available:Infants, Children, and Adolescents: Oral: 10 mg/kg/dose once daily for 7 days; maximum dose: 500 mg/dose. Note: Due to lower efficacy, should only be used when first-line agents cannot be used (Ref).Meningococcal disease, chemoprophylaxis of high-risk contactsMeningococcal disease, chemoprophylaxis of high-risk contacts: Infants, Children, and Adolescents: Oral: 10 mg/kg as a single dose; maximum dose: 500 mg/dose; Note: Not routinely recommended; may consider if fluoroquinolone resistance detected (Ref).Mycobacterium avium complex infectionMycobacterium avium complex (MAC) infection (HIV-exposed/-infected):Infants and Children (Ref):Primary prophylaxis (patients who meet age-specific CD4 count thresholds): Oral: 20 mg/kg once weekly (maximum dose: 1,200 mg/dose) (preferred regimen) or alternatively, 5 mg/kg/dose once daily (maximum dose: 250 mg/dose); may be discontinued in children ≥2 years of age receiving stable antiretroviral therapy (ART) for ≥6 months and experiencing sustained (>3 months) CD4 count recovery well above age-specific targets.Treatment (alternative to clarithromycin): Oral: 10 to 12 mg/kg/dose once daily as part of an appropriate combination regimen; maximum dose: 500 mg/dose; continue therapy for at least 12 months; following completion of treatment, initiate long-term suppression (secondary prophylaxis).Long-term suppression (secondary prophylaxis) (alternative to clarithromycin): Oral: 5 mg/kg/dose once daily as part of an appropriate combination regimen; consideration can be given to discontinuation of therapy in children ≥2 years when patient has completed ≥12 months of therapy, has no signs/symptoms of MAC disease, and has sustained (≥6 months) CD4 count recovery meeting age-specific thresholds in response to stable ART.Adolescents (Ref):Primary prophylaxis (patients with CD4 count <50 cells/mm3 who are not initiated on fully suppressive ART): Oral: 1,200 mg once weekly (preferred) or 600 mg twice weekly; may discontinue prophylaxis when patient is initiated on effective ART.Treatment and long-term suppression (secondary prophylaxis): Oral: 500 to 600 mg daily as part of an appropriate combination regimen; may discontinue when patient has completed ≥12 months of therapy, has no signs or symptoms of MAC disease, and has sustained (≥6 months) CD4 count >100 cells/mm3 in response to ART.Otitis media, acuteOtitis media, acute (AOM) (alternative agent for patients who cannot tolerate beta-lactam antibiotics): Note: Not recommended for routine empiric use due to limited efficacy against Streptococcus pneumoniae and Haemophilus influenzae (Ref).Infants ≥6 months, Children, and Adolescents:Single-dose regimen: Oral: 30 mg/kg once as a single dose; maximum dose: 1,500 mg/dose; if patient vomits within 30 minutes of dose, repeat dosing has been administered, although limited safety data are available (Ref).Three-day regimen: Oral: 10 mg/kg/dose once daily for 3 days; maximum dose: 500 mg/dose (Ref). Note: For recurrent or persistent infections, doses of 20 mg/kg/dose once daily for 3 days have been described in patients ≥6 months to <6 years of age (Ref).Five-day regimen: Oral: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose), followed by 5 mg/kg/dose (maximum dose: 250 mg/dose) once daily on days 2 to 5 (Ref).Peritonitis, prophylaxis for patients receiving peritoneal dialysis who require dental proceduresPeritonitis (peritoneal dialysis), prophylaxis for patients receiving peritoneal dialysis who require dental procedures:Infants, Children, and Adolescents: Oral: 15 mg/kg administered 30 to 60 minutes before dental procedure; maximum dose: 500 mg/dose (Ref).PertussisPertussis (Ref): Oral, IV:Infants 1 to 5 months: 10 mg/kg/dose once daily for 5 days.Infants ≥6 months, Children, and Adolescents: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose), followed by 5 mg/kg once daily on days 2 to 5 (maximum dose: 250 mg/dose).Pneumonia, community-acquiredPneumonia, community-acquired (presumed atypical pneumonia or proven C. pneumoniae or M. pneumoniae infection) (Ref): Mild infection or step-down therapy: Infants >3 months, Children, and Adolescents: Oral: 10 mg/kg once on day 1 (maximum dose: 500 mg/dose), followed by 5 mg/kg/dose (maximum dose: 250 mg/dose) once daily on days 2 to 5 (Ref).Severe infection: Infants >3 months, Children, and Adolescents: IV: 10 mg/kg/dose once daily for at least 2 days (maximum dose: 500 mg/dose); when able transition to the oral route with a single daily dose of 5 mg/kg/dose (maximum dose: 250 mg/dose) to complete a 5-day course of therapy (Ref).Recurrent asthma-like symptoms, reduction in durationRecurrent asthma-like symptoms, reduction in duration: Limited data available: Children ≤3 years: Oral: 10 mg/kg/dose once daily for 3 days; dosing based on a randomized placebo-controlled trial (n=72; episodes of recurrent asthma-like symptoms analyzed=148; mean age: 2 ± 0.6 years); patients were diagnosed with recurrent troublesome lung symptoms (asthma-like episodes) and included in the study if they had ≥5 episodes in 6 months, persistent symptoms for ≥4 weeks, or previously experienced a severe acute episode requiring an oral steroid or hospital admission; patients presenting with ≥3 days of consecutive symptoms were randomized to azithromycin or placebo. Patients received a beta-2 agonist, with the potential to receive inhaled corticosteroids (82%), montelukast (60%), and/or oral prednisolone as well. Children who received azithromycin experienced fewer days of symptoms (3.4 days) as compared to those who received placebo (7.7 days; p<0.0001); the biggest impact was noted when azithromycin was given before day 6 of symptoms (Ref).Rhinosinusitis, bacterialRhinosinusitis, bacterial: Infants ≥6 months, Children, and Adolescents: Oral: 10 mg/kg/dose once daily for 3 days; maximum dose: 500 mg/dose; Note: Although FDA approved, macrolides are not recommended for empiric therapy due to high rates of resistance (Ref).Sexual victimization, prophylaxisSexual victimization, prophylaxis: Note: Consider administering hepatitis B or human papillomavirus vaccines if needed based on patient's immunization status (Ref).Adolescents: Oral: 1,000 mg as a single dose in combination with ceftriaxone and either metronidazole or tinidazole (Ref).Streptococcus, group A; pharyngitis/tonsillitisStreptococcus, group A; pharyngitis/tonsillitis (alternative agent for severe penicillin allergy): Five-day regimen: Children and Adolescents: Oral: 12 mg/kg/dose once daily for 5 days; maximum dose: 500 mg/dose (Ref).Three-day regimen: Limited data available: Children and Adolescents: Oral: 20 mg/kg/dose once daily for 3 days; maximum dose: 1,000 mg/dose (Ref).Typhoid fever, treatmentTyphoid fever (Salmonella typhi or Salmonella paratyphi infection), treatment: Limited data available:Children and Adolescents: Oral: 10 mg/kg/dose (maximum dose: 500 mg/dose) once daily for 7 days or 20 mg/kg/dose (maximum dose: 1,000 mg/dose) once daily for 5 to 7 days (Ref).Dosing: Kidney Impairment: PediatricAltered kidney function: Infants, Children, and Adolescents: Oral, IV:Mild to severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, some experts suggest that no dosage adjustment is necessary (Ref).Hemodialysis: There are no dosage adjustments provided in the manufacturer's labeling; however, some experts suggest no dosage adjustment or supplemental doses are necessary (Ref).Peritoneal dialysis: There are no dosage adjustments provided in the manufacturer's labeling; however, some experts suggest no dosage adjustment or supplemental doses are necessary (Ref). Based on adult information, azithromycin is not removed with continuous ambulatory peritoneal dialysis (Ref).Continuous renal replacement therapy (CRRT): There are no dosage adjustments provided in the manufacturer's labeling; however, some experts suggest no dosage adjustment or supplemental doses are necessary (Ref).Dosing: Hepatic Impairment: PediatricAzithromycin is predominantly hepatically eliminated; however, there is no dosage adjustment provided in the manufacturer's labeling. Use with caution due to potential for hepatotoxicity (rare); discontinue immediately for signs or symptoms of hepatitis.Dosing: Adult(For additional information see "Azithromycin (systemic): Drug information")Note: Zmax suspension has been discontinued in the United States for >1 year.Note: ER suspension (Zmax) is not interchangeable with IR formulations. Use should be limited to approved indications. All doses are expressed as IR azithromycin unless otherwise specified.Acne vulgaris, inflammatory, moderate to severeAcne vulgaris, inflammatory, moderate to severe (alternative agent) (off-label use):Note: Use in combination with topical acne therapy. Reserve use for patients who cannot use preferred agents (Ref).Oral: Optimal dose uncertain; clinical trials have used varied pulse-dosing regimens: 500 mg once daily for 4 consecutive days per month for 3 months (Ref) or 500 mg once daily for 3 days in the first week, followed by 500 mg once weekly until week 10 (Ref) or 500 mg once daily for 3 consecutive days each week in month 1, followed by 500 mg once daily for 2 consecutive days each week in month 2, then 500 mg once daily for 1 day each week in month 3 (Ref). Treatment should ideally be limited to 3 to 4 months to minimize the risk of resistance (Ref).BabesiosisBabesiosis (off-label use):Mild to moderate disease: Oral: 500 mg on day 1, followed by 250 mg once daily in combination with atovaquone (Ref); higher doses of azithromycin (up to 1 g daily) may be used in highly immunocompromised patients (Ref).Severe disease, initial therapy: IV: 500 mg once daily in combination with atovaquone; may switch to oral azithromycin once symptoms improve (Ref).Severe disease, oral step-down therapy: Oral: 250 to 500 mg once daily in combination with atovaquone (Ref). Note: Higher doses of azithromycin (up to 1 g daily) may be used in immunocompromised patients (Ref).Duration of therapy: 7 to 10 days; a longer duration of ≥6 weeks, including 2 weeks after resolution of parasitemia, may be necessary for patients at high risk of relapse (eg, highly immunocompromised patients) (Ref).Bartonella spp. infectionBartonella spp. infection (off-label use):Patients with HIV:Treatment: Note: Not for treatment of endocarditis or CNS infections.Bacillary angiomatosis, cat scratch disease, peliosis hepatitis, bacteremia, or osteomyelitis (alternative agent): IV, Oral: 500 mg once daily for ≥3 months (Ref).Suppressive therapy: Note: For patients who experience a relapse after receiving a ≥3-month course of primary treatment (Ref).Oral: 500 mg once daily. Continue until patient has received ≥3 months of therapy and CD4 count is >200 cells/mm3 for ≥6 months; some experts discontinue only if Bartonella titers have also decreased 4-fold (Ref).Patients without HIV:Cat scratch disease:Lymphadenitis: Oral: 500 mg as a single dose, then 250 mg once daily for 4 additional days (Ref).Hepatosplenic disease, prolonged systemic illness: IV, Oral: 500 mg as a single dose, then 250 mg once daily in combination with rifampin for 10 to 14 days (Ref). For patients unable to tolerate rifampin, may give azithromycin monotherapy: 500 mg once daily for 5 days (Ref).CNS infection, neuroretinitis (alternative agent): IV, Oral: 500 mg as a single dose, then 250 mg once daily, in combination with rifampin. Duration is 10 to 14 days for CNS infection and 4 to 6 weeks for neuroretinitis (Ref).Bronchiectasis, prevention of pulmonary exacerbationsBronchiectasis (noncystic fibrosis), prevention of pulmonary exacerbations (off-label use): Oral: 500 mg 3 times weekly (Ref) or 250 mg once daily (Ref). An initial dose of 250 mg 3 times weekly, with subsequent titration according to patient response, may be considered to minimize adverse effects (Ref). Note: Recommended for patients with ≥2 (Ref) or ≥3 (Ref) exacerbations per year; for those who do not have Pseudomonas aeruginosa infection, have P. aeruginosa but cannot take an inhaled antibiotic, or continue to have exacerbations despite an inhaled antibiotic. Patients should be screened for nontuberculous mycobacterial infection prior to treatment, and azithromycin should not be given if present (Ref).Bronchiolitis obliteransBronchiolitis obliterans (off-label use):Bronchiolitis obliterans syndrome in lung transplant recipients, treatment: Oral: 250 mg 3 times weekly (Ref); some experts recommend an initial dose of 250 mg daily for the first 5 days (Ref). Usually given for a 3-month trial period (Ref), but some experts continue indefinitely, regardless of response to therapy (Ref). Note: When studied to prevent bronchiolitis obliterans syndrome in patients with hematologic malignancy who underwent allogeneic hematopoietic cell transplantation, rates of cancer relapse and mortality were increased among patients receiving long-term azithromycin, leading to early trial termination (Ref).Diffuse panbronchiolitis or symptomatic cryptogenic bronchiolitis obliterans, treatment: Oral: 250 to 500 mg once daily or 3 times weekly (Ref). After a 3- to 6-month trial, long-term therapy may be continued based on response (Ref).Cesarean delivery, preoperative prophylaxisCesarean delivery (intrapartum or after rupture of membranes), preoperative prophylaxis (off-label use): IV: 500 mg as a single dose 1 hour prior to surgical incision; use in combination with standard preoperative antibiotics (Ref).Chronic obstructive pulmonary disease, acute exacerbationChronic obstructive pulmonary disease, acute exacerbation:Acute exacerbation, treatment: Note: Avoid use in patients with risk factors for Pseudomonas infection or poor outcomes (eg, ≥65 years of age with major comorbidities, FEV1 <50% predicted, frequent exacerbations) (Ref).Oral: 500 mg in a single loading dose on day 1, followed by 250 mg once daily on days 2 to 5 (Ref)or 500 mg once daily for 3 days (Ref).Prevention of exacerbations (off-label use): Oral: 250 to 500 mg 3 times weekly (Ref) or 250 mg once daily (Ref). Note: Consider for patients with frequent exacerbations (eg, ≥2 per year) despite optimal medical management (Ref) or >3 exacerbations per year (at least 1 of which required hospital admission) (Ref).Cystic fibrosis, anti-inflammatoryCystic fibrosis, anti-inflammatory (off-label use):Note: Some experts reserve for patients with chronic pseudomonal infection or frequent exacerbations despite other therapies (Ref).Oral: 250 mg (<40 kg) or 500 mg (≥40 kg) 3 times weekly (Ref) or 250 mg once daily (Ref). Note: Patients should be screened for nontuberculous mycobacterial infection prior to treatment and azithromycin should not be given if present (Ref).Diarrhea, infectiousDiarrhea, infectious (off-label use):Campylobacter gastroenteritis: Oral: 1 g as a single dose or 500 mg once daily for 3 days (Ref). If symptoms have not resolved after 24 hours following single-dose therapy, continue with 500 mg once daily for 2 more days (Ref). For HIV-infected patients, 500 mg once daily for 5 days is recommended (Ref). Note: Increased nausea may occur with the 1 g single-dose regimen (Ref), which may be reduced by administering azithromycin as 2 divided doses on the same day (Ref).Cholera (alternative agent): Oral: 1 g as a single dose (Ref).Shigella gastroenteritis: Note: Confirm susceptibility if possible (Ref). Oral: 500 mg once daily for 3 days (Ref); 5 days of therapy should be given for Shigella dysenteriae type 1 infection or for patients with HIV coinfection (Ref).Travelers' diarrhea, empiric treatment:Note: Most cases are self-limited and may not warrant antimicrobial therapy. Some experts reserve antimicrobial therapy for severe diarrhea (eg, fever with blood, pus, or mucus in stool) (Ref) or certain high-risk travelers (eg, those with an immunocompromising condition) (Ref).Oral: 1 g as a single dose or 500 mg once daily for 3 days (Ref). If symptoms have not resolved after 24 hours following single-dose therapy, continue with 500 mg once daily for 2 more days. A 3-day course of 500 mg once daily is the preferred regimen for dysentery or febrile diarrhea (Ref). Increased nausea may occur with the 1 g single-dose regimen (Ref), which may be reduced by administering azithromycin as 2 divided doses on the same day (Ref).Endocarditis prophylaxis, dental or invasive respiratory tract procedureEndocarditis prophylaxis, dental or invasive respiratory tract procedure (alternative agent for penicillin-allergic patients) (off-label use): Oral: 500 mg 30 to 60 minutes prior to procedure; if inadvertently not given prior to the procedure, may be administered up to 2 hours after the procedure. Note: Reserve for select situations (cardiac condition with the highest risk of adverse endocarditis outcomes and procedure likely to result in bacteremia with an organism that can cause endocarditis) (Ref).Lyme disease, erythema migransLyme disease (Borrelia spp. infection), erythema migrans (alternative agent) (off-label use): Oral: 500 mg once daily for 7 days (range: 5 to 10 days). Note: Use with caution and only when recommended agents cannot be used (due to decreased efficacy compared to other agents) (Ref).Mycobacterial infectionMycobacterial (nontuberculous) infection:Mycobacterium avium complex (MAC) infection:Disseminated disease in patients with HIV:Treatment: Oral: 500 to 600 mg daily as part of a combination therapy regimen (Ref).Primary prophylaxis (patients with CD4 count <50 cells/mm3 who are not initiated on fully suppressive antiretroviral therapy [ART]): Oral: 1.2 g once weekly (preferred) or 600 mg twice weekly; may discontinue prophylaxis when patient is initiated on effective ART (Ref).Secondary prophylaxis: Oral: 500 to 600 mg daily as part of an appropriate combination regimen; may discontinue when patient has completed ≥12 months of therapy, has no signs/symptoms of MAC disease, and has sustained (>6 months) CD4 count >100 cells/mm3 in response to ART (Ref).Pulmonary disease (nodular/bronchiectatic disease) (off-label use): Oral: 500 mg 3 times weekly as part of an appropriate combination regimen; continue treatment until patient is culture negative on therapy for ≥1 year (Ref).Pulmonary disease (severe nodular/bronchiectatic or cavitary disease) (off-label use): Oral: 250 to 500 mg once daily as part of an appropriate combination regimen (Ref); continue treatment until patient is culture negative on therapy for ≥1 year (Ref). Preliminary data suggest a relationship between peak concentration and clinical outcome among patients receiving daily therapy for pulmonary MAC (Ref); as such, some experts recommend checking levels and/or using higher doses of azithromycin (Ref).Pulmonary disease in patients with cystic fibrosis (off-label use): Oral: 250 to 500 mg once daily as part of an appropriate combination regimen; continue treatment until patient is culture negative on therapy for ≥1 year. Note: Intermittent dosing (3 times weekly) is not recommended for patients with cystic fibrosis (Ref).Mycobacterial (nontuberculous, rapidly growing) infection (off-label use):Note: Presence of inducible erm gene can result in decreased susceptibility even with a “susceptible” MIC result; perform susceptibility testing before and after ≥14 days of clarithromycin incubation to evaluate for the presence of an active erm gene, which may preclude use of azithromycin (Ref).Pulmonary, skin, soft tissue, or bone infection: Oral: 250 to 500 mg once daily as part of an appropriate combination regimen and continued for ≥6 to 12 months for pulmonary and bone infections, and ≥4 months for skin/soft tissue infections (Ref). Note: Patients should be under the care of a clinician with expertise in managing mycobacterial infection (Ref).PertussisPertussis (off-label use): Oral: 500 mg on day 1, followed by 250 mg once daily on days 2 to 5 (Ref).Pneumonia, community acquiredPneumonia, community acquired: Outpatient: Oral: 500 mg on day 1, followed by 250 mg once daily for 4 days or 500 mg once daily for 3 days (Ref). Note: May use as monotherapy (alternative agent) for outpatients without comorbidities or risk factors for antibiotic-resistant pathogens only if local pneumococcal resistance is <25%. Must be used as part of an appropriate combination regimen in outpatients with comorbidities (Ref); some experts prefer to use as part of an appropriate combination regimen in all outpatients, regardless of comorbidities (Ref).Inpatient: Oral, IV: 500 mg once daily for a minimum of 3 days, as part of an appropriate combination regimen (Ref).Sexually transmitted infectionsSexually transmitted infections:Cervical infection, empiric therapy for cervicitis or pathogen-directed therapy for Chlamydia trachomatis (alternative agent): Oral: 1 g as a single dose, preferably under direct observation; give in combination with ceftriaxone if the patient is at high risk for gonorrhea, if follow-up is a concern, or if the local prevalence of gonorrhea is high (eg, >5%) (Ref).Chancroid (due to Haemophilus ducreyi): Oral: 1 g as a single dose. Note: Data are limited concerning efficacy in HIV infected patients (Ref).Gonococcal infection, uncomplicated (infection of the cervix, rectum [off-label use], or urethra) (alternative agent):Note: Reserve for patients who cannot use ceftriaxone (Ref).Oral: 2 g as a single dose in combination with IM gentamicin (preferred) or oral gemifloxacin (Ref). When treatment failure is suspected (eg, detection of N. gonorrhoeae after treatment without additional sexual exposure), consult an infectious diseases specialist. Report failures to the CDC through state and local health departments (Ref).Granuloma inguinale (donovanosis) (off-label use): Oral: 1 g once weekly or 500 mg once daily for >3 weeks and until resolution of lesions. Note: If symptoms do not improve within the first few days of therapy, the addition of a second agent may be considered (Ref).Lymphogranuloma venereum (alternative agent) (off-label use): Oral: 1 g once weekly for 3 weeks. Note: Consider a test of cure for C. trachomatis 4 weeks after therapy completion (Ref).Mycoplasma genitalium (alternative agent) (off-label use): Note: Azithromycin resistance is rapidly emerging; the CDC only recommends azithromycin for documented susceptible infection, but susceptibility testing is not widely available (Ref).Oral: 1 g on day 1, followed by 500 mg once daily on days 2 through 4 (Ref).Pelvic inflammatory disease, mild to moderate (alternative agent): Note: Reserve for patients who cannot use first-line options and are unlikely to have infection caused by N. gonorrhoeae (Ref).Oral, IV: 500 mg IV once daily for 1 to 2 days, then 250 mg orally once daily to complete a 7-day course, in combination with metronidazole (Ref).Urethral infection, empiric therapy for urethritis or pathogen-directed therapy for Chlamydia trachomatis (alternative agent): Oral: 1 g as a single dose, preferably under direct observation or 500 mg on day 1 then 250 mg once daily for 4 days (some experts prefer this dose for urethritis if adherence is not a concern (Ref)); give in combination with ceftriaxone if there is microscopic evidence of gonococcal urethritis or if there is high clinical suspicion of gonococcal infection (Ref).Streptococcus, group AStreptococcus, group A (alternative agent for patients with severe penicillin allergy):Pharyngitis: Oral: 12 mg/kg (maximum: 500 mg) on day 1, followed by 6 mg/kg (maximum: 250 mg) once daily on days 2 through 5 (Ref) or 12 mg/kg (maximum: 500 mg) once daily for 5 days (Ref).Secondary prophylaxis in patients with rheumatic fever (prevention of recurrent attacks) (off-label use): Note: Optimal dose not well defined (Ref).Oral: 250 mg once daily (Ref). Duration depends on risk factors, age, and presence of valvular disease (Ref).Surgical prophylaxis, uterine evacuationSurgical prophylaxis, uterine evacuation (induced abortion or pregnancy loss) (alternative agent) (off-label use): Oral: 500 mg as a single dose 1 hour before the procedure; may be administered up to 24 hours before the procedure (Ref). Note: The optimal dosing regimen has not been established; various protocols are in use (Ref).Typhoid and paratyphoid feverTyphoid and paratyphoid fever (S. typhi or S. paratyphi infection), uncomplicated, treatment (off-label use): Oral: 1 g once daily or 1 g once on day 1, followed by 500 mg once daily; total duration: 5 to 7 days (Ref).Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Oral, IV:Mild to severe impairment: No dosage adjustment necessary (Ref).Hemodialysis: No dosage adjustment or supplemental dose necessary (Ref).Peritoneal dialysis: Minimally dialyzed (Ref): No dosage adjustment or supplemental dose necessary (Ref).CRRT: No dosage adjustment or supplemental dose necessary (Ref).Dosing: Hepatic Impairment: AdultAzithromycin is predominantly hepatically eliminated; however, there is no dosage adjustment provided in the manufacturer's labeling. Use with caution due to potential for hepatotoxicity (rare); discontinue immediately for signs or symptoms of hepatitis.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productPacket, Oral: Zithromax: 1 g (3 ea, 10 ea) [cherry-banana flavor]Generic: 1 g (1 ea, 3 ea, 10 ea)Solution Reconstituted, Intravenous [preservative free]: Zithromax: 500 mg (1 ea)Generic: 500 mg (1 ea)Suspension Reconstituted, Oral: Zithromax: 100 mg/5 mL (15 mL) [cherry-vanilla-banana flavor]Zithromax: 200 mg/5 mL (15 mL, 22.5 mL, 30 mL) [cherry flavor]Generic: 100 mg/5 mL (15 mL); 200 mg/5 mL (15 mL, 22.5 mL, 30 mL)Tablet, Oral: Zithromax: 250 mg, 500 mg, 600 mg [DSC]Zithromax Tri-Pak: 500 mgZithromax Z-Pak: 250 mgGeneric: 250 mg, 500 mg, 600 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution Reconstituted, Intravenous: Zithromax: 500 mg (5 mL)Generic: 500 mg (1 ea)Suspension Reconstituted, Oral: Zithromax: 100 mg/5 mL (15 mL); 200 mg/5 mL (15 mL, 22.5 mL)Generic: 100 mg/5 mL (15 mL, 22.5 mL); 200 mg/5 mL (15 mL, 22.5 mL, 37.5 mL)Tablet, Oral: Zithromax: 250 mgGeneric: 250 mg, 500 mg [DSC], 600 mgProduct AvailabilityZmax suspension has been discontinued in the US for more than 1 year.Administration: PediatricOral: May administer without regard to food; do not administer with antacids that contain aluminum or magnesium.Oral suspension, multiple doses: Shake well before use.Oral suspension 1,000 mg packet for a single dose: Mix the entire contents of the packet with approximately 60 mL of water. Administer the entire contents immediately after mixing; add an additional 60 mL of water, mix, and drink. Do not use to administer any other dose except 1,000 mg.Parenteral: Do not give IM or by IV bolus. Administer IV infusion at a final concentration of 1 mg/mL over 3 hours; for a 2 mg/mL concentration, infuse over 1 hour; do not infuse over a period of less than 60 minutes.Administration: AdultIV: Infuse over 1 hour (2 mg/ml infusion) or over 3 hours (1 mg/ml infusion). Not for IM or IV bolus administration.Oral: Immediate release suspension and tablet may be taken without regard to food; extended release suspension should be taken on an empty stomach (at least 1 hour before or 2 hours following a meal), within 12 hours of reconstitution.Storage/StabilityInjection (Zithromax): Store intact vials of injection at room temperature. Reconstituted solution is stable for 24 hours when stored below 30°C (86°F). The diluted solution D5W, D5LR, D51/4NS, D51/3NS, D51/2NS (with or without 20 mEq/L KCl), Normosol-M in D5, Normosol-R in D5, LR, NS, or 1/2NS is stable for 24 hours at or below room temperature (30°C [86°F]) and for 7 days if stored under refrigeration (5°C [41°F]).Suspension, immediate release (Zithromax): Store dry powder below 30°C (86°F). Store reconstituted suspension at 5°C to 30°C (41°F to 86°F) and use within 10 days. Suspension, extended release (Zmax): Store dry powder ≤30°C (86°F). Following reconstitution, store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not refrigerate or freeze. Should be consumed within 12 hours following reconstitution.Tablet (Zithromax): Store between 15°C to 30°C (59°F to 86°F).UseOral:Oral suspension (100 mg per 5 mL; 200 mg per 5 mL), tablets (250 and 500 mg): Treatment of acute otitis media due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae (FDA approved in pediatric patients ages ≥6 months); treatment of community-acquired pneumonia due to Chlamydia (Chlamydophila) pneumoniae, Mycoplasma pneumoniae, H. influenzae, or S. pneumoniae in patients appropriate for oral therapy (FDA approved in ages ≥6 months and adults); treatment of pharyngitis/tonsillitis due to Streptococcus pyogenes in individuals who cannot use first-line therapy (FDA approved in ages ≥2 years and adults); treatment of acute bacterial sinusitis or acute exacerbations of chronic bronchitis due to H. influenzae, M. catarrhalis, or S. pneumoniae (FDA approved in adults); treatment of uncomplicated skin and skin structure infections due to Staphylococcus aureus, S. pyogenes, or Streptococcus agalactiae (FDA approved in adults); treatment of urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae (FDA approved in adults); treatment of chancroid (FDA approved in adult males). Has also been used for treatment of babesiosis, bartonellosis, cholera, cystic fibrosis lung disease, infectious diarrhea, pertussis, typhoid fever, endocarditis prophylaxis in penicillin allergic patients, prophylaxis of peritonitis in patients undergoing invasive dental procedures, and chemoprophylaxis for meningococcal disease in high-risk contact.Oral suspension (1,000 mg per 5 mL packet), tablet (600 mg): Treatment of urethritis and cervicitis due to C. trachomatis; prevention of disseminated Mycobacterium avium complex (MAC) disease; treatment of disseminated MAC disease in combination with ethambutol (All indications: FDA approved in adults).Parenteral: Treatment of community-acquired pneumonia due to susceptible C. pneumoniae, Legionella pneumophila, M. pneumoniae, H. influenzae, S. aureus, S. pneumoniae; treatment of pelvic inflammatory disease due to susceptible C. trachomatis, N. gonorrhoeae, or Mycoplasma hominis (All indications: FDA approved in ≥16 years and adults).Medication Safety IssuesSound-alike/look-alike issues:Azithromycin may be confused with azathioprine, erythromycinZithromax may be confused with Fosamax, Zinacef, ZoviraxPediatric patients: High-risk medication:KIDs List: Azithromycin (systemic), when used in neonates, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list and should be avoided due to risk of hypertrophic pyloric stenosis, unless treating Bordetella pertussis or Chlamydia trachomatis pneumonia; risk vs benefit should be assessed when using for Ureaplasma spp.(strong recommendation; high quality of evidence) (PPA [Meyers 2020]).Adverse Reactions (Significant): ConsiderationsAltered cardiac conductionAzithromycin is associated with altered cardiac conduction, including prolonged QT interval on ECG (Ref) and polymorphic ventricular tachycardia (Ref). May be associated with increased cardiac risk and/or death; however, data are conflicting (Ref).Mechanism: Inhibits the delayed rectifier potassium channel, which is encoded by the human ether-à-go-go related gene 1 (hERG1) with much less affinity than erythromycin, causing prolonging of the action potential of cardiac myocytes, prolonging the QT interval (Ref).Onset: Variable; altered cardiac conduction reported to occur within minutes after the administration of the first dose up to 7 days after initiation (Ref).Risk factors:• Females (Ref)• Older patients (Ref)• Heart disease (Ref)• High baseline cardiovascular disease risk (Ref)• History of drug-induced torsades de pointes (Ref)• Congenital long QT syndrome (LQTS) (Ref)• Baseline QTc interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 milliseconds (Ref)• Coadministration of medications that prolong the QT interval or drug interactions that increase serum drug concentrations of QT prolonging medications (Ref)• Hypokalemia and hypomagnesemia (Ref)• Bradycardia (Ref)Clostridioides difficile infectionClostridioides difficile infection (CDI) has been reported with azithromycin, including Clostridioides difficile associated diarrhea and Clostridioides difficile colitis.Onset: Variable; may start on the first day of antibiotic therapy or up to 3 months postantibiotic (Ref).Risk factors: • Antibiotic exposure (highest risk factor) (Ref).• Type of antibiotic (azithromycin considered moderate risk) (Ref)• Long durations in a hospital or other healthcare setting (recent or current) (Ref)• Older adults (Ref)• Immunocompromised conditions (Ref)• A serious underlying condition (Ref)• GI surgery/manipulation (Ref)• Antiulcer medications (eg, proton pump inhibitors and H2 blockers) (Ref)• Chemotherapy (Ref)Drug-induced liver injuryAzithromycin is associated with drug-induced liver injury, including cholestatic hepatitis, hepatocellular hepatitis, and mixed cholestatic/hepatocellular hepatitis. Most patients fully recover; however, severe cutaneous reactions, chronic liver injury, and serious complications leading to death or liver transplantation may occur (Ref).Mechanism: Non-dose-related; not fully understood. An in vitro study was unable to predict if the mechanism was related to bile acid transporter inhibition, mitochondrial dysfunction, or oxidative stress and concluded that hepatotoxicity could be caused by a mechanism that was not evaluated or could be due to unknown metabolite effects (Ref). May be related to hypersensitivity (Ref).Onset: Intermediate; typically occurs within 1 to 3 weeks after initiation (Ref)Risk factors:• Underlying chronic liver disease (Ref)• Hypersensitivity to azithromycin; cross-reactivity among macrolides may occur (Ref)Hypersensitivity reactions (delayed)Delayed hypersensitivity reactions have been reported with azithromycin, ranging from maculopapular skin rash and fixed drug eruption to severe cutaneous adverse reactions (SCARs). SCARs include acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis (Ref). Azithromycin has also been associated with development of a maculopapular rash in patients with concurrent infectious mononucleosis (Ref).Mechanism: Non-dose-related; immunologic; delayed hypersensitivity reactions, including SCARs, involve a T-cell mediated drug-specific immune response (Ref). The mechanism for the development of a nonspecific rash in patients with infectious mononucleosis may be a transient virus-mediated immune alteration that leads to the development of a reversible hypersensitivity reaction (Ref).Onset: Variable; type IV reactions are delayed hypersensitivity reactions that typically occur days to weeks after drug exposure but may occur more rapidly (usually within 1 to 4 days) upon reexposure (Ref).Risk factors:• Limited information regarding cross-reactivity among macrolides (Ref)Hypersensitivity reactions (immediate)Immediate hypersensitivity reactions, including angioedema, urticaria and anaphylaxis, have been reported with azithromycin (Ref).Mechanism: Non-dose-related; immunologic. Although IgE has not been identified in relationship to immediate hypersensitivity reactions to azithromycin, most immediate hypersensitivity reactions are IgE-mediated, with specific antibodies formed against a drug allergen following initial exposure (Ref).Onset: Rapid; generally occurs within 1 hour of administration but may occur up to 6 hours after exposure (Ref).Risk factors:• Limited information regarding cross-reactivity among macrolides (Ref)OtotoxicityAzithromycin is associated with ototoxicity, including hearing loss and tinnitus. Ototoxicity usually manifests in bilateral symmetrical hearing loss of 40 to 50 dB. In most cases, ototoxicity is reversible and resolves within 1 to 5 weeks after discontinuation (Ref). Irreversible hearing loss has been reported, albeit rarely (Ref).Mechanism: Dose- and time-related; linked to cumulative doses of azithromycin. Azithromycin may exert temporary ototoxic effects on outer hair cells via reversible reduction in transient evoked otoacoustic emissions (Ref).Onset: Varied; reported cases of tinnitus have occurred as early as 24 hours; however, the majority of hearing loss cases have occurred with prolonged durations of therapy (ie, ≥4 weeks) (Ref).Risk factors: • Generally greater with higher doses (ie, 500 to 600 mg) (Ref)• Prolonged durations of therapy (ie, ≥4 weeks) (Ref)• Serum azithromycin levels of ≥0.8 +/- 0.4 µg/mL (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%: Gastrointestinal: Diarrhea (≤14%; high single-dose regimens tend to be associated with increased incidence), nausea (≤7%; high single-dose regimens: 5% to 18%)1% to 10%:Cardiovascular: Chest pain (≤1%), facial edema (children: ≤1%), palpitations (adults: ≤1%)Dermatologic: Diaphoresis (children: ≤1%), eczema (children: ≤1%), fungal dermatitis (children: ≤1%), pruritus (≤2%), skin photosensitivity (adults: ≤1%), skin rash (≤2%; single-dose regimens tend to be associated with increased incidence), urticaria (≤1%), vesiculobullous dermatitis (children: ≤1%)Endocrine & metabolic: Increased lactate dehydrogenase (1% to 3%)Gastrointestinal: Abdominal pain (1% to 7%; single-dose regimens tend to be associated with increased incidence), anorexia (≤2%), constipation (≤1%), dysgeusia (adults: ≤1%), dyspepsia (≤1%), enteritis (children: ≤1%), flatulence (≤1%), gastritis (≤1%), melena (adults: ≤1%), oral candidiasis (≤1%), stomatitis (≤1%), vomiting (adults: ≤2%; adults, single 2 g dose: 2% to 7%; children, single-dose regimens tend to be associated with increased incidence: 1% to 6%)Genitourinary: Genital candidiasis (adults: ≤1%), vaginitis (adults: ≤3%)Hypersensitivity: Angioedema (≤1%)Infection: Fungal infection (children: ≤1%)Local: Local inflammation (adults, IV: 3%), pain at injection site (adults, IV: 7%)Nervous system: Agitation (≤1%), dizziness (≤1%), drowsiness (≤1%), fatigue (≤1%), headache (≤1%), insomnia (children: ≤1%), malaise (children: ≤1%), nervousness (children: ≤1%), pain (children: ≤1%), vertigo (≤1%)Neuromuscular & skeletal: Hyperkinetic muscle activity (children: ≤1%), increased creatine phosphokinase in blood specimen (1% to 2%)Respiratory: Bronchospasm (≤1%), cough (children: ≤1%), pleural effusion (children: ≤1%)Miscellaneous: Fever (children: ≤1%)Postmarketing:Cardiovascular: Prolonged QT interval on ECG (rare: <1%) (Russo 2006), syncope (Cocco 2015), torsades de pointes (rare: <1%) (Kezerashvili 2007), ventricular tachycardia (rare: <1%) (Kim 2005)Dermatologic: Acute generalized exanthematous pustulosis (rare: <1%) (Campanón-Toro 2017), erythema multiforme (Isik 2007), Stevens-Johnson syndrome (rare: <1%) (Xu 2018), toxic epidermal necrolysisGastrointestinal: Ageusia (Schiffman 2018), Clostridioides difficile associated diarrhea (rare: <1%) (Brown 2013), Clostridioides difficile colitis (rare: <1%) (Brown 2013), pancreatitis, pyloric stenosis (infantile hypertrophic) (Smith 2015), tongue discolorationHematologic & oncologic: Thrombocytopenia (Butt 2019)Hepatic: Cholestatic hepatitis (rare: <1%) (Martinez 2015), hepatic failure (rare: <1%) (Martinez 2015), hepatic necrosis (rare: <1%) (Martinez 2015), hepatocellular hepatitis (rare: <1%) (Martinez 2015)Hypersensitivity: Anaphylaxis (rare: <1%) (Ünal 2018)Immunologic: Drug reaction with eosinophilia and systemic symptoms (rare: <1%) (Sriratanaviriyakul 2014)Nervous system: Aggressive behavior, altered sense of smell (Schiffman 2018), anosmia (Schiffman 2018), anxiety (Adachi 2003), exacerbation of myasthenia gravis (Pradhan 2009), hyperactive behavior, paresthesia, seizure (Schiff 2010)Neuromuscular & skeletal: Arthralgia, astheniaOtic: Deafness (Etminan 2017), hearing loss (Li 2014), tinnitus (Tseng 1997)Renal: Acute kidney injury, interstitial nephritis (Woodruff 2015)ContraindicationsHypersensitivity to azithromycin, erythromycin, other macrolide (eg, azalide or ketolide) antibiotics, or any component of the formulation; history of cholestatic jaundice/hepatic dysfunction associated with prior azithromycin useNote: The manufacturer does not list concurrent use of pimozide as a contraindication; however, azithromycin is listed as a contraindication in the manufacturer's labeling for pimozide.Warnings/PrecautionsConcerns related to adverse effects:• Superinfection: Prolonged use may result in fungal superinfection.Disease-related concerns:• Bronchiolitis obliterans: When studied to prevent bronchiolitis obliterans syndrome in patients with hematologic malignancy who underwent allogeneic hematopoietic cell transplantation, rates of cancer relapse and mortality were increased among patients receiving long-term azithromycin, leading to early trial termination (Bergeron 2017; FDA Drug Safety Communication 2018).• Gonorrhea/syphilis: May mask or delay symptoms of incubating gonorrhea or syphilis, so appropriate culture and susceptibility tests should be performed prior to initiating a treatment regimen.• Myasthenia gravis: Use with caution in patients with myasthenia gravis; exacerbation and new onset of symptoms have occurred.Special populations:• Infants: Use of azithromycin in neonates and infants <6 weeks of age has been associated with infantile hypertrophic pyloric stenosis (IHPS); the strongest association occurred with exposure during the first 2 weeks of life; observe for nonbilious vomiting or irritability with feeding (Eberly 2015). The risks and benefits of azithromycin use should be carefully considered in neonates; some experts recommend avoidance except for in the treatment of pertussis or C. trachomatis pneumonia; specific risk-benefit ratio should be considered before use for Ureaplasma spp. eradication (Meyers 2020).Dosage form specific issues:• Oral suspensions: Immediate release and extended release suspensions are not interchangeable.Metabolism/Transport EffectsSubstrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits P-glycoprotein/ABCB1Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAfatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Risk D: Consider therapy modificationAliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren.Risk C: Monitor therapyAmisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapyAtorvastatin: Azithromycin (Systemic) may enhance the myopathic (rhabdomyolysis) effect of Atorvastatin.Risk C: Monitor therapyBacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii.Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modificationBCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical).Risk X: Avoid combinationBCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization).Risk C: Monitor therapyBerotralstat: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Berotralstat.Management: Decrease the berotralstat dose to 110 mg daily when combined with P-glycoprotein (P-gp) inhibitors. Risk D: Consider therapy modificationBilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine.Risk X: Avoid combinationCardiac Glycosides: Macrolide Antibiotics may increase the serum concentration of Cardiac Glycosides.Risk C: Monitor therapyCeliprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol.Risk C: Monitor therapyChloroquine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Chloroquine.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyCholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine.Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combinationClofazimine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Clofazimine.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyColchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased.Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a P-gp inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction monograph for details. Risk D: Consider therapy modificationCycloSPORINE (Systemic): Azithromycin (Systemic) may increase the serum concentration of CycloSPORINE (Systemic).Risk C: Monitor therapyDabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate.Risk C: Monitor therapyDabrafenib: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Dabrafenib.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyDomperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationDOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional).Risk X: Avoid combinationDOXOrubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Liposomal).Risk C: Monitor therapyEdoxaban: Azithromycin (Systemic) may increase the serum concentration of Edoxaban.Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30mg daily when combined with azithromycin. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined. Risk D: Consider therapy modificationEtoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide.Risk C: Monitor therapyEtoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate.Risk C: Monitor therapyEverolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus.Risk C: Monitor therapyFexinidazole: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyFluorouracil Products: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Fluorouracil Products.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyGadobenate Dimeglumine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyGlecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir.Risk C: Monitor therapyHalofantrine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Halofantrine.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyHaloperidol: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyImmune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Risk C: Monitor therapyInotuzumab Ozogamicin: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyLactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol.Risk C: Monitor therapyLapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib.Risk C: Monitor therapyLarotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib.Risk C: Monitor therapyLefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin.Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Risk D: Consider therapy modificationLevoketoconazole: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Levoketoconazole.Risk X: Avoid combinationLofexidine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Lofexidine.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyLovastatin: Azithromycin (Systemic) may enhance the myopathic (rhabdomyolysis) effect of Lovastatin.Risk C: Monitor therapyMidostaurin: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Midostaurin.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyMizolastine: Macrolide Antibiotics may increase the serum concentration of Mizolastine.Risk X: Avoid combinationMorphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic).Risk C: Monitor therapyNadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol.Risk C: Monitor therapyNaldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine.Risk C: Monitor therapyNaloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol.Risk C: Monitor therapyNelfinavir: May increase the serum concentration of Azithromycin (Systemic). Risk C: Monitor therapyOndansetron: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Ondansetron.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPAZOPanib: Azithromycin (Systemic) may enhance the QTc-prolonging effect of PAZOPanib. Azithromycin (Systemic) may increase the serum concentration of PAZOPanib.Risk X: Avoid combinationPentamidine (Systemic): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combinationPiperaquine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Piperaquine.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyProbucol: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Probucol.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationQT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Antipsychotics (Moderate Risk): Azithromycin (Systemic) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class IC Antiarrhythmics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-Prolonging Inhalational Anesthetics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-Prolonging Inhalational Anesthetics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Quinolone Antibiotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyRanolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine.Risk C: Monitor therapyRed Yeast Rice: Azithromycin (Systemic) may enhance the myopathic (rhabdomyolysis) effect of Red Yeast Rice.Risk C: Monitor therapyRelugolix: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix.Management: Avoid coadministration of relugolix with oral P-gp inhibitors whenever possible. If combined, take relugolix at least 6 hours prior to the P-gp inhibitor and monitor patients more frequently for adverse reactions. Risk D: Consider therapy modificationRelugolix, Estradiol, and Norethindrone: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix, Estradiol, and Norethindrone.Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider therapy modificationRifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin.Risk C: Monitor therapyRimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant.Management: Avoid administration of another dose of rimegepant within 48 hours if given concomitantly with a P-glycoprotein (P-gp) inhibitor. Risk D: Consider therapy modificationRisperiDONE: Azithromycin (Systemic) may enhance the QTc-prolonging effect of RisperiDONE. Azithromycin (Systemic) may increase the serum concentration of RisperiDONE.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyRomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin.Risk C: Monitor therapySaquinavir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Saquinavir.Risk C: Monitor therapySertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combinationSilodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin.Risk C: Monitor therapySimvastatin: Azithromycin (Systemic) may enhance the myopathic (rhabdomyolysis) effect of Simvastatin.Risk C: Monitor therapySincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide.Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modificationSirolimus (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Conventional).Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider therapy modificationSirolimus (Protein Bound): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Protein Bound).Risk X: Avoid combinationSodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate.Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modificationTacrolimus (Systemic): Azithromycin (Systemic) may increase the serum concentration of Tacrolimus (Systemic).Risk C: Monitor therapyTalazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib.Risk C: Monitor therapyTegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod.Risk C: Monitor therapyTeniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide.Risk C: Monitor therapyTenofovir Disoproxil Fumarate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tenofovir Disoproxil Fumarate.Risk C: Monitor therapyTopotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan.Risk X: Avoid combinationTyphoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected.Management: Avoid use of live attenuated typhoid vaccine (Ty21a)in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modificationUbrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant.Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor. Risk D: Consider therapy modificationVinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal).Risk X: Avoid combinationVitamin K Antagonists (eg, warfarin): Macrolide Antibiotics may increase the serum concentration of Vitamin K Antagonists.Risk C: Monitor therapyFood InteractionsRate and extent of GI absorption may be altered depending upon the formulation. Azithromycin suspension, not tablet form, has significantly increased absorption (46%) with food. Management: Immediate release suspension and tablet may be taken without regard to food; extended release suspension should be taken on an empty stomach (at least 1 hour before or 2 hours following a meal).Dietary ConsiderationsSome products may contain sodium and/or sucrose.Oral suspension, immediate release, may be administered with or without food. Oral suspension, extended release, should be taken on an empty stomach (at least 1 hour before or 2 hours following a meal). Tablet may be administered with food to decrease GI effects. Pregnancy ConsiderationsAzithromycin crosses the placenta (Ramsey 2003).The maternal serum half-life of azithromycin is unchanged in early pregnancy and decreased at term; however, high concentrations of azithromycin are sustained in the myometrium and adipose tissue (Fischer 2012; Ramsey 2003).Azithromycin may be used as an alternative or adjunctive prophylactic antibiotic in patients undergoing unplanned cesarean delivery (ACOG 2018). Azithromycin is recommended for the treatment of several infections, including chlamydia, and granuloma inguinale, and prophylaxis of Mycobacterium avium complex in select pregnant patients (consult current guidelines) (CDC [Workowski 2021]; HHS [OI adult] 2022). Azithromycin may also be used in certain situations prior to vagin*l delivery in patients at high risk for endocarditis (ACOG 2018). Azithromycin may be useful for lymphogranuloma venereum during pregnancy; however, dosing and duration of therapy have not been specifically studied in pregnant patients. The treatment of cervicitis in pregnancy is the same as nonpregnant patients (CDC [Workowski 2021]).Azithromycin is used as an alternative treatment of Lyme disease. Vertical transmission from mother to fetus is not well documented; it is unclear if infection increases the risk of adverse pregnancy outcomes. When treatment for Lyme disease in pregnancy is needed, the indications and dosing of azithromycin are the same as in nonpregnant patients (IDSA/AAN/ACR [Lantos 2021]; Lambert 2020; SOGC [Smith 2020]).Monitoring ParametersLiver function tests, CBC with differential.Mechanism of ActionInhibits RNA-dependent protein synthesis at the chain elongation step; binds to the 50S ribosomal subunit resulting in blockage of transpeptidationPharmaco*kinetics (Adult data unless noted)Absorption: Oral: Rapid from the GI tractDistribution: Extensive tissue; distributes well into skin, lungs, sputum, tonsils, and cervix; penetration into CSF is poor; Vd: 31 to 33 L/kg Protein binding (concentration dependent and dependent on alpha1-acid glycoprotein concentrations): Oral, IV: 7% to 51% Metabolism: Hepatic to inactive metabolites Bioavailability: Oral: Tablet, immediate release oral suspension: 34% to 52%; extended release oral suspension: 28% to 43%; variable effect with food (increased with immediate or delayed release oral suspension, unchanged with tablet) Half-life elimination: Terminal: Oral, IV: Infants and Children 4 months to 15 years: 54.5 hours Adults: Immediate release: 68 to 72 hours; Extended release: 59 hoursTime to peak, serum: Oral: Immediate release: ~2 to 3 hours; Extended release: 3 to 5 hours Excretion: Oral, IV: Biliary (major route 50%, unchanged); urine (6% to 14% unchanged)Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: Cmax and AUC increased 61% and 35%, respectively, in subjects with severe renal impairment.Older adult: In elderly women, a higher Cmax was observed but there was no change in drug accumulation.Anti-infective considerations:Parameters associated with efficacy: Concentration and time dependent, associated with AUC24/minimum inhibitory concentration; goal: ≥25 (Bauernfeind 1995; Craig 1998; Craig 2001; den Hollander 1998; Van Bambeke 2001).Expected drug exposure in normal renal function:AUC:Pediatric patients:Oral suspension: Multiple dose: 10 mg/kg/dose (maximum dose: 500 mg/dose) on day 1, followed by 5 mg/kg/dose (maximum dose: 250 mg/dose) daily on days 2 to 5.Infants ≥6 months of age and children ≤5 years of age: AUC24: 1.841 ± 0.651 mg•hour/L (Nahata 1995).Children ≥6 years of age and adolescents <16 years of age: AUC24: 3.109 ± 1.033 mg•hour/L (Nahata 1993).IV: Infants ≥6 months of age, children, and adolescents <16 years of age: Single dose: 10 mg/kg (maximum dose: 500 mg): AUC0-72: 8.2 ± 1.7 mg•hour/L (Jacobs 2005).Adults:Oral IR tablet:Single dose, 500 mg: AUC0-72: 4.3 ± 1.2 mg•hour/L.Multiple dose (steady state): 500 mg once daily for 3 days: AUC0-∞: 17.4 ± 6.2 mg•hour/L; 500 mg day 1,250 mg once daily on days 2 to 5: AUC0-∞: 14.9 ± 3.1 mg•hour/L.Oral ER tablet: Single dose, 2 g: AUC0-120: 14.8 ± 3.16 mg•hour/L (Liu 2007).IV: Single dose, 500 mg: AUC24: 8.03 ± 0.86 mg•hour/L.Postantibiotic effect: Gram-positive/gram-negative respiratory pathogens: ~2 to 4 hours, varies based on organism (Debbia 1990; Ferrara 1996; Ramadan 1995).Parameters associated with toxicity: Serum azithromycin levels of ≥0.8 ± 0.4 mg/L have been associated with ototoxicity (Brown 1997).Pricing: USPack (Azithromycin Oral)1 g (per each): $29.13Pack (Zithromax Oral)1 g (per each): $29.64Solution (reconstituted) (Azithromycin Intravenous)500 mg (per each): $3.60 - $17.30Solution (reconstituted) (Zithromax Intravenous)500 mg (per each): $7.31Suspension (reconstituted) (Azithromycin Oral)100 mg/5 mL (per mL): $2.33200 mg/5 mL (per mL): $1.16Suspension (reconstituted) (Zithromax Oral)100 mg/5 mL (per mL): $2.12200 mg/5 mL (per mL): $2.71Tablets (Azithromycin Oral)250 mg (per each): $7.77 - $7.78500 mg (per each): $15.54 - $15.57600 mg (per each): $8.05 - $18.68Tablets (Zithromax Oral)250 mg (per each): $2.59500 mg (per each): $3.57Tablets (Zithromax Tri-Pak Oral)500 mg (per each): $83.62Tablets (Zithromax Z-Pak Oral)250 mg (per each): $2.59Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAjustin (KR);Aratro (ES);Atizor (CL);ATM-200 (TZ);Aza-250 (HK);Aza-500 (HK);Azadose (FR);Azas (KR);Azath (KR);Azatril (EE, VN);Azax (TR, UA);Azbact (LK);Azce (LK);Azee (HK, MY);Azeemycin (PH);Azenil (IL);Azent (PH);Azi-500 (PH);Azibact (DE, IN);Azibiot (CR, DO, GT, HN, LV, NI, PA, RO, SV, UA);Azicine (HK, MY, VN);Azilide-250 (PH);Azilide-500 (PH);Azimac (SA);Azimacron (EG);Azimax (MY, ZW);Azimax-250 (HK, SG);Azimed (HR);Azin (BD, PH);Azinobin (CO);Aziphar (VN);Aziraz (EG);Azirocin (KR);Azith (AU, TH);Azithral (IN);Azithrin (MT);Azithro (MY);Azithrom (TW);Azitops (KR);Azitrex (EC);Azitrix (PT);Azitrocin (IT, PH);Azitromax (NO, SE);Azitrox (RO, SK);Aziwok (BF, BJ, CI, ET, GH, GM, GN, IN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM);Azm (LK);Azo-500 (PH);Azomax (BH, KW);Azomycin (AE, KW, QA, SA);Azomyne (JO, LB, QA);Azox (JO);Azro (AE, CY, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE);Azromax (IE);Aztrin (ID);Azyth (PH);Azytro (MY);Binozyt (HK, KR, LK, SG, TH, VN);Clindal AZ (BR, HK);Cronopen (AR);Decantin (PH);Enaz DS (PH);Floctil (HK, MY, TH);Geozit (PH);Glazi (VN);Imexa (HK, MY);Inedol (PE);Jazit (PH);Koptin (CR, DO, GT, HN, NI, PA, SV);Kromicin (CO);Macromax (PH);Macrozit (CO, PE);Maxmor (ID);Mazit (QA);Meithromax (TH);Mezatrin (ID);Neazi (VN);OD Mac (PH);Odazyth (BD);Onzet (TH);Ormax (UA);Shepherd (CN);Sumamed (BG, CN, CZ, EE, LV, PL, RO, SK);Texis (CR, DO, GT, HN, NI, PA, SV);Thromaxin (PH);Tromix (CO);Ultreon (DE);Unizithrin (EG);Uzet (LK);Vinzam (BD);Weihong (CN);Wiltrozin (PH);Xithrone (AE, CY, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE);Xitro (PH);Zaha-250 (TZ);Zaret (CO);Zarom (ID);Zedbac (GB);Zedd (AU);Zemax (TH);Zenith (PH);Zeto (IL);Zetron (LB, QA);Zicho (ID);Zimac (SA);Zimax (BH, LB);Zimericina (CO);Zinfect (TR);Zistic (ID);Zithrax (ID);Zithromac SR (JP);Zithromax (AE, AT, AU, BB, BD, BF, BH, BJ, CH, CI, CL, CN, CR, CY, EG, ET, FI, FR, GB, GH, GM, GN, GR, GT, HK, HN, ID, IE, IL, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MT, MU, MW, MY, NE, NG, NI, NL, NZ, OM, PA, PH, PK, PT, PY, QA, SA, SC, SD, SE, SG, SL, SN, SV, SY, TH, TN, TR, TW, TZ, UG, YE, ZA, ZM, ZW);Zithromax IV (MY, SG);Zithrotel (TH);Zithrox (AE, CY, IQ, IR, JO, KW, LB, LK, LY, OM, SA, SY, YE);Zitrim (CO);Zitrocin (AU, PY);Zitrolin (ID);Zitromax (AR, BE, BR, DK, EC, ES, IS, IT, LU, PE, TR, UY, VE);Zitromed (ID);Zmax (IL, SG, ZW);Zmax One Dose (PH);Zocin (AE, BH, JO, QA);Zomax (AE, CY, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);Zymed (ID);Zynomax (MY);Zyomycin (UA);Zythrocin (TW)For country code abbreviations (show table)Abtahi H, Peiman S, Foroumandi M, Safavi E. 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CloseMethotrexate: Pediatric drug informationMethotrexate: Pediatric drug information(For additional information see "Methotrexate: Drug information" and see "Methotrexate: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningMethotrexate Oral:Adverse reactions:Serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the bone marrow, GI tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate.Methotrexate can cause the following severe or fatal adverse reactions. Monitor closely and modify dose or discontinue methotrexate as appropriate. Bone marrow suppression, serious infections, renal toxicity and increased toxicity with renal impairment, GI toxicity, hepatic toxicity, pulmonary toxicity, hypersensitivity, and dermatologic reactions.Hypersensitivity:Methotrexate is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis.Pregnancy:Methotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception.Methotrexate Injection:Intrathecal and high-dose therapy:For intrathecal and high-dose therapy, use preservative-free formulation of methotrexate and diluents. Do NOT use formulations or diluents containing preservatives for intrathecal and high-dose therapy because they contain benzyl alcohol. Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free methotrexate injection for treatment of neonates or low-birth-weight infants and for intrathecal use. Do not use benzyl alcohol–containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available.HypersensitivityMethotrexate is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis.Appropriate use:Serious adverse reactions, including deaths, have been reported with methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Closely monitor for adverse reactions of the bone marrow, GI tract, liver, lungs, skin, and kidneys. Patients should be informed by their physician of the risks involved and be under a physician's care throughout therapy.The use of methotrexate high-dose regimens recommended for osteosarcoma requires meticulous care. High-dose regimens of methotrexate injection for other neoplastic diseases are investigational, and a therapeutic advantage has not been established.Pregnancy:Methotrexate can cause embryo-fetal toxicity, including fetal death and/or congenital anomalies. Use in rheumatoid arthritis, polyarticular-course juvenile idiopathic arthritis, and psoriasis is contraindicated in pregnancy. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females and males of reproductive potential to use effective contraception during and after treatment with methotrexate.Bone marrow suppression:Unexpectedly severe (sometimes fatal) bone marrow suppression and aplastic anemia have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).Renal impairment:Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration.Hepatotoxicity:Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.Pneumonitis:Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.GI toxicity:Unexpectedly severe (sometimes fatal) GI toxicity has been reported with concomitant administration of methotrexate (usually in high dosage) along with some NSAIDs. Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise hemorrhagic enteritis and death from intestinal perforation may occur.Secondary malignancy:Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.Tumor lysis syndrome:Like other cytotoxic drugs, methotrexate may induce tumor lysis syndrome in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.Dermatologic toxicity:Severe, occasionally fatal skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, IM, IV, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy.Opportunistic infections:Potentially fatal opportunistic infections, especially Pneumocystis jirovecii pneumonia, may occur with methotrexate therapy.Other serious reactions:Other serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, GI tract, lungs, and skin. Withhold or discontinue methotrexate injection as appropriate.Radiotherapy:Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.Experienced physician (injection):Methotrexate should be used only by health care providers whose knowledge and experience include the use of antimetabolite therapy.Brand Names: USOtrexup;Rasuvo;RediTrex;Trexall;XatmepBrand Names: CanadaACH-Methotrexate;JAMP-Methotrexate [DSC];Metoject;PMS-MethotrexateTherapeutic CategoryAntineoplastic Agent, Antimetabolite;Antirheumatic, Disease ModifyingDosing: PediatricNote: Dosing may be presented as mg/m2 or mg/kg; verify dosage unit for calculations; maximum doses may be presented in mg or g; extra precautions should be taken. Frequency of dosing is indication specific (generally weekly or specific days within a protocol); patient harm (including fatality) may occur if administered incorrectly (eg, if a weekly dose is given daily); extra precautions should be taken to verify appropriate frequency.For oncology uses, regimens with corresponding dosing and frequency are highly variable and subject to frequent changes; typical dose ranges presented; specific protocols should be consulted. Doses ≥12 g/m2 (IV) are associated with a high emetic potential, while a 5 g/m2 (IV) dose is associated with a moderate emetic potential (Ref); antiemetics may be recommended to prevent nausea and vomiting. Methotrexate doses between 100 to 500 mg/m2 may require leucovorin calcium rescue. Methotrexate doses >500 mg/m2 require leucovorin calcium rescue; see Leucovorin monograph.Acute lymphoblastic leukemia of infancyAcute lymphoblastic leukemia (ALL) of infancy: Limited data available: Note: Intrathecal therapy is also administered (refer to specific reference for intrathecal dosing used within protocol); other combination chemotherapy variable based on protocol and phase of treatment; refer to specific protocol:Intensification and Consolidation: Infant (<1 year of age) at diagnosis: IV: 4,000 to 5,000 mg/m2 over 24 hours every 7 days for 2 doses; specific days depend on protocol phase (Ref).Acute lymphoblastic leukemia/lymphoma, immature B-cellAcute lymphoblastic leukemia (ALL)/lymphoma (LBL), immature B-cell: Limited data available; multiple regimens reported:Note: Intrathecal therapy is also administered (refer to specific reference for intrathecal dosing used within protocol); methotrexate should be used as part of a combination regimen; refer to specific protocols:Interim maintenance:High-dose methotrexate: Children and Adolescents: IV: 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43 (with leucovorin rescue) in combination with vincristine, mercaptopurine, and intrathecal methotrexate (Ref).Escalating-dose methotrexate (Capizzi [C-MTX]): Children and Adolescents: IV: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total in combination with vincristine, pegaspargase, and intrathecal methotrexate (Ref). Maintenance: Children and Adolescents: Oral: 20 mg/m2 once weekly in combination with vincristine, prednisone, mercaptopurine, and intrathecal methotrexate. On weeks intrathecal methotrexate is administered, consider holding the oral methotrexate for that week; refer to specific protocol (Ref).CNS prophylaxis intrathecal therapy: Infants, Children, and Adolescents: Intrathecal: Age-based dosing: Days of administration vary based on risk status and protocol; refer to institutional protocols or reference for details (Ref):<1 year: 6 mg.1 to <2 years: 8 mg.2 to <3 years: 10 mg.3 to ≤8 years: 12 mg.>8 years: 15 mg.Acute lymphoblastic leukemia/lymphoma, immature T-cellAcute lymphoblastic leukemia (ALL)/lymphoma (LBL), immature T-cell:Limited data available; multiple regimens reported:Note: Intrathecal therapy is also administered (refer to specific reference for intrathecal dosing used within protocol); methotrexate should be used as part of a combination regimen; refer to specific protocols:Interim maintenance:Escalating-dose methotrexate (Capizzi [C-MTX]): Children and Adolescents: IV: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total in combination with vincristine and pegaspargase (Ref).CNS prophylaxis intrathecal therapy: Children and Adolescents: Intrathecal: Age-adjusted dosing: Days of administration vary based on risk status and protocol; refer to protocol for details (Ref):1 to <2 years: 8 mg.2 to <3 years: 10 mg.3 to <9 years: 12 mg.≥9 years: 15 mg.CNS tumors, malignantCNS tumors, malignant (medulloblastoma, PNET, ependymoma, brainstem glioma): Limited data available:Children <10 years: IV: 400 mg/kg on day 4 with leucovorin rescue until level less than 0.1 micromolar (µM); administer methotrexate every 21 days for 5 cycles (in combination with cisplatin, vincristine, etoposide, and cyclophosphamide; then followed by an autotransplant) (Ref).Crohn diseaseCrohn disease:Limited data available:BSA-directed dosing: 15 mg/m2 once weekly; maximum dose: 25 mg/dose (Ref).Fixed dosing (Ref).20 to 29 kg: 10 mg once weekly.30 to 39 kg: 15 mg once weekly.40 to 49 kg: 20 mg once weekly.≥50 kg: 25 mg once weekly.Children and Adolescents: Oral, SUBQ: Note: Should be used in patients intolerant or unresponsive to purine analog therapy (eg, azathioprine, mercaptopurine); use in combination with folic acid supplementation.DermatomyositisDermatomyositis: Limited data available:Children and Adolescents:IM or SUBQ (preferred): Initial: 15 to 20 mg/m2 or 1 mg/kg (whichever is less) once weekly; maximum dose: 40 mg/dose; used in combination with corticosteroids and with either folic acid or folinic acid supplementation (Ref).Oral (not preferred): Initial: 15 mg/m2 or 1 mg/kg (whichever is less) once weekly; maximum dose: 40 mg/dose; used in combination with corticosteroids (Ref).Graft-versus-host disease, acute prophylaxisGraft-versus-host disease (aGVHD), acute prophylaxis: Limited data available:Note: Multiple regimens reported and may vary by dose and frequency of dosing.Standard dose: Children and Adolescents: IV: 15 mg/m2/dose on day 1 and 10 mg/m2/dose on days 3 and 6 after allogeneic transplant (in combination with cyclosporine and prednisone) (Ref) or 15 mg/m2/dose on day 1 and 10 mg/m2/dose on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine) (Ref). Leucovorin rescue may be administered according to protocol.Mini-dose: Children and Adolescents: IV: 5 mg/m2/dose; frequency of dosing reported is variable; following haploidentical stem cell transplant, doses were administered on days 5, 7, 10, and 15 in combination with posttransplant cyclophosphamide and cyclosporine and leucovorin rescue administered 24 hours after methotrexate dose (Ref); following cord blood transplant, doses were administered on days 1, 3, and 6 in combination with tacrolimus (Ref).Juvenile idiopathic arthritis; polyarticularJuvenile idiopathic arthritis (JIA); polyarticular: Note: Therapy should be individualized based on disease severity and activity; when initiating therapy, a trial of at least 3 months is considered adequate; however, if there is no response or only minimal response after 6 to 8 weeks, changing therapy or adding additional therapy may be appropriate. Due to variable bioavailability of oral administration and GI side effects, some experts suggest subcutaneous administration over oral, especially when doses are >10 mg/m2 (Ref). When switching between dosage forms and routes of administration, dosage adjustment may be needed.BSA-directed dosing: Children and Adolescents: Oral, IM, SUBQ: Initial: 10 to 15 mg/m2 once weekly; adjust gradually up to 20 to 30 mg/m2 once weekly; maximum dose: 25 mg/dose. To reduce GI side effects and improve bioavailability and efficacy, consider parenteral administration (IM, SUBQ) of doses >10 mg/m2 (Ref).Weight-directed dosing: Children and Adolescents: Oral, SUBQ: Initial: 0.5 mg/kg once weekly; maximum initial dose: 15 mg/dose; if symptoms worsen or are unchanged after 4 weeks, may increase to SUBQ: 1 mg/kg; maximum dose: 25 mg/dose (Ref).Meningeal leukemia, prophylaxis or treatmentMeningeal leukemia, prophylaxis or treatment: Note: Frequency and duration of treatment based on protocol; treatment dosing may be a frequency of every 2 to 7 days (based on protocol); for treatment, often used in combination with cytarabine and hydrocortisone (triple intrathecal therapy); refer to institutional protocols or references for details. Optimal intrathecal chemotherapy dosing should be based on age rather than on BSA; CSF volume correlates with age and not to BSA (Ref):Infants, Children, and Adolescents: Intrathecal (Ref):<1 year: 6 mg/dose.1 to <2 years: 8 mg/dose.2 to <3 years: 10 mg/dose.3 to <9 years: 12 mg/dose.≥9 years: 15 mg/dose.Non-Hodgkin lymphoma, mature B-cellNon-Hodgkin lymphoma, mature B-cell:Intermediate risk: Limited data available (Ref): Note: Some regimens may include periodic intrathecal methotrexate doses; refer to institution-specific protocols or references cited; only intravenous dosing provided.Induction 1 and 2 (COPADM regimen) and Consolidation 1 and 2 (CYM regimen): Children and Adolescents: IV: 3,000 mg/m2 over 3 hours with leucovorin rescue; combination chemotherapy varied with protocol phase.High risk: Limited data available (Ref): Note: Some regimens may include periodic intrathecal methotrexate doses; refer to institution-specific protocols or references cited; only intravenous dosing provided.Infants ≥6 months, Children, and Adolescents: IV: 8,000 mg/m2 over 4 hours once followed by leucovorin rescue; specific day of therapy and combination chemotherapy depend on protocol phase and clinical factors (eg, CNS positive).Non-Hodgkin lymphoma, mature T-cellNon-Hodgkin lymphoma, mature T-cell (anaplastic large cell lymphoma [ALCL]): Limited data available: Note: Both intravenous and intrathecal methotrexate dosing were part of protocol; use extra precaution ensuring route and dose.Infants, Children, and Adolescents: IV: 3,000 mg/m2 over 3 hours with leucovorin rescue (in combination with multi-agent chemotherapy, depending on cycle) for a total of 6 cycles (Ref).OsteosarcomaOsteosarcoma: High-dose methotrexate: Children and Adolescents: IV: 12 g/m2 (maximum dose: 20 g/dose) over 4 hours (followed by leucovorin rescue) for 4 doses during induction (before surgery) at weeks 3, 4, 8, and 9, and for 8 doses during maintenance (after surgery) at weeks 15, 16, 20, 21, 25, 26, 30, and 31 (in combination with doxorubicin and cisplatin) (Ref); reported frequencies and durations have varied (Ref).Psoriasis, severe; recalcitrant to topical therapyPsoriasis, severe; recalcitrant to topical therapy: Limited data available: Children and Adolescents: Oral, SUBQ: Usual reported range: 0.2 to 0.4 mg/kg once weekly; maximum reported dose: 25 mg/dose; reported treatment duration is highly variable: 6 to 178 weeks (Ref).Scleroderma, localizedScleroderma, localized (juvenile): Limited data available: Infants, Children, and Adolescents: Oral, SUBQ (preferred): 1 mg/kg once weekly; maximum dose: 25 mg/dose; alone or in combination with corticosteroids; duration of therapy: 12 months (Ref).Uveitis, recalcitrantUveitis, recalcitrant: Limited data available:Children and Adolescents:BSA-directed dosing: Oral, SUBQ: Most frequently reported: 15 mg/m2 once weekly, usual range: 10 to 25 mg/m2 (Ref); the SUBQ route may be preferred for patients with GI symptoms, poor bioavailability, or doses >15 mg/m2; a maximum dose of 25 mg/dose was reported in other pediatric uveitis trials (Ref).Weight-directed dosing: SUBQ: 0.5 to 1 mg/kg once weekly; maximum dose: 25 mg/dose (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing adjustment for toxicity: Infants, Children, and Adolescents:Nonhematologic toxicity: Diarrhea, stomatitis, or vomiting which may lead to dehydration: Discontinue until recovery.Hematologic toxicity:Psoriasis, arthritis (JIA): Significant blood count decrease: Discontinue immediately.Oncologic uses:Myelosuppression: Withhold, reduce dose, or discontinue methotrexate as appropriate; refer to individual protocol; provide supportive care as needed.Profound granulocytopenia and fever: Evaluate immediately; consider broad-spectrum parenteral antimicrobial coverage. Withhold, reduce dose, or discontinue methotrexate as appropriate.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling. The following adjustments have been recommended:Infants, Children, and Adolescents:Oncology doses/uses: Refer to specific protocols for adjustments; the higher oncology doses may require more aggressive dosing adjustments than those recommended.Nononcology doses/uses: The following have been recommended (Ref):CrCl >50 mL/minute/1.73 m2: No adjustment necessary.CrCl 10 to 50 mL/minute/1.73 m2: Administer 50% of dose.CrCl <10 mL/minute/1.73 m2: Administer 30% of dose.Hemodialysis: Administer 30% of dose.Peritoneal dialysis (PD): Administer 30% of dose.Continuous renal replacement therapy (CRRT): Administer 50% of dose.Dosing: Hepatic Impairment: PediatricAll patients: There are no dosage adjustments provided in the manufacturer's labeling; use with caution in patients with impaired hepatic function or preexisting hepatic dysfunction. In pediatric oncology patients, refer to specific protocols for adjustments; the higher oncology doses may require more aggressive dosing adjustments. The following adjustments have been recommended in adults (Ref):Bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose.Bilirubin >5 mg/dL: Avoid use.Dosing: Adult(For additional information see "Methotrexate: Drug information")Note: Safety: Fatal errors have occurred when methotrexate was administered as a daily dose instead of a weekly dose. Verify the indication before administration; oral methotrexate is typically only administered daily for an oncology-related indication (Ref). Patient should be under the care of a clinician experienced with using methotrexate.Oncology uses:Note: Methotrexate doses between 100 to 500 mg/m2 may require leucovorin calcium rescue. Doses >500 mg/m2 require leucovorin calcium rescue (refer to "Dosing: Adjustment for Toxicity" for leucovorin calcium dosing). Only preservative-free formulations should be used for intrathecal administration and for high-dose methotrexate regimens. Methotrexate doses ≥250 mg/m2 (IV) are associated with moderate emetic potential; antiemetics may be recommended to prevent nausea and vomiting.Acute lymphoblastic leukemiaAcute lymphoblastic leukemia: Meningeal leukemia prophylaxis or treatment: Intrathecal: 12 to 15 mg (maximum 15 mg/dose) every 2 to 7 days; continue for 1 dose beyond cerebrospinal fluid (CSF) cell count normalization (manufacturer's labeling). Note: Optimal intrathecal chemotherapy dosing should be based on age rather than on BSA; CSF volume correlates with age and not to BSA (Ref).CALGB 8811 regimen (as a component of combination chemotherapy): Early intensification: Intrathecal: 15 mg on day 1 of early intensification phase, repeat in 4 weeks (Ref).CNS prophylaxis/interim maintenance phase:Intrathecal: 15 mg on days 1, 8, 15, 22, and 29 (Ref).Oral: 20 mg/m2 on days 36, 43, 50, 57, and 64 (Ref).Prolonged maintenance: Oral: 20 mg/m2 on days 1, 8, 15, and 22 every 4 weeks for 24 months from diagnosis (Ref).Dose-intensive regimen (as a component of combination chemotherapy):IV: 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning on day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD) (Ref).CNS prophylaxis: Intrathecal: 12 mg on day 2 of each cycle; duration depends on risk (Ref).Maintenance: IV: 10 mg/m2/day for 5 days every month for 2 years (in combination with prednisone, vincristine, and mercaptopurine) (Ref).Protocol 8787 regimen (as part of a multiphase, multiagent regimen): Patients <60 years of age:CNS prophylaxis: Intrathecal: 12 mg at the start of induction, then 12 mg with first postremission chemotherapy, then 12 mg once weekly for 4 more doses, for a total of 6 doses (patients with CNS disease at diagnosis required a total of 10 doses) (Ref).Consolidation phases (1C, 2C, and 3C): IV: 220 mg/m2 bolus, followed by 60 mg/m2/hour for 36 hours beginning on days 1 and 15 (followed by leucovorin rescue) of each 28-day consolidation cycle (in combination with mercaptopurine) (Ref).Maintenance: Oral: 20 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (in combination with mercaptopurine) until in complete remission for 30 months (Ref).Acute promyelocytic leukemia maintenance phaseAcute promyelocytic leukemia maintenance phase (off-label use):Oral: 15 mg/m2 once weekly for 2 years (Ref) or 20 mg/m2 once weekly for 1 year (Ref).IM: 15 mg/m2 once weekly for 2 years (Ref).Bladder cancerBladder cancer (off-label use):Locally advanced or metastatic disease:Dose-dense MVAC regimen: IV: 30 mg/m2 on day 1 every 14 days (in combination with vinblastine, doxorubicin, cisplatin, and growth factor support) until disease progression or unacceptable toxicity (Ref).MVAC regimen: IV: 30 mg/m2 on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, and cisplatin) for up to 6 cycles (Ref) or 30 mg/m2 on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, and cisplatin) until disease progression or unacceptable toxicity (Ref) or 30 mg/m2 on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, cisplatin, and filgrastim) for up to 6 cycles or until loss of clinical benefit (Ref).Neoadjuvant treatment:Note: Patients with non-organ confined disease at cystectomy who did not receive cisplatin-based neoadjuvant chemotherapy should be offered an adjuvant cisplatin-based chemotherapy regimen (Ref).Dose-dense MVAC regimen: IV: 30 mg/m2 on day 1 every 14 days (in combination with vinblastine, doxorubicin, cisplatin, and pegfilgrastim) for 3 or 4 cycles (Ref).MVAC regimen: IV: 30 mg/m2 on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, and cisplatin) for 3 cycles (Ref).CMV regimen: IV: 30 mg/m2 on days 1 and 8 every 21 days (in combination with cisplatin, vinblastine, and leucovorin) for 3 cycles (Ref).Breast cancerBreast cancer: CMF regimen: IV: 40 mg/m2 days 1 and 8 every 4 weeks (in combination with cyclophosphamide and fluorouracil) for 6 to 12 cycles (Ref).Gestational trophoblastic neoplasiaGestational trophoblastic neoplasia:Gestational trophoblastic neoplasia, low-risk disease (off-label dosing):8-day regimen: IM: 1 mg/kg every 48 hours (on days 1, 3, 5, and 7) for 4 doses (with leucovorin 30 hours after each methotrexate dose), repeat cycle every 14 days until hCG level is normal, followed by 2 to 3 more cycles as consolidation therapy (Ref).5-day regimen: IV/IM: 0.4 mg/kg (maximum dose: 25 mg) once daily for 5 days, repeat every 14 days until hCG level is normal, followed by 2 to 3 more cycles as consolidation therapy (Ref).Gestational trophoblastic neoplasia, high-risk metastatic disease (off-label dosing):EMA-CO regimen: IV: 100 mg/m2 IV push followed by 200 mg/m2 over 12 hours on day 1 (with leucovorin 24 hours after the start of methotrexate; in combination with dactinomycin, etoposide, vincristine, and cyclophosphamide) every 14 days and continuing for at least 2 cycles after hCG level is normal (Ref).EMA-EP regimen: Patients without brain metastases: IV: 100 mg/m2 IV push followed by 200 mg/m2 over 12 hours on day 1 every 2 weeks (in combination with etoposide, leucovorin, dactinomycin, and cisplatin), continue for 2 cycles after hCG level is normal (Ref).Patients with brain metastases: IV: 100 mg/m2 IV push followed by 1,000 mg/m2 over 12 hours on day 1 every 2 weeks (in combination with etoposide, leucovorin, dactinomycin, and cisplatin), continue for 4 cycles after hCG level is normal (Ref).EP-EMA regimen: EMA: IV: 300 mg/m2 over 12 hours on day 1 (in combination with etoposide, leucovorin, and dactinomycin); alternating weekly with EP (etoposide and cisplatin) (Ref).Graft-vs-host disease, acute, prophylaxisGraft-vs-host disease, acute, prophylaxis (off-label use): IV: 15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6 after allogeneic transplant (in combination with cyclosporine and prednisone) (Ref) or 15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine) (Ref) or 15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine, followed by leucovorin); may omit day 11 methotrexate for ≥ grade 2 toxicity (Ref).Head and neck cancerHead and neck cancer (squamous cell carcinoma): IV: 40 mg/m2 once weekly until disease progression or unacceptable toxicity (Ref).Large granular lymphocyte leukemia, symptomaticLarge granular lymphocyte leukemia, symptomatic (off-label use): Oral: Initial: 5 to 7.5 mg once weekly (with or without prednisone), escalate up to 15 to 20 mg once weekly or 10 mg/m2/week over 1 to 3 months; methotrexate was administered in split doses in the morning and evening on one day per week (Ref) or 10 mg/m2/week (administered in divided doses in the morning and evening on one day per week), in combination with prednisone, followed by a prednisone taper after 30 days (Ref) or 10 mg/m2/week (administered in divided doses in the morning and evening on one day per week), with or without prednisone; discontinue treatment if no response after 4 months (Ref) or 7.5 mg/m2 once weekly (Ref).Mycosis fungoidesMycosis fungoides (cutaneous T-cell lymphoma): Oral or IM: 25 to 75 mg orally once weekly (as a single agent) or 10 mg/m2 orally twice weekly (as part of a combination regimen) or 5 to 50 mg IM once weekly (for early stage) or 15 to 37.5 mg IM twice weekly (if poor response to weekly therapy) (manufacturer's labeling) or 25 mg orally once weekly, may increase to 50 mg orally once weekly (Ref).Non-Hodgkin lymphomaNon-Hodgkin lymphoma:Burkitt lymphoma:Modified CODOX-M/IVAC regimen ± rituximab (Ref): Cycles 1 and 3 of CODOX-M (CODOX-M alternates with IVAC).Adults ≤65 years of age: IV: 300 mg/m2 over 1 hour on day 10 followed by 2,700 mg/m2 over 23 hours (with leucovorin rescue).Adults >65 years of age: IV: 100 mg/m2 over 1 hour on day 10 followed by 900 mg/m2 over 23 hours (with leucovorin rescue).High-dose methotrexate/cytarabine alternating with Hyper-CVAD: IV: 1,000 mg/m2 over 24 hours on day 1 during even courses (2, 4, 6, and 8) of 21-day treatment cycles (with leucovorin rescue) (Ref).9251 regimen: IV: 150 mg/m2 over 30 minutes followed by 1,350 mg/m2 over 23.5 hours (with leucovorin rescue) on day 1 of cycles 2 through 7 (in combination with cyclophosphamide, prednisone, ifosfamide, mesna, vincristine, cytarabine, etoposide, dexamethasone, doxorubicin, and CNS prophylaxis) (Ref).Mantle cell lymphoma: High-dose methotrexate/cytarabine alternating with Hyper-CVAD (± rituximab): IV: 200 mg/m2 bolus on day 1 or day 2 followed by 800 mg/m2 over 24 hours during even courses (2, 4, 6, and 8) of 21-day treatment cycles (with leucovorin rescue) (Ref).Nonleukemic meningeal cancerNonleukemic meningeal cancer (off-label use): Intrathecal: 12 mg/dose twice weekly for 4 weeks, then weekly for 4 doses, then monthly for 4 doses (Ref) or 10 mg twice weekly for 4 weeks, then weekly for 1 month, then every 2 weeks for 2 months (Ref) or 10 to 15 mg twice weekly for 4 weeks, then once weekly for 4 weeks, then a maintenance regimen of once a month (Ref).OsteosarcomaOsteosarcoma: Adults ≤30 years of age: MAP regimen: IV: 12 g/m2 (maximum: 20 g/dose) over 4 hours (followed by leucovorin rescue) for 4 doses during induction (before surgery) at weeks 4, 5, 9, and 10, and for 8 doses during maintenance (after surgery) at weeks 15, 16, 20, 21, 24, 25, 28, and 29 (in combination with doxorubicin and cisplatin) (Ref); other combinations, intervals, age ranges, and doses (8 to 14 g/m2/dose) have been described (with leucovorin rescue), refer to specific reference for details (Ref).Primary CNS lymphoma, newly diagnosedPrimary CNS lymphoma, newly diagnosed (off-label use): IV: 8 g/m2 over 4 hours (followed by leucovorin rescue) every 14 days until complete response or a maximum of 8 cycles; if complete response, follow with 2 consolidation cycles at the same dose every 14 days (with leucovorin rescue), followed by 11 maintenance cycles of 8 g/m2 every 28 days (with leucovorin rescue) (Ref) or R-MPV regimen: 3.5 g/m2 over 2 hours on day 2 every 2 weeks (in combination with rituximab, vincristine, procarbazine, and leucovorin [with intra-Ommaya methotrexate 12 mg between days 5 and 12 of each cycle if positive CSF cytology]) for 5 to 7 induction cycles followed by reduced-dose whole brain radiotherapy and then cytarabine (Ref) or autologous stem cell transplant (Ref) or R-MP regimen (patients ≥65 years of age): 3 g/m2 over 4 hours on days 2, 16, and 30 of a 42-day cycle (in combination with rituximab, procarbazine, and leucovorin) for 3 cycles (Ref) or MT-R regimen: 8 g/m2 once every 2 weeks (adjusted for creatinine clearance [refer to protocol for details] and in combination with leucovorin, temozolomide, and rituximab) for 7 doses, then followed by high-dose consolidation chemotherapy (Ref) or 3.5 g/m2 on weeks 1, 3, 5, 7, and 9 (in combination with leucovorin, temozolomide, and rituximab), followed by whole-brain radiotherapy and then post-radiation temozolomide (Ref).Primary cutaneous anaplastic large cell lymphomaPrimary cutaneous anaplastic large cell lymphoma (off-label use): Oral: 15 to 25 mg once weekly (range: 10 to 60 mg once weekly); based on response, may increase dosing interval up to once every 2 weeks after the weekly dose has been optimized (Ref) or 5 to 50 mg once weekly (median dose: 20 to 25 mg once weekly) for up to 48 weeks or until disease progression or unacceptable toxicity (Ref).Soft tissue sarcomaSoft tissue sarcoma (desmoid tumors, aggressive fibromatosis), advanced (off-label use): IV: 30 mg/m2 every 7 to 10 days (dose usually rounded to 50 mg) in combination with vinblastine for 1 year (Ref).Nononcology uses:Note: During chronic therapy, treat with folic acid to reduce the risk of adverse effects; leucovorin may be considered in patients who do not respond to folic acid (Ref). In patients with inadequate response or intolerance to oral methotrexate therapy at doses ≥15 mg/week, may consider switching to parenteral administration (using a 1:1 dose conversion) or dividing the weekly oral dose (eg, in 2 to 3 divided doses administered every 12 hours over 12 to 24 hours) (Ref).Atopic dermatitis or eczema, moderate to severeAtopic dermatitis or eczema, moderate to severe (alternative agent) (off-label use):Oral, SUBQ, IM: Initial: 10 to 15 mg once weekly (in combination with folic acid). Adjust dose by 2.5 to 5 mg/week every 2 to 4 weeks if needed based on response (usual dosage range: 7.5 to 25 mg/week) (Ref). Consider discontinuation if no improvement after 12 to 16 weeks on dosages ≥15 mg/week (Ref).Bullous pemphigoidBullous pemphigoid (alternative agent) (adjunctive agent) (off-label use):Oral, IM, SUBQ: Initial: 5 mg once weekly (in combination with folic acid); often also given in combination with glucocorticoids. Increase dose as tolerated by 2.5 mg/week approximately every 4 weeks if needed (usual dosage range: 5 to 20 mg/week). Once disease control is achieved, gradually taper therapy (eg, every 2 to 4 weeks) to minimum effective dose (Ref). Consider discontinuation if no improvement after 4 weeks on dosages ≥15 mg/week (Ref).Crohn disease, moderate to severeCrohn disease, moderate to severe (alternative agent) (adjunctive agent) (off-label use):Note: For use as part of an appropriate combination regimen for induction of remission and as an alternative monotherapy for maintenance of remission (Ref). Patient should be under the care of a clinician experienced with using methotrexate for this condition.IM, SUBQ, Oral: Initial: 15 to 25 mg administered IM or SUBQ once weekly (in combination with folic acid); an initial dose of 12.5 to 15 mg/week administered orally or parenterally may be used when adding to biologic therapy. For lower initial doses, may gradually increase dose (eg, by 5 mg/week every month) if needed (maximum: 25 mg/week). If remission is sustained after 4 months, may reduce dose to 15 mg/week administered orally or parenterally (Ref).Dermatomyositis, cutaneousDermatomyositis, cutaneous (alternative agent) (adjunctive agent) (off-label use):Note: In patients with mild disease, may be used as combination therapy when response to initial systemic therapy (eg, with hydroxychloroquine) is inadequate, or as an alternative initial systemic therapy in patients who cannot take preferred agents. In patients with severe disease, may be used as initial systemic therapy with or without hydroxychloroquine (Ref).Oral, SUBQ, IM: Initial: 5 to 15 mg once weekly (in combination with folic acid). May increase dose by 2.5 mg/week every 1 to 2 weeks up to a goal of 25 mg/week, or directly to 25 mg/week after 2 weeks on the initial dose, if needed based on response (Ref).Dermatomyositis/polymyositisDermatomyositis/Polymyositis (alternative agent) (adjunctive agent) (off-label use):Note: For use as an adjunct to glucocorticoids, or as an alternative initial therapy in patients who cannot receive glucocorticoids (Ref).Oral, SUBQ, IM: Initial: 7.5 to 15 mg once weekly (in combination with folic acid); adjust dose by 2.5 mg/week every 2 to 4 weeks if needed based on response (usual dose: 15 to 25 mg once weekly) (Ref).Discoid lupus erythematosus and subacute cutaneous lupus erythematosus, refractoryDiscoid lupus erythematosus and subacute cutaneous lupus erythematosus, refractory (adjunctive agent) (off-label use):SUBQ (preferred), IM, Oral: 10 to 25 mg once weekly (in combination with folic acid) (Ref).Eosinophilic granulomatosis with polyangiitisEosinophilic granulomatosis with polyangiitis (Churg-Strauss) (alternative agent) (off-label use):Note: May be used as an alternative induction therapy (in combination with glucocorticoids) in patients with mild disease, or as maintenance therapy; efficacy data are limited (Ref).Oral, SUBQ: Initial: 15 mg once weekly (in combination with folic acid), then increase dose by 5 mg/week every 2 to 8 weeks up to 25 mg/week if tolerated. If remission is sustained after 12 to 18 months, may gradually taper dosage until discontinued (Ref).Giant cell arteritisGiant cell arteritis (alternative agent) (adjunctive agent) (off-label use):Note: For use as an alternative to tocilizumab in patients who require glucocorticoid-sparing therapy; clinical experience suggests limited efficacy (Ref).Oral, SUBQ: Initial: 10 to 15 mg once weekly (in combination with folic acid) (Ref). Adjust dose by 2.5 mg/week if needed based on response (usual dosage range: 7.5 to 15 mg/week); may discontinue therapy after 24 months if disease remission is achieved (Ref).Granulomatosis with polyangiitis and microscopic polyangiitisGranulomatosis with polyangiitis and microscopic polyangiitis (off-label use):Note: For use as maintenance therapy (regardless of initial disease severity) to extend remission and prevent relapse; may also be used as induction therapy (in combination with glucocorticoids) only for patients with non–organ- and non–life-threatening disease (Ref).Oral, SUBQ, IM: Initial: 15 to 20 mg once weekly (in combination with folic acid), then increase dose by 2.5 to 5 mg/week every 2 to 8 weeks based on response up to 25 mg/week. If remission is sustained after 1 to 2 years, may gradually taper dosage (eg, reduce by 2.5 mg/week each month) until discontinued (Ref).Morphea or localized sclerodermaMorphea or localized scleroderma (off-label use):Note: For use in patients with severe skin and/or musculoskeletal involvement, either as monotherapy or in combination with glucocorticoids (Ref).SUBQ, Oral: 12.5 to 25 mg once weekly (in combination with folic acid). May gradually taper therapy after 6 to 12 months of disease inactivity (usual total duration: 1 to 2 years) (Ref). Note: May consider a second (or third) course of methotrexate in patients who experience disease relapse (Ref).Psoriasis, moderate to severePsoriasis, moderate to severe:Note: Patient should be under the care of a clinician experienced with using methotrexate for this condition.Oral, IM, SUBQ: Initial: 10 to 15 mg once weekly (in combination with folic acid). Adjust dose gradually (eg, every 4 to 8 weeks) if needed based on response (usual dosage range: 7.5 to 25 mg/week) (Ref).Rheumatoid arthritisRheumatoid arthritis:Note: Patient should be under the care of a clinician experienced with using methotrexate for this condition.Oral, SUBQ, IM: Initial: 7.5 to 15 mg once weekly (in combination with folic acid). Increase dose by 2.5 to 5 mg/week every 4 to 12 weeks if needed based on response (maximum: 25 mg/week); current guidelines suggest titrating to a target dose of ≥15 mg/week within 4 to 6 weeks of initiation. Once disease remission is achieved, may gradually reduce dose (eg, by 2.5 mg/week every 1 to 2 months) to 15 mg/week to limit adverse effects (Ref).Sarcoidosis, pulmonarySarcoidosis, pulmonary (adjunctive agent) (off-label use):Note: For use as an adjunctive agent in patients whose disease progresses despite glucocorticoids or in those who require glucocorticoid-sparing therapy (Ref).Oral, SUBQ, IM: Initial: 5 to 7.5 mg once weekly (in combination with folic acid). Increase dose gradually (eg, by 2.5 mg/week every 2 weeks) if needed up to 20 mg/week; usual dosage range: 10 to 15 mg/week (Ref).Scleritis, idiopathic, noninfectiousScleritis, idiopathic, noninfectious (adjunctive agent) (off-label use):Note: For use in patients with persistent or progressive disease or who require glucocorticoid-sparing therapy; in patients with necrotizing scleritis, alternative agents should be considered (Ref).SUBQ, Oral: Initial: 7.5 to 15 mg once weekly (in combination with glucocorticoids and folic acid). Increase dose by 5 mg/week every week if needed based on response (maximum: 25 mg/week); may gradually taper and discontinue therapy if disease remission is maintained for 6 to 12 months after glucocorticoids are stopped (Ref).Still disease, adult-onset, moderate to severeStill disease, adult-onset, moderate to severe (adjunctive agent) (off-label use):Note: For use as an adjunct to glucocorticoids in patients with moderate to severe, arthritis-predominant disease (Ref).Oral, SUBQ: Initial: 10 to 15 mg once weekly (in combination with folic acid); increase dose by 2.5 mg/week every week if needed after the first 4 weeks based on response (maximum: 25 mg/week) (Ref). Once disease control is achieved for ≥3 months, gradually taper therapy (eg, by 2.5 to 5 mg/week every 2 to 3 months) to minimum effective dose; may discontinue therapy based on response (Ref).Systemic lupus erythematosusSystemic lupus erythematosus (adjunctive agent) (off-label use):Note: For use in patients with arthritis-predominant disease who require glucocorticoid-sparing therapy, or in patients with persistent arthritis symptoms despite first-line therapy (Ref).Oral, SUBQ: Initial: 5 to 15 mg once weekly (in combination with folic acid). Increase dose gradually (eg, by 2.5 mg/week every 4 weeks) if needed based on response (maximum: 20 to 25 mg/week) (Ref).Systemic sclerosis or sclerodermaSystemic sclerosis or scleroderma (off-label use):Note: For use in patients with diffuse skin involvement, or in patients with overlapping skin and musculoskeletal involvement; methotrexate should not be used in patients with pulmonary involvement (Ref).Oral, SUBQ: Initial: 10 mg once weekly (in combination with folic acid); adjust dose by 2.5 mg/week every 4 weeks up to target dose of 15 to 25 mg/week (Ref).Takayasu arteritisTakayasu arteritis (off-label use): Oral, SUBQ: Initial: 15 mg once weekly in combination with a glucocorticoid and folic acid. Increase dose by 2.5 to 5 mg/week every 1 to 2 weeks if needed based on response (maximum: 25 mg/week) (Ref).Termination of intrauterine pregnancy, first trimesterTermination of intrauterine pregnancy, first trimester (alternative agent) (off-label use):Note: For use only as an alternative to mifepristone/misoprostol combination or misoprostol-only regimens in patients at ≤49 days of gestation (Ref). Do not administer folic acid (including folic acid-containing vitamins) during methotrexate therapy for this indication (Ref).IM: 50 mg/m2 once, followed by vagin*l misoprostol 3 to 7 days later (Ref); maximum dose has not been established; some experts do not exceed a methotrexate dose of 100 mg (Ref).Tubal ectopic pregnancyTubal ectopic pregnancy (off-label use):Note: May be used as an alternative to surgery for selected patients who meet all the following criteria: no fetal cardiac activity, hemodynamic stability, serum beta-hCG ≤5,000 milli-international units/mL, and ability to comply with posttreatment follow-up. May be given as single-dose or multiple-dose protocol; some experts prefer the single-dose regimen (Ref). Regimens are named for the minimum number of planned doses; actual number of doses given may be greater.Single-dose regimen: Note: Do not administer folic acid during methotrexate therapy during this regimen (Ref).IM: 50 mg/m2 on day 1; maximum dose has not been established; some experts do not exceed 100 mg. Measure serum hCG level on days 1, 4 and 7; if the hCG decrease from day 4 to 7 is <15%, administer a second 50 mg/m2 dose on day 7 and measure serum hCG level again on day 14; if the hCG decrease from day 7 to 14 is <15%, administer a third 50 mg/m2 dose (maximum dose has not been established; some experts do not exceed 100 mg/dose for each dose). Consider surgical management if hCG does not adequately decrease after 3 doses (Ref).Two-dose regimen: Note: Do not administer folic acid during methotrexate therapy during this regimen (Ref).IM: 50 mg/m2 on days 1 and 4; maximum dose has not been established; some experts do not exceed 100 mg/dose for each dose. Measure serum hCG level on days 4 and 7; if the hCG decrease from day 4 to 7 is <15%, administer a third 50 mg/m2 dose and measure serum hCG level again on day 11; if hCG decrease from day 7 to 11 is <15%, administer a fourth 50 mg/m2 dose and measure serum hCG level on day 14 (some experts do not exceed 100 mg/dose for each dose). Consider surgical management if hCG does not adequately decrease after 4 doses (Ref).Multidose regimen (in combination with leucovorin): IM: 1 mg/kg on day 1; maximum dose has not been established; some experts do not exceed 100 mg. Measure hCG level on days 1, 3, 5, 7, and 14. Administer subsequent 1 mg/kg doses on days 3, 5, 7, and 14 only if there is a <15% decline in hCG from previous measurement; maximum dose has not been established; some experts do not exceed 100 mg/dose for each dose. Administer leucovorin on days 2, 4, 6, 8, and 15 only if methotrexate was given on the previous day. Consider surgical management if hCG does not adequately decrease after 5 doses (total treatment may be between 1 and 5 doses) (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.There are no dosage adjustments provided in the manufacturer's labeling. Limited data are available describing methotrexate dosage adjustment in kidney impairment. The following general and regimen-specific dosage adjustments have been recommended:General dosage adjustment recommendations:Kintzel 1995:CrCl >60 mL/minute: No dose adjustment necessary.CrCl 46 to 60 mL/minute: Administer 65% of normal dose.CrCl 31 to 45 mL/minute: Administer 50% of normal dose.CrCl <30 mL/minute: Avoid use.Aronoff 2007:CrCl >50 mL/minute: No dose adjustment necessary.CrCl 10 to 50 mL/minute: Administer 50% of dose.CrCl <10 mL/minute: Avoid use.Hemodialysis, intermittent (thrice weekly):Cases of methotrexate toxicity (including death) have been reported in hemodialysis patients receiving methotrexate, even at low methotrexate doses. Avoid use (Ref).Case reports describing methotrexate administration in patients with cancer with close monitoring of methotrexate concentrations, leucovorin rescue, and frequent and/or extended dialysis using high-flux membranes to facilitate methotrexate removal have been published (Ref).Peritoneal dialysis: Cases of methotrexate toxicity (including death) have been reported in peritoneal dialysis patients receiving methotrexate, even at low doses. Avoid use (Ref).CRRT: Administer 50% of methotrexate dose (Ref).Regimen-specific dosage adjustments:Acute lymphoblastic lymphoma, dose-intensive (Hyper-CVAD) regimen (usual methotrexate dose: 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours with leucovorin rescue (Ref)): IV:SCr <1.5 mg/dL: No methotrexate dosage adjustment necessary.SCr 1.5 to 2 mg/dL: Administer 75% of methotrexate dose.SCr >2 mg/dL: Administer 50% of methotrexate dose.Breast cancer, CMF regimen (usual methotrexate dose: 40 mg/m2 days 1 and 8 every 4 weeks [in combination with cyclophosphamide and fluorouracil]); CrCl is calculated using the co*ckcroft-Gault equation (Ref).Females ≥65 years of age: IV:CrCl >80 mL/minute: No methotrexate dosage adjustment necessary.CrCl 51 to 80 mL/minute: Reduce methotrexate dose to 30 mg/m2.CrCl 30 to 50 mL/minute: Reduce methotrexate dose to 20 mg/m2.CrCl <30 mL/minute: Avoid methotrexate use.Primary CNS lymphoma, high dose methotrexate (usual methotrexate dose: 8 g/m2 over 4 hours with leucovorin rescue (Ref)); CrCl is measured or can be calculated using the co*ckcroft-Gault equation (Ref): IV:CrCl ≥100 mL/minute: No methotrexate dosage adjustment necessary.CrCl 50 to 99 mL/minute: Calculate dose using percentage reduction of CrCl below 100 mL/minute. Example: If CrCl is 80 mL/minute, adjust dose to 0.8 × 8 g/m2 = 6.4 g/m2.CrCl <50 mL/minute: Avoid methotrexate use.Dosing: Hepatic Impairment: AdultHepatic impairment prior to treatment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution and consider a reduced dose in patients with impaired hepatic function or preexisting hepatic damage. The following adjustments have been recommended (Ref):Bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose.Bilirubin >5 mg/dL: Avoid use.Hepatotoxicity during treatment: Withhold, consider a reduced dose, or discontinue methotrexate as appropriate.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution, Injection: Generic: 250 mg/10 mL (10 mL); 50 mg/2 mL (2 mL)Solution, Injection [preservative free]: Generic: 1 g/40 mL (40 mL); 250 mg/10 mL (10 mL); 50 mg/2 mL (2 mL)Solution, Oral: Xatmep: 2.5 mg/mL (60 mL, 120 mL) [contains methylparaben sodium, propylparaben sodium]Solution Auto-injector, Subcutaneous [preservative free]: Otrexup: 10 mg/0.4 mL (0.4 mL); 12.5 mg/0.4 mL (0.4 mL); 15 mg/0.4 mL (0.4 mL); 17.5 mg/0.4 mL (0.4 mL); 20 mg/0.4 mL (0.4 mL); 22.5 mg/0.4 mL (0.4 mL); 25 mg/0.4mL (0.4 mL)Rasuvo: 7.5 mg/0.15 mL (0.15 mL); 10 mg/0.2 mL (0.2 mL); 12.5 mg/0.25 mL (0.25 mL); 15 mg/0.3 mL (0.3 mL); 17.5 mg/0.35 mL (0.35 mL); 20 mg/0.4 mL (0.4 mL); 22.5 mg/0.45 mL (0.45 mL); 25 mg/0.5 mL (0.5 mL); 30 mg/0.6 mL (0.6 mL)Solution Prefilled Syringe, Subcutaneous [preservative free]: RediTrex: 7.5 mg/0.3 mL (0.3 mL); 10 mg/0.4 mL (0.4 mL); 12.5 mg/0.5 mL (0.5 mL); 15 mg/0.6 mL (0.6 mL); 17.5 mg/0.7 mL (0.7 mL); 20 mg/0.8 mL (0.8 mL); 22.5 mg/0.9 mL (0.9 mL); 25 mg/mL (1 mL)Solution Reconstituted, Injection [preservative free]: Generic: 1 g (1 ea)Tablet, Oral: Trexall: 5 mg, 7.5 mg, 10 mg, 15 mg [scored]Generic: 2.5 mgGeneric Equivalent Available: USMay be product dependentDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Injection: Generic: 5 mg/2 mL (2 mL); 10 mg/mL (2 mL); 25 mg/mL (2 mL, 10 mL, 20 mL, 40 mL, 100 mL, 200 mL)Solution Prefilled Syringe, Injection: Metoject: 7.5 mg/0.75 mL ([DSC]); 10 mg/mL ([DSC]); 15 mg/1.5 mL ([DSC])Generic: 7.5 mg/0.3 mL (0.3 mL); 10 mg/0.4 mL (0.4 mL); 15 mg/0.6 mL (0.6 mL); 20 mg/0.8 mL (0.8 mL); 25 mg/mL (1 mL)Solution Prefilled Syringe, Subcutaneous: Metoject: 22.5 mg/0.45 mL (0.45 mL); 25 mg/0.5 mL (0.5 mL)Generic: 22.5 mg/0.45 mL (0.45 mL); 25 mg/0.5 mL (0.5 mL)Solution Prefilled Syringe, Subcutaneous, as sodium: Metoject: 10 mg/0.2 mL (0.2 mL); 12.5 mg/0.25 mL (0.25 mL); 15 mg/0.3 mL (0.3 mL); 17.5 mg/0.35 mL (0.35 mL); 20 mg/0.4 mL (0.4 mL)Generic: 15 mg/0.3 mL (1 ea, 4 ea); 17.5 mg/0.35 mL (0.35 mL); 20 mg/0.4 mL (0.4 mL)Tablet, Oral: Generic: 2.5 mg, 10 mgProduct AvailabilityJylamvo 2 mg/mL oral solution: FDA approved November 2022; anticipated availability currently unknown. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.Administration: PediatricDoses ≥12 g/m2 (IV) are associated with a high emetic potential, while a 5 g/m2 (IV) dose is associated with a moderate emetic potential (Ref); antiemetics may be recommended to prevent nausea and vomiting.Oral: Often preferred when low doses are being administered; administer on an empty stomach (at least 1 hour before or 2 hours after food or drink except water). Oral solution (Xatmep) contains 2.5 mg/mL concentrated solution; administer with an accurate measuring device (eg, calibrated oral syringe); do not use a household teaspoon (overdosage may occur).Parenteral:IM: May be administered at concentration ≤25 mg/mL; autoinjectors should not be used for IM administration.IV:IV push: May be administered as slow IV push at a concentration ≤25 mg/mL; some have suggested a rate of ≤10 mg/minute (Ref).Bolus IV infusion, or 24-hour continuous infusion: Route and rate of administration depend upon indication and/or protocol; refer to specific references. For high-dose infusion, preservative-free formulation must be used [US Boxed Warning]. Specific dosing schemes vary, but high dose must be followed by leucovorin calcium to prevent toxicity.SubQ: May be administered SubQ (dependent upon indication and product).Otrexup and Rasuvo are for once weekly subcutaneous use in the abdomen or thigh; do not inject within 2 inches of the navel or in areas where the skin is tender, bruised, red, scaly, hard or has scars or stretch marks. Patient may self-administer after appropriate training on preparation and administration and with appropriate follow-up monitoring. All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects.Intrathecal: May be administered intrathecally; must use preservative-free formulation for intrathecal administration.Administration: AdultDoses ≥250 mg/m2 (IV) are associated with moderate emetic potential; antiemetics may be recommended to prevent nausea and vomiting.Methotrexate may be administered orally, IM, IV, intrathecally, or SUBQ; IV administration may be as slow push (10 mg/minute), bolus infusion, or 24-hour continuous infusion (route and rate of administration depend on indication and/or protocol; refer to specific references). Must use preservative-free formulation for intrathecal or high-dose methotrexate administration.When administered IM for indications that may terminate a pregnancy, also consult local policies or regulations related to administration.Specific dosing schemes vary, but high doses should be followed by leucovorin calcium rescue to prevent toxicity.Oral solution: Ensure accuracy when dispensing and administering to prevent dosing errors. A calibrated oral syringe/dosing cup that can measure and deliver the prescribed dose accurately should be used; do not use a household teaspoon or tablespoon to measure dose.Otrexup, Rasuvo, and RediTrex are autoinjectors or prefilled syringes for once-weekly SUBQ use in the abdomen or thigh; patient may self-administer after appropriate training and with appropriate follow-up monitoring. Use a different injectable formulation for administration of routes other than SUBQ or for doses <7.5 mg/week or >25 mg/week. All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects.Hazardous Drugs Handling ConsiderationsHazardous agent (NIOSH 2016 [group 1]).Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).Storage/StabilityInjection: Note: Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation.IV, IM, or SUBQ: Store intact vials, autoinjectors, and prefilled syringes between 20°C and 25°C (68°F and 77°F); excursions may be permitted between 15°C and 30°C (59°F and 86°F). Protect from light (keep in carton until time of use). Solution diluted in D5W or NS is stable for 24 hours at room temperature (21°C to 25°C [69°F to 77°F]).Intrathecal: Intrathecal dilutions are preservative free and should be used as soon as possible after preparation. After preparation, store intrathecal medications (until use) in an isolated location or container clearly marked with a label identifying as "intrathecal" use only.Oral:Tablets: Store between 20°C and 25°C (68°F and 77°F). Protect from light.Oral solution: Store at 2°C to 8°C (36°F to 46°F) in a tightly closed container. Patients may store either refrigerated (2°C to 8°C [36°F to 46°F]) or for up to 60 days at room temperature (20°C to 25°C [68°F to 77°F]). Excursions permitted to 15°C to 30°C (59°F to 86°F). Avoid freezing and excessive heat.UseOncologic indications: Treatment of trophoblastic neoplasms (gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole), acute lymphocytic leukemia, osteosarcoma, breast cancer, head and neck cancer (epidermoid), cutaneous T-Cell lymphoma (advanced mycosis fungoides), lung cancer (squamous cell and small cell) (oral, parenteral: FDA approved in pediatric patients [age not specified] and adults); treatment of meningeal leukemia (parenteral: FDA approved in pediatric patients [age not specified] and adults); has also been used for CNS tumors (including nonleukemic meningeal cancers), acute promyelocytic leukemia (maintenance treatment), and soft tissue sarcoma (desmoid tumors).Nononcologic indications: Treatment of active polyarticular juvenile idiopathic arthritis (JIA) in patients who have failed to respond to other agents (oral [eg, Trexall, Xatmep], parenteral [eg, Otrexup, Rasuvo, Reditrex]: FDA approved in ages 2 to 16 years); treatment of psoriasis (severe, recalcitrant, disabling) and severe, active rheumatoid arthritis in patients whose disease is unresponsive to or who are intolerant of first-line therapy, including full-dose nonsteroidal anti-inflammatory drugs (oral [eg, Trexall, Xatmep], parenteral [eg, Otrexup, Rasuvo, Reditrex]: FDA approved in adults). Has also been used for the treatment of and maintenance of remission in Crohn disease, dermatomyositis, uveitis, and scleroderma.Medication Safety IssuesSound-alike/look-alike issues:Methotrexate may be confused with mercaptopurine, methylPREDNISolone sodium succinate, metOLazone, metroNIDAZOLE, mitoXANTRONE, MXT Patch, PRALAtrexate.Trexall may be confused with Paxil.High alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication (with special emphasis on nononcologic uses) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.Administration issues:Fatal errors have occurred when oral methotrexate was administered as a daily dose instead of a weekly dose. Verify the indication before administration; methotrexate is typically only administered daily for an oncology-related indication (ISMP 2020). The ISMP recommends hospitals use a weekly dosage regimen default for oral methotrexate orders in electronic order entry systems, with a hard stop verification required of appropriate oncology indication for all daily oral methotrexate orders. Provide patient and/or caregiver education for patients discharged on oral methotrexate (ISMP 2020).Intrathecal medication safety: The American Society of Clinical Oncology (ASCO)/Oncology Nursing Society (ONS) chemotherapy administration safety standards (ASCO/ONS [Neuss 2016]) recommend the following safety measures for intrathecal chemotherapy:• Intrathecal medication should not be prepared during the preparation of any other agents.• After preparation, keep in an isolated location or container clearly marked with a label identifying as "intrathecal" use only.• Delivery to the patient should only be with other medications also intended for administration into the central nervous system.• Administer immediately after a time-out/double-check procedure.Other safety concerns:MTX is an error-prone abbreviation (mistaken as mitoxantrone or multivitamin).International issues:Trexall [US] may be confused with Trexol brand name for tramadol [Mexico]; Truxal brand name for chlorprothixene [multiple international markets].Adverse Reactions (Significant): ConsiderationsDermatologic toxicitySevere dermatologic reactions have been reported with methotrexate use, including erythema multiforme, erythroderma, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (Ref). Skin reactions have been noted with single or multiple low and high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Methotrexate-induced skin necrosis has been described that mimics SJS/TEN but differs in pathology and presumed mechanism (Ref). Mucocutaneous ulcers have been reported within preexisting skin lesions (eg, psoriasis); this may be an initial presenting sign of long-term methotrexate toxicity (Ref). Other dermatologic reactions reported include pustular rash (Ref), hyperpigmentation (Ref), papular rash (Ref); skin photosensitivity (eg, photodermatitis reactivation, skin abnormalities related to radiation recall, dyschromia) (Ref); acral erythema (also known as hand-foot syndrome and palmar-plantar erythrodysesthesia) (Ref); and accelerated nodulosis in patients with rheumatoid arthritis (RA) (Ref). Compared to classic rheumatoid nodule, accelerated nodules have a more rapid onset, are smaller, and mainly affect the hands (Ref).Mechanism: SJS and TEN are delayed type IV hypersensitivity reactions involving a T-cell mediated drug-specific immune response (Ref). Methotrexate-induced skin necrosis is caused by direct toxicity to keratinocytes (Ref). Similarly, acute mucocutaneous lesions are the result of methotrexate toxicity to the mucosa (Ref).Onset: Varied; SJS and TEN typically occur days to weeks after drug exposure (Ref). Skin necrosis occurs 3 to 90 days post-initiation (Ref); although, may occur after a single dose (Ref). Mucocutaneous ulcerations have occurred with acute and, less commonly, chronic treatment (Ref). Symptom onset with photo-recall (also known as UV recall) occurs within weeks to years of ultraviolet (UV) exposure, whereas UV enhancement is observed within 1 week of UV exposure (Ref). Accelerated nodulosis typically occurs from 3 months to 12 years after initiation (Ref).Risk factors:• Age >55 years (Ref)• Drug-drug interactions (eg, nonsteroidal anti-inflammatory agents [NSAIDs], sulfamethoxazole/trimethoprim) (Ref)• Folate deficiency and low serum albumin level (Ref)• Increase in methotrexate dose (Ref)• Kidney impairment (Ref)• Photodermatitis reactivation: Sunburn (Ref)• Photosensitivity reactions: Concurrent voriconazole (Ref)• Skin necrosis: Age >60 years, chronic kidney disease, high initial methotrexate dose without folic acid supplement, leukopenia (Ref)GI toxicityGI toxicity is a frequently occurring adverse reaction of methotrexate. Although stomatitis (including severe stomatitis) occurs more frequently with high-dose methotrexate, life-threatening GI events and fatalities have been reported with low-dose methotrexate (Ref). Other dose-limiting GI manifestations include abdominal distress, diarrhea, gastrointestinal hemorrhage, gastrointestinal ulcer, indigestion, nausea, sore throat, stomach pain, and vomiting (Ref). Stomatitis can be an early sign of methotrexate toxicity, as high tissue turnover rates make GI and mucosal cells especially sensitive to chemotherapy (Ref). Ulcerative stomatitis and diarrhea can progress to life-threatening enteritis and intestinal perforation. GI hemorrhage and ulcers are reported more frequently in patients with a history of ulcerative colitis or peptic ulcer disease (Ref).Mechanism:Dose-related; mucositis and stomatitis after high-dose methotrexate are caused by cellular damage to rapidly dividing epithelial cells along the entire GI tract; inadequate or delayed leucovorin rescue can lead to impaired epithelial cell growth and regeneration in patients treated with high-dose methotrexate (Ref). Endothelial and connective tissue insult along with mucosal barrier injury result in early development of mucositis and stomatitis (Ref).Non–dose-related; additional reports have been published where intestinal toxicity occurred as a result of inflammatory effects of methotrexate in the intestinal epithelium and submucosal tissues. This mechanism appears to be non-dose-related and explains the toxicity observed with low-dose methotrexate (Ref). Nausea and vomiting occur as a result of insult to the chemoreceptor trigger zone inducing emesis. Methotrexate has low emetogenic potential (Ref).Onset: Varied; nausea, vomiting, and diarrhea occur as early as 24 hours post high-dose methotrexate infusion and as long as 7 days post infusion. Similar symptoms appear 24 hours after low-dose methotrexate weekly dose (Ref). Oral mucositis occurs within the first week of low-dose methotrexate therapy with unintentional overdose (Ref). high-dose methotrexate-induced stomatitis and mucositis occur after the first course of treatment or up to 14 days post high-dose methotrexate infusion (Ref).Risk factors:High-dose methotrexate:• Drug-drug interactions, especially concomitant use with nonsteroidal anti-inflammatory drugs (NSAIDs)Low-dose methotrexate:• Drug-drug interactions (Ref)• High starting doses (>15 mg/week to 25 mg/week) (Ref)• History of peptic ulcer disease (Ref) or ulcerative colitis• Kidney impairment (Ref)• Preexisting folate deficiency (Ref)• Unintentional daily dosing (Ref)• Higher frequency of nausea in adolescents and younger adults, SubQ methotrexate use, and duration of therapy >1 year (Ref)• Higher risk of diarrhea associated with younger age and previous GI events (Ref)Hematologic toxicityUnexpectedly severe (sometimes fatal) bone marrow depression with agranulocytosis, anemia, aplastic anemia, leukopenia, neutropenia (including febrile neutropenia), pancytopenia, and thrombocytopenia may occur with low-dose methotrexate used for conditions such as rheumatoid arthritis (RA) or psoriasis (Ref). Neutropenia is encountered most frequently, but anemia and thrombocytopenia also occur. May also occur with high-dose methotrexate, most commonly in the presence of kidney dysfunction and specific concurrent medications delaying methotrexate clearance (Ref). Aplastic anemia has been reported when high-dose methotrexate is concomitantly administered with a nonsteroidal anti-inflammatory drug (NSAID). (Ref).Mechanism: Non–dose-related; hematologic toxicity occurs secondary to methotrexate’s interference with stem cell DNA synthesis. Fast turnover of stem cells together with a high number of cells in the S phase cycle makes these cells especially labile to methotrexate-induced hematologic toxicity (Ref).Onset: Varied; with low-dose methotrexate occurring at any time during treatment, from a rapid onset to many years of treatment (Ref).Risk factors:• Note: Methotrexate bone marrow suppression with low-dose methotrexate, especially pancytopenia, can occur in the absence of identifiable risk factors (Ref)• Absence of supplemental folic acid (Ref)• Age >65 years (Ref)• Concurrent infection (Ref)• Concurrent use of NSAIDs, ciprofloxacin, penicillin-type drugs, sulfamethoxazole/trimethoprim, probenecid, phenytoin, and proton pump inhibitors (Ref)• Dosing errors (ie, administering daily or 2 to 4 days per week) increase toxicity more often than once weekly dosing (Ref)• Hypoalbuminemia or displacement of methotrexate from albumin (Ref)• Fluid accumulations and third spacing (ie, ascites, pleural effusions) (Ref)• Preexisting kidney impairment (Ref)HepatotoxicityMethotrexate causes frequent increased liver enzymes. Less frequently, these elevations lead to chronic hepatotoxicity in the form of hepatic fibrosis and hepatic cirrhosis (Ref). Acute liver enzyme elevations are transient and asymptomatic and may not be predictive of subsequent hepatic disease (Ref). Delayed hepatic toxicity in the form of fibrosis or cirrhosis after 2 years or more of low-dose methotrexate use and a total dose of at least 1.5 g can be fatal (Ref). Cases of fibrosis have also been reported in rheumatoid arthritis (RA) patients receiving regular folic acid supplementation (Ref). Patients being treated for psoriasis may be predisposed to higher reported levels of liver enzymes more frequently than patients treated for RA (Ref). Fibrosis and cirrhosis may also occur without symptoms or liver enzyme elevations in psoriasis patients (Ref).Mechanism: Dose-related; impaired function of folate cell transporters leading to excessive methotrexate in liver cells, accumulation of hom*ocysteine causing oxidative stress, and inflammation resulting in fatty liver; depletion of hepatic folate stores and local toxicity due to folate deficiency; direct damage from methotrexate metabolites to hepatocytes and fibrosis forming as a result of adenosine production in response to toxins such as ethanol, viruses, or drugs (Ref).Onset: Varied; higher frequency of hepatotoxicity after first infusion with high-dose methotrexate (Ref). Patients may exhibit increases in liver enzymes within 7 months of initiation (Ref). Biopsy-proven liver abnormalities have been detected in patients after 1 year (Ref).Risk factors:• Alcohol consumption (Ref)• Concurrent use of hepatotoxic medications (eg, azathioprine, retinoids, sulfasalazine, leflunomide)• Cumulative dose >1.5 g and duration of therapy ≥2 years• Females (Ref)• Older adults (Ref)• Metabolic syndrome (Ref)• Preexisting kidney disease (Ref)• Preexisting hepatic disease, particularly nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (Ref)InfectionMethotrexate rarely increases the risk for developing life-threatening or fatal infection (Ref), including bacterial, fungal, or viral infections, exacerbation of hepatitis B (Ref), septicemia (Ref), tuberculosis (primary infection or reactivation) (Ref), disseminated herpes zoster infection (Ref), and cytomegalovirus disease. Immune suppression may lead to potentially fatal opportunistic infections, especially pneumonia due to Pneumocystis jirovecii (PJP) (Ref).Mechanism: Unknown; immunosuppression may occur due to T-cell apoptosis and clonal deletion (Ref). Patients with rheumatoid arthritis (RA) have a high rate of infection when compared to healthy control population; therefore, infections (including opportunistic infections) arising during therapy may be due to RA or the immunosuppressive effects of methotrexate (Ref).Onset: Varied; may occur at any time during treatment; however, most infections occur in the first 2 years (Ref).Risk factors:• Low-dose methotrexate (ie, ≤15 mg per week) (Ref)• Duration of use (Ref)• Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), ciprofloxacin, penicillin-type drugs, sulfamethoxazole/trimethoprim, probenecid, phenytoin, and proton pump inhibitors (Ref)NephrotoxicityMethotrexate may cause acute kidney injury (Ref). Increases in serum creatinine may persist more than 4 months after therapy discontinuation (Ref). Other kidney adverse reactions reported with methotrexate use include azotemia, cystitis, proteinuria, and hematuria.Mechanism: Dose-related; acute kidney injury arises from 2 primary mechanisms: Crystal nephropathy and direct tubular toxicity (Ref). Methotrexate parent drug and metabolite accumulation in renal tubules cause crystal nephropathy and renal tubular obstruction that presents with asymptomatic serum creatinine elevations that progresses to tubular necrosis and kidney injury. Secondly, direct tubular toxicity and cellular injury occur as a result of oxygen radical formation in the kidney (Ref). A third mechanism of methotrexate-induced kidney injury is hyperhom*ocysteinemia in patients with deficient folate metabolism (Ref). Methotrexate-induced kidney damage decreases clearance and results in sustained and elevated plasma methotrexate concentrations which then lead to systemic toxicities including further kidney impairment, myelosuppression, hepatotoxicity, stomatitis, and in rare cases, multi-organ failure (Ref).Onset: Varied; occurs as early as 36 hours after high-dose methotrexate infusion and as late as 9 years after chronic low-dose methotrexate (Ref).Risk factors:• Age >49 years (Ref)• Concurrent use of salicylates, sulfonamides, nonsteroidal anti-inflammatory drugs (NSAIDs), ciprofloxacin, penicillin-type drugs, probenecid, and proton pump inhibitors (Ref)• Conditions associated with extravascular fluid accumulation (eg, ascites, pleural effusions, intracranial fluid) (Ref)• Higher doses or rapid infusion (Ref)• Low albumin (Ref)• Preexisting kidney impairment (Ref)• Sex (males > females) (Ref)• Tumor lysis syndrome (Ref)• Volume depletion (Ref)• Acidic urine (Ref)NeurotoxicityNeurotoxicity secondary to methotrexate administration has been reported manifesting as encephalopathy, headache, hemiparesis, and leukoencephalopathy. Seizure activity has also been reported. Aseptic meningitis, myelopathy, and chemical arachnoiditis have been reported with intrathecal (IT), intraventricular, or IV methotrexate. Chemical conjunctivitis occurs rarely and can be managed with local treatment and methotrexate can be safely administered intraocular to control autoimmune diseases that affect the eye (Ref). Chronic leukoencephalopathy is a delayed complication of IT or IV high-dose methotrexate (that can lead to significant long-term neurological impairment). It has been reported in CNS lymphoma patients with repeated cycles of high-dose methotrexate even in the absence of cranial irradiation. Neurotoxicity may be reversible in some instances, but fatalities have occurred (Ref). Acute neurotoxicity often resolves spontaneously, rarely having long-term sequelae (Ref). Acute encephalopathy, aseptic meningitis, and myelopathy often resolve within hours after each episode (Ref). Neurotoxicity rarely occurs with low-dose methotrexate administration.Mechanism: Dose-related; may occur secondary to accumulations of adenosine and hom*ocysteine in the CNS resulting in endothelial injury, ischemia, demyelination, and white matter necrosis (Ref). Methotrexate may also cause direct toxic effects to the nervous system (Ref). More recently, single nucleotide polymorphisms have been investigated as contributing to the development of leukoencephalopathy (Ref).Onset: Varied; acute neurotoxicity symptoms occur within 24 hours (Ref). Acute encephalopathy, aseptic meningitis, and myelopathy can occur within minutes to hours after IT or IV methotrexate with repeated episodes occurring hours later (Ref). May also be delayed, like myelopathy developing several days to weeks after treatment (Ref). Chronic leukoencephalopathy may begin with gradual impairment of cognitive function months after methotrexate treatment (Ref). However, intellectual decline is observed at least 1 year after treatment (Ref).Risk factors:• Concurrent CNS radiation (Ref)• Higher cumulative dose (Ref)• Higher hom*ocysteine levels (Ref)• Higher plasma methotrexate to leucovorin ratio (Ref)• Hypertension (Ref)• Females (Ref)• Age ≥10 years (Ref)• Polymorphisms in genes associated with neurodevelopment (Ref)• Shorter intervals between IT/IV doses (Ref)Pulmonary toxicityMethotrexate-induced pulmonary toxicity, including acute, subacute, and chronic interstitial pneumonitis has been reported with low-dose methotrexate treatment (Ref). Pulmonary toxicity, such as pneumonitis, is rarely observed with high-dose methotrexate; however, cases have been published (Ref). Pneumonitis is not always fully reversible, and fatalities have been reported (Ref).Mechanism: Multiple proposed mechanisms; pneumonitis is considered an immune or hypersensitivity reaction related to toxic accumulations of methotrexate in lung tissue (Ref). Others have suggested methotrexate-induced injury to alveolar epithelial walls may play a role (Ref).Onset: Varied; classified as either early-onset (<6 months) or late-onset (>6 months) (Ref). Most often occurs within the first year; however, has occurred as early as days after initiation (Ref) and as late as 30 years after use (Ref). May occur up to 20 months after discontinuation (Ref).Risk factors: • Low-dose methotrexate (Ref)• Age >60 years (Ref)• Chronic kidney disease (Ref)• Diabetes (Ref)• Hypoalbuminemia (Ref)• Males (Ref)• Preexisting lung disease (Ref)• Previous use of disease-modifying antirheumatic drugs (DMARDs) (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions vary by route, dosage, and indication.>10%:Gastrointestinal: Diarrhea (16%) (Sherbini 2022), nausea (31%) (Sherbini 2022), oral mucosal ulcer (11%) (Sherbini 2022), vomiting (≤11%)Hepatic: Hepatic cirrhosis (chronic therapy; <1% to ≥10%) (Dubey 2016), hepatotoxicity (in patients treated with 1, 2, or 5 g/m2, grades ≥3: ≥10%) (Ozdemir 2016), increased liver enzymes (14% to 15%; increased serum alanine aminotransferase: >1 × ULN: 20%; >2 × ULN: 4% [Sherbini 2022])Nervous system: Dizziness (13%) (Sherbini 2022), fatigue (31%) (Sherbini 2022), headache (19%) (Sherbini 2022)Respiratory: Cough (16%) (Sherbini 2022)1% to 10%:Dermatologic: Alopecia (≤10%), burning sensation of skin (psoriasis: 3% to 10%), dermatitis (rheumatoid arthritis: 1% to 3%), pruritus (9%) (Sherbini 2022), skin photosensitivity (3% to 10%), skin rash (≤3%)Endocrine & metabolic: Weight loss (5%) (Sherbini 2022)Gastrointestinal: Anorexia (4%) (Sherbini 2022), sore throat (8%) (Sherbini 2022), stomach pain (9%) (Sherbini 2022), stomatitis (2% to 10%)Hematologic & oncologic: Anemia (3% [Sherbini 2022]; severe anemia [after 2 years of low-dose methotrexate: ≥4% to <10%] [Dubey 2016]), leukopenia (1% to 3%; WBC <3000/mm3), neutropenia (≤1%) (Sherbini 2022), pancytopenia (rheumatoid arthritis: 1% to 3%), thrombocytopenia (rheumatoid arthritis: 3% to 10%; platelet count <100,000/mm3)Hepatic: Hepatic fibrosis (chronic therapy: ≥4% to <10%) (Dubey 2016; MacDonald 2005)Infection: Chest infection (3%) (Sherbini 2022)Ophthalmic: Blurred vision (5%) (Sherbini 2022)Respiratory: Dyspnea (6%) (Sherbini 2022), interstitial pneumonitis (rheumatoid arthritis: 1%)Miscellaneous: Fever (3%) (Sherbini 2022)Frequency not defined:Cardiovascular: Arterial thrombosis, chest pain, deep vein thrombosis, hypotension, pericarditis, pulmonary embolism, thrombophlebitis, vasculitisDermatologic: Acne vulgaris, diaphoresis, dyschromia, ecchymoses, erythematous rash, exacerbation of psoriasis (plaque erosion), exfoliative dermatitis, furunculosis, skin necrosis, telangiectasiaEndocrine & metabolic: Decreased serum albumin, diabetes mellitus, gynecomastia, menstrual diseaseGastrointestinal: Aphthous stomatitis, enteritis, gastrointestinal hemorrhage, gastrointestinal ulcer, gingivitis, hematemesis, intestinal perforation, melena, pancreatitisGenitourinary: Azotemia, cystitis, defective oogenesis, defective spermatogenesis, dysuria, hematuria, impotence, infertility, oligospermia, proteinuria, vagin*l dischargeHematologic & oncologic: Agranulocytosis, bone marrow depression (nadir: 7 to 10 days), eosinophilia, hypogammaglobulinemia, lymphadenopathy, malignant lymphoma, non-Hodgkin lymphoma (in patients receiving low-dose oral methotrexate), tumor lysis syndromeHepatic: Hepatic failure, hepatitis (acute)Hypersensitivity: Nonimmune anaphylaxisInfection: Cryptococcosis, cytomegalovirus disease (including cytomegaloviral pneumonia), herpes simplex infection, nocardiosis, sepsis, vaccinia (disseminated; following smallpox immunization)Nervous system: Abnormal cranial sensation (has been reported at low dosage), aphasia, cerebral thrombosis, chemical arachnoiditis (intrathecal; acute), chills, cognitive dysfunction (has been reported at low dosage), drowsiness, dysarthria, hemiparesis, leukoencephalopathy (may be chronic), malaise, mood changes (has been reported at low dosage), paresis, speech disturbanceNeuromuscular & skeletal: Arthralgia, bone fracture (stress), myalgia, osteonecrosis (with radiotherapy), osteoporosisOphthalmic: Conjunctivitis, eye pain, retinal thrombosis, transient blindnessOtic: TinnitusRespiratory: Chronic obstructive pulmonary disease, epistaxis, pharyngitis, pneumonia, pulmonary alveolitis, pulmonary fibrosis, respiratory failure, upper respiratory tract infectionMiscellaneous: Nodule, tissue necrosis (with radiotherapy)Postmarketing:Cardiovascular: Pericardial effusion (Whitfield 2020)Dermatologic: Dermal ulcer (Bahnson 2021), erythema multiforme (Blanes 2005), palmar-plantar erythrodysesthesia (Karol 2017), papular rash (Mebazaa 2008), photodermatitis (reactivation) (DeVore 2010), skin abnormalities related to radiation recall (Lee 2012), Stevens-Johnson syndrome (Lee 2012), toxic epidermal necrolysis (Sancheti 2016), urticaria (Pugi 2012)Endocrine & metabolic: Decreased libido (AlEssa 2021)Gastrointestinal: Abdominal distress (Braun 2008), mesenteric ischemia (acute; Morgan 2011)Genitourinary: Crystalluria (Santiago 2020)Hematologic & oncologic: Aplastic anemia (Dubey 2016), febrile neutropenia (Bayraktar 2021), lymphoproliferative disorder (including intestinal follicular lymphoma, large B-cell lymphoma, and T-cell lymphoma [follicular]) (Muto 2021, Osaki 2021), skin carcinoma (Solomon 2020)Hepatic: Exacerbation of hepatitis B (Ostuni 2003)Hypersensitivity: Anaphylaxis (Pugi 2012), angioedema (Freeman 1999), hypersensitivity angiitis (Dewan 2021), severe hypersensitivity reaction (including hyperpigmentation, pustular rash, and severe stomatitis) (Shafie 2021)Infection: Herpes zoster infection (Patel 2015), histoplasmosis (LeMense 1994), infection (Ibrahim 2018; Lee 2020), septicemia (Tiewsoh 2021)Local: Hypersensitivity at injection site (including fixed drug eruption at injection site) (Sadoghi 2021)Nervous system: Cerebrovascular accident (Morgan 2011), encephalopathy (Teshima 2021), seizure (Dabagh 2020), severe neurotoxicity (Dabagh 2020)Neuromuscular & skeletal: Myelopathy (intrathecal; subacute) (Bidikian 2021)Ophthalmic: Dry eye syndrome, eye irritation (Doroshow 1981), optic neuropathy (Clare 2005)Renal: Acute kidney injury (Gilani 2012, May 2014, Verstappen 2007, Wiczer 2015, Widemann 2004)Respiratory: Acute respiratory distress (Morgan 2011), Mycobacterium avium complex (LeMense 1994), pleural effusion (Whitfield 2020), pleuritic chest pain (Sharma 1999), pneumonia due to Pneumocystis jirovecii (Albrecht 2010; Krebs 1996), tuberculosis (Binymin 2001)ContraindicationsHistory of severe hypersensitivity (including anaphylaxis) to methotrexate or any component of the formulation; breastfeeding (product-specific; refer to manufacturer's labeling).Additional contraindications for patients with psoriasis, rheumatoid arthritis or polyarticular-course juvenile idiopathic arthritis: Pregnancy, alcoholism, alcoholic liver disease or other chronic liver disease, immunodeficiency syndromes (overt or laboratory evidence); preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia).Canadian labeling: Additional contraindications (not in the US labeling): Severe renal impairment (including end-stage renal disease with or without dialysis); females of childbearing potential (until pregnancy is excluded); concomitant use with nitrous oxide anesthesia.Warnings/PrecautionsConcerns related to adverse effects:• Infections: Use methotrexate with extreme caution in patients with an active infection.Disease-related concerns:• Renal impairment: Dosing adjustment may be required.Concurrent drug therapy issues:• Nonsteroidal anti-inflammatory drugs: Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) prior to or during high dose methotrexate therapy; may increase and prolong serum methotrexate levels. Doses used for psoriasis may still lead to unexpected toxicities; use with caution when administering NSAIDs or salicylates with lower doses of methotrexate for rheumatoid arthritis (RA).• Proton pump inhibitors: Concomitant use of proton pump inhibitors with methotrexate (primarily high-dose methotrexate) may elevate and prolong serum methotrexate levels and metabolite (hydroxymethotrexate) levels (based on case reports and pharmaco*kinetic studies). May lead to toxicities; use with caution.• Vaccines: Immunization may be ineffective during methotrexate treatment. Immunization with live vaccines is not recommended; cases of disseminated vaccinia infections due to live vaccines have been reported.• Vitamins: Vitamins containing folate may decrease response to systemic methotrexate (in patients with neoplastic diseases); folate deficiency may increase methotrexate toxicity. Folic acid supplementation may be indicated in patients receiving methotrexate for non-neoplastic conditions.Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.Other warnings/precautions:• Administration schedules: Fatal errors have occurred when methotrexate was administered as a daily dose instead of a weekly dose. Verify the indication before administration; methotrexate is typically only administered daily for an oncology-related indication. The ISMP Targeted Medication Safety Best Practices for Hospitals recommends hospitals use a weekly dosage regimen default for oral methotrexate orders in electronic order entry systems, with a hard stop verification required of appropriate oncology indication for all daily oral methotrexate orders, and provide patient and/or caregiver education for patients discharged on oral methotrexate (ISMP 2020).• Intrathecal safety: When used for intrathecal administration, intrathecal medications should not be prepared during the preparation of any other agents. After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only. Delivery of intrathecal medications to the patient should only be with other medications also intended for administration into the CNS, and administer immediately after a time-out/double-check procedure (ASCO/ONS [Neuss 2016]).• Methotrexate overexposure: Glucarpidase is an enzyme that rapidly hydrolyzes extracellular methotrexate into inactive metabolites, allowing for a rapid reduction of methotrexate concentrations. Glucarpidase may be used for methotrexate overexposure; it is approved for the treatment of toxic plasma methotrexate concentrations (>1 micromole/L) in patients with delayed clearance due to renal impairment. Refer to Glucarpidase monograph.Metabolism/Transport EffectsSubstrate of BCRP/ABCG2, OAT1/3, OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapyAbrocitinib: May enhance the immunosuppressive effect of Methotrexate. Risk X: Avoid combinationAcitretin: May enhance the hepatotoxic effect of Methotrexate. Risk X: Avoid combinationAlcohol (Ethyl): May enhance the hepatotoxic effect of Methotrexate. Management: Limit alcohol consumption in patients taking methotrexate. The use of methotrexate for the treatment of psoriasis or rheumatoid arthritis is contraindicated in patients with alcoholism or alcoholic liver disease. Risk D: Consider therapy modificationAlitretinoin (Systemic): May enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapyAminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).Risk X: Avoid combinationAminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).Risk C: Monitor therapyBaricitinib: Methotrexate may enhance the immunosuppressive effect of Baricitinib.Management: Concomitant use of baricitinib with high-dose or IV methotrexate is not recommended. Use with antirheumatic doses of methotrexate is permitted, and if combined, patients should be monitored for infection. Risk D: Consider therapy modificationBCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).Risk X: Avoid combinationBCG Products: Methotrexate may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of BCG Products.Risk X: Avoid combinationBile Acid Sequestrants: May decrease the absorption of Methotrexate. Risk C: Monitor therapyBrincidofovir: Methotrexate may diminish the therapeutic effect of Brincidofovir.Risk C: Monitor therapyCephalothin: May diminish the therapeutic effect of Methotrexate. Risk C: Monitor therapyChloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapyCiprofloxacin (Systemic): May increase the serum concentration of Methotrexate. Risk C: Monitor therapyCladribine: Methotrexate may enhance the immunosuppressive effect of Cladribine.Risk X: Avoid combinationCloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.Risk C: Monitor therapyCoccidioides immitis Skin Test: Methotrexate may diminish the diagnostic effect of Coccidioides immitis Skin Test.Management: Consider discontinuing methotrexate several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modificationCola-Containing Drinks: May increase the serum concentration of Methotrexate. Risk C: Monitor therapyCOVID-19 Vaccines: Methotrexate may diminish the therapeutic effect of COVID-19 Vaccines.Management: Rheumatology guidelines recommend holding methotrexate for 1 to 2 weeks after vaccine administration as permitted by underlying disease. This is specific to patients using methotrexate for rheumatic and musculoskeletal disease. Risk D: Consider therapy modificationCycloSPORINE (Systemic): May increase the serum concentration of Methotrexate. This may result in nausea, vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Methotrexate may increase the serum concentration of CycloSPORINE (Systemic). This may result in nephrotoxicity. Risk C: Monitor therapyDapsone (Systemic): May increase the serum concentration of Methotrexate. Management: Avoid coadministration of dapsone and methotrexate if possible. If coadministration is required, monitor closely for methotrexate toxicities (eg, hematological, gastrointestinal, nephrotoxicity toxicities). Risk D: Consider therapy modificationDeferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone.Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modificationDengue Tetravalent Vaccine (Live): Methotrexate may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live).Risk X: Avoid combinationDenosumab: May enhance the immunosuppressive effect of Methotrexate. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants, such as methotrexate. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modificationDeucravacitinib: May enhance the immunosuppressive effect of Methotrexate. Risk X: Avoid combinationDexketoprofen: May increase the serum concentration of Methotrexate. Management: Concurrent use of dexketoprofen with methotrexate doses of 15 mg/week or more is inadvisable.Use with lower methotrexate doses should only be performed with caution and increased monitoring. Risk D: Consider therapy modificationDichlorphenamide: May increase the serum concentration of Methotrexate. Risk X: Avoid combinationDiethylamine Salicylate: May increase the serum concentration of Methotrexate. Risk C: Monitor therapyDipyrone: Methotrexate may enhance the adverse/toxic effect of Dipyrone. Specifically, the risk for agranulocytosis and pancytopenia may be increased. Dipyrone may enhance the adverse/toxic effect of Methotrexate.Risk X: Avoid combinationFebuxostat: May enhance the adverse/toxic effect of Methotrexate. Risk C: Monitor therapyFexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole.Risk X: Avoid combinationFilgotinib: Methotrexate may enhance the immunosuppressive effect of Filgotinib.Management: Concomitant use of filgotinib with high-dose or IV methotrexate is not recommended. Use with antirheumatic doses of methotrexate is permitted. Risk X: Avoid combinationFoscarnet: May enhance the nephrotoxic effect of Methotrexate. Risk X: Avoid combinationFosphenytoin-Phenytoin: Methotrexate may decrease the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase the serum concentration of Methotrexate. Specifically, fosphenytoin-phenytoin may displace methotrexate from serum proteins, increasing the concentration of free, unbound drug.Risk C: Monitor therapyIbrutinib: May increase the serum concentration of Methotrexate. Risk C: Monitor therapyInebilizumab: Methotrexate may enhance the immunosuppressive effect of Inebilizumab.Risk C: Monitor therapyInfluenza Virus Vaccines: Methotrexate may diminish the therapeutic effect of Influenza Virus Vaccines.Management: Administer influenza vaccines at least 2 weeks prior to initiating methotrexate if possible. If vaccination occurs less than 2 weeks prior to or during methotrexate therapy, revaccinate 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modificationInhibitors of the Proton Pump (PPIs and PCABs): May increase the serum concentration of Methotrexate. Management: Consider temporarily interrupting PPI or PCAB therapy in patients receiving high-dose methotrexate. If coadministered, monitor for increased methotrexate toxicity (eg, mucositis, myalgias) and/or delayed methotrexate elimination. Risk D: Consider therapy modificationLeflunomide: Methotrexate may enhance the adverse/toxic effect of Leflunomide. Specifically, the risks of hepatoxicity and hematologic toxicity may be increased.Management: If leflunomide is coadministered with methotrexate, initiate leflunomide 20 mg once daily without use of a loading dose. Monitor for methotrexate-induced hepatic toxicity frequently (see monograph for details) and monitor blood counts monthly. Risk D: Consider therapy modificationLenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim.Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modificationLevETIRAcetam: May increase the serum concentration of Methotrexate. Risk C: Monitor therapyLipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim.Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modificationLoop Diuretics: Methotrexate may diminish the therapeutic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Methotrexate. Methotrexate may increase the serum concentration of Loop Diuretics.Risk C: Monitor therapyMercaptopurine: Methotrexate may increase the serum concentration of Mercaptopurine. Conversely, intracellular concentrations of thioguanine nucleotides may be decreased with the combination.Risk C: Monitor therapyMethoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic).Risk C: Monitor therapyMipomersen: May enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapyNatalizumab: Methotrexate may enhance the immunosuppressive effect of Natalizumab.Risk X: Avoid combinationNeomycin (Systemic): May decrease the serum concentration of Methotrexate. Neomycin (Systemic) may increase the serum concentration of Methotrexate. Risk C: Monitor therapyNitisinone: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapyNitrous Oxide: May enhance the adverse/toxic effect of Methotrexate. Risk X: Avoid combinationNonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Methotrexate. Management: Avoid coadministration of higher dose methotrexate (such as that used for the treatment of oncologic conditions) and NSAIDs. Use caution if coadministering lower dose methotrexate and NSAIDs. Risk D: Consider therapy modificationNonsteroidal Anti-Inflammatory Agents (Topical): May increase the serum concentration of Methotrexate. Risk C: Monitor therapyOcrelizumab: Methotrexate may enhance the immunosuppressive effect of Ocrelizumab.Risk C: Monitor therapyOfatumumab: Methotrexate may enhance the immunosuppressive effect of Ofatumumab.Risk C: Monitor therapyOlaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib.Risk C: Monitor therapyPalifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oralmucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modificationPEMEtrexed: May increase the serum concentration of Methotrexate. Management: Avoid coadministration of pemetrexed and methotrexate if possible. If coadministration is required, monitor closely for methotrexate toxicities (eg, hematological, gastrointestinal, nephrotoxicity toxicities). Risk D: Consider therapy modificationPenicillins: May increase the serum concentration of Methotrexate. Risk C: Monitor therapyPidotimod: Methotrexate may diminish the therapeutic effect of Pidotimod.Risk C: Monitor therapyPimecrolimus: May enhance the immunosuppressive effect of Methotrexate. Risk X: Avoid combinationPneumococcal Vaccines: Methotrexate may diminish the therapeutic effect of Pneumococcal Vaccines.Risk C: Monitor therapyPoliovirus Vaccine (Live/Trivalent/Oral): Methotrexate may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral).Risk X: Avoid combinationPolymethylmethacrylate: Methotrexate may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate.Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving methotrexate. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modificationPorfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer.Risk C: Monitor therapyPretomanid: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapyProbenecid: May increase the serum concentration of Methotrexate. Management: If possible, the concomitant use of methotrexate and probenecid should be avoided. If used concomitantly, monitor closely for increased methotrexate serum concentrations and toxicities. Methotrexate dose reductions may be needed. Risk D: Consider therapy modificationPromazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapyPyrimethamine: May enhance the adverse/toxic effect of Methotrexate. Risk C: Monitor therapyRabies Vaccine: Methotrexate may diminish the therapeutic effect of Rabies Vaccine.Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modificationRopeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b.Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modificationRubella- or Varicella-Containing Live Vaccines: Methotrexate may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines.Risk X: Avoid combinationRuxolitinib (Topical): Methotrexate may enhance the immunosuppressive effect of Ruxolitinib (Topical).Risk X: Avoid combinationSalicylates: May increase the serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Management: Consider avoiding coadministration of methotrexate and salicylates. If coadministration cannot be avoided, monitor for increased toxic effects of methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Risk D: Consider therapy modificationSapropterin: Methotrexate may decrease the serum concentration of Sapropterin. Specifically, methotrexate may decrease tissue concentrations of tetrahydrobiopterin.Risk C: Monitor therapySipuleucel-T: Methotrexate may diminish the therapeutic effect of Sipuleucel-T.Management: Consider reducing the dose or discontinuing the use of methotrexate prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modificationSphingosine 1-Phosphate (S1P) Receptor Modulator: Methotrexate may enhance the immunosuppressive effect of Sphingosine 1-Phosphate (S1P) Receptor Modulator.Risk C: Monitor therapySulfaSALAzine: May enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapySulfonamide Antibiotics: May enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and therapeutic doses of sulfonamides (eg, trimethoprim/sulfamethoxazole). Patients receiving prophylactic doses of trimethoprim/sulfamethoxazole and methotrexate should be carefully monitored. Risk D: Consider therapy modificationTacrolimus (Topical): Methotrexate may enhance the immunosuppressive effect of Tacrolimus (Topical).Risk X: Avoid combinationTafamidis: May increase the serum concentration of Methotrexate. Risk C: Monitor therapyTalimogene Laherparepvec: Methotrexate may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased.Risk X: Avoid combinationTaurursodiol: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk X: Avoid combinationTegafur: Methotrexate may enhance the adverse/toxic effect of Tegafur.Risk C: Monitor therapyTeriflunomide: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapyTertomotide: Methotrexate may diminish the therapeutic effect of Tertomotide.Risk X: Avoid combinationTheophylline Derivatives: Methotrexate may increase the serum concentration of Theophylline Derivatives.Risk C: Monitor therapyTofacitinib: Methotrexate may enhance the immunosuppressive effect of Tofacitinib.Management: Concomitant use of tofacitinib with high-dose or IV methotrexate is not recommended. Use with antirheumatic doses of methotrexate is permitted, and if combined, patients should be monitored for infection. Risk D: Consider therapy modificationTrimethoprim: May enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and either sulfamethoxazole or trimethoprim. If used concomitantly, monitor for the development of signs and symptoms of methotrexate toxicity (e.g., bone marrow suppression). Risk D: Consider therapy modificationTyphoid Vaccine: Methotrexate may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of Typhoid Vaccine.Risk X: Avoid combinationUpadacitinib: Methotrexate may enhance the immunosuppressive effect of Upadacitinib.Management: Concomitant use of upadacitinib with high-dose or IV methotrexate is not recommended. Use with antirheumatic doses of methotrexate is permitted, and if combined, patients should be monitored for infection. Risk D: Consider therapy modificationVaccines (Inactivated/Non-Replicating): Methotrexate may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating).Management: Administer vaccines at least 2 weeks prior to methotrexate initiation, if possible. If patients are vaccinated less than 14 days prior to or during methotrexate therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationVaccines (Live): Methotrexate may enhance the adverse/toxic effect of Vaccines (Live). Methotrexate may diminish the therapeutic effect of Vaccines (Live).Management: Low-dose methotrexate (0.4 mg/kg/week or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns. Higher doses of methotrexate should be avoided. Risk D: Consider therapy modificationValproate Products: Methotrexate may decrease the serum concentration of Valproate Products.Risk C: Monitor therapyVerteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin.Risk C: Monitor therapyVoriconazole: Methotrexate may enhance the photosensitizing effect of Voriconazole.Risk C: Monitor therapyYellow Fever Vaccine: Methotrexate may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of Yellow Fever Vaccine.Risk X: Avoid combinationFood InteractionsMethotrexate peak serum levels may be decreased if taken with food. Management: Administer without regard to food.Dietary ConsiderationsSome products may contain sodium.Reproductive ConsiderationsVerify the pregnancy status of patients who could become pregnant prior to initiating therapy. Effective contraception is recommended for patients who may become pregnant during therapy and for at least 6 months after the final methotrexate dose. Effective contraception is recommended for patients with partners who may become pregnant during therapy and for at least 3 months after the final dose of methotrexate. Patients treated with methotrexate for gestational trophoblastic diseases should use reliable contraception during therapy and throughout the follow-up period (SOGC [Eiriksson 2021]).Patients treated for inflammatory bowel disease, psoriasis, or rheumatic and musculoskeletal diseases should discontinue methotrexate at least 3 months prior to becoming pregnant (ACR [Sammaritano 2020]; Mahadevan 2019; Rademaker 2018). Because methotrexate can cause embryo-fetal toxicity, including fetal death, use is contraindicated during pregnancy in patients with non-neoplastic diseases.When methotrexate is used for the treatment of rheumatic and musculoskeletal diseases in patients undergoing ovarian stimulation for oocyte retrieval or embryo cryopreservation, methotrexate may be continued in patients whose rheumatic or musculoskeletal condition is stable and discontinuation of treatment may lead to uncontrolled disease (ACR [Sammaritano 2020]).The use of methotrexate may impair fertility and cause menstrual irregularities or oligospermia during treatment and following therapy. It is not known if infertility may be reversed in all affected patients. When used for the medical management of ectopic pregnancy, methotrexate has not been shown to adversely affect fertility or ovarian reserve. Future pregnancies should be delayed until resolution of the ectopic pregnancy has been confirmed and at least 3 months after the last methotrexate dose (ACOG 2018).Use of methotrexate may be considered for patients with rheumatic and musculoskeletal diseases or psoriasis who are planning to father a child (recommendation based on limited human data) (ACR [Sammaritano 2020]; Lamb 2019; Rademaker 2018).Pregnancy ConsiderationsMethotrexate crosses the placenta (Schleuning 1987).Following exposure during the first trimester, methotrexate may increase the risk of spontaneous abortion, skull anomalies, facial dysmorphism, CNS, limb and cardiac abnormalities; intellectual impairment may also occur. Intrauterine growth restriction and functional abnormalities may occur following second or third trimester exposure.Consider the benefits and risks of methotrexate and risks to the fetus when prescribing methotrexate to a pregnant patient with a neoplastic disease. Methotrexate is approved for the treatment of trophoblastic neoplasms (gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole). The use of methotrexate for the treatment of rheumatoid arthritis, polyarticular-course juvenile idiopathic arthritis, and psoriasis is contraindicated in pregnancy.Methotrexate is recommended for the medical management of tubal ectopic pregnancy in appropriately selected patients. Intrauterine pregnancy should be excluded prior to methotrexate use. Various protocols are available; the choice should consider the initial hCG level and the risks and benefits of methotrexate treatment to the individual patient (ACOG 2018). Methotrexate administered by intra-gestational injection with or without systemic methotrexate or other treatments is recommended for the management of cesarean scar pregnancies; however, various protocols have been described and the optimal regimen is not known. Use of systemic methotrexate alone is not recommended for the treatment of cesarean scar pregnancy (Liu 2020; Salari 2020; SOGC [Miller 2020]). Use of methotrexate for other nontubal ectopic pregnancies (eg, cervical or abdominal) has been described; however, data are insufficient to make specific dosing recommendations (RCOG [Elson 2016]; SOGC [Po 2021]).Methotrexate has been used for the medical termination of intrauterine pregnancy with a gestational age up to 49 days when misoprostol/mifepristone is not available or contraindications to that combination are present. A regimen containing methotrexate should not be used in patients with hemoglobin <9.5 g/dL, intrauterine device in place, diagnosis of inflammatory bowel disease, active hepatic or renal disease, hemorrhagic disorders, or concomitant use of anticoagulation therapy (Creinin 1996; SOGC [Costescu 2016]; Stubblefield 2004).Monitoring ParametersLaboratory tests should be performed on day 5 or day 6 of the weekly methotrexate cycle (eg, psoriasis, RA, JIA) to detect the leukopenia nadir and to avoid elevated LFTs 1 to 2 days after taking dose.Indication-specific recommendations: Note: Additional recommendations may vary based upon patient age and specific protocols (refer to specific references); for all pediatric patients receiving long-term therapy (ie, chronic disease), growth parameters should also be monitored.Psoriasis: CBC with differential and platelets (baseline, 7 to 14 days after initiating therapy or dosage increase, every 2 to 4 weeks for first few months, then every 1 to 3 months); BUN and serum creatinine (baseline and every 2 to 3 months); consider PPD for latent TB screening (baseline); LFTs (baseline, monthly for first 6 months, then every 1 to 2 months); chest x-ray (baseline if underlying lung disease); pulmonary function test (if methotrexate-induced lung disease suspected).Liver biopsy:Patients with risk factors for hepatotoxicity: Baseline or after 2 to 6 months of therapy and with each 1 to 1.5 g cumulative dose interval in adults.Patients without risk factors for hepatotoxicity: If persistent elevations in 5 of 9 AST levels during a 12-month period, or decline of serum albumin below the normal range with normal nutritional status. In adults, consider biopsy after cumulative dose of 3.5 to 4 g and after each additional 1.5 g.Juvenile idiopathic arthritis: Children and Adolescents: PPD screening (baseline and annually); CBC with differential and platelets, C-reactive protein, ESR, ferritin, and LDH [baseline, at follow-up visits (1 to 2 weeks, 1, 2, 6, and 9 months] and with any treatment change (DeWitt 2012). Also based on adult recommendations in RA, consider serum creatinine and LFTs (baseline then every 2 to 4 weeks for initial 3 months of therapy, then every 8 to 12 weeks for 3 to 6 months of therapy and then every 12 weeks after 6 months of therapy) and liver biopsy: Baseline (if persistent abnormal baseline LFTs, history of alcoholism, or chronic hepatitis B or C) or during treatment if persistent LFT elevations (6 of 12 tests abnormal over 1 year or 5 of 9 results when LFTs performed at 6-week intervals).Rheumatoid arthritis:CBC with differential and platelets, serum creatinine and LFTs (baseline, then every 2 to 4 weeks for initial 3 months of therapy, then every 8 to 12 weeks for 3 to 6 months of therapy and then every 12 weeks after 6 months of therapy); chest x-ray (baseline); pulmonary function test (if methotrexate-induced lung disease suspected); hepatitis B or C testing (baseline).Liver biopsy: Baseline (if persistent abnormal baseline LFTs, history of alcoholism, or chronic hepatitis B or C) or during treatment if persistent LFT elevations (6 of 12 tests abnormal over 1 year or 5 of 9 results when LFTs performed at 6-week intervals).Cancer: Baseline and frequently during treatment: CBC with differential and platelets, serum creatinine, BUN, LFTs; chest x-ray (baseline); serum methotrexate concentrations and urine pH (with high-dose therapy); pulmonary function test (if methotrexate-induced lung disease suspected).Crohn disease:Children and Adolescents: In pediatric trials, frequency of monitoring varied with study protocol and duration; may vary based on clinical status and concurrent medication; consider the following: CBC with differential and platelets, LFTs, C-reactive protein, and ESR (baseline, then every 2 to 4 weeks during initial 8 to 12 weeks of therapy, then every 4 to 12 weeks while on therapy); chest x-ray and PFTs (annually) (Mack 1998; Sandhu 2010; Turner 2007; Weiss 2009). Also, based on adult recommendations for Crohn disease, consider serum creatinine (baseline, then every 2 to 4 weeks for initial 3 months of therapy, then every 8 to 12 weeks for 3 to 6 months of therapy and then every 12 weeks after 6 months of therapy), hepatitis B or C testing (baseline) and liver biopsy: Baseline (if persistent abnormal baseline LFTs, history of alcoholism, or chronic hepatitis B or C) or during treatment if persistent LFT elevations (6 of 12 tests abnormal over 1 year or 5 of 9 results when LFTs performed at 6-week intervals).Adults: CBC with differential and platelets, serum creatinine and LFTs (baseline then every 2 to 4 weeks for initial 3 months of therapy, then every 8 to 12 weeks for 3 to 6 months of therapy and then every 12 weeks after 6 months of therapy); chest x-ray (baseline); pulmonary function test (if methotrexate-induced lung disease suspected); hepatitis B or C testing (baseline) and liver biopsy: Baseline (if persistent abnormal baseline LFTs, history of alcoholism, or chronic hepatitis B or C) or during treatment if persistent LFT elevations (6 of 12 tests abnormal over 1 year or 5 of 9 results when LFTs performed at 6-week intervals).Ectopic pregnancy: Prior to therapy, measure serum hCG, CBC with differential, liver function tests, serum creatinine. Serum hCG concentrations should decrease between treatment days 4 and 7. If hCG decreases by >15%, additional courses are not needed; however, continue to measure hCG weekly until no longer detectable. If <15% decrease is observed, repeat dose per regimen (Barnhart 2009).Reference RangeTherapeutic levels: Variable; toxic concentration: Variable; therapeutic range is dependent upon therapeutic approach. Note: 0.1 micromole/L = 100 nanomole/L.High-dose regimens produce drug levels that are between 0.1 to 1 micromole/L 24 to 72 hours after drug infusion.Toxic: Low-dose therapy: >0.2 micromole/L; high-dose therapy: >1 micromole/L.Mechanism of ActionMethotrexate is a folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication. Methotrexate binds to and inhibits dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis, thus interfering with DNA synthesis, repair, and cellular replication. Methotrexate is cell cycle specific for the S phase of the cycle. Actively proliferative tissues are more susceptible to the effects of methotrexate.The mechanism in the treatment of rheumatoid arthritis and polyarticular-course juvenile idiopathic arthritis is unknown, but may affect immune function. In psoriasis, methotrexate is thought to target rapidly proliferating epithelial cells in the skin.In Crohn disease, it may have immune modulator and anti-inflammatory activity.Pharmaco*kinetics (Adult data unless noted)Onset of action: Antirheumatic: 3 to 6 weeks; additional improvement may continue longer than 12 weeks.Absorption:Oral: Highly variable; dose dependent; decreased absorption at higher doses (pediatric patients: >40 mg/m2; adult patients: >80 mg/m2); possibly due to saturation effect.IM injection: Complete.Distribution: Penetrates slowly into third space fluids (eg, pleural effusions, ascites), exits slowly from these compartments (slower than from plasma); sustained concentrations retained in kidney and liver.Vd: IV: 0.18 L/kg (initial); 0.4 to 0.8 L/kg (steady state).Protein binding: ~50%.Metabolism: Partially metabolized by intestinal flora (after oral administration) to DAMPA by carboxypeptidase; hepatic aldehyde oxidase converts methotrexate to 7-hydroxy methotrexate; polyglutamates are produced intracellularly and are just as potent as methotrexate; their production is dose- and duration-dependent and they are slowly eliminated by the cell once formed. Polyglutamated forms can be converted back to methotrexate.Bioavailability: Oral: Children: Highly variable: 23% to 95%; Adults: Low doses (≤30 mg/m2): ~60%; in general, bioavailability is dose dependent and decreases as the dose increases (especially at doses >80 mg/m2 [>40 mg/m2 in pediatric patients]).Half-life elimination:Children: ALL: 0.7 to 5.8 hours (dose range: 6.3 to 30 mg/m2); pJIA: 0.9 to 2.3 hours (dose range: 3.75 to 26.2 mg/m2).Adults: Low dose (oral): 3 to 10 hours; High dose (IV): 8 to 15 hours.Time to peak, serum: Oral: Children: 0.7 to 4 hours (reported for a 15 mg/m2 dose); Adults: 0.75 to 6 hours; IM: Children and Adults: 30 to 60 minutes.Excretion: Dose and route dependent; IV: Urine (80% to 90% as unchanged drug; 5% to 7% as 7-hydroxy methotrexate); feces (≤10%).Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: An increase in serum levels occurs because of decreased elimination in patients with renal function impairment.Extemporaneous PreparationsTo prepare a 2 mg/mL methotrexate oral solution, first prepare a stock diluent solution by mixing 250 mL of 0.05% saccharin in cherry-flavored glycol or aqueous base, add sodium bicarbonate 20 g, then add a sufficient quantity of chloroform water solution to a final volume of 1,000 mL. Chloroform water solution may be prepared with 2.5 mL of pharmaceutical-grade chloroform added to 997.5 mL of distilled water. Prepare the 2 mg/mL methotrexate oral solution using 1.6 mL of 25 mg/mL methotrexate injection (preservative free) and add to 18.4 mL of stock diluent solution. The methotrexate 2 mg/mL oral solution is stable for 1 month at room temperature or refrigerated in clear or amber glass storage bottles.Lam MS. Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. Pharmacotherapy. 2011;31(2):164-192.Pricing: USSolution (Methotrexate Sodium (PF) Injection)1 g/40mL (per mL): $1.00 - $1.1050 mg/2 mL (per mL): $2.02 - $6.21250 mg/10 mL (per mL): $1.08 - $1.14Solution (Methotrexate Sodium Injection)50 mg/2 mL (per mL): $4.36250 mg/10 mL (per mL): $4.03Solution (Xatmep Oral)2.5 mg/mL (per mL): $21.14Solution (reconstituted) (Methotrexate Sodium Injection)1 g (per each): $54.00 - $76.32Solution Auto-injector (Otrexup Subcutaneous)10 mg/0.4 mL (per 0.4 mL): $206.4412.5 mg/0.4 mL (per 0.4 mL): $206.4415 mg/0.4 mL (per 0.4 mL): $206.4417.5 mg/0.4 mL (per 0.4 mL): $206.4420 mg/0.4 mL (per 0.4 mL): $206.4422.5 mg/0.4 mL (per 0.4 mL): $206.4425 mg/0.4 mL (per 0.4 mL): $206.44Solution Auto-injector (Rasuvo Subcutaneous)7.5 mg/0.15 mL (per 0.15 mL): $157.5010 mg/0.2 mL (per 0.2 mL): $157.5012.5 mg/0.25 mL (per 0.25 mL): $157.5015 mg/0.3 mL (per 0.3 mL): $157.5017.5 mg/0.35ml (per 0.35 mL): $157.5020 mg/0.4 mL (per 0.4 mL): $157.5022.5 mg/0.45ml (per 0.45 mL): $157.5025 mg/0.5 mL (per 0.5 mL): $157.5030 mg/0.6 mL (per 0.6 mL): $157.50Solution Prefilled Syringe (RediTrex Subcutaneous)7.5 mg/0.3 mL (per 0.3 mL): $93.7510 mg/0.4 mL (per 0.4 mL): $93.7512.5 mg/0.5 mL (per 0.5 mL): $93.7515 mg/0.6 mL (per 0.6 mL): $93.7517.5 mg/0.7 mL (per 0.7 mL): $93.7520 mg/0.8 mL (per 0.8 mL): $93.7522.5 mg/0.9 mL (per 0.9 mL): $93.7525 mg/mL (per mL): $93.75Tablets (Methotrexate Oral)2.5 mg (per each): $3.56 - $6.24Tablets (Methotrexate Sodium Oral)2.5 mg (per each): $3.56 - $4.05Tablets (Trexall Oral)5 mg (per each): $21.147.5 mg (per each): $31.7110 mg (per each): $42.2815 mg (per each): $63.42Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAbitrexate (IL, SG, TH, ZA, ZW);Alltrex (LK, PH);Artrait (AR, PE);Atrexel (MX);Bertanel (ES);Biotrexate (IN);Brimexate (IT);Canceren (KR);Cytotrex (LK);Ebetrex (LV, SE);Ebetrexat (AE, AT, BG, LB);Ebetrexate (BE);Emthexat (SE);Emthexate (AT, BE, GR, HK, ID, JO, KW, MY, NL, PH, PK, PT, TH, TR, ZA);Emthexate PF (EG, KR);Emthrxate (SI);Ervemin (AR);Hytas (BR);Imutrex (LK);Jylamvo (BE);Lantarel (DE);Ledertrexate (BE, FR, LU, MX, NZ);Ledertrexato (PT);Maxtrex (GB);Medsatrexate (MX);Meisusheng (CN);Merox-50 (ET);Metex (LV, NO, PT);Methaccord (AU);Methacor (ZA);Methoblastin (AU, NZ);Methocip (EG);Methofill (IE);Methotrexat (HR);Methotrexat Bigmar (CH);Methotrexat Ebewe (HU);Methotrexat Farmos (CH);Methotrexat Lachema (HU);Methotrexat Lederle (CH);Methotrexat Teva (CH);Methotrexate (HK, ID, MY, PH, TH);Methotrexate Faulding (SE);Methotrexate Pharmacia (SE);Methotrexate Wyeth Lederle (SE);Methotrexate ”Lederle” (HU);Methotrexate[inj.] (HR, IT);Methotrexato (EC);Methox (BD);Methtrexx (CH);Metoject (CH, CZ, DK, ES, FR, HU, IE, IL, LB, RO, RU, SE, SK, UA);Metotreksat (HR);Metotressato Teva (IT);Metotrexato (CL);Metotrexato DBL (IT);Metrex (LK, PY);Mexat (CO);Midu (CN);Mtrex (BD);MTX (EG);MTX Hexal (LU);Neotrexate (IN);Nordimet (CH);Novatrex (FR);Onkomet (TH);Otaxem (MX);P&U Methotrexate (ZA);Pterin (PH);Quinux (ES);Reumaflex (IT);Reumatrex (PE);Rheu-Trex (ID);Rheumatrex (JP);Sactiva (IT);Sanotrexat (ID);Securact (IT);Tasxate (TH);Texate (MX);Trexan (CZ, EE, FI, HN, HU, LT, PL, SG, TR, TW);Trexate (NZ);Trexject (AU);Trexol (LK);Trexonate (BD);Trexxol (ET);Trixilem (MX, TH);Unitrexates (VN);Xantromid (PY);Zexat (RU);Zexate (ET, PH, UY, VE, VN, ZW);Zlatel (GB)For country code abbreviations (show table)<800> Hazardous Drugs–Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). Rockville, MD: United States Pharmacopeia Convention; 2020:74-92.Adès L, Sanz MA, Chevret S, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008;111(3):1078-1084. [PubMed 17975017]Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]AlEssa RK, AlJasser MI. Methotrexate-associated reduced libido: a case report and review of the literature. Clin Exp Dermatol. 2021;46(7):1350-1352. doi:10.1111/ced.14745 [PubMed 33998691]Aithal GP, Haugk B, Das S, Card T, Burt AD, Record CO. Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified? Aliment Pharmacol Ther. 2004;19(4):391-399. doi:10.1046/j.1365-2036.2004.01819.x [PubMed 14871278]Ajmani S, Preet Singh Y, Prasad S, et al. 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CloseLevofloxacin (systemic): Drug informationLevofloxacin (systemic): Drug information(For additional information see "Levofloxacin (systemic): Patient drug information" and see "Levofloxacin (systemic): Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningSerious adverse reactions:Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together, including tendinitis and tendon rupture, peripheral neuropathy, and CNS effects. Discontinue levofloxacin immediately and avoid the use of fluoroquinolones in patients who experience any of these serious adverse reactions. Because fluoroquinolones have been associated with serious adverse reactions, reserve levofloxacin for use in patients who have no alternative treatment options for the following indications: uncomplicated urinary tract infection, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis.Exacerbation of myasthenia gravis:Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis.Brand Names: USLevaquin [DSC]Brand Names: CanadaACT Levofloxacin;APO-Levofloxacin;MINT-Levofloxacin;RIVA-Levofloxacin;SANDOZ Levofloxacin;TEVA-Levofloxacin [DSC]Pharmacologic CategoryAntibiotic, Fluoroquinolone;Antibiotic, Respiratory FluoroquinoloneDosing: AdultAnthraxAnthrax: Note: Consult public health officials for event-specific recommendations.Inhalational exposure (postexposure prophylaxis [PEP]) (alternative agent):Oral: 750 mg every 24 hours for 42 to 60 days.Note: Anthrax vaccine should also be administered to exposed individuals (Ref). Duration of therapy: If the PEP anthrax vaccine series is administered on schedule (for all regimens), antibiotics may be discontinued in immunocompetent adults aged 18 to 65 years at 42 days after initiation of vaccine or 2 weeks after the last dose of the vaccine (whichever comes last and not to exceed 60 days); if the vaccination series cannot be completed, antibiotics should continue for 60 days (Ref). In addition, adults with immunocompromising conditions or receiving immunosuppressive therapy, patients >65 years of age, and patients who are pregnant or breastfeeding should receive antibiotics for 60 days (Ref).Cutaneous (without systemic involvement), treatment (off-label use):Oral: 750 mg every 24 hours for 7 to 10 days after naturally acquired infection; treat for 60 days for bioterrorism-related cases. Note: Patients with cutaneous lesions of the head or neck or extensive edema should be treated for systemic involvement (Ref).Systemic (meningitis excluded), treatment (alternative agent) (off-label use):IV: 750 mg every 24 hours, in combination with other appropriate agents for 2 weeks or until clinically stable, whichever is longer (Ref).Meningitis, treatment (alternative agent) (off-label use):IV: 750 mg every 24 hours, in combination with other appropriate agents for 2 to 3 weeks or until clinically stable, whichever is longer (Ref).Note: Antitoxin should also be administered for patients with suspected systemic anthrax. Following the course of IV combination therapy for systemic anthrax infection (including meningitis), patients exposed to aerosolized spores require oral monotherapy to complete a total antimicrobial course of 60 days (Ref).Bite wound infection, prophylaxis or treatmentBite wound infection, prophylaxis or treatment (animal or human bite) (alternative agent) (off-label use):Oral, IV: 750 mg once daily, in combination with an agent appropriate for anaerobes. Duration of therapy is 3 to 5 days for prophylaxis (Ref); duration of treatment for established infection is typically 5 to 14 days and varies based on patient-specific factors, including clinical response (Ref).Chronic obstructive pulmonary disease, acute exacerbationChronic obstructive pulmonary disease, acute exacerbation: Note: Some experts reserve for outpatients with risk factors for poor outcomes (eg, ≥65 years of age, FEV1 <50% predicted, frequent exacerbations, significant comorbidities) or for inpatients without risk factors for Pseudomonas infection (Ref).Oral, IV: 500 mg once daily (Ref) for 5 to 7 days (Ref); use 750 mg once daily if P. aeruginosa is suspected (Ref).Diabetic foot infectionDiabetic foot infection (off-label use):Note: When used as empiric therapy, levofloxacin should be used in combination with other appropriate agents.Mild to moderate infection: Oral: 500 mg every 24 hours (750 mg every 24 hours if P. aeruginosa is suspected) (Ref).Moderate to severe infection (alternative agent): IV: 750 mg every 24 hours (Ref).Helicobacter pylori eradicationHelicobacter pylori eradication (salvage regimen) (off-label use):Note: Reserve use for levofloxacin susceptible isolates or if the population resistance rate is <15% (Ref).Levofloxacin triple regimen: Oral: Levofloxacin 500 mg once daily, in combination with amoxicillin 750 mg 3 times daily, plus a double-dose proton pump inhibitor twice daily; continue regimen for 14 days (Ref).Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failureIntra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure (off-label use):Note: Empiric oral regimens may be appropriate for patients with mild to moderate infection. Other patients may be switched from IV to oral therapy when clinically improved and able to tolerate an oral diet (Ref).Cholecystitis, acute: IV, Oral: 750 mg once daily (Ref); continue for 1 day after gallbladder removal or until clinical resolution in patients managed nonoperatively (Ref). Note: The addition of anaerobic therapy (eg, metronidazole) is recommended if biliary-enteric anastomosis is present (Ref).Other intra-abdominal infections (eg, perforated appendix, diverticulitis, intra-abdominal abscess): Note: For acute diverticulitis, some experts suggest deferring antibiotics in otherwise healthy patients who are immunocompetent with mild disease (Ref).IV, Oral: 750 mg once daily in combination with metronidazole. Total duration of therapy (which may include transition to oral antibiotics) is 4 to 5 days following adequate source control (Ref); for diverticulitis or uncomplicated appendicitis managed without intervention, duration is 10 to 14 days (Ref).Neutropenia, antibacterial prophylaxis in high-risk patients anticipated to have an ANC ≤100 cells/mm3 for >7 daysNeutropenia (chemotherapy-induced), antibacterial prophylaxis in high-risk patients anticipated to have an ANC ≤100 cells/mm3 for >7 days (off-label use): Oral: 500 or 750 mg once daily (Ref). Some clinicians will provide antibacterial prophylaxis if ANC is anticipated to be <500 cells/mm3 for >7 days (Ref). For hematopoietic cell transplant recipients, begin at the time of stem cell infusion and continue until recovery of neutropenia or until initiation of empiric antibiotic therapy for neutropenic fever (Ref).Odontogenic soft tissue infection, pyogenicOdontogenic soft tissue infection, pyogenic (alternative agent) (off-label use):Note: For patients unable to take beta-lactams (Chow 2022).IV, Oral: 750 mg once daily in combination with metronidazole; continue until clinical resolution, typically for 7 to 14 days. Use in addition to appropriate surgical management (eg, drainage and/or extraction) (Chow 2022).OsteomyelitisOsteomyelitis (off-label use):Oral, IV: 750 mg once daily for ≥6 weeks (Ref).PlaguePlague (Yersinia pestis): Note: Consult public health officials for event-specific recommendations:Treatment: Oral, IV: 750 mg every 24 hours for 7 to 14 days and for at least a few days after clinical resolution (Ref). For plague meningitis, use as part of an appropriate combination regimen (Ref).Postexposure prophylaxis: Oral: 500 to 750 mg once daily for 7 days; use 750 mg once daily in patients who are pregnant (Ref).PneumoniaPneumonia:Community-acquired pneumonia: Outpatients with comorbidities or inpatients:Note: Some experts reserve fluoroquinolones for patients who cannot take other preferred regimens (Ref).Oral, IV: 750 mg once daily. For inpatients with severe pneumonia or risk factors for methicillin-resistant Staphylococcus aureus, use as part of an appropriate combination regimen. Duration is for a minimum of 5 days; a longer course may be required for patients with an immunocompromising condition, severe or complicated infection, or for P. aeruginosa infection. Patients should be clinically stable with normal vital signs prior to discontinuation (Ref).Hospital-acquired or ventilator-associated pneumonia:Note: For empiric therapy, use in combination with other appropriate agents (Ref).Oral, IV: 750 mg every 24 hours. Duration of therapy varies based on disease severity and response to therapy; treatment is typically given for 7 days (Ref).ProstatitisProstatitis:Acute bacterial prostatitis (off-label use): Oral, IV: 500 mg once daily for 4 to 6 weeks (Ref).Chronic bacterial prostatitis: Oral: 500 mg once daily for 4 to 6 weeks (Ref).Prosthetic joint infectionProsthetic joint infection (off-label use): Treatment:Gram-negative bacilli: Oral, IV: 750 mg once daily (Ref).Staphylococcus aureus, oral continuation therapy (following pathogen-specific IV therapy in patients undergoing 1-stage exchange or debridement with retention of prosthesis): Oral: 500 to 750 mg once daily in combination with rifampin; duration is a minimum of 3 months, depending on patient-specific factors (Ref).Chronic suppressive therapy for gram-negative bacilli: Oral: 500 mg once daily (Ref).Rhinosinusitis, acute bacterialRhinosinusitis, acute bacterial (alternative agent):Note: In uncomplicated acute bacterial rhinosinusitis, initial observation and symptom management without antibiotic therapy is appropriate in most patients. Reserve antibiotic therapy for poor follow-up or lack of improvement over the observation period (Ref). Due to risks associated with use, reserve fluoroquinolones for those who have no alternative treatment options (Ref).Oral: 500 mg or 750 mg once daily for 5 to 7 days (Ref).Salmonella infectionSalmonella (nontyphoidal) infection (alternative agent):GI infection: Oral, IV: 500 mg once daily for 3 to 14 days (7 to 14 days in patients with HIV with a CD4 count ≥200 cells/mm3). Immunosuppressed patients (eg, patients with HIV and CD4 count <200 cells/mm3) require longer duration of treatment (eg, weeks to months) and may require a higher dose (eg, 750 mg once daily). Note: Reserve antibiotic treatment for patients with severe illness or at high risk of invasive disease (eg, extremes of age, immunosuppression); reserve parenteral therapy for those who cannot tolerate oral agents (Ref).Bacteremia: Oral, IV: 500 or 750 mg once daily for 14 days. Note: Immunosuppressed patients (eg, HIV-infected with CD4 count <200 cells/mm3) and those with an extraintestinal focus of infection warrant a longer duration of treatment (eg, weeks to months) (Ref).Sexually transmitted infectionsSexually transmitted infections:Cervicitis/urethritis due to Chlamydia trachomatis (alternative agent) (off-label use): Oral: 500 mg once daily for 7 days (Ref).Epididymitis, acute (off-label use):Patients ≥35 years of age and who are at low risk for sexually transmitted diseases (ie, likely caused by enteric organisms): Oral: 500 mg once daily for 10 days. Note: In patients <35 years of age or who are at risk of sexually transmitted diseases, fluoroquinolones are not recommended due to widespread resistance of N. gonorrhoeae to these agents (Ref).Males of any age who practice insertive anal sex (ie, likely caused by sexually transmitted Chlamydia trachomatis or N. gonorrhoeae, and enteric organisms): Oral: 500 mg once daily for 10 days, in combination with a single dose of ceftriaxone (Ref).Pelvic inflammatory disease, outpatient therapy, mild to moderate disease (alternative agent) (off-label use):Note: Reserve for patients who cannot use first-line options and are at low risk for fluoroquinolone-resistant N. gonorrhoeae (eg, prevalence is <5% in the location where the infection was acquired) (Ref).Oral: 500 mg once daily in combination with metronidazole for 14 days (Ref).Shigella GI infectionShigella GI infection (alternative agent) (off-label use): Note: Use only if ciprofloxacin MIC is <0.12 mcg/mL (Ref).Oral: 500 or 750 mg once daily for 3 days; the duration should be extended to 5 to 7 days for those with S. dysenteriae type 1 infection or HIV coinfection (Ref).Skin and skin structure infectionSkin and skin structure infection:Purulent cellulitis or abscess (for patients with or at risk for gram-negative infection): Oral, IV: 750 mg once daily in combination with other appropriate agents. Treat for 5 to 14 days depending on severity and clinical response. Note: Systemic antibiotics are only indicated for treatment of abscess in certain instances (eg, immunocompromised patients, signs of systemic infection, large or multiple abscesses, indwelling device, high risk for adverse outcome with endocarditis) (Ref).Surgical site incisional infection (off-label use):Intestinal or genitourinary tract surgery: IV: 750 mg every 24 hours in combination with metronidazole (Ref).Perineum or axilla surgery: Oral, IV: 750 mg every 24 hours in combination with metronidazole (Ref).Surgical prophylaxisSurgical (preoperative) prophylaxis (alternative agent) (off-label use):IV: 500 mg beginning 120 minutes prior to initial surgical incision; use in combination with other appropriate agents may be warranted (procedure dependent) (Ref). Note: Postoperative prophylaxis is not recommended for clean and clean-contaminated surgeries (Ref).Tuberculosis, drug-resistantTuberculosis, drug-resistant (off-label use):Oral, IV: 750 mg to 1 g once daily in combination with additional appropriate antituberculosis agents (Ref).Duration: Individualize based on rapidity of culture conversion, extent of disease, and patient-specific factors, including clinical response and toxicity (Ref).Urinary tract infectionUrinary tract infection: Cystitis, acute uncomplicated or acute simple cystitis (infection limited to the bladder without signs/symptoms of upper tract, prostate, or systemic infection) (alternative agent): Note: Use is discouraged due to safety concerns and increasing resistance; reserve for those who have no alternative treatment options (Ref). However, for men who have severe symptoms or concern for early prostate involvement, some experts prefer fluoroquinolones (Ref).Oral: 250 mg once daily for 3 days (females) (Ref) or 5 days (males) (Ref).Urinary tract infection, complicated, (including pyelonephritis): Note: If the prevalence of fluoroquinolone resistance is >10%, an initial dose of a long-acting parenteral antimicrobial (eg, ceftriaxone) followed by oral therapy is recommended for outpatients (Ref).Oral, IV: 750 mg once daily for 5 to 7 days (Ref).Missed dose: Administer as soon as possible if ≥8 hours until next scheduled dose; otherwise, wait until next scheduled dose.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Altered kidney function: Oral, IV:Levofloxacin Dose Adjustments in Altered Kidney FunctionCrCl (mL/minute) If usual recommended dose is 250 mg every 24 hoursIf usual recommended dose is 500 mg every 24 hoursIf usual recommended dose is 750 mg every 24 hoursaaTreatment of tuberculosis: CrCl >30 mL/minute: No dosage adjustment necessary. CrCl <30 mL/minute or on hemodialysis/peritoneal dialysis: Administer 750 mg or 1 g 3 times per week (Ref). Patients receiving hemodialysis 3 times/week: Administer dose after hemodialysis on dialysis days. b Severe infections and GFRCKD-EPI >80 mL/minute/1.73 m2: Monte Carlo simulations suggest a dose of 500 mg every 12 hours may be necessary to obtain pharmacodynamic targets when minimum inhibitory concentration ≥0.5 mg/L (Ref).cWhen scheduled dose falls on a dialysis day, administer post dialysis (Ref).≥50No dosage adjustment necessaryNo dosage adjustment necessaryNo dosage adjustment necessaryb20 to <50No dosage adjustment necessary500 mg initial dose, then 250 mg every 24 hours750 mg every 48 hours<20250 mg every 48 hours (except for uncomplicated UTI, where no dosage adjustment is required)500 mg initial dose, then 250 mg every 48 hours750 mg initial dose, then 500 mg every 48 hoursHemodialysis, intermittent (thrice weekly)c: Dialyzable (21% [4-hour dialysis session utilizing high-flux dialyzers]) (Ref)250 mg every 48 hours (Ref)500 mg initial dose, then either 250 mg every 48 hours (Ref) or 125 mg every 24 hours (Ref) (if daily dosing improves adherence (Ref))750 mg initial dose, then either 500 mg every 48 hours (Ref) or 250 mg every 24 hours (if daily dosing improves adherence (Ref))Peritoneal dialysis250 mg every 48 hours (Ref)500 mg initial dose, then either 250 mg every 48 hours (Ref) or 125 mg every 24 hours (if daily dosing improves adherence [expert opinion derived from Kanamori 2001])750 mg initial dose, then either 500 mg every 48 hours (Ref) or 250 mg every 24 hours (if daily dosing improves adherence (Ref))Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2 ): Augmented renal clearance (ARC) is a condition that occurs in certain critically-ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).Note: Dose based on expert opinion derived from Monte Carlo simulations only (Ref).Oral, IV: 750 mg loading dose followed by 500 mg every 12 hours or 1 g every 24 hours.CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations assume high-flux dialyzers and flow rates of ~1,500 to 3,000 mL/hour, and minimal residual kidney function unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.CVVH/CVVHD/CVVHDF: Oral, IV:Dose Adjustments in CRRT (CVVH/CVVHD/CVVHDF)If usual recommended dose is 250 mg every 24 hours If usual recommended dose is 500 mg every 24 hoursIf usual recommended dose is 750 mg every 24 hoursNo dosage adjustment necessary (Ref)500 mg initial dose, then 250 mg every 24 hours (Ref) or500 mg every 48 hours (Ref)750 mg initial dose, then 500 mg every 24 hours (Ref) or 750 mg every 48 hours (Ref)PIRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.Oral, IV (dialysate flow rate 160 mL/minute, 8-hour session):Dose Adjustments in PIRRTIf usual recommended dose is 250 mg every 24 hours If usual recommended dose is 500 mg every 24 hoursIf usual recommended dose is 750 mg every 24 hoursNo dosage adjustment necessary (Ref)500 mg initial dose, then 250 mg every 24 hours (after PIRRT treatment when possible) (Ref)750 mg every 48 hours (after PIRRT treatment when possible) (Ref)Dosing: Hepatic Impairment: AdultIV, Oral: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). However, dosage adjustment unlikely due to limited hepatic metabolism.Dosing: Pediatric(For additional information see "Levofloxacin (systemic): Pediatric drug information")Note: Concentration of oral suspension may vary (commercially available or extemporaneous compounded); use caution. In pediatric patients, fluoroquinolones are not routinely first-line therapy, but after assessment of risks and benefits, can be considered a reasonable alternative for situations where no safe and effective substitute is available (eg, multidrug resistance) or in situations where the only alternative is parenteral therapy and levofloxacin offers an oral therapy option (Ref).General dosing, susceptible infection (Ref):Infants ≥6 months, Children, and Adolescents:6 months to <5 years: Oral, IV: 8 to 10 mg/kg/dose twice daily.≥5 years: Oral, IV: 10 mg/kg/dose once daily; maximum dose: 750 mg/day.AnthraxAnthrax: Limited data available in infants <6 months of age: Note: Levofloxacin is not preferred therapy for any prophylaxis or treatment regimens; use should be considered when patients are unable to tolerate first-line therapy (eg, ciprofloxacin or others depending upon disease presentation). Although longer durations of therapy are recommended in guidelines in some cases based on risk:benefit assessments (eg, up to 60 days), specific safety data for levofloxacin in pediatric patients is limited to 14 days (Ref).Infants, Children, and Adolescents:Cutaneous, without systemic involvement; treatment (Ref): Appropriate for all strains regardless of penicillin susceptibility or if susceptibility unknown. Treatment duration: 7 to 10 days for naturally-acquired infection, and up to 60 days for biological weapon-related event.<50 kg: Oral: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.≥50 kg: Oral: 500 mg every 24 hours.Inhalational (postexposure prophylaxis) (Ref): Reserve levofloxacin use for penicillin-resistant strains or prior to susceptibility testing. Begin therapy as soon as possible after exposure.<50 kg: Oral (preferred), IV: 8 mg/kg/dose every 12 hours for 60 days; maximum dose: 250 mg/dose.≥50 kg: Oral (preferred), IV: 500 mg every 24 hours for 60 days.Systemic anthrax (excluding meningitis); treatment (Ref): Note: A fluoroquinolone is appropriate for all strains regardless of penicillin susceptibility or if susceptibility unknown; ciprofloxacin is preferred.Initial treatment: Use in combination with a protein synthesis inhibitor (eg, clindamycin); continue therapy for at least 14 days or longer until clinical criteria for stability are met.<50 kg: IV: 10 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.≥50 kg: IV: 500 mg every 24 hours.Oral step-down therapy: Use in combination with a protein synthesis inhibitor (eg, clindamycin). Duration of therapy to complete treatment course is variable; some patients may require up to 60 days additional prophylaxis from onset of illness.<50 kg: Oral: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.≥50 kg: Oral: 500 mg every 24 hours.Systemic anthrax; disseminated infection including meningitis (or when meningitis cannot be ruled out): Initial triple therapy: Use in combination with another bactericidal antimicrobial (beta-lactam or glycopeptide [depending on susceptibility]) and a protein synthesis inhibitor (eg, linezolid); continue therapy for at least 2 to 3 weeks or longer until clinical criteria for stability are met.<50 kg: IV: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.≥50 kg: IV: 500 mg every 24 hours.Oral step-down therapy: Use in combination with a protein synthesis inhibitor (eg, clindamycin). Duration of therapy to complete treatment course is variable; some patients may require up to 60 days additional prophylaxis from onset of illness.<50 kg: Oral: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.≥50 kg: Oral: 500 mg every 24 hour.Bacteremia prophylaxis in patients with acute myeloid leukemia or relapsed acute lymphocytic leukemiaBacteremia prophylaxis in patients with acute myeloid leukemia (AML) or relapsed acute lymphocytic leukemia (ALL): Note: Recommended only during period when patient is severely neutropenic (ie, when absolute neutrophil count [ANC] is <500 cells/mm3) (Ref).Infants ≥6 months and Children <5 years: Oral, IV: 10 mg/kg/dose every 12 hours (Ref).Children ≥5 years and Adolescents: Oral, IV: 10 mg/kg/dose every 24 hours; maximum dose: 750 mg/dose (Ref).Catheter; exit-site or tunnel infectionCatheter (peritoneal dialysis); exit-site or tunnel infection: Infants, Children, and Adolescents: Oral: 10 mg/kg/dose every 48 hours; maximum initial dose: 500 mg; maximum subsequent doses: 250 mg (Ref).Chlamydia trachomatis, urogenital infectionsChlamydia trachomatis, urogenital infections: Adolescents: Oral: 500 mg every 24 hours for 7 days (Ref).Cystic fibrosis pulmonary exacerbationCystic fibrosis pulmonary exacerbation: Limited data available (Ref):Infants ≥6 months, Children, and Adolescents:6 months to <5 years: Oral, IV: 10 mg/kg/dose twice daily.≥5 years: Oral, IV: 10 mg/kg/dose once daily; maximum dose: 750 mg/day.Epididymitis, nongonococcalEpididymitis, nongonococcal: Adolescents: Oral: 500 mg once daily for 10 days (Ref).Mycobacterium avium Complex, severe or disseminated disease, HIV-exposed/-infectedMycobacterium avium Complex, severe or disseminated disease, HIV-exposed/-infected: Adolescents: Oral: 500 mg once daily in combination with other antibiotics (Ref).Otitis media, acuteOtitis media, acute (AOM) (alternative agent): Limited data available: Note: Not recommended for routine empiric use; may be considered for patients with severe penicillin allergy, persistent or recurrent infection, or resistant causative bacteria (Ref).Infants ≥6 months and Children <5 years: Oral: 10 mg/kg/dose every 12 hours for 10 days (Ref).Children ≥5 years and Adolescents: Oral: 10 mg/kg/dose every 24 hours for 10 days; maximum dose: 750 mg/dose (Ref).Pelvic inflammatory diseasePelvic inflammatory disease: Adolescents: Oral: 500 mg once daily for 14 days with or without concomitant metronidazole; Note: Due to resistant organisms, the CDC recommends use as an alternative therapy only if standard parenteral cephalosporin therapy is not feasible and community prevalence, and individual risk of quinolone-resistant gonococcal organisms is low. Culture sensitivity must be confirmed (Ref).Plague, prophylaxis or treatmentPlague (Yersinia pestis), prophylaxis or treatment:Infants ≥6 months, Children, and Adolescents: Note: Begin therapy as soon as possible after exposure:<50 kg: Oral, IV: 8 mg/kg/dose every 12 hours for 10 to 14 days; maximum dose: 250 mg/dose.≥50 kg: Oral, IV: 500 mg every 24 hours for 10 to 14 days.Pneumonia, community-acquiredPneumonia, community-acquired (CAP) (Ref): Note: May consider addition of vancomycin or clindamycin to empiric therapy if community-acquired MRSA suspected. Levofloxacin is not the preferred agent for CAP but may be used as an alternative agent when necessary.Typical pathogens (eg, H. influenzae, S. pneumoniae): Note: Oral administration is generally reserved for mild infections or step-down therapy.Infants ≥6 months and Children <5 years: Oral, IV: 8 to 10 mg/kg/dose every 12 hours; maximum daily dose: 750 mg/day.Children ≥5 years and Adolescents ≤16 years: Oral, IV: 8 to 10 mg/kg/dose once every 24 hours; maximum daily dose: 750 mg/day.Atypical pathogens (eg, Mycoplasma pneumonia or Chlamydia ssp):IV:Infants ≥6 months and Children <5 years: IV: 8 to 10 mg/kg/dose every 12 hours; maximum daily dose: 750 mg/day.Children ≥5 years and Adolescents ≤16 years: IV: 8 to 10 mg/kg/dose once every 24 hours; maximum daily dose: 750 mg/day.Oral: Mild infection/step-down therapy: Adolescents with skeletal maturity: Oral: 500 mg once daily.Rhinosinusitis, acute bacterialRhinosinusitis, acute bacterial: Note: Recommended in the following types of patients: Type I penicillin allergy, after failure of initial therapy or in patients at risk for antibiotic resistance (eg, daycare attendance, age <2 years, recent hospitalization, antibiotic use within the past month) (Ref).Children and Adolescents: Oral, IV: 10 to 20 mg/kg/day divided every 12 to 24 hours for 10 to 14 days; maximum daily dose: 500 mg/day.Surgical prophylaxisSurgical prophylaxis: Children and Adolescents: IV: 10 mg/kg as a single dose 120 minutes prior to procedure; maximum dose: 500 mg/dose; Note: While fluoroquinolones have been associated with an increased risk of tendinopathy/tendon rupture in all ages, use of these agents for single-dose prophylaxis is generally safe (Ref).Tuberculosis, multidrug-resistantTuberculosis (TB), multidrug-resistant: Limited data available: Note: Use in combination with at least 3 to 4 additional anti-TB agents (overall multidrug regimen dependent upon susceptibility profile/patterns) (Ref):Infants, Children, and Adolescents: Oral: 15 to 20 mg/kg/dose once daily; usual maximum daily dose: 1,000 mg/day; higher doses (1,250 to 1,500 mg/day) have been reported in adults (Ref).Urethritis, nongonococcalUrethritis, nongonococcal: Adolescents: Oral: 500 mg every 24 hours for 7 days (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricInfants, Children, and Adolescents: IV, Oral: The following adjustments have been recommended (Ref). Note: Renally adjusted dose recommendations are based on doses of 5 to 10 mg/kg/dose every 12 hours in ages ≤5 years and 5 to 10 mg/kg/dose every 24 hours in ages >5 years.GFR ≥30 mL/minute/1.73 m2: No adjustment necessaryGFR 10 to 29 mL/minute/1.73 m2: 5 to 10 mg/kg/dose every 24 hoursGFR <10 mL/minute/1.73 m2: 5 to 10 mg/kg/dose every 48 hoursIntermittent hemodialysis: 5 to 10 mg/kg/dose every 48 hours; not removed by hemodialysis; supplemental levofloxacin doses are not requiredPeritoneal dialysis (PD): 5 to 10 mg/kg/dose every 48 hours; not removed by peritoneal dialysis; supplemental levofloxacin doses are not requiredContinuous renal replacement therapy (CRRT): 10 mg/kg/dose every 24 hoursDosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling; has not been studied; however, dosage adjustment unlikely to be necessary due to limited hepatic metabolism.Dosing: Older AdultRefer to adult dosing.Dosing: Obesity: AdultThe recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.Class 1, 2, and 3 obesity (BMI ≥30 kg/m2):IV, Oral: No dosage adjustment necessary (Ref). Dose adjustments based on CrCl in patients with obesity remain the most important approach to ensuring patients receive optimal drug exposure. In patients with BMI ≥40 kg/m2 and CrCl >110 mL/minute, consider using therapeutic drug monitoring (if available) or alternative treatment options (Ref). Refer to adult dosing for indication-specific doses.Rationale for recommendations: Levofloxacin is predominantly eliminated by the kidneys and is the most hydrophilic of the quinolones. Although there are limited data on the pharmaco*kinetics of levofloxacin in patients with BMI ≥30 kg/m2, the data suggest CrCl (particularly measured by co*ckcroft-Gault equation) is the predominant patient factor guiding altered dosing (Ref). In one observational study in patients with BMI ≥40 kg/m2, levofloxacin AUC was not related to any body size metric; however, levofloxacin AUC was associated with CrCl (measured using co*ckcroft-Gault with ideal body weight). A dose of 750 mg may be unlikely to achieve target endpoints in patients with BMI ≥40 kg/m2 and CrCl >110 mL/minute, especially organisms with higher minimum inhibitory concentrations (eg, Pseudomonas sp.) (Ref). A small pharmaco*kinetic study and a separate case study found no clear effects of obesity on levofloxacin dosing requirements, suggesting that weight-based dosing is not required (Ref).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Intravenous [preservative free]: Generic: 250 mg/50 mL (50 mL); 500 mg/100 mL (100 mL); 750 mg/150 mL (150 mL); 25 mg/mL (20 mL, 30 mL)Solution, Oral: Generic: 25 mg/mL (10 mL, 100 mL, 200 mL, 480 mL)Tablet, Oral: Levaquin: 500 mg [DSC], 750 mg [DSC]Generic: 250 mg, 500 mg, 750 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution, Intravenous: Generic: 5 mg/mL (50 mL, 100 mL, 150 mL)Tablet, Oral: Generic: 250 mg, 500 mg, 750 mgMedication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Levaquin tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020634s073lbl.pdf#page=54Administration: AdultOral: Tablets may be administered without regard to meals. Oral solution should be administered at least 1 hour before or 2 hours after meals. Maintain adequate hydration of patient to prevent crystalluria. Administer at least 2 hours before or 2 hours after antacids containing magnesium or aluminum, sucralfate, metal cations (eg, iron), multivitamin preparations with zinc, or didanosine chewable/buffered tablets or the pediatric powder for solution.IV: Infuse 250 to 500 mg IV solution over 60 minutes; infuse 750 mg IV solution over 90 minutes. Too rapid of infusion can lead to hypotension. Avoid administration through an intravenous line with a solution containing multivalent cations (eg, magnesium, calcium). Maintain adequate hydration of patient to prevent crystalluria or cylindruria.Administration: PediatricOral: Maintain adequate hydration to prevent crystalluria or cylindruria. Administer at least 2 hours before or 2 hours after antacids containing magnesium or aluminum, sucralfate, metal cations (eg, iron), multivitamin preparations with zinc, or didanosine chewable/buffered tablets or the pediatric powder for solution.Tablets: May administer without regard to meals.Oral solution: Administer 1 hour before or 2 hours after meals.Missed dose: Administer as soon as possible if ≥8 hours until next scheduled dose; otherwise, wait until next scheduled dose.Parenteral: Administer by slow IV infusion over 60 to 90 minutes (250 to 500 mg over 60 minutes; 750 mg over 90 minutes); avoid rapid or bolus IV infusion due to risk of hypotension. Avoid administration through an intravenous line with a solution containing multivalent cations (eg, magnesium, calcium). Maintain adequate hydration to prevent crystalluria or cylindruria; not for IM, SubQ, or intrathecal administration.Use: Labeled IndicationsTreatment of community-acquired pneumonia, including multidrug-resistant strains of Streptococcus pneumoniae (MDRSP); nosocomial pneumonia; chronic obstructive pulmonary disease, acute exacerbation; rhinosinusitis, acute bacterial (ABRS); prostatitis (chronic bacterial); urinary tract infection (uncomplicated or complicated); acute pyelonephritis; skin or skin structure infections (uncomplicated or complicated); inhalational anthrax (postexposure) to reduce incidence or disease progression; prophylaxis and treatment of plague due to Yersinia pestisLimitations of use: Because fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions (eg, tendinopathy and tendon rupture, peripheral neuropathy, CNS effects), reserve levofloxacin for use in patients who have no alternative treatment options for acute exacerbation of chronic bronchitis, acute bacterial sinusitis, and uncomplicated urinary tract infections.Use: Off-Label: AdultAnthrax; Bite wound infection, prophylaxis or treatment (animal or human bite); Cervicitis or urethritis due to Chlamydia trachomatis infection; Diabetic foot infection; Epididymitis, acute; Helicobacter pylori eradication; Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure; Neutropenia (chemotherapy-induced), antibacterial prophylaxis; Odontogenic soft tissue infection, pyogenic; Osteomyelitis; Pelvic inflammatory disease; Prostatitis (acute bacterial); Prosthetic joint infection; Salmonella (nontyphoidal) infection; Shigella infection; Surgical (preoperative) prophylaxis; Surgical site incisional infection; TuberculosisMedication Safety IssuesSound-alike/look-alike issues:Levaquin may be confused with Levoxyl, Levsin/SL, LovenoxLevoFLOXacin may be confused with levETIRAcetam, levodopa, Levophed, levothyroxineInternational issues:Levaquin [Argentina, Brazil, US, Venezuela] may be confused with Lariam brand name for mefloquine [multiple international markets]Adverse Reactions (Significant): ConsiderationsAortic aneurysm/aortic dissectionFluoroquinolones have been associated with aortic aneurysm and aortic dissection with risk of aortic aneurysm higher than aortic dissection. Overall risk with levofloxacin may be higher than ciprofloxacin and moxifloxacin (Ref).Mechanism: Time-related; upregulation of matrix metalloproteinase (MMP) enzymes capable of damaging components of the extracellular matrix, including collagen and elastin (Ref). MMP-2 and MMP-9 have been shown to play a role in development of aneurysms via degradation of collagen fibril (Ref). May also have a direct effect on the viability of chondrocytes and tenocytes responsible for collagen synthesis, due to generation of reactive oxygen species, caspase activation, and apoptosis (Ref).Onset: Delayed in most cases. Studies evaluating risk generally evaluated the time period of 60 days after the initiation of fluoroquinolone therapy (Ref).Risk factors:• Older adults with peripheral vascular disease or a history of aneurysms, atherosclerosis, hypertension, or genetic conditions predisposing to aortic aneurysm (eg, Marfan syndrome, Ehlers-Danlos syndrome) (Ref)• Longer courses of therapy (>14 days) (Ref)• Severe emotional or physical stress has been correlated to the onset of pain (Ref)Arthropathy/arthralgiaArthropathy, or joint disease, has been observed in both animal and pediatric human studies following treatment with fluoroquinolone antibiotics, including levofloxacin (Ref). In a pooled safety data analysis of ~2,500 pediatric patients, musculoskeletal events including arthralgia were observed more frequently at 2 months and 12 months after treatment with levofloxacin than comparative treatment; no physical joint abnormalities were observed (Ref). Long-term follow-up (up to 5 years) of ~200 of the initial patients demonstrated no difference in musculoskeletal adverse events including ongoing arthropathy, between levofloxacin and comparator (Ref). Arthropathy and arthralgias appear to resolve after discontinuation of treatment with no long-term sequelae (Ref). Though the true incidence is unknown, arthropathy and arthralgia are considered to be infrequent, but potentially serious adverse reactions.Mechanism: Unknown; several hypotheses have been proposed including inhibition of mitochondria DNA synthesis in immature chondrocytes, direct toxic effect of fluoride on cartilage, magnesium chelation and subsequent deficiency in cartilage, and defective proteoglycan and procollagen synthesis with decreased incorporation of tritiated thymidine by chondrocytes (Ref).Onset: Varied; may occur within a day of initiation or months following discontinuation (Ref).Risk factors:• Higher doses (Ref)• Prolonged exposure (Ref)CNS effects/neuroexcitationFluoroquinolones have been associated with a range of psychiatric and neurologic effects, from dizziness and restlessness to toxic psychosis (Ref). More common reactions include confusion, agitation, insomnia, and drowsiness. More severe reactions, including delusions, hallucinations, suicidal ideation, suicidal tendencies, and toxic psychosis are less common (Ref). Neuroexcitation may include seizure in some patients (Ref).Mechanism: GABA binding disruption, NMDA binding alterations, and increased excitatory neurotransmitters (Ref). Mitochondrial dysfunction has been hypothesized to contribute (Ref).Onset: Varied; neuroexcitatory phenomena generally occur in the first week of therapy, often after 2 to 3 days (Ref).Risk factors:• Older adults (Ref)• Kidney impairment with unadjusted or higher doses (Ref)• Concurrent therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with enhanced neuroexcitation (less risk with levofloxacin) (Ref)• Concurrent theophylline (less risk with levofloxacin) (Ref)• History of seizures, seizure disorders, CNS disorders, or concurrent therapy with medications known to lower seizure threshold may increase risk of seizures (Ref)• History of or risk factor for mental illness (eg, depression)Clostridioides difficile infectionClostridioides difficile infection (CDI), including Clostridioides difficile associated diarrhea and Clostridioides difficile colitis, has been reported.Onset: Varied; may start on the first day of antibiotic therapy or up to 3 months postantibiotic (Ref).Risk factors:• Antibiotic exposure (highest risk factor) (Ref)• Type of antibiotic (fluroquinolones among the highest risk) (Ref)• Long durations in a hospital or other health care setting (recent or current) (Ref)• Older adults (Ref)• Immunocompromised conditions (Ref)• A serious underlying condition (Ref)• GI surgery/manipulation (Ref)• Antiulcer medications (eg, proton pump inhibitors and H2 blockers) (Ref)• Chemotherapy (Ref)Glucose regulation/dysglycemiaHyperglycemia and hypoglycemia have been associated with the use of fluoroquinolones, including levofloxacin.Mechanism: Increase in insulin release via blockade of adenosine triphosphate-sensitive potassium channels in the pancreatic beta cells, but the significance at clinical concentrations has been questioned (Ref). Additionally, effects on gluconeogenesis, glucose transport (via expression of GLUT-1), and mitochondrial dysfunction have been implicated (Ref).Onset: Varied; corresponds to the initiation of therapy but may be delayed by 2 to 3 days. Events requiring emergent care or hospitalization occurred between day 3 and day 10 of therapy (Ref).Risk factors:• Patients with diabetes are at highest risk; however, cases in patients without diabetes have been reported (Ref)• Concurrent therapy with hypoglycemic agents, including insulin (Ref)HepatotoxicityLiver injury/drug-induced liver injury: May cause liver injury (hepatotoxicity); both cholestatic and hepatocellular patterns are represented in reported clinical presentations (Ref). Published reports include at least 1 fatal case (Ref).Mechanism: Immunologic reactions account for many events; direct toxicity related to mitochondrial dysfunction and increased oxidative stress may also be responsible for some reactions (Ref).Onset: Varied; acute liver injury generally occurred within 14 days of initiation (most cases within 6 days) range of 1 to 39 days.Risk factors:• Most fatal events occurred in patients ≥65 years of ageHypersensitivity reactions (immediate and delayed)Hypersensitivity reactions include anaphylaxis, nonimmune anaphylaxis (previously called anaphylactoid reactions) (Ref) and delayed cutaneous reactions.Delayed cutaneous reactions include severe dermatologic reactions, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis (Ref). Less severe reactions include fixed drug eruption and bullous pemphigoid reactions (Ref).Immunologically mediated organ-specific reactions include pancreatitis, interstitial nephritis, hemolytic anemia, thrombocytopenia, and some cases of hepatitis (Ref).Mechanism: Nonimmune anaphylaxis results from binding directly to specific receptors (MGPRX2) on mast cells and basophils, causing direct stimulation of histamine release (and other mediators) (Ref). Importantly, these cases may occur without prior exposure. In other cases, anaphylaxis may be mediated by IgE, formed with prior exposure to the drug (Ref).Delayed reactions are mediated by activated T cells. Chemical activation of fluoroquinolones was not required for immune reactions to occur, which implies direct activation (pharmacologic interaction) without covalent binding to host proteins/hapten formation (Ref).Onset: Anaphylaxis (nonimmune and immune): Rapid; may occur within an hour of administration (Ref). Other reactions, particularly various maculopapular cutaneous reactions or organ-specific reactions: Varied; occur after days to weeks of therapy (Ref).Risk factors:• Nonimmune anaphylaxis may be dose and/or infusion rate related (concentration-related) (Ref).Myasthenia gravisFluoroquinolones, including levofloxacin, may cause an exacerbation of myasthenia gravis. Disease exacerbations vary in severity from muscular weakness to severe compromise (myasthenic crisis characterized by acute respiratory failure) (Ref).Mechanism: Neuromuscular blockade is the most frequently cited mechanism, although alterations in mitochondrial energy production has also been suggested as a contributing mechanism (Ref).Onset: Rapid; Within hours of the initiation of therapy with a fluoroquinolone (Ref).Risk factors:• Patients with myasthenia gravis (diagnosed and undiagnosed) (Ref).Peripheral neuropathyFluoroquinolones have been associated with peripheral neuropathy and other effects, including axonal neuropathy and Guillain-Barré syndrome (GBS) (Ref). Associated with many types of disturbances of special senses, including several case reports indicating a very slow recovery and/or permanent state of disability (Ref).Mechanism: Mitochondrial effects related to reactive oxygen species and apoptotic changes (Ref).Onset: Varied; may present as early as the first day of therapy (Ref).Risk factors:• Males (Ref)• Older adults (>60 years of age) (Ref)• Duration of therapy (Ref)• Type 1 diabetes may also be a risk factor (data are limited) (Ref)• History of peripheral neuropathyPhototoxicity/photoallergyPhototoxicity/skin photosensitivity account for a proportion of the overall cutaneous adverse reactions (Ref). Hyperpigmentation (brown-grey) in areas exposed to sunlight has also been reported with levofloxacin (Ref). Levofloxacin is considered a lower risk among the fluoroquinolone class (Ref).Mechanism: Non-dose-related; immunologic. Reactive intermediates are generated by ultraviolet exposure and attach to proteins of Langerhans cells, triggering immune reactions (Ref).Onset: Rapid; in a study with ofloxacin, occurred within 24 hours of initiation and sun exposure (Ref).Risk factors:• Duration and intensity of sun exposure• Cystic fibrosis (Ref)• Prior phototoxic reaction to another fluoroquinolone (Ref)QT prolongationFluoroquinolones may be associated with prolonged QT interval on ECG and ventricular arrhythmias, such as torsades de pointes (TdP). Levofloxacin may have a lower risk than other fluoroquinolones, particularly moxifloxacin (Ref). Change in QTc from baseline for moxifloxacin was found to be +16.34 to 17.83 ms, while the change with levofloxacin was +3.53 to 4.88 ms (Ref).Mechanism: May alter the rapid delayed rectifier potassium current, resulting in prolonged repolarization (Ref). Prolonged repolarization can alter action potentials in cardiac cells and promote arrhythmogenic activity (Ref).Onset: Varied; effect is concentration dependent, initially observed at supra-therapeutic doses (Ref). High dose or accumulation may influence timing/concentrations.Risk factors:Drug-induced QTc prolongation/ TdP (in general)• Females (Ref)• Age >65 years (Ref)• Structural heart disease (eg, history of myocardial infarction or heart failure) (Ref)• History of drug-induced TdP (Ref)• Genetic defects of cardiac ion channels (Ref)• Congenital long QT syndrome (Ref)• Baseline QT interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 msec (Ref)• Electrolyte disturbances (eg, hypocalcemia, hypokalemia, hypomagnesemia) (Ref)• Bradycardia (Ref)• Hepatic impairment (Ref)• Kidney impairment (Ref)• Loop diuretic use (Ref)• Sepsis (Ref)• Concurrent administration of multiple medications (≥ 2) that prolong the QT interval or increase drug interactions that increase serum drug concentrations of QT prolonging medications (Ref)Tendinopathy/tendon ruptureMay cause tendinopathy or rupture of tendon. Achilles is most commonly cited, but inflammation/rupture of many other tendons (including hand, rotator cuff, biceps, and thumb) has been reported (Ref).Mechanism: Dose and time-related; upregulation of MMPs capable of damaging components of the extracellular matrix, including collagen and elastin (Ref). Direct effect on the viability of chondrocytes and tenocytes responsible for collagen synthesis, due to generation of reactive oxygen species, and caspase activation and apoptosis (Ref).Onset: Varied; per the manufacturer's labeling, tendinopathy or tendon rupture may occur within hours or days of initiation or may be delayed for several months after discontinuation.Risk factors:• Age >60 years (Ref)• Corticosteroid therapy (Ref)• Kidney failure (Ref)• Diabetes mellitus (Ref)• Previous tendon disorders (eg, rheumatoid arthritis) (Ref)• Solid organ transplant recipients (Ref)• Strenuous physical activity (Ref)• Longer duration of therapy and higher dosages (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.1% to 10%:Cardiovascular: Chest pain (1%), edema (1%)Dermatologic: Pruritus (1%), skin rash (2%)Gastrointestinal: Abdominal pain (2%), constipation (3%), diarrhea (5%), dyspepsia (2%), nausea (7%), vomiting (2%)Genitourinary: Vaginitis (1%)Infection: Candidiasis (1%)Local: Injection site reaction (1%)Nervous system: Dizziness (3%), headache (6%), insomnia (4%)Respiratory: Dyspnea (1%)<1%:Cardiovascular: Palpitations, phlebitis, syncope, ventricular arrhythmia, ventricular tachycardiaDermatologic: UrticariaEndocrine & metabolic: Hyperglycemia, hyperkalemia, hypoglycemiaGastrointestinal: Anorexia, Clostridioides difficile colitis, esophagitis, gastritis, gastroenteritis, glossitis, pancreatitis, stomatitisGenitourinary: Genital candidiasisHematologic & oncologic: Anemia, granulocytopenia, thrombocytopeniaNervous system: Abnormal dreams, abnormal gait, agitation, anxiety, confusion, depression, drowsiness, hallucination, hypertonia, nightmares, paresthesia, seizure, vertigoNeuromuscular & skeletal: Arthralgia, hyperkinetic muscle activity, myalgia, skeletal pain, tremorRenal: Acute kidney injuryRespiratory: EpistaxisPostmarketing:Cardiovascular: Aortic aneurysm (rare: <1%) (Meng 2018; Pasternak 2018), aortic dissection (rare: <1%) (Meng 2018; Pasternak 2018), hypersensitivity angiitis, hypotension, prolonged QT interval on ECG (rare: <1%) (Teng 2019), tachycardia (rare: <1%), torsades de pointes (rare: <1%) (Teng 2019), vasodilationDermatologic: Acute generalized exanthematous pustulosis, erythema multiforme, hyperpigmentation (rare: <1%) (Connors 2018), phototoxicity (rare: <1%), skin photosensitivity (rare: <1%), Stevens-Johnson syndrome, toxic epidermal necrolysisGastrointestinal: Ageusia, Clostridioides difficile associated diarrhea, dysgeusiaGenitourinary: Casts in urine, crystalluriaHematologic & oncologic: Agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia, increased INR, leukopenia, pancytopenia, prolonged prothrombin time, thrombotic thrombocytopenic purpuraHepatic: Hepatic failure, hepatotoxicity (idiosyncratic; rare: <1%) (Chalasani 2014; Gulen 2015; Schloss 2018)Hypersensitivity: Anaphylactic shock, anaphylaxis, angioedema, fixed drug eruption, nonimmune anaphylaxis, serum sicknessImmunologic: Drug reaction with eosinophilia and systemic symptoms (Charfi 2015)Nervous system: Abnormal electroencephalogram, altered sense of smell, anosmia, delirium, disorientation, disturbance in attention, encephalopathy (rare), exacerbation of myasthenia gravis, Guillain-Barre syndrome (rare: <1%) (Ali 2014), increased intracranial pressure, memory impairment, nervousness, paranoid ideation, peripheral neuropathy (rare: <1%; may be irreversible), psychosis, restlessness, suicidal ideation, suicidal tendencies, toxic psychosis, voice disorderNeuromuscular & skeletal: Muscular paralysis (musculospiral) (Pan 2017), rhabdomyolysis, rupture of tendon (less frequent: ≥1% to <4%) (van der Linden 2002), tendinopathy (less frequent: ≥1% to <4%) (van der Linden 2002)Ophthalmic: Blurred vision, decreased visual acuity, diplopia, scotoma, uveitisOtic: Hypoacusis, tinnitusRenal: Interstitial nephritisRespiratory: Bronchospasm, hypersensitivity pneumonitisMiscellaneous: Fever, multi-organ failureContraindicationsHypersensitivity to levofloxacin, any component of the formulation, or other quinolonesCanadian labeling: Additional contraindications (not in US labeling): History of tendinopathy or tendon rupture associated with use of any quinolone antimicrobial agentWarnings/PrecautionsConcerns related to adverse effects:• Superinfection: Prolonged use may result in fungal or bacterial superinfection.Disease-related concerns:• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required.Special populations:• Older adult: Adverse effects (eg, hepatotoxicity, tendon rupture, QT changes, aortic dissection) may be increased in the elderly.• G6PD deficiency: Hemolytic reactions may (rarely) occur with fluoroquinolone use in patients with G6PD deficiency (Luzzatto 2020).• Pediatric: Safety of use in pediatric patients for >14 days of therapy has not been studied; increased incidence of musculoskeletal disorders (eg, arthralgia, tendon rupture) has been observed in children.Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.Warnings: Additional Pediatric ConsiderationsIn pediatric patients, fluoroquinolones are not routinely first-line therapy, but after assessment of risks and benefits, can be considered a reasonable alternative for situations where no safe and effective substitute is available (eg, multidrug resistance) or in situations where the only alternative is parenteral therapy and levofloxacin offers an oral therapy option (AAP [Jackson 2016]).Concentration of oral suspension may vary (commercially available or extemporaneous compound); use caution. Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).Metabolism/Transport EffectsSubstrate of OAT1/3Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Agents with Blood Glucose Lowering Effects: Quinolones may enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use.Risk C: Monitor therapyAminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).Risk X: Avoid combinationAminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).Risk C: Monitor therapyAmiodarone: Levofloxacin-Containing Products (Systemic) may enhance the QTc-prolonging effect of Amiodarone.Risk X: Avoid combinationAmisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapyAmphetamines: May enhance the cardiotoxic effect of Quinolones. Risk C: Monitor therapyAntacids: May decrease the absorption of Quinolones. Of concern only with oral administration of quinolones. Management: Avoid concurrent administration of quinolones and antacids to minimize the impact of this interaction. Recommendations for optimal dose separation vary by specific quinolone. Risk D: Consider therapy modificationBacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii.Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modificationBCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical).Risk X: Avoid combinationBCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization).Risk C: Monitor therapyCalcium Salts: May decrease the absorption of Quinolones. Of concern only with oral administration of both agents. Management: Consider administering an oral quinolone at least 2 hours before or 6 hours after the dose of an oral calcium supplement to minimize this interaction. Monitor for decrease therapeutic effects of quinolones during coadministration. Risk D: Consider therapy modificationCholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine.Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combinationCorticosteroids (Systemic): May enhance the adverse/toxic effect of Quinolones. Specifically, the risk of tendonitis and tendon rupture may be increased. Risk C: Monitor therapyDabrafenib: QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of Dabrafenib.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyDelamanid: May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of Delamanid. Management: Avoid concomitant use of delamanid and quinolone antibiotics if possible. If coadministration is considered to be unavoidable, frequent monitoring of electrocardiograms throughout the full delamanid treatment period should occur. Risk D: Consider therapy modificationDidanosine: Quinolones may decrease the serum concentration of Didanosine. Didanosine may decrease the serum concentration of Quinolones.Management: Administer oral quinolones at least 2 hours before or 6 hours after didanosine. Monitor for decreased therapeutic effects of quinolones, particularly if doses cannot be separated as recommended. This does not apply to unbuffered enteric coated didanosine. Risk D: Consider therapy modificationDomperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationFluorouracil Products: QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of Fluorouracil Products.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyHaloperidol: May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyHydroxychloroquine: May enhance the hyperglycemic effect of Levofloxacin-Containing Products (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Levofloxacin-Containing Products (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Levofloxacin-Containing Products (Systemic). Risk C: Monitor therapyImmune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Risk C: Monitor therapyIron Preparations: May decrease the serum concentration of Quinolones. Management: Give oral quinolones at least several hours before (4 h for moxi- and sparfloxacin, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for lome-, 3 h for gemi-, and 2 h for enox-, levo-, nor-, oflox-, peflox, or nalidixic acid) oral iron. Risk D: Consider therapy modificationLactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol.Risk C: Monitor therapyLanthanum: May decrease the serum concentration of Quinolones. Management: Administer oral quinolone antibiotics at least one hour before or four hours after lanthanum. Risk D: Consider therapy modificationLevoketoconazole: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Levoketoconazole.Risk X: Avoid combinationMagnesium Salts: May decrease the serum concentration of Quinolones. Management: Administer oral quinolones several hours before (4 h for moxi/pe/spar/enox-, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for lome/pe/enox-, 3 h for gemi-, and 2 h for levo-, nor-, or ofloxacin or nalidixic acid) oral magnesium salts. Risk D: Consider therapy modificationMethadone: Levofloxacin-Containing Products (Systemic) may enhance the QTc-prolonging effect of Methadone.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationMethoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic).Risk C: Monitor therapyMethylphenidate: May enhance the cardiotoxic effect of Quinolones. Risk C: Monitor therapyMultivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Quinolones. Specifically, polyvalent cations in multivitamin products may decrease the absorption of orally administered quinolone antibiotics. Management: Administer oral quinolones at least 2 hours before, or 6 hours after, the dose of a multivitamin that contains polyvalent cations (ie, calcium, iron, magnesium, selenium, zinc). Monitor for decreased quinolone efficacy. Risk D: Consider therapy modificationMultivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Quinolones. Specifically, minerals in the multivitamin/mineral product may impair absorption of quinolone antibiotics. Management: Administer oral quinolones at least 2 hours before, or 6 hours after, the dose of a multivitamin that contains polyvalent cations (ie, calcium, iron, magnesium, selenium, zinc). Monitor for decreased therapeutic effects of quinolones. Risk D: Consider therapy modificationMycophenolate: Quinolones may decrease the serum concentration of Mycophenolate. Specifically, quinolones may decrease concentrations of the active metabolite of mycophenolate.Risk C: Monitor therapyNadifloxacin: May enhance the adverse/toxic effect of Quinolones. Risk X: Avoid combinationNonsteroidal Anti-Inflammatory Agents: May enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolones. Risk C: Monitor therapyOndansetron: May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combinationPorfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer.Risk C: Monitor therapyProbenecid: May decrease the excretion of Quinolones. Specifically, probenecid may decreased the renal excretion of quinolone antibiotics. Probenecid may increase the serum concentration of Quinolones. Risk C: Monitor therapyQT-prolonging Antidepressants (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class IA Antiarrhythmics (Highest Risk): Levofloxacin-Containing Products (Systemic) may enhance the QTc-prolonging effect of QT-prolonging Class IA Antiarrhythmics (Highest Risk).Risk X: Avoid combinationQT-prolonging Class IC Antiarrhythmics (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class III Antiarrhythmics (Highest Risk): Levofloxacin-Containing Products (Systemic) may enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk).Risk X: Avoid combinationQT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Levofloxacin-Containing Products (Systemic). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Kinase Inhibitors (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Miscellaneous Agents (Highest Risk): Levofloxacin-Containing Products (Systemic) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk).Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of other QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk).Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapySertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combinationSevelamer: May decrease the absorption of Quinolones. Management: Administer oral quinolones at least 2 hours before or 6 hours after sevelamer. Risk D: Consider therapy modificationSodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate.Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modificationStrontium Ranelate: May decrease the serum concentration of Quinolones. Management: In order to minimize any potential impact of strontium ranelate on quinolone antibiotic concentrations, it is recommended that strontium ranelate treatment be interrupted during quinolone therapy. Risk X: Avoid combinationSucralfate: May decrease the serum concentration of Quinolones. Management: Avoid concurrent administration of quinolones and sucralfate to minimize the impact of this interaction. Recommendations for optimal dose separation vary by specific quinolone. Risk D: Consider therapy modificationTacrolimus (Systemic): LevoFLOXacin (Systemic) may enhance the QTc-prolonging effect of Tacrolimus (Systemic). LevoFLOXacin (Systemic) may increase the serum concentration of Tacrolimus (Systemic).Risk C: Monitor therapyTyphoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected.Management: Avoid use of live attenuated typhoid vaccine (Ty21a)in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modificationVerteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin.Risk C: Monitor therapyVitamin K Antagonists (eg, warfarin): Quinolones may enhance the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapyZinc Salts: May decrease the serum concentration of Quinolones. Management: Give oral quinolones at several hours before (4 h for moxi- and sparfloxacin, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for lome-, 3 h for gemi-, and 2 h for enox-, levo-, nor-, pe- or ofloxacin or nalidixic acid) oral zinc salts. Risk D: Consider therapy modificationFood InteractionsAdministration with food prolonged time to peak by ~1 hour and decreased the peak concentration by ~14% and ~25% for the tablet and oral solution, respectively. Management: Tablet may be administered without regard to food; oral solution should be administered at least 1 hour before or 2 hours after food.Pregnancy ConsiderationsLevofloxacin crosses the placenta and can be detected in the amniotic fluid and cord blood (Ozyüncü 2010a; Ozyüncü 2010b).Based on available data, an increased risk of major birth defects, miscarriage, or other adverse fetal and maternal outcomes have not been observed following levofloxacin use during pregnancy (Acar 2019; Yefet 2018; Ziv 2018).Levofloxacin is an alternative agent for treatment of drug-resistant tuberculosis. Active tuberculosis infection is associated with adverse fetal outcomes, including intrauterine growth restriction, low birth weight, preterm birth, and perinatal death (Esmail 2018; Miele 2020), as well as adverse maternal outcomes, including increased risks for anemia and cesarean delivery. Placental transmission may rarely occur with active maternal disease (Miele 2020). Data are limited for use of second-line drugs in pregnancy (ie, fluroquinolones). Individualized regimens should be utilized to treat multidrug-resistant tuberculosis in pregnant patients; evidence to support a specific regimen is not available. Based on susceptibility testing, levofloxacin may be used to treat multidrug-resistant tuberculosis during pregnancy when needed (ATS/CDC/ERS/IDSA [Nahid 2019]; HHS [OI adult 2020]; WHO 2020).Levofloxacin is approved to reduce the incidence or disease progression of inhalational anthrax (postexposure). Untreated anthrax infection during pregnancy is associated with preterm labor, fetal distress, and fetal loss. However, levofloxacin is not the preferred fluoroquinolone for the prophylaxis or treatment of anthrax in pregnant and postpartum patients (Meaney-Delman 2014).Untreated plague (Yersinia pestis) infection in pregnant patients may result in hemorrhage (including postpartum hemorrhage), maternal and fetal death, preterm birth, and stillbirth. Limited data suggest maternal-fetal transmission of Y. pestis can occur if not treated. Pregnant patients should be treated for Y. pestis; parenteral antibiotics are preferred for initial treatment when otherwise appropriate. Levofloxacin is one of the fluoroquinolones recommended for use (in combination with an aminoglycoside) for treating pregnant patients with bubonic, pharyngeal, pneumonic, or septicemic plague. Recommendations for treating pregnant patients with plague meningitis are the same as in nonpregnant patients. Levofloxacin may also be used for pre- and postexposure prophylaxis in pregnant patients exposed to Y. pestis (CDC [Nelson 2021]).Antibiotics other than levofloxacin are recommended for the treatment of uncomplicated urinary tract infections and pyelonephritis during pregnancy (Betschart 2020).Breastfeeding ConsiderationsLevofloxacin is present in breast milk.Breast milk concentrations were measured in a woman receiving levofloxacin for treatment of a septic knee. Therapy was started as levofloxacin 500 mg/day IV for 9 days, followed by 14 days of oral therapy. A total of 26 breast milk samples were taken starting 10 days after the initiation of therapy and continuing after therapy was completed. During therapy, breast milk was expressed, but not fed to her preterm infant (27 weeks estimated gestation age). Steady-state peak milk concentration was 8.2 mcg/mL and occurred 5 hours after the dose. The half-life in the breast milk was approximately 7 hours, but small amounts were still detectable in the milk 65 hours after the last dose (Cahill 2005). Using a milk concentration of 8.2 mcg/mL, the estimated exposure to the breast-feeding infant would be 1.23 mg/kg/day (relative infant dose [RID] 6% based on a therapeutic infant dose of 20 mg/kg/day). In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).Levofloxacin may be considered for use in breastfeeding patients requiring antibiotics for inhalational anthrax (postexposure); according to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. However, patients with active cutaneous anthrax lesions on the breast should avoid direct infant contact; feeding from the affected breast should be avoided until 48 hours after the appropriate antibiotic therapy (Meaney-Delman 2014).For other indications, the manufacturer does not recommend use of levofloxacin in breastfeeding patients during therapy or for 2 days after the last levofloxacin dose due to concerns of potential serious adverse reactions; alternatively, lactating patients can pump and discard breast milk during therapy and for 2 days after the last levofloxacin dose. The risk of articular damage in breastfed infants exposed to other quinolones (ie, ciprofloxacin) is considered low even in children receiving high therapeutic doses. Therefore, some sources do not consider maternal use of these agents to be a reason to discontinue breastfeeding as long as the infant is monitored for GI symptoms (eg, diarrhea) that could occur following antibiotic exposure (Kaplan 2015). Other sources recommend avoiding quinolone antibiotics if alternative agents are available (WHO 2002).The risk for transmission of plague (Yersinia pestis) via breast milk is considered low. Patients with pneumonic plague can breastfeed if both the mother and infant are receiving antibiotic treatment or the infant is receiving postexposure prophylaxis, considering the risk of exposure to the drug via breast milk. If the infant is not being treated, breast milk should be expressed for at least 48 hours of maternal antibiotic therapy to limit person-to-person contact with the infant. The expressed breast milk may be given to the infant. Once maternal clinical improvement is observed, direct breastfeeding may resume (CDC [Nelson 2021]).In general, antibiotics that are present in breast milk may cause non–dose-related modification of bowel flora. Monitor infants for GI disturbances (WHO 2002).Dietary ConsiderationsTablets may be taken without regard to meals. Oral solution should be administered on an empty stomach (at least 1 hour before or 2 hours after a meal).Monitoring ParametersEvaluation of organ system functions (renal, hepatic, and hematopoietic) is recommended periodically during therapy; the possibility of crystalluria should be assessed; WBC and signs of infection, altered mental status, signs and symptoms of tendinopathy (tendon pain, swelling, inflammation, or rupture) or peripheral neuropathy; signs and symptoms of disordered glucose regulation (especially in patients with diabetes mellitus); rash; signs and symptoms of hypersensitivity reaction.Mechanism of ActionAs the S(-) enantiomer of the fluoroquinolone, ofloxacin, levofloxacin, inhibits DNA-gyrase in susceptible organisms thereby inhibits relaxation of supercoiled DNA and promotes breakage of DNA strands. DNA gyrase (topoisomerase II), is an essential bacterial enzyme that maintains the superhelical structure of DNA and is required for DNA replication and transcription, DNA repair, recombination, and transposition.Pharmaco*kineticsAbsorption: Rapid and complete; levofloxacin oral tablet and solution formulations are bioequivalent Distribution: Widely distributed in the body, including blister fluid, skin tissue, macrophages, prostate, and lung tissue; CSF concentrations ~15% of serum concentrations Vd: (Chien 2005):Infants ≥6 months, Children, and Adolescents ≤16 years: Mean range: 1.44 to 1.57 L/kg; reported values not statistically different between pediatric age subgroups; distribution not age-dependent Adults: 1.27 L/kg Protein binding: ~24% to 38%; primarily to albuminMetabolism: Minimally hepaticBioavailability: ~99%Half-life elimination:Infants ≥6 months and Children ≤5 years: ~4 hours (Chien 2005)Children 5 to 10 years: 4.8 hours (Chien 2005)Children 10 to 12 years: 5.4 hours (Chien 2005)Children 12 to 16 years: 6 hours (Chien 2005)Adults: ~6 to 8 hoursAdults, renal impairment: 27 ± 10 hours (CrCl 20 to 49 mL/minute); 35 ± 5 hours (CrCl <20 mL/minute)Time to peak, serum: Oral: 1 to 2 hoursExcretion: Urine (~87% as unchanged drug, <5% as metabolites); feces (<4%)Clearance: IV (Chien 2005): Infants and Children 6 months to 2 years: 0.35 ± 0.13 L/hour/kgChildren 2 to 5 years: 0.32 ± 0.08 L/hour/kgChildren 5 to 10 years: 0.25 ± 0.05 L/hour/kgChildren 10 to 12 years: 0.19 ± 0.05 L/hour/kgChildren 12 to 16 years: 0.18 ± 0.03 L/hour/kgAdults: 0.15 ± 0.02 L/hour/kgPharmaco*kinetics: Additional ConsiderationsRenal impairment: Cl is reduced and half-life prolonged in patients with CrCl less than 50 mL/minute.Anti-infective considerations:Parameters associated with efficacy:Concentration dependent, associated with AUC24/minimum inhibitory concentration (MIC), goal: >87 (90% positive predictive value for pathogen eradication) (Cojutti 2017; Drusano 2004); and Cmax (peak)/MIC, goal ≥12 (clinical and microbiologic cures) (Abdul-Aziz 2020; Preston 1998). Note: In critically ill patients, some experts recommend AUC24/MIC goal >125 to 250 (Abdul-Aziz 2020).Organism specific:S. pneumoniae: AUC24/MIC ≥30 (bactericidal) (Ambrose 2001; Garrison 2003; Lacy 1999; Lister 1999).Mycobacterium tuberculosis: AUC24/MIC ≥146 (bacteriostatic at 24 hours) (Deshpande 2018).Pseudomonas aeruginosa: AUC24/MIC ≥80 (bactericidal) (Griffith 2006).Expected drug exposure in patients with normal renal function:AUC:Adults (multiple dose): AUC24:500 mg daily: Oral: 47.5 ± 6.7 mg•hour/L; IV: 54.6 ± 11.1 mg•hour/L.750 mg daily: Oral: 90.7 ± 17.6 mg•hour/L; IV: 108 ± 34 mg•hour/L.Cmax (peak):Pediatric patients:7 mg/kg (single dose) (Chien 2005):Infants and children 6 months to <5 years of age: Oral: 4.21 to 4.56 mg/L; IV: 5.19 to 6.02 mg/L.Children and adolescents 5 to 16 years of age: Oral: 3.99 to 4.76 mg/L; IV: 6.12 to 7.3 mg/L.15 mg/kg daily (steady state) (Thee 2014):Infants and children <6 years of age: Oral: Median: 6.86 to 7 mg/L (interquartile range: 4.69 to 8.06 mg/L).Children 6 to 8 years of age: Oral: Median: 4.98 mg/L (interquartile range: 4.52 to 7.48 mg/L).Adults (multiple dose):500 mg daily: Oral: 5.7 ± 1.4 mg/L; IV: 6.4 ± 0.8 mg/L.750 mg daily: Oral: 8.6 ± 1.9 mg/L; IV: 12.1 ± 4.1 mg/L.Postantibiotic effect: Bacterial killing continues after levofloxacin concentration falls below the MIC of targeted pathogen and varies based on the organism; generally, 1 to 3 hours (Fu 1992; Houston 1994; Licata 1997; Spangler 1998).Pricing: USSolution (levoFLOXacin in D5W Intravenous)250 mg/50 mL (per mL): $0.04 - $0.18500 mg/100 mL (per mL): $0.03 - $0.15750 mg/150 mL (per mL): $0.02 - $0.10Solution (levoFLOXacin Intravenous)25 mg/mL (per mL): $2.20 - $2.24Solution (levoFLOXacin Oral)25 mg/mL (per mL): $1.40Tablets (levoFLOXacin Oral)250 mg (per each): $0.12 - $17.53500 mg (per each): $0.22 - $20.09750 mg (per each): $0.34 - $36.12Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAbiflox (UA);Adlox (IN);Amlevo (VN);Auxxil (CL, PY);Avoxin (JO);Axoflon (PH);Bacflocin (TW);Bioworld (EG);Bredelin (CR, DO, GT, HN, NI, PA, SV);Conlevo (EC);Corvox (ID);Cravit (CN, HK, ID, JP, MY, PK, SG, TH, TW, VN);Cravox (ID);Elequine (BB, BM, BS, EC, JM, NL, PR, SR, TT);Evocs-III (CR, DO, GT, HN, NI, PA, SV);Evolox (RO);Evoxil (MT);Exacinop (EG);Fenalex (CR, DO, GT, HN, NI, PA, SV);Flexid (HR);Floxacap (ID);Floxel (PH);Floxidin (ID);Floxium (UA);Fovelid (HR);Getzlox (VN);Glevo (ZW);Gravixin (TH);Hailon (CN);Kevork (EG);L-Stafloxin (VN);Lamiwin (TZ);Lecifex (VN);Lecrav (ID);Lectacin (VN);Leflodal (TW);Leflox (BD);Lefloxin (TH);Lefocin (KR);Lemed (HK);LEO (BD);Leroxacin (KR);Lesacin (KR);Levalox (HR);Levaquin (AR, BR, CO, PE);Levflox (PH);Levo (IL);Levobact (PH, UA);Levocin (ID, PH, TH);Levoflox (BH, QA, ZW);Levokacin (KR);Levomac (ET, ZW);Levomicin (KR);Levoquin (HK, PH);Levores (ID, MY);Levox (JO, LK, PH, ZW);Levoxa (MT);Levoxacin (IT);Levoxl (HK);Levunid (PE);Lexacin (HK);Lexlo (BD);Locikline (MY);Lovequin (ID);Loxamox (LB);Lquin (PH);Lufi (LK);LUFI-500 (SG);Matador (BH, LB);Mosardal (ID);Nexquin (TZ);Nirliv (TH);Nirlix (LK);Nofaxin (KR);Olfovel (TH);Omnivox (PH);Pneumocal (PH);Ponaris (PE);Prolecin (ID);Prolecin IV (ID);Quinomed L (AR);Qure (ET);Reskuin (ID);Resquin (LK);Rinvox (ID);Rozoxin (TW);Tavager (IE);Tavanic (AE, AR, AT, BE, BG, BH, BM, BS, CH, CL, CR, CY, CZ, DE, DO, EE, EG, ES, FI, FR, GB, GT, HN, IE, IL, JM, JO, KW, LB, LT, LU, MT, NI, NL, PA, PE, PL, PT, PY, QA, RO, SA, SE, SK, SV, VE);Truxa (EC, UY);Uniflox (BH);Uroflox (EC);Vocin (HK, TH);Voflox (TH);Volequin (ID);VoLox (ID);Voxatic (ID);Wilovex (PH);Xalecin (TH);Zenilev (ID);Zidalex (ID)For country code abbreviations (show table)Abdul-Aziz MH, Alffenaar JC, Bassetti M, et al; Infection Section of European Society of Intensive Care Medicine (ESICM); Pharmaco*kinetic/pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID); Infectious Diseases Group of International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT); Infections in the ICU and Sepsis Working Group of International Society of Antimicrobial Chemotherapy (ISAC). 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CloseVitamin K (phytonadione, phytomenadione): Drug informationVitamin K (phytonadione, phytomenadione): Drug information(For additional information see "Vitamin K (phytonadione, phytomenadione): Patient drug information" and see "Vitamin K (phytonadione, phytomenadione): Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningHypersensitivity reactions with IV and IM use:Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after IV and IM injection of phytonadione. Reactions have occurred despite dilution to avoid rapid IV infusion and upon first dose. Avoid the IV and IM routes of administration unless the SUBQ route is not feasible and the serious risk is justified.Brand Names: USMephytonBrand Names: CanadaAquaMEPHYTON;Konakion;MephytonPharmacologic CategoryVitamin, Fat SolubleDosing: AdultNote: Due to risk of a severe infusion reaction, including anaphylaxis, the maximum rate of IV administration is 1 mg/minute.Reversal of anticoagulation due to warfarin or other coumarin or indandione derivativesReversal of anticoagulation due to warfarin or other coumarin or indandione derivatives:Note: Dose and route depend on the severity of bleeding and/or INR.Urgent reversal: IV administration is recommended. For life-threatening bleeding, vitamin K should be administered in combination with clotting factors (eg, 4-factor prothrombin complex concentrate [PCC], or fresh frozen plasma if 4-factor PCC is not available) (Ref). Following IV administration, reversal begins in ~2 hours with expected full reversal within 24 hours (Ref).Nonurgent reversal: Oral administration is recommended to reduce INR in ~24 to 48 hours (Ref). Avoid other routes: SUBQ administration is not recommended due to unpredictable absorption (Ref). Avoid IM administration due to risk of hematoma formation.Usual dosage range:Oral: Initial: 2.5 to 10 mg, depending on the INR. Administer as a single dose. Measure INR after 12 to 48 hours and administer another dose as needed.IV: Initial: 2.5 to 10 mg, depending on the INR and severity of bleeding. Administer as a single dose over 10 to 20 minutes (maximum infusion rate: 1 mg/minute). Measure INR after 6 to 12 hours and administer another dose as needed.Note: High doses of vitamin K (eg, >10 to 15 mg) may cause warfarin resistance for ≥1 week; if anticoagulation is needed, an alternative agent may be necessary (Ref).Reversal of Anticoagulation From WarfarinIndicationManagement considerationsVitamin K administrationa1 mg oral dose may be administered using 0.5 mL of 2 mg/mL parenteral preparation by mouth.bPatriquin 2011.cACCP [Hirsh 2008].dACCP [Holbrook 2012].eASH [Witt 2018].fAHA/ACC [Nishimura 2014]; ACC/AHA [Otto 2021].gFarrow 2020.hPCC=prothrombin complex concentrate.iACCP [Ageno 2012].jNCS/SCCM [Frontera 2016].kACCP [Douketis 2012].lDouketis 2021.mHull 2020.Supratherapeutic INR and no evidence of bleedingINR above therapeutic range but <4.5Consider holding the next dose of warfarin and/or reduce maintenance dose; increase INR monitoring.Elevated INR may be due to transient factors, so warfarin dose reduction is not always necessary.Routine administration of vitamin K is not recommended.bINR 4.5 to 10Discontinue warfarin, monitor INR frequently, and resume an appropriately reduced warfarin dose when INR is in desired range.May consider administering oral vitamin K if additional risk factors for bleeding exist.Routine administration of vitamin K is not recommended.If administered, one dose of oral vitamin K 1 to 2.5 mg is recommended.a,c,d,eINR >10Discontinue warfarin, monitor INR frequently, and resume an appropriately reduced warfarin dose when INR is in desired range.Consider administering oral vitamin K depending on bleeding and thrombotic risks.If administered, one dose of oral vitamin K 2.5 to 5 mg is usually recommended; recheck INR after 12 to 24 hours; may administer a second dose if necessary.c,dFor patients with a mechanical prosthetic heart valve, a lower oral vitamin K dose of 1 to 2.5 mg may be administered to avoid overcorrection of INR.a,fSome data suggest that vitamin K is not routinely needed in the absence of bleeding.gBleedingMinor bleedingDiscontinue warfarin, monitor INR frequently, and resume warfarin at an appropriately adjusted dose when it is safe to do so.Consider administering oral vitamin K depending on INR, site of bleeding, risk of progression to more serious bleeding, and thrombotic risk.If administered, oral vitamin K 2.5 to 5 mg is recommended; if INR remains elevated after 24 hours, may administer another dose.bMajor bleeding into a critical site and/or life- threatening bleeding (including intracranial hemorrhage)Discontinue warfarin and urgently administer a 4-factor PCCh in combination with IV vitamin K; monitor INR frequently and assess for hemostasis.Administer IV vitamin K 10 mg over 10 to 20 minutes (maximum infusion rate: 1 mg/minute) as soon as possible in combination with a 4-factor PCC; if INR remains elevated after 12 to 24 hours, may administer another dose of vitamin K.c,d,i,jInvasive procedure or surgeryElectiveThrombotic and bleeding risks vary depending on individual circ*mstances. The 2017 ACC expert consensus decision pathway, “Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation” may guide whether to interrupt warfarin therapy, how long before an elective procedure or surgery warfarin should be discontinued (if necessary), whether bridging with a parenteral anticoagulant is needed, and when to restart warfarin therapy after the procedure/surgery.If it is decided to discontinue warfarin, therapy is typically stopped 5 days before the procedure/surgery. If INR remains >1.5, oral vitamin K is recommended the day before the procedure/surgery. Recheck INR on the day of the procedure/surgery.Administer oral vitamin K 1 to 2.5 mg once if needed the day before the procedure/surgery.a,b,kUrgentFor urgent procedures or surgeries in patients at high bleeding risk, vitamin K with or without a 4-factor PCC may be needed.Administer IV vitamin K 1 to 10 mg over 10 to 20 minutes (maximum infusion rate: 1 mg/minute) with or without a 4-factor PCC, depending on urgency of the procedure/surgery and risk of bleeding.l,mRefer to institutional policies and procedures.Reversal of anticoagulation due to long-acting anticoagulant rodenticidesReversal of anticoagulation due to long-acting anticoagulant rodenticides: Consultation with a clinical toxicologist or poison control center and hematologist is highly recommended when making treatment decisions, including dose, route, and duration of therapy (Ref).No significant bleeding or minor bleeding (eg, epistaxis, ecchymosis):Note: Ideal dosing has not been established.INR <4 and no bleeding: No vitamin K required; monitor and observe closely (Ref).INR >4 or minor bleeding: Oral:Some experts recommend an initial dose of 10 mg per day in otherwise healthy patients; titrate as needed based on serial PT and INR measurements (Ref). The reported daily dosage range is variable (up to 800 mg per day (Ref)). Patients may require treatment for several months and should be under the care of a hematologist (Ref); compliance with treatment and monitoring is of utmost importance during outpatient therapy (Ref).Serious bleeding (eg, intracranial, GU, GI bleeding):Note: Ideal dosing has not been established. For life-threatening bleeding, vitamin K should be administered in combination with clotting factors (eg, 4-factor prothrombin complex concentrate [PCC] or 3-factor PCC in combination with either recombinant factor VIIa or fresh frozen plasma if 4-factor PCC is not available) (Ref). Treatment should begin with IV vitamin K and then transition to oral therapy (Ref).IV, Oral: Reported initial doses are variable and range from 10 to 300 mg per day; titrate as needed based on serial PT and INR measurements (Ref). Clinicians may choose to initiate therapy according to recommendations for reversal of anticoagulation due to warfarin or other coumarin or indandione derivatives at doses indicated for major bleeding at any INR elevation (Ref). The reported daily dosage range is variable (up to 800 mg per day (Ref)). Patients may require treatment with oral vitamin K for several months and should be under the care of a hematologist (Ref); compliance with treatment and monitoring is of utmost importance during outpatient therapy (Ref).Vitamin K deficiencyVitamin K deficiency (without liver disease): Note: Vitamin K deficiency in healthy adults is rare; deficiency tends to be associated with specific conditions (eg, bariatric surgery, biliary disease, malnutrition, cystic fibrosis, prolonged use of broad-spectrum antibiotics) (Ref). Avoid oral route in situations associated with GI malabsorption.Treatment of coagulopathy: IV, Oral, SUBQ: Usual dose: 10 mg once; may repeat in 48 to 72 hours if coagulopathy persists (Ref); range: 1 to 25 mg (manufacturer's labeling); maximum IV infusion rate: 1 mg/minute (Ref). Note: SUBQ administration is not recommended in patients with generalized edema (eg, anasarca) (Ref).Bariatric surgery:Prevention of vitamin K deficiency, supplementation:Laparoscopic adjustable gastric band, Roux-en-Y gastric bypass, or sleeve gastrectomy: Oral: 90 to 120 mcg once daily (Ref).Biliopancreatic diversion/duodenal switch: Oral: 300 mcg once daily (Ref).Acute vitamin K repletion for malabsorption: IV: 10 mg once over 10 to 20 minutes (Ref).Chronic vitamin K repletion for malabsorption: IV: 1 to 2 mg once weekly (Ref).Oral: 1 to 2 mg once daily (Ref).Note: In the United States and Canada, low-dose oral preparations can be found over the counter. A pharmacist can help the patient locate a low-dose supplement from a reliable supplier or prepare a compounded oral solution.Cystic fibrosis with pancreatic insufficiency:Prevention of vitamin K deficiency, supplementation: Oral: 2.5 to 5 mg once weekly. Note: Additional supplementation may be required during antibiotic therapy (Ref).Liver disease, treatment of coagulopathyLiver disease, treatment of coagulopathy (off-label use): Note: Consider use if vitamin K deficiency is suspected (eg, due to poor nutrition, cholestatic disease, diarrheal illness, or antibiotic use); vitamin K does not correct clotting factor deficiency due to parenchymal liver dysfunction and is not typically used for variceal bleeding (Ref).Major bleeding (nonvariceal):IV: 10 mg once over 10 to 20 minutes (maximum infusion rate: 1 mg/minute) (Ref).Minor bleeding (nonvariceal):Oral: 10 mg once daily for 3 days (Ref).IV: 10 mg once over 10 to 20 minutes (maximum infusion rate: 1 mg/minute) (Ref).Nonbleeding: Oral, IV, SUBQ: 5 to 10 mg once (maximum IV infusion rate: 1 mg/minute). Note: Oral route is preferred unless there is concern for poor absorption (Ref).Warfarin-associated INR variation due to vitamin K deficiencyWarfarin-associated INR variation due to vitamin K deficiency (off-label use): Note: For use in patients with poor INR control due to suspected vitamin K deficiency (eg, insufficient dietary intake). Ensure proper warfarin adherence and consult with the anticoagulation specialist managing the patient before prescribing.Oral: 100 to 200 mcg once daily (Ref).Note: In the United States and Canada, low-dose (eg, 100 mcg) oral preparations can be found over the counter. A pharmacist can help the patient locate a low-dose supplement from a reliable supplier or prepare a compounded oral solution.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling.Dosing: Pediatric(For additional information see "Vitamin K (phytonadione, phytomenadione): Pediatric drug information")Note: Route of administration varies with indication; careful evaluation of route of administration is important. The oral route is preferred in the treatment of nonbleeding patients with warfarin-associated coagulopathy; SubQ administration has fallen out of favor for this indication due to erratic and unpredictable absorption (Ref). The IV route may be used in select nonbleeding patients and should be used in patients with major bleeding due to warfarin-associated coagulopathy (Ref). The IV and SubQ routes may be used in the treatment of vitamin K deficiency bleeding (Ref). The IM route should be avoided due to the risk of hematoma formation except in the prevention/treatment of vitamin K deficiency bleeding (Ref). Dosing presented in mcg and mg; verify dosing units.Parenteral nutrition, maintenance requirementParenteral nutrition, maintenance requirement: Limited data available (Ref): Note: Patients receiving warfarin may not require TPN supplementation of phytonadione.Infants: IV: 10 mcg/kg/day as an additive to parenteral nutrition solution.Children and Adolescents: IV: 200 mcg/day as an additive to parenteral nutrition solution.Reversal of vitamin K antagonistsReversal of vitamin K antagonists (eg, warfarin): Limited data available:Infants, Children, and Adolescents:Weight-based dosing (preferred): Chest recommendations: IV: 0.03 mg/kg/dose is recommended for excessively prolonged INR (usually INR >8; no evidence of bleeding) due to vitamin K-antagonist (eg, warfarin): if significant bleeding, consider use of fresh frozen plasma, prothrombin complex concentrates, or recombinant factor VIIa (Ref).Fixed dosing: Note: Smaller pediatric patients should receive doses on the low end of dosing range; excessive dosages may cause warfarin-resistance (Ref).No bleeding, rapid reversal needed, patient will require further oral anticoagulant therapy: SubQ, IV: 0.5 to 2 mg.No bleeding, rapid reversal needed, patient will not require further oral anticoagulant therapy: SubQ, IV: 2 to 5 mg.Significant bleeding, not life-threatening: SubQ, IV: 0.5 to 2 mg; Note: Use in combination with fresh frozen plasma.Significant bleeding, life-threatening: SubQ, IV: 5 mg; Note: Consider use with prothrombin complex concentrate containing factors II, VII, IX, X.Vitamin K deficiency, prevention, and supplementationVitamin K deficiency, prevention, and supplementation (disease-specific): Limited data available:Biliary atresia (Ref): Note: Dose and route are determined by INR value:Infants 1 to 6 months:INR >1.2 to 1.5: 2.5 mg once daily orally.INR >1.5 to 1.8: Initial: 2 to 5 mg IM once followed by 2.5 mg once daily orally.INR >1.8: Initial: 2 to 5 mg IM once followed by 5 mg once daily orally.Cholestasis: Infants, Children, and Adolescents: Oral: 2.4 to 15 mg/day (Ref).Cystic fibrosis: Infants, Children, and Adolescents: Oral: 0.3 to 0.5 mg/day (Ref).Liver disease: Infants, Children, and Adolescents: Oral: 2.5 to 5 mg/day (Ref).Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in manufacturer's labeling.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in manufacturer's labeling; dosing adjustment unlikely necessary.Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Injection, aqueous colloidal: 1 mg/0.5 mL (0.5 mL); 10 mg/mL (1 mL)Injection, aqueous colloidal [preservative free]: 1 mg/0.5 mL (0.5 mL)Tablet, oral:Mephyton: 5 mg [scored]Generic: 100 mcg, 5 mgGeneric Equivalent Available: USYesDosage Forms ConsiderationsInjectable products may contain alcohol, benzyl alcohol, polysorbate 80, propylene glycol, or polyoxyethylated/polyethoxylated castor oil (Cremophor EL).Administration: AdultIV: After dilution of dose in a minimum of 50 mL of compatible solution, administer slowly using an infusion pump over 10 to 20 minutes depending on dose at a rate not to exceed 1 mg/minute (Ref). The injectable route should be used only if the oral route is not feasible or there is a greater urgency to reverse anticoagulation. The IV route may be used in selected nonbleeding patients and should be used in patients with major bleeding due to warfarin-associated coagulopathy (Ref).SUBQ: SUBQ route is generally not recommended due to erratic and unpredictable absorption (Ref).IM: IM route should be avoided due to the risk of hematoma formation.Oral: The parenteral formulation may also be used for small oral doses (eg, 1 mg) or situations in which tablets cannot be swallowed (Ref); may administer undiluted or diluted in a beverage (eg, orange juice) (Ref).Administration: PediatricOral: May be administered with or without food. The parenteral formulation may also be used for small oral doses (eg, 1 mg) or situations in which tablets cannot be swallowed (Ref).Parenteral: Note: Limit IV administration to situations where an alternative route of administration is not feasible and the benefit of therapy outweighs the risk of hypersensitivity reactions; proper dosing, dilution, and administration will minimize risk (Ref). Allergic reactions have also occurred with IM and SUBQ injections, albeit less frequently.SUBQ: Administer undiluted.IM: Administer undiluted; for use in neonatal patients, verify appropriate concentration (1 mg/0.5 mL).IV: After dilution, infuse slowly. In pediatric patients, IV doses have been infused over 10 to 30 minutes (Ref); maximum rate of infusion: 1 mg/minute (Ref).Use: Labeled IndicationsReversal of anticoagulation due to warfarin or other coumarin or indandione derivatives (eg, brodifacoum): Treatment of anticoagulant-induced deficiency of vitamin K–dependent clotting factors caused by coumarin or indandione derivatives, including warfarin and long-acting anticoagulant rodenticides (eg, brodifacoum, bromadiolone, difenacoum) (Card 2014; Devgun 2020; Feinstein 2020; Gunja 2011).Vitamin K deficiency (without liver disease): Treatment of deficiency secondary to factors limiting absorption or synthesis of vitamin K (eg, obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis of the pancreas, regional enteritis) or drug-induced interference with vitamin K metabolism (eg, salicylates, antibacterial therapy).Vitamin K deficiency bleeding (formerly known as hemorrhagic disease) of the newborn: Prophylaxis and treatment of vitamin K deficiency bleeding (formerly known as hemorrhagic disease) of the newborn (injection only).Use: Off-Label: AdultLiver disease, treatment of coagulopathy; Warfarin-associated INR variation due to vitamin K deficiencyMedication Safety IssuesSound-alike/look-alike issues: Mephyton may be confused with melphalan, methadoneAdverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.Frequency not defined:Cardiovascular: Chest pain, flushing, hypotension, tachycardia, weak pulseCentral nervous system: DizzinessDermatologic: Diaphoresis, eczematous rash, erythema, erythematous rash, pruritic plaques of the skin, urticariaGastrointestinal: DysgeusiaHepatic: HyperbilirubinemiaHypersensitivity: Anaphylactoid reaction, anaphylaxis, hypersensitivity reactionLocal: Injection site reaction (including pain, swelling, tenderness)Respiratory: Cyanosis, dyspneaMiscellaneous: Lesion (scleroderma-like)ContraindicationsHypersensitivity to phytonadione or any component of the formulationWarnings/PrecautionsConcerns related to adverse effects:• Dermatologic toxicity: Cutaneous reactions have occurred after parenteral administration, including delayed-type hypersensitivity reactions, eczematous reactions, scleroderma-like patches, and urticaria; onset may occur within 1 day to a year. If skin reactions occur, discontinue therapy and treat appropriately.• Hypersensitivity/anaphylactoid reactions: Hypersensitivity reactions, including anaphylaxis, chest pain, cyanosis, diaphoresis, dyspnea, flushing, cardiorespiratory arrest, shock, tachycardia, weakness, and death, have occurred. Anaphylaxis typically, but not always, occurred when patients received large IV doses administered rapidly with formulations containing polyethoxylated castor oil (also called polyoxyethylated castor oil); proper dosing, dilution, and administration will minimize risk (ACCP [Ageno 2012]; Britt 2018; Riegert-Johnson 2002).Disease-related concerns:• Anticoagulant-induced coagulopathy: In patients receiving a therapeutic vitamin K antagonist (VKA) (eg, warfarin), administer a dose of phytonadione that will quickly lower the INR into a safe range without causing resistance to warfarin. High phytonadione doses (eg, >10 to 15 mg) may lead to warfarin resistance for ≥1 week.• Liver disease, coagulopathy: If initial doses do not reverse coagulopathy, then higher doses are unlikely to have any effect. Note: Ineffective in hereditary hypoprothrombinemia.• Long-acting anticoagulant rodenticide (LAAR) ingestion: Patients with LAAR-induced coagulopathy require much larger doses and longer treatment durations (up to months) after exposure compared to that needed to reverse warfarin-induced coagulopathy (Devgun 2020; Gunja 2011).Special populations:• Neonates: Use with caution in neonates, especially premature infants; severe hemolytic anemia, jaundice, and hyperbilirubinemia have been reported with larger than recommended doses (10 to 20 mg).Dosage form specific issues:• Aluminum: The parenteral product may contain aluminum; toxic aluminum concentrations may be seen with high doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is associated with CNS and bone toxicity; tissue loading may occur at lower doses (Federal Register 2002). See manufacturer's labeling.• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.• Polyoxyethylated castor oil: Some injectable dosage forms contain polyoxyethylated castor oil (Cremophor EL) which is associated with hypersensitivity reactions.• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.Other warnings/precautions:• Appropriate route: Oral administration is the safest and requires the presence of bile salts for absorption. In obstructive jaundice or with biliary fistulas, concurrent administration of bile salts would be necessary for proper absorption. Manufacturers recommend the SubQ route over other parenteral routes, however, SubQ is less predictable when compared to the oral route, and efficacy may be delayed. Therefore, the SubQ route has fallen out of favor due to erratic and unpredictable absorption (Crowther 2002; DeZee 2006; Raj 1999). The IV route may be used in selected nonbleeding patients and should be used in patients with major bleeding due to warfarin-associated coagulopathy (ACCP [Guyatt 2012]; Patriquin 2011). IM route should be avoided due to the risk of hematoma formation (except, for example, in the neonatal and pediatric populations for prevention/treatment of vitamin K deficiency bleeding). Efficacy (eg, control of bleeding, decrease in INR) is delayed regardless of route of administration; patient management may require other treatments in the interim.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Orlistat: May decrease the absorption of Vitamins (Fat Soluble). Management: Administer oral fat soluble vitamins at least 2 hours before or 2 hours after the administration of orlistat. Avoid concomitant administration due to the risk of impaired vitamin absorption. Risk D: Consider therapy modificationVitamin K Antagonists (eg, warfarin): Phytonadione may diminish the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapyPregnancy ConsiderationsPhytonadione crosses the placenta in limited concentrations (Kazzi 1990).The dietary requirements of vitamin K are the same in pregnant and nonpregnant women (IOM 2001). In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003). Use of preservative free solutions are preferred when the injection is needed during pregnancy.Breastfeeding ConsiderationsPhytonadione is present in breast milk.Small amounts of dietary vitamin K can be detected in breast milk and the dietary requirements of vitamin K are the same in breastfeeding and non-breastfeeding women (IOM 2001). According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Use of preservative free solutions are preferred when the injection is needed in breastfeeding women.Dietary ConsiderationsDietary adequate intake (IOM 2001; Vanek 2012):1 to 6 months: 2 mcg/day7 to 12 months: 2.5 mcg/day1 to 3 years: 30 mcg/day4 to 8 years: 55 mcg/day9 to 13 years: 60 mcg/day14 to 18 years: 75 mcg/day>18 years: Males: 120 mcg/day; Females: 90 mcg/dayMonitoring ParametersLong-acting anticoagulant rodenticide poisoning: PT/INR; consider serial measurement of plasma coumarin concentration (eg, plasma brodifacoum concentrations) to help guide treatment duration decisions. At least 3 samples collected over the period of 1 week has been suggested to determine treatment duration; an additional measurement taken 2 weeks after treatment discontinuation is recommended to rule out rebound elevation and ensure maintenance of safe concentrations (Nosal 2021).Mechanism of ActionPromotes liver synthesis of clotting factors (II, VII, IX, X); however, the exact mechanism as to this stimulation is unknown. Menadiol is a water soluble form of vitamin K; phytonadione has a more rapid and prolonged effect than menadione; menadiol sodium diphosphate (K4) is half as potent as menadione (K3).Pharmaco*kineticsOnset of action: Increased coagulation factors: Oral: 6 to 10 hours; IV: 1 to 2 hours.Peak effect: INR values return to normal: Oral: 24 to 48 hours; IV: 12 to 14 hours.Absorption: Oral: From intestines in presence of bile; SUBQ: Variable; IM: Readily.Metabolism: Rapidly hepatic.Excretion: Urine and feces.Pricing: USCapsules (K1-1000 Oral)1 mg (per each): $0.11Solution (Phytonadione Injection)1 mg/0.5 mL (per 0.5 mL): $7.20 - $29.6810 mg/mL (per mL): $51.32Tablets (Mephyton Oral)5 mg (per each): $70.51Tablets (Phytonadione Oral)5 mg (per each): $66.99Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalBonadiona (CR, DO, GT, HN, NI, PA, SV);Dynaphyto (PH);Haemokion (AE, CY, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE);Hema-K (PH);Hematron (PH);Kanakion (PT);Kanavit (CZ);Katimin-1 (TW);Kenadion (IN);Konakion (10 mg) (AE, AU, BG, CY, DE, EC, GB, GH, IE, IL, IQ, IR, IT, JO, KE, KW, LB, LY, NL, OM, SA, SE, SY, TZ, UG, YE, ZM);Konakion (BE, DK, ES, HU, IS, LU, NO, SI, TR, ZW);Konakion 10 mg (AT, FI, HN);Konakion MM (BH, CL, HR, KW, LB, LK, LV, MX);Konakion MM Paediatric (BB, BM, BS, BZ, GY, JM, SR, TT);Konakion MM Pediatric (AR, AU, BR, CH, CO, NZ, PE, PK, PY, UY, VN);Mepro K (ID);Neokay (GB);Phytomen (PH);Prohem (ID);Univitan K1 (HK);Vitacon (PL);Vitak (JP);Vitamin K (HK);Vitamin K1 (KR);Vitamine K!1 Roche (FR);Vitka Infant (ID)For country code abbreviations (show table)Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e44s-e88s. doi:10.1378/chest.11-2292 [PubMed 22315269]Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]Aluminum in large and small volume parenterals used in total parenteral nutrition. Fed Regist. 2002;67(244):77792-77793. To be codified at 21 CFR §201.323.American Academy of Pediatrics Committee on Fetus and Newborn. Controversies Concerning Vitamin K and the Newborn. American Academy of Pediatrics Committee on Fetus and Newborn. Pediatrics. 2003;112(1, pt 1):191-192. [PubMed 12837888]American Academy of Pediatrics Committee on Nutrition. Kleinman RE, Greer FR, eds. Pediatric Nutrition Handbook. 8th ed. American Academy of Pediatrics; 2019.Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6)(suppl):160s-198s. doi:10.1378/chest.08-0670 [PubMed 18574265]Bailey B. Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women? Birth Defects Res A Clin Mol Teratol. 2003;67(2):133-140. [PubMed 12769509]Baugh CW, Levine M, Cornutt D, et al. Anticoagulant reversal strategies in the emergency department setting: recommendations of a multidisciplinary expert panel. Ann Emerg Med. 2020;76(4):470-485. doi:10.1016/j.annemergmed.2019.09.001 [PubMed 31732375]Bolton-Maggs P, Brook L. The Use of Vitamin K for Reversal of Over-Warfarinization In Children. Br J Haematol. 2002;118(3):924. [PubMed 12181071]Borowitz D, Baker RD, Stallings V. Consensus Report on Nutrition for Pediatric Patients With Cystic Fibrosis. J Pediatr Gastroenterol Nutr. 2002;35(3):246-259. [PubMed 12352509]Britt RB, Brown JN. Characterizing the severe reactions of parenteral vitamin K1. Clin Appl Thromb Hemost. 2018;24(1):5-12. doi:10.1177/1076029616674825 [PubMed 28301903]Bronsky J, Campoy C, Braegger C; ESPGHAN/ESPEN/ESPR/CSPEN working group on pediatric parenteral nutrition. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Vitamins. Clin Nutr. 2018;37(6, pt B):2366-2378. [PubMed 30100105]Calello DP. Anticoagulant rodenticide poisoning: management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 21, 2022.Card DJ, Francis S, Deuchande K, Harrington DJ. Superwarfarin poisoning and its management. BMJ Case Rep. 2014;2014:bcr2014206360. doi:10.1136/bcr-2014-206360 [PubMed 25312896]Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. 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CloseVancomycin: Drug informationVancomycin: Drug information(For additional information see "Vancomycin: Patient drug information" and see "Vancomycin: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningRisk of embryo-fetal toxicity due to excipients:A formulation of vancomycin injection contains the excipients polyethylene glycol (PEG 400) and N-acetyl D-alanine (NADA), which resulted in fetal malformations in animal reproduction studies at dose exposures approximately 8 and 32 times, respectively, higher than the exposures at the human equivalent dose. If use of vancomycin is needed during the first or second trimester of pregnancy, use other available formulations of vancomycin.Brand Names: USFirvanq;Vancocin;Vancosol Pack [DSC]Brand Names: CanadaJAMP Vancomycin;JAMP-Vancomycin;Vancocin;Vancomycin HClPharmacologic CategoryGlycopeptideDosing: AdultUsual dosage range: Note: Initial IV dosing in nonobese patients should be based on actual body weight; subsequent dosing should generally be adjusted based on therapeutic monitoring. Trough monitoring has traditionally been used for therapeutic monitoring; however, for serious methicillin-resistant S. aureus (MRSA) infections (eg, bacteremia, infective endocarditis, meningitis, osteomyelitis, pneumonia, sepsis), AUC monitoring is preferred (Ref). For patients with uncomplicated skin and soft tissue infections who are not obese and have normal renal function, therapeutic monitoring is generally not needed (Ref). Risk of toxicity (eg, acute kidney injury) increases as a function of trough concentration, especially when trough is maintained above 15 to 20 mg/L; recent data suggest risk increases along the vancomycin AUC continuum, especially when daily AUC exceeds 650 to 1,300 mg•h/L (Ref).Oral: Note: Ineffective for treating systemic infections: 125 to 500 mg 4 times daily.IV: Note: Ineffective for treating C. difficile infections.Intermittent infusion: 15 to 20 mg/kg/dose (rounded to the nearest 250 mg) every 8 to 12 hours initially; for serious MRSA infections (eg, bacteremia, infective endocarditis, meningitis, osteomyelitis, pneumonia, sepsis), adjust based on therapeutic monitoring to achieve a target AUC/minimum inhibitory concentration (MIC) determined by broth microdilution (MICBMD) ratio of 400 to 600 (assuming a vancomycin MICBMD of 1 mg/L; see "Reference Range" for more information). Trough-only monitoring (target trough: 15 to 20 mg/L) is no longer recommended in patients with serious MRSA infections (Ref), but may be needed in nonserious MRSA or non-MRSA infections. Early and frequent monitoring for dosage adjustments is recommended, especially when empiric doses exceed 4 g/day (Ref).Loading dose: Seriously ill patients with documented/suspected MRSA infection: A loading dose of 20 to 35 mg/kg (based on actual body weight; maximum: 3 g/dose) may be considered to rapidly achieve target concentrations. After administration of the loading dose, the initiation of the maintenance dose should occur at the next dosing interval (eg, for a prescribed interval of every 8 hours, initiate the maintenance dose 8 hours after the start of the loading dose) (Ref).Continuous infusion: Note: May be considered for critically ill patients who are unable to achieve AUC target with intermittent infusion dosing. Loading dose: 15 to 20 mg/kg, followed by a maintenance continuous infusion dose of 30 to 40 mg/kg/day (up to 60 mg/kg/day) to achieve a target steady state concentration of 20 to 25 mg/L (Ref).Indication-specific dosing:Bloodstream infectionBloodstream infection:Empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref). Treat uncomplicated S. aureus infection for ≥14 days from first negative blood culture, with longer courses warranted for endocarditis or metastatic sites of infection (Ref).Empiric therapy or pathogen-specific therapy for methicillin-resistant coagulase-negative staphylococci: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring. Treat uncomplicated bacteremia for 5 to 7 days from day of first negative blood culture, with longer courses warranted for endocarditis or metastatic sites of infection (Ref). For catheter-related bloodstream infections, consider antibiotic lock therapy for catheter salvage, in addition to systemic therapy (Ref).Antibiotic lock technique (catheter-salvage strategy) (off-label use): Note: For infections caused by susceptible organisms when the catheter cannot be removed; use in addition to systemic antibiotics. Catheter salvage is not recommended for S. aureus(Ref).Intracatheter: Prepare lock solution to final concentration of vancomycin 2.5 to 5 mg/mL; may be combined with heparin. Instill into each lumen of the catheter access port using a volume sufficient to fill the catheter (2 to 5 mL) with a dwell time of up to 72 hours, depending on frequency of catheter use. Withdraw lock solution prior to catheter use; replace with fresh vancomycin lock solution after catheter use. Antibiotic lock therapy is given for the same duration as systemic antibiotics (Ref).Cerebrospinal fluid shunt infectionCerebrospinal fluid shunt infection (off-label use): As a component of empiric therapy or pathogen-specific therapy (eg, methicillin-resistant S. aureus or coagulase-negative staphylococci):IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref).Intraventricular (adjunct to systemic therapy; use a preservative-free preparation): 5 to 20 mg/day; some experts recommend adjusting dosage and administration interval based on cerebrospinal fluid (CSF) vancomycin concentrations (goal: 10 to 20 times MIC of causative organism), ventricular size, and daily output from ventricular drain (Ref); data for monitoring are limited (Ref). When intraventricular vancomycin is administered via a ventricular drain, clamp drain for 15 to 60 minutes after administration (allows solution to equilibrate in CSF) (Ref). Note: Intraventricular administration is generally reserved for use in patients who fail parenteral therapy despite removal of CSF shunt or when CSF shunt cannot be removed (Ref).Clostridioides difficile infection, prophylaxisClostridioides difficile infection, prophylaxis (off-label use):Note: For patients with a recent history of C. difficile infection (CDI) who subsequently require systemic antibiotics. Some experts reserve for patients who are older (≥65 years of age) or are significantly immunocompromised who have been hospitalized with severe CDI in the past 3 months (Ref); other experts consider use for any patients with CDI in the prior 12 months (Ref).Oral: 125 mg once daily; continue for 5 to 7 days after completion of systemic antibiotics (Ref).Clostridioides difficile infection, treatmentClostridioides difficile infection, treatment: Note: Criteria for disease severity is based on expert opinion and should not replace clinical judgment. There is no role for vancomycin doses other than 125 mg and 500 mg (Ref).Initial, nonfulminant infection (alternative agent): Oral: 125 mg 4 times daily (Ref). Usual duration is 10 days; if delayed response to treatment, a longer duration (eg, up to 14 days) may be considered (Ref). If antibiotic(s) for a primary infection are essential, some experts extend CDI treatment one week beyond other antibiotic(s) (Ref).Recurrent, nonfulminant infection (alternative agent): Note: Regimen selection depends on prior treatment (Ref).Oral: 125 mg 4 times daily (Ref). Some experts reserve for patients who did not receive vancomycin for the initial episode (Ref). Usual duration is 10 days; if delayed response to treatment, a longer duration (eg, up to 14 days) may be considered (Ref). If antibiotic(s) for a primary infection are essential, some experts extend CDI treatment one week beyond other antibiotic(s) (Ref).Pulsed-tapered regimen: Oral: 125 mg 4 times daily for 10 to 14 days, then 125 mg twice daily for 7 days, then 125 mg once daily for 7 days, then 125 mg every 2 or 3 days for 2 to 8 weeks (Ref).Combination regimen with rifaximin: Note: Rifaximin resistance may be a concern; some experts avoid in patients who have previously received rifamycins, and others do not routinely recommend this regimen (Ref).Oral: 125 mg 4 times daily for 10 days followed by rifaximin (Ref).Fulminant infection (ie, ileus, megacolon, and/or hypotension/shock): Oral or via nasogastric tube: 500 mg 4 times daily with IV metronidazole; if ileus is present, may consider vancomycin retention enema (Ref). Usual duration is 10 days; if delayed response to treatment, a longer duration (eg, up to 14 days) may be considered (Ref). If antibiotic(s) for a primary infection are essential, some experts extend CDI treatment one week beyond other antibiotic(s) (Ref).Fulminant infection with ileus: Rectal retention enema (off-label route): 500 mg in 100 mL NS; retained for as long as possible and replaced every 6 hours. Use in combination with oral vancomycin (if the ileus is partial) or in place of oral vancomycin (if the ileus is complete) plus IV metronidazole (Ref). Note: Optimal regimen not established. Use of rectal vancomycin should be reserved for patients who have not responded to standard therapy and performed by individuals with expertise in administration, as there is risk of colonic perforation. Usual duration is 10 days; if delayed response to treatment, a longer duration (eg, up to 14 days) may be considered. If antibiotic(s) for a primary infection are essential, some experts extend CDI treatment one week beyond other antibiotic(s) (Ref).Cystic fibrosis, acute pulmonary exacerbation, moderate to severeCystic fibrosis, acute pulmonary exacerbation, moderate to severe (off-label use): Empiric or pathogen-directed therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 hours initially; adjust based on therapeutic monitoring (Ref). Duration is usually 10 to 14 days depending on clinical response (Ref).Diabetic foot infection, moderate to severeDiabetic foot infection, moderate to severe (off-label use): Empiric or pathogen-directed therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). Duration (which may include appropriate oral step-down therapy) is usually 2 to 4 weeks in the absence of osteomyelitis (Ref).Endocarditis, treatmentEndocarditis, treatment:Enterococcus (native or prosthetic valve) (penicillin-resistant strains or patients unable to tolerate beta-lactams): IV: 15 mg/kg/dose every 12 hours initially; adjust to obtain a trough concentration of 10 to 20 mg/L (Ref); some experts favor a trough of 15 to 20 mg/L (Ref). Administer in combination with gentamicin for 6 weeks (Ref).S. aureus, methicillin-resistant or methicillin-susceptible (severe-beta lactam hypersensitivity) (alternative agent): IV:Native valve: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref). Duration of therapy is 6 weeks (Ref).Prosthetic valve: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref). Duration of therapy is at least 6 weeks (combine with rifampin for the entire duration of therapy and gentamicin for the first 2 weeks) (Ref).Viridans group streptococci and S. bovis (native or prosthetic valve) (penicillin or ceftriaxone intolerance): IV: 15 mg/kg/dose every 12 hours initially; adjust based on therapeutic monitoring. Duration of therapy is 4 weeks (native valve) or 6 weeks (prosthetic valve) (Ref).Endophthalmitis, treatmentEndophthalmitis, treatment (off-label use): Intravitreal: Usual dose: 1 mg per 0.1 mL NS or sterile water injected into vitreum, usually in combination with ceftazidime (Ref). A repeat dose(s) may be considered at 24 to 48 hours based on culture result, severity of the infection, and response to treatment (Ref).Intra-abdominal infection, health care–associatedIntra-abdominal infection, health care–associated (off-label use): Empiric or pathogen-directed therapy for Enterococcus spp. in high-risk patients (eg, postoperative infection or health care–associated infection in patients with prior use of antibiotics that select for Enterococcus, immunocompromising condition, valvular heart disease, or prosthetic intravascular material): IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). Use as part of an appropriate combination regimen (Ref). Total duration of therapy (which may include transition to oral antibiotics) is 4 to 5 days following adequate source control (Ref).Intracranial abscess or spinal epidural abscessIntracranial abscess (brain abscess, intracranial epidural abscess) or spinal epidural abscess (off-label use): As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring. A loading dose may be considered in seriously ill patients (Ref). Duration generally ranges from 4 to 8 weeks for brain abscess and spinal epidural abscess and 6 to 8 weeks for intracranial epidural abscess (Ref).Meningitis, bacterialMeningitis, bacterial (off-label use): As a component of empiric therapy or pathogen-specific therapy (eg, methicillin-resistant S. aureus or penicillin- and cephalosporin-resistant S. pneumoniae): IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref).OsteomyelitisOsteomyelitis:As a component of empiric therapy or pathogen-specific therapy (eg, methicillin-resistant S. aureus): IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially (Ref); adjust based on therapeutic monitoring. A loading dose may be considered in seriously ill patients (Ref). Duration is generally ≥6 weeks; shorter courses are appropriate if the affected bone is completely resected (Ref).Peritonitis, treatmentPeritonitis, treatment (peritoneal dialysis patients) (off-label use): Note: Intraperitoneal administration is preferred to IV administration. Adjust to obtain a trough concentration between 15 and 20 mg/L (Ref). Consider a 25% dose increase in patients with significant residual renal function (urine output >100 mL/day) (Ref).Intermittent (preferred): Intraperitoneal: 15 to 30 mg/kg added to one exchange of dialysate every 5 to 7 days (allow to dwell for ≥6 hours); supplemental doses and more frequent monitoring of serum levels may be needed for patients receiving automated peritoneal dialysis (Ref).Continuous (with every exchange): Intraperitoneal: Loading dose: 30 mg/kg added to first exchange of dialysate; maintenance dose: 1.5 mg/kg/bag for each subsequent exchange of dialysate (Ref).PneumoniaPneumonia, as a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref). Note: Duration of therapy varies based on disease severity and response to therapy; treatment is typically given for 7 days. When used for empiric therapy, give as part of an appropriate combination regimen (Ref).Prosthetic joint infectionProsthetic joint infection (off-label use): IV:Pathogen-specific therapy for methicillin-resistant or susceptible S. aureus (alternative agent in beta-lactam intolerance): 15 to 20 mg/kg/dose every 8 to 12 hours initially (Ref); adjust based on therapeutic monitoring. A loading dose may be considered in seriously ill patients (Ref). Duration ranges from 2 to 6 weeks depending on prosthesis management, use of rifampin, and other patient-specific factors (Ref).Pathogen-specific therapy for Enterococcus spp (penicillin susceptible [alternative agent] or penicillin resistant): 15 mg/kg/dose every 12 hours initially; adjust based on therapeutic monitoring. Duration: 4 to 6 weeks (Ref). Note: In select cases (eg, debridement and retention of prosthesis or one-stage arthroplasty), give oral suppressive antibiotic therapy with an appropriate regimen following completion of initial treatment (Ref).Sepsis/septic shockSepsis/septic shock: As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours; adjust based on therapeutic monitoring (Ref). A loading dose is recommended; administer within 1 hour of suspected or confirmed sepsis (Ref). Duration is dependent on underlying source and patient response; short courses are preferred, when appropriate (Ref).Septic arthritis, without prosthetic materialSeptic arthritis, without prosthetic material: As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus or coagulase-negative staphylococci: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust dose on therapeutic monitoring. A loading dose may be considered in seriously ill patients (Ref). Total treatment duration is 3 to 4 weeks (in the absence of osteomyelitis), including appropriate oral step-down therapy (Ref); some experts recommend 4 weeks of parenteral therapy for patients with concomitant bacteremia (Ref).Skin and soft tissue infectionSkin and soft tissue infection (hospitalized patient): As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 mg/kg/dose every 12 hours initially (Ref). For patients with uncomplicated skin and soft tissue infections who are not obese and have normal renal function, therapeutic monitoring is generally not needed; for complicated or severe infections, adjust based on therapeutic monitoring (Ref). Note: For empiric therapy of necrotizing infection, must be used in combination with other agents (Ref).Streptococcus, maternal prophylaxis for prevention of neonatal diseaseStreptococcus (group B), maternal prophylaxis for prevention of neonatal disease (alternative agent) (off-label use):IV: 20 mg/kg at the onset of labor or prelabor rupture of membranes, then every 8 hours until delivery; maximum single dose: 2 g (Ref). Some experts prefer vancomycin 2 g initially and then 1 g every 12 hours thereafter until delivery (Ref). Note: Vancomycin is reserved for patients with penicillin allergy at high risk for anaphylaxis that have documented clindamycin-resistant group B Streptococcus or no available susceptibility data (Ref).Surgical prophylaxisSurgical prophylaxis (in combination with other appropriate agents when coverage for methicillin-resistant S. aureus is indicated or for gram-positive coverage in patients unable to tolerate beta-lactams) (off-label use): IV: 15 mg/kg (usual maximum: 2 g/dose initially (Ref)) started within 60 to 120 minutes prior to initial surgical incision. Vancomycin doses may be repeated intraoperatively in 2 half-lives (approximately 8 to 12 hours in patients with normal renal function) if procedure is lengthy or if there is excessive blood loss (Ref). In cases where an extension of prophylaxis is warranted postoperatively, total duration should be ≤24 hours (Ref). Postoperative prophylaxis is not recommended in clean and clean-contaminated surgeries (Ref).Surgical site infectionSurgical site infection: As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 mg/kg/dose every 12 hours initially; adjust based on therapeutic monitoring (Ref).Toxic shock syndrome, staphylococcalToxic shock syndrome, staphylococcal: As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref). Duration varies based on underlying etiology; 10 to 14 days of treatment is recommended in the absence of bacteremia or other distinct focus of infection (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Oral: There are no dosage adjustments provided in the manufacturer's labeling. However, dosage adjustment unlikely due to low systemic absorption.IV:Note: Initial IV dosing in nonobese patients should be based on actual body weight; subsequent dosing should generally be adjusted based on therapeutic monitoring. Trough monitoring has traditionally been used for therapeutic monitoring; however, for serious methicillin-resistant S. aureus (MRSA) infections (eg, bacteremia, infective endocarditis, meningitis, osteomyelitis, pneumonia, sepsis), AUC monitoring is preferred (Ref). A ratio of AUC over 24 hours to minimum inhibitory concentration (AUC/MIC) of ≥400 is the primary pharmaco*kinetic/pharmacodynamic predictor of vancomycin efficacy in serious MRSA infections (Ref). Serum concentration monitoring should be conducted within the first 48 hours of therapy for patients with suspected or documented serious infections due to MRSA, with subsequent dosing adjusted to maintain AUC/MIC between 400 to 600 in order to maximize efficacy and minimize risk of vancomycin nephrotoxicity (Ref).Altered kidney function:Intermittent infusion: Note: The following table provides general recommendations (expert opinion derived from ASHP/IDSA/PIDS/SIDP [Rybak 2020]; Golightly 2013). Refer to institution-specific policies and procedures for more detailed guidance.Vancomycin Initial Dose Adjustments in Altered Kidney FunctionCrCl (mL/minute)Suggested loading dose (when applicable)aSuggested initial maintenance doseSuggested dosing intervalaLoading doses recommended in critically ill patients with suspected/documented serious MRSA infections. A loading dose of up to 35 mg/kg may be considered in critically ill patients with sepsis. Obese patients usually require 20 to 25 mg/kg loading doses. Maximum recommended loading dose is 3 g (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).bMonitor vancomycin serum concentrations more frequently, especially early on in therapy, to achieve target concentrations as these patients may have unstable or less predictable drug clearance. Care should be taken not to administer maintenance doses when serum concentrations remain >20 mg/L (Golightly 2013; expert opinion).>90 to <13025 to 30 mg/kg15 to 20 mg/kg8 to 12 hours50 to 9020 to 25 mg/kg15 to 20 mg/kg12 hours15 to <5020 to 25 mg/kg10 to 15 mg/kg24 hours<15b20 to 25 mg/kg10 to 15 mg/kg48 to 72 hoursContinuous infusion: Loading dose: Administer an appropriate loading dose (eg, 15 to 20 mg/kg) (Ref); higher loading doses may be considered in critically ill patients with sepsis (Ref); also refer to institution-specific policies and procedures.Maintenance dose: Various protocols have been developed (Ref); recommendations may vary based on the population studied. The following is an example protocol (Ref), and doses should be adjusted to achieve a target steady state concentration of 20 to 25 mg/L (Ref); also refer to institution-specific policies and procedures.CrCl >80 to 119 mL/minute: 30 mg/kg administered over 24 hours.CrCl >50 to 80 mL/minute: 25 mg/kg administered over 24 hours.CrCl 25 to 50 mL/minute:14 mg/kg administered over 24 hours.CrCl <25 mL/minute: 7 mg/kg administered over 24 hours.Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post-trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).Intermittent infusion: Loading dose (when applicable): 25 to 35 mg/kg (Ref) followed by 15 to 20 mg/kg every 8 hours depending on degree of augmented kidney function; some patients may require more frequent dosing (eg, 15 mg/kg every 6 hours) to attain target concentrations (Ref); utilize frequent serum concentration monitoring.Continuous infusion:Loading dose: Administer an appropriate loading dose (eg, 15 to 20 mg/kg) (Ref); higher loading doses (eg, 25 mg/kg) have been used in some protocols and may vary based on population studied (Ref); also refer to institution-specific policies and procedures.Maintenance dose: 40 to 60 mg/kg/day depending on degree of augmented kidney function with frequent serum concentration monitoring; adjust to achieve a target steady state concentration of 20 to 25 mg/L (Ref).Hemodialysis, intermittent (thrice weekly): Dialyzable (25% to 40% depending on dialyzer permeability) (Ref).Vancomycin Dosing Depending on Dose Timing and Dialyzer PermeabilityaDose timing and dialyzer permeabilityVancomycin dosebaASHP/IDSA/PIDS/SIDP [Rybak 2020]bInitial recommended loading/maintenance doses. The optimal pharmaco*kinetic/pharmacodynamic target in this population is unknown, but targeting predialysis concentrations of 15 to 20 mg/L are likely to achieve AUCs of 400 to 600 mg•hour/L (ASHP/IDSA/PIDS/SIDP [Rybak 2020]; Crew 2015). Predialysis serum concentrations should be obtained no less than weekly and should determine subsequent dosing (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).cThrice-weekly dose administration. Typically, patients may require ~25% larger doses for the 3-day interdialytic period (eg, Friday to Monday) to maintain sufficient vancomycin exposure on the third day.Dose given after dialysis endsLow permeability (low flux)Loading dose: 25 mg/kgMaintenance dose: 7.5 mg/kgcHigh permeability (high flux)Loading dose: 25 mg/kgMaintenance dose: 10 mg/kgcDose given during last hours of dialysis (intradialytic)Low permeability (low flux)Loading dose: 30 mg/kgMaintenance dose: 7.5 to 10 mg/kgcHigh permeability (high flux)Loading dose: 35 mg/kgMaintenance dose: 10 to 15 mg/kgcPeritoneal dialysis:Loading dose: 20 to 25 mg/kg (Ref). A vancomycin serum concentration should be obtained ~48 to 72 hours after the loading dose, and subsequent doses (usually 10 to 15 mg/kg) should be administered based on attainment of goal serum concentrations (Ref). Doses may vary based on infection site and severity, as well as the presence or absence of residual renal function. Some experts use maintenance doses of up to 20 mg/kg/dose (Ref).CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Close monitoring of response and adverse reactions due to drug accumulation is important.Loading dose: 20 to 25 mg/kg followed by 7.5 to 10 mg/kg every 12 hours with more frequent serum concentration monitoring (Ref). In patients with suspected or confirmed serious MRSA infections, dose adjustments should be made based on AUC monitoring occurring in the first 24 to 48 hours of therapy (Ref).PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Close monitoring of response and adverse reactions due to drug accumulation is important.Loading dose (administer even if PIRRT is occurring): 20 to 25 mg/kg, followed by 15 mg/kg after each PIRRT session ends (or during the final 60 to 90 minutes of the session) with more frequent serum concentration monitoring (Ref). In patients with suspected or confirmed serious MRSA infections, dose adjustments should be made based on AUC monitoring occurring in the first 24 to 48 hours of therapy (Ref).Dosing: Hepatic Impairment: AdultOral: There are no dosage adjustments provided in the manufacturer’s labeling. However, dosage adjustment unlikely due to low systemic absorption.IV:There are no dosage adjustments provided in the manufacturer’s labeling. However, degrees of hepatic dysfunction do not affect the pharmaco*kinetics of vancomycin (Ref).Dosing: Pediatric(For additional information see "Vancomycin: Pediatric drug information")Note: For IV dosing, initial dosage recommendations for patients with normal kidney function presented; doses should be adjusted based on serum concentration monitoring; doses require adjustment in renal impairment. Consider single-dose administration with serum concentration monitoring rather than scheduled dosing in patients with urine output <1 mL/kg/hour or if serum creatinine significantly increases from baseline. Dosing presented in mg/kg/dose and mg/kg/day; routes of administration may vary (eg, IV, oral, intrathecal, intracatheter, intraperitoneal, rectal); use caution.Optimal dose and frequency not established in patients receiving extracorporeal membrane oxygenation (ECMO); available data are limited (Ref). Patient-specific considerations (eg, reason for ECMO) and variability with ECMO procedure itself make extrapolation of pharmaco*kinetic data and dosing to all patients receiving ECMO difficult; closely monitor serum concentrations and determine individual dosing needs in these patients.General dosing, susceptible infection: Infants, Children, and Adolescents: IV: Initial: 45 to 60 mg/kg/day divided every 6 to 8 hours; dose and frequency should be individualized based on serum concentrations (Ref). Note: Based on adult data, an AUC24 target of 400 mg•hour/L is recommended in patients with serious methicillin-resistant S. aureus (MRSA) infections; specific dosing recommendations may be higher when targeting this range (Ref). See "MRSA infection, serious; treatment".In general, monitoring of serum concentrations and assurance of adequate hydration status is recommended; utilize local antibiogram and protocols for further guidance.Antibiotic lock therapy; catheter salvageAntibiotic lock therapy; catheter salvage: Limited data available: Optimal dose not established:Note: For infections caused by susceptible organisms when the vascular catheter cannot be removed; use in addition to systemic antibiotics. Catheter salvage not effective in all cases; removal of catheter is recommended for infections with S. aureus (Ref). Dosing regimens variable; consider age and size of patient and catheter size (including number of lumens) when determining dose due to potential for lock to be delivered intravenously.Infants, Children, and Adolescents: Intracatheter: Usual concentrations of lock solution: 2 to 5 mg/mL of vancomycin with or without heparin additive; most common concentrations reported: vancomycin 2 mg/mL, 2.5 mg/mL, or 5 mg/mL; refer to institutional protocol if available (Ref). Concentrations described in literature range from 0.025 to 10 mg/mL with or without heparin or citrate (Ref); a vancomycin concentration of 5 mg/mL has been shown to be more efficacious than 1 mg/mL when biofilm present (Ref). Instill into each lumen of the catheter access port using a volume sufficient to fill the catheter, with a dwell time of ideally ≥8 to 12 hours and up to 72 hours, depending on frequency of catheter use. Withdraw lock solution prior to catheter use; replace with fresh vancomycin lock solution after catheter use. Antibiotic lock therapy is given for the same duration as systemic antibiotics (Ref). Note: If heparin is utilized in the lock solution, the dose used should not approach therapeutic unit/kg dose.C. difficile infection; treatmentC. difficile infection; treatment:Manufacturer's labeling: Infants, Children, and Adolescents: Oral: 40 mg/kg/day divided every 6 to 8 hours for 7 to 10 days; maximum daily dose: 2,000 mg/day.Guideline recommendations:Non-severe infection, initial or first recurrence: Children and Adolescents: Oral: 10 mg/kg/dose 4 times daily for 10 days; maximum dose: 125 mg/dose (Ref).Severe/fulminant infection, initial: Children and Adolescents:Oral: 10 mg/kg/dose 4 times daily for 10 days; maximum dose: 500 mg/dose; may consider adding IV metronidazole in critically ill patients (Ref). If patient is unable to tolerate oral therapy, may use nasogastric administration (Ref).Rectal: Note: Consider use when ileus is present. Limited data available: Rectal enema: 500 mg in 100 mL NS; dose volume is determined by age (Ref); the optimal doses have not been established in pediatric patients; suggested volumes for children: 1 to 3 years: 50 mL; 4 to 9 years: 75 mL; >10 years: 100 mL (Ref); administer 4 times daily with or without IV metronidazole (Ref).Second or subsequent recurrence: Children and Adolescents: Pulsed-tapered regimen: Oral: 10 mg/kg/dose 4 times daily for 10 to 14 days; then 10 mg/kg/dose twice daily for 7 days, then 10 mg/kg/dose once daily for 7 days, then 10 mg/kg/dose every 2 or 3 days for 2 to 8 weeks; maximum dose: 125 mg/dose (Ref).Endocarditis, treatmentEndocarditis, treatment: Note: Dosage adjustment to target trough serum concentrations of 10 to 15 mg/L is recommended in pediatric endocarditis by the AHA (Ref). Dosage adjustment to target AUC24 of 400 mg•hour/L has been recommended in the treatment of proven or suspected MRSA infections based on adult data (Ref).Empiric therapy/culture negative: Children and Adolescents: IV: Initial: 60 mg/kg/day divided every 6 hours; initial maximum daily dose: 2,000 mg/day; use in combination with other antibiotics for at least 4 to 6 weeks; longer duration may be required if prosthetic material is present or in cases of recurrent endocarditis (Ref).Streptococcus (including enterococcus): Children and Adolescents: IV: Initial: 40 mg/kg/day divided every 8 to 12 hours; initial maximum daily dose: 2,000 mg/day; treat for at least 4 to 6 weeks; a longer duration and additional antibiotics may be required depending on organism and presence of prosthetic material (Ref).S. aureus:Non-methicillin resistant: Children and Adolescents: IV: Initial: 40 mg/kg/day divided every 8 to 12 hours; initial maximum daily dose: 2,000 mg/day; treat for at least 4 to 6 weeks; a longer duration and additional antibiotics may be required depending on organism and presence of prosthetic material (Ref).Methicillin-resistant: Children and Adolescents: IV: Initial: 40 mg/kg/day divided every 8 to 12 hours for at least 6 weeks; usual initial maximum daily dose: 2,000 mg/day (Ref); however, higher initial doses have been recommended for patients with serious MRSA infection with normal renal function, though dosing based on studies and models that were not specific to endocarditis (Ref). See "MRSA infection, serious; treatment".EnterocolitisEnterocolitis (S. aureus): Infants, Children, and Adolescents: Oral: 40 mg/kg/day divided every 6 to 8 hours for 7 to 10 days; maximum daily dose: 2,000 mg/day.Meningitis, including health care-associated meningitisMeningitis, including health care-associated meningitis: Infants, Children, and Adolescents: IV: Initial: 15 mg/kg/dose every 6 hours (Ref). Higher initial doses have been recommended for patients with serious MRSA infection with normal renal function, though dosing based on studies and models that were not specific to meningitis (Ref). See "MRSA infection, serious; treatment".MRSA infection, serious; treatmentMRSA infection, serious; treatment: Note: Doses should be adjusted based on patient-specific serum concentrations to a target AUC24 of 400 mg•hour/L, but potentially up to 600 mg•hour/L, based on adult data. In pediatric patients, an AUC24 of ≥400 mg•hour/L has been associated with trough concentrations of 7 to 10 mg/L, though trough concentrations do not clearly predict AUC on an individual level and trough-only monitoring is not recommended (Ref). Some studies have indicated that doses on the lower end of the range (ie, 60 mg/kg/day divided every 6 hours) will achieve target AUC24 in most children (Ref). To minimize risk of acute kidney injury, maintain AUC24 <800 mg•hour/L and trough <15 mg/L. For obese patients, start with a one-time loading dose of 20 mg/kg (based on total body weight), then start maintenance dosing (Ref).Infants ≥3 months and Children <12 years: IV: Initial: 60 to 80 mg/kg/day in divided doses every 6 hours; initial maximum daily dose: 3,600 mg/day.Children ≥12 years and Adolescents: IV: Initial: 60 to 70 mg/kg/day in divided doses every 6 to 8 hours; initial maximum daily dose: 3,600 mg/day.PeritonitisPeritonitis (peritoneal dialysis) (Ref): Limited data available:Prophylaxis: Infants, Children, and Adolescents:Touch contamination of PD line (if known MRSA colonization): Intraperitoneal: 25 mg per liter.High-risk gastrointestinal procedures: Note: Use should be reserved for patients at high risk for MRSA: IV: 10 mg/kg administered 60 to 90 minutes before procedure; maximum dose: 1,000 mg.Treatment: Infants, Children, and Adolescents:Intermittent: Intraperitoneal: Initial dose: 30 mg/kg in the long dwell; subsequent doses: 15 mg/kg/dose every 3 to 5 days during the long dwell; Note: Increased clearance may occur in patients with residual renal function; subsequent doses should be based on serum concentration obtained 2 to 4 days after the previous dose; redosing should occur when serum concentration <15 mcg/mL.Continuous: Intraperitoneal: Loading dose: 1,000 mg per liter of dialysate; maintenance dose: 25 mg per liter.Pneumonia, community-acquiredPneumonia, community-acquired: Infants >3 months, Children, and Adolescents: IV: Initial: 40 to 60 mg/kg/day in divided doses every 6 to 8 hours; (Ref). Note: Higher doses may be necessary when treating MRSA infections; doses should be adjusted based on patient-specific serum concentrations to a target AUC24 of 400 mg•hour/L (Ref). See "MRSA infection, serious; treatment".Skin and skin structure infections, complicatedSkin and skin structure infections, complicated: Note: Duration of treatment should be individualized and is dependent on severity of infection, adequacy of source control, and clinical improvement. For necrotizing fasciitis, continue treatment until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours.Necrotizing infections, mixed (non-MRSA): Infants, Children, and Adolescents: IV: Initial: 10 to 13 mg/kg/dose every 8 hours (Ref).Serious MRSA infection, including necrotizing infection and pyomyositis: Note: Dosage adjustment to target AUC24 of 400 mg•hour/L recommended for serious MRSA infections based on adult data. A loading dose of 20 mg/kg (based on total body weight) is recommended in obese patients (Ref).Infants ≥3 months and Children <12 years: IV: Initial: 60 mg/kg/day in divided doses every 6 hours; maximum daily dose: 3,600 mg/day (Ref). Based on pharmaco*kinetic modeling studies, doses up to 80 mg/kg/day may be necessary to achieve target AUC24 (Ref).Children ≥12 years and Adolescents: IV: Initial: 60 mg/kg/day in divided doses every 6 to 8 hours; maximum daily dose: 3,600 mg/day (Ref). Based on pharmaco*kinetic modeling studies, doses up to 70 mg/kg/day may be necessary to achieve target AUC24 (Ref).Surgical prophylaxisSurgical (perioperative) prophylaxis: Infants, Children, and Adolescents: IV: 15 mg/kg/dose within 120 minutes prior to surgical incision. May be administered in combination with other antibiotics depending upon the surgical procedure (Ref).VentriculitisVentriculitis (including health care-associated ventriculitis and cerebrospinal fluid [CSF] shunt infections):Infants, Children, and Adolescents: Limited data available: Intraventricular or intrathecal: Use a preservative-free preparation: 5 to 20 mg/day; usual dose: 10 or 20 mg/day (Ref); due to the smaller CSF volume in infants, some guidelines recommend decreasing the infant dose; adult dosage recommendations are based on ventricle size (Ref).Continuous infusion dosing: Limited data available; optimal dosing unknown:Infants, Children, and Adolescents: IV: Loading dose: 10 to 15 mg/kg/dose administered over 1 to 2 hours, followed by maintenance infusion of 40 to 60 mg/kg/day; adjust dose to achieve target serum concentration (Ref). Note: Required dose to achieve target concentration varies significantly between patients and depending on age, renal function, and target concentration; total daily doses of 30 to 110 mg/kg/day have been reported (Ref). Pediatric patients with cancer or who are critically ill may require higher doses to achieve target concentrations (Ref). Note: When transitioning from intermittent to continuous infusion, an initial loading dose may not be required; the total daily dose will likely need reduced depending on patient-specific factors, concentrations achieved during intermittent dosing, and clinical considerations (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricOral: There are no dosage adjustments provided in manufacturer's labeling; however, dosage adjustment unlikely due to low systemic absorption.IV: Note: Vancomycin levels should be monitored in patients with any renal impairment:Infants, Children, and Adolescents: The following adjustments have been recommended (Ref): Note: Renally-adjusted dose recommendations are based on intravenous doses of 10 mg/kg/dose every 6 hours or 15 mg/kg/dose every 8 hours.GFR 30 to 50 mL/minute/1.73 m2: 10 mg/kg/dose every 12 hours.GFR 10 to 29 mL/minute/1.73 m2: 10 mg/kg/dose every 18 to 24 hours.GFR <10 mL/minute/1.73 m2: 10 mg/kg/dose; redose based on serum concentrations.Intermittent hemodialysis: 10 mg/kg/dose; redose based on serum concentrations.Peritoneal dialysis (PD): 10 mg/kg/dose; redose based on serum concentrations.Continuous renal replacement therapy (CRRT): 10 mg/kg/dose every 12 to 24 hours; monitor serum concentrations.Dosing: Hepatic Impairment: PediatricOral: There are no dosage adjustments provided in the manufacturer's labeling; however, dosage adjustment unlikely needed due to low systemic absorption.IV: There are no dosage adjustments provided in the manufacturer's labeling; however, degrees of hepatic dysfunction do not affect the pharmaco*kinetics of vancomycin (Ref).Dosing: Older AdultRefer to adult dosing.Dosing: Obesity: AdultThe recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.Example of dosing regimen:Class 1, 2, or 3 obesity (BMI ≥30 kg/m2):Loading dose: Note: Consider utilizing a loading dose when rapid attainment of target concentrations is necessary (eg, sepsis, documented/suspected methicillin-resistant S. aureus infection) (Ref).Initial: IV: 20 to 25 mg/kg using actual body weight; maximum loading dose: 3 g. After administration of the loading dose, initiate maintenance dose at the next dosing interval (Ref). In critically ill patients, may consider loading doses of 20 to 35 mg/kg using actual body weight; maximum loading dose: 3 g (Ref).Maintenance dose: IV: Use actual body weight and the following clearance (CL) equations to calculate a maintenance dose; empiric maintenance doses >4.5 g/day are unlikely to be necessary (Ref). Note: If vancomycin therapy is continued, individualize vancomycin dose using early Bayesian approach (ie, 2 serum concentrations within first 24 to 48 hours) to achieve target AUC (Ref).1. Calculate estimated vancomycin CL (Ref).Estimate CL (L/hour): 9.656 – [0.078 × age] – [2.009 × SCr] + [0.04 × actual body weight0.75] + [1.09 × sex].Where adult age is in years; SCr is serum creatinine in mg/dL; actual body weight in kg scaled to an exponent of 0.75; and sex is 1 if male and 0 if female.2. Calculate empiric vancomycin maintenance regimen (Ref).Estimate daily dose (rounded to nearest 250 mg): Estimated CL (L/hour) × 500 mg•hour/L.Where 500 mg•hour/L is the mid-range AUC target selected for a minimum inhibitory concentration (MIC) of 1 mg/L. When the vancomycin CL is estimated to be ≤3 L/hour, administer the dose every 24 hours or divide the daily dose every 12 hours. If CL is estimated to be >3 L/hour, divide the daily dose and administer every 6 to 12 hours (Ref).Rationale for recommendations:Vancomycin is a hydrophilic antimicrobial with a low to medium Vd and CL that is proportional to glomerular filtration rate. Vancomycin Vd correlates with actual body weight but does not increase proportionately with increasing body size (Ref) and has been reported to be lower in patients with obesity compared to individuals who are not obese (0.3 to 0.5 L/kg vs 0.68 L/kg) (Ref). Because vancomycin loading doses are dependent on Vd, lower loading doses are generally needed in patients with obesity and the dose can be capped once a threshold dose is reached (Ref). Vancomycin CL can be estimated by variables used to estimate kidney function. Estimated vancomycin CL in patients with obesity is ~6 L/hour and rarely exceeds 9 L/hour. The empiric maintenance daily dose can be calculated by an estimate of CL and the AUC/MIC target of 400 to 600 (Ref). Using a targeted AUC approach may reduce the total daily dose (TDD) of vancomycin versus a target trough concentration; lower TDD may reduce the risk of acute kidney injury (Ref). Optimal dosing and monitoring regimens are uncertain; refer to institutional protocol.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productCapsule, Oral, as hydrochloride: Vancocin: 125 mg, 250 mg [contains fd&c blue #2 (indigotine)]Generic: 125 mg, 250 mgKit, Intravenous, as hydrochloride: Vancosol Pack: 1 g/100 mL in NaCl 0.9% [DSC]Solution, Intravenous, as hydrochloride: Generic: 750 mg/150 mL (150 mL); 1000 mg/200 mL (200 mL); 1250 mg/250 mL (250 mL); 1500 mg/300 mL (300 mL); 1750 mg/350 mL (350 mL)Solution, Intravenous, as hydrochloride [preservative free]: Generic: 500 mg/100 mL (100 mL); 2000 mg/400 mL (400 mL); 1 g/200 mL in Dextrose 5% (200 mL); 1 g/200 mL in NaCl 0.9% (200 mL); 500 mg/100 mL in Dextrose 5% (100 mL); 750 mg/150 mL in Dextrose 5% (150 mL)Solution Reconstituted, Intravenous [preservative free]: Generic: 1.25 g (1 ea)Solution Reconstituted, Intravenous, as hydrochloride: Generic: 500 mg (1 ea); 1 g (1 ea); 1.5 g (1 ea); 10 g (1 ea)Solution Reconstituted, Intravenous, as hydrochloride [preservative free]: Generic: 250 mg (1 ea [DSC]); 500 mg (1 ea); 750 mg (1 ea); 1 g (1 ea); 1.5 g (1 ea); 5 g (1 ea); 10 g (1 ea); 100 g (1 ea)Solution Reconstituted, Oral, as hydrochloride: Firvanq: 25 mg/mL (150 mL, 300 mL); 50 mg/mL (150 mL, 300 mL) [contains fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10), sodium benzoate; grape flavor]Firvanq: 50 mg/mL (150 mL, 300 mL) [contains fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10), sodium benzoate; white grape flavor]Generic: 250 mg/5 mL (80 mL, 150 mL, 300 mL)Generic Equivalent Available: USYesDosage Forms ConsiderationsFirst-Vancomycin oral solution is a compounding kit. Refer to manufacturer’s labeling for compounding instructions.Dosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Capsule, Oral, as hydrochloride: Vancocin: 125 mg, 250 mg [contains fd&c blue #2 (indigotine)]Generic: 125 mg, 250 mgSolution, Intravenous, as hydrochloride: Generic: 1 g/200 mL in NaCl 0.9% (200 mL)Solution Reconstituted, Intravenous, as hydrochloride: Generic: 500 mg (1 ea, 10 mL); 1000 mg (1 ea); 1 g (1 ea, 20 mL, 30 mL); 5 g (1 ea); 10 g (1 ea)Administration: AdultIntravenous: Administer vancomycin with a final concentration not to exceed 5 mg/mL by IV intermittent infusion over at least 60 minutes (recommended infusion period of ≥30 minutes for every 500 mg administered (Ref)); in adult patients in need of fluid restriction, a concentration up to 10 mg/mL may be used, but risk of infusion-related reactions is increased. Not for IM administration.If a maculopapular rash appears on the face, neck, trunk, and/or upper extremities (vancomycin infusion reaction [formerly “red man syndrome”]), slow the infusion rate to over 11/2 to 2 hours and increase the dilution volume (Ref). Hypotension, shock, and cardiac arrest (rare) have also been reported with too rapid of infusion. Administration of antihistamines prior to infusion may prevent or minimize this reaction (Ref).Irritant; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation.Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Information conflicts regarding the use of dry cold or dry warm compresses (Ref); however, dry warm compresses may be of benefit in increasing local blood flow to enhance drug removal from the extravasation site. Intradermal hyaluronidase may be considered for refractory cases (Ref).Hyaluronidase: Intradermal: Inject a total of 1 mL (15 units/mL) as 5 separate 0.2 mL injections (using a tuberculin syringe) along injection site and edematous area (Ref).Antibiotic lock technique (off-label use): Instill prepared vancomycin lock solution into each lumen of the catheter access port using a volume sufficient to fill the catheter (2 to 5 mL) with a dwell time of 48 to 72 hours (dependent on frequency of catheter use). Withdraw lock solution prior to catheter use; replace with fresh vancomycin lock solution after catheter use (Ref).Intraventricular (off-label route): Use preservative-free preparations only. May be administered intraventricularly with a final concentration of 2.5 to 10 mg/mL for the treatment of CSF shunt infections. When administered through a ventricular drain, clamp drain for 15 to 60 minutes before opening the drain to allow vancomycin solution to equilibrate in the CSF (Ref).Intravitreal (off-label route): May administer vancomycin intravitreally with a final concentration of 1 mg/0.1 mL NS or sterile water (Ref).Oral:Solution (Firvanq): Shake reconstituted oral solution well before each use.Injection: Reconstituted powder for injection (not premixed solution) may be diluted and used for oral administration; common flavoring syrups may be added to improve taste. The unflavored, diluted solution may also be administered via nasogastric tube.Rectal (off-label route): May be administered as a retention enema per rectum (Ref); 500 mg in 100 to 500 mL of NS, volume may depend on length of segment being treated. If sodium chloride causes hyperchloremia could use solution with lower chloride concentration (eg, LR) (Ref).Administration: PediatricOral:Oral solution (Firvanq): Shake reconstituted oral solution well before each use.Powder for injection: Reconstituted powder for injection (not premixed solution) may be diluted and used for oral administration; common flavoring syrups may be added to improve taste. The unflavored, diluted solution may also be administered via nasogastric tube.Parenteral:IV:Intermittent: Administer intermittent IV infusion over 60 minutes. Vancomycin infusion reaction (formerly "red man syndrome") may occur if the infusion is too rapid. It is not an allergic reaction, but may be characterized by hypotension and/or a maculopapular rash appearing on the face, neck, trunk, and/or upper extremities; if this should occur, slow the infusion rate to administer dose over 90 to 120 minutes (Ref) and increase the dilution volume; the reaction usually dissipates in 30 to 60 minutes; administration of antihistamines just before the infusion may also prevent or minimize this reaction.Continuous: After loading dose, administer over 24 hours (Ref).Irritant; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation. If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Information varies regarding the use of dry cold or dry warm compresses (Ref); however, dry warm compresses may be of benefit in increasing local blood flow to enhance drug removal from the extravasation site. Intradermal hyaluronidase may be considered for refractory cases (Ref).Intrathecal/Intraventricular: Use preservative-free preparations only. Administer as diluted solution (1 to 10 mg/mL) over 1 to 2 minutes (Ref). When administered through a ventricular drain, clamp drain for 15 to 60 minutes to allow vancomycin solution to equilibrate in the cerebrospinal fluid (CSF) (Ref).Intracatheter (vascular); antibiotic lock technique: Instill prepared vancomycin lock solution into each lumen of the catheter access port using a volume sufficient to fill the catheter with a dwell time of ≥8 to 12 hours and up to 72 hours (dependent on frequency of catheter use). Withdraw lock solution prior to catheter use; replace with fresh vancomycin lock solution after catheter use (Ref).Rectal: Instill vancomycin enema solution via rectal foley; retain for 1 hour. In pediatric patients the optimal doses have not been established; suggested volumes for pediatric patients: 1 to 3 years of age: 50 mL; 4 to 9 years of age: 75 mL; >10 years of age: 100 mL (Ref).Use: Labeled IndicationsClostridioides difficile infection, treatment (oral): Treatment of C. difficile infection (CDI) in adults and pediatric patients <18 years of age.Endocarditis (injection):Corynebacteria (diphtheroids): Treatment of diphtheroid endocarditis in combination with either rifampin, an aminoglycoside, or both in early-onset prosthetic valve endocarditis caused by diphtheroids.Enterococcal: Treatment of endocarditis caused by enterococci (eg, Enterococcus faecalis), in combination with an aminoglycoside.Staphylococcal: Treatment of staphylococcal endocarditis.Streptococcal: Treatment of endocarditis due to Streptococcus viridans or Streptococcus bovis, as monotherapy or in combination with an aminoglycoside.Enterocolitis (oral): Treatment of enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) in adults and pediatric patients <18 years of age. Note: Staphylococcal enterocolitis is uncommon; the disease and treatment are not well described in the literature (Iwata 2014; Lin 2010).Staphylococcal infections (injection): Treatment of serious or severe infections (eg, bloodstream infections, bone infections, lower respiratory tract infections, skin and skin structure infections) caused by susceptible strains of methicillin-resistant (beta-lactam-resistant) staphylococci; empiric therapy of infections when methicillin-resistant staphylococci are suspected.Use: Off-Label: AdultCatheter-related bloodstream infection, antibiotic lock technique (catheter-salvage therapy); Cerebrospinal fluid shunt infection; Clostridioides difficile infection, prophylaxis; Clostridioides difficile infection, treatment (rectal administration); Cystic fibrosis, acute pulmonary exacerbation; Diabetic foot infection, moderate to severe; Endophthalmitis, treatment; Intra-abdominal infection, health care–associated; Intracranial abscess (brain abscess, intracranial epidural abscess) or spinal epidural abscess; Meningitis, bacterial; Peritonitis, treatment (peritoneal dialysis patients); Prosthetic joint infection; Streptococcus (group B), maternal prophylaxis for prevention of neonatal disease; Surgical prophylaxisMedication Safety IssuesSound-alike/look-alike issues: IV vancomycin may be confused with INVanzVancomycin may be confused with clindamycin, gentamicin, tobramycin, valACYclovir, vecuronium, VibramycinHigh alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication (intrathecal administration) among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.Adverse Reactions (Significant): ConsiderationsAnaphylaxisVancomycin may rarely cause life-threatening immune-mediated anaphylaxis, which may present as generalized and extensive pruritus and/or erythema of skin, respiratory distress, bronchospasm, hypoxia, and hypotension. Clinical presentation is similar to vancomycin infusion reaction (a nonimmune-mediated anaphylactoid infusion-related reaction; formerly called “red man syndrome”), making it difficult for clinicians to distinguish between the 2 reactions (Ref).Mechanism: Non-dose-related; immunologic; IgE-mediated with specific antibodies formed against a drug allergen following initial exposure (immunologically mediated) or result in direct mast cell stimulation (Ref). IgE binding and cross-linking of the high affinity IgE receptor (FcεRI) on the surface of mast cells causes release of histamine and other mediators that can result in urticaria, flushing, airway obstruction, hypotension, and tachycardia (Ref).Onset: Rapid; IgE-mediated reactions generally occur within 1 hour of administration but may occur up to 6 hours after exposure (Ref). In a systematic review analyzing 7 case reports of vancomycin-induced anaphylaxis, the median time to onset of signs/symptoms was 2 minutes (range: 1 to 35 minutes) (Ref).Risk factors:• Previous exposure to vancomycin (necessary for IgE-mediated anaphylaxis) (Ref)Clostridioides difficile infectionAlthough oral vancomycin is used for the treatment of Clostridioides difficile infection (CDI), Clostridioides difficile-associated diarrhea and Clostridioides difficile colitis have been reported with intravenous vancomycin (Ref). Clinical symptoms range from mild diarrhea to life-threatening colitis, toxic megacolon, and sepsis. In patients with severe CDI, frequent symptoms include watery diarrhea, abdominal pain, fever, nausea, anorexia, and malaise (Ref).Mechanism: Non-dose-related; antibiotics disrupt the indigenous gut microbiota which promotes C. difficile spore germination, growth, and toxin production, leading to epithelial damage and colitis (Ref).Onset: Varied; may start on the first day of antibiotic therapy or up to 3 months postantibiotic (Ref).Risk factors:• Antibiotic exposure (highest risk factor); antibiotics most frequently associated with C. difficile include clindamycin, fluoroquinolones, and third-/fourth-generation cephalosporins (Ref)• Long durations in a hospital or other health care setting (recent or current) (Ref)• Advanced age (Ref)• Immunocompromised conditions or a serious underlying condition (Ref)• GI surgery/manipulation (Ref)• Antiulcer medications, such as proton pump inhibitors and H2 blockers (suggested risk factors) (Ref)• Chemotherapy (suggested risk factor) (Ref)Drug-induced immune thrombocytopeniaDrug-induced immune thrombocytopenia (DITP) has been associated with use. Vancomycin-induced ITP has been associated with severe bleeding characterized by petechial hemorrhages, ecchymoses, and oozing from the buccal mucosa. Rarely, acutely-ill patients have experienced gross hematuria, lower GI hemorrhage, intrapulmonary hemorrhage, and excessive bleeding from venipuncture sites (Ref).Mechanism: Non-dose-related; immunologic; platelet-reactive antibodies of the IgG class, the IgM class, or both, have been detected in patients with thrombocytopenia while receiving vancomycin. These antibodies reacted with platelets only in the presence of vancomycin, suggesting that the mechanism is similar to quinine-induced thrombocytopenia rather than a hapten-specific antibody (Ref).Onset: Varied; DITP; typically occurs within 1 to 2 weeks after initiating therapy or longer in patients with intermittent exposure (Ref). In case reports, the mean time to platelet nadir count was ~8 days following first exposure. However, there are rare case reports describing a rapid onset (within 24 hours) of acute severe thrombocytopenia, primarily in settings of reexposure to vancomycin (Ref).Hypersensitivity reactions (delayed)Maculopapular rash and severe cutaneous adverse reactions (SCARs), including drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrosis (TEN), Stevens-Johnson syndrome (SJS), and acute generalized exanthematous pustulosis (AGEP), have occurred rarely with use and may be life-threatening (Ref). In addition, vancomycin-induced dermatologic disorder (linear IgA bullous dermatosis [LABD]) has been reported rarely and clinical presentation may mimic TEN, making it difficult to distinguish (Ref). Other reactions include erythema multiforme, exfoliative dermatitis, and hypersensitivity angiitis (Ref).Mechanism: Non-dose-related; immunologic. Delayed hypersensitivity reactions are mediated by T-cells or antibodies other than IgE (eg, IgG-mediated, such as some cytopenias) (Ref). SCARs are delayed type IV hypersensitivity reactions involving a T-cell mediated drug-specific immune response (Ref). The mechanism behind vancomycin-induced LABD is unknown; LABD is a rare immune-mediated blistering disorder resulting in linear deposition of IgA at the basem*nt membrane zone (Ref).Onset: Delayed; type IV reactions are delayed hypersensitivity reactions that typically occur days to weeks after drug exposure but may occur more rapidly (usually within 1 to 4 days) upon reexposure (Ref). DRESS usually does not develop until after 2 weeks of administration (Ref). In a systematic case review, a median onset of 9 days and 21 days was observed for SJS/TEN and DRESS, respectively (Ref). In vancomycin-induced LABD, lesions typically appear 1 to 15 days after the first vancomycin dose (Ref); a median latency of 7 days was observed in a systematic review (Ref).Risk factors:• Patients with end-stage renal disease (suggested risk factor) (Ref)• In DRESS, a strong association was observed for patients with the HLA-A*32:01 allele in a study involving predominantly European ancestry (Ref)• Cross-reactivity with teicoplanin (Ref)NephrotoxicitySystemic exposure is associated with nephrotoxicity (usually reversible), which may result in acute kidney injury (or acute renal failure), predominantly occurring in patients with multiple risk factors (Ref). Cases of systemic absorption and nephrotoxicity with oral vancomycin have been reported (Ref).Mechanism: Non-dose-related; most commonly attributed to acute tubular necrosis (or renal tubular necrosis), resulting from direct oxidative stress on proximal tubule cells or obstructive tubular cast formation. In addition, acute interstitial nephritis has also been described, characterized by tubular and interstitial inflammation, resulting from an immunologically mediated (non-IgE) process (Ref).Onset: Intermediate; usually occurs 5 to 7 days and up to 14 days following monotherapy (Ref). Acute interstitial nephritis was observed at a median onset of 26 days in a systematic case review (Ref).Risk factors:• Vancomycin exposure (trough levels ≥15 mg/L, larger AUC [>650 to 1,300 mg-h/L], high daily doses [>4 g/day]) (Ref)• Duration of therapy >7 days (Ref)• Obesity (Ref)• Preexisting kidney dysfunction (Ref)• Critical illness (Ref)• Concurrent nephrotoxin therapy or concurrent prolonged use of piperacillin/tazobactam (Ref)• Older adults >65 years:• Parenteral: Less commonly associated risk factor (Ref)• Oral: Increases the risk of systemic absorption from oral vancomycinNeutropenia/pancytopeniaNeutropenia (severe) and agranulocytosis have been observed in numerous case reports and case series; in some cases, drug fever also accompanied the neutropenia (Ref). Reversible pancytopenia has also been reported in case reports (Ref).Mechanism: Non-dose-related; available data suggest a peripheral mechanism mediated by antibodies and direct toxicity to the bone marrow (Ref).Onset: Varied; usually occurs after 7 to 12 days of treatment, with most cases occurring after 20 days (Ref). However, 1 case report described an onset of 8 weeks following discontinuation of a 3-week course, and then upon rechallenge, neutropenia recurred 3 days following reinitiation (Ref).Risk factors:• Prolonged exposure (ie, >7 days) (Ref)• Teicoplanin: In patients experiencing neutropenia who were switched to teicoplanin (another glycopeptide), 50% of these patients also developed teicoplanin-induced neutropenia (Ref)OtotoxicityVancomycin is infrequently associated with ototoxicity, manifested as tinnitus, sensorineural hearing loss, dizziness, or vertigo; some cases have reported irreversible hearing loss (Ref). Of note, vancomycin has not been found to be ototoxic in animal models (Ref).Mechanism: Non-dose-related; proposed to be via direct damage to the auditory branch of the eighth cranial nerve, although data are conflicting and unclear if ototoxicity is directly attributable to vancomycin or to other confounding factors (Ref).Risk factors:• Older adults (Ref)• Coadministration with ototoxic agents (eg, aminoglycosides) (Ref)• Kidney dysfunction (potential risk factor) (Ref)Vancomycin infusion reactionVancomycin infusion reaction, a non-IgE-mediated drug reaction most often characterized by an erythematous rash, generalized flushing, and pruritus, may occur. Severe reactions, which are uncommon, may also include hypotension, chest pain, and dyspnea. Rarely, vancomycin infusion reaction may be life-threatening and cause severe hypotension and cardiac arrest or cardiovascular collapse. Clinical presentation can be similar to IgE-mediated anaphylaxis making it difficult for clinicians to distinguish between the 2 reactions (Ref). Reactions usually cease promptly after infusion is stopped.Mechanism: Non-IgE-mediated drug reaction caused by histamine release from mast cells and basophils found in the skin, lung, GI tract, myocardium, and vascular system (Ref). The mast cell receptor MRGPRX2 has also been identified as a cause of non-IgE-mediated drug reactions (Ref).Onset: Rapid; usually occurs 4 to 10 minutes after the start of the infusion with the first dose but may also occur at any time (Ref).Risk factors:• Typically caused by rapid IV infusion (<1 hour) of large doses (Ref)• Concomitant medications that also induce histamine release including ciprofloxacin; barbiturates; opioids (except fentanyl which rarely induces histamine); certain neuromuscular antagonists (atracurium, cisatracurium, doxacurium, mivacurium, succinylcholine, tubocurarine); propofol; plasma expanders (dextran, polygeline); and radiocontrast agents (Ref).Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.IV:Frequency not defined:Cardiovascular: Chest pain, flushing, hypotension, shock, vasculitisDermatologic: Bullous dermatitis, erythema of skin, exfoliative dermatitis (Forrence 1990), pruritus, Stevens-Johnson syndrome (Lin 2014)Hematologic & oncologic: Agranulocytosis (di Fonzo 2018), eosinophilia, leukopenia, thrombocytopeniaHypersensitivity: Hypersensitivity reaction (Kupstaite 2010)Local: Injection site phlebitis, irritation at injection site, pain at injection siteNervous system: Chills, dizziness, malaise, vertigoNeuromuscular & skeletal: MyalgiaOtic: Hearing loss (Klibanov 2003), ototoxicity (Forouzesh 2009), tinnitus (Traber 1981)Renal: Increased blood urea nitrogen (Bergman 1988), increased serum creatinine, interstitial nephritis (Bergman 1988), renal tubular necrosis (Shah-Khan 2011)Respiratory: Dyspnea, wheezingMiscellaneous: Fever (Smith 1999)Postmarketing:Cardiovascular: Hypersensitivity angiitis (rare: <1%) (Pingili 2017)Dermatologic: Acute generalized exanthematous pustulosis (rare: <1%) (Mawri 2015), dermatologic disorder (linear IgA bullous dermatosis) (rare: <1%) (Tashima 2014), erythema multiforme (rare: <1%) (Khicher 2019), maculopapular rash (Marik 1997), toxic epidermal necrolysis (rare: <1%) (Changela 2013)Gastrointestinal: Clostridioides difficile associated diarrhea (rare: <1%) (Hecht 1989), Clostridioides difficile colitis (rare: <1%) (Hecht 1989), peritonitis (following intraperitoneal administration during CAPD) (Freiman 1992)Hematologic & oncologic: Henoch-Schonlein purpura (Min 2017), immune thrombocytopenia (Al Jafar 2015; Mohammadi 2017), neutropenia (reversible) (literature suggests an incidence ranging from 2% to 12%) (Black 2011; di Fonzo 2018), pancytopenia (rare: <1%) (Carmichael 1986)Hypersensitivity: Anaphylaxis (rare: <1%) (Anne 1994), fixed drug eruption (Gilmore 2004), vancomycin infusion reaction (literature suggests an incidence ranging from 4% to as high as 47%) (Alvarez-Arango 2021; Austin 2020; Symons 1985; Wazny 2001)Immunologic: Drug reaction with eosinophilia and systemic symptoms (rare: <1%) (Cacoub 2011)Renal: Acute kidney injury (Sawada 2018), nephrotoxicity (common: ≥10%) (Lodise 2009)Oral:>10%:Endocrine & metabolic: Hypokalemia (13%)Gastrointestinal: Abdominal pain (15%), nausea (17%)1% to 10%:Cardiovascular: Peripheral edema (6%)Gastrointestinal: Diarrhea (9%), flatulence (8%), vomiting (9%)Genitourinary: Urinary tract infection (8%)Nervous system: Fatigue (5%), headache (7%)Neuromuscular & skeletal: Back pain (6%)Renal: Nephrotoxicity (5%)Miscellaneous: Fever (9%)Frequency not defined:Cardiovascular: HypotensionGastrointestinal: Clostridioides difficile colitis, constipationHematologic & oncologic: AnemiaNervous system: Depression, insomniaRenal: Increased serum creatinine, renal failure syndrome, renal insufficiencyPostmarketing:Cardiovascular: VasculitisDermatologic: Acute generalized exanthematous pustulosis, dermatologic disorder (linear IgA bullous dermatosis) (Tashima 2014), exfoliative dermatitis (rare: <1%) (Forrence 1990), pruritus, skin rash, Stevens-Johnson syndrome (rare: <1%) (An 2011), toxic epidermal necrolysis (rare: <1%) (An 2011), urticariaHematologic & oncologic: Eosinophilia, thrombocytopeniaHypersensitivity: Anaphylaxis, flushing (Arroyo-Mercado 2019), nonimmune anaphylaxisImmunologic: Drug reaction with eosinophilia and systemic symptoms (Cacoub 2011)Nervous system: Chills, dizziness, drug fever, pain, vertigoNeuromuscular & skeletal: Muscle spasm (chest and back)Otic: TinnitusRespiratory: Dyspnea, wheezingContraindicationsHypersensitivity to vancomycin or any component of the formulationWarnings/PrecautionsConcerns related to adverse effects:• Extravasation and thrombophlebitis: IV vancomycin is an irritant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. Pain, tenderness, and necrosis may occur with extravasation. If thrombophlebitis occurs, slow infusion rates, dilute solution (eg, 2.5 to 5 g/L) and rotate infusion sites.• Superinfection: Prolonged use may result in fungal or bacterial superinfection.Disease-related concerns:• Inflammatory bowel disease: Clinically significant serum concentrations have been reported in patients with inflammatory disorders of the intestinal mucosa who have taken oral vancomycin (multiple doses) for the treatment of C. difficile-associated diarrhea. Although use may be warranted, the risk for adverse reactions may be higher in this situation; consider monitoring serum trough concentrations in patients with renal insufficiency, severe colitis, and a prolonged course (IDSA/SHEA [McDonald 2018]; Pettit 2015).• Renal impairment: Use with caution in patients with renal impairment or those receiving other nephrotoxic drugs; dosage modification required and close monitoring is recommended in patients with preexisting renal impairment and those at high risk for renal impairment. Accumulation may occur after multiple oral doses of vancomycin in patients with renal impairment; consider monitoring serum concentrations in this circ*mstance.Other warnings/precautions:• Appropriate use: Oral vancomycin is only indicated for the treatment of CDI or enterocolitis due to S. aureus and is not effective for systemic infections; parenteral vancomycin is not effective for the treatment of enterocolitis.• Intraocular administration (off-label route): Hemorrhagic occlusive retinal vasculitis (HORV), including permanent visual loss, has been reported in patients receiving intracameral or intravitreal administration of vancomycin during or after cataract surgery.• Intraperitoneal administration (off-label route): Use caution when administering intraperitoneally (IP); in some continuous ambulatory peritoneal dialysis (CAPD) patients, chemical peritonitis (cloudy dialysate, fever, severe abdominal pain) has occurred. Symptoms are self-limited and usually clear after vancomycin discontinuation.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Aminoglycosides: Vancomycin may enhance the nephrotoxic effect of Aminoglycosides. Vancomycin may enhance the neurotoxic effect of Aminoglycosides.Management: Consider avoiding coadministration of aminoglycosides and vancomycin unless clinically indicated. If coadministered, monitor closely for signs of nephrotoxicity and neurotoxicity. Risk D: Consider therapy modificationBacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii.Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modificationBCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical).Risk X: Avoid combinationBCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization).Risk C: Monitor therapyBile Acid Sequestrants: May diminish the therapeutic effect of Vancomycin. Management: Avoid concurrent administration of oral vancomycin and bile acid sequestrants when possible.If use of both agents is necessary, consider separating doses by at least 2 hours to minimize the significance of the interaction. Risk D: Consider therapy modificationCholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine.Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combinationColistimethate: Vancomycin may enhance the nephrotoxic effect of Colistimethate.Management: Avoid coadministration of colistimethate and vancomycin whenever possible due to the potential for additive or synergistic nephrotoxicity. If coadministration cannot be avoided, closely monitor renal function. Risk D: Consider therapy modificationImmune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Risk C: Monitor therapyLactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol.Risk C: Monitor therapyNeuromuscular-Blocking Agents: Vancomycin may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents.Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Vancomycin. Risk C: Monitor therapyPiperacillin: May enhance the nephrotoxic effect of Vancomycin. Risk C: Monitor therapySodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate.Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modificationTaurolidine: Vancomycin may diminish the therapeutic effect of Taurolidine.Risk C: Monitor therapyTyphoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected.Management: Avoid use of live attenuated typhoid vaccine (Ty21a)in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modificationReproductive ConsiderationsPregnancy status should be evaluated in patients who may become pregnant prior to using the IV formulation containing the excipients polyethylene glycol (PEG 400) and N-acetyl D-alanine (NADA).Pregnancy ConsiderationsVancomycin crosses the placenta and can be detected in fetal serum, amniotic fluid, and cord blood (Bourget 1991; Reyes 1989). Adverse fetal effects, including sensorineural hearing loss or nephrotoxicity, have not been reported following maternal use during the second or third trimesters of pregnancy.The pharmaco*kinetics of vancomycin may be altered during pregnancy and pregnant patients may need a higher dose of vancomycin. Maternal half-life is unchanged, but the volume of distribution and the total plasma clearance may be increased (Bourget 1991). Individualization of therapy through serum concentration monitoring may be warranted.Vancomycin is recommended for the treatment of mild, moderate, or severe Clostridioides difficile infections in pregnant patients. Standard doses should be used (ACG [Surawicz 2013]).Vancomycin is recommended as an alternative option to prevent the transmission of group B streptococcal (GBS) disease from mothers to newborns. Untreated asymptomatic GBS disease can result in maternal urinary tract infection, intraamniotic infection, endometritis, preterm labor, and/or stillbirth. Vertical transmission from the mother can cause sepsis, pneumonia, or meningitis in the newborn. Vancomycin IV is recommended for use in women who are at high risk for anaphylaxis to penicillin (or whose risk is unknown), and the GBS isolate is resistant to clindamycin. Dose and rate of infusion should be based on maternal weight and renal function, similar to nonpregnant patients (ACOG 2020).In patients known to be colonized with methicillin-resistant S. aureus (MRSA), a single dose of vancomycin is recommended as part of the antibiotic regimen for prophylactic use prior to cesarean delivery. Monotherapy with vancomycin does not provide sufficient coverage for cesarean delivery surgical prophylaxis (ACOG 2018).Based on limited data, vancomycin is considered likely compatible with pregnancy when used for the treatment of airway diseases, such as cystic fibrosis (ERS/TSANZ [Middleton 2020]).The formulation of vancomycin injection containing the excipients polyethylene glycol (PEG 400) and N-acetyl D-alanine (NADA) has caused fetal malformations in animal reproduction studies. If use of vancomycin is needed during the first or second trimesters of pregnancy, use other available formulations of vancomycin.Breastfeeding ConsiderationsVancomycin is present in breast milk following IV administration.Information related to the presence of vancomycin in breast milk is available from a mother who received vancomycin 1 g IV every 12 hours during pregnancy and for at least 1 week prior to sampling. Vancomycin 12.7 mcg/mL was detected in breast milk 4 hours after a maternal dose (Reyes 1989).Vancomycin exhibits minimal oral absorption; therefore, the amount available to pass into the milk would be limited following oral administration and unlikely to provide clinically relevant exposure to an infant exposed via breast milk.In general, antibiotics that are present in breast milk may cause non-dose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush or diarrhea (WHO 2002).Vancomycin is recommended for the treatment of Clostridioides difficile infections in breastfeeding women (ACG [Surawicz 2013]) and is considered compatible with breastfeeding when used for the treatment of airway diseases, such as cystic fibrosis (ERS/TSANZ [Middleton 2020]). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.Dietary ConsiderationsMay be taken with food.Monitoring ParametersIV: Periodic renal function tests, CBC, pregnancy test prior to use for formulation containing PEG 400 and NADA excipients, serial auditory function testing may be helpful to minimize risk of ototoxicity, serum trough vancomycin concentrations in select patients (eg, aggressive dosing, life-threatening infection, seriously ill, unstable renal function, concurrent nephrotoxins, prolonged courses).AUC monitoring: Frequency of AUC monitoring should be based on clinical judgement; frequent or daily monitoring may be appropriate for hemodynamically unstable patients; hemodynamically stable patients may only require once-weekly monitoring (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Trough monitoring:Hemodynamically stable patients: Draw trough concentrations at least once weekly (ASHP/IDSA/SIDP [Rybak 2009]).Hemodynamically unstable patients: Draw trough concentrations more frequently or in some instances daily (ASHP/IDSA/SIDP [Rybak 2009]).Prolonged courses (>3 to 5 days): Draw at least one steady-state trough concentration; repeat as clinically appropriate (ASHP/IDSA/SIDP [Rybak 2009]).Note: Drawing >1 trough concentration prior to the fourth dose for short course (<3 days) or lower intensity dosing (target trough concentrations <15 mg/L) is not recommended. For patients with uncomplicated skin and soft tissue infections who are not obese and have normal renal function, serum trough monitoring is generally not needed (IDSA [Liu 2011]).Oral/rectal therapy: Serum sample monitoring is not typically required; systemic absorption of enteral vancomycin may occur in patients with mucosal disruption due to colitis, especially in patients with renal failure. Monitoring serum vancomycin levels may be considered for patients with renal failure who have severe colitis and require a prolonged course of enteral vancomycin (IDSA/SHEA [McDonald 2018]; Pettit 2015).Reference RangeIV:Timing of serum samples:First-order pharmaco*kinetic analytic equations or Bayesian software to estimate AUC: Requires collection of 2 serum concentrations, postdistributional peak concentration (Cmax) drawn 1 to 2 hours after infusion and trough concentration (Cmin) drawn at the end of the dosing interval. It is preferable that a near steady-state postdistributional peak and trough concentration within the same dosing interval (if possible) are used with the equation-based method. Bayesian-derived AUC monitoring does not require steady-state serum concentrations (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Trough monitoring: Draw trough concentration just before the administration of a dose at steady-state conditions. Steady-state conditions generally occur approximately after the third dose; therefore, may begin monitoring vancomycin trough concentrations before the fourth dose (usually within 1 hour of administration). More specific recommendations for timing of serum samples may be found in "Monitoring Parameters" (Alvarez 2016; ASHP/IDSA/SIDP [Rybak 2009]).Target concentrations:Intermittent infusion:AUC/minimum inhibitory concentration determined by broth microdilution (MICBMD): 400 to 600, assuming MICBMD of 1 mg/L. When MICBMD is >1 mg/L, probability of attaining an AUC/MIC target of ≥400 is low with conventional dosing; higher doses may risk unnecessary toxicity. When MICBMD is <1 mg/L, decreasing the dose to achieve the AUC/MIC target is not recommended (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Trough: 10 to 20 mg/L; target within this range depends on site and severity of infection, as well as clinical response. For pathogens with a minimum inhibitory concentration (MIC) ≤1 mg/L, the minimum trough concentration should be 15 mg/L to meet target AUC/MIC of ≥400. For complicated infections (eg, bacteremia, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia caused by S. aureus) or infections associated with severe sepsis or septic shock, trough concentrations of 15 to 20 mg/L are recommended to improve penetration and improve clinical outcomes (ASHP/IDSA/SIDP [Rybak 2009]; Liu 2011). The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines for hospital-acquired pneumonia and the IDSA meningitis guidelines also recommend trough concentrations of 15 to 20 mg/L (Kalil 2016; Tunkel 2004; Tunkel 2017).Continuous infusion: Target steady-state concentration: 20 to 25 mg/L (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Concentrations associated with toxicity: Serum concentration >80 mg/L.Intraventricular (off-label route): Limited data available (IDSA [Tunkel 2004; Tunkel 2017]; Smetana 2018): Prior to administration of the next intraventricular dose, withdraw a sample of cerebrospinal fluid (CSF). This trough CSF concentration divided by the vancomycin MIC for the isolated bacterial pathogen (inhibitory quotient) should exceed 10 to 20.Mechanism of ActionInhibits bacterial cell wall synthesis by blocking glycopeptide polymerization through binding tightly to D-alanyl-D-alanine portion of cell wall precursorPharmaco*kineticsAbsorption: Oral: Poor; Rectal: significant absorption through inflamed colonic mucosa may occur; Intraperitoneal (IP): 60% of an IP dose absorbed in 6 hours.Distribution: Distributes widely in body tissue and fluids, except for cerebrospinal fluid (CSF).Vd:Neonates, term: 0.57 to 0.69 L/kg (de Hoog 2004).Infants: 0.56 L/kg (Rainkie 2015).Children ≤6 years of age: 0.61 L/kg (Rainkie 2015).Children >6 years of age: 0.47 L/kg (Rainkie 2015).Adolescents: 0.49 L/kg (Rainkie 2015).Adults: 0.4 to 1 L/kg (ASHP/IDSA/SIDP [Rybak 2009]); 0.3 to 0.5 L/kg in patients who are morbidly obese (Adane 2015; Bauer 1998; Hong 2015).Relative diffusion from blood into CSF: Good only with inflammation (exceeds usual MICs).Children:CSF concentrations: 0.2 to 17.3 mg/L (de Hoog 2004).CSF:blood level ratio: Normal meninges: Nil; Inflamed meninges: 7.1% to 68% (de Hoog 2004).Adults:Uninflamed meninges: 0 to 4 mg/L; serum concentration dependent (ASHP/IDSA/SIDP [Rybak 2009]).Inflamed meninges: 6 to 11 mg/L; serum concentration dependent (ASHP/IDSA/SIDP [Rybak 2009]).CSF:serum level ratio: Normal meninges: Nil; Inflamed meninges: ~80% (Shokouhi 2014).Protein binding: ~55%.Metabolism: No apparent metabolism.Half-life elimination: Biphasic: Terminal:Preterm neonates (GA: 32 to 34 weeks); PNA ~3 to 5 days: 5.9 to 9.8 hours (Schaad 1980).Term neonates; PNA ~2 to 3 days: 6.7 hours (Schaad 1980).Infants: 2.8 hours (Rainkie 2015).Children <6 years of age: 2.4 hours (Rainkie 2015).Children ≥6 years of age: 2.9 hours (Rainkie 2015).Adolescents: 3.2 hours (Rainkie 2015).Adults: 4 to 6 hours; significantly prolonged with renal impairment.End-stage renal disease: 7.5 days.Time to peak, serum: IV: Immediately after completion of infusion.Excretion: Primarily via glomerular filtration; IV: Urine (75% as unchanged drug in the first 24 hours); Oral: Primarily feces.Clearance: presence of malignancy in children is associated with an increase in vancomycin clearance.Neonates: 0.63 to 1.5 mL/minute/kg; dependent on GA and/or PMA (de Hoog 2004).Pediatric patients: Median: 1.1 mL/minute/kg (range: 0.33 to 1.87 mL/minute/kg) (Marsot 2012).Adults: 1.6 to 6.2 L/hour (Matzke 1984); patients who are obese: ~6 L/hour (rarely exceeds 9 L/hour) (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Pharmaco*kinetics: Additional ConsiderationsPediatric: Extracorporeal membrane oxygenation (ECMO): Reported pharmaco*kinetic parameters in pediatric patients receiving ECMO vary widely based on ECMO circuitry/filters, age, weight, kidney function, and underlying diseases. In general, volume of distribution may be increased and clearance may be increased or decreased; reported parameters vary significantly; elimination half-life appears to be dependent upon renal function (Amaker 1996; Buck 1998; Cies 2017; Moffett 2018; Mulla 2005; Zylbersztajn 2018).Older adult: Total systemic and renal clearance may be reduced.Anti-infective considerations:Parameters associated with efficacy: Note: Ratios, including the minimum inhibitory concentration (MIC), depend upon the methodology used; MIC determined by E-test is typically 1.5 to 2 times MIC determined by broth microdilution (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Staphylococcus aureus: AUC/MICBMD ≥400 mg•hour/L (ASHP/IDSA/PIDS/SIDP [Rybak 2020]; Kullar 2011; Lodise 2014; Moise-Broder 2004); specific cutoff for efficacy has varied slightly between studies.Enterococcus spp.: AUC/MICEtest ≥389 (Jumah 2018).Coagulase-negative staphylococci (neonates): AUC24 ≥300 mg•hour/L in first 24 hours of therapy or AUC24 ≥424 mg•hour/L in the second 24 hours of therapy (Gwee 2022).Parameters associated with toxicity: Nephrotoxicity: AUC ≥600 to 650 mg•hour/L (adults); ≥800 mg•hour/L (pediatrics); risk continues to increase along AUC continuum (Aljefri 2019; ASHP/IDSA/PIDS/SIDP [Rybak 2020]; Fiorito 2018; Le 2015; Lodise 2020); Cmin ≥15 mg/L (ASHP/IDSA/PIDS/SIDP [Rybak 2020]; van Hal 2013).Postantibiotic effect: A short postantibiotic effect has been observed in E. faecalis (0.5 to 1 hour) and S. aureus (0.6 to 2 hours); slightly longer in S. epidermidis (4.3 to 6.5 hours) (Hanberger 1991; Löwdin 1998).Pricing: USCapsules (Vancocin Oral)125 mg (per each): $103.35250 mg (per each): $190.55Capsules (Vancomycin HCl Oral)125 mg (per each): $31.31250 mg (per each): $57.72Solution (Vancomycin HCl in Dextrose Intravenous)1GM/200ML 5% (per mL): $0.16500 mg/100 mL 5% (per mL): $0.09750MG/150ML 5% (per mL): $0.10Solution (Vancomycin HCl in NaCl Intravenous)1GM/200ML 0.9% (per mL): $0.14500 mg/100 mL 0.9% (per mL): $0.09750MG/150ML 0.9% (per mL): $0.10Solution (Vancomycin HCl Intravenous)500 mg/100 mL (per mL): $0.11750 mg/150 mL (per mL): $0.101000 mg/200 mL (per mL): $0.101250 mg/250 mL (per mL): $0.091500MG/300ML (per mL): $0.091750MG/350ML (per mL): $0.092000MG/400ML (per mL): $0.08Solution (reconstituted) (Firvanq Oral)25 mg/mL (per mL): $0.9050 mg/mL (per mL): $1.14Solution (reconstituted) (Vancomycin HCl Intravenous)1 g (per each): $4.14 - $19.541.25 g (per each): $24.121.5 g (per each): $28.94 - $29.225 g (per each): $19.72 - $108.3110 g (per each): $39.18 - $260.68100 g (per each): $600.00500 mg (per each): $2.96 - $9.79750 mg (per each): $8.02 - $11.81Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAekovan (PH);Alvarcin (CR, DO, GT, HN, NI, PA, SV);Celovan (HK);Citerin (MX);Covan (BD);Covancin (IN);Cytovan (IN);Dhacocin (MY, SG);Edicin (BG, CZ, EE, RO, RU, SK, TH, TR, UA);Estavam (MX);Forstaf (IN);Icoplax (AR, PE);Kovan (CL);Levovanox (IT);Mersa (PH);Normedia (SE);Riveran (AR, PE);Vacsol (MX);Vagran (VE);Vamysin (BE);Vanauras (MX);Vanaurus (CR, DO, EC, GT, HN, NI, PA, SV);Vancard (BD);Vancep (ID);Vancin (BD);Vancin-S (TH);Vanco (TW);Vanco-SAAR (DE);Vanco-Teva (IL);Vancoavenir (IL);Vancobac (BD);Vancobact (EG);Vancocid (TH);Vancocin (AE, AT, AU, BB, BG, HU, IE, JO, LB, LK, MT, NL, RU, SA, SI, VN, ZA);Vancocin CP (CN, IN, MX, PK, TW);Vancocin HCl (BF, BJ, CH, CI, DK, ET, GB, GH, GM, GN, HK, KE, LR, MA, ML, MR, MU, MW, NE, NG, PH, SC, SD, SE, SL, SN, TN, TW, TZ, UG, ZM, ZW);Vancocina (IT);Vancocine (FR);Vancodex (ID);Vancoled (AE, KR, KW, VN);Vancolon (AE, BH, EG, ET, KW, LB, PH, QA, SA);Vancomax (PE, PY);Vancomet (PH);Vanconix (BD);Vancorin (TR);Vancorus (RU);Vancosam (LK);Vancosan (BR, FI, IS, LT, LV);Vancotech (LK);Vancotek (AR);Vancotex (MY);Vancotrat (BR);Vancox (MX);Vancozin (EG, KR);Vanlyo (TW);Vanmicira (CZ);Vantocil (ID);Varedet (AR, PE, PY, UY);Vivocin (MY);Voncon (GR);Vondem (GR);Voxin (GR)For country code abbreviations (show table)Adane ED, Herald M, Koura F. 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CloseSitagliptin: Drug informationSitagliptin: Drug information(For additional information see "Sitagliptin: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USJanuviaBrand Names: CanadaJanuviaPharmacologic CategoryAntidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) InhibitorDosing: AdultNote: Due to lack of additive glycemic benefit, use in combination with a glucagon-like peptide-1 (GLP-1) receptor agonist should be avoided (Ref). May require a dose reduction of insulin and/or insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia.Diabetes mellitus, type 2, treatmentDiabetes mellitus, type 2, treatment: Note: May be used as an adjunctive agent or alternative monotherapy for select patients, including those in whom initial therapy with lifestyle intervention and metformin failed, or who cannot take metformin, particularly in patients close to glycemic goals when avoidance of hypoglycemia and/or weight gain is desirable; use is not associated with improvement in cardiovascular or renal outcomes (Ref).Oral: 100 mg once daily.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Oral: Altered kidney function:eGFR ≥45 mL/minute/1.73 m2: No dosage adjustment necessary.eGFR ≥30 to <45 mL/minute/1.73 m2: 50 mg once daily.eGFR <30 mL/minute/1.73 m2: 25 mg once daily.Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable (13.5% removed during 3- to 4-hour hemodialysis session) (Ref): 25 mg once daily; may administer without regard to timing of dialysis.Peritoneal dialysis: 25 mg once daily.Dosing: Hepatic Impairment: AdultMild to moderate impairment (Child-Pugh classes A and B): No dosage adjustment necessary.Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Januvia: 25 mg, 50 mg, 100 mgGeneric Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Januvia: 25 mg, 50 mg, 100 mgMedication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021995s050lbl.pdf#page=27, must be dispensed with this medication.Administration: AdultOral: Administer without regard to meals.Use: Labeled IndicationsDiabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, as monotherapy or combination therapy.Medication Safety IssuesSound-alike/look-alike issues:Januvia may be confused with Enjuvia, Janumet, JantovenSITagliptin may be confused with SAXagliptin, SUMAtriptanAdverse Reactions (Significant): ConsiderationsArthralgiaArthralgia, including severe and disabling cases, has been reported with dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin (Ref). Specific inflammatory joint complications may include polyarthritis, polyarthropathy, rheumatoid arthritis, and severe synovitis (Ref). Patients may or may not exhibit an increase in rheumatoid factors (Ref).Mechanism: Not well established; one hypothesis includes cytokine-induced inflammation (Ref).Onset: Varied; onset may occur within 1 day to years after treatment initiation. Symptoms may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-4 inhibitor therapy resumes (Ref).In one study, most patients who reported arthralgias did so within 3 months of initiation of DPP-4 inhibitors and symptoms resolved within 1 month after discontinuation (Ref).Risk factors:• Longer duration of therapy; data is conflicting (Ref).Dermatologic reactionsDipeptidyl peptidase-4 (DPP-4) inhibitor use, including sitagliptin, has been associated with development or exacerbation of bullous pemphigoid (Ref). Although most DPP-4 inhibitors have been associated with the development of bullous pemphigoid, vildagliptin is associated with a higher risk (Ref). In addition, severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome or toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms have been reported with sitagliptin (Ref). Other dermatologic reactions that have occurred following sitagliptin use are maculopapular rash and fixed drug eruption (Ref).Mechanism: Non-dose-related; immunologic.Bullous pemphigoid: Exact mechanism unknown (Ref). Some skin cells (including keratinocytes) express DPP-4, leading to an increase in cytokine production, tissue differentiation, and collagen metabolism; whether this leads to an alteration in the properties of the epidermal basem*nt membrane is unknown.Delayed hypersensitivity reactions (including SCARs): Mediated by T-cells (Ref).Onset:Bullous pemphigoid: Delayed; median onset of ~6 months (range: 6 to 1,751 days) (Ref). Most cases of bullous pemphigoid typically resolve following discontinuation; some require symptomatic treatment (Ref).Delayed hypersensitivity reactions: Varied; typically occur days to weeks after drug exposure (Ref).Risk factors:• Age; although older age may be a risk factor for the development of bullous pemphigoid, some studies have not shown age to be a factor (Ref).• Males; some studies have suggested that male patients with diabetes may be at higher risk than female patients (Ref), although a meta-analysis of case-controlled studies did not find sex to be a predisposing risk factor (Ref).Heart failureAn increased risk of hospitalization due to heart failure (HF) was identified as a potential issue with dipeptidyl peptidase-4 (DPP-4) inhibitors, specifically saxagliptin and alogliptin, following results from the SAVOR TIMI 53 and EXAMINE trials, respectively (Ref). In contrast, the TECOS and CARMELINA trials showed no increased risk of hospitalization due to HF with sitagliptin or linagliptin, respectively, including in patients with preexisting HF (Ref). A meta-analysis of 182 trials found that, overall, use of a DPP-4 inhibitor was not associated with an increased risk of HF (OR: 1.05; 95% CI: 0.96 to 1.15; I2 = 0%); a significantly higher risk of HF was seen with saxagliptin (OR: 1.22; 95% CI: 1.03 to 1.45), but not for other DPP-4 inhibitors (Ref). The American Diabetes Association (ADA) suggests DPP-4 inhibitors (except saxagliptin) may be considered in patients with HF; however, other agents are preferred (ADA 2021). The American Heart Association considers sitagliptin to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: Major) (Ref).Mechanism: Unknown (Ref).Onset: Variable; the American Heart Association suggests the impact of DPP-4 inhibitors on myocardial dysfunction may be seen within weeks to ≥1 year (Ref).Risk factors:• Presence of risk factors for HF or preexisting HF (Ref)Hypersensitivity reactions (immediate)Anaphylaxis and angioedema have been reported with sitagliptin (Ref).Mechanism: Non-dose-related; immunologic.Angioedema: Considered a non-mast-cell-mediated process involving impaired catabolism of bradykinin (Ref). Sitagliptin and other dipeptidyl peptidase-4 (DPP-4) inhibitors can inactivate substance P and bradykinin (Ref).Anaphylaxis: Considered to be an IgE-mediated reaction (Ref).Onset: Varied; events have generally been noted within the first 3 months of therapy and may occur with the initial dose (Ref).Risk factors:• Concomitant use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or p-glycoprotein inhibitors (Ref)• Hereditary angioedema (Ref)• History of angioedema with other DPP-4 inhibitorsPancreatic eventsCases of acute pancreatitis (including hemorrhagic pancreatitis and necrotizing pancreatitis with some fatalities), chronic pancreatitis, and pancreatic cancer have been reported with use of incretin-based therapies (eg, dipeptidyl peptidase-4 [DPP-4] inhibitors, glucagon-like peptide 1 [GLP-1] receptor agonists), including sitagliptin (Ref).Mechanism: Causality has not been firmly established (Ref). DPP-4 inhibitors indirectly stimulate GLP-1 receptors in pancreatic islet beta cells and exocrine duct cells which may cause an overgrowth of the cells that cover the smaller ducts, thereby resulting in hyperplasia, increased pancreatic weight, duct occlusion, back pressure, and subsequent acute or chronic pancreatic inflammation (Ref).Risk factors:• Patients with a prior history of pancreatitis may be at an increased risk for acute pancreatitis• Patients with acute pancreatitis due to any cause are at an increased risk for progression to recurrent acute pancreatitis and then to chronic pancreatitis; patients with chronic pancreatitis are at an increased risk for pancreatic cancer (Ref)• Risk factors for pancreatitis due to any cause include, but are not limited to, hypertriglyceridemia, cholelithiasis, alcohol use, and obesityAdverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.1% to 10%:Endocrine & metabolic: Hypoglycemia (1%)Respiratory: Nasopharyngitis (5%)Frequency not defined: Gastrointestinal: Diarrhea, nauseaPostmarketing:Dermatologic: Bullous pemphigoid (García-Díez 2018; Tanaka 2019), skin rash (Nakai 2014), Stevens-Johnson syndrome (Desai 2010), toxic epidermal necrolysis (Desai 2010)Gastrointestinal: Acute pancreatitis (including hemorrhagic pancreatitis and necrotizing pancreatitis) (Butler 2013; Elashoff 2011; Scheen 2018), constipation (Williams-Herman 2010), oral mucosa ulcer (Jinbu 2013), stomatitis, vomitingHepatic: Increased liver enzymes (Shahbaz 2018)Hypersensitivity: Anaphylaxis (Desai 2010), angioedema (Arcani 2017; Gosmanov 2012; Skalli 2010), drug reaction with eosinophilia and systemic symptoms (Sin 2012)Nervous system: Headache (Zaghloul 2018)Neuromuscular & skeletal: Arthralgia (FDA safety alert; Mascolo 2016), myalgia (Tarapues 2013)Renal: Acute kidney injury (possibly requiring dialysis) (Shih 2016), interstitial nephritis (Alsaad 2016)ContraindicationsSerious hypersensitivity (eg, anaphylaxis, angioedema) to sitagliptin or any component of the formulationWarnings/PrecautionsDisease-related concerns:• Bariatric surgery:– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; Melissas 2013).– Glucagon-like peptide-1 exposure and therapeutic efficacy: Closely monitor for signs and symptoms of pancreatitis; gastric bypass and sleeve gastrectomy may increase endogenous secretion of glucagon-like peptide-1 (Korner 2009; Peterli 2012). A single-dose, placebo-controlled study evaluated short-term therapy (4 weeks) with sitagliptin in gastric bypass patients having persistent or recurrent type 2 diabetes and found it to be well tolerated and provided a small but significant reduction in postprandial blood glucose (Shah 2018).• Renal impairment: Use with caution in patients with moderate to severe renal dysfunction and end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis; dosing adjustment required.Other warnings/precautions:• Appropriate use: Not indicated for use in patients with type 1 diabetes.Metabolism/Transport EffectsSubstrate of CYP2C8 (minor), CYP3A4 (minor), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyAndrogens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyAngiotensin-Converting Enzyme Inhibitors: Dipeptidyl Peptidase-IV Inhibitors may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased.Risk C: Monitor therapyBeta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyBeta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyBortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyDigoxin: SITagliptin may increase the serum concentration of Digoxin.Risk C: Monitor therapyDirect Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyEtilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyGuanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyHyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyHypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents.Risk C: Monitor therapyInsulins: Dipeptidyl Peptidase-IV Inhibitors may enhance the hypoglycemic effect of Insulins.Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modificationMaitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyMonoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyPegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyProthionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyQuinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapyRitodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapySalicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapySelective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapySulfonylureas: Dipeptidyl Peptidase-IV Inhibitors may enhance the hypoglycemic effect of Sulfonylureas.Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modificationThiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyReproductive ConsiderationsDipeptidyl peptidase 4 (DPP-4) inhibitors are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)Pregnancy ConsiderationsInformation related to the use of sitagliptin in pregnancy is limited (Sun 2017).Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2021; Blumer 2013).Agents other than sitagliptin are currently recommended to treat diabetes mellitus during pregnancy (ADA 2021).Breastfeeding ConsiderationsIt is not known if sitagliptin is present in breast milk.According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.Dietary ConsiderationsIndividualized medical nutrition therapy (MNT) based on American Diabetes Association (ADA) recommendations is an integral part of therapy.Monitoring ParametersSerum glucose; renal function prior to initiation and periodically during treatment; signs/symptoms of heart failure, hypersensitivity, and/or pancreatitis; development of blisters or erosions.HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).Reference RangeRecommendations for glycemic control in patients with diabetes:Nonpregnant adults (ADA 2021):HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).Older adults (≥65 years of age) (ADA 2021):Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health)Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health)Classification of hypoglycemia (ADA 2021):Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.Mechanism of ActionSitagliptin inhibits dipeptidyl peptidase-4 (DPP-4) enzyme resulting in prolonged active incretin levels. Incretin hormones (eg, glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells. Decreased glucagon secretion results in decreased hepatic glucose production. Under normal physiologic circ*mstances, incretin hormones are released by the intestine throughout the day and levels are increased in response to a meal; incretin hormones are rapidly inactivated by the DPP-4 enzyme.Pharmaco*kineticsAbsorption: RapidDistribution: ~198 LProtein binding: 38%Metabolism: Not extensively metabolized; minor metabolism via CYP3A4 and 2C8 to metabolites (inactive) suggested by in vitro studiesBioavailability: ~87%Half-life elimination: 12.4 hoursTime to peak, plasma: 1 to 4 hoursExcretion: Urine 87% (~79% as unchanged drug, 16% as metabolites); feces 13%Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: Plasma AUC levels of sitagliptin were increased approximately 2- and 4-fold in patients with moderate and severe renal impairment, including patients with ESRD on hemodialysis, respectively.Older adult: Elderly patients had ~19% higher plasma concentration.Pricing: USTablets (Januvia Oral)25 mg (per each): $20.8650 mg (per each): $20.86100 mg (per each): $20.86Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalFazique (CR, DO, GT, HN, MX, NI, PA, SV);Glactiv (JP);Glipita (BD);Inosita (LK);Janaglip (EG);Januvia (AE, AR, AT, AU, BB, BE, BH, BM, BR, BS, BZ, CH, CL, CN, CO, CY, CZ, DE, DK, EE, EG, ES, ET, FR, GB, GR, GY, HK, HR, HU, ID, IE, IL, IN, IS, IT, JM, JO, JP, KR, KW, LB, LK, LT, LU, LV, MT, MX, MY, NL, NO, NZ, PE, PH, PL, PR, PT, QA, RO, RU, SA, SE, SG, SI, SK, SR, TH, TR, TT, TW, TZ, UA, UY, VN, ZA, ZW);Januvia XR (HK);Janvia (BD);Nimegon (BR);Ristaben (CL, EE, IE);Sigtin (TW);Sijatin (TW);Sitagen (LK);Sitalia (BD);Sitap (BD);Sitrg (LK);Sliptin (BD);Tesavel (EE, ES, IE, IT, NL, PL, PT);Xelevia (AR, CZ, DE, DK, EE, ES, FR, GR, HR, HU, IE, IT, LT, MT, NL, PH, PT, RO, SK, TR)For country code abbreviations (show table)Alexopoulos AS, Blair R, Peters AL. 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Circulation. 2019;139(3):362-365. doi:10.1161/CIRCULATIONAHA.118.038399 [PubMed 30586788]Topic 9482 Version 252.0

CloseMethylprednisolone: Pediatric drug informationMethylprednisolone: Pediatric drug information(For additional information see "Methylprednisolone: Drug information" and see "Methylprednisolone: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USDEPO-Medrol;Medrol;P-Care D40 [DSC];P-Care D80 [DSC];SOLU-MedrolBrand Names: CanadaDepo-Medrol;Medrol;SOLU-medrol;Solu-MEDROL;Uni-Med [DSC]Therapeutic CategoryAdrenal Corticosteroid;Anti-inflammatory Agent;Antiasthmatic;Corticosteroid, Systemic;GlucocorticoidDosing: PediatricNote: Adjust dose depending upon condition being treated and response of patient. The lowest possible dose should be used to control the condition; when dose reduction is possible, the dose should be reduced gradually. In life-threatening situations, parenteral doses larger than the oral dose may be needed. Only sodium succinate salt may be given IV.General dosing; anti-inflammatory or immunosuppressive (Ref):Methylprednisolone sodium succinate (immediate acting): Infants, Children, and Adolescents: Oral, IV, IM: 0.11 to 1.6 mg/kg/day in 3 to 4 divided doses.Methylprednisolone acetate (long acting): Infants, Children, and Adolescents:IM: 0.11 to 1.6 mg/kg/dose; frequency depends upon condition being treated, usually administered as a one-time dose or every 1 to 2 weeks.Intra-articular: Dosing varies based on affected joint; general range: 4 to 80 mg every 1 to 5 weeks.Anaphylaxis, adjunctive therapyAnaphylaxis, adjunctive therapy: Limited data available:Note: Administer epinephrine first when treating anaphylaxis. Corticosteroids are considered second- or third-line therapy and do not result in prompt resolution of airway obstruction or shock. Use of corticosteroids for anaphylaxis is controversial; they have little to no benefit on initial symptoms; typically administered to prevent biphasic or prolonged episodes of anaphylaxis (Ref).Infants, Children, and Adolescents: IV, IM (succinate): 1 to 2 mg/kg/dose as a single dose; maximum dose: 125 mg/dose (Ref).AsthmaAsthma:Acute exacerbation: Outpatient management (short-course "burst") (Ref):Oral: Note: Burst should be continued until symptoms resolve or patient achieves peak expiratory flow 80% of personal best; usually requires 3 to 10 days of treatment (~5 days on average); longer treatment may be required.Infants and Children <12 years: Oral: 1 to 2 mg/kg/day in 1 or 2 divided doses for 3 to 10 days; maximum daily dose: 60 mg/day.Children ≥12 years and Adolescents: Oral: 40 to 60 mg/day in 1 or 2 divided doses for 3 to 10 days.IM (acetate): Note: This may be given in place of short-course "burst" of oral steroids in patients who are vomiting or if compliance is a problem.Children ≤4 years: IM: 7.5 mg/kg as a one-time dose; maximum dose: 240 mg.Children ≥5 years and Adolescents: IM: 240 mg as a one-time dose.Emergency/acute care management:Infants and Children <12 years: Oral, IV (succinate): 1 to 2 mg/kg/day in 2 divided doses; maximum daily dose: 60 mg/day; continue until peak expiratory flow is 70% of predicted or personal best (Ref). Some experts suggest infants and children ≤5 years may receive IV doses of 1 mg/kg/dose every 6 hours on day 1, followed by transition to oral corticosteroids to complete a 3 to 5 days course (Ref).Children ≥12 years and Adolescents: Oral, IV (succinate): 40 to 80 mg/day in 1 or 2 divided doses until peak expiratory flow is 70% of predicted or personal best (Ref).Status asthmaticus: Children and Adolescents: IV (succinate): Loading dose: 2 mg/kg/dose, then 0.5 to 1 mg/kg/dose every 6 hours (Ref).Long-term treatment (non-acute), severe, persistent asthma (Ref): Infants and Children <12 years: Oral: 0.25 to 2 mg/kg/day once daily in the morning or every other day as needed for asthma control; maximum daily dose: 60 mg/day.Children ≥12 years and Adolescents: Oral: 7.5 to 60 mg once daily in the morning or every other day as needed for asthma control.Graft-versus-host disease, acuteGraft-versus-host disease, acute (GVHD): Limited data available: Infants, Children, and Adolescents: IV (succinate): 1 to 2 mg/kg/dose once daily; if using low dose (1 mg/kg) and no improvement after 3 days, increase dose to 2 mg/kg. Continue therapy for 5 to 7 days; if improvement observed, may taper by 10% of starting dose every 4 days; if no improvement, then considered steroid-refractory GVHD and additional agents should be considered (Ref).Immune thrombocytopenia, moderate to severe bleeding or at risk for severe bleedingImmune thrombocytopenia, moderate to severe bleeding or at risk for severe bleeding: Limited data available:Infants, Children, and Adolescents: IV (succinate): Initial: Pulse: 30 mg/kg/dose once daily for 1 to 3 doses; number of doses is determined by patient clinical status, initial and postdose platelet counts, and if used in conjunction with other therapies; maximum dose: 1,000 mg/dose; follow with oral corticosteroid therapy as clinically indicated (Ref).Juvenile idiopathic arthritis, systemicJuvenile idiopathic arthritis, systemic: Note: Therapy should be individualized based on disease severity and activity (Ref). Limited data available:Children and Adolescents: IV (succinate): Pulse therapy: 30 mg/kg/day once daily for 3 days; maximum dose: 1,000 mg/dose. Follow pulse therapy with oral corticosteroids; evaluate initial response at 1 to 2 weeks and then at 1 month of therapy; if condition worsens or unchanged at either time interval, may repeat methylprednisolone 30 mg/kg/dose at weekly intervals as clinically indicated (Ref).Kawasaki diseaseKawasaki disease: Limited data available; optimal regimen not established; efficacy variable:Primary adjunctive treatment, patients at high risk for intravenous immune globulin (IVIG) resistance or coronary artery aneurysms: Note: Use in combination with IVIG and aspirin:Infants and Children: IV (succinate): 1.6 mg/kg/day in divided doses every 8 hours for 5 days or until afebrile, then transition to oral prednisolone; maximum daily dose: 48 mg/day; some centers use less frequent dosing intervals (eg, every 12 hours) to minimize adverse effects (Ref). Note: Dosing based on use of IV prednisolone product (2 mg/kg/day), which is not available in the United States; dosing converted to equivalent methylprednisolone dosing; however, clinical necessity of conversion is unknown.Treatment, refractory/resistant disease: Note: Reserve use for patients who remain febrile after initial IVIG dose:Pulse dosing: Infants and Children: IV (succinate): 30 mg/kg/dose once daily for 1 or 3 days; may be given in combination with additional IVIG dose (Ref).Taper dosing: Infants and Children: IV (succinate): 1.6 mg/kg/day in divided doses every 8 hours for 5 days or until afebrile, then transition to oral prednisolone; maximum daily dose: 48 mg/day; give in combination with aspirin and an additional dose of IVIG (Ref). Note: Dosing based on use of IV prednisolone product (2 mg/kg/day) which is not available in the United States; dosing converted to equivalent methylprednisolone dosing; however, clinical necessity of conversion is unknown.Lupus nephritis, proliferativeLupus nephritis, proliferative (induction): Limited data available: Children and Adolescents: IV (succinate): Initial pulse therapy: 30 mg/kg/dose once daily for 3 doses; maximum dose: 1,000 mg/dose (Ref). Reported dosage range: 10 to 30 mg/kg/dose or 500 to 1,000 mg/m2/dose once daily for 3 days. Following pulse therapy transition to oral corticosteroids and taper as clinically indicated. May be given as part of an appropriate combination dosage regimen (Ref).Multisystem inflammatory syndrome in children associated with SARS-CoV-2Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: Limited data available:Infants, Children, and Adolescents:Initial therapy: IV (succinate): 1 to 2 mg/kg/day divided twice daily in combination with IVIG; duration is dependent on clinical course; may then transition to oral steroids, with taper over at least 2 to 3 weeks (Ref). Note: High-dose corticosteroid therapy at doses of 10 to 30 mg/kg/day (maximum dose: 1,000 mg/dose) for 1 to 3 days has also been reported as initial therapy of MIS-C in patients with more severe disease (eg, shock symptoms) (Ref).Intensification therapy (in patients who do not improve within 24 hours of initial MIS-C therapy with low- to moderate-dose corticosteroid therapy and IVIG): IV (succinate): 10 to 30 mg/kg/day (maximum dose: 1,000 mg/dose) for 1 to 3 days (Ref).Nephrotic syndrome, steroid resistantNephrotic syndrome, steroid resistant: Limited data available, variable regimens reported: Children and Adolescents: Pulse therapy: IV (succinate): 15 to 30 mg/kg/dose or 500 mg/m2/dose once daily for 3 days; maximum dose: 1,000 mg/dose. Transition to oral corticosteroid and taper as clinically indicated (Ref). Additional pulse doses may be required; some regimens include multiple pulses over a few months until remission (Ref).Pneumocystis pneumonia, adjunctive therapy for moderate or severe infectionPneumocystis pneumonia (PCP), adjunctive therapy for moderate or severe infection: Limited data available: Note: Recommended when on room air PaO2 <70 mm Hg or PAO2-PaO2 ≥35 mm Hg. Begin as soon as possible after diagnosis and within 72 hours of PCP therapy.Infants and Children: IV (succinate): 1 mg/kg/dose every 6 hours on days 1 to 7, then 1 mg/kg/dose twice daily on days 8 to 9, then 0.5 mg/kg/dose twice daily on days 10 and 11, and 1 mg/kg/dose once daily on days 12 to 16 (Ref).Adolescents: IV (succinate): 30 mg twice daily on days 1 to 5, then 30 mg once daily on days 6 to 10, then 15 mg once daily on days 11 to 21 (Ref).Radiocontrast media reaction, prevention of rebound reactionRadiocontrast media reaction, prevention of rebound reaction: Limited data available: Note: If patient is experiencing anaphylaxis, administer epinephrine first. Corticosteroids may be utilized to prevent rebound reactions.Infants, Children, and Adolescents: IV (succinate): 1 mg/kg/dose; maximum dose: 40 mg/dose (Ref).Ulcerative colitis, acute, severeUlcerative colitis, acute, severe:Limited data available: Children and Adolescents: IV (succinate): 1 to 1.5 mg/kg/day once daily or in divided doses 2 times daily; maximum daily dose: 60 mg/day. Higher doses should be reserved for patients with severe disease and/or who have failed oral steroids. Transition to oral therapy when clinically appropriate. If inadequate response after 3 to 5 days of IV therapy, initiate second-line therapy (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling. The pharmaco*kinetic and pharmacodynamic properties of methylprednisolone in kidney impairment are not well understood (Ref). Methylprednisolone clearance appears unaltered in patients with uremia (Ref) and it is slightly dialyzable (Ref).Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Adult(For additional information see "Methylprednisolone: Drug information")Note: Dosing: Evidence to support an optimal dose and duration are lacking for most indications; recommendations provided are general guidelines only and primarily based on expert opinion. In general, glucocorticoid dosing should be individualized and the minimum effective dose/duration should be used. Hypothalamic-pituitary-adrenal suppression: Although some patients may become hypothalamic-pituitary-adrenal (HPA) suppressed with lower doses or briefer exposure, some experts consider HPA-axis suppression likely in any adult receiving >16 mg/day (daytime dosing) or ≥4 mg per 24 hours (evening or night dosing) for >2 weeks, or with Cushingoid appearance (Ref); do not abruptly discontinue treatment in these patients; dose tapering may be necessary (Ref). Safety: Only the methylprednisolone succinate formulation (Solu-Medrol) may be given IV. Methylprednisolone acetate suspension (Depo-Medrol) is intended for IM or intra-articular administration only; do not administer the acetate preparation IV (Ref).Usual dosage range:IV (succinate): 40 to 125 mg/day given in a single daily dose or in divided doses; rarely, for certain conditions, may go up to 1 to 2 mg/kg/day.Initial high-dose “pulse” therapy for select indications (eg, severe systemic rheumatic disorders): 7 to 15 mg/kg/dose (or 500 mg to 1 g/dose) given once daily for 3 to 5 days.Oral: 16 to 64 mg/day once daily or in divided doses.The following dosing is from the commercially available tapered-dosage product (eg, dose-pack containing 21 × 4 mg tablets):Day 1: 24 mg on day 1 administered as 8 mg (2 tablets) before breakfast, 4 mg (1 tablet) after lunch, 4 mg (1 tablet) after supper, and 8 mg (2 tablets) at bedtime or 24 mg (6 tablets) as a single dose or divided into 2 or 3 doses upon initiation (regardless of time of day).Day 2: 20 mg on day 2 administered as 4 mg (1 tablet) before breakfast, 4 mg (1 tablet) after lunch, 4 mg (1 tablet) after supper, and 8 mg (2 tablets) at bedtime.Day 3: 16 mg on day 3 administered as 4 mg (1 tablet) before breakfast, 4 mg (1 tablet) after lunch, 4 mg (1 tablet) after supper, and 4 mg (1 tablet) at bedtime.Day 4: 12 mg on day 4 administered as 4 mg (1 tablet) before breakfast, 4 mg (1 tablet) after lunch, and 4 mg (1 tablet) at bedtime.Day 5: 8 mg on day 5 administered as 4 mg (1 tablet) before breakfast and 4 mg (1 tablet) at bedtime.Day 6: 4 mg on day 6 administered as 4 mg (1 tablet) before breakfast.IM (acetate or succinate): 40 to 60 mg as a single dose.Intra-articular (acetate suspension): Note: Dose ranges per manufacturer's labeling. Specific dose is determined based upon joint size, severity of inflammation, amount of articular fluid present, and clinician judgment.Larger joint (eg, knee, shoulder, hip): 20 to 80 mg.Medium joint (eg, wrist, ankle, elbow): 10 to 40 mg.Small joint (eg, toe, finger): 4 to 10 mg.Intralesional (acetate) (alternative agent): Note: Other agents (eg, triamcinolone acetonide) may be more commonly employed (Ref).Usual dosage range: 20 to 60 mg; for large lesions, it may be necessary to distribute doses ranging from 20 to 40 mg by repeated local injections; 1 to 4 injections are usually employed with intervals between injections varying with the type of lesion being treated and clinical response.Acute respiratory distress syndrome, moderate to severeAcute respiratory distress syndrome, moderate to severe (off-label use): Note: May consider in most patients with persistent or refractory, moderate to severe acute respiratory distress syndrome, who are relatively early in the disease course (within 14 days) (Ref). Use ideal body weight to calculate dose. If patient is extubated between days 1 to 14, advance to day 15 of therapy and taper according to the following schedule. Do not abruptly discontinue since this may cause deterioration due to inflammatory response (Ref).IV (succinate): Loading dose of 1 mg/kg over 30 minutes, followed by a gradual taper:Days 1 to 14: 1 mg/kg/day in divided doses or as a continuous infusion.Days 15 to 21: 0.5 mg/kg/day in divided doses or as a continuous infusion.Days 22 to 25: 0.25 mg/kg/day in divided doses or as a continuous infusion.Days 26 to 28: 0.125 mg/kg/day in divided doses or as a continuous infusion.Allergic conditionsAllergic conditions:Anaphylaxis (adjunct to epinephrine for prevention of late-phase/biphasic reaction): Note: Do not use for initial or sole treatment of anaphylaxis because corticosteroids do not result in the prompt relief of upper or lower airway obstruction or shock (Ref). Some experts limit use to patients with severe or persistent steroid-responsive symptoms (eg, bronchospasm in patients with asthma) (Ref).IV (succinate): 1 to 2 mg/kg (Ref) or 40 to 125 mg as a single dose (Ref).Angioedema (acute allergic) and/or new-onset urticaria: Note: For moderate to severe symptoms without signs of anaphylaxis. Use epinephrine if anaphylaxis symptoms (eg, risk of airway or cardiovascular compromise) are present (Ref). In patients with new-onset urticaria, reserve use for those with significant angioedema or with symptoms that are unresponsive to antihistamines (Ref). The optimal dosing strategy has not been defined (Ref).IV (succinate): Initial: 60 to 80 mg; switch to an oral corticosteroid as soon as possible, tapering the dose for a total treatment duration of ≤10 days (Ref).Oral: Note: Dose is based on prednisone equivalency. An example regimen is 16 to 48 mg daily initially, followed by a taper over 5 to 7 days (Ref). The total treatment duration should not exceed 10 days (Ref).Asthma, acute exacerbationAsthma, acute exacerbation: Note: For moderate to severe exacerbations or in patients who do not respond promptly and completely to short-acting beta agonists; administer within 1 hour of presentation to emergency department (Ref).Oral, IV (succinate): 40 to 60 mg/day in 1 or 2 divided doses for 5 to 7 days (Ref); doses up to 60 to 80 mg every 6 to 12 hours have been used in critically ill patients (Ref). If symptoms do not resolve and peak expiratory flow is not at least 70% of personal best, then longer treatment may be required (Ref).Chronic obstructive pulmonary disease, acute exacerbationChronic obstructive pulmonary disease, acute exacerbation (off-label use): Note: In patients with severe but not life-threatening exacerbations, oral regimens are recommended. Use IV route in patients who cannot tolerate oral therapy (eg, shock, mechanically ventilated) (Ref).Oral; IV (succinate): 40 to 60 mg daily for 5 to 14 days (Ref). Doses up to 60 mg every 6 hours have been used in critically ill patients, although outcome data are limited. Note: Dose is based on an equivalent dose of prednisone; optimal dose has not been established. If patient improves with therapy, may discontinue without taper. If patient does not improve, a longer duration of therapy may be indicated (Ref).COVID-19, hospitalized patientsCOVID-19, hospitalized patients (alternative agent) (off-label use): Note: Methylprednisolone is recommended for treatment of COVID-19 in hospitalized patients requiring supplemental oxygen or ventilatory support when dexamethasone is not available or there are specific indications for methylprednisolone. Dosing is extrapolated from a study that used dexamethasone; the equivalent dose of methylprednisolone (or other glucocorticoid) may be substituted if necessary (Ref).Oral; IV (succinate): 32 mg once daily or 16 mg twice daily for up to 10 days (or until discharge, if sooner) as part of an appropriate combination regimen (Ref).Deceased organ donor managementDeceased organ donor management (hormonal resuscitation for the deceased organ donor) (off-label use): Note: Data supporting benefit are conflicting; if given, it should be administered after blood has been collected for tissue typing (Ref).IV (succinate): Regimens include: 1 g (as an IV infusion) or 15 mg/kg (as an IV infusion) or 250 mg (as an IV bolus) followed by a continuous infusion at 100 mg/hour; usually given as part of combination hormone therapy (Ref).Giant cell arteritis, treatmentGiant cell arteritis, treatment: Note: Due to the rapidly progressive nature of the disease, start treatment immediately once diagnosis is highly suspected (Ref). In patients presenting without threatened/evolving vision loss, an oral glucocorticoid is suggested as initial therapy rather than IV methylprednisolone (Ref).Initial pulse therapy in patients presenting with threatened/evolving vision loss: IV (succinate): 500 mg to 1 g daily for 3 days, followed by an oral glucocorticoid (eg, prednisone) (Ref).Gout, treatmentGout, treatment (acute flares):Note: Avoid use in patients with known or suspected septic arthritis (Ref).Intra-articular (acetate): Note: Consider in patients with gout flare limited to 1 or 2 affected joints; clinicians must have sufficient expertise to perform arthrocentesis and injection (Ref). May mix with an equal volume of local anesthetic (Ref). Dose is individualized based on joint size, disease severity, and clinician judgment (Ref). Typical doses are:Large joint (eg, knee): 40 mg as a single dose (Ref).Medium joint (eg, wrist, ankle, elbow): 30 mg as a single dose (Ref).Small joint (eg, toe, finger): 10 mg as a single dose (Ref).Oral: Note: Some experts reserve use for patients who are not candidates for intra-articular glucocorticoids or when intra-articular glucocorticoid administration is not feasible (Ref).24 to 32 mg/day given once daily or in 2 divided doses until symptom improvement (usually 2 to 5 days), then taper gradually as tolerated (typically over 7 to 10 days); a slower taper (eg, over 14 to 21 days) may be required, particularly in patients with multiple recent flares (Ref).IM (acetate or succinate) (alternative route): Note: Reserve for patients who are not candidates for oral therapies or intra-articular glucocorticoid administration.Initial: 40 to 60 mg as a single dose; may repeat once or twice at ≥48-hour intervals if benefit fades or there is no flare resolution (Ref).IV (succinate) (alternative route): Note: Reserve for hospitalized patients who are not candidates for oral therapies or intra-articular glucocorticoid administration.Initial: 20 mg twice daily until clinical improvement (usually 2 to 5 days), then reduce each dose by 50% until tapered; transition to an equivalent dose of an oral glucocorticoid (eg, prednisone) as soon as possible to complete taper (Ref).Graft-versus-host disease, acute, treatmentGraft-vs-host disease, acute, treatment (off-label use): Note: For grade ≥2 acute graft-versus-host disease. An optimal regimen has not been identified; refer to institutional protocols as variations exist. Treatment is dependent on the severity and the rate of progression (Ref).IV (succinate): Initial: 2 mg/kg/day in 2 divided doses; dose may vary based on organ involvement and severity. Continue for several weeks, then taper over several months (Ref).Immune-mediated adverse reactions associated with checkpoint inhibitor therapyImmune-mediated adverse reactions associated with checkpoint inhibitor therapy:Note: Consider withholding checkpoint inhibitor therapy for most grade 2 toxicities, withholding the checkpoint inhibitor for grade 3 toxicity, and permanently discontinuing for most grade 4 toxicities (Ref). Refer to each checkpoint inhibitor monograph for specific dosage modification and management details.Cardiovascular toxicity: Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, or vasculitis; for patients without an immediate response to high-dose corticosteroids (eg, prednisone): IV: 1 g once daily in combination with other immunosuppressive therapy; once clinically stable, taper methylprednisolone over a minimum of 4 weeks (Ref). Dermatologic toxicity:Bullous dermatoses, grade 3 or 4: IV: 1 to 2 mg/kg/day; convert to oral corticosteroids when appropriate; taper over at least 4 weeks (Ref).Rash or inflammatory dermatitis, grade 4: IV: 1 to 2 mg/kg/day with slow tapering once toxicity resolves (Ref).Severe cutaneous adverse reaction, grade 3: IV: 0.5 to 1 mg/kg/day; convert to oral corticosteroids on response; taper over 4 at least weeks (Ref).Severe cutaneous adverse reaction, grade 4: IV: 1 to 2 mg/kg/day with tapering when toxicity resolves to normal (Ref).GI toxicity: Colitis, grade 4 (may also consider for grade 3, particularly with concurrent upper GI inflammation): IV: 1 to 2 mg/kg/day until symptoms improve to grade 1 and then taper over 4 to 6 weeks (Ref). Hematologic conditions: Acquired thrombotic thrombocytopenic purpura, grade 3 or 4: IV: 1 g once daily for 3 days; begin the first dose immediately after plasma exchange. If no exacerbation within 3 to 5 days after stopping plasma exchange, taper corticosteroids over 2 to 3 weeks (Ref).Hepatotoxicity: Hepatitis, grade 3: IV: 1 to 2 mg/kg/day; attempt taper around 4 to 6 weeks when symptoms improve to ≤ grade 1; re-escalate if needed. If steroid refractory, consider liver biopsy (Ref).Hepatitis, grade 4: IV: 2 mg/kg/day; attempt taper around 4 to 6 weeks when symptoms improve to ≤ grade 1; re-escalate if needed. If steroid refractory, consider liver biopsy (Ref).Note: Based on data from a retrospective cohort study in patients with grade 3 or 4 immune-mediated hepatitis, initial treatment with methylprednisolone 1 mg/kg/day demonstrated similar time to ALT normalization (compared with higher methylprednisolone doses), while reducing the potential for corticosteroid-related complications (Ref).Musculoskeletal toxicities: Myositis, grade 3 or 4 with severe compromise: IV: 1 to 2 mg/kg/day or higher dose bolus (Ref). Nervous system toxicities:Aseptic meningitis, moderate to severe symptoms: IV: 1 mg/kg/day, taper after 2 to 4 weeks (Ref). Autonomic neuropathy, grade 3 or 4: IV: 1 g once daily for 3 days, followed by oral corticosteroid taper (Ref).Demyelinating diseases, grade 3 or 4: IV: 1 g once daily (Ref).Encephalitis: Any grade: IV: 1 to 2 mg/kg/day; taper over at least 4 to 6 weeks (Ref).Severe or progressing symptoms or the presence of oligoclonal bands: IV: 1 g once daily for 3 to 5 days (in combination with IVIG or plasmapheresis); taper over at least 4 to 6 weeks (Ref).Guillain-Barré syndrome: Note: Corticosteroids are usually not recommended for idiopathic Guillain-Barré syndrome (GBS); however, a trial of methylprednisolone may be reasonable with checkpoint inhibitor immune-mediated GBS (refer to guideline for details). IV: 2 to 4 mg/kg/day followed by a slow taper; for grade 3 or 4 GBS, may consider pulse dosing of 1 g once daily for 5 days (with taper over 4 to 6 weeks) (Ref). Peripheral neuropathy, grade 3 or 4: Initial dose: IV: 2 to 4 mg/kg/day followed by a slow taper; refer to guideline for further details (Ref).Ocular toxicity: Uveitis or iritis, grade 4: IV: 0.8 to 1.6 mg/kg/day in combination with intravitreal or periocular or topical ophthalmic corticosteroids (Ref). Pulmonary toxicity: Pneumonitis grade 3 or 4: IV: 1 to 2 mg/kg/day with taper over 4 to 6 weeks (or longer for chronic pneumonitis); if not improved within 48 hours, may add additional immunosuppressant agent (Ref).Corticosteroid conversion and tapering (general recommendations): When converting from IV corticosteroids to oral, the initial conversion from methylprednisolone ≥1 mg/kg IV is to oral prednisone 1 mg/kg/day at minimum (refer to Prednisone monograph for prednisone tapering). Steroid tapering should occur slowly, generally over 4 weeks or longer, with the length of the taper correlating with the severity of the immune-mediated adverse event, the initial corticosteroid dose, and individual patient response. For immune-mediated hepatitis, steroid taper may be attempted at ~4 to 6 weeks (when ≤ grade 1); re-escalate, if needed. Monitor closely for rebound or recurrence (Ref).Immune thrombocytopeniaImmune thrombocytopenia (initial therapy): Note: Goal of therapy is to provide a safe platelet count to prevent clinically important bleeding rather than normalization of the platelet count (Ref).Patients with severe bleeding (in combination with other treatments): IV (succinate): 1 g once daily for 3 doses and then stop (no taper) (Ref). Note: Due to the short-term response, maintenance therapy with an oral glucocorticoid (eg, prednisone) may be required (Ref).Inflammatory bowel diseaseInflammatory bowel disease:Crohn disease, acute (eg, severe/fulminant disease and/or unable to take oral) (adjunctive agent): Note: Not for long-term use (Ref). In patients with localized peritonitis, some experts recommend against initiating corticosteroids due to the potential of masking further clinical deterioration; however, if already receiving corticosteroids, continued use may be appropriate (Ref).IV (succinate): 40 to 60 mg/day (Ref).Note: For patients who have been receiving chronic treatment with a corticosteroid, a small increase in their daily dose may be required during an acute exacerbation (Ref). Steroid-sparing agents (eg, biologic agents, immunomodulators) should be introduced with a goal of discontinuing corticosteroid therapy as soon as possible (Ref).Ulcerative colitis, acute (severe or fulminant): Note: Not for long-term use.IV (succinate): 40 to 60 mg/day in 1 to 3 divided doses. If response to treatment is inadequate after 5 days (severe) or 3 days (fulminant), second-line therapy is initiated (Ref).Iodinated contrast media allergic-like reaction, preventionIodinated contrast media allergic-like reaction, prevention: Note: Generally reserved for patients with a prior allergic-like or unknown-type iodinated contrast reaction who will be receiving another iodinated contrast agent. Nonurgent premedication with an oral corticosteroid is generally preferred when contrast administration is scheduled to begin in ≥12 hours; however, consider an urgent (accelerated) regimen with an IV corticosteroid for those requiring contrast in <12 hours. Efficacy of premedication regimens starting <4 to 5 hours before the use of contrast has not been demonstrated (Ref).Nonurgent regimen:Oral: 32 mg administered 12 hours and 2 hours before contrast medium administration in combination with oral or IV diphenhydramine (Ref).Urgent (accelerated) regimen:IV (succinate): 40 mg every 4 hours until contrast medium administration in combination with IV diphenhydramine (Ref). Some experts administer methylprednisolone 40 mg at 5 hours and 1 hour before contrast medium administration in combination with diphenhydramine (Ref).Multiple sclerosis, acute exacerbationMultiple sclerosis, acute exacerbation: Note: For patients with an acute exacerbation resulting in neurologic symptoms and increased disability or impairments in vision, strength, or cerebellar function (Ref).Initial pulse therapy: IV (succinate): 500 mg to 1 g daily for 3 to 7 days (5 days typically), either alone or followed by an oral taper with prednisone (Ref).Myopathies, treatmentMyopathies (dermatomyositis/polymyositis), treatment:Initial pulse therapy in patients presenting with severe systemic involvement or profound weakness: IV (succinate): 1 g daily for 3 to 5 days, followed by oral prednisone (Ref).Nausea and vomiting of pregnancy, severe/refractoryNausea and vomiting of pregnancy, severe/refractory (off-label use): Note: Reserve use as an add-on therapy when all other pharmacologic regimens have failed.IV (succinate): 16 mg every 8 hours for 3 days. If no response within 3 days, discontinue treatment. If symptoms improve, complete 3-day course of treatment, then taper dose over 2 weeks (Ref).Pneumocystis pneumonia, adjunctive therapy for moderate to severe diseasePneumocystis pneumonia, adjunctive therapy for moderate to severe disease (off-label use): Note: Recommended for patients with PaO2 <70 mm Hg on room air or PAO2-PaO2 ≥35 mm Hg on room air (Ref); some experts additionally recommend for patients with oxygen saturation <92% on room air (Ref). Dosing is based on an equivalent dose of prednisone.IV (succinate): 30 mg twice daily on days 1 to 5 beginning as early as possible, followed by 30 mg once daily on days 6 to 10, then 15 mg once daily on days 11 to 21 (Ref).Prostate cancer, metastatic, castration resistantProstate cancer, metastatic, castration-resistant (off-label use): Oral: 4 mg twice daily (in combination with micronized abiraterone acetate) (Ref).Sarcoidosis, severe, acuteSarcoidosis, severe, acute (off-label use):Note: For use in patients with life-threatening extrapulmonary disease manifestations (eg, ventricular arrhythmias, transverse myelitis) or rapidly progressive disease (eg, severe optic neuritis) (Ref).Fixed dose: IV (succinate): 500 mg/day to 1 g per day for 3 to 5 days, followed by an oral glucocorticoid (eg, prednisone) (Ref).Weight-based dosing: IV (succinate): 10 to 20 mg/kg/day for 3 days, followed by an oral glucocorticoid (eg, prednisone) (Ref).Systemic rheumatic disorders, organ-threatening or life-threateningSystemic rheumatic disorders (eg, antineutrophil cytoplasmic antibody-associated vasculitis, mixed cryoglobulinemia syndrome, polyarteritis nodosa, rheumatoid arthritis, systemic lupus erythematosus), organ-threatening or life-threatening: Note: The following dosage ranges are for guidance only; dosing should be highly individualized, taking into account disease severity, the specific disorder, and disease manifestations.Initial pulse therapy (optional): IV (succinate): 7 to 15 mg/kg/day (maximum dose: 500 mg to 1 g/day) typically for up to 3 days, followed by an oral glucocorticoid (eg, prednisone); may be given as part of an appropriate combination regimen. Lower doses (eg, 250 mg/day) may be appropriate in some patients (eg, less severe manifestations) (Ref).Warm autoimmune hemolytic anemiaWarm autoimmune hemolytic anemia:IV (succinate): 250 mg to 1 g daily for 1 to 3 days, followed by an oral glucocorticoid (eg, prednisone) (Ref); a clinician experienced with the treatment of hemolytic anemia should be involved with therapy.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Note: The pharmaco*kinetics and pharmacodynamics of methylprednisolone in kidney impairment are not well understood (Ref). Methylprednisolone clearance appears unaltered in patients with uremia (Ref) and it is slightly dialyzable (Ref).Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (Ref).Hemodialysis, intermittent (thrice weekly):No supplemental dose or dosage adjustment necessary (Ref).Peritoneal dialysis: No dosage adjustment necessary (Ref).CRRT: No dosage adjustment necessary (Ref).PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling; use with caution.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productKit, Injection, as acetate: P-Care D40: 40 mg/mL [DSC] [contains polyethylene glycol (macrogol)]P-Care D80: 40 mg/mL [DSC] [contains polyethylene glycol (macrogol)]Solution Reconstituted, Injection, as sodium succinate [strength expressed as base]: SOLU-Medrol: 500 mg (1 ea)SOLU-Medrol: 2 g (1 ea [DSC]) [contains benzyl alcohol]Generic: 40 mg (1 ea); 125 mg (1 ea); 500 mg (1 ea); 1000 mg (1 ea)Solution Reconstituted, Injection, as sodium succinate [strength expressed as base, preservative free]: SOLU-Medrol: 40 mg (1 ea) [contains lactose]SOLU-Medrol: 125 mg (1 ea); 500 mg (1 ea); 1000 mg (1 ea); 2 g (1 ea)Suspension, Injection, as acetate: DEPO-Medrol: 20 mg/mL (5 mL); 40 mg/mL (5 mL, 10 mL) [contains benzyl alcohol, polyethylene glycol (macrogol), polysorbate 80]DEPO-Medrol: 40 mg/mL (1 mL) [contains polyethylene glycol (macrogol)]DEPO-Medrol: 80 mg/mL (5 mL) [contains benzyl alcohol, polyethylene glycol (macrogol), polysorbate 80]DEPO-Medrol: 80 mg/mL (1 mL) [contains polyethylene glycol (macrogol)]Generic: 40 mg/mL (1 mL, 5 mL, 10 mL); 80 mg/mL (1 mL, 5 mL)Suspension, Injection, as acetate [preservative free]: DEPO-Medrol: 40 mg/mL (1 mL) [contains polyethylene glycol (macrogol)]Generic: 40 mg/mL (1 mL); 80 mg/mL (1 mL)Tablet, Oral: Medrol: 2 mg, 8 mg, 16 mg, 32 mg [DSC], 4 mg [scored]Generic: 8 mg, 16 mg, 32 mg, 4 mgTablet Therapy Pack, Oral: Medrol: 4 mg (21 ea) [scored]Generic: 4 mg (21 ea)Generic Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution Reconstituted, Injection, as sodium succinate [strength expressed as base]: SOLU-medrol: 40 mg (1 ea) [contains benzyl alcohol, lactose]Solu-MEDROL: 125 mg (1 ea) [contains benzyl alcohol]Solu-MEDROL: 500 mg (1 ea)Solu-MEDROL: 500 mg (1 ea) [contains benzyl alcohol]Solu-MEDROL: 1000 mg (1 ea)Generic: 40 mg (1 ea); 500 mg (1 ea); 1000 mg (1 ea)Suspension, Injection, as acetate: Depo-Medrol: 20 mg/mL (5 mL) [contains benzyl alcohol]Depo-Medrol: 40 mg/mL (1 mL)Depo-Medrol: 40 mg/mL (2 mL, 5 mL) [contains benzyl alcohol]Depo-Medrol: 80 mg/mL (1 mL)Depo-Medrol: 80 mg/mL (5 mL) [contains benzyl alcohol]Generic: 40 mg/mL ([DSC]); 80 mg/mL ([DSC])Tablet, Oral: Medrol: 16 mg, 4 mgAdministration: PediatricOral: Administer after meals or with food or milk to decrease GI upset. If prescribed once daily, administer dose in the early morning to mimic the normal diurnal variation of endogenous cortisol.Parenteral:IM: Acetate, succinate: Avoid injection into the deltoid muscle due to a high incidence of subcutaneous atrophy. Avoid injection or leakage into the dermis. Do not inject into areas that have evidence of acute local infection. Discard contents of single-dose vial after use.IV: Succinate:IV push: May administer as a slow IV injection. Recommended rates range from over several minutes (dose not specified (Ref)) to over at least 5 minutes for doses ≤250 mg (Ref). Also refer to institution-specific policies and procedures.Intermittent IV infusion: Rate dependent upon dose and severity of condition; typically administered as an intermittent infusion over 15 to 60 minutes. Administer doses >250 mg over at least 30 to 60 minutes; severe adverse effects, including hypotension, cardiac arrhythmia, and sudden death, have been reported in patients receiving methylprednisolone doses ≥250 mg administered over <30 minutes (Ref). Pulse doses of 15 to 30 mg/kg used in rheumatic or kidney diseases in pediatric patients have been infused over 1 to 4 hours (Ref). Also refer to institution-specific policies and procedures. Do not administer acetate form IV.Administration: AdultOral: Administer tablets after meals or with food or milk to decrease GI upset. If prescribed once daily, administer in the morning.IM (acetate, succinate): Avoid injection into the deltoid muscle due to a high incidence of subcutaneous atrophy. Avoid injection or leakage into the dermis. Do not inject into areas that have evidence of acute local infection.IV (succinate):IV push: May administer as a slow IV injection. Recommended rates range from over several minutes (dose not specified (Ref)) to over at least 5 minutes for doses ≤250 mg (Ref). Also refer to institution-specific policies and procedures.Intermittent IV infusion: Rate dependent upon dose and severity of condition; typically administered as an intermittent infusion over 15 to 60 minutes. Administer doses >250 mg over at least 30 to 60 minutes; severe adverse effects, including hypotension, cardiac arrhythmia, and sudden death, have been reported in patients receiving methylprednisolone doses ≥250 mg administered over <30 minutes (Ref). Also refer to institution-specific policies and procedures. Note: In some spinal cord injury trials, bolus doses (30 mg/kg) have been administered over 15 minutes. Do not administer acetate form IV.Intra-articular or soft tissue (acetate): See manufacturer's labeling for details.Intralesional: Inject directly into the lesion. For large lesions, administer multiple small injections (20 to 40 mg) into the area of the lesion. Avoid injection of sufficient material to cause blanching because this may be followed by a small slough.Storage/StabilityMethylprednisolone acetate injection and tablets: Store at 20°C to 25°C (68°F to 77°F). Do not autoclave vials.Methylprednisolone sodium succinate injection: Store intact vials at 20°C to 25°C (68°F to 77°F). Protect from light. Do not autoclave. Store reconstituted vials at 20°C to 25°C (68°F to 77°F) and use within 48 hours. When further diluted with D5W, NS, or D5NS, may store at ≤25°C (77°F) for up to 4 hours or at 2°C to 8°C (36°F to 46°F) for up to 24 hours.UseSystemic: Oral, IM (acetate or succinate), IV (succinate only): Anti-inflammatory or immunosuppressant agent in the treatment of a variety of diseases including those of hematologic (eg, immune thrombocytopenia [oral and IV only]), allergic, inflammatory, GI (eg, ulcerative colitis), ophthalmic, neoplastic, nervous system (eg, acute exacerbations of multiple sclerosis [oral and succinate (IV/IM) only]), renal (eg, nephrotic syndrome), respiratory (eg, asthma), rheumatic (eg, rheumatoid arthritis [juvenile idiopathic arthritis], systemic lupus erythematosus), and/or autoimmune origin (FDA approved in ages >1 month and adults); has also been used for acute spinal cord injury, Kawasaki disease, Pneumocystis pneumonia, multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, and prevention and treatment of graft-versus-host disease following allogeneic bone marrow transplantation.Local: Depot formulations (Depo-Medrol): (FDA approved in pediatric patients [age not specified] and adults).Intra-articular (or soft tissue) (acetate only): Gout (acute flare), acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and/or synovitis of osteoarthritis.Intralesional (acetate only): Alopecia areata; discoid lupus erythematosus; infiltrated, inflammatory lesions associated with granuloma annulare, lichen planus, neurodermatitis, and psoriatic plaques; keloids; necrobiosis lipoidica diabeticorum; may be helpful in cystic tumors of an aponeurosis or tendon (ganglia).Medication Safety IssuesSound-alike/look-alike issues:MethylPREDNISolone may be confused with medroxyPROGESTERone, methotrexate, methylTESTOSTERone, predniSONEDEPO-Medrol may be confused with Depo-Provera, SOLU-MedrolMedrol may be confused with MebaralSOLU-Medrol may be confused with salmeterol, Solu-CORTEFInternational issues:Medrol [US, Canada, and multiple international markets] may be confused with Medral brand name for omeprazole [Mexico]Adverse Reactions (Significant): ConsiderationsAdrenal suppression (tertiary adrenal insufficiency)Adrenal suppression (tertiary adrenal insufficiency) may occur with glucocorticoids, including methylprednisolone, and results from inadequate stimulation of the adrenal glands (Ref). Glucocorticoid-induced adrenal insufficiency usually resolves with discontinuation of methylprednisolone, but symptoms may persist for 6 to 12 months (Ref). Adrenal insufficiency may lead to adrenal crisis, a life-threatening emergency that may present like a hypotensive shock state (Ref). High-dose methylprednisolone therapy for conditions such as Crohn disease in females who are pregnant may cause adrenal suppression in the newborn (Ref).Mechanism: Dose- and time-related; occurs due to lack of or diminished cortisol production by the adrenal gland (Ref). Exogenous glucocorticoids produce a similar negative feedback mechanism as endogenous cortisol, causing a subsequent decrease in adrenocorticotrophic hormone (ACTH) secretion; thus, cortisol production is suppressed, resulting in adrenal atrophy and subsequent insufficiency (ie, hypothalamic-pituitary-adrenal-axis [HPA-axis] suppression) (Ref). In times of stress (eg, critical illness, trauma, surgery), the body requires stress doses in patients taking glucocorticoids chronically (Ref).Onset: Varied; acute (minutes after administration) and/or chronic (2 to 20 hours to days) (Ref). Chronic glucocorticoid use does not allow for the HPA axis to recover quickly (Ref).Risk factors:• High doses for prolonged periods: Although some patients may become HPA suppressed with lower doses or briefer exposure, some experts consider HPA-axis suppression likely in any adult receiving a dose comparable to prednisone >20 mg/day (daytime dosing) or a dose comparable to prednisone ≥5 mg per 24 hours (evening or night dosing) for >3 weeks or with cushingoid appearance (Ref)• Nighttime administration may inhibit early morning ACTH surge (Ref)• Potency of glucocorticoids (Ref)• Abrupt withdrawal (Ref)• Concurrent interacting medications (eg, carbamazepine, St John's wort, mitotane, rifampicin, itraconazole, diltiazem, thyroid replacement therapy) (Ref)• History of previous adrenal crisis (Ref)• Use of glucocorticoid therapy delivered by various routes of administration (oral and inhaled greater risk than topical or intra-articular) (Ref)CNS and psychiatric/behavioral effectsGlucocorticoids, including methylprednisolone, may cause a myriad of CNS and psychiatric/behavioral adverse reactions (Ref). Patients may develop apathy or depression. More commonly, patients develop excitatory psychiatric disturbances (including agitation, anxiety, distractibility, fear, hypomania, insomnia, irritability, lethargy, labile mood, mania, pressured speech, restlessness, and tearfulness) (Ref). Exact incidences are unclear but range from 1.8% to 57% (Ref). Severe psychiatric effects have been reported in 6% of adults receiving high-dose regimens, while depression or mania have been reported in 36% (Ref). Larger doses of methylprednisolone (500 to 1,000 mg) may be associated with more hypomania or mania (Ref). Discontinuation or dose reductions generally resolve symptoms over days to weeks (Ref).Mechanism: Dose-related; not clearly established. Methylprednisolone and other glucocorticoids may alter feedback on the hypothalamic-pituitary-adrenal axis, which may lead to mood changes (Ref). Glucocorticoids may induce glutamate release, which may be responsible for neuronal toxicity (Ref). Exogenous glucocorticoids may also inhibit synthesis of cortical GABAergic steroids (Ref).Onset: Varied; most cases occur early in treatment (within the first 5 days), average of 11.5 days. The majority develop within 6 weeks of initiation (Ref).Risk factors:• Higher doses (comparable to prednisone ≥80 mg) (Ref)Possible additional risk factors:• Age >30 years (Ref)• Females (Ref)• History of neuropsychiatric disorders (Ref)Cushingoid features/Cushing syndromeGlucocorticoids may cause a cushingoid appearance (truncal obesity, facial adipose tissue, dorsocervical adipose tissue) which are adverse reactions related to patient's physical features (Ref). Reactions are more metabolic than weight gain, which is related to fluid retention (edema) (Ref). Iatrogenic Cushing syndrome resulting from glucocorticoid therapy increases morbidity and mortality and decreases quality of life (Ref).Mechanism: Dose- and time-related; excess cortisol from exogenous source (methylprednisolone) results in suppression of adrenocorticotrophic hormone, commonly called iatrogenic Cushing syndrome (Ref).Onset: Delayed; may develop within the first 2 months of glucocorticoid therapy, with the risk dependent on the dose and duration of treatment (Ref).Risk factors:• Higher doses (Ref)• Longer duration of use (Ref)• Drug interactions prolonging the half-life of glucocorticoids via cytochrome P450 (Ref)• BMI (high) (Ref)• Daily caloric intake (>30 kcal/kg/day) (Ref)GI effectsGlucocorticoids, including methylprednisolone, may cause GI effects, including peptic ulcer (with possible perforation and hemorrhage), dyspepsia, gastritis, abdominal distention, and ulcerative esophagitis (Ref). Meta-analyses suggest that glucocorticoid monotherapy carries little to no risk of peptic ulcer disease in the general population (Ref).Mechanism: Dose-related; glucocorticoids inhibit gastroprotective prostaglandin synthesis and reduce gastric mucus and bicarbonate secretion (Ref). Glucocorticoid immunosuppressive effects may prevent wound healing as well as mask GI signs and symptoms (Ref).Risk factors:• Higher methylprednisolone doses (≥4 mg/day) (Ref)• Concurrent aspirin or nonsteroidal anti-inflammatory drugs (Ref)• Hospitalized (but not ambulatory) patients (Ref)• Recent methylprednisolone users (7 to 28 days) versus remote or nonusers (Ref)HyperglycemiaGlucocorticoids, including methylprednisolone, may provoke new-onset hyperglycemia in patients without a history of diabetes and may cause an exacerbation of diabetes mellitus (Ref). Glucose levels have been noted to increase 68% above baseline (Ref). Certain patient populations (eg, transplant, cancer, chronic rheumatologic conditions) are at particular risk due to medication combinations (Ref). Resolution may occur within 12 to 16 hours after methylprednisolone discontinuation (Ref).Mechanism: Dose- and time-related; increased insulin resistance (Ref). May also interfere with insulin signaling by direct effects on the insulin receptor and the glucose transporter and may promote gluconeogenesis via liver stimulation (Ref).Onset: Rapid; 6 hours, with a peak of 8 hours (Ref). Rapid onset of steroid-induced hyperglycemia occurred within 2 days after initiation of glucocorticoids with a peak in the late afternoon following daily dosing in the morning (Ref).Risk factors:• Dose and type of glucocorticoid (Ref)• Duration of use (Ref)• Divided dosing versus once-daily dosing (Ref)• IV and oral routes of administration (Ref)• Older age (Ref)• Males (Ref)• BMI >25 kg/m2 (Ref)• African American or Hispanic (Ref)• eGFR <40 mL/minute/1.73 m2 (Ref)• HbA1c ≥6% (Ref)• History of gestational diabetes (Ref)• Family history of diabetes mellitus (Ref)• Concurrent use of mycophenolate mofetil and calcineurin inhibitors (Ref)• Previous history of impaired fasting glucose or impaired glucose tolerance (Ref)InfectionGlucocorticoids, including methylprednisolone, have immunosuppressive and anti-inflammatory effects that are reversible with discontinuation. Infection may occur after prolonged use, including Pneumocystis jirovecii pneumonia (PJP), herpes zoster, tuberculosis, and other more common bacterial infections (Ref).Mechanism: Dose- and time-related; related to pharmacologic action (ie, multiple activities on cell macrophage production and differentiation, inhibition of T-cell activation, effects on dendritic cells (Ref).Onset: Varied; in one study, the median duration of glucocorticoid use prior to PJP diagnosis was 12 weeks but also occurred earlier or later in some cases (Ref).Risk factors:• Higher dose and longer duration of glucocorticoid (Ref); however, may also increase risk at lower doses (eg, prednisone ≤5 mg/day or equivalent) (Ref)• Comorbidities (Ref)• Immunocompromised state (Ref)• Concurrent medications (immunosuppressive) (Ref)• Rheumatoid arthritis (Ref)• Interstitial lung disease (Ref)• Older adults (Ref)• Males (Ref)• Low performance status (Ref)Neuromuscular and skeletal effectsGlucocorticoid (including methylprednisolone)-induced neuromuscular and skeletal effects can take the form of various pathologies in patients ranging from osteoporosis and vertebral compression fracture to myopathy to osteonecrosis in adult and pediatric patients (Ref). Glucocorticoid use is the most common cause of secondary osteoporosis; may be underrecognized and undertreated due to underestimation of risk in this patient population (Ref). Vertebral fractures are the most common glucocorticoid-related fracture (Ref). Myopathies can also occur secondary to direct skeletal muscle catabolism (Ref). Acute steroid myopathy is rare (Ref).Mechanism: Dose- and time-related; glucocorticoids have direct/indirect effects on bone remodeling with osteoblast recruitment decreasing and apoptosis increasing (Ref). Myopathies or myasthenia result from reductions in protein synthesis and protein catabolism, which can manifest as proximal muscle weakness and atrophy in the upper and lower extremities (Ref)Onset: Delayed; vertebral fracture risk is increased within 3 months of initiation and peaks at 12 months (Ref).Risk factors:Drug-related risks:• Cumulative dose of glucocorticoids prednisone >5 g or equivalent (Ref)• Children receiving ≥4 courses of glucocorticoids (Ref)• Prednisone ≥2.5 to 7.5 mg daily or equivalent for ≥3 months (Ref)• Myopathy may occur at prednisone doses ≥10 mg/day or equivalent, with higher doses potentiating more of a rapid onset (Ref)• Fluorinated glucocorticoid preparations (eg, dexamethasone, betamethasone, triamcinolone) have a higher risk of myopathies than methylprednisolone (Ref)General fracture risks:• Age >55 years (Ref)• BMI <18.5 kg/m2 (Ref)• Bone mineral T score below -1.5 (Ref)• Endocrine disorders (eg, hypogonadism, hyper- or hypoparathyroidism) (Ref)• Excess alcohol use (>2 units/day) (Ref)• Females (Ref)• History of falls (Ref)• Malabsorption (Ref)• Menopause and duration of menopause (Ref)• White race (Ref)• Patients with cancer (Ref)• Previous fracture (Ref)• Smoking (Ref)• Underlying inflammatory condition in all ages (eg, inflammatory bowel disease, rheumatoid arthritis) (Ref)Ocular effectsGlucocorticoid (including methylprednisolone)-induced ocular effects may include increased intraocular pressure (IOP), glaucoma (open-angle), and subcapsular posterior cataract in adult and pediatric patients (Ref). Cataracts may persist after discontinuation of glucocorticoid therapy (Ref).Mechanism: Dose- and time-related; glucocorticoids can induce cataracts by covalently bonding to lens proteins, causing destabilization of the protein structure, and oxidative changes leading to cataracts formation (Ref). There are various proposed mechanisms of IOP contributing to glaucoma, including accumulation of polymerized glycosaminoglycans in the trabecular meshwork, producing edema and increasing outflow resistance (Ref). Another mechanism may include inhibition of phagocytic endothelial cells, leading to accumulation of aqueous debris (Ref). Glucocorticoids can also alter the trabecular meshwork causing an increase in nuclear size and DNA content (Ref). In addition, they can decrease the synthesis of prostaglandins which regulate the aqueous outflow (Ref).Onset: Delayed; cataracts may occur at least 1 year after initiation of chronic glucocorticoid therapy (Ref). IOP may occur at 4 years or more after initiation (Ref).Risk factors:• Dose (Ref)• Topical > Systemic (Ref)• Duration of use in all ages (Ref)• Family history of open-angle glaucoma (Ref)• Type I diabetes mellitus (Ref)• High myopia (Ref)• Pseudophakia (Ref)• Prior vitrectomies (Ref)• Connective tissue disease and sex (eg, rheumatoid arthritis in males) (Ref)• Older patients or age <6 years (Ref)• Genetics (Ref)• Angle recessive glaucoma (Ref)Adverse ReactionsThe following adverse drug reactions are derived from product labeling unless otherwise specified. Reactions listed may include other corticosteroids and may not be specifically reported for methylprednisolone.Postmarketing:Cardiovascular: Bradycardia, cardiac arrhythmia, cardiomegaly, circulatory shock, edema, embolism (fat), heart failure (in susceptible patients), hypertension, hypertrophic cardiomyopathy (premature infants), myocardial rupture (after recent myocardial infarction), syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis, venous thrombosis (Johannesdottir 2013)Dermatologic: Acne vulgaris, allergic dermatitis, atrophic striae, burning sensation of skin, diaphoresis, ecchymoses, epidermal thinning, erythema of skin, exfoliation of skin, facial erythema, hyperpigmentation, hypertrichosis, hypopigmentation, inadvertent suppression of skin test reaction, skin atrophy, skin rash, thinning hair (scalp), urticaria, xerodermaEndocrine & metabolic: Adrenal suppression (Dineen 2019), calcinosis (intraarticular or intralesional), Cushing syndrome (iatrogenic) (Pivonello 2016), Cushingoid appearance (Liu 2013), decreased serum potassium, exacerbation of diabetes mellitus (Tamez-Pérez 2015), fluid retention, growth retardation (children), hirsutism, hyperglycemia (Tamez-Pérez 2015), hypokalemic alkalosis, impaired glucose tolerance (Tamez-Pérez 2015), menstrual disease, moon face (Liu 2013), negative nitrogen balance (due to protein catabolism), prediabetes, sodium retention, weight gainGastrointestinal: Abdominal distention (Liu 2013), hiccups, impaired intestinal carbohydrate absorption, increased appetite, intestinal perforation, nausea, pancreatitis, peptic ulcer (with possible perforation and hemorrhage) (Liu 2013), ulcerative esophagitis (Liu 2013)Genitourinary: Glycosuria, spermatozoa disorder (including asthenospermia and oligospermia)Hematologic & oncologic: Leukocytosis, petechiaHepatic: Hepatitis, hepatomegaly, increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferaseHypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction, nonimmune anaphylaxisInfection: Infection (Youssef 2016), sterile abscessLocal: Postinjection flare (intraarticular)Nervous system: Amyotrophy, apathy (Ciriaco 2013; Warrington 2006), depression (Ciriaco 2013; Warrington 2006), emotional lability, euphoria, headache, increased intracranial pressure (with papilledema), insomnia, malaise, myasthenia, neuritis, neuropathy, paresthesia, personality changes, psychiatric disturbance (including agitation, anxiety, distractibility, euphoria, fear, hypomania, insomnia, irritability, labile mood, lethargy, pressured speech, restlessness, tearfulness) (Ciriaco 2013; Warrington 2006), seizure, tingling of skin, vertigoNeuromuscular & skeletal: Bone fracture (Buckley 2018), Charcot arthropathy, lipotrophy, myopathy (Liu 2013), osteonecrosis (femoral and humoral heads) (Liu 2013), osteoporosis (Buckley 2018), rupture of tendon (especially rupture of Achilles tendon), steroid myopathy (Haran 2018), vertebral compression fracture (Buckley 2018)Ophthalmic: Blindness, glaucoma (Phulke 2017), increased intraocular pressure (Phulke 2017), subcapsular posterior cataract (Phulke 2017)Respiratory: Pulmonary edemaMiscellaneous: Wound healing impairmentContraindicationsHypersensitivity to methylprednisolone or any component of the formulation; systemic fungal infection (except intra-articular injection for localized joint conditions); intrathecal administration; live or attenuated virus vaccines (with immunosuppressive doses of corticosteroids); use in premature infants (formulations containing benzyl alcohol preservative only); immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura) (IM administration only)Additional contraindication: Methylprednisolone sodium succinate 40 mg vial only: Hypersensitivity to cow's milk or its components or other dairy products which may contain trace amounts of milk ingredients (known or suspected).Canadian labeling: Additional contraindications (not in US labeling):Methylprednisolone tablets: Herpes simplex of the eye, vaccinia and varicella (except for short-term or emergency therapy)Methylprednisolone acetate injection: Epidural or intravascular administration; intra-articular injections in unstable joints; herpes simplex of the eye, vaccinia and varicella (except for short-term or emergency therapy)Methylprednisolone sodium succinate: Epidural administration; herpes simplex keratitis, vaccinia and varicella, arrested tuberculosis, acute psychoses, Cushing syndrome, peptic ulcer, markedly elevated serum creatinine (except for short-term or emergency therapy)Documentation of allergenic cross-reactivity for corticosteroids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.Warnings/PrecautionsConcerns related to adverse effects:• Adrenal suppression: May cause hypercortisolism or suppression of hypothalamic-pituitary-adrenal (HPA) axis, particularly in younger children or in patients receiving high doses for prolonged periods. HPA axis suppression may lead to adrenal crisis. Withdrawal and discontinuation of a corticosteroid should be done slowly and carefully. Particular care is required when patients are transferred from systemic corticosteroids to inhaled products due to possible adrenal insufficiency or withdrawal from steroids, including an increase in allergic symptoms. Adult patients receiving >20 mg per day of prednisone (or equivalent) may be most susceptible. Fatalities have occurred due to adrenal insufficiency in asthmatic patients during and after transfer from systemic corticosteroids to aerosol steroids; aerosol steroids do not provide the systemic steroid needed to treat patients having trauma, surgery, or infections.• Anaphylactoid reactions: Rare cases of anaphylactoid reactions have been observed in patients receiving corticosteroids.• Dermal changes: Avoid injection or leakage into the dermis; dermal and/or subdermal skin depression may occur at the site of injection. Avoid deltoid muscle injection; subcutaneous atrophy may occur.• Hepatic effects: High doses of methylprednisolone IV (usually doses of 1 g/day in adults) may induce a toxic form of acute hepatitis (rare); serious hepatic injury may occur, resulting in acute liver failure and death. Time to onset can be several weeks or longer; resolution has been observed after discontinuation of therapy. Discontinue methylprednisolone if toxic hepatitis occurs. Avoid use of high doses in patients with a history of methylprednisone-induced toxic hepatitis.• Immunosuppression: Prolonged use of corticosteroids may increase the incidence of secondary infection, cause activation of latent infections, mask acute infection (including fungal infections), prolong or exacerbate viral or parasitic infections, or limit response to killed or inactivated vaccines. Exposure to chickenpox or measles should be avoided; corticosteroids should not be used to treat ocular herpes simplex. Corticosteroids should not be used for cerebral malaria, fungal infections, or viral hepatitis. Close observation is required in patients with latent tuberculosis and/or TB reactivity; restrict use in active TB (only fulminating or disseminated TB in conjunction with antituberculosis treatment). Amebiasis should be ruled out in any patient with recent travel to tropic climates or unexplained diarrhea prior to initiation of corticosteroids. Use with extreme caution in patients with Strongyloides infections; hyperinfection, dissemination and fatalities have occurred.• Kaposi sarcoma: Prolonged treatment with corticosteroids has been associated with the development of Kaposi sarcoma (case reports); discontinuation may result in clinical improvement (Goedert 2002).• Myopathy: Acute myopathy has been reported with high dose corticosteroids, usually in patients with neuromuscular transmission disorders; may involve ocular and/or respiratory muscles; monitor creatine kinase; recovery may be delayed.• Psychiatric disturbances: Corticosteroid use may cause psychiatric disturbances, including euphoria, insomnia, mood swings, personality changes, severe depression, or psychotic manifestations. Preexisting psychiatric conditions may be exacerbated by corticosteroid use.• Septic arthritis: May occur as a complication to parenteral therapy; institute appropriate antimicrobial therapy as required.Disease-related concerns:• Cardiovascular disease: Use with caution in patients with heart failure (HF) and/or hypertension; use has been associated with fluid retention, electrolyte disturbances, and hypertension. Use with caution following acute myocardial infarction (MI); corticosteroids have been associated with myocardial rupture.• Diabetes: Use corticosteroids with caution in patients with diabetes mellitus; may alter glucose production/regulation leading to hyperglycemia.• Gastrointestinal disease: Use with caution in patients with GI diseases (diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, ulcerative colitis, abscess or other pyogenic infection) due to perforation risk.• Head injury: Increased mortality was observed in patients receiving high-dose IV methylprednisolone; high-dose corticosteroids should not be used for the management of head injury.• Hepatic impairment: Use with caution in patients with hepatic impairment, including cirrhosis; long-term use has been associated with fluid retention.• Myasthenia gravis: Use may cause transient worsening of myasthenia gravis (MG) (eg, within first 2 weeks of treatment); monitor for worsening MG (AAN [Narayanaswami 2021]).• Ocular disease: Use with caution in patients with cataracts and/or glaucoma; increased intraocular pressure, open-angle glaucoma, and cataracts have occurred with prolonged use. Not recommended for the treatment of optic neuritis; may increase frequency of new episodes. Use with caution in patients with a history of ocular herpes simplex; corneal perforation has occurred; do not use in active ocular herpes simplex. Consider routine eye exams in chronic users.• Osteoporosis: Use with caution in patients with osteoporosis; high doses and/or long-term use of corticosteroids have been associated with increased bone loss and osteoporotic fractures.• Renal impairment: Use with caution in patients with renal impairment; fluid retention may occur.• Seizure disorders: Use corticosteroids with caution in patients with a history of seizure disorder; seizures have been reported with adrenal crisis.• Septic shock or sepsis syndrome: Corticosteroids should not be administered for the treatment of sepsis in the absence of shock (SCCM/ESICM [Annane 2017]). A study has failed to demonstrate efficacy in septic shock or sepsis syndrome treatment; use may increase mortality in some populations (eg, patients with elevated serum creatinine, patients who develop secondary infections after use).• Systemic sclerosis (scleroderma): Use of higher dose corticosteroid therapy (in adults, ≥15 mg/day of prednisone or equivalent) in patients with systemic sclerosis may increase the risk of scleroderma renal crisis; avoid use when possible (Steen 1998; Trang 2012).• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of corticosteroids increases in hyperthyroid patients and decreases in hypothyroid ones.Special populations:• Older adult: Use with caution in the elderly with the smallest possible effective dose for the shortest duration.• Pediatric: May affect growth velocity; growth should be routinely monitored in pediatric patients.Dosage form specific issues: • Benzyl alcohol and derivatives: Methylprednisolone acetate IM injection (multiple-dose vial) and the diluent for methylprednisolone sodium succinate injection may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997], CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. Additionally, benzyl alcohol may also be toxic to neural tissue when administered locally (eg, intra-articular, intralesional). See manufacturer's labeling.• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.Other warnings/precautions:• Discontinuation of therapy: Withdraw therapy with gradual tapering of dose.• Epidural injection: Corticosteroids are not approved for epidural injection. Serious neurologic events (eg, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, stroke), some resulting in death, have been reported with epidural injection of corticosteroids, with and without use of fluoroscopy.• Stress: Patients may require higher doses when subject to stress (ie, trauma, surgery, severe infection).Warnings: Additional Pediatric ConsiderationsMay cause osteoporosis (at any age) or inhibition of bone growth in pediatric patients. Use with caution in patients with osteoporosis. In a population-based study of children, risk of fracture was shown to be increased with >4 courses of corticosteroids; underlying clinical condition may also impact bone health and osteoporotic effect of corticosteroids (Leonard 2007). Increased intraocular pressure (IOP) may occur, especially with prolonged use; in children, increased IOP has been shown to be dose dependent and produce a greater IOP in children <6 years of age than older children treated with ophthalmic dexamethasone (Lam 2005). Hypertrophic cardiomyopathy has been reported in premature neonates.Metabolism/Transport EffectsSubstrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAbrocitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Abrocitinib.Management: The use of abrocitinib in combination with other immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationAcetylcholinesterase Inhibitors: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur.Risk C: Monitor therapyAldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin.Risk X: Avoid combinationAmphotericin B: Corticosteroids (Systemic) may enhance the hypokalemic effect of Amphotericin B.Risk C: Monitor therapyAndrogens: Corticosteroids (Systemic) may enhance the fluid-retaining effect of Androgens.Risk C: Monitor therapyAntacids: May decrease the bioavailability of Corticosteroids (Oral). Management: Consider separating doses by 2 or more hours. Budesonide enteric coated tablets could dissolve prematurely if given with drugs that lower gastric acid, with unknown impact on budesonide therapeutic effects. Risk D: Consider therapy modificationAntidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.Risk C: Monitor therapyAprepitant: May increase the serum concentration of MethylPREDNISolone. Management: Decrease oral methylprednisolone dose by 50%, and decrease intravenous methylprednisolone dose by 25%, with aprepitant. No dose adjustment is required when used with only a single 40 mg oral dose or 32 mg injectable dose of aprepitant. Risk D: Consider therapy modificationBaricitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Baricitinib.Management: The use of baricitinib in combination with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationBCG Products: Corticosteroids (Systemic) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of BCG Products.Risk X: Avoid combinationBile Acid Sequestrants: May decrease the absorption of Corticosteroids (Oral). Risk C: Monitor therapyBrincidofovir: Corticosteroids (Systemic) may diminish the therapeutic effect of Brincidofovir.Risk C: Monitor therapyCalcitriol (Systemic): Corticosteroids (Systemic) may diminish the therapeutic effect of Calcitriol (Systemic).Risk C: Monitor therapyCAR-T Cell Immunotherapy: Corticosteroids (Systemic) may enhance the adverse/toxic effect of CAR-T Cell Immunotherapy. Specifically, the severity and duration of neurologic toxicities may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of CAR-T Cell Immunotherapy.Management: Avoid use of corticosteroids as premedication before treatment with CAR-T cell immunotherapy agents. Corticosteroids are indicated and may be required for treatment of toxicities such as cytokine release syndrome or neurologic toxicity. Risk D: Consider therapy modificationCladribine: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Cladribine.Risk X: Avoid combinationClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyCoccidioides immitis Skin Test: Corticosteroids (Systemic) may diminish the diagnostic effect of Coccidioides immitis Skin Test.Management: Consider discontinuing systemic corticosteroids (dosed at 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks) several weeks prior to coccidioides immitis skin antigen testing. Risk D: Consider therapy modificationCorticorelin: Corticosteroids (Systemic) may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response to corticorelin may be blunted by recent or current corticosteroid therapy.Risk C: Monitor therapyCosyntropin: Corticosteroids (Systemic) may diminish the diagnostic effect of Cosyntropin.Risk C: Monitor therapyCOVID-19 Vaccine (Adenovirus Vector): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector).Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters) Risk D: Consider therapy modificationCOVID-19 Vaccine (Inactivated Virus): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus).Risk C: Monitor therapyCOVID-19 Vaccine (mRNA): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA).Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modificationCOVID-19 Vaccine (Subunit): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit).Risk C: Monitor therapyCOVID-19 Vaccine (Virus-like Particles): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles).Risk C: Monitor therapyCycloSPORINE (Systemic): May enhance the neuroexcitatory and/or seizure-potentiating effect of MethylPREDNISolone. MethylPREDNISolone may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapyCYP3A4 Inducers (Moderate): May decrease the serum concentration of MethylPREDNISolone. Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Risk D: Consider therapy modificationCYP3A4 Inhibitors (Moderate): May increase the serum concentration of MethylPREDNISolone. Risk C: Monitor therapyCYP3A4 Inhibitors (Strong): May increase the serum concentration of MethylPREDNISolone. Risk C: Monitor therapyDeferasirox: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapyDengue Tetravalent Vaccine (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live).Risk X: Avoid combinationDenosumab: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and systemic corticosteroids. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modificationDesirudin: Corticosteroids (Systemic) may enhance the anticoagulant effect of Desirudin. More specifically, corticosteroids may increase hemorrhagic risk during desirudin treatment.Management: Discontinue treatment with systemic corticosteroids prior to desirudin initiation.If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: Consider therapy modificationDesmopressin: Corticosteroids (Systemic) may enhance the hyponatremic effect of Desmopressin.Risk X: Avoid combinationDeucravacitinib: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Management: The use of deucravacitinib in combination with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationEstrogen Derivatives: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapyFexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFilgotinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Filgotinib.Management: Coadministration of filgotinib with systemic corticosteroids at doses equivalent to greater than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks is not recommended. Risk D: Consider therapy modificationFosaprepitant: May increase the serum concentration of MethylPREDNISolone. Management: Decrease the oral methylprednisolone dose by 50%, and decrease the intravenous methylprednisolone dose by 25%, when combined with fosaprepitant. Risk D: Consider therapy modificationFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationGallium Ga 68 Dotatate: Corticosteroids (Systemic) may diminish the diagnostic effect of Gallium Ga 68 Dotatate.Risk C: Monitor therapyGrowth Hormone Analogs: Corticosteroids (Systemic) may diminish the therapeutic effect of Growth Hormone Analogs. Growth Hormone Analogs may decrease serum concentrations of the active metabolite(s) of Corticosteroids (Systemic).Risk C: Monitor therapyHyaluronidase: Corticosteroids (Systemic) may diminish the therapeutic effect of Hyaluronidase.Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider therapy modificationImmune Checkpoint Inhibitors: Corticosteroids (Systemic) may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Management: Carefully consider the need for corticosteroids, at doses of a prednisone-equivalent of 10 mg or more per day, during the initiation of immune checkpoint inhibitor therapy. Use of corticosteroids to treat immune related adverse events is still recommended Risk D: Consider therapy modificationIndium 111 Capromab Pendetide: Corticosteroids (Systemic) may diminish the diagnostic effect of Indium 111 Capromab Pendetide.Risk X: Avoid combinationInebilizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Inebilizumab.Risk C: Monitor therapyInfluenza Virus Vaccines: Corticosteroids (Systemic) may diminish the therapeutic effect of Influenza Virus Vaccines.Management: Administer influenza vaccines at least 2 weeks prior to initiation of systemic corticosteroids at immunosuppressive doses. Influenza vaccines administered less than 14 days prior to or during such therapy should be repeated 3 months after therapy. Risk D: Consider therapy modificationIsoniazid: Corticosteroids (Systemic) may decrease the serum concentration of Isoniazid.Risk C: Monitor therapyLeflunomide: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Leflunomide.Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as systemic corticosteroids. Risk D: Consider therapy modificationLicorice: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapyLoop Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Loop Diuretics.Risk C: Monitor therapyLutetium Lu 177 Dotatate: Corticosteroids (Systemic) may diminish the therapeutic effect of Lutetium Lu 177 Dotatate.Management: Avoid repeated use of high-doses of corticosteroids during treatment with lutetium Lu 177 dotatate. Use of corticosteroids is still permitted for the treatment of neuroendocrine hormonal crisis. The effects of lower corticosteroid doses is unknown. Risk D: Consider therapy modificationMacimorelin: Corticosteroids (Systemic) may diminish the diagnostic effect of Macimorelin.Risk X: Avoid combinationMetyraPONE: Corticosteroids (Systemic) may diminish the diagnostic effect of MetyraPONE.Management: Consider alternatives to the use of the metyrapone test in patients taking systemic corticosteroids. Risk D: Consider therapy modificationMifamurtide: Corticosteroids (Systemic) may diminish the therapeutic effect of Mifamurtide.Risk X: Avoid combinationMiFEPRIStone: May diminish the therapeutic effect of Corticosteroids (Systemic). MiFEPRIStone may increase the serum concentration of Corticosteroids (Systemic). Management: Avoid mifepristone in patients who require long-term corticosteroid treatment of serious illnesses or conditions (eg, for immunosuppression following transplantation). Corticosteroid effects may be reduced by mifepristone treatment. Risk X: Avoid combinationNatalizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Natalizumab.Risk X: Avoid combinationNeuromuscular-Blocking Agents (Nondepolarizing): May enhance the adverse neuromuscular effect of Corticosteroids (Systemic). Increased muscle weakness, possibly progressing to polyneuropathies and myopathies, may occur. Management: If concomitant therapy is required, use the lowest dose for the shortest duration to limit the risk of myopathy or neuropathy. Monitor for new onset or worsening muscle weakness, reduction or loss of deep tendon reflexes, and peripheral sensory decriments Risk D: Consider therapy modificationNicorandil: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nicorandil. Gastrointestinal perforation has been reported in association with this combination.Risk C: Monitor therapyNirmatrelvir and Ritonavir: May increase the serum concentration of MethylPREDNISolone. Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective).Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (Nonselective): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective).Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (Topical): May enhance the adverse/toxic effect of Corticosteroids (Systemic). Specifically, the risk of gastrointestinal bleeding, ulceration, and perforation may be increased. Risk C: Monitor therapyOcrelizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ocrelizumab.Risk C: Monitor therapyOfatumumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ofatumumab.Risk C: Monitor therapyPidotimod: Corticosteroids (Systemic) may diminish the therapeutic effect of Pidotimod.Risk C: Monitor therapyPimecrolimus: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Risk X: Avoid combinationPneumococcal Vaccines: Corticosteroids (Systemic) may diminish the therapeutic effect of Pneumococcal Vaccines.Risk C: Monitor therapyPoliovirus Vaccine (Live/Trivalent/Oral): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral).Risk X: Avoid combinationPolymethylmethacrylate: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Polymethylmethacrylate. Specifically, the risk for hypersensitivity or implant clearance may be increased.Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modificationQuinolones: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Quinolones. Specifically, the risk of tendonitis and tendon rupture may be increased.Risk C: Monitor therapyRabies Vaccine: Corticosteroids (Systemic) may diminish the therapeutic effect of Rabies Vaccine.Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modificationRitodrine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Ritodrine.Risk C: Monitor therapyRubella- or Varicella-Containing Live Vaccines: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines.Risk X: Avoid combinationRuxolitinib (Topical): Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ruxolitinib (Topical).Risk X: Avoid combinationSalicylates: May enhance the adverse/toxic effect of Corticosteroids (Systemic). These specifically include gastrointestinal ulceration and bleeding. Corticosteroids (Systemic) may decrease the serum concentration of Salicylates. Withdrawal of corticosteroids may result in salicylate toxicity. Risk C: Monitor therapySargramostim: Corticosteroids (Systemic) may enhance the therapeutic effect of Sargramostim. Specifically, corticosteroids may enhance the myeloproliferative effects of sargramostim.Risk C: Monitor therapySipuleucel-T: Corticosteroids (Systemic) may diminish the therapeutic effect of Sipuleucel-T.Management: Consider reducing the dose or discontinuing immunosuppressants, such as systemic corticosteroids, prior to initiating sipuleucel-T therapy. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone given for 2 or more weeks are immunosuppressive. Risk D: Consider therapy modificationSodium Benzoate: Corticosteroids (Systemic) may diminish the therapeutic effect of Sodium Benzoate.Risk C: Monitor therapySphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Risk C: Monitor therapySuccinylcholine: Corticosteroids (Systemic) may enhance the neuromuscular-blocking effect of Succinylcholine.Risk C: Monitor therapyTacrolimus (Systemic): Corticosteroids (Systemic) may decrease the serum concentration of Tacrolimus (Systemic). Conversely, when discontinuing corticosteroid therapy, tacrolimus concentrations may increase.Risk C: Monitor therapyTacrolimus (Topical): Corticosteroids (Systemic) may enhance the immunosuppressive effect of Tacrolimus (Topical).Risk X: Avoid combinationTalimogene Laherparepvec: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased.Risk X: Avoid combinationTertomotide: Corticosteroids (Systemic) may diminish the therapeutic effect of Tertomotide.Risk X: Avoid combinationThiazide and Thiazide-Like Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics.Risk C: Monitor therapyTofacitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Tofacitinib.Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationTyphoid Vaccine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Typhoid Vaccine.Risk X: Avoid combinationUpadacitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Upadacitinib.Management: Coadministration of upadacitinib with systemic corticosteroids at doses equivalent to greater than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks is not recommended. Risk D: Consider therapy modificationUrea Cycle Disorder Agents: Corticosteroids (Systemic) may diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Corticosteroids (Systemic) may increase protein catabolism and plasma ammonia concentrations, thereby increasing the doses of Urea Cycle Disorder Agents needed to maintain these concentrations in the target range.Risk C: Monitor therapyVaccines (Inactivated/Non-Replicating): Corticosteroids (Systemic) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating).Management: Administer vaccines at least 2 weeks prior to immunosuppressive corticosteroids if possible. If patients are vaccinated less than 14 days prior to or during such therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationVaccines (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Vaccines (Live).Management: Avoid live vaccines during and for 1 month after therapy with immunosuppressive doses of corticosteroids (equivalent to prednisone > 2 mg/kg or 20 mg/day in persons over 10 kg for at least 2 weeks). Give live vaccines prior to therapy whenever possible. Risk D: Consider therapy modificationVitamin K Antagonists (eg, warfarin): Corticosteroids (Systemic) may enhance the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapyYellow Fever Vaccine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Yellow Fever Vaccine.Risk X: Avoid combinationDietary ConsiderationsTake tablets with meals to decrease GI upset; need diet rich in pyridoxine, vitamin C, vitamin D, folate, calcium, phosphorus, and protein. Reproductive ConsiderationsCorticosteroids do not decrease fertility in patients with inflammatory bowel disease (IBD) who wish to become pregnant; however, active IBD may decrease fertility; pregnancy should be planned after a 3- to 6-month remission (Mahadevan 2019).Pregnancy ConsiderationsMethylprednisolone crosses the placenta (Anderson 1981). Some products contain benzyl alcohol, which may also cross the placenta.Some studies have shown an association between first trimester systemic corticosteroid use and oral clefts; however, information is conflicting and may be influenced by maternal dose, duration/frequency of exposure, and indication for use. Additional data are needed to evaluate any potential risk of systemic corticosteroids and other adverse pregnancy outcomes (eg, gestational diabetes mellitus, low birth weight, preeclampsia, preterm birth) (ACOG 776 2019; Bandoli 2017; Skuladottir 2014). Hypoadrenalism may occur in newborns following maternal use of corticosteroids; monitor infants exposed to prolonged or high doses of methylprednisolone in utero (Homar 2008; Kurtoğlu 2011).Methylprednisolone is a preferred oral corticosteroid for the treatment of maternal conditions during pregnancy because placental enzymes limit passage to the embryo (ACOG 776 2019).When systemic corticosteroids are needed in pregnancy for rheumatic disorders, nonfluorinated corticosteroids such as methylprednisolone are preferred. Chronic high doses should be avoided (ACR [Sammaritano 2020]). Methylprednisolone may also be used to treat acute exacerbations of multiple sclerosis during pregnancy (Canibaño 2020; Dobson 2019).Corticosteroids may be used as needed for disease flares in pregnant patients with inflammatory bowel disease; however, maintenance therapy should be avoided (Mahadevan 2019).Uncontrolled asthma is associated with adverse events on pregnancy (increased risk of perinatal mortality, preeclampsia, preterm birth, low birth weight infants, cesarean delivery, and the development of gestational diabetes). Poorly controlled asthma or asthma exacerbations may have a greater fetal/maternal risk than what is associated with appropriately used asthma medications. Maternal treatment improves pregnancy outcomes by reducing the risk of some adverse events (eg, preterm birth, gestational diabetes). Maternal asthma symptoms should be monitored monthly during pregnancy. Inhaled corticosteroids are recommended for the treatment of asthma during pregnancy; however, systemic corticosteroids should be used to control acute exacerbations or treat severe persistent asthma (ERS/TSANZ [Middleton 2020]; GINA 2021).Methylprednisolone may be considered for adjunctive treatment of severe nausea and vomiting in pregnant patients. Due to risks of adverse fetal events associated with first trimester exposure, use is reserved for refractory cases in women with dehydration (ACOG 189 2018).High dose methylprednisolone may be used in the management of immune thrombocytopenia in pregnant patients refractory to oral corticosteroids; use in combination with other therapies is suggested (Provan 2019).Systemic corticosteroids are used off label in the management of COVID-19 (NIH 2022b). Methylprednisolone was not the corticosteroid evaluated in the initial study and large numbers of pregnant patients were not included (Horby 2021). However, in patients who do not require corticosteroids for other indications, or in those who have already completed a course of corticosteroids to enhance fetal lung development, equivalent doses of methylprednisolone may be preferred for use in pregnant patients with severe or critical COVID-19 due to limited placental transfer and less fetal risk. A treatment algorithm is available for pregnant patients with severe or critical COVID-19; the algorithm differentiates recommendations based on the patient's requirement for corticosteroids for fetal lung maturation. Close glucose monitoring is recommended (Saad 2020). The risk of severe illness from COVID-19 infection is increased in symptomatic pregnant patients compared to nonpregnant patients (ACOG 2022). Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.The Transplant Pregnancy Registry International (TPR) is a registry that follows pregnancies that occur in maternal transplant recipients or those fathered by male transplant recipients. The TPR encourages reporting of pregnancies following solid organ transplant by contacting them at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.Monitoring ParametersBlood pressure, serum glucose, electrolytes, hemoglobin, occult blood loss, and clinical presence of adverse effects. Monitor intraocular pressure (if therapy >6 weeks), bone mineral density (long-term use), and weight; growth in pediatric patients (with chronic use); assess hypothalamic-pituitary-adrenal axis (HPA) suppression.Mechanism of ActionIn a tissue-specific manner, corticosteroids regulate gene expression subsequent to binding specific intracellular receptors and translocation into the nucleus. Corticosteroids exert a wide array of physiologic effects including modulation of carbohydrate, protein, and lipid metabolism and maintenance of fluid and electrolyte homeostasis. Moreover cardiovascular, immunologic, musculoskeletal, endocrine, and neurologic physiology are influenced by corticosteroids. Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.Pharmaco*kinetics (Adult data unless noted)Onset of action: IV (succinate): Within 1 hour; Intra-articular (acetate): 1 weekDuration: Intra-articular (acetate): 1 to 5 weeksAbsorption: Oral: Well absorbed (Czock 2005)Bioavailability: Oral: 88% ± 23% (Czock 2005)Distribution: Vd: IV (succinate): 24 L ± 6 L (Czock 2005)Metabolism: Hepatic to metabolites (Czock 2005)Half-life elimination:Adolescents: IV: 1.9 ± 0.7 hours (age range: 12 to 20 years; Rouster-Stevens 2008)Adults: Oral: 2.5 ± 1.2 hours (Czock 2005); IV (succinate): 0.25 ± 0.1 hour (Czock 2005)Time to peak, plasma:Oral: 2.1 ± 0.7 hours (Czock 2005)IV (succinate): 0.8 hours (Czock 2005)Excretion: Urine (1.3% [oral], 9.2% [IV succinate] as unchanged drug) (Czock 2005)Pharmaco*kinetics: Additional ConsiderationsOlder adult: Decreased clearance and increased half-life (Czock 2005).Obesity: Decreased clearance and increased half-life (Czock 2005; Dunn 1991).Additional InformationSodium content of 1 g sodium succinate injection: 2.01 mEq; methylprednisolone sodium succinate 53 mg = methylprednisolone base 40 mgPricing: USSolution (reconstituted) (methylPREDNISolone Sodium Succ Injection)40 mg (per each): $5.76 - $7.30125 mg (per each): $9.12 - $13.98500 mg (per each): $26.40 - $27.741000 mg (per each): $39.00 - $50.27Solution (reconstituted) (SOLU-Medrol Injection)2 g (per each): $113.1040 mg (per each): $7.26125 mg (per each): $11.69500 mg (per each): $29.141000 mg (per each): $52.78Suspension (DEPO-Medrol Injection)20 mg/mL (per mL): $8.5340 mg/mL (per mL): $13.6380 mg/mL (per mL): $23.67Suspension (methylPREDNISolone Acetate Injection)40 mg/mL (per mL): $10.44 - $11.5780 mg/mL (per mL): $17.16 - $19.58Tablet Therapy Pack (Medrol Oral)4 mg (per each): $0.37Tablet Therapy Pack (methylPREDNISolone Oral)4 mg (per each): $1.43 - $1.65Tablets (Medrol Oral)2 mg (per each): $1.974 mg (per each): $0.378 mg (per each): $2.1416 mg (per each): $3.45Tablets (methylPREDNISolone Oral)4 mg (per each): $1.43 - $2.238 mg (per each): $2.0116 mg (per each): $3.11 - $3.5432 mg (per each): $4.62 - $5.18Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAdrelan (PH);Advantan (MX);Adventan (ES);Cipridanol (PY);Comedrol (ID);Cryosolona (MX);Depo Medrol (AE, BH, JO, KW, LB, QA, SA);Depo-Medrol (BB, EG, ET, HR, IS, LU, LV, MX, NO, SI, SK, UA, VN, ZW);Depo-Medrone (IE, MT);Epizolone-Depot (ET);Flason (ID);Flumethyl (ID);Lexcomet (ID);Lexxema (ES);M-Nisol (LK);M-Prednihexal (DE);Meapron (KR);Medason (HK);Medexa (VN);Medisolu (KR);Medixon (ID, MY, PH);Medlon (VN);Mednin (TW);Medrate (DE);Medrol (AE, BB, BE, BH, BM, BS, BZ, CH, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EC, EE, ES, FI, FR, GB, GR, GT, GY, HN, HR, ID, IE, IL, IN, IQ, IR, IT, JM, JO, KR, KW, LT, LU, LV, LY, MT, NI, NL, NO, NZ, OM, PA, PH, PL, PT, QA, RO, RU, SA, SE, SI, SK, SR, SV, SY, TT, UA, VE, YE, ZA);Medrone (GB);Melsone (IN);Menisone (TW);Mepresone (PH);Mesolone (KR);Metcor (ID);Metcort (PH);Methylon (KR);Methylprednisolone David Bull (LU);Methysol (KR);Metrite (LK);Metypred (UA);Neo-Drol (LK);Nisolon-M (KR);Predlitem (MX);Prednivex (LK, PH);Prednol (TR);Prednox (PH);Prena (KR);Pretilon (ID);Prolon (ID);Sanexon (ID, LK);Sol-U-Pred (LK);Sologen (KR);Solomet (FI);Solu Medrol (BF, BJ, CI, ET, GH, GM, GN, KE, LK, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);Solu-Medon (VN);Solu-Medrol (AE, AU, BB, BG, BH, CL, CN, CR, CY, DO, EG, GT, HK, HN, HR, IS, JO, JP, KW, LB, LT, LU, LV, MX, MY, NI, PA, PK, QA, RO, SA, SI, SK, SV, TH, TR, UA, UY);Solu-Medrone (IE, MT);Solu-Moderin (ES);Solu-Pred (MY);Somidex (TH);Sonicor (ID);Thimelon (ID);Thylmedi (VN);Tisolon-4 (ID);Tropidrol (ID);Urbason (AT, DE, EG, ES, HR, NL);Urbason Retard (IT);Yalone (ID)For country code abbreviations (show table)Abraham E, Evans T. 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CloseMethylprednisolone: Drug informationMethylprednisolone: Drug information(For additional information see "Methylprednisolone: Patient drug information" and see "Methylprednisolone: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USDEPO-Medrol;Medrol;P-Care D40 [DSC];P-Care D80 [DSC];SOLU-MedrolBrand Names: CanadaDepo-Medrol;Medrol;SOLU-medrol;Solu-MEDROL;Uni-Med [DSC]Pharmacologic CategoryCorticosteroid, SystemicDosing: AdultNote: Dosing: Evidence to support an optimal dose and duration are lacking for most indications; recommendations provided are general guidelines only and primarily based on expert opinion. In general, glucocorticoid dosing should be individualized and the minimum effective dose/duration should be used. Hypothalamic-pituitary-adrenal suppression: Although some patients may become hypothalamic-pituitary-adrenal (HPA) suppressed with lower doses or briefer exposure, some experts consider HPA-axis suppression likely in any adult receiving >16 mg/day (daytime dosing) or ≥4 mg per 24 hours (evening or night dosing) for >2 weeks, or with Cushingoid appearance (Ref); do not abruptly discontinue treatment in these patients; dose tapering may be necessary (Ref). Safety: Only the methylprednisolone succinate formulation (Solu-Medrol) may be given IV. Methylprednisolone acetate suspension (Depo-Medrol) is intended for IM or intra-articular administration only; do not administer the acetate preparation IV (Ref).Usual dosage range:IV (succinate): 40 to 125 mg/day given in a single daily dose or in divided doses; rarely, for certain conditions, may go up to 1 to 2 mg/kg/day.Initial high-dose “pulse” therapy for select indications (eg, severe systemic rheumatic disorders): 7 to 15 mg/kg/dose (or 500 mg to 1 g/dose) given once daily for 3 to 5 days.Oral: 16 to 64 mg/day once daily or in divided doses.The following dosing is from the commercially available tapered-dosage product (eg, dose-pack containing 21 × 4 mg tablets):Day 1: 24 mg on day 1 administered as 8 mg (2 tablets) before breakfast, 4 mg (1 tablet) after lunch, 4 mg (1 tablet) after supper, and 8 mg (2 tablets) at bedtime or 24 mg (6 tablets) as a single dose or divided into 2 or 3 doses upon initiation (regardless of time of day).Day 2: 20 mg on day 2 administered as 4 mg (1 tablet) before breakfast, 4 mg (1 tablet) after lunch, 4 mg (1 tablet) after supper, and 8 mg (2 tablets) at bedtime.Day 3: 16 mg on day 3 administered as 4 mg (1 tablet) before breakfast, 4 mg (1 tablet) after lunch, 4 mg (1 tablet) after supper, and 4 mg (1 tablet) at bedtime.Day 4: 12 mg on day 4 administered as 4 mg (1 tablet) before breakfast, 4 mg (1 tablet) after lunch, and 4 mg (1 tablet) at bedtime.Day 5: 8 mg on day 5 administered as 4 mg (1 tablet) before breakfast and 4 mg (1 tablet) at bedtime.Day 6: 4 mg on day 6 administered as 4 mg (1 tablet) before breakfast.IM (acetate or succinate): 40 to 60 mg as a single dose.Intra-articular (acetate suspension): Note: Dose ranges per manufacturer's labeling. Specific dose is determined based upon joint size, severity of inflammation, amount of articular fluid present, and clinician judgment.Larger joint (eg, knee, shoulder, hip): 20 to 80 mg.Medium joint (eg, wrist, ankle, elbow): 10 to 40 mg.Small joint (eg, toe, finger): 4 to 10 mg.Intralesional (acetate) (alternative agent): Note: Other agents (eg, triamcinolone acetonide) may be more commonly employed (Ref).Usual dosage range: 20 to 60 mg; for large lesions, it may be necessary to distribute doses ranging from 20 to 40 mg by repeated local injections; 1 to 4 injections are usually employed with intervals between injections varying with the type of lesion being treated and clinical response.Acute respiratory distress syndrome, moderate to severeAcute respiratory distress syndrome, moderate to severe (off-label use): Note: May consider in most patients with persistent or refractory, moderate to severe acute respiratory distress syndrome, who are relatively early in the disease course (within 14 days) (Ref). Use ideal body weight to calculate dose. If patient is extubated between days 1 to 14, advance to day 15 of therapy and taper according to the following schedule. Do not abruptly discontinue since this may cause deterioration due to inflammatory response (Ref).IV (succinate): Loading dose of 1 mg/kg over 30 minutes, followed by a gradual taper:Days 1 to 14: 1 mg/kg/day in divided doses or as a continuous infusion.Days 15 to 21: 0.5 mg/kg/day in divided doses or as a continuous infusion.Days 22 to 25: 0.25 mg/kg/day in divided doses or as a continuous infusion.Days 26 to 28: 0.125 mg/kg/day in divided doses or as a continuous infusion.Allergic conditionsAllergic conditions:Anaphylaxis (adjunct to epinephrine for prevention of late-phase/biphasic reaction): Note: Do not use for initial or sole treatment of anaphylaxis because corticosteroids do not result in the prompt relief of upper or lower airway obstruction or shock (Ref). Some experts limit use to patients with severe or persistent steroid-responsive symptoms (eg, bronchospasm in patients with asthma) (Ref).IV (succinate): 1 to 2 mg/kg (Ref) or 40 to 125 mg as a single dose (Ref).Angioedema (acute allergic) and/or new-onset urticaria: Note: For moderate to severe symptoms without signs of anaphylaxis. Use epinephrine if anaphylaxis symptoms (eg, risk of airway or cardiovascular compromise) are present (Ref). In patients with new-onset urticaria, reserve use for those with significant angioedema or with symptoms that are unresponsive to antihistamines (Ref). The optimal dosing strategy has not been defined (Ref).IV (succinate): Initial: 60 to 80 mg; switch to an oral corticosteroid as soon as possible, tapering the dose for a total treatment duration of ≤10 days (Ref).Oral: Note: Dose is based on prednisone equivalency. An example regimen is 16 to 48 mg daily initially, followed by a taper over 5 to 7 days (Ref). The total treatment duration should not exceed 10 days (Ref).Asthma, acute exacerbationAsthma, acute exacerbation: Note: For moderate to severe exacerbations or in patients who do not respond promptly and completely to short-acting beta agonists; administer within 1 hour of presentation to emergency department (Ref).Oral, IV (succinate): 40 to 60 mg/day in 1 or 2 divided doses for 5 to 7 days (Ref); doses up to 60 to 80 mg every 6 to 12 hours have been used in critically ill patients (Ref). If symptoms do not resolve and peak expiratory flow is not at least 70% of personal best, then longer treatment may be required (Ref).Chronic obstructive pulmonary disease, acute exacerbationChronic obstructive pulmonary disease, acute exacerbation (off-label use): Note: In patients with severe but not life-threatening exacerbations, oral regimens are recommended. Use IV route in patients who cannot tolerate oral therapy (eg, shock, mechanically ventilated) (Ref).Oral; IV (succinate): 40 to 60 mg daily for 5 to 14 days (Ref). Doses up to 60 mg every 6 hours have been used in critically ill patients, although outcome data are limited. Note: Dose is based on an equivalent dose of prednisone; optimal dose has not been established. If patient improves with therapy, may discontinue without taper. If patient does not improve, a longer duration of therapy may be indicated (Ref).COVID-19, hospitalized patientsCOVID-19, hospitalized patients (alternative agent) (off-label use): Note: Methylprednisolone is recommended for treatment of COVID-19 in hospitalized patients requiring supplemental oxygen or ventilatory support when dexamethasone is not available or there are specific indications for methylprednisolone. Dosing is extrapolated from a study that used dexamethasone; the equivalent dose of methylprednisolone (or other glucocorticoid) may be substituted if necessary (Ref).Oral; IV (succinate): 32 mg once daily or 16 mg twice daily for up to 10 days (or until discharge, if sooner) as part of an appropriate combination regimen (Ref).Deceased organ donor managementDeceased organ donor management (hormonal resuscitation for the deceased organ donor) (off-label use): Note: Data supporting benefit are conflicting; if given, it should be administered after blood has been collected for tissue typing (Ref).IV (succinate): Regimens include: 1 g (as an IV infusion) or 15 mg/kg (as an IV infusion) or 250 mg (as an IV bolus) followed by a continuous infusion at 100 mg/hour; usually given as part of combination hormone therapy (Ref).Giant cell arteritis, treatmentGiant cell arteritis, treatment: Note: Due to the rapidly progressive nature of the disease, start treatment immediately once diagnosis is highly suspected (Ref). In patients presenting without threatened/evolving vision loss, an oral glucocorticoid is suggested as initial therapy rather than IV methylprednisolone (Ref).Initial pulse therapy in patients presenting with threatened/evolving vision loss: IV (succinate): 500 mg to 1 g daily for 3 days, followed by an oral glucocorticoid (eg, prednisone) (Ref).Gout, treatmentGout, treatment (acute flares):Note: Avoid use in patients with known or suspected septic arthritis (Ref).Intra-articular (acetate): Note: Consider in patients with gout flare limited to 1 or 2 affected joints; clinicians must have sufficient expertise to perform arthrocentesis and injection (Ref). May mix with an equal volume of local anesthetic (Ref). Dose is individualized based on joint size, disease severity, and clinician judgment (Ref). Typical doses are:Large joint (eg, knee): 40 mg as a single dose (Ref).Medium joint (eg, wrist, ankle, elbow): 30 mg as a single dose (Ref).Small joint (eg, toe, finger): 10 mg as a single dose (Ref).Oral: Note: Some experts reserve use for patients who are not candidates for intra-articular glucocorticoids or when intra-articular glucocorticoid administration is not feasible (Ref).24 to 32 mg/day given once daily or in 2 divided doses until symptom improvement (usually 2 to 5 days), then taper gradually as tolerated (typically over 7 to 10 days); a slower taper (eg, over 14 to 21 days) may be required, particularly in patients with multiple recent flares (Ref).IM (acetate or succinate) (alternative route): Note: Reserve for patients who are not candidates for oral therapies or intra-articular glucocorticoid administration.Initial: 40 to 60 mg as a single dose; may repeat once or twice at ≥48-hour intervals if benefit fades or there is no flare resolution (Ref).IV (succinate) (alternative route): Note: Reserve for hospitalized patients who are not candidates for oral therapies or intra-articular glucocorticoid administration.Initial: 20 mg twice daily until clinical improvement (usually 2 to 5 days), then reduce each dose by 50% until tapered; transition to an equivalent dose of an oral glucocorticoid (eg, prednisone) as soon as possible to complete taper (Ref).Graft-versus-host disease, acute, treatmentGraft-vs-host disease, acute, treatment (off-label use): Note: For grade ≥2 acute graft-versus-host disease. An optimal regimen has not been identified; refer to institutional protocols as variations exist. Treatment is dependent on the severity and the rate of progression (Ref).IV (succinate): Initial: 2 mg/kg/day in 2 divided doses; dose may vary based on organ involvement and severity. Continue for several weeks, then taper over several months (Ref).Immune-mediated adverse reactions associated with checkpoint inhibitor therapyImmune-mediated adverse reactions associated with checkpoint inhibitor therapy:Note: Consider withholding checkpoint inhibitor therapy for most grade 2 toxicities, withholding the checkpoint inhibitor for grade 3 toxicity, and permanently discontinuing for most grade 4 toxicities (Ref). Refer to each checkpoint inhibitor monograph for specific dosage modification and management details.Cardiovascular toxicity: Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, or vasculitis; for patients without an immediate response to high-dose corticosteroids (eg, prednisone): IV: 1 g once daily in combination with other immunosuppressive therapy; once clinically stable, taper methylprednisolone over a minimum of 4 weeks (Ref). Dermatologic toxicity:Bullous dermatoses, grade 3 or 4: IV: 1 to 2 mg/kg/day; convert to oral corticosteroids when appropriate; taper over at least 4 weeks (Ref).Rash or inflammatory dermatitis, grade 4: IV: 1 to 2 mg/kg/day with slow tapering once toxicity resolves (Ref).Severe cutaneous adverse reaction, grade 3: IV: 0.5 to 1 mg/kg/day; convert to oral corticosteroids on response; taper over 4 at least weeks (Ref).Severe cutaneous adverse reaction, grade 4: IV: 1 to 2 mg/kg/day with tapering when toxicity resolves to normal (Ref).GI toxicity: Colitis, grade 4 (may also consider for grade 3, particularly with concurrent upper GI inflammation): IV: 1 to 2 mg/kg/day until symptoms improve to grade 1 and then taper over 4 to 6 weeks (Ref). Hematologic conditions: Acquired thrombotic thrombocytopenic purpura, grade 3 or 4: IV: 1 g once daily for 3 days; begin the first dose immediately after plasma exchange. If no exacerbation within 3 to 5 days after stopping plasma exchange, taper corticosteroids over 2 to 3 weeks (Ref).Hepatotoxicity: Hepatitis, grade 3: IV: 1 to 2 mg/kg/day; attempt taper around 4 to 6 weeks when symptoms improve to ≤ grade 1; re-escalate if needed. If steroid refractory, consider liver biopsy (Ref).Hepatitis, grade 4: IV: 2 mg/kg/day; attempt taper around 4 to 6 weeks when symptoms improve to ≤ grade 1; re-escalate if needed. If steroid refractory, consider liver biopsy (Ref).Note: Based on data from a retrospective cohort study in patients with grade 3 or 4 immune-mediated hepatitis, initial treatment with methylprednisolone 1 mg/kg/day demonstrated similar time to ALT normalization (compared with higher methylprednisolone doses), while reducing the potential for corticosteroid-related complications (Ref).Musculoskeletal toxicities: Myositis, grade 3 or 4 with severe compromise: IV: 1 to 2 mg/kg/day or higher dose bolus (Ref). Nervous system toxicities:Aseptic meningitis, moderate to severe symptoms: IV: 1 mg/kg/day, taper after 2 to 4 weeks (Ref). Autonomic neuropathy, grade 3 or 4: IV: 1 g once daily for 3 days, followed by oral corticosteroid taper (Ref).Demyelinating diseases, grade 3 or 4: IV: 1 g once daily (Ref).Encephalitis: Any grade: IV: 1 to 2 mg/kg/day; taper over at least 4 to 6 weeks (Ref).Severe or progressing symptoms or the presence of oligoclonal bands: IV: 1 g once daily for 3 to 5 days (in combination with IVIG or plasmapheresis); taper over at least 4 to 6 weeks (Ref).Guillain-Barré syndrome: Note: Corticosteroids are usually not recommended for idiopathic Guillain-Barré syndrome (GBS); however, a trial of methylprednisolone may be reasonable with checkpoint inhibitor immune-mediated GBS (refer to guideline for details). IV: 2 to 4 mg/kg/day followed by a slow taper; for grade 3 or 4 GBS, may consider pulse dosing of 1 g once daily for 5 days (with taper over 4 to 6 weeks) (Ref). Peripheral neuropathy, grade 3 or 4: Initial dose: IV: 2 to 4 mg/kg/day followed by a slow taper; refer to guideline for further details (Ref).Ocular toxicity: Uveitis or iritis, grade 4: IV: 0.8 to 1.6 mg/kg/day in combination with intravitreal or periocular or topical ophthalmic corticosteroids (Ref). Pulmonary toxicity: Pneumonitis grade 3 or 4: IV: 1 to 2 mg/kg/day with taper over 4 to 6 weeks (or longer for chronic pneumonitis); if not improved within 48 hours, may add additional immunosuppressant agent (Ref).Corticosteroid conversion and tapering (general recommendations): When converting from IV corticosteroids to oral, the initial conversion from methylprednisolone ≥1 mg/kg IV is to oral prednisone 1 mg/kg/day at minimum (refer to Prednisone monograph for prednisone tapering). Steroid tapering should occur slowly, generally over 4 weeks or longer, with the length of the taper correlating with the severity of the immune-mediated adverse event, the initial corticosteroid dose, and individual patient response. For immune-mediated hepatitis, steroid taper may be attempted at ~4 to 6 weeks (when ≤ grade 1); re-escalate, if needed. Monitor closely for rebound or recurrence (Ref).Immune thrombocytopeniaImmune thrombocytopenia (initial therapy): Note: Goal of therapy is to provide a safe platelet count to prevent clinically important bleeding rather than normalization of the platelet count (Ref).Patients with severe bleeding (in combination with other treatments): IV (succinate): 1 g once daily for 3 doses and then stop (no taper) (Ref). Note: Due to the short-term response, maintenance therapy with an oral glucocorticoid (eg, prednisone) may be required (Ref).Inflammatory bowel diseaseInflammatory bowel disease:Crohn disease, acute (eg, severe/fulminant disease and/or unable to take oral) (adjunctive agent): Note: Not for long-term use (Ref). In patients with localized peritonitis, some experts recommend against initiating corticosteroids due to the potential of masking further clinical deterioration; however, if already receiving corticosteroids, continued use may be appropriate (Ref).IV (succinate): 40 to 60 mg/day (Ref).Note: For patients who have been receiving chronic treatment with a corticosteroid, a small increase in their daily dose may be required during an acute exacerbation (Ref). Steroid-sparing agents (eg, biologic agents, immunomodulators) should be introduced with a goal of discontinuing corticosteroid therapy as soon as possible (Ref).Ulcerative colitis, acute (severe or fulminant): Note: Not for long-term use.IV (succinate): 40 to 60 mg/day in 1 to 3 divided doses. If response to treatment is inadequate after 5 days (severe) or 3 days (fulminant), second-line therapy is initiated (Ref).Iodinated contrast media allergic-like reaction, preventionIodinated contrast media allergic-like reaction, prevention: Note: Generally reserved for patients with a prior allergic-like or unknown-type iodinated contrast reaction who will be receiving another iodinated contrast agent. Nonurgent premedication with an oral corticosteroid is generally preferred when contrast administration is scheduled to begin in ≥12 hours; however, consider an urgent (accelerated) regimen with an IV corticosteroid for those requiring contrast in <12 hours. Efficacy of premedication regimens starting <4 to 5 hours before the use of contrast has not been demonstrated (Ref).Nonurgent regimen:Oral: 32 mg administered 12 hours and 2 hours before contrast medium administration in combination with oral or IV diphenhydramine (Ref).Urgent (accelerated) regimen:IV (succinate): 40 mg every 4 hours until contrast medium administration in combination with IV diphenhydramine (Ref). Some experts administer methylprednisolone 40 mg at 5 hours and 1 hour before contrast medium administration in combination with diphenhydramine (Ref).Multiple sclerosis, acute exacerbationMultiple sclerosis, acute exacerbation: Note: For patients with an acute exacerbation resulting in neurologic symptoms and increased disability or impairments in vision, strength, or cerebellar function (Ref).Initial pulse therapy: IV (succinate): 500 mg to 1 g daily for 3 to 7 days (5 days typically), either alone or followed by an oral taper with prednisone (Ref).Myopathies, treatmentMyopathies (dermatomyositis/polymyositis), treatment:Initial pulse therapy in patients presenting with severe systemic involvement or profound weakness: IV (succinate): 1 g daily for 3 to 5 days, followed by oral prednisone (Ref).Nausea and vomiting of pregnancy, severe/refractoryNausea and vomiting of pregnancy, severe/refractory (off-label use): Note: Reserve use as an add-on therapy when all other pharmacologic regimens have failed.IV (succinate): 16 mg every 8 hours for 3 days. If no response within 3 days, discontinue treatment. If symptoms improve, complete 3-day course of treatment, then taper dose over 2 weeks (Ref).Pneumocystis pneumonia, adjunctive therapy for moderate to severe diseasePneumocystis pneumonia, adjunctive therapy for moderate to severe disease (off-label use): Note: Recommended for patients with PaO2 <70 mm Hg on room air or PAO2-PaO2 ≥35 mm Hg on room air (Ref); some experts additionally recommend for patients with oxygen saturation <92% on room air (Ref). Dosing is based on an equivalent dose of prednisone.IV (succinate): 30 mg twice daily on days 1 to 5 beginning as early as possible, followed by 30 mg once daily on days 6 to 10, then 15 mg once daily on days 11 to 21 (Ref).Prostate cancer, metastatic, castration resistantProstate cancer, metastatic, castration-resistant (off-label use): Oral: 4 mg twice daily (in combination with micronized abiraterone acetate) (Ref).Sarcoidosis, severe, acuteSarcoidosis, severe, acute (off-label use):Note: For use in patients with life-threatening extrapulmonary disease manifestations (eg, ventricular arrhythmias, transverse myelitis) or rapidly progressive disease (eg, severe optic neuritis) (Ref).Fixed dose: IV (succinate): 500 mg/day to 1 g per day for 3 to 5 days, followed by an oral glucocorticoid (eg, prednisone) (Ref).Weight-based dosing: IV (succinate): 10 to 20 mg/kg/day for 3 days, followed by an oral glucocorticoid (eg, prednisone) (Ref).Systemic rheumatic disorders, organ-threatening or life-threateningSystemic rheumatic disorders (eg, antineutrophil cytoplasmic antibody-associated vasculitis, mixed cryoglobulinemia syndrome, polyarteritis nodosa, rheumatoid arthritis, systemic lupus erythematosus), organ-threatening or life-threatening: Note: The following dosage ranges are for guidance only; dosing should be highly individualized, taking into account disease severity, the specific disorder, and disease manifestations.Initial pulse therapy (optional): IV (succinate): 7 to 15 mg/kg/day (maximum dose: 500 mg to 1 g/day) typically for up to 3 days, followed by an oral glucocorticoid (eg, prednisone); may be given as part of an appropriate combination regimen. Lower doses (eg, 250 mg/day) may be appropriate in some patients (eg, less severe manifestations) (Ref).Warm autoimmune hemolytic anemiaWarm autoimmune hemolytic anemia:IV (succinate): 250 mg to 1 g daily for 1 to 3 days, followed by an oral glucocorticoid (eg, prednisone) (Ref); a clinician experienced with the treatment of hemolytic anemia should be involved with therapy.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Note: The pharmaco*kinetics and pharmacodynamics of methylprednisolone in kidney impairment are not well understood (Ref). Methylprednisolone clearance appears unaltered in patients with uremia (Ref) and it is slightly dialyzable (Ref).Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (Ref).Hemodialysis, intermittent (thrice weekly):No supplemental dose or dosage adjustment necessary (Ref).Peritoneal dialysis: No dosage adjustment necessary (Ref).CRRT: No dosage adjustment necessary (Ref).PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling; use with caution.Dosing: Pediatric(For additional information see "Methylprednisolone: Pediatric drug information")Note: Adjust dose depending upon condition being treated and response of patient. The lowest possible dose should be used to control the condition; when dose reduction is possible, the dose should be reduced gradually. In life-threatening situations, parenteral doses larger than the oral dose may be needed. Only sodium succinate salt may be given IV.General dosing; anti-inflammatory or immunosuppressive (Ref):Methylprednisolone sodium succinate (immediate acting): Infants, Children, and Adolescents: Oral, IV, IM: 0.11 to 1.6 mg/kg/day in 3 to 4 divided doses.Methylprednisolone acetate (long acting): Infants, Children, and Adolescents:IM: 0.11 to 1.6 mg/kg/dose; frequency depends upon condition being treated, usually administered as a one-time dose or every 1 to 2 weeks.Intra-articular: Dosing varies based on affected joint; general range: 4 to 80 mg every 1 to 5 weeks.Anaphylaxis, adjunctive therapyAnaphylaxis, adjunctive therapy: Limited data available:Note: Administer epinephrine first when treating anaphylaxis. Corticosteroids are considered second- or third-line therapy and do not result in prompt resolution of airway obstruction or shock. Use of corticosteroids for anaphylaxis is controversial; they have little to no benefit on initial symptoms; typically administered to prevent biphasic or prolonged episodes of anaphylaxis (Ref).Infants, Children, and Adolescents: IV, IM (succinate): 1 to 2 mg/kg/dose as a single dose; maximum dose: 125 mg/dose (Ref).AsthmaAsthma:Acute exacerbation: Outpatient management (short-course "burst") (Ref):Oral: Note: Burst should be continued until symptoms resolve or patient achieves peak expiratory flow 80% of personal best; usually requires 3 to 10 days of treatment (~5 days on average); longer treatment may be required.Infants and Children <12 years: Oral: 1 to 2 mg/kg/day in 1 or 2 divided doses for 3 to 10 days; maximum daily dose: 60 mg/day.Children ≥12 years and Adolescents: Oral: 40 to 60 mg/day in 1 or 2 divided doses for 3 to 10 days.IM (acetate): Note: This may be given in place of short-course "burst" of oral steroids in patients who are vomiting or if compliance is a problem.Children ≤4 years: IM: 7.5 mg/kg as a one-time dose; maximum dose: 240 mg.Children ≥5 years and Adolescents: IM: 240 mg as a one-time dose.Emergency/acute care management:Infants and Children <12 years: Oral, IV (succinate): 1 to 2 mg/kg/day in 2 divided doses; maximum daily dose: 60 mg/day; continue until peak expiratory flow is 70% of predicted or personal best (Ref). Some experts suggest infants and children ≤5 years may receive IV doses of 1 mg/kg/dose every 6 hours on day 1, followed by transition to oral corticosteroids to complete a 3 to 5 days course (Ref).Children ≥12 years and Adolescents: Oral, IV (succinate): 40 to 80 mg/day in 1 or 2 divided doses until peak expiratory flow is 70% of predicted or personal best (Ref).Status asthmaticus: Children and Adolescents: IV (succinate): Loading dose: 2 mg/kg/dose, then 0.5 to 1 mg/kg/dose every 6 hours (Ref).Long-term treatment (non-acute), severe, persistent asthma (Ref): Infants and Children <12 years: Oral: 0.25 to 2 mg/kg/day once daily in the morning or every other day as needed for asthma control; maximum daily dose: 60 mg/day.Children ≥12 years and Adolescents: Oral: 7.5 to 60 mg once daily in the morning or every other day as needed for asthma control.Graft-versus-host disease, acuteGraft-versus-host disease, acute (GVHD): Limited data available: Infants, Children, and Adolescents: IV (succinate): 1 to 2 mg/kg/dose once daily; if using low dose (1 mg/kg) and no improvement after 3 days, increase dose to 2 mg/kg. Continue therapy for 5 to 7 days; if improvement observed, may taper by 10% of starting dose every 4 days; if no improvement, then considered steroid-refractory GVHD and additional agents should be considered (Ref).Immune thrombocytopenia, moderate to severe bleeding or at risk for severe bleedingImmune thrombocytopenia, moderate to severe bleeding or at risk for severe bleeding: Limited data available:Infants, Children, and Adolescents: IV (succinate): Initial: Pulse: 30 mg/kg/dose once daily for 1 to 3 doses; number of doses is determined by patient clinical status, initial and postdose platelet counts, and if used in conjunction with other therapies; maximum dose: 1,000 mg/dose; follow with oral corticosteroid therapy as clinically indicated (Ref).Juvenile idiopathic arthritis, systemicJuvenile idiopathic arthritis, systemic: Note: Therapy should be individualized based on disease severity and activity (Ref). Limited data available:Children and Adolescents: IV (succinate): Pulse therapy: 30 mg/kg/day once daily for 3 days; maximum dose: 1,000 mg/dose. Follow pulse therapy with oral corticosteroids; evaluate initial response at 1 to 2 weeks and then at 1 month of therapy; if condition worsens or unchanged at either time interval, may repeat methylprednisolone 30 mg/kg/dose at weekly intervals as clinically indicated (Ref).Kawasaki diseaseKawasaki disease: Limited data available; optimal regimen not established; efficacy variable:Primary adjunctive treatment, patients at high risk for intravenous immune globulin (IVIG) resistance or coronary artery aneurysms: Note: Use in combination with IVIG and aspirin:Infants and Children: IV (succinate): 1.6 mg/kg/day in divided doses every 8 hours for 5 days or until afebrile, then transition to oral prednisolone; maximum daily dose: 48 mg/day; some centers use less frequent dosing intervals (eg, every 12 hours) to minimize adverse effects (Ref). Note: Dosing based on use of IV prednisolone product (2 mg/kg/day), which is not available in the United States; dosing converted to equivalent methylprednisolone dosing; however, clinical necessity of conversion is unknown.Treatment, refractory/resistant disease: Note: Reserve use for patients who remain febrile after initial IVIG dose:Pulse dosing: Infants and Children: IV (succinate): 30 mg/kg/dose once daily for 1 or 3 days; may be given in combination with additional IVIG dose (Ref).Taper dosing: Infants and Children: IV (succinate): 1.6 mg/kg/day in divided doses every 8 hours for 5 days or until afebrile, then transition to oral prednisolone; maximum daily dose: 48 mg/day; give in combination with aspirin and an additional dose of IVIG (Ref). Note: Dosing based on use of IV prednisolone product (2 mg/kg/day) which is not available in the United States; dosing converted to equivalent methylprednisolone dosing; however, clinical necessity of conversion is unknown.Lupus nephritis, proliferativeLupus nephritis, proliferative (induction): Limited data available: Children and Adolescents: IV (succinate): Initial pulse therapy: 30 mg/kg/dose once daily for 3 doses; maximum dose: 1,000 mg/dose (Ref). Reported dosage range: 10 to 30 mg/kg/dose or 500 to 1,000 mg/m2/dose once daily for 3 days. Following pulse therapy transition to oral corticosteroids and taper as clinically indicated. May be given as part of an appropriate combination dosage regimen (Ref).Multisystem inflammatory syndrome in children associated with SARS-CoV-2Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: Limited data available:Infants, Children, and Adolescents:Initial therapy: IV (succinate): 1 to 2 mg/kg/day divided twice daily in combination with IVIG; duration is dependent on clinical course; may then transition to oral steroids, with taper over at least 2 to 3 weeks (Ref). Note: High-dose corticosteroid therapy at doses of 10 to 30 mg/kg/day (maximum dose: 1,000 mg/dose) for 1 to 3 days has also been reported as initial therapy of MIS-C in patients with more severe disease (eg, shock symptoms) (Ref).Intensification therapy (in patients who do not improve within 24 hours of initial MIS-C therapy with low- to moderate-dose corticosteroid therapy and IVIG): IV (succinate): 10 to 30 mg/kg/day (maximum dose: 1,000 mg/dose) for 1 to 3 days (Ref).Nephrotic syndrome, steroid resistantNephrotic syndrome, steroid resistant: Limited data available, variable regimens reported: Children and Adolescents: Pulse therapy: IV (succinate): 15 to 30 mg/kg/dose or 500 mg/m2/dose once daily for 3 days; maximum dose: 1,000 mg/dose. Transition to oral corticosteroid and taper as clinically indicated (Ref). Additional pulse doses may be required; some regimens include multiple pulses over a few months until remission (Ref).Pneumocystis pneumonia, adjunctive therapy for moderate or severe infectionPneumocystis pneumonia (PCP), adjunctive therapy for moderate or severe infection: Limited data available: Note: Recommended when on room air PaO2 <70 mm Hg or PAO2-PaO2 ≥35 mm Hg. Begin as soon as possible after diagnosis and within 72 hours of PCP therapy.Infants and Children: IV (succinate): 1 mg/kg/dose every 6 hours on days 1 to 7, then 1 mg/kg/dose twice daily on days 8 to 9, then 0.5 mg/kg/dose twice daily on days 10 and 11, and 1 mg/kg/dose once daily on days 12 to 16 (Ref).Adolescents: IV (succinate): 30 mg twice daily on days 1 to 5, then 30 mg once daily on days 6 to 10, then 15 mg once daily on days 11 to 21 (Ref).Radiocontrast media reaction, prevention of rebound reactionRadiocontrast media reaction, prevention of rebound reaction: Limited data available: Note: If patient is experiencing anaphylaxis, administer epinephrine first. Corticosteroids may be utilized to prevent rebound reactions.Infants, Children, and Adolescents: IV (succinate): 1 mg/kg/dose; maximum dose: 40 mg/dose (Ref).Ulcerative colitis, acute, severeUlcerative colitis, acute, severe:Limited data available: Children and Adolescents: IV (succinate): 1 to 1.5 mg/kg/day once daily or in divided doses 2 times daily; maximum daily dose: 60 mg/day. Higher doses should be reserved for patients with severe disease and/or who have failed oral steroids. Transition to oral therapy when clinically appropriate. If inadequate response after 3 to 5 days of IV therapy, initiate second-line therapy (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling. The pharmaco*kinetic and pharmacodynamic properties of methylprednisolone in kidney impairment are not well understood (Ref). Methylprednisolone clearance appears unaltered in patients with uremia (Ref) and it is slightly dialyzable (Ref).Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Older AdultRefer to adult dosing.Dosing: Obesity: AdultThe recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.Class 1, 2, and 3 obesity (BMI ≥30 kg/m2):IV, Oral:Non-weight–based dosing: No dosage adjustment necessary (Ref). Refer to adult dosing for indication-specific doses.Weight-based dosing: Use ideal body weight to avoid overdosing and subsequent toxicity (Ref). Refer to adult dosing for indication-specific doses.Rationale for recommendations: Corticosteroids are lipophilic compounds; however, the reported pharmaco*kinetic variability due to obesity is limited and inconsistent. One study reported similar Vd values with reduced clearance with IV methylprednisolone in males with obesity compared to males without obesity, resulting in a longer half-life (Ref). Dosing based on actual body weight could lead to supratherapeutic levels (Ref).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productKit, Injection, as acetate: P-Care D40: 40 mg/mL [DSC] [contains polyethylene glycol (macrogol)]P-Care D80: 40 mg/mL [DSC] [contains polyethylene glycol (macrogol)]Solution Reconstituted, Injection, as sodium succinate [strength expressed as base]: SOLU-Medrol: 500 mg (1 ea)SOLU-Medrol: 2 g (1 ea [DSC]) [contains benzyl alcohol]Generic: 40 mg (1 ea); 125 mg (1 ea); 500 mg (1 ea); 1000 mg (1 ea)Solution Reconstituted, Injection, as sodium succinate [strength expressed as base, preservative free]: SOLU-Medrol: 40 mg (1 ea) [contains lactose]SOLU-Medrol: 125 mg (1 ea); 500 mg (1 ea); 1000 mg (1 ea); 2 g (1 ea)Suspension, Injection, as acetate: DEPO-Medrol: 20 mg/mL (5 mL); 40 mg/mL (5 mL, 10 mL) [contains benzyl alcohol, polyethylene glycol (macrogol), polysorbate 80]DEPO-Medrol: 40 mg/mL (1 mL) [contains polyethylene glycol (macrogol)]DEPO-Medrol: 80 mg/mL (5 mL) [contains benzyl alcohol, polyethylene glycol (macrogol), polysorbate 80]DEPO-Medrol: 80 mg/mL (1 mL) [contains polyethylene glycol (macrogol)]Generic: 40 mg/mL (1 mL, 5 mL, 10 mL); 80 mg/mL (1 mL, 5 mL)Suspension, Injection, as acetate [preservative free]: DEPO-Medrol: 40 mg/mL (1 mL) [contains polyethylene glycol (macrogol)]Generic: 40 mg/mL (1 mL); 80 mg/mL (1 mL)Tablet, Oral: Medrol: 2 mg, 8 mg, 16 mg, 32 mg [DSC], 4 mg [scored]Generic: 8 mg, 16 mg, 32 mg, 4 mgTablet Therapy Pack, Oral: Medrol: 4 mg (21 ea) [scored]Generic: 4 mg (21 ea)Generic Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution Reconstituted, Injection, as sodium succinate [strength expressed as base]: SOLU-medrol: 40 mg (1 ea) [contains benzyl alcohol, lactose]Solu-MEDROL: 125 mg (1 ea) [contains benzyl alcohol]Solu-MEDROL: 500 mg (1 ea)Solu-MEDROL: 500 mg (1 ea) [contains benzyl alcohol]Solu-MEDROL: 1000 mg (1 ea)Generic: 40 mg (1 ea); 500 mg (1 ea); 1000 mg (1 ea)Suspension, Injection, as acetate: Depo-Medrol: 20 mg/mL (5 mL) [contains benzyl alcohol]Depo-Medrol: 40 mg/mL (1 mL)Depo-Medrol: 40 mg/mL (2 mL, 5 mL) [contains benzyl alcohol]Depo-Medrol: 80 mg/mL (1 mL)Depo-Medrol: 80 mg/mL (5 mL) [contains benzyl alcohol]Generic: 40 mg/mL ([DSC]); 80 mg/mL ([DSC])Tablet, Oral: Medrol: 16 mg, 4 mgAdministration: AdultOral: Administer tablets after meals or with food or milk to decrease GI upset. If prescribed once daily, administer in the morning.IM (acetate, succinate): Avoid injection into the deltoid muscle due to a high incidence of subcutaneous atrophy. Avoid injection or leakage into the dermis. Do not inject into areas that have evidence of acute local infection.IV (succinate):IV push: May administer as a slow IV injection. Recommended rates range from over several minutes (dose not specified (Ref)) to over at least 5 minutes for doses ≤250 mg (Ref). Also refer to institution-specific policies and procedures.Intermittent IV infusion: Rate dependent upon dose and severity of condition; typically administered as an intermittent infusion over 15 to 60 minutes. Administer doses >250 mg over at least 30 to 60 minutes; severe adverse effects, including hypotension, cardiac arrhythmia, and sudden death, have been reported in patients receiving methylprednisolone doses ≥250 mg administered over <30 minutes (Ref). Also refer to institution-specific policies and procedures. Note: In some spinal cord injury trials, bolus doses (30 mg/kg) have been administered over 15 minutes. Do not administer acetate form IV.Intra-articular or soft tissue (acetate): See manufacturer's labeling for details.Intralesional: Inject directly into the lesion. For large lesions, administer multiple small injections (20 to 40 mg) into the area of the lesion. Avoid injection of sufficient material to cause blanching because this may be followed by a small slough.Administration: PediatricOral: Administer after meals or with food or milk to decrease GI upset. If prescribed once daily, administer dose in the early morning to mimic the normal diurnal variation of endogenous cortisol.Parenteral:IM: Acetate, succinate: Avoid injection into the deltoid muscle due to a high incidence of subcutaneous atrophy. Avoid injection or leakage into the dermis. Do not inject into areas that have evidence of acute local infection. Discard contents of single-dose vial after use.IV: Succinate:IV push: May administer as a slow IV injection. Recommended rates range from over several minutes (dose not specified (Ref)) to over at least 5 minutes for doses ≤250 mg (Ref). Also refer to institution-specific policies and procedures.Intermittent IV infusion: Rate dependent upon dose and severity of condition; typically administered as an intermittent infusion over 15 to 60 minutes. Administer doses >250 mg over at least 30 to 60 minutes; severe adverse effects, including hypotension, cardiac arrhythmia, and sudden death, have been reported in patients receiving methylprednisolone doses ≥250 mg administered over <30 minutes (Ref). Pulse doses of 15 to 30 mg/kg used in rheumatic or kidney diseases in pediatric patients have been infused over 1 to 4 hours (Ref). Also refer to institution-specific policies and procedures. Do not administer acetate form IV.Use: Labeled IndicationsOral, IM (acetate or succinate), and IV (succinate only) administration: Anti-inflammatory or immunosuppressant agent in the treatment of a variety of diseases, including those of hematologic (eg, immune thrombocytopenia, warm autoimmune hemolytic anemia), allergic (eg, asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity, perennial or seasonal allergic rhinitis [oral only], serum sickness, transfusion reactions, new-onset urticaria), GI (eg, Crohn disease, ulcerative colitis), inflammatory, neoplastic, neurologic (eg, multiple sclerosis), rheumatic (eg, antineutrophil cytoplasmic antibody-associated vasculitis, dermatomyositis/polymyositis, giant-cell arteritis, gout [acute flare], giant cell arteritis, mixed cryoglobulinemia syndrome, polyarteritis nodosa, rheumatoid arthritis, systemic lupus erythematosus), and/or autoimmune origin.Intra-articular or soft tissue administration (acetate only): Gout (acute flare), acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and/or synovitis of osteoarthritis.Intralesional administration (acetate only): Alopecia areata; discoid lupus erythematosus; keloids; localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; and necrobiosis lipoidica diabeticorum. May be useful in cystic tumor of an aponeurosis or tendon (ganglia).Use: Off-Label: AdultAcute respiratory distress syndrome, moderate to severe; Cardiac transplant: Acute cellular rejection (treatment); Cardiac transplant: Antibody-mediated rejection (treatment); Chronic obstructive pulmonary disease (acute exacerbation); COVID-19, hospitalized patients; Deceased organ donor management (hormonal resuscitation for the deceased organ donor); Graft-vs-host disease, acute; Nausea and vomiting of pregnancy, severe/refractory; Pneumocystis pneumonia, adjunctive therapy for moderate to severe disease; Prostate cancer, metastatic, castration-resistant; Sarcoidosis, severe, acuteMedication Safety IssuesSound-alike/look-alike issues:MethylPREDNISolone may be confused with medroxyPROGESTERone, methotrexate, methylTESTOSTERone, predniSONEDEPO-Medrol may be confused with Depo-Provera, SOLU-MedrolMedrol may be confused with MebaralSOLU-Medrol may be confused with salmeterol, Solu-CORTEFInternational issues:Medrol [US, Canada, and multiple international markets] may be confused with Medral brand name for omeprazole [Mexico]Adverse Reactions (Significant): ConsiderationsAdrenal suppression (tertiary adrenal insufficiency)Adrenal suppression (tertiary adrenal insufficiency) may occur with glucocorticoids, including methylprednisolone, and results from inadequate stimulation of the adrenal glands (Ref). Glucocorticoid-induced adrenal insufficiency usually resolves with discontinuation of methylprednisolone, but symptoms may persist for 6 to 12 months (Ref). Adrenal insufficiency may lead to adrenal crisis, a life-threatening emergency that may present like a hypotensive shock state (Ref). High-dose methylprednisolone therapy for conditions such as Crohn disease in females who are pregnant may cause adrenal suppression in the newborn (Ref).Mechanism: Dose- and time-related; occurs due to lack of or diminished cortisol production by the adrenal gland (Ref). Exogenous glucocorticoids produce a similar negative feedback mechanism as endogenous cortisol, causing a subsequent decrease in adrenocorticotrophic hormone (ACTH) secretion; thus, cortisol production is suppressed, resulting in adrenal atrophy and subsequent insufficiency (ie, hypothalamic-pituitary-adrenal-axis [HPA-axis] suppression) (Ref). In times of stress (eg, critical illness, trauma, surgery), the body requires stress doses in patients taking glucocorticoids chronically (Ref).Onset: Varied; acute (minutes after administration) and/or chronic (2 to 20 hours to days) (Ref). Chronic glucocorticoid use does not allow for the HPA axis to recover quickly (Ref).Risk factors:• High doses for prolonged periods: Although some patients may become HPA suppressed with lower doses or briefer exposure, some experts consider HPA-axis suppression likely in any adult receiving a dose comparable to prednisone >20 mg/day (daytime dosing) or a dose comparable to prednisone ≥5 mg per 24 hours (evening or night dosing) for >3 weeks or with cushingoid appearance (Ref)• Nighttime administration may inhibit early morning ACTH surge (Ref)• Potency of glucocorticoids (Ref)• Abrupt withdrawal (Ref)• Concurrent interacting medications (eg, carbamazepine, St John's wort, mitotane, rifampicin, itraconazole, diltiazem, thyroid replacement therapy) (Ref)• History of previous adrenal crisis (Ref)• Use of glucocorticoid therapy delivered by various routes of administration (oral and inhaled greater risk than topical or intra-articular) (Ref)CNS and psychiatric/behavioral effectsGlucocorticoids, including methylprednisolone, may cause a myriad of CNS and psychiatric/behavioral adverse reactions (Ref). Patients may develop apathy or depression. More commonly, patients develop excitatory psychiatric disturbances (including agitation, anxiety, distractibility, fear, hypomania, insomnia, irritability, lethargy, labile mood, mania, pressured speech, restlessness, and tearfulness) (Ref). Exact incidences are unclear but range from 1.8% to 57% (Ref). Severe psychiatric effects have been reported in 6% of adults receiving high-dose regimens, while depression or mania have been reported in 36% (Ref). Larger doses of methylprednisolone (500 to 1,000 mg) may be associated with more hypomania or mania (Ref). Discontinuation or dose reductions generally resolve symptoms over days to weeks (Ref).Mechanism: Dose-related; not clearly established. Methylprednisolone and other glucocorticoids may alter feedback on the hypothalamic-pituitary-adrenal axis, which may lead to mood changes (Ref). Glucocorticoids may induce glutamate release, which may be responsible for neuronal toxicity (Ref). Exogenous glucocorticoids may also inhibit synthesis of cortical GABAergic steroids (Ref).Onset: Varied; most cases occur early in treatment (within the first 5 days), average of 11.5 days. The majority develop within 6 weeks of initiation (Ref).Risk factors:• Higher doses (comparable to prednisone ≥80 mg) (Ref)Possible additional risk factors:• Age >30 years (Ref)• Females (Ref)• History of neuropsychiatric disorders (Ref)Cushingoid features/Cushing syndromeGlucocorticoids may cause a cushingoid appearance (truncal obesity, facial adipose tissue, dorsocervical adipose tissue) which are adverse reactions related to patient's physical features (Ref). Reactions are more metabolic than weight gain, which is related to fluid retention (edema) (Ref). Iatrogenic Cushing syndrome resulting from glucocorticoid therapy increases morbidity and mortality and decreases quality of life (Ref).Mechanism: Dose- and time-related; excess cortisol from exogenous source (methylprednisolone) results in suppression of adrenocorticotrophic hormone, commonly called iatrogenic Cushing syndrome (Ref).Onset: Delayed; may develop within the first 2 months of glucocorticoid therapy, with the risk dependent on the dose and duration of treatment (Ref).Risk factors:• Higher doses (Ref)• Longer duration of use (Ref)• Drug interactions prolonging the half-life of glucocorticoids via cytochrome P450 (Ref)• BMI (high) (Ref)• Daily caloric intake (>30 kcal/kg/day) (Ref)GI effectsGlucocorticoids, including methylprednisolone, may cause GI effects, including peptic ulcer (with possible perforation and hemorrhage), dyspepsia, gastritis, abdominal distention, and ulcerative esophagitis (Ref). Meta-analyses suggest that glucocorticoid monotherapy carries little to no risk of peptic ulcer disease in the general population (Ref).Mechanism: Dose-related; glucocorticoids inhibit gastroprotective prostaglandin synthesis and reduce gastric mucus and bicarbonate secretion (Ref). Glucocorticoid immunosuppressive effects may prevent wound healing as well as mask GI signs and symptoms (Ref).Risk factors:• Higher methylprednisolone doses (≥4 mg/day) (Ref)• Concurrent aspirin or nonsteroidal anti-inflammatory drugs (Ref)• Hospitalized (but not ambulatory) patients (Ref)• Recent methylprednisolone users (7 to 28 days) versus remote or nonusers (Ref)HyperglycemiaGlucocorticoids, including methylprednisolone, may provoke new-onset hyperglycemia in patients without a history of diabetes and may cause an exacerbation of diabetes mellitus (Ref). Glucose levels have been noted to increase 68% above baseline (Ref). Certain patient populations (eg, transplant, cancer, chronic rheumatologic conditions) are at particular risk due to medication combinations (Ref). Resolution may occur within 12 to 16 hours after methylprednisolone discontinuation (Ref).Mechanism: Dose- and time-related; increased insulin resistance (Ref). May also interfere with insulin signaling by direct effects on the insulin receptor and the glucose transporter and may promote gluconeogenesis via liver stimulation (Ref).Onset: Rapid; 6 hours, with a peak of 8 hours (Ref). Rapid onset of steroid-induced hyperglycemia occurred within 2 days after initiation of glucocorticoids with a peak in the late afternoon following daily dosing in the morning (Ref).Risk factors:• Dose and type of glucocorticoid (Ref)• Duration of use (Ref)• Divided dosing versus once-daily dosing (Ref)• IV and oral routes of administration (Ref)• Older age (Ref)• Males (Ref)• BMI >25 kg/m2 (Ref)• African American or Hispanic (Ref)• eGFR <40 mL/minute/1.73 m2 (Ref)• HbA1c ≥6% (Ref)• History of gestational diabetes (Ref)• Family history of diabetes mellitus (Ref)• Concurrent use of mycophenolate mofetil and calcineurin inhibitors (Ref)• Previous history of impaired fasting glucose or impaired glucose tolerance (Ref)InfectionGlucocorticoids, including methylprednisolone, have immunosuppressive and anti-inflammatory effects that are reversible with discontinuation. Infection may occur after prolonged use, including Pneumocystis jirovecii pneumonia (PJP), herpes zoster, tuberculosis, and other more common bacterial infections (Ref).Mechanism: Dose- and time-related; related to pharmacologic action (ie, multiple activities on cell macrophage production and differentiation, inhibition of T-cell activation, effects on dendritic cells (Ref).Onset: Varied; in one study, the median duration of glucocorticoid use prior to PJP diagnosis was 12 weeks but also occurred earlier or later in some cases (Ref).Risk factors:• Higher dose and longer duration of glucocorticoid (Ref); however, may also increase risk at lower doses (eg, prednisone ≤5 mg/day or equivalent) (Ref)• Comorbidities (Ref)• Immunocompromised state (Ref)• Concurrent medications (immunosuppressive) (Ref)• Rheumatoid arthritis (Ref)• Interstitial lung disease (Ref)• Older adults (Ref)• Males (Ref)• Low performance status (Ref)Neuromuscular and skeletal effectsGlucocorticoid (including methylprednisolone)-induced neuromuscular and skeletal effects can take the form of various pathologies in patients ranging from osteoporosis and vertebral compression fracture to myopathy to osteonecrosis in adult and pediatric patients (Ref). Glucocorticoid use is the most common cause of secondary osteoporosis; may be underrecognized and undertreated due to underestimation of risk in this patient population (Ref). Vertebral fractures are the most common glucocorticoid-related fracture (Ref). Myopathies can also occur secondary to direct skeletal muscle catabolism (Ref). Acute steroid myopathy is rare (Ref).Mechanism: Dose- and time-related; glucocorticoids have direct/indirect effects on bone remodeling with osteoblast recruitment decreasing and apoptosis increasing (Ref). Myopathies or myasthenia result from reductions in protein synthesis and protein catabolism, which can manifest as proximal muscle weakness and atrophy in the upper and lower extremities (Ref)Onset: Delayed; vertebral fracture risk is increased within 3 months of initiation and peaks at 12 months (Ref).Risk factors:Drug-related risks:• Cumulative dose of glucocorticoids prednisone >5 g or equivalent (Ref)• Children receiving ≥4 courses of glucocorticoids (Ref)• Prednisone ≥2.5 to 7.5 mg daily or equivalent for ≥3 months (Ref)• Myopathy may occur at prednisone doses ≥10 mg/day or equivalent, with higher doses potentiating more of a rapid onset (Ref)• Fluorinated glucocorticoid preparations (eg, dexamethasone, betamethasone, triamcinolone) have a higher risk of myopathies than methylprednisolone (Ref)General fracture risks:• Age >55 years (Ref)• BMI <18.5 kg/m2 (Ref)• Bone mineral T score below -1.5 (Ref)• Endocrine disorders (eg, hypogonadism, hyper- or hypoparathyroidism) (Ref)• Excess alcohol use (>2 units/day) (Ref)• Females (Ref)• History of falls (Ref)• Malabsorption (Ref)• Menopause and duration of menopause (Ref)• White race (Ref)• Patients with cancer (Ref)• Previous fracture (Ref)• Smoking (Ref)• Underlying inflammatory condition in all ages (eg, inflammatory bowel disease, rheumatoid arthritis) (Ref)Ocular effectsGlucocorticoid (including methylprednisolone)-induced ocular effects may include increased intraocular pressure (IOP), glaucoma (open-angle), and subcapsular posterior cataract in adult and pediatric patients (Ref). Cataracts may persist after discontinuation of glucocorticoid therapy (Ref).Mechanism: Dose- and time-related; glucocorticoids can induce cataracts by covalently bonding to lens proteins, causing destabilization of the protein structure, and oxidative changes leading to cataracts formation (Ref). There are various proposed mechanisms of IOP contributing to glaucoma, including accumulation of polymerized glycosaminoglycans in the trabecular meshwork, producing edema and increasing outflow resistance (Ref). Another mechanism may include inhibition of phagocytic endothelial cells, leading to accumulation of aqueous debris (Ref). Glucocorticoids can also alter the trabecular meshwork causing an increase in nuclear size and DNA content (Ref). In addition, they can decrease the synthesis of prostaglandins which regulate the aqueous outflow (Ref).Onset: Delayed; cataracts may occur at least 1 year after initiation of chronic glucocorticoid therapy (Ref). IOP may occur at 4 years or more after initiation (Ref).Risk factors:• Dose (Ref)• Topical > Systemic (Ref)• Duration of use in all ages (Ref)• Family history of open-angle glaucoma (Ref)• Type I diabetes mellitus (Ref)• High myopia (Ref)• Pseudophakia (Ref)• Prior vitrectomies (Ref)• Connective tissue disease and sex (eg, rheumatoid arthritis in males) (Ref)• Older patients or age <6 years (Ref)• Genetics (Ref)• Angle recessive glaucoma (Ref)Adverse ReactionsThe following adverse drug reactions are derived from product labeling unless otherwise specified. Reactions listed may include other corticosteroids and may not be specifically reported for methylprednisolone.Postmarketing:Cardiovascular: Bradycardia, cardiac arrhythmia, cardiomegaly, circulatory shock, edema, embolism (fat), heart failure (in susceptible patients), hypertension, hypertrophic cardiomyopathy (premature infants), myocardial rupture (after recent myocardial infarction), syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis, venous thrombosis (Johannesdottir 2013)Dermatologic: Acne vulgaris, allergic dermatitis, atrophic striae, burning sensation of skin, diaphoresis, ecchymoses, epidermal thinning, erythema of skin, exfoliation of skin, facial erythema, hyperpigmentation, hypertrichosis, hypopigmentation, inadvertent suppression of skin test reaction, skin atrophy, skin rash, thinning hair (scalp), urticaria, xerodermaEndocrine & metabolic: Adrenal suppression (Dineen 2019), calcinosis (intraarticular or intralesional), Cushing syndrome (iatrogenic) (Pivonello 2016), Cushingoid appearance (Liu 2013), decreased serum potassium, exacerbation of diabetes mellitus (Tamez-Pérez 2015), fluid retention, growth retardation (children), hirsutism, hyperglycemia (Tamez-Pérez 2015), hypokalemic alkalosis, impaired glucose tolerance (Tamez-Pérez 2015), menstrual disease, moon face (Liu 2013), negative nitrogen balance (due to protein catabolism), prediabetes, sodium retention, weight gainGastrointestinal: Abdominal distention (Liu 2013), hiccups, impaired intestinal carbohydrate absorption, increased appetite, intestinal perforation, nausea, pancreatitis, peptic ulcer (with possible perforation and hemorrhage) (Liu 2013), ulcerative esophagitis (Liu 2013)Genitourinary: Glycosuria, spermatozoa disorder (including asthenospermia and oligospermia)Hematologic & oncologic: Leukocytosis, petechiaHepatic: Hepatitis, hepatomegaly, increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferaseHypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction, nonimmune anaphylaxisInfection: Infection (Youssef 2016), sterile abscessLocal: Postinjection flare (intraarticular)Nervous system: Amyotrophy, apathy (Ciriaco 2013; Warrington 2006), depression (Ciriaco 2013; Warrington 2006), emotional lability, euphoria, headache, increased intracranial pressure (with papilledema), insomnia, malaise, myasthenia, neuritis, neuropathy, paresthesia, personality changes, psychiatric disturbance (including agitation, anxiety, distractibility, euphoria, fear, hypomania, insomnia, irritability, labile mood, lethargy, pressured speech, restlessness, tearfulness) (Ciriaco 2013; Warrington 2006), seizure, tingling of skin, vertigoNeuromuscular & skeletal: Bone fracture (Buckley 2018), Charcot arthropathy, lipotrophy, myopathy (Liu 2013), osteonecrosis (femoral and humoral heads) (Liu 2013), osteoporosis (Buckley 2018), rupture of tendon (especially rupture of Achilles tendon), steroid myopathy (Haran 2018), vertebral compression fracture (Buckley 2018)Ophthalmic: Blindness, glaucoma (Phulke 2017), increased intraocular pressure (Phulke 2017), subcapsular posterior cataract (Phulke 2017)Respiratory: Pulmonary edemaMiscellaneous: Wound healing impairmentContraindicationsHypersensitivity to methylprednisolone or any component of the formulation; systemic fungal infection (except intra-articular injection for localized joint conditions); intrathecal administration; live or attenuated virus vaccines (with immunosuppressive doses of corticosteroids); use in premature infants (formulations containing benzyl alcohol preservative only); immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura) (IM administration only)Additional contraindication: Methylprednisolone sodium succinate 40 mg vial only: Hypersensitivity to cow's milk or its components or other dairy products which may contain trace amounts of milk ingredients (known or suspected).Canadian labeling: Additional contraindications (not in US labeling):Methylprednisolone tablets: Herpes simplex of the eye, vaccinia and varicella (except for short-term or emergency therapy)Methylprednisolone acetate injection: Epidural or intravascular administration; intra-articular injections in unstable joints; herpes simplex of the eye, vaccinia and varicella (except for short-term or emergency therapy)Methylprednisolone sodium succinate: Epidural administration; herpes simplex keratitis, vaccinia and varicella, arrested tuberculosis, acute psychoses, Cushing syndrome, peptic ulcer, markedly elevated serum creatinine (except for short-term or emergency therapy)Documentation of allergenic cross-reactivity for corticosteroids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.Warnings/PrecautionsConcerns related to adverse effects:• Adrenal suppression: May cause hypercortisolism or suppression of hypothalamic-pituitary-adrenal (HPA) axis, particularly in younger children or in patients receiving high doses for prolonged periods. HPA axis suppression may lead to adrenal crisis. Withdrawal and discontinuation of a corticosteroid should be done slowly and carefully. Particular care is required when patients are transferred from systemic corticosteroids to inhaled products due to possible adrenal insufficiency or withdrawal from steroids, including an increase in allergic symptoms. Adult patients receiving >20 mg per day of prednisone (or equivalent) may be most susceptible. Fatalities have occurred due to adrenal insufficiency in asthmatic patients during and after transfer from systemic corticosteroids to aerosol steroids; aerosol steroids do not provide the systemic steroid needed to treat patients having trauma, surgery, or infections.• Anaphylactoid reactions: Rare cases of anaphylactoid reactions have been observed in patients receiving corticosteroids.• Dermal changes: Avoid injection or leakage into the dermis; dermal and/or subdermal skin depression may occur at the site of injection. Avoid deltoid muscle injection; subcutaneous atrophy may occur.• Hepatic effects: High doses of methylprednisolone IV (usually doses of 1 g/day in adults) may induce a toxic form of acute hepatitis (rare); serious hepatic injury may occur, resulting in acute liver failure and death. Time to onset can be several weeks or longer; resolution has been observed after discontinuation of therapy. Discontinue methylprednisolone if toxic hepatitis occurs. Avoid use of high doses in patients with a history of methylprednisone-induced toxic hepatitis.• Immunosuppression: Prolonged use of corticosteroids may increase the incidence of secondary infection, cause activation of latent infections, mask acute infection (including fungal infections), prolong or exacerbate viral or parasitic infections, or limit response to killed or inactivated vaccines. Exposure to chickenpox or measles should be avoided; corticosteroids should not be used to treat ocular herpes simplex. Corticosteroids should not be used for cerebral malaria, fungal infections, or viral hepatitis. Close observation is required in patients with latent tuberculosis and/or TB reactivity; restrict use in active TB (only fulminating or disseminated TB in conjunction with antituberculosis treatment). Amebiasis should be ruled out in any patient with recent travel to tropic climates or unexplained diarrhea prior to initiation of corticosteroids. Use with extreme caution in patients with Strongyloides infections; hyperinfection, dissemination and fatalities have occurred.• Kaposi sarcoma: Prolonged treatment with corticosteroids has been associated with the development of Kaposi sarcoma (case reports); discontinuation may result in clinical improvement (Goedert 2002).• Myopathy: Acute myopathy has been reported with high dose corticosteroids, usually in patients with neuromuscular transmission disorders; may involve ocular and/or respiratory muscles; monitor creatine kinase; recovery may be delayed.• Psychiatric disturbances: Corticosteroid use may cause psychiatric disturbances, including euphoria, insomnia, mood swings, personality changes, severe depression, or psychotic manifestations. Preexisting psychiatric conditions may be exacerbated by corticosteroid use.• Septic arthritis: May occur as a complication to parenteral therapy; institute appropriate antimicrobial therapy as required.Disease-related concerns:• Cardiovascular disease: Use with caution in patients with heart failure (HF) and/or hypertension; use has been associated with fluid retention, electrolyte disturbances, and hypertension. Use with caution following acute myocardial infarction (MI); corticosteroids have been associated with myocardial rupture.• Diabetes: Use corticosteroids with caution in patients with diabetes mellitus; may alter glucose production/regulation leading to hyperglycemia.• Gastrointestinal disease: Use with caution in patients with GI diseases (diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, ulcerative colitis, abscess or other pyogenic infection) due to perforation risk.• Head injury: Increased mortality was observed in patients receiving high-dose IV methylprednisolone; high-dose corticosteroids should not be used for the management of head injury.• Hepatic impairment: Use with caution in patients with hepatic impairment, including cirrhosis; long-term use has been associated with fluid retention.• Myasthenia gravis: Use may cause transient worsening of myasthenia gravis (MG) (eg, within first 2 weeks of treatment); monitor for worsening MG (AAN [Narayanaswami 2021]).• Ocular disease: Use with caution in patients with cataracts and/or glaucoma; increased intraocular pressure, open-angle glaucoma, and cataracts have occurred with prolonged use. Not recommended for the treatment of optic neuritis; may increase frequency of new episodes. Use with caution in patients with a history of ocular herpes simplex; corneal perforation has occurred; do not use in active ocular herpes simplex. Consider routine eye exams in chronic users.• Osteoporosis: Use with caution in patients with osteoporosis; high doses and/or long-term use of corticosteroids have been associated with increased bone loss and osteoporotic fractures.• Renal impairment: Use with caution in patients with renal impairment; fluid retention may occur.• Seizure disorders: Use corticosteroids with caution in patients with a history of seizure disorder; seizures have been reported with adrenal crisis.• Septic shock or sepsis syndrome: Corticosteroids should not be administered for the treatment of sepsis in the absence of shock (SCCM/ESICM [Annane 2017]). A study has failed to demonstrate efficacy in septic shock or sepsis syndrome treatment; use may increase mortality in some populations (eg, patients with elevated serum creatinine, patients who develop secondary infections after use).• Systemic sclerosis (scleroderma): Use of higher dose corticosteroid therapy (in adults, ≥15 mg/day of prednisone or equivalent) in patients with systemic sclerosis may increase the risk of scleroderma renal crisis; avoid use when possible (Steen 1998; Trang 2012).• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of corticosteroids increases in hyperthyroid patients and decreases in hypothyroid ones.Special populations:• Older adult: Use with caution in the elderly with the smallest possible effective dose for the shortest duration.• Pediatric: May affect growth velocity; growth should be routinely monitored in pediatric patients.Dosage form specific issues: • Benzyl alcohol and derivatives: Methylprednisolone acetate IM injection (multiple-dose vial) and the diluent for methylprednisolone sodium succinate injection may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997], CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. Additionally, benzyl alcohol may also be toxic to neural tissue when administered locally (eg, intra-articular, intralesional). See manufacturer's labeling.• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.Other warnings/precautions:• Discontinuation of therapy: Withdraw therapy with gradual tapering of dose.• Epidural injection: Corticosteroids are not approved for epidural injection. Serious neurologic events (eg, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, stroke), some resulting in death, have been reported with epidural injection of corticosteroids, with and without use of fluoroscopy.• Stress: Patients may require higher doses when subject to stress (ie, trauma, surgery, severe infection).Warnings: Additional Pediatric ConsiderationsMay cause osteoporosis (at any age) or inhibition of bone growth in pediatric patients. Use with caution in patients with osteoporosis. In a population-based study of children, risk of fracture was shown to be increased with >4 courses of corticosteroids; underlying clinical condition may also impact bone health and osteoporotic effect of corticosteroids (Leonard 2007). Increased intraocular pressure (IOP) may occur, especially with prolonged use; in children, increased IOP has been shown to be dose dependent and produce a greater IOP in children <6 years of age than older children treated with ophthalmic dexamethasone (Lam 2005). Hypertrophic cardiomyopathy has been reported in premature neonates.Metabolism/Transport EffectsSubstrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Abrocitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Abrocitinib.Management: The use of abrocitinib in combination with other immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationAcetylcholinesterase Inhibitors: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur.Risk C: Monitor therapyAldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin.Risk X: Avoid combinationAmphotericin B: Corticosteroids (Systemic) may enhance the hypokalemic effect of Amphotericin B.Risk C: Monitor therapyAndrogens: Corticosteroids (Systemic) may enhance the fluid-retaining effect of Androgens.Risk C: Monitor therapyAntacids: May decrease the bioavailability of Corticosteroids (Oral). Management: Consider separating doses by 2 or more hours. Budesonide enteric coated tablets could dissolve prematurely if given with drugs that lower gastric acid, with unknown impact on budesonide therapeutic effects. Risk D: Consider therapy modificationAntidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.Risk C: Monitor therapyAprepitant: May increase the serum concentration of MethylPREDNISolone. Management: Decrease oral methylprednisolone dose by 50%, and decrease intravenous methylprednisolone dose by 25%, with aprepitant. No dose adjustment is required when used with only a single 40 mg oral dose or 32 mg injectable dose of aprepitant. Risk D: Consider therapy modificationBaricitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Baricitinib.Management: The use of baricitinib in combination with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationBCG Products: Corticosteroids (Systemic) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of BCG Products.Risk X: Avoid combinationBile Acid Sequestrants: May decrease the absorption of Corticosteroids (Oral). Risk C: Monitor therapyBrincidofovir: Corticosteroids (Systemic) may diminish the therapeutic effect of Brincidofovir.Risk C: Monitor therapyCalcitriol (Systemic): Corticosteroids (Systemic) may diminish the therapeutic effect of Calcitriol (Systemic).Risk C: Monitor therapyCAR-T Cell Immunotherapy: Corticosteroids (Systemic) may enhance the adverse/toxic effect of CAR-T Cell Immunotherapy. Specifically, the severity and duration of neurologic toxicities may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of CAR-T Cell Immunotherapy.Management: Avoid use of corticosteroids as premedication before treatment with CAR-T cell immunotherapy agents. Corticosteroids are indicated and may be required for treatment of toxicities such as cytokine release syndrome or neurologic toxicity. Risk D: Consider therapy modificationCladribine: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Cladribine.Risk X: Avoid combinationClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyCoccidioides immitis Skin Test: Corticosteroids (Systemic) may diminish the diagnostic effect of Coccidioides immitis Skin Test.Management: Consider discontinuing systemic corticosteroids (dosed at 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks) several weeks prior to coccidioides immitis skin antigen testing. Risk D: Consider therapy modificationCorticorelin: Corticosteroids (Systemic) may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response to corticorelin may be blunted by recent or current corticosteroid therapy.Risk C: Monitor therapyCosyntropin: Corticosteroids (Systemic) may diminish the diagnostic effect of Cosyntropin.Risk C: Monitor therapyCOVID-19 Vaccine (Adenovirus Vector): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector).Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters) Risk D: Consider therapy modificationCOVID-19 Vaccine (Inactivated Virus): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus).Risk C: Monitor therapyCOVID-19 Vaccine (mRNA): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA).Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modificationCOVID-19 Vaccine (Subunit): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit).Risk C: Monitor therapyCOVID-19 Vaccine (Virus-like Particles): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles).Risk C: Monitor therapyCycloSPORINE (Systemic): May enhance the neuroexcitatory and/or seizure-potentiating effect of MethylPREDNISolone. MethylPREDNISolone may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapyCYP3A4 Inducers (Moderate): May decrease the serum concentration of MethylPREDNISolone. Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Risk D: Consider therapy modificationCYP3A4 Inhibitors (Moderate): May increase the serum concentration of MethylPREDNISolone. Risk C: Monitor therapyCYP3A4 Inhibitors (Strong): May increase the serum concentration of MethylPREDNISolone. Risk C: Monitor therapyDeferasirox: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapyDengue Tetravalent Vaccine (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live).Risk X: Avoid combinationDenosumab: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and systemic corticosteroids. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modificationDesirudin: Corticosteroids (Systemic) may enhance the anticoagulant effect of Desirudin. More specifically, corticosteroids may increase hemorrhagic risk during desirudin treatment.Management: Discontinue treatment with systemic corticosteroids prior to desirudin initiation.If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: Consider therapy modificationDesmopressin: Corticosteroids (Systemic) may enhance the hyponatremic effect of Desmopressin.Risk X: Avoid combinationDeucravacitinib: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Management: The use of deucravacitinib in combination with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationEstrogen Derivatives: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapyFexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFilgotinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Filgotinib.Management: Coadministration of filgotinib with systemic corticosteroids at doses equivalent to greater than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks is not recommended. Risk D: Consider therapy modificationFosaprepitant: May increase the serum concentration of MethylPREDNISolone. Management: Decrease the oral methylprednisolone dose by 50%, and decrease the intravenous methylprednisolone dose by 25%, when combined with fosaprepitant. Risk D: Consider therapy modificationFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationGallium Ga 68 Dotatate: Corticosteroids (Systemic) may diminish the diagnostic effect of Gallium Ga 68 Dotatate.Risk C: Monitor therapyGrowth Hormone Analogs: Corticosteroids (Systemic) may diminish the therapeutic effect of Growth Hormone Analogs. Growth Hormone Analogs may decrease serum concentrations of the active metabolite(s) of Corticosteroids (Systemic).Risk C: Monitor therapyHyaluronidase: Corticosteroids (Systemic) may diminish the therapeutic effect of Hyaluronidase.Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider therapy modificationImmune Checkpoint Inhibitors: Corticosteroids (Systemic) may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Management: Carefully consider the need for corticosteroids, at doses of a prednisone-equivalent of 10 mg or more per day, during the initiation of immune checkpoint inhibitor therapy. Use of corticosteroids to treat immune related adverse events is still recommended Risk D: Consider therapy modificationIndium 111 Capromab Pendetide: Corticosteroids (Systemic) may diminish the diagnostic effect of Indium 111 Capromab Pendetide.Risk X: Avoid combinationInebilizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Inebilizumab.Risk C: Monitor therapyInfluenza Virus Vaccines: Corticosteroids (Systemic) may diminish the therapeutic effect of Influenza Virus Vaccines.Management: Administer influenza vaccines at least 2 weeks prior to initiation of systemic corticosteroids at immunosuppressive doses. Influenza vaccines administered less than 14 days prior to or during such therapy should be repeated 3 months after therapy. Risk D: Consider therapy modificationIsoniazid: Corticosteroids (Systemic) may decrease the serum concentration of Isoniazid.Risk C: Monitor therapyLeflunomide: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Leflunomide.Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as systemic corticosteroids. Risk D: Consider therapy modificationLicorice: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapyLoop Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Loop Diuretics.Risk C: Monitor therapyLutetium Lu 177 Dotatate: Corticosteroids (Systemic) may diminish the therapeutic effect of Lutetium Lu 177 Dotatate.Management: Avoid repeated use of high-doses of corticosteroids during treatment with lutetium Lu 177 dotatate. Use of corticosteroids is still permitted for the treatment of neuroendocrine hormonal crisis. The effects of lower corticosteroid doses is unknown. Risk D: Consider therapy modificationMacimorelin: Corticosteroids (Systemic) may diminish the diagnostic effect of Macimorelin.Risk X: Avoid combinationMetyraPONE: Corticosteroids (Systemic) may diminish the diagnostic effect of MetyraPONE.Management: Consider alternatives to the use of the metyrapone test in patients taking systemic corticosteroids. Risk D: Consider therapy modificationMifamurtide: Corticosteroids (Systemic) may diminish the therapeutic effect of Mifamurtide.Risk X: Avoid combinationMiFEPRIStone: May diminish the therapeutic effect of Corticosteroids (Systemic). MiFEPRIStone may increase the serum concentration of Corticosteroids (Systemic). Management: Avoid mifepristone in patients who require long-term corticosteroid treatment of serious illnesses or conditions (eg, for immunosuppression following transplantation). Corticosteroid effects may be reduced by mifepristone treatment. Risk X: Avoid combinationNatalizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Natalizumab.Risk X: Avoid combinationNeuromuscular-Blocking Agents (Nondepolarizing): May enhance the adverse neuromuscular effect of Corticosteroids (Systemic). Increased muscle weakness, possibly progressing to polyneuropathies and myopathies, may occur. Management: If concomitant therapy is required, use the lowest dose for the shortest duration to limit the risk of myopathy or neuropathy. Monitor for new onset or worsening muscle weakness, reduction or loss of deep tendon reflexes, and peripheral sensory decriments Risk D: Consider therapy modificationNicorandil: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nicorandil. Gastrointestinal perforation has been reported in association with this combination.Risk C: Monitor therapyNirmatrelvir and Ritonavir: May increase the serum concentration of MethylPREDNISolone. Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective).Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (Nonselective): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective).Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (Topical): May enhance the adverse/toxic effect of Corticosteroids (Systemic). Specifically, the risk of gastrointestinal bleeding, ulceration, and perforation may be increased. Risk C: Monitor therapyOcrelizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ocrelizumab.Risk C: Monitor therapyOfatumumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ofatumumab.Risk C: Monitor therapyPidotimod: Corticosteroids (Systemic) may diminish the therapeutic effect of Pidotimod.Risk C: Monitor therapyPimecrolimus: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Risk X: Avoid combinationPneumococcal Vaccines: Corticosteroids (Systemic) may diminish the therapeutic effect of Pneumococcal Vaccines.Risk C: Monitor therapyPoliovirus Vaccine (Live/Trivalent/Oral): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral).Risk X: Avoid combinationPolymethylmethacrylate: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Polymethylmethacrylate. Specifically, the risk for hypersensitivity or implant clearance may be increased.Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modificationQuinolones: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Quinolones. Specifically, the risk of tendonitis and tendon rupture may be increased.Risk C: Monitor therapyRabies Vaccine: Corticosteroids (Systemic) may diminish the therapeutic effect of Rabies Vaccine.Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modificationRitodrine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Ritodrine.Risk C: Monitor therapyRubella- or Varicella-Containing Live Vaccines: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines.Risk X: Avoid combinationRuxolitinib (Topical): Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ruxolitinib (Topical).Risk X: Avoid combinationSalicylates: May enhance the adverse/toxic effect of Corticosteroids (Systemic). These specifically include gastrointestinal ulceration and bleeding. Corticosteroids (Systemic) may decrease the serum concentration of Salicylates. Withdrawal of corticosteroids may result in salicylate toxicity. Risk C: Monitor therapySargramostim: Corticosteroids (Systemic) may enhance the therapeutic effect of Sargramostim. Specifically, corticosteroids may enhance the myeloproliferative effects of sargramostim.Risk C: Monitor therapySipuleucel-T: Corticosteroids (Systemic) may diminish the therapeutic effect of Sipuleucel-T.Management: Consider reducing the dose or discontinuing immunosuppressants, such as systemic corticosteroids, prior to initiating sipuleucel-T therapy. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone given for 2 or more weeks are immunosuppressive. Risk D: Consider therapy modificationSodium Benzoate: Corticosteroids (Systemic) may diminish the therapeutic effect of Sodium Benzoate.Risk C: Monitor therapySphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Risk C: Monitor therapySuccinylcholine: Corticosteroids (Systemic) may enhance the neuromuscular-blocking effect of Succinylcholine.Risk C: Monitor therapyTacrolimus (Systemic): Corticosteroids (Systemic) may decrease the serum concentration of Tacrolimus (Systemic). Conversely, when discontinuing corticosteroid therapy, tacrolimus concentrations may increase.Risk C: Monitor therapyTacrolimus (Topical): Corticosteroids (Systemic) may enhance the immunosuppressive effect of Tacrolimus (Topical).Risk X: Avoid combinationTalimogene Laherparepvec: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased.Risk X: Avoid combinationTertomotide: Corticosteroids (Systemic) may diminish the therapeutic effect of Tertomotide.Risk X: Avoid combinationThiazide and Thiazide-Like Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics.Risk C: Monitor therapyTofacitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Tofacitinib.Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationTyphoid Vaccine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Typhoid Vaccine.Risk X: Avoid combinationUpadacitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Upadacitinib.Management: Coadministration of upadacitinib with systemic corticosteroids at doses equivalent to greater than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks is not recommended. Risk D: Consider therapy modificationUrea Cycle Disorder Agents: Corticosteroids (Systemic) may diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Corticosteroids (Systemic) may increase protein catabolism and plasma ammonia concentrations, thereby increasing the doses of Urea Cycle Disorder Agents needed to maintain these concentrations in the target range.Risk C: Monitor therapyVaccines (Inactivated/Non-Replicating): Corticosteroids (Systemic) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating).Management: Administer vaccines at least 2 weeks prior to immunosuppressive corticosteroids if possible. If patients are vaccinated less than 14 days prior to or during such therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationVaccines (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Vaccines (Live).Management: Avoid live vaccines during and for 1 month after therapy with immunosuppressive doses of corticosteroids (equivalent to prednisone > 2 mg/kg or 20 mg/day in persons over 10 kg for at least 2 weeks). Give live vaccines prior to therapy whenever possible. Risk D: Consider therapy modificationVitamin K Antagonists (eg, warfarin): Corticosteroids (Systemic) may enhance the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapyYellow Fever Vaccine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Yellow Fever Vaccine.Risk X: Avoid combinationReproductive ConsiderationsCorticosteroids do not decrease fertility in patients with inflammatory bowel disease (IBD) who wish to become pregnant; however, active IBD may decrease fertility; pregnancy should be planned after a 3- to 6-month remission (Mahadevan 2019).Pregnancy ConsiderationsMethylprednisolone crosses the placenta (Anderson 1981). Some products contain benzyl alcohol, which may also cross the placenta.Some studies have shown an association between first trimester systemic corticosteroid use and oral clefts; however, information is conflicting and may be influenced by maternal dose, duration/frequency of exposure, and indication for use. Additional data are needed to evaluate any potential risk of systemic corticosteroids and other adverse pregnancy outcomes (eg, gestational diabetes mellitus, low birth weight, preeclampsia, preterm birth) (ACOG 776 2019; Bandoli 2017; Skuladottir 2014). Hypoadrenalism may occur in newborns following maternal use of corticosteroids; monitor infants exposed to prolonged or high doses of methylprednisolone in utero (Homar 2008; Kurtoğlu 2011).Methylprednisolone is a preferred oral corticosteroid for the treatment of maternal conditions during pregnancy because placental enzymes limit passage to the embryo (ACOG 776 2019).When systemic corticosteroids are needed in pregnancy for rheumatic disorders, nonfluorinated corticosteroids such as methylprednisolone are preferred. Chronic high doses should be avoided (ACR [Sammaritano 2020]). Methylprednisolone may also be used to treat acute exacerbations of multiple sclerosis during pregnancy (Canibaño 2020; Dobson 2019).Corticosteroids may be used as needed for disease flares in pregnant patients with inflammatory bowel disease; however, maintenance therapy should be avoided (Mahadevan 2019).Uncontrolled asthma is associated with adverse events on pregnancy (increased risk of perinatal mortality, preeclampsia, preterm birth, low birth weight infants, cesarean delivery, and the development of gestational diabetes). Poorly controlled asthma or asthma exacerbations may have a greater fetal/maternal risk than what is associated with appropriately used asthma medications. Maternal treatment improves pregnancy outcomes by reducing the risk of some adverse events (eg, preterm birth, gestational diabetes). Maternal asthma symptoms should be monitored monthly during pregnancy. Inhaled corticosteroids are recommended for the treatment of asthma during pregnancy; however, systemic corticosteroids should be used to control acute exacerbations or treat severe persistent asthma (ERS/TSANZ [Middleton 2020]; GINA 2021).Methylprednisolone may be considered for adjunctive treatment of severe nausea and vomiting in pregnant patients. Due to risks of adverse fetal events associated with first trimester exposure, use is reserved for refractory cases in women with dehydration (ACOG 189 2018).High dose methylprednisolone may be used in the management of immune thrombocytopenia in pregnant patients refractory to oral corticosteroids; use in combination with other therapies is suggested (Provan 2019).Systemic corticosteroids are used off label in the management of COVID-19 (NIH 2022b). Methylprednisolone was not the corticosteroid evaluated in the initial study and large numbers of pregnant patients were not included (Horby 2021). However, in patients who do not require corticosteroids for other indications, or in those who have already completed a course of corticosteroids to enhance fetal lung development, equivalent doses of methylprednisolone may be preferred for use in pregnant patients with severe or critical COVID-19 due to limited placental transfer and less fetal risk. A treatment algorithm is available for pregnant patients with severe or critical COVID-19; the algorithm differentiates recommendations based on the patient's requirement for corticosteroids for fetal lung maturation. Close glucose monitoring is recommended (Saad 2020). The risk of severe illness from COVID-19 infection is increased in symptomatic pregnant patients compared to nonpregnant patients (ACOG 2022). Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.The Transplant Pregnancy Registry International (TPR) is a registry that follows pregnancies that occur in maternal transplant recipients or those fathered by male transplant recipients. The TPR encourages reporting of pregnancies following solid organ transplant by contacting them at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.Breastfeeding ConsiderationsMethylprednisolone is present in breast milk (Boz 2018; Cooper 2015; Strijbos 2015; Zengin Karahan 2020).Information related to the presence of methylprednisolone in breast milk is available from a study following maternal administration of methylprednisolone 1,000 mg IV infused over 2 hours. Using the highest milk concentration (5.55 mcg/mL), the estimated daily infant dose via breast milk was 0.8325 mg/kg/day, providing a relative infant dose (RID) of methylprednisolone of 2.8% to 5.6% compared to a weight-adjusted infant dose of 15 to 30 mg/kg/day. The maximum milk concentration occurred 1 hour after the maternal dose and methylprednisolone was below the limits of quantification 12 hours after the dose (Cooper 2015). In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).The manufacturer notes that when used systemically, maternal use of corticosteroids have the potential to cause adverse events in a breastfeeding infant (eg, growth suppression, interfere with endogenous corticosteroid production) and therefore recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.Corticosteroids are generally considered acceptable in patients who are breastfeeding when used in usual doses; however, monitoring of the breastfeeding infant is recommended (WHO 2002). Methylprednisolone is classified as a nonfluorinated corticosteroid; when systemic corticosteroids are needed in a lactating patient for rheumatic disorders, low doses of nonfluorinated corticosteroids are preferred (ACR [Sammaritano 2020]).If there is concern about exposure to the infant, waiting 2 to 4 hours after administration of methylprednisolone IV decreases exposure via breast milk (recommendation based on methylprednisolone pulse dosing for multiple sclerosis) (Cooper 2015; Zengin Karahan 2020). In addition, some guidelines recommend waiting 4 hours after the maternal dose of an oral systemic corticosteroid before breastfeeding (based on a study using prednisolone) (ACR [Sammaritano 2020]; Ost 1985).Dietary ConsiderationsTake tablets with meals to decrease GI upset; need diet rich in pyridoxine, vitamin C, vitamin D, folate, calcium, phosphorus, and protein. Monitoring ParametersBlood pressure, blood glucose, electrolytes; weight; intraocular pressure (use >6 weeks); bone mineral density; growth and development in children; HPA axis suppressionMechanism of ActionIn a tissue-specific manner, corticosteroids regulate gene expression subsequent to binding specific intracellular receptors and translocation into the nucleus. Corticosteroids exert a wide array of physiologic effects including modulation of carbohydrate, protein, and lipid metabolism and maintenance of fluid and electrolyte homeostasis. Moreover cardiovascular, immunologic, musculoskeletal, endocrine, and neurologic physiology are influenced by corticosteroids. Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.Pharmaco*kineticsOnset of action: IV (succinate): Within 1 hour; Intra-articular (acetate): 1 weekDuration: Intra-articular (acetate): 1 to 5 weeksAbsorption: Oral: Well absorbed (Czock 2005)Bioavailability: Oral: 88% ± 23% (Czock 2005)Distribution: Vd: IV (succinate): 24 L ± 6 L (Czock 2005)Metabolism: Hepatic to metabolites (Czock 2005)Half-life elimination:Adolescents: IV: 1.9 ± 0.7 hours (age range: 12 to 20 years; Rouster-Stevens 2008)Adults: Oral: 2.5 ± 1.2 hours (Czock 2005); IV (succinate): 0.25 ± 0.1 hour (Czock 2005)Time to peak, plasma:Oral: 2.1 ± 0.7 hours (Czock 2005)IV (succinate): 0.8 hours (Czock 2005)Excretion: Urine (1.3% [oral], 9.2% [IV succinate] as unchanged drug) (Czock 2005)Pharmaco*kinetics: Additional ConsiderationsOlder adult: Decreased clearance and increased half-life (Czock 2005).Obesity: Decreased clearance and increased half-life (Czock 2005; Dunn 1991).Pricing: USSolution (reconstituted) (methylPREDNISolone Sodium Succ Injection)40 mg (per each): $5.76 - $7.30125 mg (per each): $9.12 - $13.98500 mg (per each): $26.40 - $27.741000 mg (per each): $39.00 - $50.27Solution (reconstituted) (SOLU-Medrol Injection)2 g (per each): $113.1040 mg (per each): $7.26125 mg (per each): $11.69500 mg (per each): $29.141000 mg (per each): $52.78Suspension (DEPO-Medrol Injection)20 mg/mL (per mL): $8.5340 mg/mL (per mL): $13.6380 mg/mL (per mL): $23.67Suspension (methylPREDNISolone Acetate Injection)40 mg/mL (per mL): $10.44 - $11.5780 mg/mL (per mL): $17.16 - $19.58Tablet Therapy Pack (Medrol Oral)4 mg (per each): $0.37Tablet Therapy Pack (methylPREDNISolone Oral)4 mg (per each): $1.43 - $1.65Tablets (Medrol Oral)2 mg (per each): $1.974 mg (per each): $0.378 mg (per each): $2.1416 mg (per each): $3.45Tablets (methylPREDNISolone Oral)4 mg (per each): $1.43 - $2.238 mg (per each): $2.0116 mg (per each): $3.11 - $3.5432 mg (per each): $4.62 - $5.18Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAdrelan (PH);Advantan (MX);Adventan (ES);Cipridanol (PY);Comedrol (ID);Cryosolona (MX);Depo Medrol (AE, BH, JO, KW, LB, QA, SA);Depo-Medrol (BB, EG, ET, HR, IS, LU, LV, MX, NO, SI, SK, UA, VN, ZW);Depo-Medrone (IE, MT);Epizolone-Depot (ET);Flason (ID);Flumethyl (ID);Lexcomet (ID);Lexxema (ES);M-Nisol (LK);M-Prednihexal (DE);Meapron (KR);Medason (HK);Medexa (VN);Medisolu (KR);Medixon (ID, MY, PH);Medlon (VN);Mednin (TW);Medrate (DE);Medrol (AE, BB, BE, BH, BM, BS, BZ, CH, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EC, EE, ES, FI, FR, GB, GR, GT, GY, HN, HR, ID, IE, IL, IN, IQ, IR, IT, JM, JO, KR, KW, LT, LU, LV, LY, MT, NI, NL, NO, NZ, OM, PA, PH, PL, PT, QA, RO, RU, SA, SE, SI, SK, SR, SV, SY, TT, UA, VE, YE, ZA);Medrone (GB);Melsone (IN);Menisone (TW);Mepresone (PH);Mesolone (KR);Metcor (ID);Metcort (PH);Methylon (KR);Methylprednisolone David Bull (LU);Methysol (KR);Metrite (LK);Metypred (UA);Neo-Drol (LK);Nisolon-M (KR);Predlitem (MX);Prednivex (LK, PH);Prednol (TR);Prednox (PH);Prena (KR);Pretilon (ID);Prolon (ID);Sanexon (ID, LK);Sol-U-Pred (LK);Sologen (KR);Solomet (FI);Solu Medrol (BF, BJ, CI, ET, GH, GM, GN, KE, LK, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);Solu-Medon (VN);Solu-Medrol (AE, AU, BB, BG, BH, CL, CN, CR, CY, DO, EG, GT, HK, HN, HR, IS, JO, JP, KW, LB, LT, LU, LV, MX, MY, NI, PA, PK, QA, RO, SA, SI, SK, SV, TH, TR, UA, UY);Solu-Medrone (IE, MT);Solu-Moderin (ES);Solu-Pred (MY);Somidex (TH);Sonicor (ID);Thimelon (ID);Thylmedi (VN);Tisolon-4 (ID);Tropidrol (ID);Urbason (AT, DE, EG, ES, HR, NL);Urbason Retard (IT);Yalone (ID)For country code abbreviations (show table)Abraham E, Evans T. Corticosteroids and Septic Shock [editorial]. JAMA. 2002;288(7):886-887. [PubMed 12186608]Adams A, MacDermott EJ, Lehman TJ. Pharmacotherapy of lupus nephritis in children: a recommended treatment approach. Drugs. 2006;66(9):1191-1207. [PubMed 16827597]Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]Akahoshi S, Hasegawa Y. Steroid-induced iatrogenic adrenal insufficiency in children: a literature review. Endocrines. 2020;1(2):125-137. doi:10.3390/endocrines1020012Akikusa JD, Feldman BM, Gross GJ, Silverman ED, Schneider R. Sinus bradycardia after intravenous pulse methylprednisolone. Pediatrics. 2007;119(3):e778-782. [PubMed 17308245]Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]Allen RK, Sellars RE, Sandstrom PA. A prospective study of 32 patients with neurosarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2003;20(2):118-125. 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CloseRituximab (intravenous) including biosimilars: Pediatric drug informationRituximab (intravenous) including biosimilars: Pediatric drug information(For additional information see "Rituximab (intravenous) including biosimilars: Drug information" and see "Rituximab (intravenous) including biosimilars: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningInfusion-related reactions:Rituximab administration can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue rituximab infusion for severe reactions and provide medical treatment for grade 3 or 4 infusion-related reactions.Mucocutaneous reactions:Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products.Hepatitis B virus reactivation:Hepatitis B virus (HBV) reactivation can occur in patients treated with rituximab products, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with rituximab. Discontinue rituximab and concomitant medications in the event of HBV reactivation.Progressive multifocal leukoencephalopathy:Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products.Brand Names: USRiabni;Rituxan;Ruxience;TruximaBrand Names: CanadaRiabni;Rituxan;Riximyo;Ruxience;TruximaTherapeutic CategoryAntineoplastic Agent, Anti-CD20;Antineoplastic Agent, Monoclonal Antibody;Antirheumatic Miscellaneous;Immunosuppressant Agent;Monoclonal AntibodyDosing: PediatricPrior to rituximab therapy, patients should be brought up to date with all nonlive vaccination if possible; any nonlive vaccines should be administered ≥4 weeks prior to first rituximab dose. Pretreatment with acetaminophen and an antihistamine (diphenhydramine typically used in pediatric trials) is recommended for all indications.For oncology uses: A uricostatic agent (eg, allopurinol) and aggressive hydration are recommended for patients at risk for tumor lysis syndrome (high tumor burden or lymphocytes >25,000/mm3) and dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol. Screen all patients for hepatitis B virus (HBV) infection (measure hepatitis B surface antigen [HBsAg] and hepatitis B core antibody [anti-HBc]) (see "Monitoring Parameters"); consider antiviral prophylaxis to prevent hepatitis B reactivation for all patients receiving rituximab (oncology and nononcology indications) with resolved HBV infection (Ref).Acute lymphoblastic leukemia, mature B-cell, CD 20+; relapsed/refractoryAcute lymphoblastic leukemia, mature B-cell, CD 20+ (B-ALL); relapsed/refractory: Limited data available: Children ≥5 years and Adolescents: IV infusion: 375 mg/m2 administered on days 1 and 3 of courses 1 and 2 and on day 1 only of course 3; used in combination with ifosfamide, carboplatin, and etoposide (ICE) (Ref).Autoimmune hemolytic anemiaAutoimmune hemolytic anemia: Limited data available: Infants ≥4 months, Children, and Adolescents: IV infusion: 375 mg/m2 once weekly for 4 doses (Ref).Graft-versus-host disease, chronic; steroid-refractoryGraft-versus-host disease, chronic (cGVHD); steroid-refractory: Limited data available: Children and Adolescents: IV: 375 mg/m2 once weekly for 4 doses followed by monthly infusions has been reported; in preliminary data, GVHD musculoskeletal and dermal manifestations were observed to respond better than ophthalmic, hepatic, or gastrointestinal manifestations (Ref).Granulomatosis with polyangiitisGranulomatosis with polyangiitis (GPA, Wegener granulomatosis): Note: In addition to an antihistamine and acetaminophen, patients should also be premedicated 30 minutes prior to each infusion with methylprednisolone (eg, 100 mg IV in adults or equivalent). Patients should receive Pneumocystis jirovecii pneumonia (PCP) prophylaxis during rituximab therapy and for at least 6 months following the last rituximab dose.Children ≥2 years and Adolescents:Induction (active GPA): IV: 375 mg/m2 once weekly for 4 doses.Note: Use rituximab in combination with corticosteroids (ie, methylprednisolone or oral corticosteroid taper). Prior to the first dose of rituximab, methylprednisolone should be administered for 3 days (30 mg/kg/dose once daily; maximum dose: 1,000 mg/dose) followed by oral corticosteroid taper per usual clinical practice and patient response.Maintenance (once disease control achieved): IV: 250 mg/m2 every 2 weeks for 2 doses, followed by 250 mg/m2 every 6 months based upon clinical response. Begin maintenance regimen within 16 to 24 weeks of last rituximab induction dose. If rituximab was not part of induction regimen, begin rituximab within 4 weeks of achieving disease control.Immune thrombocytopenic purpura, chronicImmune thrombocytopenic purpura, chronic: Limited data available: Children and Adolescents: IV infusion: 375 mg/m2 once weekly for 4 doses (Ref).Leukemia, acute B-cell; CD20+; advanced stage, previously untreatedLeukemia, acute B-cell; CD20+; advanced stage, previously untreated: Infants ≥6 months, Children, and Adolescents: IV infusion: 375 mg/m2/dose in combination with systemic Lymphome Malin B (LMB) chemotherapy regimen; administer 2 doses during each induction course (day −2 and day 1), and 1 dose on day 1 of each of the 2 consolidation cycles (6 doses total).Microscopic polyangiitisMicroscopic polyangiitis (MPA): Note: In addition to an antihistamine and acetaminophen, patients should also be premedicated 30 minutes prior to each infusion with methylprednisolone (eg, 100 mg IV in adults or equivalent). Patients should receive PCP prophylaxis during rituximab therapy and for at least 6 months following the last rituximab dose.Children ≥2 years and Adolescents:Induction (active MPA): IV: 375 mg/m2 once weekly for 4 doses.Note: Use rituximab in combination with corticosteroids (ie, methylprednisolone or oral corticosteroid taper). Prior to the first dose of rituximab, methylprednisolone should be administered for 3 days (30 mg/kg/dose once daily; maximum dose: 1,000 mg/dose) followed by oral corticosteroid taper per usual clinical practice and patient response.Maintenance (once disease control achieved): IV: 250 mg/m2 every 2 weeks for 2 doses, followed by 250 mg/m2 every 6 months based upon clinical response. Begin maintenance regimen within 16 to 24 weeks of last rituximab induction dose. If rituximab was not part of induction regimen, begin rituximab within 4 weeks of achieving disease control.Nephrotic syndrome, steroid-dependentNephrotic syndrome, steroid-dependent: Limited data available; use should be reserved for patients with frequent relapses despite optimal combinations of prednisone and corticosteroid-sparing therapy or intolerance to therapy (Ref). Children and Adolescents: IV infusion: 375 mg/m2 once weekly for 1 to 4 doses; a maximum dose of 500 mg/dose has been reported in some, but not all, reports; dosing based on small trials, case series, and retrospective analyses (Ref).Non-Hodgkin lymphoma B-cell, CD 20+; relapsed and refractoryNon-Hodgkin lymphoma B-cell, CD 20+; relapsed and refractory: Limited data available: Children ≥11 years and Adolescents: IV infusion: 375 mg/m2 administered on days 1 and 3 of courses 1 and 2 and on day 1 only of course 3; used in combination with ICE (Ref).Non-Hodgkin lymphoma; CD20+, diffuse large B-cell, Burkitt lymphoma, Burkitt-like lymphoma; previously untreated, advanced stageNon-Hodgkin lymphoma; CD20+, diffuse large B-cell (DLBCL), Burkitt lymphoma, Burkitt-like lymphoma; previously untreated, advanced stage: Infants ≥6 months, Children, and Adolescents: IV infusion: 375 mg/m2/dose in combination with systemic Lymphome Malin B (LMB) chemotherapy regimen; administer 2 doses during each induction course (day −2 and day 1), and 1 dose on day 1 of each of the 2 consolidation cycles (6 doses total).Posttransplant lymphoproliferative disorderPosttransplant lymphoproliferative disorder: Limited data available: Infants ≥11 months, Children, and Adolescents: IV infusion: 375 mg/m2 once weekly for 3 to 4 doses (Ref).Primary mediastinal large B-cell lymphomaPrimary mediastinal large B-cell lymphoma: Limited data available: Children and Adolescents: IV: 375 mg/m2 every 21 to 28 days for 6 to 8 doses; use in combination with multi-agent chemotherapy (Ref).Systemic lupus erythematosus; refractorySystemic lupus erythematosus; refractory: Limited data available; various dosing regimens reported in small open-labeled trials and case series; experts suggest rituximab as an option in nonresponders if more than one initial therapy has failed (Ref): Children ≥6 years and Adolescents: IV infusion: Usual regimen: Initial dose: 187.5 mg/m2 once (day 1) followed by 375 mg/m2 once weekly for 1 to 3 doses (days 8, 15, 22) (Ref); other reports omit the lower initial dose and administer 375 mg/m2 once weekly beginning on day 1 for 2 to 4 doses (days 8, 15, 22) (Ref). Others have reported a higher dose regimen of 750 mg/m2 on days 1 and 15 (maximum dose: 1,000 mg/dose) (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Adult(For additional information see "Rituximab (intravenous) including biosimilars: Drug information")Note: Patient should be under the care of a clinician experienced with using rituximab for the specific indication. Pretreatment screening: Avoid use in patients with severe active infection. Screen for hepatitis B virus before starting therapy; additional pretreatment screening (eg, hepatitis C, HIV, tuberculosis) may be warranted. For patients with latent or active infection, consult infectious disease or other appropriate specialists before initiating therapy (Ref). Pretreatment immunizations: Administer appropriate immunizations prior (eg, ≥4 weeks) to starting therapy when feasible. Antimicrobial prophylaxis: Refer to institutional protocols and manufacturer's labeling; prophylaxis against opportunistic infection and/or viral reactivation may be warranted during and up to 12 months after completion of rituximab therapy. Premedication: Manufacturer's labeling recommends premedicating ~30 minutes prior to administration with acetaminophen, an antihistamine, and methylprednisolone 100 mg IV (or equivalent) for adults. For uses requiring concomitant administration with a glucocorticoid (eg, some oncology uses), administer glucocorticoid component of the chemotherapy regimen prior to rituximab infusion. Premedication practice may vary; refer to institutional protocols. For oncology uses, antihyperuricemic therapy and aggressive hydration are recommended for patients at risk for tumor lysis syndrome (high tumor burden or lymphocytes ≥25,000/mm3).Dosage forms note: In the United States, Riabni (rituximab-arrx), Ruxience (rituximab-pvvr), and Truxima (rituximab-abbs) are approved biosimilars to Rituxan (rituximab). In Canada, Riximyo, Ruxience, and Truxima are approved biosimilars to Rituxan (rituximab); refer to Canadian product monographs for biosimilar-specific labeled indications.Acute lymphoblastic leukemia, B-cell precursor, CD20-positiveAcute lymphoblastic leukemia, B-cell precursor, CD20-positive (off-label use): GRAALL 2005-R: Adults <60 years of age: IV: 375 mg/m2 on days 1 and 7 of induction (and days 1 and 7 of salvage cycle, if needed), on days 1 and 29 of consolidation 1 and 2, on days 1 and 7 of late intensification, on days 1 and 29 of consolidation 3, and on day 1 of reinductions 1, 3, 5, 7, 9, and 11 of the maintenance phase for a total of 16 to 18 rituximab doses. Note: Administer rituximab after hydration and before chemotherapy; administer rituximab after steroids, if both are administered on the same day. If the initial WBC is >30,000/mm3 on day 1 after the steroid prophase, split rituximab administration into 100 mg/m2 on days 1 and 2, followed by 175 mg/m2 on day 3 (total dose: 375 mg/m2). Refer to protocol for further information regarding concomitant chemotherapy agents, dosing, and administration (Ref).Rituximab in combination with hyper-CVAD: Adults <60 years of age: IV: 375 mg/m2 on days 1 and 11 of hyper-CVAD cycles (cyclophosphamide, mesna, dexamethasone, doxorubicin, and vincristine) and on days 1 and 8 of high-dose methotrexate and cytarabine cycles, for a total of 8 rituximab doses over the first 4 courses; rituximab was also administered with early and late hyper-CVAD intensifications during months 6 and 18 of maintenance therapy (on days 1 and 11). Refer to protocol for further information regarding concomitant chemotherapy agents, dosing, and administration (Ref).Antibody-mediated rejection, treatmentAntibody-mediated rejection, treatment (adjunctive agent) (off-label use):Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols. Administer as part of an appropriate combination regimen. If plasmapheresis is utilized, administer after completion of plasmapheresis (Ref). Heart transplantation (off-label use): IV: 375 mg/m2 once weekly for 1 to 4 doses (Ref). Kidney transplantation (off-label use):Note: For use in patients with evidence of microvascular inflammation on biopsy (Ref). IV: 375 mg/m2 once weekly for 1 to 4 doses (Ref). Some experts administer a single dose of 200 to 375 mg/m2 (Ref).Lung transplantation (off-label use): IV: 375 mg/m2 once; may administer a second dose of 375 mg/m2 after ~2 weeks if donor-specific antibodies are still present (Ref). Pancreas transplantation (off-label use): IV: 375 mg/m2 administered in 2-week intervals for a total of 1 to 4 doses (Ref).Burkitt lymphomaBurkitt lymphoma (off-label use): IV: 375 mg/m2 on days 1 and 11 of cycles 1 and 3 and days 2 and 8 of cycles 2 and 4 (Ref) or 375 mg/m2 at the start of each chemotherapy cycle, followed by 2 additional doses 3 and 6 weeks after the completion of chemotherapy (Ref) or 50 mg/m2 on day 8 and 375 mg/m2 on days 10 and 12 of cycle 2 followed by 375 mg/m2 on day 8 of cycles 3 to 7 (Ref).Chronic lymphocytic leukemiaChronic lymphocytic leukemia Rituxan and rituximab biosimilars: IV: 375 mg/m2 on the day prior to fludarabine/cyclophosphamide in cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with fludarabine and cyclophosphamide).Off-label chronic lymphocytic leukemia (CLL) combinations:Previously untreated chronic lymphocytic leukemia: IV: 375 mg/m2 on the day prior to bendamustine in cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with bendamustine) (Ref) or 375 mg/m2 on days 1 and 4 of cycle 1 (or 50 mg/m2 on day 1, followed by 325 mg/m2 on day 3, followed by 375 mg/m2 on day 5 of cycle 1), then 375 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with fludarabine; refer to protocol for rituximab dosing and infusion parameters) (Ref) or 50 mg/m2 on day 1 of cycle 2, followed by 325 mg/m2 on day 2 of cycle 2, followed by 500 mg/m2 on day 1 of cycles 3 to 7 (in combination with ibrutinib in patients <70 years of age with IGHV-unmutated CLL without 17p deletion) (Ref).Relapsed or refractory chronic lymphocytic leukemia: IV: 375 mg/m2 on day 1, followed by 500 mg/m2 every 14 days for 4 doses and then 500 mg/m2 every 28 days for 3 doses (in combination with idelalisib) (Ref) or 375 mg/m2 on the day prior to bendamustine in cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with bendamustine) (Ref) or 375 mg/m2 on day 1 of cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with bendamustine and ibrutinib) (Ref) or 375 mg/m2 on day 1 of cycle 1 (following completion of dose ramp-up for venetoclax), then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with venetoclax) (Ref).Dermatomyositis/Polymyositis, refractory diseaseDermatomyositis and polymyositis, refractory disease (alternative agent) (off-label use): Note: For use in patients who do not respond sufficiently to conventional induction regimens (eg, systemic glucocorticoids plus azathioprine or methotrexate). Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols. IV: 1 g once every 2 weeks for 2 doses (Ref).Eosinophilic granulomatosis with polyangiitisEosinophilic granulomatosis with polyangiitis (Churg-Strauss) (off-label use):Note: For use in patients with severe disease (in combination with glucocorticoids) to initiate disease remission or to re-induce remission following relapse. May also be considered as alternative maintenance therapy in patients with severe disease (if remission was induced with rituximab) or in those who are unable to receive first-line therapies (Ref).IV: 375 mg/m2 once weekly for 4 doses or 1 g once every 2 weeks for 2 doses (Ref).Graft-versus-host disease, chronic, steroid-refractoryGraft-versus-host disease, chronic, steroid-refractory (off-label use): IV: 375 mg/m2 once weekly for 4 doses; a second course of 4 weekly doses may be administered 8 weeks after initial therapy for lack of or incomplete response (Ref) or 375 mg/m2 once weekly for 4 to 8 doses (Ref).Granulomatosis with polyangiitis or microscopic polyangiitisGranulomatosis with polyangiitis or microscopic polyangiitis (Rituxan and rituximab biosimilars): Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on disease severity, organ system(s) involved, and institutional protocols.Induction therapy: Note: For use in patients with active, severe disease; may also be used to re-induce remission in patients with severe disease relapse or in patients with refractory disease. In patients with nonsevere disease, rituximab may be used as alternative induction therapy (Ref).IV: 375 mg/m2 once weekly for 4 doses (manufacturer’s labeling) or 1 g once every 2 weeks for 2 doses (Ref); for either dosing regimen, administer in combination with a systemic glucocorticoid. Maintenance therapy (after achieving disease control with induction): Note: For use in patients with severe disease, or as alternative to first-line agents in patients with nonsevere disease if remission was induced with rituximab or cyclophosphamide (Ref). If induction for active disease was with rituximab, begin rituximab maintenance therapy within 4 to 6 months of the last rituximab induction dose. If induction therapy was cyclophosphamide-based, begin rituximab maintenance therapy within 1 month following WBC recovery. Duration varies according to risk of relapse and may range from 6 months to indefinite use (Ref). IV: 500 mg once every 2 weeks for 2 doses, then 500 mg or 1 g once every 4 to 6 months (Ref). Alternatively, some experts prefer to omit 500 mg once every 2 weeks for 2 doses and proceed with 500 mg or 1 g once every 4 to 6 months; other experts only re-dose intermittently with 500 mg or 1 g when peripheral CD19+ lymphocyte count reconstitutes and ANCA titers become positive (Ref).Hodgkin lymphoma, nodular lymphocyte-predominate, advancedHodgkin lymphoma, nodular lymphocyte-predominate, advanced (off-label use): IV: 375 mg/m2 once weekly for 4 weeks (Ref) or 375 mg/m2 once weekly for 4 weeks followed by maintenance dosing of 375 mg/m2 once weekly for 4 weeks every 6 months for 2 years (Ref). May be administered as a single agent or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or for relapsed disease, in combination with ifosfamide, carboplatin and etoposide (RICE) (Ref).IgG4-related diseaseIgG4-related disease (adjunctive agent) (off-label use): Note: IgG4-related disease commonly presents as type 1 (IgG4-related) autoimmune pancreatitis; IgG4-related sclerosing cholangitis; major salivary gland enlargement or sclerosing sialadenitis; orbital disease, often with proptosis; and retroperitoneal fibrosis, frequently with chronic periaortitis. Consider for use in patients who have incomplete response to induction or are unable to sufficiently reduce glucocorticoid therapy (Ref).IV: 1 g once every 15 days for 2 doses (Ref).Immune thrombocytopeniaImmune thrombocytopenia (alternative agent) (off-label use):Note: May be used as a single agent for patients who do not have an adequate platelet count response to glucocorticoids. Use in combination with other therapies has also been reported. Optimal dose, frequency, and duration have not been established and vary based on institutional protocols.IV: 375 mg/m2 once weekly for 4 doses (Ref).Lupus nephritis, diffuse or focal, resistantLupus nephritis, diffuse or focal, resistant (off-label use):Note: Consider for use in patients who are resistant to initial therapy (eg, glucocorticoids in combination with mycophenolate or cyclophosphamide). May use rituximab in combination with mycophenolate, a calcineurin inhibitor, or cyclophosphamide. Optimal dose, frequency, and duration of therapy are unknown and vary based on institutional protocols (Ref).IV: 1 g on days 0 and 15 (Ref) or 375 mg/m2 once weekly for 4 doses (Ref).Membranous nephropathy, primaryMembranous nephropathy, primary (off-label use): Note: May be used in patients with normal kidney function who are at high or very high risk for progression and select moderate-risk patients (Ref). Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols. IV: 1 g once every 2 weeks for 2 doses (Ref); alternative dosing regimens include 375 mg/m2 once weekly for 4 doses (Ref) or 375 mg/m2 once followed by a second dose of 375 mg/m2 if ≥5 circulating B cells per mcL are detected by flow cytometry 1 week after the initial dose (Ref).Minimal change disease, frequently relapsing diseaseMinimal change disease, frequently relapsing disease (alternative agent) (off-label use):Note: For use in patients with frequently relapsing disease despite glucocorticoid therapy or who are glucocorticoid dependent. Initiate after remission is induced by glucocorticoids (Ref). Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols.IV: 1 g once every 2 weeks for 2 doses; alternative regimens include 375 mg/m2 once weekly for 4 doses or 375 mg/m2 once followed by a second dose of 375 mg/m2 if ≥5 circulating B cells per mcL are detected by flow cytometry 1 week after the initial dose (Ref).Mixed cryoglobulinemia syndrome, moderate to severe diseaseMixed cryoglobulinemia syndrome, moderate to severe disease (off-label use): Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols. IV: 1 g once every 2 weeks for 2 doses (Ref) or 375 mg/m2 once weekly for 4 doses (Ref); usually administer in combination with a systemic glucocorticoid and, if due to HIV or hepatitis B virus infections, with antiviral therapy (Ref).Mucosa-associated lymphoid tissue lymphoma, advancedMucosa-associated lymphoid tissue lymphoma (gastric), advanced (off-label use): IV: 375 mg/m2 once weekly for 4 doses (Ref).Multiple sclerosisMultiple sclerosis (off-label use): Note: Optimal dose, frequency, and duration of therapy have not been established. Dosing regimens vary based on institutional protocols.IV: 1 g once every 2 weeks for 2 doses; then repeat 1 g once every 6 to 12 months (Ref). Alternatively, may administer 500 mg to 1 g once every 6 to 12 months (Ref).Myasthenia gravis, refractory or muscle-specific tyrosine kinase antibody-positiveMyasthenia gravis, refractory or muscle-specific tyrosine kinase antibody-positive (off-label use): Note: Recommended as an early option in patients with muscle-specific tyrosine kinase antibody-positive disease, or in refractory myasthenia gravis when response to other agents is insufficient or limited by toxicity (Ref). Optimal dose, frequency, and duration of therapy have not been established. Dosing regimens vary based on institutional protocols. IV: 1 g once every 2 weeks for 2 doses or 375 mg/m2 once weekly for 4 weeks; may repeat full or partial course at preplanned intervals (eg, 6 months) or as clinically indicated based on symptoms and lymphocyte recovery (Ref).Neuromyelitis optica, relapse preventionNeuromyelitis optica, relapse prevention (alternative therapy) (off-label use): Note: Optimal dose, frequency, and duration of therapy have not been established. Dosing regimens vary based on institutional protocols. IV: 1 g once every 2 weeks for 2 doses or 375 mg/m2 once weekly for 4 weeks; then repeat 1 g once every 6 months or earlier if CD19+ lymphocytes become detectable (Ref).Non-Hodgkin lymphomasNon-Hodgkin lymphomasDiffuse large B-cell, previously untreated (Rituxan and rituximab biosimilars): IV: 375 mg/m2 on day 1 of each chemotherapy cycle for up to 8 doses (in combination with CHOP chemotherapy [or other anthracycline-based regimen]). For patients ≤60 years of age with limited stage aggressive B-cell lymphoma and a favorable prognosis, a randomized trial demonstrated noninferiority with 4 cycles of rituximab-CHOP chemotherapy when compared to 6 cycles (Ref).Diffuse large B-cell, relapsed or refractory (off-label combination): IV: 375 mg/m2 on day 1 of each 21-day chemotherapy cycle for up to 6 cycles (in combination with bendamustine and polatuzumab) (Ref).Follicular, CD20-positive, B-cell, previously untreated (Rituxan and rituximab biosimilars): IV: 375 mg/m2 on day 1 of each chemotherapy cycle for up to 8 doses (in combination with first-line chemotherapy).Maintenance therapy (as a single agent, in patients with partial or complete response to rituximab plus chemotherapy): Note: Begin 8 weeks after completion of rituximab in combination with chemotherapy. IV: 375 mg/m2 once every 8 weeks for 12 doses (Ref).Nonprogressing, low-grade, CD20-positive, B-cell, after 6 to 8 cycles of first-line CVP are completed (Rituxan and rituximab biosimilars): IV: 375 mg/m2 once weekly for 4 doses every 6 months for a maximum of 16 doses (as a single agent).Relapsed/Refractory, low-grade or follicular CD20-positive, B-cell (Rituxan and rituximab biosimilars): IV: 375 mg/m2 once weekly for 4 or 8 doses (as a single agent). Re-treatment following disease progression: 375 mg/m2 once weekly for 4 doses.Follicular lymphoma, relapsed (single-agent therapy; off-label dosing): IV: 375 mg/m2 once weekly for 4 doses followed by 375 mg/m2 once every 2 months for 4 additional doses (Ref).Follicular lymphoma, relapsed/refractory, maintenance therapy (as a single agent, in patients with response to induction therapy; off-label dosing): IV: 375 mg/m2 every 3 months until relapse or for maximum duration of 2 years (Ref).Follicular lymphoma, relapsed/refractory (off-label combination): IV: 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 (28-day cycle), followed by 375 mg/m2 on day 1 every 28 days of cycles 2 to 5 (in combination with lenalidomide) (Ref).Rituxan and rituximab biosimilars: Combination therapy with ibritumomab: IV: 250 mg/m2 IV day 1; repeat in 7 to 9 days with ibritumomab (also see Ibritumomab monograph).Splenic marginal zone lymphoma (off-label use): IV: 375 mg/m2 once weekly for 6 weeks followed by 375 mg/m2 once every 2 months for 1 to 2 years (Ref) or 375 mg/m2 once weekly for 4 weeks as monotherapy or 375 mg/m2 on day 1 of each chemotherapy cycle for up to 6 cycles; 1 to 2 additional cycles of rituximab monotherapy may be administered for consolidation or to improve response (Ref).Pemphigus vulgaris or pemphigus foliaceusPemphigus vulgaris (labeled use [Rituxan only] for moderate to severe; off-label use for mild) or pemphigus foliaceus (off-label use for mild, moderate, or severe): Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols.Initial dose: IV: 1 g once every 2 weeks for 2 doses in combination with a systemic glucocorticoid, followed by a maintenance dose (Ref). For patients with complete remission who initially presented with severe disease or who have persistently elevated anti-desmoglein (Dsg) antibodies after 3 months, consider another dose of 500 mg to 1 g administered 6 months after initial therapy (Ref).Maintenance dose (if complete remission is achieved with initial therapy): IV: 500 mg once 12 months after initial therapy, then every 6 months thereafter or based on clinical evaluation, but no sooner than every 16 weeks (Ref).Treatment of relapse: Note: Consider in patients whose last rituximab dose was ≥4 to 6 months ago or in patients who did not previously receive rituximab as initial therapy; administer in combination with a systemic glucocorticoid (Ref).IV: 1 g once every 2 weeks for 2 doses (Ref) or 1 g administered one time only (manufacturer's labeling).Posttransplant lymphoproliferative disorderPosttransplant lymphoproliferative disorder (off-label use): Note: Used in monomorphic and polymorphic CD20+ disease in conjunction with reduction of immunosuppression. May be used as a single agent or in combination with chemotherapy and/or radiation (Ref). Optimal dose, frequency, and duration of therapy have not been established and vary based on type of lymphoproliferative disease and institutional protocols.IV: 375 mg/m2 once weekly for 4 doses alone (Ref) or 375 mg/m2 once weekly for 4 doses followed 4 weeks later with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy (Ref).Primary CNS lymphomaPrimary CNS lymphoma (off-label use):Newly diagnosed: IV: 375 mg/m2 on day 3 every 14 days (in combination with high-dose methotrexate) until disease progression or unacceptable toxicity, or for 2 doses beyond a complete response followed by monthly treatments for up to a total of 1 year (Ref) or 500 mg/m2 on day 1 of each cycle for 5 to 7 induction cycles (in combination with high-dose methotrexate, vincristine, and procarbazine, followed by whole-brain radiotherapy and cytarabine consolidation) (Ref) or 375 mg/m2 once per week beginning on day 3 of remission induction and continuing for 6 doses (in combination with high-dose methotrexate, leucovorin, and temozolomide and followed by etoposide and cytarabine consolidation therapy) (Ref).Refractory disease: IV: 375 mg/m2 on day 1 every 28 days (in combination with temozolomide) for 4 cycles, followed by temozolomide monotherapy (Ref).Rheumatoid arthritisRheumatoid arthritis (Rituxan and rituximab biosimilars) (alternative agent): Note: For use in patients who have not met treatment goals despite maximally tolerated methotrexate therapy, and either an inadequate response to TNF inhibitor therapy or a history of lymphoproliferative disorder for which rituximab is an approved therapy. May be administered in combination with methotrexate, another conventional synthetic disease-modifying antirheumatic drug, or as monotherapy if other treatment options are not tolerated (Ref). Patients should be under the care of a clinician experienced with use of rituximab for this condition. IV: Initial: 1 g once every 2 weeks for 2 doses; subsequent courses of 1 g once every 2 weeks for 2 doses may be administered every 24 weeks or as indicated based on clinical evaluation, but no sooner than every 16 weeks. Note: In patients who initially respond, may consider a lower dose of 1 g once per subsequent course or 500 mg given twice (2 weeks apart) per course (Ref).Thrombotic thrombocytopenic purpura, acquiredThrombotic thrombocytopenic purpura, acquired (off-label use): Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols.Acute treatment for initial therapy or for refractory or relapsing disease: IV: 375 mg/m2 once weekly for 4 doses, typically in combination with a systemic glucocorticoid and plasma exchange; administer immediately following plasma exchange and allow ≥24 hours after rituximab before the next plasma exchange (Ref).Prophylactic therapy during remission (following treatment and recovery from an acute episode) with persistently low ADAMTS13 activity (eg, <20%) but normal platelet count: Note: The decision to treat prophylactically should be based on shared decision making to consider patient preferences regarding remission versus potential rituximab toxicity.IV: 375 mg/m2 once weekly for 1 to 4 doses depending on follow-up measurements of ADAMTS13 activity (Ref). Some experts may administer a single dose of 375 mg/m2 approximately once every 3 months to maintain remission in patients with multiple relapses and severe ADAMTS13 deficiency (Ref).Waldenström macroglobulinemiaWaldenström macroglobulinemia (off-label use):In combination with cyclophosphamide and dexamethasone: IV: 375 mg/m2 on day 1 every 21 days for 6 cycles (Ref).In combination with cyclophosphamide and fludarabine: IV: 375 mg/m2 on day 1 every 28 days for up to 6 cycles (Ref).In combination with bortezomib: IV: 375 mg/m2 on days 1, 8, 15, and 22 every 28 days during cycles 1 and 4; treatment is continued for 6 cycles, with a total of 8 rituximab doses (Ref).In combination with bortezomib and dexamethasone: IV: 375 mg/m2 on days 1, 8, 15, and 22 every 35 days during cycles 2 and 5; treatment is administered for 6 cycles, with a total of 8 rituximab doses (Ref) or 375 mg/m2 on day 11 every 21 days for 4 cycles (induction); after a 12-week break, 4 additional maintenance cycles (spaced 12 weeks apart) were administered (Ref).In combination with bendamustine: IV: 375 mg/m2 on day 1 every 28 days for 4 cycles; single rituximab doses were also administered 1 week prior to the first cycle and 4 weeks after the last cycle (for a total of 6 rituximab doses) (Ref) or 375 mg/m2 on day 1 every 28 days for up to 6 cycles (Ref).In combination with carfilzomib and dexamethasone: IV: 375 mg/m2 on days 2 and 9 every 21 days for 6 induction cycles, followed by 375 mg/m2 on day 2 every 8 weeks for 8 maintenance cycles (Ref).In combination with ibrutinib: IV: 375 mg/m2 once weekly during weeks 1 to 4 and weeks 17 to 20 (Ref).Warm autoimmune hemolytic anemiaWarm autoimmune hemolytic anemia (off-label use): Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols. IV: 375 mg/m2 once weekly for 4 doses in combination with a systemic glucocorticoid (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Kidney impairment prior to treatment initiation:Note: Theoretically, rituximab’s large molecular weight (145,000 Daltons) precludes the drug from being efficiently filtered at the glomerulus or by dialysis filters; hence, in general, dose adjustments for kidney dysfunction and/or renal replacement therapies should be unnecessary (Ref). In patients with nephrotic syndrome, urinary rituximab losses and altered pharmaco*kinetics have been observed, but the dosing implications of these findings are uncertain (Ref).Altered kidney function: IV: No dosage adjustment necessary for any degree of kidney dysfunction (Ref).Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).IV: No dosage adjustment necessary (Ref).Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (Ref):IV: No dosage adjustment or supplemental dose necessary (Ref).Peritoneal dialysis: In general, unlikely to be significantly dialyzed (expert opinion); however, significant amounts reported to be dialyzed in a patient with nephrotic syndrome (Ref):IV: No dosage adjustment necessary (Ref).CRRT:IV: No dosage adjustment necessary (Ref).PIRRT (eg, sustained, low-efficiency diafiltration):IV: No dosage adjustment necessary (Ref).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Intravenous [preservative free]: Riabni: rituximab-arrx 100 mg/10 mL (10 mL); rituximab-arrx 500 mg/50 mL (50 mL) [contains polysorbate 80]Rituxan: 100 mg/10 mL (10 mL [DSC]); 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]Ruxience: rituximab-pvvr 100 mg/10 mL (10 mL); rituximab-pvvr 500 mg/50 mL (50 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]Truxima: rituximab-abbs 100 mg/10 mL (10 mL); rituximab-abbs 500 mg/50 mL (50 mL) [contains polysorbate 80]Generic Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Concentrate, Intravenous: Riabni: 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]Rituxan: 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]Riximyo: 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]Ruxience: 10 mg/mL (10 mL, 50 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]Solution, Intravenous: Truxima: 100 mg/10 mL (10 mL); 500 mg/50 mL (50 mL) [contains polysorbate 80]Medication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Riabni: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761140s001lbl.pdf#page=41Rituxan: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103705s5465lbl.pdf#page=56Ruxience: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761103s005lbl.pdf#page=42Truxima: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761088s018lbl.pdf#page=49Administration: PediatricIV infusion: Must be diluted prior to administration; do not administer undiluted or as an IV push or rapid injection. Premedicate with acetaminophen, an antihistamine, with/without corticosteroid as indicated. For oncology uses in pediatric patients, in addition to prednisone which is part of the chemotherapeutic regimen, premedicate 30 to 60 minutes prior to the rituximab infusion with acetaminophen and an H1 antihistamine (eg, diphenhydramine). For granulomatosis with polyangiitis, microscopic polyangiitis, and Wegener granulomatosis, in addition to an antihistamine and acetaminophen, patients should also be premedicated 30 minutes prior to each infusion with methylprednisolone (eg, 100 mg IV in adults or equivalent).In pediatric trials, described infusion rates vary and are indication specific. One retrospective report (Ref) evaluated rituximab infusion in 67 pediatric patients for multiple uses (mostly autoimmune disease [58%] and oncology uses [36%]) and used a 2 mg/mL concentration. In the trial, patients were premedicated with intravenous diphenhydramine (1 mg/kg up to 50 mg/dose) and oral acetaminophen (10 mg/kg up to 650 mg/dose); corticosteroid premedication was at prescriber discretion. Overall, infusions were well tolerated; 5 (2.7% incidence) infusion related reactions were reported and were grade 1 or 2 severity). Infusions were administered with the following:First dose: Initial rate: 0.5 mg/kg/hour (maximum rate: 50 mg/hour) for 1 hour; if tolerated, then rate increase in 0.5 mg/kg/hour increments every 30 minutes up to a maximum 400 mg/hour (Ref). If hypersensitivity or infusion-related reactions occur, slow or interrupt the infusion. If symptoms completely resolve, resume infusion at 50% of the previous rate.Subsequent doses (if first dose well tolerated): Initial rate: 1 mg/kg/hour (maximum rate: 50 mg/hour [per the manufacturer]; 100 mg/hour has been reported (Ref)) for 1 hour; if tolerated, then increase rate in 1 mg/kg/hour increments every 30 minutes up to a maximum 400 mg/hour (Ref). If hypersensitivity or infusion-related reactions occur, slow or interrupt the infusion. If symptoms completely resolve, resume infusion at 50% of the previous rate.Refer to specific protocols for administration rate guidelines.Indication-specific information: Limited data available: Infusion data reported from experience in pediatric trials. If hypersensitivity or infusion-related reactions occur, slow or interrupt the infusion. If symptoms completely resolve, resume infusion at 50% of the previous rate (manufacturer's labeling).Acute leukemia: 0.5 mg/kg/hour for the first hour; if tolerated, rate was increased every 30 minutes to maximum rate of 400 mg/hour in trials (Ref); in some oncology trials, doses were infused over 6 to 8 hours (Ref).Autoimmune hemolytic anemia: Doses were infused over 5 hours (Ref).Granulomatosis with polyangiitis and microscopic polyangiitis: Note: Although an FDA-approved indication, administration to pediatric patients is not described in the manufacturer's labeling.Initial infusions: In the clinical trial (n=25, age range: 6 to 17 years), infusions were initiated at a rate of 25 mg/hour. If no hypersensitivity or infusion-related reactions occurred, infusion rates were increased in 25 mg/hour increments every 30 minutes to a maximum infusion rate of 200 mg/hour as tolerated (Ref). Note: In the clinical trial utilizing these rates of administration, the youngest patient enrolled was 6 years of age.Nephrotic syndrome: Doses were infused over 3 to 4 hours (Ref).Non-Hodgkin lymphoma: 0.5 mg/kg/hour for the first hour; if tolerated, rate was increased every 30 minutes to maximum rate of 400 mg/hour in trials (Ref).Posttransplant lymphoproliferative disorder: Doses were infused over 2 to 8 hours (Ref).Systemic lupus erythematosus: Doses of 187.5 mg/m2 were infused over 4 hours (Ref); doses of 375 mg/m2 were infused over 6 to 8 hours (Ref); the infusion time of the higher 750 mg/m2 doses was not reported.Rapid rate infusions: Children and Adolescents: Multiple regimens have been reported and most experience reported with nononcologic uses of rituximab (Ref). Note: Rapid infusion rates should not be used for initial infusions, in unstable patients, patients at risk for tumor lysis syndrome or with an absolute lymphocyte count >5,000/mm3 (Ref).90-minute infusion: IV: Infuse 20% of the dose over the first 30 minutes; if tolerated, increase rate to deliver the remaining 80% of the dose over 60 minutes (Ref). Infusion protocol reported in 17 pediatric and young adult patients (age range: 2 to 23 years of age) for 37 infusions (majority of doses were 375 mg/m2); patients were premedicated with diphenhydramine and acetaminophen (doses not reported); concentration of infusion not reported. The results showed one grade 1 infusion related reaction (hypotension) in a single patient who also took amlodipine on the morning prior to infusion (which was not recommended) (Ref).60-minute infusion: Reported only in nononcologic uses and for doses of 375 mg/m2: IV: Infuse dose over 60 minutes (Ref). Infusion protocol reported in 20 pediatric patients (mean age: 10.2 years; range: 4 months to 14 years) for 64 pediatric infusions with mostly autoimmune cytopenias, Epstein-Barr viremia, and graft-vs-host disease; patients were premedicated with diphenhydramine and acetaminophen (doses not reported); corticosteroids were administered according to clinician discretion and protocols (4 of the 20 patients did not receive corticosteroids nor have infusion-related reactions); 2 adverse events were observed; 1 resolved and the other lead to therapy discontinuation; concentration of infusion not reported (Ref).Administration: AdultNote: Refer to specific protocol for administration rate guidelines.IV: For IV administration only. Do not administer IV push or bolus. Do not administer IV rituximab subcutaneously. If an infusion-related reaction occurs, slow or stop the infusion. If the reaction abates, restart infusion at 50% of the previous rate. Discontinue infusion in the event of serious or life-threatening cardiac arrhythmias.Initial infusion: Start infusion at a rate of 50 mg/hour; if there is no infusion-related reaction, increase the rate by 50 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.Subsequent infusions:Standard infusion rate: If patient tolerated initial infusion, start at 100 mg/hour; if there is no infusion-related reaction, increase the rate by 100 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.Accelerated infusion rate (90 minutes): For adult patients with previously untreated follicular NHL and diffuse large B-cell NHL who are receiving a corticosteroid as part of their combination chemotherapy regimen, have a circulating lymphocyte count <5,000/mm3, or have no significant cardiovascular disease. After tolerance has been established (no grade 3 or 4 infusion-related event) at the recommended infusion rate in cycle 1, a rapid infusion rate may be used beginning with cycle 2. The daily corticosteroid, acetaminophen, and diphenhydramine are administered prior to treatment, then the rituximab dose is administered over 90 minutes, with 20% of the dose administered over the first 30 minutes and the remaining 80% is given over 60 minutes (Ref). If the 90-minute infusion in cycle 2 is tolerated, the same rate may be used for the remainder of the treatment regimen (through cycles 6 or 8).Storage/StabilityStorage time varies by product; refer to individual product labeling for details.Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Do not shake. Protect vials from direct sunlight.Rituxan, Truxima: Solutions diluted for infusion in NS or D5W may be stored at 2°C to 8°C (36°F to 46°F) for 24 hours and are stable at room temperature for an additional 24 hours (Rituxan or Truxima), although because there is no preservative, the manufacturers recommend storing refrigerated.Riabni: If not used immediately, solutions diluted for infusion in NS may be stored at 2°C to 8°C (36°F to 46°F) for 7 days and solutions diluted for infusion in D5W may be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours.Ruxience: Solutions diluted for infusion in NS or D5W may be stored at 2°C to 8°C (36°F to 46°F) for 24 hours; infusion should be completed within 8 hours from removal from the refrigerator.UseNononcologic uses: Treatment of granulomatosis with polyangiitis (Wegener granulomatosis) and microscopic polyangiitis in combination with glucocorticoids (Rituxan: FDA approved in ages ≥2 years and adults; Ruxience: FDA approved in adults); treatment of moderately- to severely-active rheumatoid arthritis (in combination with methotrexate) in patients with inadequate response to one or more tumor necrosis factor antagonists (Rituxan: FDA approved in adults); treatment of moderate to severe pemphigus vulgaris (Rituxan: FDA approved in adults).Oncologic uses: Treatment of previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), or mature B-cell acute leukemia (B-AL) in combination with chemotherapy (FDA approved in pediatric patients ≥6 months of age). Treatment of CD20-positive, B-cell non-Hodgkin's lymphoma (NHL) (including relapsed or refractory, low-grade or follicular B-cell NHL [as a single agent]; follicular B-cell NHL, previously untreated [in combination with first-line chemotherapy, and as single-agent maintenance therapy if response to first-line rituximab with chemotherapy]; nonprogressing, low-grade B-cell NHL [as a single agent after first-line CVP treatment]; diffuse large B-cell NHL, previously untreated [in combination with CHOP chemotherapy or other anthracycline-based regimen]) and treatment of CD20-positive chronic lymphocytic leukemia (in combination with cyclophosphamide and fludarabine) (Rituxan, Ruxience, Truxima: FDA approved in adults).Has also been used for the treatment of systemic autoimmune disorders (eg, autoimmune hemolytic anemia); refractory systemic lupus erythematosus; steroid-refractory chronic graft-versus-host disease; refractory nephrotic syndrome; chronic immune thrombocytopenia; posttransplant lymphoproliferative disorder.Note: Ruxience (rituximab-pvvr) and Truxima (rituximab-abbs), are approved as biosimilar agents; market availability unknown (see Product Availability). Approved ages and uses may vary (consult product labeling).Medication Safety IssuesSound-alike/look-alike issues:Rituxan may be confused with Remicade, Rituxan HycelaRiTUXimab may be confused with bevacizumab, brentuximab vedotin, dinutuximab, inFLIXimab, obinutuzumab, ofatumumab, polatuzumab vedotin, ramucirumab, rituximab and hyaluronidase, ruxolitinib, siltuximab, ustekinumabHigh alert medication:This medication is in a class the Institute for Safe Medication Practices includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.Administration issues:Rituximab is for intravenous (IV) administration only. Do not substitute rituximab and hyaluronidase (SubQ) for rituximab (IV). Use caution during product selection, preparation, and administration.The rituximab dose for rheumatoid arthritis is a flat dose (1,000 mg) and is not based on body surface area (BSA). Follow-up dosing for granulomatosis with polyangiitis and microscopic polyangiitis are flat doses and not based on BSA.Adverse Reactions (Significant): ConsiderationsHepatitis B virus reactivationExacerbation of hepatitis B virus (HBV) may occur in patients treated with rituximab, in some cases resulting in fulminant hepatitis, hepatic failure, and death (Ref). Reactivation has occurred in patients who are hepatitis B surface antigen (HBsAg) positive (typical reactivation) as well as in those who are HBsAg negative but are anti-HBc positive (reverse seroconversion) (Ref).Mechanism: In the immune system control of HBV infection, B-cells may act as antigen-presenting cells and prime cytotoxic T-cells for lysis of HBV-infected hepatocytes (Ref). Rituximab causes B-cell depletion (Ref), which therefore may impair control of HBV infection.Onset: Varied; typical reactivation: 3 to 6 months. Reverse seroconversion: 12 to 36 months (Ref).Risk factors:• Chronic HBV (HBsAg positive) or past HBV (HBsAg negative and anti-HBc positive with either negative or positive anti-HBs) infection (Ref)• Hematologic malignancy (Ref)• History of stem cell transplantation (Ref)• Presence of other risk factor for HBV infection (eg, high-prevalence region, household contact, high-risk behavior) (Ref)Hypogammaglobulinemia and InfectionSerious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab-based therapy (Ref). Infections have been reported in some patients with prolonged hypogammaglobulinemia. New or reactivated viral infections have included CMV viremia, herpes simplex infection, parvovirus B19 seroconversion, varicella zoster infection, West Nile virus, and hepatitis C and B.Mechanism: Dose-related; immunosuppression due to B-cell depletion, hypogammaglobulinemia, and neutropenia (Ref).Onset: Delayed; infection may occur at any time; risk may be higher in the 3 to 6 months after initiation (Ref).Risk factors:Hypogammaglobulinemia:• More than 1 dose of rituximab (Ref)• Maintenance regimens (Ref)• Older age (Ref)• Low pre-treatment immunoglobulin levels (Ref)• Exposure to mycophenolate or purine analogues (Ref)Infection:• Malignant versus non-malignant indications (Ref)• Higher number of rituximab courses (Ref)• Prolonged low levels of IgG (Ref)• G-CSF use (Ref)• Glucocorticoid use (Ref)• Chronic lung disease and/or cardiac insufficiency (Ref)• Older patients (Ref)• Extra-articular involvement in patients with rheumatic arthritis (Ref)Infusion-related reactionsSerious (including fatal) infusion-related reactions have been reported with rituximab. Reactions may include angioedema, bronchospasm, cough, hypotension, hypoxia, throat irritation, urticaria, and in more severe cases, acute respiratory distress syndrome, pulmonary infiltrates, acute myocardial infarction, ventricular fibrillation, and cardiogenic shock (Ref).Mechanism: Dose-related; may produce human antichimeric antibodies and human antihuman antibodies (Ref).Onset: Rapid; usually occur within 30 to 120 minutes after starting the infusion.Risk factors:• First infusion (~80% of fatal infusion reactions occurred in association with the first infusion)• Rapid infusion (Ref)• High tumor burden with treatment-sensitive malignant disease (Ref)• History of prior cardiopulmonary reactions• Preexisting cardiac or pulmonary conditionsProgressive multifocal leukoencephalopathy (PML)Progressive multifocal leukoencephalopathy (PML) due to John Cunningham (JC) virus infection has been reported with rituximab and may be fatal. Cases were reported in patients with hematologic malignancies receiving rituximab either with combination chemotherapy or with hematopoietic stem cell transplant. Cases were also reported in patients receiving rituximab for autoimmune diseases who had received concurrent or prior immunosuppressant therapy (Ref). Clinical findings included confusion/disorientation, motor weakness/hemiparesis, altered vision/speech, and poor motor coordination with symptoms progressing over weeks to months (Ref).Mechanism: Non–dose-related; reactivation of the JC virus (Ref).Onset: Delayed; most cases were diagnosed within 12 months of the last rituximab dose. A retrospective analysis of patients (n=57) diagnosed with PML following rituximab therapy found a median of 16 months (following rituximab initiation), 5.5 months (following last rituximab dose), and six rituximab doses preceded PML diagnosis (Ref). In a series of rheumatologic cases, a median of 12 months (range 1 to 57 months following rituximab initiation), and 5 months (range 0 to 29 months following last rituximab dose), and two rituximab courses preceded PML diagnosis (Ref).Risk factors:• Systemic lupus erythematosus (SLE) (Ref)• Undiagnosed HIV (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Patients treated with rituximab for rheumatoid arthritis (RA) may experience fewer adverse reactions. Most reported adverse reactions are from studies in which rituximab was given concomitantly with chemotherapeutic agents, glucocorticoid steroids, or methotrexate. Reported adverse reactions are for adults.>10%:Cardiovascular: Cardiac disorder (5% to 29%), flushing (5% to 14%), hypertension (6% to 12%) (table 1)Hypertension, peripheral edema (8% to 16%)Rituximab: Adverse Reaction: HypertensionDrug (Rituximab)ComparatorDoseIndicationNumber of Patients (Rituximab)Number of Patients (Comparator)Comments12%Cyclophosphamide plus glucocorticoids: 5%375 mg/m² once weekly for 4 weeksGranulomatosis with polyangiitis and microscopic polyangiitis; induction therapy9998Rituximab plus glucocorticoids6%N/AMost patients received 375 mg/m² weekly for 4 dosesRelapsed or refractory, low-grade or follicular, CD20-positive, B-cell, non-Hodgkin lymphoma356N/AN/A8%Placebo plus methotrexate: 5%2 x 1,000 mgRheumatoid arthritis540398Rituximab plus methotrexateDermatologic: Night sweats (15%), pruritus (≤17%) (table 2)Pruritus, skin rash (≤17%) (table 3)Skin RashRituximab: Adverse Reaction: PruritusDrug (Rituximab)Comparator DoseIndicationNumber of Patients (Rituximab)Number of Patients (Comparator)Comments17%No further therapy: 5%375 mg/m² once weekly for 4 doses every 6 months for up to 16 dosesPreviously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma, maintenance therapyN/AN/AIn patients who did not progress after 6 to 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP); described as "rash and/or pruritus"10%Cyclophosphamide, vincristine, prednisone (CVP): 1%N/APreviously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphomaN/AN/ARituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP)14%N/AMost patients received 375 mg/m2 weekly for 4 dosesRelapsed or refractory, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma356N/AN/A5%Placebo plus methotrexate: 1%2 x 1,000 mgRheumatoid arthritis540398Rituximab plus methotrexateRituximab: Adverse Reaction: Skin RashDrug (Rituximab)ComparatorDoseIndicationNumber of Patients (Rituximab)Number of Patients (Comparator)Comments10%Cyclophosphamide plus glucocorticoids: 17%375 mg/m² once weekly for 4 weeksGranulomatosis with polyangiitis and microscopic polyangiitis; induction therapy9998Rituximab plus glucocorticoids17%Cyclophosphamide, vincristine, and prednisone (CVP): 5%N/APreviously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphomaN/AN/ARituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP)17%No further therapy: 5%375 mg/m² once weekly for 4 doses every 6 months for up to 16 dosesPreviously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphomaN/AN/AIn patients who did not progress after 6 to 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP); described as "rash and/or pruritus"15%N/AMost patients received 375 mg/m² weekly for 4 dosesRelapsed or refractory, low-grade or follicular, CD-20 positive, B-cell non-Hodgkin lymphoma356N/AN/AEndocrine & metabolic: Hypophosphatemia (12% to 21%), weight gain (11%)Gastrointestinal: Abdominal pain (14%), diarrhea (10% to 17% grades 3/4: 1%), nausea (8% to 23%; grades 3/4: 1%)Hematologic & oncologic: Anemia (8% to 35%; grades 3/4: 3%), febrile neutropenia (grades 3/4: 9% to 15%), hypogammaglobulinemia (<1% to 58%; including IgA, IgG, or IgM below the lower limit of normal, can be prolonged) (table 4)Hypogammaglobulinemia, leukopenia (10% to 14%; grades 3/4: 4% to 23%), lymphocytopenia (48%; grades 3/4: 40%), neutropenia (8% to 14%; grades 3/4: 4% to 49%; may be prolonged neutropenia [lasting up to 42 days] or late onset [occurring >42 days after last dose]), thrombocytopenia (12%; grades 3/4: 2% to 11%)Rituximab: Adverse Reaction: HypogammaglobulinemiaDrug (Rituximab)ComparatorDoseIndicationNumber of Patients (Rituximab)Number of Patients (Comparator)Comments58%Cyclophosphamide plus glucocorticoids: 50%375 mg/m² once weekly for 4 weeksGranulomatosis with polyangiitis and microscopic polyangiitis; induction therapy9998Rituximab plus glucocorticoids; Low IgG level51%Cyclophosphamide plus glucocorticoids: 46%375 mg/m² once weekly for 4 weeksGranulomatosis with polyangiitis and microscopic polyangiitis; induction therapy9998Rituximab plus glucocorticoids; Low IgM level27%Cyclophosphamide plus glucocorticoids: 25%375 mg/m² once weekly for 4 weeksGranulomatosis with polyangiitis and microscopic polyangiitis; induction therapy9998Rituximab plus glucocorticoids; Low IgA level16%Mycophenolate mofetil (MMF) plus oral corticosteroids: N/A1,000 mg on days 1, 15, week 24, and week 26 for up to 52 weeksPemphigus vulgaris67N/ARituximab plus oral corticosteroids; prolonged hypogammaglobulinemia (defined as Ig levels below lower limit of normal for at least 4 months); IgG or IgM10%Placebo plus methotrexate: N/A2 x 1,000 mgRheumatoid arthritis540398Rituximab plus methotrexate; Low IgM level3%Placebo plus methotrexate: N/A2 x 1,000 mgRheumatoid arthritis540398Rituximab plus methotrexate; Low IgG level0.8%Placebo plus methotrexate: N/A2 x 1,000 mgRheumatoid arthritis540398Rituximab plus methotrexate; Low IgA levelHepatic: Hepatobiliary disease (17%), increased serum alanine aminotransferase (13%)Hypersensitivity: Angioedema (11%)Immunologic: Antibody development (1% to 32%)Infection: Bacterial infection (19%; including cellulitis), infection (19% to 63%%; including CMV viremia, herpes simplex infection, parvovirus B19 seroconversion, varicella zoster infection, hepatitis C, and lower respiratory tract infection) (table 5)Infection, serious infection (2% to 11%; including sepsis)Rituximab: Adverse Reaction: InfectionDrug (Rituximab)ComparatorDoseIndicationNumber of Patients (Rituximab)Number of Patients (Comparator)Comments62%Cyclophosphamide plus glucocorticoids: 47%375 mg/m² once weekly for 4 weeksGranulomatosis with polyangiitis and microscopic polyangiitis; induction therapy9998Rituximab plus glucocorticoids63%Mycophenolate mofetil (MMF) plus oral corticosteroids: N/A1,000 mg on days 1, 15, week 24, and week 26 for up to 52 weeksPemphigus vulgaris67N/ARituximab plus oral corticosteroids37%Observation: 22%375 mg/m² once weekly for 8 weeks for up to 12 dosesPreviously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma; maintenance therapyN/AN/AInitiated 8 weeks following completion of chemotherapy in patients who achieved a response with rituximab plus chemotherapy19%No further therapy: 9%375 mg/m² once weekly for 4 doses every 6 months for up to 16 dosesPreviously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma; maintenance therapyN/AN/AIn patients who did not progress after 6 to 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP)31%N/AMost patients received 375 mg/m² weekly for 4 dosesRelapsed or refractory, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma356N/AN/A39%Placebo plus methotrexate: 34%2 x 1,000 mgRheumatoid arthritis540398Rituximab plus methotrexateNervous system: Chills (3% to 33%), fatigue (13% to 39%), headache (15% to 19%), insomnia (14%), pain (12%), peripheral sensory neuropathy (30%)Neuromuscular & skeletal: Arthralgia (6% to 13%), asthenia (2% to 26%), muscle spasm (17%)Respiratory: Bronchitis, cough (13% to 15%) (table 6)Cough, epistaxis (11%), nasopharyngitis (≤16%), pulmonary disease (31%), pulmonary toxicity (18%), rhinitis (3% to 12%), upper respiratory tract infection (≤16%)Rituximab: Adverse Reaction: CoughDrug (Rituximab)ComparatorDoseIndicationNumber of Patients (Rituximab)Number of Patients (Comparator)Comments13%Cyclophosphamide plus glucocorticoids: 11%375 mg/m² once weekly for 4 weeksGranulomatosis with polyangiitis and microscopic polyangiitis; induction therapy9998Rituximab plus glucocorticoids15%Cyclophosphamide, vincristine, and prednisone (CVP): 6%N/APreviously untreated, low-grade or follicular, CD20-positive, B-cell, non-Hodgkin lymphomaN/AN/ARituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP)13%N/AMost patients received 375 mg/m² weekly for 4 dosesRelapsed or refractory, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma356N/AN/AMiscellaneous: Fever (5% to 56%), infusion related reaction (first dose: 12% to 77%; including cytokine release syndrome and nonimmune anaphylaxis; reactions can be acute; decreases with subsequent infusions) (table 7)Infusion Related ReactionRituximab: Adverse Reaction: Infusion Related ReactionDrug (Rituximab)ComparatorDoseIndicationNumber of Patients (Rituximab)Number of Patients (Comparator)Comments59%Fludarabine plus cyclophosphamide (FC): N/A375 mg/m² as an initial infusion, followed by 500 mg/m² for up to 5 dosesChronic lymphocytic leukemiaN/AN/ARituximab plus fludarabine and cyclophosphamide (R-FC)12%Cyclophosphamide plus glucocorticoids: 11%375 mg/m² once weekly for 4 weeksGranulomatosis with polyangiitis and microscopic polyangiitis; induction therapy9998Rituximab plus glucocorticoids77%N/AN/ANon-Hodgkin lymphomaN/AN/AFirst infusion22%N/A1,000 mg on days 1, 15, week 24, and week 26 for up to 52 weeksPemphigus vulgaris67N/AN/A32%Placebo plus methotrexate: 23%2 x 1,000 mgRheumatoid arthritis540398Rituximab plus methotrexate1% to 10%:Cardiovascular: Chest tightness (7%), hypotension (10%), significant cardiovascular event (2%)Dermatologic: Urticaria (2% to 8%) (table 8)UrticariaRituximab: Adverse Reaction: UrticariaDrug (Rituximab)ComparatorDoseIndicationNumber of Patients (Rituximab)Number of Patients (Comparator)Comments8%N/AMost patients received 375 mg/m² weekly for 4 dosesRelapsed or refractory, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma356N/AN/A2%Placebo plus methotrexate: <1%2 x 1,000 mgRheumatoid arthritis540398Rituximab plus methotrexateEndocrine & metabolic: Hyperglycemia (9%), hyperuricemia (2%), increased lactate dehydrogenase (7%)Gastrointestinal: Dyspepsia (3%), oral candidiasis (9%), upper abdominal pain (2%), vomiting (10%; grades 3/4: 1%)Genitourinary: Urinary tract infection (8%)Hematologic & oncologic: Pancytopenia (grades 3/4: 3%; can be prolonged)Hepatic: Exacerbation of hepatitis B (grades 3/4: 2%)Infection: Fungal infection (1%), viral infection (10%; including herpes zoster)Nervous system: Anxiety (2% to 5%), dizziness (6% to 10%), migraine (2%), paresthesia (2%), rigors (10%)Neuromuscular & skeletal: Back pain (9% to 10%), myalgia (10%)Respiratory: Bronchospasm (8%), dyspnea (7% to 10%), sinusitis (6%), throat irritation (2% to 9%) (table 9)Throat IrritationRituximab: Adverse Reaction: Throat IrritationDrug (Rituximab)ComparatorDoseIndicationNumber of Patients (Rituximab)Number of Patients (Comparator)Comments9%N/AMost patients received 375 mg/m² weekly for 4 dosesRelapsed or refractory, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma356N/AN/A2%Placebo plus methotrexate: 0%2 x 1,000 mgRheumatoid arthritis540398Rituximab plus methotrexate<1%: Hematologic & oncologic: Hemolytic anemia, pure red cell aplasiaPostmarketing:Cardiovascular: Acute myocardial infarction (Kasi 2012), cardiac tamponade (Cohen 2006), cardiogenic shock (Kasi 2012), heart failure (Kasi 2012), Kawasaki syndrome (Sato 2020), myocarditis (Ghielmini 2004), vasculitis (systemic; with rash) (Kim 2009), ventricular fibrillation (Kasi 2012), ventricular tachycardia (Kasi 2012),Dermatologic: Epidermolysis bullosa (Wu 2020), lichenoid dermatitis (Scheinfeld 2006), pemphigus (paraneoplastic) (Scheinfeld 2006), pyoderma gangrenosum (including genital presentation) (Georgakopoulos 2018, Maloney 2018), Stevens-Johnson syndrome (Scheinfeld 2006), toxic epidermal necrolysis (Scheinfeld 2006), vesiculobullous dermatitis (Scheinfeld 2006)Gastrointestinal: Crohn’s disease (Cavalcanti 2020), enterocolitis (including ileocolitis, ulcerative colitis, microscopic colitis) (Tsuzuki 2021), intestinal obstruction (Kasi 2012), intestinal perforation (mean onset: 6 days [range: 1 to 77 days in patients with non-Hodgkin lymphoma]) (Cornejo 2009, Kollmar 2002)Hematologic & oncologic: Bone marrow depression (Kasi 2012), increased serum immunoglobulins (hyperviscosity syndrome in Waldenström's macroglobulinemia), Kaposi sarcoma (including new onset and progression) (Billon 2018, Geller 2018), sarcoidosis (children: Scar sarcoidosis) (Vesely 2020), tumor lysis syndrome (Yang 1999)Hepatic: Fulminant hepatitis (Evens 2011), hepatic failure (Evens 2011)Hypersensitivity: Anaphylaxis (Liccioli 2020), serum sickness (Fouda 2020)Infection: Reactivation of HBV (Evens 2011)Nervous system: Progressive multifocal leukoencephalopathy (Carson 2009, Molloy 2012), reversible posterior leukoencephalopathy syndrome (Mustafa 2019)Neuromuscular & skeletal: Arthritis (polyarticular), lupus-like syndrome (Chessa 2021)Ophthalmic: Optic neuritis, uveitisRenal: NephrotoxicityRespiratory: Acute respiratory distress syndrome (Kasi 2012), bronchiolitis obliterans (Shen 2012), hypoxia (Kasi 2012), interstitial pulmonary disease (Wagner 2007), pleurisy, pneumonia, pulmonary infiltrates (Kasi 2012)ContraindicationsThere are no contraindications listed in the manufacturer's US labeling.Canadian labeling: Known type 1 hypersensitivity or anaphylactic reaction to murine proteins, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation; patients who have or have had progressive multifocal leukoencephalopathy (PML); patients with severe, active infectionsWarnings/PrecautionsConcerns related to adverse effects:• Bowel obstruction/perforation: Abdominal pain, bowel obstruction, and perforation have been reported (rarely fatal), with an average onset of symptoms of ~6 days (range: 1 to 77 days); evaluate abdominal pain or repeated vomiting.• Cytopenias: Rituximab is associated with lymphopenia, leukopenia, neutropenia, thrombocytopenia, and anemia; the duration of cytopenias may be prolonged and may extend months beyond treatment.• Renal toxicity: May cause fatal renal toxicity in patients with non-Hodgkin lymphomas (NHL). Patients who received combination therapy with cisplatin and rituximab for NHL experienced renal toxicity during clinical trials; this combination is not an approved treatment regimen. Renal toxicity also occurred due to tumor lysis syndrome.• Tumor lysis syndrome: Tumor lysis syndrome leading to acute renal failure requiring dialysis (sometimes fatal) may occur within 12 to 24 hours following the first dose when used as a single agent in the treatment of NHL. Hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Administer prophylaxis (antihyperuricemic therapy, aggressive hydration) in patients at high risk (high numbers of circulating malignant cells ≥25,000/mm3 or high tumor burden). Correct electrolyte abnormalities and administer supportive care as indicated.Special populations:• Older adult: There is a higher risk of cardiac (supraventricular arrhythmia) and pulmonary adverse events (pneumonia, pneumonitis), and the incidence of grade 3 or 4 adverse reactions are higher in patients ≥65 years of age.• Granulomatosis with polyangiitis/microscopic polyangiitis: The safety of concomitant immunosuppressants other than corticosteroids has not been evaluated in patients with granulomatosis with polyangiitis or microscopic polyangiitis after rituximab-induced B-cell depletion.• Pemphigus vulgaris: The safety of concomitant immunosuppressants other than corticosteroids has not been evaluated in patients with pemphigus vulgaris after rituximab-induced B-cell depletion.• Rheumatoid arthritis: There are limited data on the safety of other biologics or disease-modifying antirheumatic drugs (DMARDs) other than methotrexate in patients with rheumatoid arthritis (RA) with B-cell depletion following rituximab treatment. Monitor patients closely for infection if biologic agents or DMARDs are used concomitantly. The use of rituximab is not recommended in RA patients who have not had prior inadequate response to one or more tumor necrosis factor antagonists.Dosage form specific issues:• Administration: Rituximab is for IV administration only. Do not substitute rituximab and hyaluronidase (SUBQ) for rituximab (IV). Use caution during product selection, preparation, and administration.• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.Other warnings/precautions:• Immunizations: In the oncology setting, live vaccines should not be given before or during rituximab treatment; the safety of live vaccines following rituximab treatment has not been studied. When using for the treatment of multiple sclerosis, avoid live-attenuated vaccines in patients who currently receive or have recently discontinued rituximab; consider using live-attenuated vaccines only if risk of infection is high and killed vaccines are unavailable (AAN [Farez 2019]). Review vaccination status for all patients, and if possible, bring up to date with all immunizations (following current immunization guideline recommendations) prior to rituximab initiation and administer nonlive vaccines at least 4 weeks prior to initiating a rituximab course of therapy. Response to some immunizations may be lower in some patients receiving rituximab.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapyAbrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combinationAnifrolumab: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the immunosuppressive effect of Anifrolumab.Risk X: Avoid combinationBaricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib.Risk X: Avoid combinationBCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).Risk X: Avoid combinationBCG Products: RiTUXimab may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. RiTUXimab may diminish the therapeutic effect of BCG Products.Risk X: Avoid combinationBelimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combinationBiologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combinationBrincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir.Risk C: Monitor therapyChloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapyCladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combinationCladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine.Risk X: Avoid combinationCloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.Risk C: Monitor therapyCoccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test.Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modificationCOVID-19 Vaccines: Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of COVID-19 Vaccines.Management: Administer COVID-19 vaccine 2 to 4 weeks prior to the next scheduled dose of anti-CD20 therapy, if used chronically for the treatment of autoimmune disease. Revaccinate 6 months after completion of anti-CD20 therapy if used over a limited period. Risk D: Consider therapy modificationDeferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone.Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modificationDengue Tetravalent Vaccine (Live): RiTUXimab may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. RiTUXimab may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live).Risk X: Avoid combinationDenosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modificationDeucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combinationDipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combinationEfgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapyFexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole.Risk X: Avoid combinationFilgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combinationInebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab.Risk C: Monitor therapyInfluenza Virus Vaccines: RiTUXimab may diminish the therapeutic effect of Influenza Virus Vaccines.Management: Administer influenza vaccines 2 weeks prior to starting rituximab. Vaccination of patients treated with rituximab in the past 6 months is not recommended. If vaccinated less than 2 weeks prior to rituximab, revaccinate 6 months after rituximab treatment. Risk D: Consider therapy modificationLeflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide.Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modificationNatalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab.Risk X: Avoid combinationOcrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab.Risk C: Monitor therapyOfatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab.Risk C: Monitor therapyOlaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib.Risk C: Monitor therapyPidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod.Risk C: Monitor therapyPimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combinationPoliovirus Vaccine (Live/Trivalent/Oral): RiTUXimab may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. RiTUXimab may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral).Risk X: Avoid combinationPolymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate.Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modificationPromazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapyRabies Vaccine: RiTUXimab may diminish the therapeutic effect of Rabies Vaccine.Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modificationRopeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b.Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modificationRubella- or Varicella-Containing Live Vaccines: RiTUXimab may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. RiTUXimab may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines.Risk X: Avoid combinationRuxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical).Risk X: Avoid combinationSipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T.Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modificationSphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapyTacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical).Risk X: Avoid combinationTalimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased.Risk X: Avoid combinationTertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide.Risk X: Avoid combinationTofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib.Risk X: Avoid combinationTyphoid Vaccine: RiTUXimab may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. RiTUXimab may diminish the therapeutic effect of Typhoid Vaccine.Risk X: Avoid combinationUpadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib.Risk X: Avoid combinationVaccines (Inactivated/Non-Replicating): RiTUXimab may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating).Management: Give inactivated vaccines at least 2 weeks prior to initiation of rituximab when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 6 months after therapy is complete. Risk D: Consider therapy modificationVaccines (Live): RiTUXimab may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. RiTUXimab may diminish the therapeutic effect of Vaccines (Live).Risk X: Avoid combinationYellow Fever Vaccine: RiTUXimab may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. RiTUXimab may diminish the therapeutic effect of Yellow Fever Vaccine.Risk X: Avoid combinationReproductive ConsiderationsVerify pregnancy status prior to treatment initiation in patients who may become pregnant.The manufacturer recommends patients who may become pregnant use effective contraception during therapy and for 12 months following the last rituximab dose.Based on limited information, use of rituximab may be continued through conception in patients with rheumatic and musculoskeletal diseases who are planning a pregnancy and not able to use alternative therapies; use should be discontinued once pregnancy is confirmed. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]).Rituximab has been evaluated off-label for neuromyelitis optica spectrum disorder (NMOSD). Use of rituximab prior to pregnancy may prevent pregnancy-related attacks (Borisow 2018; Kim 2020).Based on limited information, use of rituximab may be continued in patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).Pregnancy ConsiderationsRituximab crosses the placenta and can be detected in the newborn.Rituximab is a humanized monoclonal antibody (IgG1). Placental transfer of human IgG is dependent upon the IgG subclass, maternal serum concentrations, newborn birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009). In one infant born at 41 weeks' gestation, in utero exposure occurred from week 16 to 37; rituximab concentrations were higher in the neonate at birth (32,095 ng/mL) than the mother (9,750 ng/mL) and still measurable at 18 weeks of age (700 ng/mL infant; 500 ng/mL mother) (Friedrichs 2006).Based on human data, in utero exposure to rituximab may cause fetal harm. B-cell lymphocytopenia generally lasting <6 months may occur in exposed infants; infants and newborns should be monitored for infection. Retrospective case reports of inadvertent pregnancy during rituximab treatment collected by the manufacturer (often combined with concomitant teratogenic therapies) describe premature births and infant hematologic abnormalities and infections; no specific pattern of birth defects has been observed (limited data) (Chakravarty 2011). Similar information from a British pregnancy registry and available case series have also been published (Das 2018; De co*ck 2017; Perrotta 2021).The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). Based on limited data, if pregnancy occurs during rituximab treatment, the pregnancy may continue provided rituximab treatment is withheld. In general, although the risk of B-cell depletion in the newborn is increased, if postponing rituximab treatment would significantly compromise maternal outcome in patients diagnosed with B-cell lymphoma during pregnancy, rituximab use is not discouraged during pregnancy (ESMO [Peccatori 2013]). An international consensus panel has published guidelines for hematologic malignancies during pregnancy. In patients with aggressive lymphomas, rituximab (as a component of the R-CHOP chemotherapy regimen) may be administered in the second and third trimesters, however, it should be avoided within 3 weeks of anticipated delivery (Lishner 2016).Although approved for the treatment of rheumatoid arthritis, based on available information, rituximab should be discontinued once pregnancy is detected in patients treated for rheumatic and musculoskeletal diseases; treatment during pregnancy should only be considered for pregnant patients with life- or organ-threatening disease (ACR [Sammaritano 2020]).Rituximab is used off-label for the treatment of primary immune thrombocytopenia (ITP). Although information specific to pregnancy is limited, use can be considered in pregnant patients with very severe ITP. Monitor for perinatal and neonatal immunosuppression and subsequent infection (Donohoe 2019; Provan 2019).Rituximab has been evaluated off-label for neurological indications such as multiple sclerosis (Ciplea 2020; Das 2018; Smith 2020) and neuromyelitis optica spectrum disorder (NMOSD). Maternal NMOSD may be associated with adverse pregnancy outcomes, including miscarriage and preeclampsia. Information related to the treatment of NMOSD during pregnancy is limited; however, use of rituximab prior to pregnancy may prevent pregnancy-related attacks (Borisow 2018; Chang 2020; Kim 2020; Miranda-Acuña 2019; Munger 2020; Zhu 2020).A long-term observational research study is collecting information about the diagnosis and treatment of cancer during pregnancy. For additional information about the pregnancy and cancer registry or to become a participant, contact Cooper Health (1-877-635-4499).Monitoring ParametersCBC with differential and platelets (pediatric and adult pediatric with lymphoid malignancies: baseline, prior to each treatment course, at weekly to monthly intervals and more frequently if cytopenias develop; pediatric and adult patients with granulomatosis with polyangiitis and microscopic polyangiitis: at 2- to 4-month intervals; in adult patients with rheumatoid arthritis: at 2- to 4-month intervals); continue to monitor for cytopenias after the final dose and until resolution, electrolytes (in patients at risk for tumor lysis syndrome [TLS]), renal function (in patients at risk for TLS), fluid/hydration status balance; blood pressure, vital signs.Monitor for infusion reactions; signs of active hepatitis B infection (during and for up to 12 months after therapy completion); cardiac monitoring during and after infusion (in rheumatoid arthritis patients and in patients with preexisting cardiac disease or if arrhythmias develop during or after subsequent infusions); monitor for signs/symptoms of bowel obstruction/perforation (abdominal pain, vomiting); signs or symptoms of progressive multifocal leukoencephalopathy (PML) (focal neurologic deficits, which may present as hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits); if PML is suspected, obtain brain MRI scan and lumbar puncture; signs/symptoms of TLS and/or mucocutaneous skin reactions.Screen all patients for hepatitis B virus (HBV) infection prior to therapy initiation (eg, hepatitis B surface antigen [HBsAg] and hepatitis B core antibody [anti-HBc] measurements). In addition, carriers and patients with evidence of current infection or recovery from prior hepatitis B infection should be monitored closely for clinical and laboratory signs of HBV reactivation and/or infection during therapy and for up to 2 years following completion of treatment. HBV screening recommendations from adult experience (Hwang 2015): Screen for HBV infection with HBsAg and anti-HBc tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment.Mechanism of ActionRituximab is a monoclonal antibody directed against the CD20 antigen on the surface of B-lymphocytes. CD20 regulates cell cycle initiation; and, possibly, functions as a calcium channel. Rituximab binds to the antigen on the cell surface, activating complement-dependent B-cell cytotoxicity; and to human Fc receptors, mediating cell killing through an antibody-dependent cellular toxicity. B-cells are believed to play a role in the development and progression of rheumatoid arthritis. Signs and symptoms of rheumatoid arthritis are reduced by targeting B-cells and the progression of structural damage is delayed.Pharmaco*kinetics (Adult data unless noted)Onset:Immune thrombocytopenia: Initial response: 7 to 56 days; Peak response: 14 to 180 days (ASH [Neunert 2011]).Non-Hodgkin lymphomas: B-cell depletion: Within 3 weeks.Rheumatoid arthritis: B-cell depletion: Within 2 weeks.Duration:Non-Hodgkin lymphomas: Detectable in serum 3 to 6 months after completion of treatment; B-cell depletion is sustained for up to 6 to 9 months and B-cell recovery begins ~6 months following completion of treatment; median B-cell levels return to normal by 12 months following completion of treatment.Rheumatoid arthritis: B-cell depletion persists for at least 6 months.Distribution:Pemphigus vulgaris: Median: 3.49 L (range: 2.48 to 5.22 L).Rheumatoid arthritis: 3.1 L.Granulomatosis with polyangiitis/microscopic polyangiitis:Children ≥6 years of age and Adolescents ≤17 years of age: Median: 2.28 L (range: 1.43 to 3.17 L).Adults: Median: 3.12 L (range: 2.42 to 3.91 L).Half-life elimination:Chronic lymphocytic leukemia: Median terminal half-life: 32 days (range: 14 to 62 days).Non-Hodgkin lymphomas: Median terminal half-life: 22 days (range: 6 to 52 days).Pemphigus vulgaris: Median terminal half-life: First cycle (1,000 mg on days 1, 15): 21.1 days (range: 9.3 to 36.2 days); second cycle (1,000 mg on days 168, 182): 26.2 days (range: 16.4 to 42.8 days).Rheumatoid arthritis: Mean terminal half-life: 18 days (range: 5 to 78 days).Granulomatosis with polyangiitis/microscopic polyangiitis:Children ≥6 years of age and Adolescents ≤17 years of age: Median terminal half-life: 22 days (range: 11 to 42 days).Adults: Median terminal half-life: 25 days (range: 11 to 52 days).Excretion: Clearance:Pemphigus vulgaris: Median: First cycle (1,000 mg on days 1, 15): 0.3 L/day (range: 0.16 to 1.51 L/day); second cycle (1,000 mg on days 168, 182): 0.24 L/day (range: 0.13 to 0.45 L/day).Rheumatoid arthritis: 0.335 L/day.Granulomatosis with polyangiitis/microscopic polyangiitis:Children ≥6 years and Adolescents ≤17 years of age: Median: 0.222 L/day (range: 0.0996 to 0.381 L/day).Adults: Median: 0.279 L/day (range: 0.133 to 0.653 L/day).Pricing: USSolution (Riabni Intravenous)100 mg/10 mL (per mL): $86.02500 mg/50 mL (per mL): $86.02Solution (Rituxan Intravenous)100 mg/10 mL (per mL): $112.74500 mg/50 mL (per mL): $112.74Solution (Ruxience Intravenous)100 mg/10 mL (per mL): $86.02500 mg/50 mL (per mL): $86.02Solution (Truxima Intravenous)100 mg/10 mL (per mL): $101.47500 mg/50 mL (per mL): $101.47Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalBlitzima (AT, BE, CZ, EE, HU, LV, NL, PL, PT, RO, SI, SK);Cytomab Mabtas (IN);Mabthera (AE, AR, AT, AU, BB, BE, BF, BG, BH, BJ, BM, BR, BS, BZ, CH, CI, CL, CN, CO, CR, CU, CY, CZ, DE, DK, DO, EC, EE, ES, ET, FI, FR, GB, GH, GM, GN, GR, GT, GY, HK, HN, HR, HU, IE, IL, IS, IT, JM, JO, KE, KR, LB, LK, LR, LT, LU, LV, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, NL, NO, NZ, PA, PE, PH, PK, PL, PT, PY, QA, RO, RU, SA, SC, SD, SE, SG, SI, SK, SL, SN, SR, SV, TH, TN, TR, TT, TW, TZ, UA, UG, UY, VE, VN, ZA, ZM, ZW);Mabthera SC (AU);Novex (AR);Redditux (TH);Reditux (CL, IN, LK, VN);Relito (BD);Ristova (HK);Ritemvia (AT, BE, CZ, EE, HU, LV, NL, PL, PT);Rituxan (JP);Rituxim (BD);Rituzena (BE);Rixathon (AT, BE, CZ, DE, EE, ES, GB, HU, IS, LB, LV, NL, NO, RO, SK, TH, TW);Riximyo (AT, PL, PT, SK);Ruxience (AT, SK);Truxima (CH, CZ, DE, EE, ES, FI, GB, HU, IE, IS, LU, LV, NL, PH, PT, RO, TW);Tuxella (PL)For country code abbreviations (show table)Advani RH, Hoppe RT. How I treat nodular lymphocyte predominant Hodgkin lymphoma. Blood. 2013;122(26):4182-4188. doi:10.1182/blood-2013-07-453241 [PubMed 24215035]Advani RH, Horning SJ, Hoppe RT, et al. Mature results of a phase II study of rituximab therapy for nodular lymphocyte-predominant Hodgkin lymphoma. J Clin Oncol. 2014;32(9):912-918. doi:10.1200/JCO.2013.53.2069 [PubMed 24516013]Ahmed AR, Spigelman Z, Cavacini LA, et al. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med. 2006;355(17):1772-1779. doi:10.1056/NEJMoa062930 [PubMed 17065638]Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]Alhamad T, Kukla A, Stratta RJ. Pancreas-kidney transplantation in diabetes mellitus: pancreas allograft rejection. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed May 14, 2021.Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. doi:10.1002/cpt.377 [PubMed 27060684]Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med. 2007;146(1):25-33. doi:10.7326/0003-4819-146-1-200701020-00006 [PubMed 17200219]Auger S, Duny Y, Rossi JF, Quittet P. Rituximab before splenectomy in adults with primary idiopathic thrombocytopenic purpura: a meta-analysis. Br J Haematol. 2012;158(3):386-398. [PubMed 22612239]Avivi I, Robinson S, Goldstone A. Clinical Use of Rituximab in Haematological Malignancies. Br J Cancer. 2003;89(8):1389-1394. [PubMed 14562003]Bachy E, Seymour JF, Feugier P, et al. Sustained progression-free survival benefit of rituximab maintenance in patients with follicular lymphoma: long-term results of the PRIMA study. J Clin Oncol. 2019;37(31):2815-2824. doi:10.1200/JCO.19.01073 [PubMed 31339826]Barcellini W, Zaja F, Zaninoni A, et al. Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies. Blood. 2012;119(16):3691-3697. doi:10.1182/blood-2011-06-363556 [PubMed 22267606]Barmettler S, Ong MS, Farmer JR, Choi H, Walter J. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open. 2018;1(7):e184169. doi:10.1001/jamanetworkopen.2018.4169 [PubMed 30646343]Barth MJ, Goldman S, Smith L, et al. Rituximab pharmaco*kinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukaemia: a Children's Oncology Group report. Br J Haematol. 2013;162(5):678-683. [PubMed 23802659]Based on expert opinion.Bath RM, Doering BE, Nailor MD, Goodlet KJ. Pharmacotherapy-induced hepatitis B reactivation among patients with prior functional cure: a systematic review. Ann Pharmacother. 2019;53(3):294-310. doi:10.1177/1060028018800501 [PubMed 30203666]Bellinvia A, Prestipino E, Portaccio E, et al. Experience with rituximab therapy in a real-life sample of multiple sclerosis patients. Neurol Sci. 2020;41(10):2939-2945. doi:10.1007/s10072-020-04434-1 [PubMed 32350672]Bennett CM, Rogers ZR, Kinnamon DD, et al. Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura. Blood. 2006;107(7):2639-2642. [PubMed 16352811]Bilbao-Meseguer I, Rodríguez-Gascón A, Barrasa H, Isla A, Solinís MÁ. Augmented renal clearance in critically ill patients: a systematic review. Clin Pharmaco*kinet. 2018;57(9):1107-1121. doi:10.1007/s40262-018-0636-7 [PubMed 29441476]Billon E, Stoppa AM, Mescam L, et al. Reversible rituximab-induced rectal Kaposi's sarcoma misdiagnosed as ulcerative colitis in a patient with HIV-negative follicular lymphoma. 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CloseDexamethasone (systemic): Drug informationDexamethasone (systemic): Drug information(For additional information see "Dexamethasone (systemic): Patient drug information" and see "Dexamethasone (systemic): Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USActive Injection D [DSC];Decadron [DSC];Dexabliss;Dexamethasone Intensol;DexPak 10 Day [DSC];DexPak 13 Day [DSC];DexPak 6 Day [DSC];DoubleDex;Dxevo 11-Day;Hemady;HiDex 6-Day;MAS Care-Pak;ReadySharp Dexamethasone [DSC];TaperDex 12-Day;TaperDex 6-Day;TaperDex 7-Day;TopiDex;ZCORT 7-Day [DSC]Brand Names: CanadaAPO-Dexamethasone;Dexamethasone Omega Unidose;Dexamethasone-Omega;Odan-Dexamethasone;PMS-Dexamethasone;PMS-Dexamethasone Sod Phosphat [DSC];PRO-Dexamethasone-4 [DSC]Pharmacologic CategoryAnti-inflammatory Agent;Antiemetic;Corticosteroid, SystemicDosing: AdultNote: Dosing: Evidence to support an optimal dose and duration is lacking for most indications; recommendations provided are general guidelines only and primarily based on expert opinion. In general, glucocorticoid dosing should be individualized and the minimum effective dose/duration should be used. Hypothalamic-pituitary-adrenal (HPA) suppression: Although some patients may become hypothalamic-pituitary-adrenal (HPA) suppressed with lower doses or briefer exposure, some experts consider HPA-axis suppression likely in any adult receiving >3 mg/day (daytime dosing) or ≥0.75 mg per 24 hours (evening or night dosing) for >2 weeks or with Cushingoid appearance (Ref); do not abruptly discontinue treatment in these patients; dose tapering may be necessary (Ref).Usual dosage range:Oral, IV, IM: 4 to 20 mg/day given in a single daily dose or in 2 to 4 divided doses; High dose: 0.4 to 0.8 mg/kg/day (usually not to exceed 40 mg/day).Indication-specific dosing:Acute mountain sickness/high-altitude cerebral edemaAcute mountain sickness/high-altitude cerebral edema (off-label use):Prevention, moderate- to high-risk situations(alternative agent): Note: Use in addition to gradual ascent and start the day of ascent.Oral: 2 mg every 6 hours or 4 mg every 12 hours; may be discontinued after staying at the same elevation for 2 to 4 days or if descent is initiated. Due to adverse effects, limit duration to ≤10 days (Ref); some experts limit to ≤7 days (Ref). In situations of rapid ascent to altitudes >3,500 meters (eg, rescue or military operations), 4 mg every 6 hours may be considered (Ref).Treatment:Acute mountain sickness (moderate to severe): Note: Dexamethasone does not facilitate acclimatization; further ascent should be delayed until patient is asymptomatic off medication (Ref).Oral, IM, IV: 4 mg every 6 hours, continue until 24 hours after symptoms resolve or descent completed (not longer than 7 days total) (Ref).High-altitude cerebral edema: Oral, IM, IV: 8 mg as a single dose, followed by 4 mg every 6 hours until descent is complete and symptoms resolve (Ref).Acute respiratory distress syndrome, moderate to severeAcute respiratory distress syndrome, moderate to severe (off-label use): Note: May consider in most patients with persistent or refractory moderate to severe acute respiratory distress syndrome who are relatively early in the disease course (within 14 days) (Ref). Do not abruptly discontinue since this may cause deterioration due to inflammatory response (Ref).IV: 20 mg once daily from days 1 to 5, then 10 mg once daily from days 6 to 10 (Ref).Adrenal insufficiency, adrenal crisisAdrenal insufficiency, adrenal crisis (alternative agent): Note: Dexamethasone should only be used if hydrocortisone is unavailable. Corticosteroid therapy should be combined with adequate fluid resuscitation in patients with primary adrenal insufficiency (Ref).IV: 4 mg every 12 hours; transition to hydrocortisone as soon as possible (Ref).Adrenal insufficiency, primary chronicAdrenal insufficiency, primary chronic (alternative agent): Note: For use in patients who are unable to tolerate treatment with other glucocorticoids (hydrocortisone is preferred); risk of overreplacement may be higher with dexamethasone (Ref). Use in conjunction with fludrocortisone. Dose is based on prednisolone equivalency.Chronic maintenance dosing:Oral: Usual dosage range: 0.25 to 0.75 mg once daily (Ref).Stress dosing:Note: Patients who are unable to tolerate oral medication (eg, due to vomiting or diarrhea), are in active labor, or are under surgical stress may require parenteral corticosteroid therapy (preferably with hydrocortisone) to prevent adrenal crisis (Ref).Patients with febrile illness: Oral: Double the chronic maintenance dose until recovery for fever 38°C (100.4°F) to 39°C (102.2°F) or triple the chronic maintenance dose until recovery for fever >39°C (102.2°F), then return to baseline dose within 1 to 3 days (Ref).Minor surgical stress (eg, hernia repair, procedures with local anesthetic): Oral: Continue chronic maintenance dose (no additional supplementation needed) (Ref); may give an additional 0.75 mg (equivalent to ~20 mg hydrocortisone) postoperatively if signs or symptoms of adrenal insufficiency are present (Ref).Antiemetic regimens: Chemotherapy-associated nausea and vomiting, preventionAntiemetic regimens: Chemotherapy-associated nausea and vomiting, prevention (off-label use): Note: When dexamethasone is given with rolapitant in a prechemotherapy regimen, the oral route for both is generally used. When checkpoint inhibitor therapy is administered in combination with emetogenic chemotherapy, there is no evidence to omit dexamethasone from the prophylactic antiemetic regimen (Ref).Single-day IV chemotherapy regimens: Highly emetogenic chemotherapy (>90% risk of emesis): Cisplatin and other highly emetogenic single agents: Dexamethasone dose depends on specific neurokinin 1 (NK1) receptor antagonist: Day of chemotherapy: Administer prior to chemotherapy and in combination with an NK1 receptor antagonist, and a 5-HT3 receptor antagonist, with or without olanzapine (Ref).In combination with aprepitant, fosaprepitant, netupitant/palonosetron (NEPA), or fosnetupitant/palonosetron: Oral, IV: 12 mg.In combination with rolapitant: Oral, IV: 20 mg.If NK1 receptor antagonist not used: Oral, IV: 20 mg.Postchemotherapy days:If aprepitant given: Oral, IV: 8 mg once daily on days 2 to 4 (Ref).If fosaprepitant given: Oral, IV: 8 mg once on day 2, followed by 8 mg twice daily on days 3 and 4 (Ref).If NEPA or fosnetupitant/palonosetron given: Prophylaxis with dexamethasone on subsequent days is not needed unless regimen contained cisplatin: Oral, IV: 8 mg once daily on days 2 to 4 (Ref).If rolapitant given: Oral, IV: 8 mg twice daily on days 2 to 4 (Ref).If NK1 receptor antagonist not used: Oral, IV: 8 mg twice daily on days 2 to 4 (Ref).Highly emetogenic chemotherapy (>90% risk of emesis): Breast cancer regimens that include an anthracycline combined with cyclophosphamide:Dexamethasone dose depends on specific NK1 receptor antagonist: Day of chemotherapy: Administer prior to chemotherapy and in combination with an NK1 receptor antagonist, and a 5-HT3 receptor antagonist, with or without olanzapine (Ref).In combination with aprepitant, fosaprepitant, NEPA, fosnetupitant/palonosetron: Oral, IV: 12 mg (Ref).In combination with rolapitant: Oral, IV: 20 mg (Ref).If NK1 receptor antagonist not used: Oral, IV: 20 mg (Ref).Postchemotherapy days: Dexamethasone use is not recommended (an alternative agent or agents is/are recommended) (Ref).Moderately emetogenic chemotherapy (30% to 90% risk of emesis): Carboplatin-based regimens: Dexamethasone dose depends on specific NK1 receptor antagonist (Ref):Day of chemotherapy: Administer prior to chemotherapy and in combination with an NK1 receptor antagonist and a 5-HT3 receptor antagonist (Ref).In combination with aprepitant, fosaprepitant, NEPA, or fosnetupitant/palonosetron: Oral, IV: 12 mg (Ref).In combination with rolapitant: Oral, IV: 20 mg (Ref).Postchemotherapy days: Prophylaxis is not necessary on subsequent days (Ref).Moderately emetogenic chemotherapy (30% to 90% risk of emesis): Non-carboplatin-based regimens: Day of chemotherapy: Administer prior to chemotherapy and in combination with a 5-HT3 receptor antagonist: Oral, IV: 8 mg (Ref).Postchemotherapy days: Note: Consider single-agent dexamethasone use for regimens containing agents with known potential to induce delayed emesis (eg, oxaliplatin, cyclophosphamide, doxorubicin) (Ref); a single-day dexamethasone regimen may be employed when utilizing palonosetron (Ref); however, if a first-generation 5-HT3 antagonist was used on day 1 rather than palonosetron, some experts suggest the first-generation 5-HT3 receptor antagonist be continued for postchemotherapy emetic prophylaxis on days 2 and 3 (Ref).Oral, IV: 8 mg on days 2 and 3 (Ref).Low emetogenic risk (10% to 30% risk of emesis): Oral, IV: 4 to 8 mg administered as a single agent in a single dose prior to chemotherapy; prophylaxis is not necessary on subsequent days (Ref).Antiemetic regimens: Postoperative nausea and vomiting, preventionAntiemetic regimens: Postoperative nausea and vomiting, prevention (off-label use): Note: May be used alone or in combination with one or more other prophylactic interventions depending on risk factors (Ref).IV: 4 to 10 mg once, before or after induction of anesthesia. Dose depends on risk and type of surgery (Ref).Antiemetic regimens: Radiation therapy-associated nausea and vomiting, preventionAntiemetic regimens: Radiation therapy-associated nausea and vomiting, prevention (off-label use): High emetogenic risk radiation therapy (total body irradiation): Radiation day(s): Oral, IV: 4 mg once daily prior to each fraction of radiation; give in combination with a 5-HT3 receptor antagonist (Ref).Postradiation days: Oral, IV: The appropriate duration of therapy following radiotherapy days is not well defined; ASCO guidelines recommend continuing dexamethasone 4 mg once on the day after each day of radiation if radiation is not planned for that day (Ref).Moderate emetogenic risk radiation therapy (upper abdomen, craniospinal irradiation):Radiation day(s): Oral, IV: 4 mg once daily prior to each of the first 5 fractions of radiation; give in combination with a 5-HT3 receptor antagonist (Ref).Asthma, acute exacerbationAsthma, acute exacerbation (alternative agent) (off-label use): Note: Alternative to a longer course of other corticosteroids in mild to moderate exacerbations or in patients who do not respond promptly and completely to short-acting beta-agonists; administer within 1 hour of presentation to emergency department (Ref).Oral: 12 to 16 mg daily for 1 to 2 days only (Ref); longer treatment at this dose may be associated with metabolic adverse effects (Ref).Cancer-related cachexiaCancer-related cachexia (off-label use): Oral: 3 to 4 mg once daily; short-term therapy (weeks) is recommended, although duration of treatment depends on treatment goals and risk/benefit assessment (Ref) or 3 to 6 mg/day for up to 4 weeks (Ref).Cancer-related pain, advanced cancer, adjuvant therapyCancer-related pain, advanced cancer, adjuvant therapy (off-label use): Note: Although available data are limited and with mixed results, dexamethasone may provide clinical benefit in the management of a variety of types of pain in patients with advanced cancer (Ref). Due to the risk for potential toxicity, carefully consider the risks and benefits of glucocorticoid use for treating cancer-related pain, including the availability of other treatments, duration of treatment, other symptoms, and life expectancy.Low-dose regimen for pain and other symptoms in the context of advanced cancer and short prognosis: Oral, IV: Initial: 0.75 to 1.5 mg once or twice daily; usual effective dose range: 1 to 2 mg IV or orally twice daily (Ref).Higher-dose regimen for pain crisis that is poorly responsive to initial opioid therapy: Oral, IV: Initial: 8 to 10 mg once; if responsive, then may consider 4 mg twice daily or 8 mg once daily; use the lowest dose that maintains pain relief while other analgesic treatments are added, if indicated (Ref).Cerebral edema associated with brain tumorCerebral (vasogenic) edema associated with brain tumor: Moderate to severe symptoms (eg, lowered consciousness/brainstem dysfunction):Initial: IV: 10 mg once followed by maintenance dosing (Ref).Maintenance: IV, Oral: 4 mg every 6 hours (Ref). Note: Consider taper after 7 days of therapy; taper slowly over several weeks (Ref).Mild symptoms: IV, Oral: 4 to 8 mg/day in 1 to 4 divided doses (Ref). Note: Consider taper after 7 days of therapy; taper slowly over several weeks (Ref).COVID-19, hospitalized patientsCOVID-19, hospitalized patients (off-label use): Note: Dexamethasone is recommended for treatment of COVID-19 in hospitalized patients requiring supplemental oxygen or ventilatory support (Ref). An equivalent dose of an alternative glucocorticoid may be substituted if dexamethasone is unavailable (Ref).IV, Oral: 6 mg once daily for up to 10 days (or until discharge if sooner) as part of an appropriate combination regimen (Ref).Cushing syndrome, diagnosisCushing syndrome, diagnosis: Note: Interpretation requires evaluation of one or more of the following: serum cortisol concentration, serum dexamethasone concentration, urinary cortisol excretion, or 17-hydroxycorticosteroid excretion; consultation with a clinical endocrinologist is recommended (Ref).Initial testing:Overnight 1 mg dexamethasone suppression test: Oral: 1 mg given once between 11 PM and 12 AM (Ref).Longer low-dose dexamethasone suppression test (2 mg/day for 48 hours): Note: May be preferred in patients with depression, anxiety, obsessive-compulsive disorder, morbid obesity, alcoholism, or diabetes mellitus (Ref).Oral: 0.5 mg every 6 hours for 48 hours for a total of 8 doses; start time varies (eg, 9 AM or12 PM) (Ref).Fetal lung maturation, acceleration ofFetal lung maturation, acceleration of (maternal administration) (off-label use): Note: Generally, for patients between 24 and 34 weeks of gestation, including those with ruptured membranes or multiple gestations, who are at risk of delivering within 7 days. A single course may be appropriate in some pregnant patients beginning at 23 weeks' gestation or late preterm (between 34 0/7 weeks' and 36 6/7 weeks' gestation) who are at risk of delivering within 7 days.IM: 6 mg every 12 hours for a total of 4 doses. May repeat course in select patients (eg, patients with pregnancies up to 34 weeks' gestation at risk for delivery within 7 days and >14 days have elapsed since initial course of antenatal corticosteroids) (Ref).Immune thrombocytopeniaImmune thrombocytopenia (initial therapy): Note: Goal of therapy is to provide a safe platelet count to prevent clinically important bleeding rather than normalization of the platelet count (Ref).Oral, IV: 40 mg once daily for 4 days and then stop (no taper); may be repeated up to 3 times if inadequate response (Ref). For severe bleeding with thrombocytopenia, give in combination with other therapies (Ref).Iodinated contrast media allergic-like reaction, preventionIodinated contrast media allergic-like reaction, prevention (alternative agent): Note: Generally for patients with a prior allergic-like or unknown-type iodinated contrast reaction who will be receiving another iodinated contrast agent. Nonurgent premedication with an oral corticosteroid (eg, prednisone) is generally preferred when contrast administration is scheduled to begin in ≥12 hours; however, consider an urgent (accelerated) regimen with an IV corticosteroid for those requiring contrast in <12 hours. Efficacy of premedication regimens starting <4 to 5 hours before the use of contrast has not been demonstrated (Ref).Urgent (accelerated) regimen: IV: 7.5 mg every 4 hours until contrast medium administration in combination with diphenhydramine (Ref).Meningitis, prevention of neurologic complicationsMeningitis (bacterial), prevention of neurologic complications (off-label use): Note: Administer first dose of dexamethasone shortly before or at the same time as the first dose of antibacterials. If antibacterials have already been administered, do not administer dexamethasone. In patients with pneumococcal meningitis who receive dexamethasone, some experts recommend adding rifampin to the standard initial antibacterial regimen or adding rifampin if susceptibility tests, once available, show intermediate susceptibility (MIC ≥2 mcg/mL) to ceftriaxone and cefotaxime (Ref).Developed world (suspected or confirmed pneumococcal meningitis): IV: 0.15 mg/kg/dose or 10 mg every 6 hours for 4 days; discontinue if culture data reveal non-pneumococcal etiology (Ref).Developing world (strongly suspected or confirmed bacterial meningitis): IV: 0.4 mg/kg/dose every 12 hours for 4 days; discontinue if culture data reveal non-pneumococcal etiology; not recommended in regions with high rates of HIV infection and/or malnutrition or in cases of delayed clinical presentation (Ref).Migraine, recurrence preventionMigraine, recurrence prevention (off-label use): IM, IV: 10 to 24 mg once in combination with standard migraine abortive therapy (Ref).Multiple myelomaMultiple myeloma: Note: Multiple dexamethasone-containing regimens are available. Refer to literature/guidelines for additional details. For many regimens, dexamethasone is continued until disease progression or unacceptable toxicity. Dexamethasone total weekly dose may be split over 2 days when combination therapies are administered on successive days (refer to protocol) (Ref).Frail patients (eg, >75 years of age, BMI <18.5 kg/m2, poorly controlled diabetes, corticosteroid intolerance): When administered weekly, dexamethasone is usually reduced to 20 mg once weekly for frail patients (Ref). May consider lower initial dexamethasone doses (8 to 20 mg once weekly) in patients >75 years of age or those with comorbidities, with subsequent titration based on response/tolerance (Ref).Combination regimens that do not include a monoclonal antibody:Oral:40 mg once weekly on days 1, 8, 15, and 22 every 28 days in combination with lenalidomide (Ref), pomalidomide (Ref), ixazomib and lenalidomide (Ref), ixazomib and lenalidomide for 18 cycles (Ref), carfilzomib and lenalidomide (Ref), or bortezomib and lenalidomide (Ref) or 40 mg once weekly on days 1, 8, 15, and 22 every 28 days in cycles 1 to 9, and then 40 mg once weekly on days 1, 8, and 15 every 28 days beginning at cycle 10 (in combination with carfilzomib) (Ref).or20 mg on days 1, 8, 15, and 22 every 28 days (in combination with lenalidomide) for 9 cycles, followed by lenalidomide maintenance (Ref) or 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days (in combination with bortezomib and lenalidomide) for 8 cycles (induction), followed by 40 mg on days 1, 8, 15, and 22 every 28 days (in combination with lenalidomide) for maintenance (Ref) or 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 every 28 days (in combination with carfilzomib) (Ref) or 20 mg on days 1 and 3 of each week (in combination with selinexor) (Ref) or 20 mg on days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 every 35 days (in combination with selinexor and bortezomib) (Ref).or40 mg once daily on days 1 to 4 and 9 to 12 every 28 days in combination with bortezomib and lenalidomide for 6 cycles followed by transplant (Ref) or 40 mg once daily on days 1 to 4, 9 to 12, and 17 to 20 every 28 days in combination with bortezomib and doxorubicin for 3 cycles as induction (Ref). Note: Some experts reserve this dosing (for 1 cycle, followed by 40 mg once weekly thereafter) for patients with an aggressive disease presentation or acute renal failure from light chain cast nephropathy (Ref).Combination regimens that include a monoclonal antibody:Oral, IV:40 mg weekly in combination with daratumumab and pomalidomide (Ref) or daratumumab/hyaluronidase and pomalidomide (Ref) or daratumumab and lenalidomide (Ref) or daratumumab/hyaluronidase and lenalidomide (Ref) or daratumumab and carfilzomib (Ref) or isatuximab and pomalidomide (Ref) or 20 mg once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days in combination with daratumumab and bortezomib (Ref) or 20 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 every 28 days in combination with isatuximab and carfilzomib (Ref). Note: In some studies, the dexamethasone dose is split over 2 days (20 mg before daratumumab and 20 mg the day after daratumumab infusion).or40 mg weekly, except on days elotuzumab is administered (administer dexamethasone 28 mg orally [8 mg orally in patients >75 years of age] plus 8 mg IV prior to elotuzumab) in combination with elotuzumab and pomalidomide (Ref) or elotuzumab and lenalidomide (Ref).Neoplastic epidural spinal cord compression, symptomaticNeoplastic epidural spinal cord compression, symptomatic: Note: As an adjunct to definitive treatment (radiotherapy or surgery), particularly in patients with neurologic deficits (Ref).IV (initial dose): 10 or 16 mg followed by oral dosing (Ref).Oral (after IV dose): 16 mg/day (usually given in 2 to 4 divided doses). Once definitive treatment is underway, taper gradually over 1 to 2 weeks until discontinuation (Ref).Tuberculosis, central nervous systemTuberculosis, central nervous system: Note: In general, steroids are indicated for patients with established or suspected tuberculous meningitis, regardless of HIV status (Ref).IV: Initial dose: 0.3 to 0.4 mg/kg/day for 2 weeks, then 0.2 mg/kg/day for week 3, then 0.1 mg/kg/day for week 4, followed by oral therapy (Ref).Oral: Starting week 5 of treatment: 4 mg/day, then taper by 1 mg of the daily dose each week; total combined IV/oral therapy duration: ~8 weeks (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Note: The pharmaco*kinetics and pharmacodynamics of corticosteroids in kidney impairment are not well understood (Ref). Dexamethasone half-life is decreased in patients with severe kidney impairment (Ref), potentially due to decreased protein binding (Ref); however, the clinical implications of these findings are unclear.Oral, parenteral:Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (Ref).Hemodialysis, intermittent (thrice weekly): No supplemental dose or dosage adjustment necessary (Ref).Peritoneal dialysis: No dosage adjustment necessary (Ref).CRRT: No dosage adjustment necessary (Ref).PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling.Dosing: Pediatric(For additional information see "Dexamethasone (systemic): Pediatric drug information")COVID-19, treatmentCOVID-19, treatment: Very limited data available:Note: Safety and effectiveness of dexamethasone or other corticosteroids for COVID-19 treatment have not been sufficiently evaluated in pediatric patients; use is extrapolated from adult patients; use caution. Reserve use for hospitalized patients who require high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO); not routinely recommended for pediatric patients requiring low levels of oxygen support (ie, nasal canula only). Use in profoundly immunocompromised pediatric patients should be considered only on a case-by-case basis as it has not been evaluated and may be harmful. Pediatric patients with COVID-19 should be enrolled in clinical trials whenever possible (Ref).Infants, Children, and Adolescents: IV, Oral: 0.15 to 0.3 mg/kg/dose once daily for up to 10 days; maximum dose: 6 mg/dose (Ref). Note: An equivalent dose of an alternative glucocorticoid may be substituted if dexamethasone is unavailable (Ref).Acute mountain sickness/high altitude cerebral edema; treatmentAcute mountain sickness (AMS) (moderate)/high altitude cerebral edema (HACE); treatment: Limited data available: Note: Dexamethasone does not facilitate acclimatization; further ascent should be delayed until patient is asymptomatic off medication (Ref).Infants, Children, and Adolescents: Oral, IM, IV: 0.15 mg/kg/dose every 6 hours; maximum dose: 4 mg/dose (Ref).Airway edema or extubationAirway edema or extubation: Limited data available: Infants, Children, and Adolescents: Oral, IM, IV: 0.5 mg/kg/dose (maximum dose: 10 mg/dose) administered 6 to 12 hours prior to extubation then every 6 hours for 6 doses (total dexamethasone dose: 3 mg/kg) (Ref).Anti-inflammatoryAnti-inflammatory: Infants, Children, and Adolescents: Oral, IM, IV: Initial dose range: 0.02 to 0.3 mg/kg/day or 0.6 to 9 mg/m2/day in divided doses every 6 to 12 hours; dose depends upon condition being treated and response of patient; dosage for infants and children should be based on disease severity and patient response; usual adult initial daily dose range: 0.75 to 9 mg/day.Asthma exacerbationAsthma exacerbation: Limited data available: Infants, Children, and Adolescents: Oral, IM, IV: 0.6 mg/kg once daily as a single dose or once daily for 2 days; maximum dose: 16 mg/dose (Ref); single dose regimens as low as 0.3 mg/kg/dose and as high as 1.7 mg/kg/dose have also been reported (Ref). Note:Duration >2 days is not recommended due to increased risk of metabolic effects (Ref).Bacterial meningitisBacterial meningitis (Haemophilus influenzae type b): Limited data available:Infants >6 weeks and Children: IV: 0.15 mg/kg/dose every 6 hours for the first 2 to 4 days of antibiotic treatment; start dexamethasone 10 to 20 minutes before or with the first dose of antibiotic; if antibiotics have already been administered, dexamethasone use has not been shown to improve patient outcome and is not recommended (Ref). Note: For pneumococcal meningitis, efficacy results are variable and use is controversial; risk and benefits should be considered prior to use (Ref).Cerebral edemaCerebral edema: Limited data available: Note: Dose, route, and duration may vary due to underlying cause of edema; tapering may be required. Infants, Children, and Adolescents: Oral, IM, IV: Loading dose: 1 to 2 mg/kg/dose as a single dose; maintenance: 1 to 2 mg/kg/day in divided doses every 4 to 6 hours; maximum daily dose: 16 mg/day (Ref).Chemotherapy-induced nausea and vomiting, preventionChemotherapy-induced nausea and vomiting, prevention: Reported regimens variable; optimal dose not established (Ref). Refer to individual protocols and emetogenic potential:Infants, Children, and Adolescents:POGO recommendations (Ref): Note: Reduce dose by 50% if administered concomitantly with aprepitant:Highly/severely emetogenic chemotherapy: Oral, IV: 6 mg/m2/dose every 6 hours.Moderately emetogenic chemotherapy: Oral, IV:BSA ≤0.6 m2: 2 mg every 12 hours.BSA >0.6 m2: 4 mg every 12 hours.Alternate dosing: Highly/severely emetogenic chemotherapy: IV: Usual: 10 mg/m2/dose once daily on days of chemotherapy; some patients may require every 12-hour dosing; usual range: 8 to 14 mg/m2/dose (Ref).Congenital adrenal hyperplasia, maintenanceCongenital adrenal hyperplasia, maintenance: Adolescents (fully grown): Oral: 0.25 to 0.5 mg once daily; use of a liquid dosage form may be preferable to allow for better dose titration (Ref). Note: For younger patients who are still growing, hydrocortisone or fludrocortisone are preferred.CroupCroup (laryngotracheobronchitis): Limited data available; dosing regimens variable:Infants and Children: Oral, IM, IV: 0.6 mg/kg once; reported maximum dose highly variable; usual maximum dose: 16 mg/dose (Ref); in trials, maximum doses of 10 to 20 mg/dose have been reported with similar efficacy findings for mild to moderate croup. The majority of reported experience in infants are those ≥3 months of age; data available in <3 months of age is very limited (Ref). In one evaluation of 22 children >2 years of age, a maximum dose of 12 mg/dose (at 0.6 mg/kg/dose) did not decrease endogenous glucocorticoid levels (Ref). A single oral dose of 0.15 mg/kg has also been shown effective in infants ≥3 months and children with mild to moderate croup (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricInfants, Children, and Adolescents: IM, IV, Oral:Kidney impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.Hemodialysis or peritoneal dialysis: Based on adult data, supplemental dose is not necessary (Ref).Dosing: Hepatic Impairment: PediatricInfants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling.Dosing: Older AdultRefer to adult dosing. Use cautiously in the elderly at the lowest possible dose.Dosing: Obesity: AdultThe recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.Class 1, 2 and 3 obesity (BMI ≥30 kg/m2):Oral, IV, IM:Non–weight-based dosing: No dosage adjustment necessary (Ref). Refer to adult dosing for indication-specific doses.Weight-based dosing: Use ideal body weight to avoid overdosing and subsequent toxicity (Ref). Refer to adult dosing for indication-specific doses.Rationale for recommendations: Corticosteroids are lipophilic compounds; however, the reported pharmaco*kinetic variability due to obesity is limited and inconsistent. Two small studies evaluated pharmaco*kinetic changes with oral dexamethasone in patients with obesity. One study reported lower AUC in patients with obesity compared to patients with normal weight (Ref), while another study reported a positive correlation between actual body weight and AUC (Ref). Weight-based dosing using actual body weight could lead to supratherapeutic levels (Ref).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productConcentrate, Oral: Dexamethasone Intensol: 1 mg/mL (30 mL) [contains alcohol, usp; unflavored flavor]Elixir, Oral: Decadron: 0.5 mg/5 mL (237 mL [DSC]) [contains alcohol, usp, benzoic acid, fd&c red #40 (allura red ac dye), propylene glycol]Generic: 0.5 mg/5 mL (237 mL)Kit, Injection, as sodium phosphate: ReadySharp Dexamethasone: 10 mg/mL [DSC] [contains benzyl alcohol, sodium sulfite]TopiDex: 10 mg/mL [contains benzyl alcohol]Kit, Injection, as sodium phosphate [preservative free]: Active Injection D: 10 mg/mL [DSC]DoubleDex: 10 mg/mLMAS Care-Pak: 10 mg/mLSolution, Oral: Generic: 0.5 mg/5 mL (240 mL, 500 mL)Solution, Injection, as sodium phosphate: Generic: 4 mg/mL (1 mL); 20 mg/5 mL (5 mL); 120 mg/30 mL (30 mL); 10 mg/mL (1 mL); 100 mg/10 mL (10 mL)Solution, Injection, as sodium phosphate [preservative free]: Generic: 4 mg/mL (1 mL); 10 mg/mL (1 mL)Solution Prefilled Syringe, Injection, as sodium phosphate [preservative free]: Generic: 10 mg/mL (1 mL)Tablet, Oral: Decadron: 0.5 mg [DSC] [scored; contains fd&c yellow #5 (tartrazine), quinoline yellow (d&c yellow #10)]Decadron: 0.75 mg [DSC] [scored; contains fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]Decadron: 4 mg [DSC], 6 mg [DSC] [scored]Hemady: 20 mg [contains corn starch]Generic: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, 6 mgTablet Therapy Pack, Oral: Dexabliss: 1.5 MG (39) (39 ea)DexPak 10 Day: 1.5 mg (35 ea [DSC]) [scored; contains fd&c red #40(allura red ac)aluminum lake]DexPak 13 Day: 1.5 mg (51 ea [DSC]) [scored; contains fd&c red #40(allura red ac)aluminum lake]DexPak 6 Day: 1.5 mg (21 ea [DSC]) [scored; contains fd&c red #40(allura red ac)aluminum lake]Dxevo 11-Day: 1.5 mg (39 ea)Dxevo 11-Day: 1.5 mg (39 ea) [scored]HiDex 6-Day: 1.5 mg (21 ea) [scored; contains fd&c red #40 (allura red ac dye)]TaperDex 12-Day: 1.5 mg (49 ea) [contains fd&c red #40 (allura red ac dye)]TaperDex 6-Day: 1.5 mg (21 ea) [scored; contains fd&c red #40 (allura red ac dye)]TaperDex 6-Day: 1.5 mg (21 ea) [scored; contains fd&c red #40(allura red ac)aluminum lake]TaperDex 7-Day: 1.5 mg (27 ea) [scored; contains fd&c red #40 (allura red ac dye)]ZCORT 7-Day: 1.5 mg (25 ea [DSC]) [scored]Generic: 1.5 mg (21 ea, 35 ea, 51 ea)Generic Equivalent Available: USMay be product dependentDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Elixir, Oral: Generic: 0.5 mg/5 mL (100 ea, 100 mL)Solution, Injection, as sodium phosphate: Generic: 4 mg/mL (5 mL); 10 mg/mL (1 mL, 10 mL)Tablet, Oral: Generic: 0.5 mg, 0.75 mg, 2 mg, 4 mgAdministration: AdultOral: Administer with meals to help prevent GI upset. If appropriate, may administer antacids between meals to help prevent peptic ulcers.Oral concentrate: Use only the calibrated dropper provided. Draw dose into dropper; squeeze dropper contents into a liquid or semi-solid food (water, juice, soda or soda-like beverage, applesauce, pudding). Gently stir for a few seconds. Administer the entire mixture immediately. Do not store for future use.IV: May administer 4 mg/mL or 10 mg/mL concentration undiluted over ≥1 minute (Ref) or infuse by IVPB over 5 to 30 minutes (Ref). Rapid administration of dexamethasone may be associated with perineal irritation (especially with higher doses); consider further dilution and slower administration by IVPB to avoid perineal irritation (Ref).IM: Administer 4 mg/mL or 10 mg/mL concentration by deep IM injection.Intra-articular or soft tissue injection: Note: Dexamethasone sodium phosphate (a short-acting solution) is the only formulation available for intra-articular or soft tissue injections in the United States or Canada. Other glucocorticoids, such as triamcinolone acetonide or methylprednisolone acetate, are used more commonly for intra-articular or soft tissue injection (Ref). Refer to product-specific labeling for further details.Intra-articular: Administer into affected joint.Soft tissue: Administer into affected tissue.Intralesional injection: Note: Dexamethasone sodium phosphate (a short-acting solution) is the only formulation available for intralesional injections in the United States or Canada. Another glucocorticoid, triamcinolone acetonide, is used more commonly for intralesional injection (Ref). Refer to product-specific labeling for further details.Intralesional: Administer into affected area.Administration: PediatricOral: May administer with food or milk to decrease GI adverse effects.Parenteral: Use preservative-free dosage forms in neonates.IM: May administer 4 mg/mL or 10 mg/mL undiluted.IV: May administer as undiluted solution (4 mg/mL or 10 mg/mL) slow IV push, usually over 1 to 4 minutes; rapid administration is associated with perineal discomfort (burning, tingling) (Ref); may consider further dilution of high doses and administration by IV intermittent infusion over 15 to 30 minutes (Ref).Use: Labeled IndicationsOral, IV, or IM injection: Anti-inflammatory or immunosuppressant agent in the treatment of a variety of diseases, including those of allergic, hematologic (eg, immune thrombocytopenia), dermatologic, neoplastic (leukemias, lymphomas, and multiple myeloma), rheumatic, autoimmune, nervous system, renal, and respiratory origin; primary or secondary adrenocorticoid deficiency (not first line); management of shock, cerebral edema, and as a diagnostic agent.Intra-articular or soft tissue injection: As adjunctive therapy for short-term administration in synovitis of osteoarthritis, rheumatoid arthritis, acute and subacute bursitis, acute gouty arthritis, epicondylitis, acute nonspecific tenosynovitis, and posttraumatic osteoarthritis.Intralesional injection: Keloids; localized hypertrophic, infiltrated, inflammatory lesions of lichen planus, psoriatic plaques, granuloma annulare, and lichen simplex chronicus (neurodermatitis); discoid lupus erythematosus; necrobiosis lipoidica diabeticorum; alopecia areata; cystic tumors of an aponeurosis or tendon (ganglia).Use: Off-Label: AdultAcute mountain sickness/high-altitude cerebral edema; Acute respiratory distress syndrome, moderate to severe; Antiemetic regimens: Chemotherapy-associated nausea and vomiting, prevention; Antiemetic regimens: Postoperative nausea and vomiting, prevention; Antiemetic regimens: Radiation therapy-associated nausea and vomiting, prevention; Asthma, acute exacerbation; Cancer-related cachexia; Cancer-related pain, advanced cancer, adjuvant therapy; COVID-19, hospitalized patients; Fetal lung maturation, acceleration of; Meningitis (bacterial), prevention of neurologic complications; Migraine, recurrence preventionMedication Safety IssuesSound-alike/look-alike issues:DexAMETHasone may be confused with desoximetasone, dexmedeTOMIDine, dextroamphetamineDecadron may be confused with PercodanAdverse Reactions (Significant): ConsiderationsAdrenal suppression (tertiary adrenal insufficiency)Adrenal suppression (tertiary adrenal insufficiency) may occur with glucocorticoids, including dexamethasone, and results from inadequate stimulation of the adrenal glands (Ref). Glucocorticoid-induced adrenal insufficiency usually resolves with discontinuation of dexamethasone, but symptoms may persist for 6 to 12 months (Ref). Adrenal insufficiency may lead to adrenal crisis, a life-threatening emergency that may present like a hypotensive shock state (Ref).Mechanism: Dose- and time-related; occurs due to lack of or diminished cortisol production by the adrenal gland (Ref). Exogenous glucocorticoids produce a similar negative feedback mechanism as endogenous cortisol, causing a subsequent decrease in adrenocorticotrophic hormone (ACTH) secretion; thus, cortisol production is suppressed resulting in adrenal atrophy and subsequent insufficiency (ie, hypothalamic-pituitary-adrenal-axis [HPA-axis] suppression) (Ref). In times of stress (eg, critical illness, trauma, surgery), the body requires stress doses in patients taking dexamethasone chronically (Ref). Primary adrenal insufficiency can be caused by dexamethasone alone (without fludrocortisone) because of its lack of mineralocorticoid activity (Ref).Onset: Varied; acute (minutes after administration) and/or chronic (2 to 20 hours to days) (Ref). Chronic dexamethasone use does not allow for the HPA axis to recover quickly (Ref).Risk factors: • High doses for prolonged periods: Although some patients may become HPA suppressed with lower doses or briefer exposure, some experts consider HPA axis-suppression likely in any adult receiving a dose comparable to prednisone >20 mg/day (daytime dosing) or a dose comparable to prednisone ≥5 mg per 24 hours (evening or night dosing) for >3 weeks or with cushingoid appearance (Ref)• Potency of glucocorticoids (Ref); dexamethasone is the most potent glucocorticoid for suppressing the HPA axis (Ref).• Abrupt withdrawal (Ref)• Concurrent interacting medications (eg, carbamazepine, St John's wort, mitotane, rifampicin, itraconazole, diltiazem, thyroid replacement therapy) (Ref)• History of previous adrenal crisis (Ref)• Use of glucocorticoid therapy delivered by various routes of administration (oral and inhaled greater risk than topical or intra-articular) (Ref)CNS and psychiatric/behavioral effectsGlucocorticoids, including dexamethasone, may cause a myriad of CNS and psychiatric/behavioral adverse reactions (Ref). Patients may develop apathy or depression. More commonly, patients develop excitatory psychiatric disturbances (including agitation, anxiety, distractibility, fear, hypomania, insomnia, irritability, lethargy, labile mood, mania, pressured speech, restlessness, and tearfulness) (Ref). Exact incidences are unclear but range from 1.8% to 57% (Ref). Severe psychiatric effects have been reported in 6% of adults receiving high-dose regimens, while depression or mania have been reported in 36% (Ref). Discontinuation or dose reductions generally resolve symptoms over days to weeks (Ref).Mechanism: Dose-related; not clearly established. Dexamethasone and other glucocorticoids may alter feedback on the hypothalamic-pituitary-adrenal axis, which may lead to mood changes (Ref). Glucocorticoids may induce glutamate release, which may be responsible for neuronal toxicity (Ref). Exogenous glucocorticoids may also impact GABAergic steroids (Ref).Onset: Varied; most cases occur early in treatment (within the first 5 days), average of 11.5 days. The majority develop within 6 weeks of initiation (Ref).Risk factors:• Higher doses (comparable to ≥80 mg prednisone) (Ref)Possible additional risk factors:• Age >30 years (Ref)• Females (Ref)• History of neuropsychiatric disorders (Ref)Cushingoid features/Cushing syndromeGlucocorticoids may cause a cushingoid appearance (truncal obesity, facial adipose tissue, dorsocervical adipose tissue), which are adverse reactions related to patient's physical features (Ref). Reactions are more metabolic than weight gain, which is related to fluid retention (edema) (Ref). Iatrogenic Cushing syndrome resulting from glucocorticoid therapy increases morbidity and mortality and decreases quality of life (Ref).Mechanism: Dose- and time-related; excess cortisol from exogenous source (dexamethasone) results in suppression of adrenocorticotrophic hormone (ACTH), commonly called iatrogenic Cushing syndrome (Ref).Onset: Delayed; may develop within the first 2 months of dexamethasone therapy, with the risk dependent on the dose and duration of treatment (Ref).Risk factors:• Higher doses (Ref)• Longer duration of use (Ref)• Drug interactions prolonging the half-life of glucocorticoids via cytochrome P450 (Ref)• BMI (high) (Ref)• Daily caloric intake (>30 kcal/kg/day) (Ref)GI effectsGlucocorticoids, including dexamethasone, may cause GI effects, including peptic ulcer (with possible perforation and hemorrhage), dyspepsia, gastritis, abdominal distention, and ulcerative esophagitis (Ref). Meta-analyses suggest that glucocorticoid monotherapy carries little to no risk of peptic ulcer disease in the general population (Ref). Studies have demonstrated an increased risk of focal small bowel perforation in infants with low birth weight receiving dexamethasone (Ref).Mechanism: Dose-related; glucocorticoids inhibit gastroprotective prostaglandin synthesis and reduce gastric mucus and bicarbonate secretion (Ref). Glucocorticoid immunosuppressive effects may prevent wound healing as well as mask GI signs and symptoms (Ref). Focal small bowel perforation is thought to be due to segmental degeneration of the muscularis externa (Ref).Risk factors:• Higher doses (equivalent to methylprednisolone ≥4 mg/day) (Ref)• Concurrent aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) (Ref)• Hospitalized (but not ambulatory) patients (Ref)• Infants with low birth weight (Ref)• Recent glucocorticoid users (7 to 28 days) versus remote or nonusers (Ref)HyperglycemiaGlucocorticoids, including dexamethasone, may provoke new-onset hyperglycemia in patients without a history of diabetes and may cause an exacerbation of diabetes mellitus (Ref). Glucose levels have been noted to increase 68% above baseline (Ref). Certain patient populations (eg, transplant, cancer, chronic rheumatologic conditions) are at particular risk due to medication combinations (Ref). Resolution may occur within 24 to 36 hours after dexamethasone discontinuation (Ref).Mechanism: Dose- and time-related; increased insulin resistance (Ref). May also interfere with insulin signaling by direct effects on the insulin receptor and the glucose transporter and may promote gluconeogenesis via liver stimulation (Ref).Onset: Rapid; 4 hours (Ref). Rapid onset of steroid-induced hyperglycemia occurred within 2 days after initiation of glucocorticoids with a peak in the late afternoon following daily dosing in the morning (Ref).Risk factors:• Dose and type of glucocorticoid (Ref)• Duration of use (Ref)• Divided versus once-daily dosing (Ref)• IV and oral routes of administration (Ref)• Older age (Ref)• Males (Ref)• BMI >25 kg/m2 (Ref)• African American or Hispanic (Ref)• eGFR <40 mL/minute/1.73 m2 (Ref)• HbA1c ≥6% (Ref)• History of gestational diabetes (Ref)• Family history of diabetes mellitus (Ref)• Concurrent use of mycophenolate mofetil and calcineurin inhibitors (Ref)• Previous history of impaired fasting glucose or impaired glucose tolerance (Ref)• Patients receiving palliative care (Ref)InfectionGlucocorticoids, including dexamethasone, have immunosuppressive and anti-inflammatory effects that are reversible with discontinuation. Infection may occur after prolonged use, including Pneumocystis jirovecii pneumonia (PJP), herpes zoster, tuberculosis, and other more common bacterial infections (Ref).Mechanism: Dose- and time-related; related to pharmacologic action (ie, multiple activities on cell macrophage production and differentiation, inhibition of T-cell activation, and effects on dendritic cells) (Ref).Onset: Varied; in one study, the median duration of glucocorticoid use prior to PJP diagnosis was 12 weeks but also occurred earlier or later in some cases (Ref).Risk factors:• Higher dose and longer duration of glucocorticoid (Ref); however, may also increase risk at lower doses (eg, ≤5 mg/day of prednisone or equivalent) (Ref).• Immunocompromised state (Ref)• Concurrent medications (immunosuppressive) (Ref)• Rheumatoid arthritis (Ref)• Interstitial lung disease (Ref)• Older adults (Ref)• Male (Ref)• Low performance status (Ref)Neuromuscular and skeletal effectsGlucocorticoid (including dexamethasone)-induced neuromuscular and skeletal effects can take the form of various pathologies in patients ranging from osteoporosis and vertebral compression fracture to myopathy to osteonecrosis in adult and pediatric patients (Ref). Glucocorticoid use is the most common cause of secondary osteoporosis; may be underrecognized and undertreated due to underestimation of risk in this patient population (Ref). Vertebral fractures are the most common glucocorticoid-related fracture (Ref). Myopathies can also occur secondary to direct skeletal muscle catabolism (Ref). Acute steroid myopathy is rare (Ref).Mechanism: Dose- and time-related; glucocorticoids have direct/indirect effects on bone remodeling with osteoblast recruitment decreasing and apoptosis increasing (Ref). Myopathies or myasthenia result from reductions in protein synthesis and protein catabolism, which can manifest as proximal muscle weakness and atrophy in the upper and lower extremities (Ref).Onset: Delayed; vertebral fracture risk is increased within 3 months of initiation and peaks at 12 months (Ref).Risk factors:Drug-related risks:• Cumulative dose of glucocorticoids prednisone >5 g or equivalent (Ref)• Children receiving ≥4 courses of glucocorticoids (Ref)• Prednisone ≥2.5 mg to 7.5 mg daily or equivalent for ≥3 months (Ref)• Myopathy may occur at prednisone doses ≥10 mg daily or equivalent, with higher doses potentiating more of a rapid onset (Ref)• Fluorinated glucocorticoid preparations (eg, dexamethasone, betamethasone, triamcinolone) have a higher risk of myopathies (Ref)General fracture risks:• Age >55 years (Ref)• BMI <18.5 kg/m2 (Ref)• Bone mineral T score below -1.5 (Ref)• Endocrine disorders (eg, hypogonadism, hyper- or hypoparathyroidism) (Ref)• Excess alcohol use (>2 units/day) (Ref)• Females (Ref)• History of falls (Ref)• Malabsorption (Ref)• Menopause and duration of menopause (Ref)• White race (Ref)• Patients with cancer (Ref)• Previous fracture (Ref)• Smoking (Ref)• Underlying inflammatory condition in all ages (eg, inflammatory bowel disease, rheumatoid arthritis) (Ref)Ocular effectsGlucocorticoid (including dexamethasone)-induced ocular effects may include increased intraocular pressure (IOP), glaucoma (open-angle), and subcapsular posterior cataract in adult and pediatric patients (Ref). Cataracts may persist after discontinuation of glucocorticoid therapy (Ref).Mechanism: Dose- and time-related; Glucocorticoids can induce cataracts by covalently bonding to lens proteins, causing destabilization of the protein structure, and oxidative changes leading to cataracts formation (Ref). There are various proposed mechanisms of IOP contributing to glaucoma, including accumulation of polymerized glycosaminoglycans in the trabecular meshwork, producing edema and increasing outflow resistance (Ref). Another mechanism may include inhibition of phagocytic endothelial cells, leading to accumulation of aqueous debris (Ref). Glucocorticoids can also alter the trabecular meshwork causing an increase in nuclear size and DNA content (Ref). In addition, they can decrease the synthesis of prostaglandins which regulate the aqueous outflow (Ref).Onset: Delayed; cataracts may occur at least 1 year after initiation of chronic glucocorticoid therapy (Ref). IOP may occur at 4 years or more after initiation (Ref).Risk factors:• Dose (Ref)• Topical > Systemic (Ref)• Duration of use in all ages (Ref)• Family history of open-angle glaucoma (Ref)• Type I diabetes mellitus (Ref)• High myopia (Ref)• Pseudophakia (Ref)• Prior vitrectomies (Ref)• Connective tissue disease and sex (eg, rheumatoid arthritis in males) (Ref)• Older patients or age <6 years (Ref)• Genetics (Ref)• Angle recessive glaucoma (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Some reactions listed are based on reports for other agents in this same pharmacologic class and may not be specifically reported for dexamethasone.Frequency not defined:Cardiovascular: Bradycardia, cardiac arrhythmia, cardiomegaly, circulatory shock, edema, embolism (fat), heart failure (in susceptible patients), hypertension, myocardial rupture (after recent myocardial infarction), syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitisDermatologic: Acne vulgaris, allergic dermatitis, alopecia, atrophic striae, diaphoresis, ecchymoses, erythema of skin, facial erythema, fragile skin, hyperpigmentation, hypertrichosis, hypopigmentation, inadvertent suppression of skin test reaction, perianal skin irritation (itching, burning, tingling; following rapid IV injection; more common in females, with higher doses; sudden onset with resolution in <1 minute) (Allan 1986; Neff 2002; Perron 2003; Singh 2011), skin atrophy, skin rash, subcutaneous atrophy, urticaria, xerodermaEndocrine & metabolic: Decreased serum potassium, fluid retention, growth suppression (children), hirsutism, hypokalemic alkalosis, menstrual disease, negative nitrogen balance (due to protein catabolism), sodium retention, weight gainGastrointestinal: Hiccups, increased appetite, nausea, pancreatitis, pruritus ani (following IV injection)Genitourinary: Defective spermatogenesis (increased or decreased), glycosuriaHematologic & oncologic: Kaposi sarcoma (Goedert 2002), petechiaHepatic: Hepatomegaly, increased serum transaminasesHypersensitivity: Anaphylaxis, angioedema, nonimmune anaphylaxisInfection: Sterile abscessLocal: Postinjection flare (intra-articular use)Nervous system: Amyotrophy, emotional lability, euphoria, headache, increased intracranial pressure, intracranial hypertension (idiopathic; usually following discontinuation), malaise, myasthenia, neuritis, neuropathy, paresthesia, personality changes, seizure, vertigoNeuromuscular & skeletal: Charcot arthropathy, rupture of tendonOphthalmic: ExophthalmosRespiratory: Pulmonary edemaMiscellaneous: Wound healing impairmentPostmarketing:Cardiovascular: Hypertrophic cardiomyopathy (premature infants) (Kale 2015)Endocrine & metabolic: Adrenal suppression (tertiary) (Dineen 2019), Cushing syndrome (iatrogenic) (Hopkins 2005), cushingoid appearance (Hopkins 2005), exacerbation of diabetes mellitus (Tamez-Pérez 2015), hyperglycemia (Tamez-Pérez 2015), impaired glucose tolerance (Tamez-Pérez 2015), moon face (Hopkins 2005), redistribution of body fat (Hopkins 2005)Gastrointestinal: Abdominal distention (Liu 2013), intestinal perforation (Gordon 1999, Gordon 2001), peptic ulcer (with possible perforation and hemorrhage) (Liu 2013), ulcerative esophagitis (Liu 2013)Hematologic & oncologic: Tumor lysis syndrome (Chanimov 2006)Infection: Infection (Youssef 2016)Nervous system: Apathy (Ciriaco 2013, Warrington 2006), depression (Ciriaco 2013, Warrington 2006), psychiatric disturbance (including agitation, anxiety, distractibility, euphoria, fear, hypomania, insomnia, irritability, labile mood, lethargy, pressured speech, restlessness, tearfulness) (Ciriaco 2013, Warrington 2006)Neuromuscular & skeletal: Bone fracture (Buckley 2018), myopathy (Liu 2013), osteonecrosis (femoral and humoral heads) (Liu 2013), osteoporosis (Buckley 2018), steroid myopathy (Haran 2018), vertebral compression fracture (Buckley 2018)Ophthalmic: Glaucoma (Phulke 2017), increased intraocular pressure (Phulke 2017), subcapsular posterior cataract (Urban 1986)ContraindicationsHypersensitivity to dexamethasone or any component of the formulation; systemic fungal infectionsDocumentation of allergenic cross-reactivity for corticosteroids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.Warnings/PrecautionsConcerns related to adverse effects:• Adrenal suppression: May cause hypercortisolism or suppression of hypothalamic-pituitary-adrenal axis, particularly in younger children.Disease-related concerns:• Adrenal insufficiency: Dexamethasone does not provide any mineralocorticoid activity in adrenal insufficiency (may be employed as a single dose while cortisol assays are performed). Hydrocortisone is the preferred treatment of chronic primary adrenal insufficiency and adrenal crisis (ES [Bornstein 2016]).• Cardiovascular disease: Use with caution in patients with heart failure and/or hypertension; use has been associated with fluid retention, electrolyte disturbances, and hypertension. Monitor BP. Use with caution following acute myocardial infarction; corticosteroids have been associated with myocardial rupture.• GI disease: Use with caution in patients with GI diseases (diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, ulcerative colitis, abscess, or other pyogenic infection) due to GI perforation risk. Signs of GI perforation may be masked in patients receiving corticosteroid therapy.• Head injury: Increased mortality was observed in patients receiving high-dose IV methylprednisolone. High-dose corticosteroids should not be used for the management of head injury (BTF [Carney 2016]).• Hepatic impairment: Use with caution in patients with hepatic impairment, including cirrhosis; long-term use has been associated with fluid retention.• Hepatitis B: Reactivation may occur.• Myasthenia gravis: Use may cause transient worsening of myasthenia gravis (MG) (eg, within first 2 weeks of treatment); monitor for worsening MG (AAN [Narayanaswami 2021]).• Ocular disease: Use with caution in patients with a history of ocular herpes simplex; corneal perforation has occurred; do not use in active ocular herpes simplex. Not recommended for the treatment of optic neuritis; may increase frequency of new episodes.• Pheochromocytoma: Pheochromocytoma crisis (may be fatal) has been reported after administration of systemic corticosteroids. Consider the risk of pheochromocytoma crisis in patients with suspected or confirmed pheochromocytoma.• Renal impairment: Use with caution in patients with renal impairment; fluid retention may occur.• Seizure disorders: Use corticosteroids with caution in patients with a history of seizure disorder; seizures have been reported with adrenal crisis.• Systemic sclerosis: Use with caution in patients with systemic sclerosis; an increase in scleroderma renal crisis incidence has been observed with corticosteroid use. Monitor BP and renal function in patients with systemic sclerosis treated with corticosteroids (EULAR [Kowal-Bielecka 2017]).• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of corticosteroids increases in hyperthyroid patients and decreases in hypothyroid patients.Concurrent drug therapy issues:• Immunizations: Avoid administration of live or live attenuated vaccines in patients receiving immunosuppressive doses of corticosteroids. Non-live or inactivated vaccines may be administered, although the response cannot be predicted.Special populations:• Older adult: Use with caution in elderly patients with the smallest possible effective dose for the shortest duration.• Pediatric: May affect growth velocity; growth should be routinely monitored in pediatric patients.Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP ["Inactive" 1997]; Zar 2007).• Sulfite: Some products may contain sodium sulfite, a sulfite that may cause allergic-type reactions including anaphylaxis and life-threatening or less severe asthmatic episodes in susceptible patients.Other warnings/precautions:• Discontinuation of therapy: Withdraw therapy with gradual tapering of dose.• Epidural injection: Corticosteroids are not approved for epidural injection. Serious neurologic events (eg, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, stroke), some resulting in death, have been reported with epidural injection of corticosteroids, with and without use of fluoroscopy.• Intra-articular injection: May produce systemic as well as local effects. Appropriate examination of any joint fluid present is necessary to exclude a septic process. Avoid injection into an infected site. Do not inject into unstable joints. Patients should not overuse joints in which symptomatic benefit has been obtained as long as the inflammatory process remains active. Frequent intra-articular injection may result in damage to joint tissues.Warnings: Additional Pediatric ConsiderationsIn premature neonates, the use of high-dose dexamethasone (approximately >0.5 mg/kg/day) for the prevention or treatment of bronchopulmonary dysplasia has been associated with adverse neurodevelopmental outcomes, including higher rates of cerebral palsy without additional clinical benefit over lower doses; current data do not support use of high doses; further studies are needed (Watterberg 2010).Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities, which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults, including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).Metabolism/Transport EffectsSubstrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP3A4 (weak)Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Abrocitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Abrocitinib.Management: The use of abrocitinib in combination with other immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationAcetylcholinesterase Inhibitors: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur.Risk C: Monitor therapyAldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin.Risk X: Avoid combinationAmphotericin B: Corticosteroids (Systemic) may enhance the hypokalemic effect of Amphotericin B.Risk C: Monitor therapyAndrogens: Corticosteroids (Systemic) may enhance the fluid-retaining effect of Androgens.Risk C: Monitor therapyAntacids: May decrease the bioavailability of Corticosteroids (Oral). Management: Consider separating doses by 2 or more hours. Budesonide enteric coated tablets could dissolve prematurely if given with drugs that lower gastric acid, with unknown impact on budesonide therapeutic effects. Risk D: Consider therapy modificationAntidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.Risk C: Monitor therapyAprepitant: May increase the serum concentration of DexAMETHasone (Systemic). Management: Reduce dexamethasone dose 50% with aprepitant. Aprepitant labeling incorporates this recommendation into the dose provided for dexamethasone; further reduction is not necessary. No dose adjustment may be needed with single, low-dose aprepitant for PONV. Risk D: Consider therapy modificationBaricitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Baricitinib.Management: The use of baricitinib in combination with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationBCG Products: Corticosteroids (Systemic) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of BCG Products.Risk X: Avoid combinationBile Acid Sequestrants: May decrease the absorption of Corticosteroids (Oral). Risk C: Monitor therapyBrincidofovir: Corticosteroids (Systemic) may diminish the therapeutic effect of Brincidofovir.Risk C: Monitor therapyCalcitriol (Systemic): Corticosteroids (Systemic) may diminish the therapeutic effect of Calcitriol (Systemic).Risk C: Monitor therapyCAR-T Cell Immunotherapy: Corticosteroids (Systemic) may enhance the adverse/toxic effect of CAR-T Cell Immunotherapy. Specifically, the severity and duration of neurologic toxicities may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of CAR-T Cell Immunotherapy.Management: Avoid use of corticosteroids as premedication before treatment with CAR-T cell immunotherapy agents. Corticosteroids are indicated and may be required for treatment of toxicities such as cytokine release syndrome or neurologic toxicity. Risk D: Consider therapy modificationCaspofungin: Inducers of Drug Clearance may decrease the serum concentration of Caspofungin.Management: Consider using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m2, up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance. Risk D: Consider therapy modificationCladribine: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Cladribine.Risk X: Avoid combinationClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyCloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine.Risk C: Monitor therapyCobicistat: May increase the serum concentration of DexAMETHasone (Systemic). Dexamethasone (Systemic) may also counteract the boosting effects of Cobicistat on some agents. DexAMETHasone (Systemic) may increase the serum concentration of Cobicistat. Management: Consider an alternative corticosteroid. Monitor patients receiving this combination closely for evidence of diminished response to the antiviral regimen. Risk D: Consider therapy modificationCoccidioides immitis Skin Test: Corticosteroids (Systemic) may diminish the diagnostic effect of Coccidioides immitis Skin Test.Management: Consider discontinuing systemic corticosteroids (dosed at 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks) several weeks prior to coccidioides immitis skin antigen testing. Risk D: Consider therapy modificationCorticorelin: Corticosteroids (Systemic) may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response to corticorelin may be blunted by recent or current corticosteroid therapy.Risk C: Monitor therapyCosyntropin: Corticosteroids (Systemic) may diminish the diagnostic effect of Cosyntropin.Risk C: Monitor therapyCOVID-19 Vaccine (Adenovirus Vector): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector).Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters) Risk D: Consider therapy modificationCOVID-19 Vaccine (Inactivated Virus): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus).Risk C: Monitor therapyCOVID-19 Vaccine (mRNA): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA).Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modificationCOVID-19 Vaccine (Subunit): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit).Risk C: Monitor therapyCOVID-19 Vaccine (Virus-like Particles): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles).Risk C: Monitor therapyCYP3A4 Inducers (Moderate): May decrease the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of DexAMETHasone (Systemic). Management: Consider dexamethasone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced dexamethasone efficacy. Consider avoiding this combination when treating life threatening conditions (ie, multiple myeloma). Risk D: Consider therapy modificationCYP3A4 Inhibitors (Moderate): May increase the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapyCYP3A4 Inhibitors (Strong): May increase the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapyDeferasirox: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapyDelavirdine: DexAMETHasone (Systemic) may decrease the serum concentration of Delavirdine.Risk C: Monitor therapyDengue Tetravalent Vaccine (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live).Risk X: Avoid combinationDenosumab: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and systemic corticosteroids. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modificationDesirudin: Corticosteroids (Systemic) may enhance the anticoagulant effect of Desirudin. More specifically, corticosteroids may increase hemorrhagic risk during desirudin treatment.Management: Discontinue treatment with systemic corticosteroids prior to desirudin initiation.If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: Consider therapy modificationDesmopressin: Corticosteroids (Systemic) may enhance the hyponatremic effect of Desmopressin.Risk X: Avoid combinationDeucravacitinib: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Management: The use of deucravacitinib in combination with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationDisulfiram: May enhance the adverse/toxic effect of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid combinationElvitegravir: DexAMETHasone (Systemic) may decrease the serum concentration of Elvitegravir.Management: Consider using an alternative corticosteroid.Monitor patients receiving these agents in combination for diminished antiviral response. Risk D: Consider therapy modificationEPHEDrine (Systemic): May decrease the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapyEstrogen Derivatives: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapyFexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFilgotinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Filgotinib.Management: Coadministration of filgotinib with systemic corticosteroids at doses equivalent to greater than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks is not recommended. Risk D: Consider therapy modificationFosamprenavir: DexAMETHasone (Systemic) may decrease the serum concentration of Fosamprenavir. Fosamprenavir may increase the serum concentration of DexAMETHasone (Systemic).Risk C: Monitor therapyFosaprepitant: May increase the serum concentration of DexAMETHasone (Systemic). Management: Reduce the dexamethasone dose 50% when coadministered with aprepitant. Aprepitant prescribing information incorporates this recommendation into the dose provided for dexamethasone; further reduction is not necessary. Risk D: Consider therapy modificationFosnetupitant: May increase the serum concentration of DexAMETHasone (Systemic). Management: Decrease dexamethasone doses to 12 mg on day 1, and if needed based on the emetic potential of the regimen, 8 mg daily on days 2 to 4 of chemotherapy when administered with fosnetupitant. Risk D: Consider therapy modificationFosphenytoin: May decrease the serum concentration of DexAMETHasone (Systemic). DexAMETHasone (Systemic) may decrease the serum concentration of Fosphenytoin. DexAMETHasone (Systemic) may increase the serum concentration of Fosphenytoin. Management: Consider dexamethasone dose increases when combined with fosphenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely, both increased and decreased phenytoin levels have been reported. Risk D: Consider therapy modificationFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationGallium Ga 68 Dotatate: Corticosteroids (Systemic) may diminish the diagnostic effect of Gallium Ga 68 Dotatate.Risk C: Monitor therapyGrowth Hormone Analogs: Corticosteroids (Systemic) may diminish the therapeutic effect of Growth Hormone Analogs. Growth Hormone Analogs may decrease serum concentrations of the active metabolite(s) of Corticosteroids (Systemic).Risk C: Monitor therapyHormonal Contraceptives: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hormonal Contraceptives.Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modificationHyaluronidase: Corticosteroids (Systemic) may diminish the therapeutic effect of Hyaluronidase.Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider therapy modificationImatinib: DexAMETHasone (Systemic) may decrease the serum concentration of Imatinib.Management: Avoid concurrent use of imatinib with dexamethasone when possible.If such a combination must be used, increase imatinib dose by at least 50% and monitor clinical response closely. Risk D: Consider therapy modificationImmune Checkpoint Inhibitors: Corticosteroids (Systemic) may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Management: Carefully consider the need for corticosteroids, at doses of a prednisone-equivalent of 10 mg or more per day, during the initiation of immune checkpoint inhibitor therapy. Use of corticosteroids to treat immune related adverse events is still recommended Risk D: Consider therapy modificationIndium 111 Capromab Pendetide: Corticosteroids (Systemic) may diminish the diagnostic effect of Indium 111 Capromab Pendetide.Risk X: Avoid combinationInebilizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Inebilizumab.Risk C: Monitor therapyInfluenza Virus Vaccines: Corticosteroids (Systemic) may diminish the therapeutic effect of Influenza Virus Vaccines.Management: Administer influenza vaccines at least 2 weeks prior to initiation of systemic corticosteroids at immunosuppressive doses. Influenza vaccines administered less than 14 days prior to or during such therapy should be repeated 3 months after therapy. Risk D: Consider therapy modificationIsoniazid: Corticosteroids (Systemic) may decrease the serum concentration of Isoniazid.Risk C: Monitor therapyLapatinib: DexAMETHasone (Systemic) may decrease the serum concentration of Lapatinib.Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Risk X: Avoid combinationLeflunomide: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Leflunomide.Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as systemic corticosteroids. Risk D: Consider therapy modificationLenalidomide: DexAMETHasone (Systemic) may enhance the thrombogenic effect of Lenalidomide.Management: Consider using venous thromboembolism prophylaxis (eg, low-molecular weight heparin or warfarin [INR 2.0-3.0]) in patients with multiple myeloma who are receiving lenalidomide and dexamethasone. Risk D: Consider therapy modificationLicorice: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapyLoop Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Loop Diuretics.Risk C: Monitor therapyLopinavir: DexAMETHasone (Systemic) may decrease the serum concentration of Lopinavir.Management: Consider alternative corticosteroids for coadministration with lopinavir/ritonavir due to the potential for dexamethasone to decrease lopinavir/ritonavir efficacy and result in the development of resistance. Risk D: Consider therapy modificationLutetium Lu 177 Dotatate: Corticosteroids (Systemic) may diminish the therapeutic effect of Lutetium Lu 177 Dotatate.Management: Avoid repeated use of high-doses of corticosteroids during treatment with lutetium Lu 177 dotatate. Use of corticosteroids is still permitted for the treatment of neuroendocrine hormonal crisis. The effects of lower corticosteroid doses is unknown. Risk D: Consider therapy modificationMacimorelin: Corticosteroids (Systemic) may diminish the diagnostic effect of Macimorelin.Risk X: Avoid combinationMethotrimeprazine: Products Containing Ethanol may enhance the adverse/toxic effect of Methotrimeprazine. Specifically, CNS depressant effects may be increased.Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid combinationMetyraPONE: Corticosteroids (Systemic) may diminish the diagnostic effect of MetyraPONE.Management: Consider alternatives to the use of the metyrapone test in patients taking systemic corticosteroids. Risk D: Consider therapy modificationMifamurtide: Corticosteroids (Systemic) may diminish the therapeutic effect of Mifamurtide.Risk X: Avoid combinationMiFEPRIStone: May diminish the therapeutic effect of Corticosteroids (Systemic). MiFEPRIStone may increase the serum concentration of Corticosteroids (Systemic). Management: Avoid mifepristone in patients who require long-term corticosteroid treatment of serious illnesses or conditions (eg, for immunosuppression following transplantation). Corticosteroid effects may be reduced by mifepristone treatment. Risk X: Avoid combinationNatalizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Natalizumab.Risk X: Avoid combinationNetupitant: May increase the serum concentration of DexAMETHasone (Systemic). Management: Decrease dexamethasone doses to 12 mg on day 1, and if needed based on the emetic potential of the regimen, 8 mg daily on days 2 to 4 of chemotherapy when administered with netupitant. Risk D: Consider therapy modificationNeuromuscular-Blocking Agents (Nondepolarizing): May enhance the adverse neuromuscular effect of Corticosteroids (Systemic). Increased muscle weakness, possibly progressing to polyneuropathies and myopathies, may occur. Management: If concomitant therapy is required, use the lowest dose for the shortest duration to limit the risk of myopathy or neuropathy. Monitor for new onset or worsening muscle weakness, reduction or loss of deep tendon reflexes, and peripheral sensory decriments Risk D: Consider therapy modificationNicorandil: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nicorandil. Gastrointestinal perforation has been reported in association with this combination.Risk C: Monitor therapyNiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine.Risk C: Monitor therapyNirmatrelvir and Ritonavir: May increase the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective).Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (Nonselective): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective).Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (Topical): May enhance the adverse/toxic effect of Corticosteroids (Systemic). Specifically, the risk of gastrointestinal bleeding, ulceration, and perforation may be increased. Risk C: Monitor therapyOcrelizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ocrelizumab.Risk C: Monitor therapyOfatumumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ofatumumab.Risk C: Monitor therapyOrnidazole: May enhance the adverse/toxic effect of Products Containing Ethanol. Specifically, a disulfiram-like reaction may occur. Risk X: Avoid combinationPhenytoin: May decrease the serum concentration of DexAMETHasone (Systemic). DexAMETHasone (Systemic) may decrease the serum concentration of Phenytoin. DexAMETHasone (Systemic) may increase the serum concentration of Phenytoin. Management: Consider dexamethasone dose increases when combined with phenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely when combined with dexamethasone, both increased and decreased phenytoin levels have been reported. Risk D: Consider therapy modificationPidotimod: Corticosteroids (Systemic) may diminish the therapeutic effect of Pidotimod.Risk C: Monitor therapyPimecrolimus: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Risk X: Avoid combinationPneumococcal Vaccines: Corticosteroids (Systemic) may diminish the therapeutic effect of Pneumococcal Vaccines.Risk C: Monitor therapyPoliovirus Vaccine (Live/Trivalent/Oral): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral).Risk X: Avoid combinationPolymethylmethacrylate: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Polymethylmethacrylate. Specifically, the risk for hypersensitivity or implant clearance may be increased.Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modificationQuinolones: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Quinolones. Specifically, the risk of tendonitis and tendon rupture may be increased.Risk C: Monitor therapyRabies Vaccine: Corticosteroids (Systemic) may diminish the therapeutic effect of Rabies Vaccine.Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modificationRilpivirine: DexAMETHasone (Systemic) may decrease the serum concentration of Rilpivirine.Risk X: Avoid combinationRitodrine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Ritodrine.Risk C: Monitor therapyRubella- or Varicella-Containing Live Vaccines: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines.Risk X: Avoid combinationRuxolitinib (Topical): Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ruxolitinib (Topical).Risk X: Avoid combinationSalicylates: May enhance the adverse/toxic effect of Corticosteroids (Systemic). These specifically include gastrointestinal ulceration and bleeding. Corticosteroids (Systemic) may decrease the serum concentration of Salicylates. Withdrawal of corticosteroids may result in salicylate toxicity. Risk C: Monitor therapySaquinavir: DexAMETHasone (Systemic) may decrease the serum concentration of Saquinavir.Management: Consider alternatives to this combination if possible, due to the potential for decreased saquinavir/ritonavir therapeutic effect and the potential development of resistance. Risk D: Consider therapy modificationSargramostim: Corticosteroids (Systemic) may enhance the therapeutic effect of Sargramostim. Specifically, corticosteroids may enhance the myeloproliferative effects of sargramostim.Risk C: Monitor therapySecnidazole: Products Containing Ethanol may enhance the adverse/toxic effect of Secnidazole.Risk X: Avoid combinationSelpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib.Risk C: Monitor therapySimeprevir: DexAMETHasone (Systemic) may decrease the serum concentration of Simeprevir.Risk X: Avoid combinationSipuleucel-T: Corticosteroids (Systemic) may diminish the therapeutic effect of Sipuleucel-T.Management: Consider reducing the dose or discontinuing immunosuppressants, such as systemic corticosteroids, prior to initiating sipuleucel-T therapy. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone given for 2 or more weeks are immunosuppressive. Risk D: Consider therapy modificationSirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Conventional).Risk C: Monitor therapySirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Protein Bound).Risk C: Monitor therapySodium Benzoate: Corticosteroids (Systemic) may diminish the therapeutic effect of Sodium Benzoate.Risk C: Monitor therapySphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Risk C: Monitor therapySuccinylcholine: Corticosteroids (Systemic) may enhance the neuromuscular-blocking effect of Succinylcholine.Risk C: Monitor therapyTacrolimus (Systemic): Corticosteroids (Systemic) may decrease the serum concentration of Tacrolimus (Systemic). Conversely, when discontinuing corticosteroid therapy, tacrolimus concentrations may increase.Risk C: Monitor therapyTacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic).Risk C: Monitor therapyTacrolimus (Topical): Corticosteroids (Systemic) may enhance the immunosuppressive effect of Tacrolimus (Topical).Risk X: Avoid combinationTalimogene Laherparepvec: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased.Risk X: Avoid combinationTemsirolimus: DexAMETHasone (Systemic) may decrease serum concentrations of the active metabolite(s) of Temsirolimus.Risk C: Monitor therapyTertomotide: Corticosteroids (Systemic) may diminish the therapeutic effect of Tertomotide.Risk X: Avoid combinationThalidomide: DexAMETHasone (Systemic) may enhance the dermatologic adverse effect of Thalidomide. DexAMETHasone (Systemic) may enhance the thrombogenic effect of Thalidomide.Management: Consider using venous thromboembolism prophylaxis (eg, low-molecular-weight heparin or warfarin [INR 2.0 to 3.0]) in patients with multiple myeloma receiving both thalidomide and dexamethasone. Monitor for increased dermatologic adverse effects (eg, rash) Risk D: Consider therapy modificationThiazide and Thiazide-Like Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics.Risk C: Monitor therapyTofacitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Tofacitinib.Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationTyphoid Vaccine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Typhoid Vaccine.Risk X: Avoid combinationUbrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant.Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Risk D: Consider therapy modificationUpadacitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Upadacitinib.Management: Coadministration of upadacitinib with systemic corticosteroids at doses equivalent to greater than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks is not recommended. Risk D: Consider therapy modificationUrea Cycle Disorder Agents: Corticosteroids (Systemic) may diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Corticosteroids (Systemic) may increase protein catabolism and plasma ammonia concentrations, thereby increasing the doses of Urea Cycle Disorder Agents needed to maintain these concentrations in the target range.Risk C: Monitor therapyVaccines (Inactivated/Non-Replicating): Corticosteroids (Systemic) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating).Management: Administer vaccines at least 2 weeks prior to immunosuppressive corticosteroids if possible. If patients are vaccinated less than 14 days prior to or during such therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationVaccines (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Vaccines (Live).Management: Avoid live vaccines during and for 1 month after therapy with immunosuppressive doses of corticosteroids (equivalent to prednisone > 2 mg/kg or 20 mg/day in persons over 10 kg for at least 2 weeks). Give live vaccines prior to therapy whenever possible. Risk D: Consider therapy modificationVitamin K Antagonists (eg, warfarin): Corticosteroids (Systemic) may enhance the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapyVoriconazole: DexAMETHasone (Systemic) may decrease the serum concentration of Voriconazole.Risk C: Monitor therapyYellow Fever Vaccine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Yellow Fever Vaccine.Risk X: Avoid combinationReproductive ConsiderationsThe manufacturer’s labeling for use of dexamethasone as part of combination therapy for multiple myeloma recommends pregnancy testing prior to use in patients who may become pregnant. Patients who may become pregnant should use effective contraception during therapy and for at least 1 month after the last dexamethasone dose. Consult individual monographs for additional information related to pregnancy testing and contraception when combination therapy is used for multiple myeloma.Dexamethasone may alter the motility of and number of spermatozoa.Pregnancy ConsiderationsDexamethasone crosses the placenta (Brownfoot 2013); and is partially metabolized by placental enzymes to an inactive metabolite (Murphy 2007).Some studies have shown an association between first trimester systemic corticosteroid use and oral clefts or decreased birth weight; however, information is conflicting and may be influenced by maternal dose/indication for use (Lunghi 2010; Park-Wyllie 2000; Pradat 2003). Hypoadrenalism may occur in newborns following maternal use of corticosteroids during pregnancy; monitor.Dexamethasone is classified as a fluorinated corticosteroid. When systemic corticosteroids are needed in pregnancy for rheumatic disorders, nonfluorinated corticosteroids (eg, prednisone) are preferred. Chronic high doses should be avoided for the treatment of maternal disease (ACR [Sammaritano 2020]).Use of the overnight dexamethasone 1 mg suppression test for Cushing syndrome is not recommended during pregnancy due to the increased risk of false positives. In addition, dexamethasone is generally avoided for the treatment of pregnant patients with adrenal insufficiency (ES [Nieman 2008]; ESE [Luger 2021]).Antenatal corticosteroid administration promotes fetal lung maturity and is associated with the reduction of intraventricular hemorrhage, necrotizing enterocolitis, neonatal mortality, and respiratory distress syndrome. A single course of dexamethasone is recommended for patients between 24 0/7 and 33 6/7 weeks' gestation who are at risk of delivering within 7 days. This recommendation includes those with ruptured membranes or multiple gestations. A single course of dexamethasone may be considered for patients beginning at 23 0/7 weeks' gestation who are at risk of delivering within 7 days, in consultation with the family regarding resuscitation. In addition, a single course of dexamethasone may be given to patients between 34 0/7 weeks and 36 6/7 weeks who are at risk of preterm delivery within 7 days and who have not previously received corticosteroids if induction or delivery will proceed ≥24 hours and ≤7 days; delivery should not be delayed for administration of antenatal corticosteroids. Use of concomitant tocolytics is not currently recommended and administration of late preterm corticosteroids has not been evaluated in patients with intrauterine infection, multiple gestations, pregestational diabetes, or patients who delivered previously by cesarean section at term. Multiple repeat courses are not recommended. However, in patients with pregnancies less than 34 weeks' gestation at risk for delivery within 7 days and who had a course of antenatal corticosteroids >14 days prior, a single repeat course may be considered; use of a repeat course in patients with preterm prelabor rupture of membranes is controversial (ACOG 2016; ACOG 2017; ACOG 2020).Dexamethasone is used off label in the management of COVID-19. Use is recommended for hospitalized pregnant patients with COVID-19 who require mechanical ventilation, or who require supplemental oxygen without mechanical ventilation (NIH 2022). In patients who do not require dexamethasone for fetal lung maturity, or in those who have already completed a course of dexamethasone to enhance fetal lung development, treatment recommendations are available using alternative corticosteroids which have more limited placental transfer and may provide less fetal risk. A treatment algorithm is available for pregnant patients with severe or critical COVID-19 requiring corticosteroids for fetal lung maturation and those who do not (Saad 2020). The risk of severe illness from COVID-19 infection is increased in symptomatic pregnant patients compared to nonpregnant patients (ACOG 2022). Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.Some products contain alcohol, benzyl alcohol or sodium sulfite; use of preservative-free or alternative formulations in pregnancy is recommended.Breastfeeding ConsiderationsCorticosteroids are present in breast milk; information specific to dexamethasone has not been located.The manufacturer notes that when used systemically, maternal use of corticosteroids have the potential to cause adverse events in a breastfeeding infant (eg, growth suppression, interfere with endogenous corticosteroid production).Single doses of dexamethasone are considered compatible with breastfeeding; information related to prolonged use is not available (WHO 2002). If there is concern about exposure to the infant, some guidelines recommend waiting 4 hours after the maternal dose of an oral systemic corticosteroid before breastfeeding in order to decrease potential exposure to the breastfed infant (based on a study using prednisolone) (Leachman 2006; Makol 2011; Ost 1985). Dexamethasone is classified as a fluorinated corticosteroid. When systemic corticosteroids are needed in a lactating patient for rheumatic disorders, low doses of nonfluorinated corticosteroids (eg, prednisone) are preferred (ACR [Sammaritano 2020]). Due to the potential for serious adverse reactions in the breastfeeding infant, some manufacturers recommend a decision be made to discontinue breastfeeding or to discontinue the drug, considering the importance of treatment to the mother. The manufacturer's labeling for use of dexamethasone as part of combination therapy for multiple myeloma recommends breastfeeding be discontinued during therapy and for 2 weeks after the last dexamethasone dose.Dietary ConsiderationsMay be taken with meals to decrease GI upset. May need diet with increased potassium, pyridoxine, vitamin C, vitamin D, folate, calcium, and phosphorus.Monitoring ParametersHb, occult blood loss, BP, serum potassium, blood glucose, creatine kinase (if symptoms of myopathy occur), bone mineral density; intraocular pressure with systemic use >6 weeks; consider routine eye exams with chronic use; weight and height in children; hypothalamic-pituitary-adrenal axis suppression.Oncology patients: Evaluate pregnancy status (in females of reproductive potential when receiving for multiple myeloma treatment). The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.Mechanism of ActionDexamethasone is a long-acting corticosteroid with minimal sodium-retaining potential. It decreases inflammation by suppression of neutrophil migration, decreased production of inflammatory mediators, and reversal of increased capillary permeability; suppresses normal immune response. Dexamethasone induces apoptosis in multiple myeloma cells. Dexamethasone's mechanism of antiemetic activity is unknown.Pharmaco*kineticsOnset of action: IV: Rapid.Immune thrombocytopenia: Oral: Initial response: 2 to 14 days; Peak response: 4 to 28 days (Neunert 2011).Duration: IV: Short.Absorption: Oral: 61% to 86% (Czock 2005).Metabolism: Hepatic.Half-life elimination:Extremely low birth-weight infants with BPD: 9.26 ± 3.34 hours (range: 5.85 to 16.1 hours) (Charles 1993).Children 4 months to 16 years: 4.34 ± 4.14 hours (range: 2.33 to 9.54 hours) (Richter 1983).Adults: Oral: 4 ± 0.9 hours (Czock 2005); IV: ~1 to 5 hours (Hochhaus 2001; Miyabo 1981; Rohdewald 1987; Tóth 1999).Time to peak, serum: Oral: 1 to 2 hours (Czock 2005); IM: ~30 to 120 minutes (Egerman 1997; Hochhaus 2001); IV: 5 to 10 minutes (free dexamethasone) (Miyabo 1981; Rohdewald 1987).Excretion: Urine (~10%) (Duggan 1975; Miyabo 1981).Pricing: USConcentrate (Dexamethasone Intensol Oral)1 mg/mL (per mL): $1.07Elixir (Dexamethasone Oral)0.5 mg/5 mL (per mL): $0.11 - $0.27Kit (DoubleDex Injection)10 mg/mL (per each): $598.00Kit (MAS Care-Pak Injection)10 mg/mL (per each): $605.00Solution (Dexamethasone Oral)0.5 mg/5 mL (per mL): $0.27Solution (Dexamethasone Sod Phosphate PF Injection)10 mg/mL (per mL): $2.10 - $8.22Solution (Dexamethasone Sodium Phosphate Injection)4 mg/mL (per mL): $0.93 - $3.4710 mg/mL (per mL): $1.49 - $1.7220 mg/5 mL (per mL): $0.21 - $1.51100 mg/10 mL (per mL): $0.48 - $1.70120 mg/30 mL (per mL): $0.39 - $1.63Tablet Therapy Pack (Dexamethasone Oral)1.5MG (21) (per each): $8.06 - $8.541.5MG (35) (per each): $8.551.5MG (51) (per each): $8.54Tablet Therapy Pack (Dxevo 11-Day Oral)1.5 mg (per each): $17.79Tablet Therapy Pack (HiDex 6-Day Oral)1.5MG (21) (per each): $33.29Tablet Therapy Pack (TaperDex 12-Day Oral)1.5MG (49) (per each): $5.68Tablet Therapy Pack (TaperDex 6-Day Oral)1.5 mg (per each): $10.801.5MG (21) (per each): $10.80Tablet Therapy Pack (TaperDex 7-Day Oral)1.5MG (27) (per each): $8.66Tablets (Dexamethasone Oral)0.5 mg (per each): $0.14 - $0.210.75 mg (per each): $0.25 - $0.271 mg (per each): $0.30 - $0.371.5 mg (per each): $0.48 - $3.702 mg (per each): $0.59 - $0.744 mg (per each): $1.19 - $1.206 mg (per each): $1.78 - $1.90Tablets (Hemady Oral)20 mg (per each): $31.31Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAacidexam (BE);Alin (CR, DO, GT, HN, NI, PA, SV);Asiadexa (VN);Camidexon (ID);Corodex (UY);Cortyk (CL);D Cort (BD);Decadron (AE, BH, CO, CY, EC, IT, JO, KW, LB, PY, QA, SA);Decan (PH, SG);Decasone (ZA);Decdan (IN);Dectancyl (VN);Deltasone (EG);Desalark (IT);Dexa-Sine (BE);Dexacor (BD);Dexacort Forte (IL);Dexaflam (DE);Dexafree (CH, FR, PL, PT);Dexamax (PH);Dexamed (CZ, JO, RO, SG, TR);Dexamed Elixir (LK);Dexamet Solution for Injection (HK);Dexanocorten (EG);Dexasone (EG, MY);Dexazone (QA);Dexcor (BD);Dexmethsone (AU, NZ);Dexo (ET);Dexona (ET, IN);Dexona-E (LK);Dexone (ZW);Dexovit (LK);Dexsol (IE);Fortecortin (AT, BG, CH, DE, ES);Lenadex (JP);Lodexa (TH);Lodexa-5 (TH);Maradex (VE);Martapan (GB);Medicort (PE);Meradexone (BD);Metacort (PH);Methodex (LK);Millicorten (QA);Naxidex (LK);Nexadron Oftal (AR);Odeson (BD);Oftan Dexa (EE);Opnol (SE);Oradexon (CL, FI, ID, NL, PT, SA);Ordex (BD);Ronic (ET);Sonexa (BD);Spersadex (CH, DE, HK, NO, ZA);Sterodex (IL);Steron (BD);Vedex (LK);Vextasone (MY);Vherdex (PH);Visumetazone (IT);Wymesone (IN)For country code abbreviations (show table)Abouir K, Gosselin P, Guerrier S, et al. 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[PubMed 17555487]Topic 9100 Version 680.0

CloseAcyclovir (systemic): Pediatric drug informationAcyclovir (systemic): Pediatric drug information(For additional information see "Acyclovir (systemic): Drug information" and see "Acyclovir (systemic): Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USZoviraxBrand Names: CanadaAPO-Acyclovir;MINT-Acyclovir;MYLAN-Acyclovir;TEVA-Acyclovir;ZoviraxTherapeutic CategoryAntiviral Agent, Oral;Antiviral Agent, ParenteralDosing: NeonatalHerpes simplex virus (HSV) infection, treatment: Note: Duration of therapy depends on site of infection and clinical response; for CNS and disseminated infections, treat for ≥21 days; for skin and mucous membrane infections, treat for 14 days (Ref).Preterm and term neonates:Weight-based dosing: Preterm and term neonates: IV: 20 mg/kg/dose every 8 hours (Ref).Postmenstrual age-directed dosing (Ref):Preterm and term neonates: IV: Note: Dosing is based on pharmaco*kinetic modeling and has not been evaluated prospectively (Ref).PMADose<30 weeks20 mg/kg/dose every 12 hours30 to <36 weeks20 mg/kg/dose every 8 hours36 to 41 weeks20 mg/kg/dose every 6 to 8 hoursHSV, chronic suppression following any HSV infection: Limited data available: Preterm and term neonates: Oral: 300 mg/m2/dose every 8 hours for 6 months; begin after completion of IV treatment course; adjust dose monthly to account for growth (Ref).Varicella (chickenpox), treatment: Limited data available; optimal dose has not been established:Preterm and term neonates: IV: 10 to 15 mg/kg/dose every 8 hours for 7 to 10 days; continue for ≥48 hours after the last new lesions have appeared; doses of 20 mg/kg/dose every 8 hours have also been reported (Ref).Dosing: Altered kidney function: Neonatal:Term neonates (Ref): IV:CrCl >50 mL/minute/1.73 m2: No adjustments necessary.CrCl 25 to 50 mL/minute/1.73 m2 or SCr 0.8 to 1.1 mg/dL: Administer the usual recommended dose every 12 hours.CrCl 10 to <25 mL/minute/1.73 m2 or SCr >1.1 to 1.5 mg/dL: Administer the usual recommended dose every 24 hours.CrCl <10 mL/minute/1.73 m2 or SCr >1.5 mg/dL: Administer 50% of the usual recommended dose every 24 hours (eg, if the usual recommended dose is 10 mg/kg/dose every 8 hours, administer 5 mg/kg/dose every 24 hours).Dosing: PediatricNote: Obese patients should be dosed using ideal body weight. Parenteral IV doses >15 mg/kg/dose or 500 mg/m2 may be associated with an increased risk of nephrotoxicity; close monitoring of renal function is recommended (Ref).Cytomegalovirus prophylaxisCytomegalovirus (CMV) prophylaxis: Low-risk allogeneic hematopoietic stem cell transplant (HSCT) in seropositive recipient. Note: Begin at engraftment and continue to day 100; requires close monitoring for CMV reactivation (due to weak activity); not for use in patients at high risk for CMV disease (Ref):Oral:Infants, Children, and Adolescents <40 kg: 600 mg/m2/dose 4 times daily; maximum dose: 800 mg/dose.Children and Adolescents ≥40 kg: 800 mg 4 times daily.IV: Infants, Children, and Adolescents: 500 mg/m2/dose every 8 hours.Varicella zoster virus, acute retinal necrosis, treatment, HIV-exposed/-infectedVaricella zoster virus, acute retinal necrosis, treatment, HIV-exposed/-infected:Initial treatment: Note: Follow up IV therapy with oral valacyclovir or acyclovir therapy (valacyclovir preferred) (Ref).Infants and Children: IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days (Ref).Adolescents: IV: 10 mg/kg/dose every 8 hours for 10 to 14 days; recommended to be used in combination with 1 to 2 doses of intravitreal ganciclovir (Ref).Maintenance treatment (alternative to valacyclovir): Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 4 to 6 weeks to begin after 10- to 14-day course of IV acyclovir (Ref).Herpes zoster, treatmentHerpes zoster (shingles), treatment:Immunocompetent host: Ambulatory therapy: Children ≥12 years and Adolescents: Oral: 800 mg every 4 hours (5 doses per day) for 5 to 7 days (Ref).Hospitalized patient:Infants and Children <2 years: IV: 10 mg/kg/dose every 8 hours for 7 to 10 days (Ref).Children ≥2 years and Adolescents: IV: 500 mg/m2/dose every 8 hours for 7 to 10 days; some experts recommend 10 mg/kg/dose every 8 hours (Ref).Immunocompromised host, non-HIV-exposed/-infected: IV: Infants, Children, and Adolescents: 10 mg/kg/dose every 8 hours for 7 to 10 days (Ref).HIV-exposed/-infected:Mild, uncomplicated disease and no or moderate immune suppression:Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 to 10 days; maximum dose: 800 mg/dose; consider longer course if resolution of lesions is slow (Ref).Adolescents (alternative therapy): Oral: 800 mg 5 times daily for 7 to 10 days, longer if lesions resolve slowly (Ref).Severe immune suppression or complicated disease; trigeminal nerve involvement, extensive multidermatomal zoster or extensive cutaneous lesions or visceral involvement:Infants: IV: 10 mg/kg/dose every 8 hours until resolution of cutaneous lesions and visceral disease clearly begins, then convert to oral therapy to complete a 10- to 14-day total course of therapy (Ref).Children: IV: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours until resolution of cutaneous lesions and visceral disease clearly begins, then convert to oral therapy to complete a 10- to 14-day total course of therapy (Ref).Adolescents: IV: 10 mg/kg/dose every 8 hours until clinical improvement is evident, then convert to oral therapy to complete a 10- to 14-day total course of therapy (Ref).Herpes simplex virus neonatal infection, treatment and suppressive therapy in very young infantsHerpes simplex virus (HSV) neonatal infection, treatment and suppressive therapy in very young infants (independent of HIV status):Treatment (disseminated, CNS, or skin, eye, or mouth disease): Infants 1 to 3 months: IV: 20 mg/kg/dose every 8 hours; treatment duration: For cutaneous and mucous membrane infections (skin, eye, or mouth): 14 days; for CNS or disseminated infection: 21 days (Ref).Chronic suppressive therapy following any neonatal HSV infection: Infants: Oral: 300 mg/m2/dose every 8 hours for 6 months; begin after completion of a 14- to 21-day-course of IV therapy dependent upon type of infection (Ref).HSV encephalitis, treatmentHSV encephalitis, treatment:Independent of HIV status:Infants and Children 3 months to <12 years: IV: 10 to 15 mg/kg/dose every 8 hours for 14 to 21 days. Note: Due to increased risk of neurotoxicity and nephrotoxicity, higher doses (20 mg/kg) are not routinely recommended (Ref).Children ≥12 years and Adolescents: IV: 10 mg/kg/dose every 8 hours for 14 to 21 days (Ref).HSV genital infectionHSV genital infection: First infection, mild to moderate:Non-HIV-exposed/-infected:Children <12 years: Oral: 40 to 80 mg/kg/day divided in 3 to 4 doses per day for 7 to 10 days; maximum daily dose: 1,200 mg/day (Ref).Children and Adolescents ≥12 years: Oral: 200 mg every 4 hours while awake (5 times daily) or 400 mg 3 times daily for 7 to 10 days; treatment can be extended beyond 10 days if healing is not complete (Ref).HIV-exposed/-infected:Children: Oral: 20 mg/kg/dose 3 times daily for 7 to 10 days; maximum dose: 400 mg/dose (Ref).Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days (Ref).First infection, severe (independent of HIV status): IV: Children and Adolescents ≥12 years: 5 mg/kg/dose every 8 hours for 5 to 7 days or 5 to 10 mg/kg/dose every 8 hours for 2 to 7 days, followed with oral therapy to complete at least 10 days of therapy (Ref).Recurrent infection:Children <12 years (independent of HIV status): Oral: 20 mg/kg/dose 3 times daily for 5 days; maximum dose: 400 mg/dose (Ref).Children and Adolescents ≥12 years:Non-HIV-exposed/-infected: Oral: 200 mg every 4 hours while awake (5 times daily) for 5 days, or 400 mg 3 times daily for 5 days, or 800 mg twice daily for 5 days or 800 mg 3 times daily for 2 days (Ref).HIV-exposed/-infected: Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days (Ref).Suppression, chronic:Non-HIV-exposed/-infected:Children <12 years: Limited data available: Oral: 20 mg/kg/dose twice daily; maximum dose: 400 mg/dose (Ref).Children and Adolescents ≥12 years: Oral: 400 mg twice daily; reassess therapy after 12 months (Ref).HIV-exposed/-infected: Infants and Children: Oral: 20 mg/kg/dose twice daily; maximum dose: 800 mg/dose (Ref).Adolescents: Oral: 400 mg twice daily (Ref).HSV orolabial diseaseHSV orolabial disease (ie, gingivostomatitis, herpes labialis):Non-HIV-exposed/-infected: Primary infection: Infants, Children, and Adolescents: Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; usual maximum dose: 800 mg/dose (Ref).HIV-exposed/-infected (Ref):Mild, symptomatic:Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 to 10 days; maximum dose: 400 mg/dose.Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days (Ref).Moderate to severe, symptomatic: Note: Switch to oral therapy once lesions begin to regress and continue oral therapy until lesions completely healed.Infants and Children: IV: 5 to 10 mg/kg/dose every 8 hours.Adolescents: IV: 5 mg/kg/dose every 8 hours.HSV mucocutaneous infectionHSV mucocutaneous infection: Immunocompetent host: Infants, Children, and Adolescents:Treatment:IV: 5 mg/kg/dose every 8 hours (Ref).Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; maximum dose: 800 mg/dose (Ref).Suppression, chronic: Limited data available; no pediatric data; some experts recommend oral 20 mg/kg/dose 2 to 3 times daily for 6 to 12 months, then reevaluate need; maximum dose: 400 mg/dose (Ref).Immunocompromised host: Treatment:IV:Infants and Children: IV: 10 mg/kg/dose every 8 hours for 7 to 14 days (Ref).Adolescents: IV: 5 to 10 mg/kg/dose every 8 hours; change to oral therapy after lesions begin to regress (Ref).Oral: Children ≥2 years and Adolescents: 1,000 mg/day in 3 to 5 divided doses for 7 to 14 days (Ref).Suppression, chronic (cutaneous, ocular) episodes:Non-HIV-exposed/-infected:Children ≥12 years and Adolescents: Oral: 400 mg twice daily; reassess at 12 months (Ref).HIV-exposed/-infected:Infants and Children: Oral: 20 mg/kg/dose twice daily; maximum dose: 800 mg/dose; reassess after 12 months (Ref).Adolescents: Oral: 400 mg twice daily; reassess at 12 months (Ref).HSV progressive or disseminated infection, treatmentHSV progressive or disseminated infection, treatment (immunocompromised host):Non-HIV-exposed/-infected: Infants, Children, and Adolescents: IV: 10 mg/kg/dose every 8 hours for 7 to 14 days (Ref).HIV-exposed/-infected: Infants, Children, and Adolescents: IV: 10 mg/kg/dose every 8 hours for 21 days; higher doses (up to 20 mg/kg/dose) may be used in children <12 years of age (Ref).HSV, acute retinal necrosis, treatment, HIV-exposed/-infectedHSV, acute retinal necrosis, treatment, HIV-exposed/-infected: Infants and Children (Ref):Initial treatment: IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days. Note: Follow up IV therapy with oral acyclovir or valacyclovir maintenance therapy.Maintenance treatment (alternative to valacyclovir): Begin after 10- to 14-day course of IV acyclovir: Oral: 20 mg/kg/dose 4 times daily for 4 to 6 weeks.HSV prophylaxis; immunocompromised hosts, seropositiveHSV prophylaxis; immunocompromised hosts, seropositive:HSCT in seropositive recipient (Ref):Prevention of early reactivation: Note: Begin at conditioning and continue until engraftment or resolution of mucositis; whichever is longer (~30 days post-HSCT)Infants, Children, and Adolescents <40 kg:IV: 250 mg/m2/dose every 8 hours or 125 mg/m2/dose every 6 hours; maximum daily dose: 80 mg/kg/dayOral: 60 to 90 mg/kg/day in 2 to 3 divided doses; maximum dose: 800 mg/dose twice dailyChildren and Adolescents ≥40 kg:IV: 250 mg/m2/dose every 12 hoursOral: 400 to 800 mg twice dailyPrevention of late reactivation: Note: Treatment during first year after HSCT.Infants, Children, and Adolescents <40 kg: Oral: 60 to 90 mg/kg/day in 2 to 3 divided doses; maximum daily dose: 800 mg twice dailyChildren and Adolescents ≥40 kg: Oral: 800 mg twice dailyOther immunocompromised hosts who are HSV seropositive: IV: Infants, Children, and Adolescents: 5 mg/kg/dose every 8 hours during period of risk (Ref).Oral: Children ≥2 years and Adolescents: 200 mg every 4 hours while awake (5 doses daily) or 200 mg every 8 hours; administer during periods of risk (Ref).Varicella or herpes zoster, prophylaxisVaricella (chickenpox) or herpes zoster (shingles), prophylaxisHSCT: Prophylaxis of disease reactivation: Note: Continue therapy for 1 year after HSCT (Ref):Infants, Children, and Adolescents <40 kg: Oral: 60 to 80 mg/kg/day in 2 to 3 divided dosesChildren and Adolescents ≥40 kg: Oral: 800 mg twice dailyHIV-exposed/-infected: Limited data available: Note: Consider use if >96 hours postexposure or if VZV-immune globulin is not available; begin therapy 7 to 10 days after exposure; some experts begin therapy at first appearance of rash (Ref).Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 days; maximum dose: 800 mg/dose (Ref).Adolescents: Oral: 800 mg 5 times daily for 5 to 7 days (Ref).Other immunocompromised hosts: Infants, Children, and Adolescents: Oral: 20 mg/kg/dose 4 times daily for 7 days; maximum dose: 800 mg/dose. Note: Consider use if VZV-immune globulin or IVIG is not available; begin therapy 7 to 10 days after exposure (Ref).Varicella, treatmentVaricella (chickenpox), treatment: Begin treatment within the first 24 hours of rash onset:Immunocompetent host: Ambulatory therapy: Oral: Infants, Children, and Adolescents: 20 mg/kg/dose 4 times daily for 5 days; maximum daily dose: 3,200 mg/day (Ref).Hospitalized patient: IV: Infants, Children, and Adolescents: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 to 14 days (Ref); some experts recommend 15 to 20 mg/kg/dose for severe disseminated or CNS infection (Ref).Immunocompromised host, non-HIV-exposed/-infected:Infants and Children <2 years: IV: 10 mg/kg/dose every 8 hours; duration dependent upon clinical response, typically 7 to 14 days (Ref).Children ≥2 years and Adolescents: IV: 500 mg/m2/dose every 8 hours duration dependent upon clinical response, typically 7 to 14 days; some experts recommend 10 mg/kg/dose every 8 hours (Ref).HIV-exposed/-infected: Mild, uncomplicated disease and no or moderate immune suppression:Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 to 10 days and until no new lesions for 48 hours; maximum dose: 800 mg/dose (Ref).Adolescents (alternative therapy): Oral: 800 mg 5 times daily for 5 to 7 days (Ref).Severe, complicated disease or severe immune suppression:Infants: IV: 10 mg/kg/dose every 8 hours for 7 to 10 days and until no new lesions for 48 hours (Ref).Children: IV: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 to 10 days or until no new lesions for 48 hours (Ref).Adolescents: IV: 10 mg/kg/dose every 8 hours for 7 to 10 days; may convert to oral therapy after defervescence and if no evidence of visceral involvement is evident (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricMonitor closely for neurotoxicity (Ref).Infants, Children and Adolescents: IV:CrCl >50 mL/minute/1.73 m2: No dosage adjustment necessaryCrCl 25 to 50 mL/minute/1.73 m2: Administer the usual recommended dose every 12 hoursCrCl 10 to <25 mL/minute/1.73 m2: Administer the usual recommended dose every 24 hoursCrCl <10 mL/minute/1.73 m2: Administer 50% of the usual recommended dose every 24 hours (eg, if the usual recommended dose is 10 mg/kg/dose every 8 hours, then administer 5 mg/kg/dose every 24 hours)Intermittent hemodialysis (IHD): Dialyzable (60% reduction following a 6-hour session): 5 mg/kg/dose every 24 hours; administer after hemodialysis on dialysis days (Ref)Peritoneal dialysis (PD): 5 mg/kg/dose every 24 hours; no supplemental dose needed (Ref)Continuous renal replacement therapy (CRRT): 10 mg/kg/dose every 12 hours (Ref)Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Adult(For additional information see "Acyclovir (systemic): Drug information")Note: Use ideal body weight or adjusted body weight for weight-based dosing in patients with obesity to avoid overdosing and subsequent toxicity (eg, acute renal failure) (Ref).Bell palsy, new onsetBell palsy, new onset (adjunctive therapy) (alternative agent) (off-label use): Oral: 400 mg 5 times daily for 10 days in combination with corticosteroids; begin within 3 days of symptom onset. Note: Antiviral therapy alone is not recommended (Ref); some experts only recommend addition of an antiviral to steroid therapy in patients with severe Bell palsy (Ref).Cytomegalovirus, prevention in low-risk allogeneic hematopoietic cell transplant recipientsCytomegalovirus, prevention in low-risk allogeneic hematopoietic cell transplant recipients (alternative agent) (off-label use): Note: Begin at engraftment and continue to day 100; requires close monitoring for cytomegalovirus (CMV) reactivation (due to weak activity); not for use in patients at high risk for CMV disease (Ref):IV: 500 mg/m2/dose every 8 hours for up to 4 weeks or until hospital discharge, followed by oral therapy (Ref).Oral: Following initial IV therapy: 800 mg 4 times daily (Ref).Herpes simplex virus, central nervous system infectionHerpes simplex virus, central nervous system infection (encephalitis or meningitis): IV: 10 mg/kg/dose every 8 hours. Duration for encephalitis is 14 to 21 days and for meningitis is 10 to 14 days; treatment of encephalitis requires IV therapy while treatment of meningitis may include step-down oral antiviral therapy. Note: Empiric herpes simplex virus (HSV) therapy should be initiated in all patients with suspected encephalitis (Ref).Herpes simplex virus, mucocutaneous infectionHerpes simplex virus, mucocutaneous infection:Esophagitis (off-label use):Immunocompetent patients: Oral: 400 mg 3 times daily or 200 mg 5 times daily for 7 to 10 days (Ref).Immunocompromised patients: Oral: 400 mg 5 times daily for 14 to 21 days (Ref).Patients with severe odynophagia or dysphagia: IV: 5 mg/kg/dose every 8 hours; patients who rapidly improve can be switched to an oral antiviral to complete a total of 7 to 14 days of therapy (Ref).Genital:Immunocompetent patients:Treatment, initial episode:Oral: 400 mg 3 times daily for 7 to 10 days; extend duration if lesions have not healed completely after 10 days (Ref).IV (for severe disease): 5 to 10 mg/kg/dose every 8 hours; once clinically improved, may switch to oral antiviral therapy to complete >10 days of therapy total (Ref).Treatment, recurrent episode: Oral: 800 mg twice daily for 5 days or 800 mg 3 times daily for 2 days. Note: Treatment is most effective when initiated during the prodrome or within 1 day of lesion onset (Ref).Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 400 mg twice daily. Note: Reassess need periodically (eg, annually) (Ref).Immunocompromised patients (including patients with HIV):Treatment, initial or recurrent episode:Oral: 400 mg 3 times daily for 5 to 10 days (7 to 10 days for initial episode in patients with HIV); extend treatment duration if lesions have not healed completely after 10 days (Ref).IV (for severe disease): 5 to 10 mg/kg/dose every 8 hours; may transition to oral antiviral therapy once lesions begin to regress and continue for >10 days of therapy and until complete resolution (Ref).Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 400 to 800 mg 2 to 3 times daily. Note: Reassess need periodically (eg, annually) (Ref).Pregnant patients:Treatment, initial episode: Oral: 400 mg 3 times daily for 7 to 10 days; extend treatment duration if lesion has not healed completely after 10 days (Ref).Treatment, recurrent episode (symptomatic): Oral: 400 mg 3 times daily or 800 mg twice daily for 5 days (Ref). Note: Some experts reserve treatment of recurrent episodes for patients with severe and/or frequent symptoms (Ref).Treatment, severe or disseminated disease: IV: 5 to 10 mg/kg every 8 hours for 2 to 7 days, then change to oral therapy for primary infection to complete 10 days of therapy (Ref).Suppressive therapy, for patients with a genital HSV lesion anytime during pregnancy: Oral: 400 mg 3 times daily, beginning at 36 weeks gestation and continued until delivery (Ref); some experts recommend discontinuing suppressive therapy at the onset of labor (Ref). Note: For patients with a primary infection during the third trimester, may consider suppressive therapy earlier than 36 weeks' gestation (Ref).Orolabial: Note: Initiate therapy at earliest symptom.Immunocompetent and immunocompromised patients (including patients with HIV):Treatment, initial or recurrent episode:Oral: 400 mg 3 times daily for 5 to 10 days and until complete lesion resolution in immunocompromised patients (Ref)IV (for severe disease in immunocompromised patients): 5 mg/kg/dose every 8 hours; switch to oral acyclovir (or similar antiviral) once lesions begin to regress and continue until complete resolution (Ref).Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 400 mg twice daily (Ref). Note: Reassess need periodically (eg, annually) (Ref).Herpes simplex virus, prevention in immunocompromised patientsHerpes simplex virus, prevention in immunocompromised patients (off-label use):Seropositive hematopoietic cell transplant recipients (allogeneic or autologous) or seropositive patients undergoing leukemia induction chemotherapy:IV: 250 mg/m2/dose every 12 hours (Ref)Oral: 400 to 800 mg twice daily (Ref)Note: Initiate with the chemotherapeutic or conditioning regimen and continue until recovery of WBC count and resolution of mucositis; duration may be extended in patients with frequent recurrences or graft-vs-host disease (Ref).Solid organ transplant recipients (HSV-seropositive patients who do not require CMV prophylaxis): Oral: 400 to 800 mg twice daily for ≥1 month (Ref); some experts recommend continuing for 3 to 6 months after transplantation and during periods of lymphodepletion associated with treatment of rejection (Ref).Herpes zoster, treatmentHerpes zoster (shingles), treatment: Note: Initiate at earliest sign or symptom. Antiviral treatment is most effective ≤72 hours after rash onset but may be initiated >72 hours in certain situations (eg, new lesions continue to appear); for immunocompromised patients, initiate treatment even if >72 hours after symptom onset unless all lesions have crusted (Ref).Acute localized dermatomal lesion(s): Oral: 800 mg 5 times daily for 7 to 10 days; for slowly improving lesions, may extend therapy until resolution (Ref). For select immunocompromised patients at high risk of dissemination (eg, recent transplant, graft-versus-host disease), some experts suggest regimens used for disseminated zoster (Ref).Disseminated zoster (extensive cutaneous lesions or visceral involvement): IV: 10 mg/kg/dose every 8 hours (Ref). When formation of new lesions has ceased and signs/symptoms of visceral infection are improving, switch to an oral antiviral to complete a total of 10 to 14 days of therapy (Ref).Herpes zoster ophthalmicusHerpes zoster ophthalmicus (off-label use): Immunocompromised patients or patients who require hospitalization for sight-threatening disease: IV: 10 mg/kg/dose every 8 hours for 7 days (Ref)Varicella, treatmentVaricella (chickenpox), treatment: Ideally initiate therapy within 24 hours of symptom onset, but may start later if the patient still has active lesions:Immunocompetent patients with uncomplicated infection: Oral: 800 mg 5 times daily for ≥5 to 7 days and until all lesions have crusted (Ref)Immunocompromised patients (including patients with HIV):Severe or complicated infection: IV: 10 mg/kg/dose every 8 hours for 7 to 10 days (Ref). May switch to oral antiviral after defervescence if no evidence of visceral involvement; continue until all lesions have crusted (Ref).Uncomplicated infection: Oral: 800 mg 5 times daily for 5 to 7 days (Ref); some experts recommend a minimum duration of 7 days, extending the course until all lesions have crusted (Ref).Varicella zoster virus, acute retinal necrosisVaricella zoster virus, acute retinal necrosis (off-label use): IV: 10 mg/kg/dose every 8 hours for 10 to 14 days, followed by ~6 weeks of valacyclovir (Ref); in patients with HIV, intravitreal ganciclovir should be added (Ref).Varicella zoster virus, encephalitisVaricella zoster virus, encephalitis (off-label use): IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days (Ref)Varicella zoster virus, prevention in immunocompromised patientsVaricella zoster virus, prevention in immunocompromised patients (off-label use):Seropositive hematopoietic cell transplant recipients (allogeneic and autologous): Oral: 800 mg twice daily (Ref). Note: Initiate with the chemotherapeutic or conditioning regimen and continue for 1 year; may extend duration in patients requiring ongoing immunosuppression (some experts continue prophylaxis in these patients until 6 months after discontinuation of all systemic immunosuppression) (Ref).Solid organ transplant recipients (VZV-seropositive patients who do not require CMV prophylaxis): Oral: 200 mg 3 to 5 times daily for 3 to 6 months after transplantation and during periods of lymphodepletion associated with treatment of rejection (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Note: Monitor closely for neurotoxicity (Ref). For usual recommended doses not described in the following sections, a comparable reduction in the dose and/or frequency may be considered based on CrCl or the type of dialysis, taking into consideration the goals of therapy and the anticipated duration of treatment (Ref).Altered kidney function:Acyclovir Dose Adjustments for Kidney Impairment aCrClbOralIVIf the usual dose is 400 mg every 12 hoursIf the usual dose is 200 mg 5 times daily If the usual dose is 800 mg 5 times dailyIf the usual dose is 5 mg/kg/dose every 8 hoursIf the usual dose is 10 mg/kg/dose every 8 hoursaRecommendations are from manufacturer’s labeling unless otherwise noted.bThe manufacturer's labeling dosing adjustments are reported as mL/minute/1.73 m2 based on data using CrCl adjusted for BSA (Blum 1982; de Miranda 1983).cWhile toxicity is not likely to occur with an unadjusted dose in patients with a CrCl of 10 to 25 mL/minute/1.73 m2 (as recommended in the manufacturer’s labeling), the exposure from the reduced dose is expected to be comparable to exposure achieved in patients receiving the usual recommended dose with normal kidney function (ie, CrCl >50 mL/minute/1.73 m2) (expert opinion).dManufacturer’s labeling recommends 800 mg every 12 hours. However, due to reports of neurotoxicity in patients with end-stage kidney disease (Almond 1995; Beales 1994; Davenport 1992), a reduced dose is preferred (expert opinion).>50 mL/minute/1.73 m2No dosage adjustment necessary.No dosage adjustment necessary.No dosage adjustment necessary.No dosage adjustment necessary.No dosage adjustment necessary.25 to 50 mL/minute/1.73 m2No dosage adjustment necessary.No dosage adjustment necessary.No dosage adjustment necessary.5 mg/kg/dose every 12 hours10 mg/kg/dose every 12 hours10 to <25 mL/minute/1.73 m2No dosage adjustment necessary or reduce to 200 mg every 12 hourscNo dosage adjustment necessary or reduce to 200 mg every 8 hoursc800 mg every 8 hours5 mg/kg/dose every 24 hours10 mg/kg/dose every 24 hours<10 mL/minute/1.73 m2 (not on dialysis)200 mg every 12 hours200 mg every 12 hours200 mg every 12 hours or 400 mg every 12 hours (severe infections)d2.5 mg/kg/dose every 24 hours5 mg/kg/dose every 24 hoursAugmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): IV, Oral: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).Use the indication-specific maximum allowable dose along with therapeutic drug monitoring when available (Ref).Hemodialysis, intermittent (thrice weekly): Dialyzable (60% reduction following a 6-hour session (Ref)). Therapeutic drug monitoring of acyclovir is recommended when available (Ref).Oral:If the usual recommended dose is 200 mg 5 times daily or 400 mg every 12 hours: Administer 200 mg every 12 hours. Administer after dialysis when given on a dialysis day or administer an additional dose after each dialysis (Ref).If the usual recommended dose is 800 mg 5 times daily: Administer a loading dose of 400 mg, followed by a maintenance dose of 200 mg every 12 hours, plus an additional 400 mg dose after each dialysis session (Ref). Note: Dose based on pharmaco*kinetic data and computer modeling.IV: 2.5 to 5 mg/kg/dose every 24 hours. Administer after dialysis when given on a dialysis day (Ref). Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.Peritoneal dialysis: Dialyzable (12% reduction during continuous ambulatory peritoneal dialysis (Ref)): Therapeutic drug monitoring of acyclovir is recommended when available (Ref).Oral:If the usual recommended dose is 200 mg 5 times daily or 400 mg every 12 hours: Administer 200 mg every 12 hours (Ref).If the usual recommended dose is 800 mg 5 times daily: Administer 600 to 800 mg every 24 hours (Ref).IV: 2.5 to 5 mg/kg/dose every 24 hours, no supplemental dose needed (Ref). Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important. Therapeutic drug monitoring of acyclovir is recommended when available (Ref).IV: 5 to 10 mg/kg/dose every 12 to 24 hours (Ref). Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important. Therapeutic drug monitoring of acyclovir is recommended when available (Ref).IV: 5 to 10 mg/kg/dose every 12 to 24 hours (Ref). On non-PIRRT days, dose as for CrCl <10 mL/minute/1.73 m2. Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.Dosing: Hepatic Impairment: AdultOral, IV: There are no dosage adjustments provided in the manufacturer's labeling; use caution in patients with severe impairment.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productCapsule, Oral: Zovirax: 200 mg [DSC] [contains fd&c blue #2 (indigotine), parabens]Generic: 200 mgSolution, Intravenous, as sodium [strength expressed as base]: Generic: 50 mg/mL (20 mL)Solution, Intravenous, as sodium [strength expressed as base, preservative free]: Generic: 50 mg/mL (10 mL, 20 mL)Suspension, Oral: Zovirax: 200 mg/5 mL (473 mL [DSC]) [contains methylparaben, propylparaben]Zovirax: 200 mg/5 mL (473 mL) [contains methylparaben, propylparaben; banana flavor]Generic: 200 mg/5 mL (473 mL)Tablet, Oral: Zovirax: 400 mg [DSC]Zovirax: 800 mg [DSC] [contains fd&c blue #2 (indigotine)]Generic: 400 mg, 800 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution, Intravenous: Generic: 25 mg/mL (20 mL)Solution, Intravenous, as sodium [strength expressed as base]: Generic: 50 mg/mL (10 mL, 20 mL)Suspension, Oral: Zovirax: 200 mg/5 mL (125 mL) [contains methylparaben, propylparaben]Tablet, Oral: Generic: 200 mg, 400 mg, 800 mgAdministration: PediatricOral: May administer with or without food; shake suspension well before use. Maintain adequate hydration during therapy.Parenteral: Administer by slow IV infusion over at least 1 hour; rapid infusion is associated with nephrotoxicity due to crystalluria and renal tubular damage and should be avoided. Maintain adequate hydration during therapy. Do not administer IV push, IM, or SubQ.Acyclovir IV is an irritant (depending on concentration); avoid extravasation. If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Apply dry warm compresses. Intradermal hyaluronidase may be considered for refractory cases (Ref).Administration: AdultOral: Administer with or without food.IV: Avoid rapid infusion; infuse over 1 hour to prevent renal damage; maintain adequate hydration of patient; check for phlebitis and rotate infusion sites. Do not administer IM or SubQ. Acyclovir IV is an irritant (depending on concentration); avoid extravasation.Storage/StabilityCapsule, oral suspension, tablet: Store at controlled room temperature of 15°C to 25°C (59°F to 77°F); protect capsule and tablet from moisture.Powder for injection: Store undiluted vials at 15°C to 25°C (59°F to 77°F). Following reconstitution (final concentration 50 mg/mL), solution is stable for 12 hours at room temperature.Solution for injection: Store solution at 20°C to 25°C (68°F to 77°F).Do not refrigerate reconstituted solutions or solutions diluted for infusion as they may precipitate. Once diluted for infusion with NS or D5W, use within 24 hours.UseParenteral: Treatment of initial and prophylaxis of recurrent mucosal and cutaneous herpes simplex (HSV 1 and HSV 2) infections in immunocompromised patients (FDA approved in all ages); treatment of severe initial episodes of herpes genitalis in immunocompetent patients (FDA approved in ages ≥12 years and adults); treatment of herpes simplex encephalitis, including neonatal herpes simplex virus (FDA approved in all ages); treatment of herpes zoster (shingles) infections in immunocompromised patients (FDA approved in all ages).Oral: Treatment of varicella (chickenpox) in immunocompetent patients (FDA approved in ages ≥2 years and adults); treatment of initial episodes and prophylaxis of recurrent herpes simplex (HSV 2, genital herpes) and acute treatment of herpes zoster (shingles) (FDA approved in adults).Has also been used for treatment of varicella-zoster infections in healthy, nonpregnant persons >13 years of age, children >12 months of age who have a chronic skin or lung disorder or are receiving long-term aspirin therapy, and immunocompromised patients; oral therapy has also been used for suppression following parenteral treatment of neonatal HSV infection.Medication Safety IssuesSound-alike/look-alike issues:Acyclovir may be confused with famciclovir, ganciclovir, Retrovir, valacyclovir, valganciclovirZovirax may be confused with Doribax, Valtrex, Zithromax, Zostrix, Zyloprim, ZyvoxAdverse Reactions (Significant): ConsiderationsAcute kidney injuryAcyclovir may cause acute kidney injury, resulting most often from obstructive nephropathy but may also be due to interstitial nephritis or renal tubular necrosis in adult and pediatric patients (Ref). Kidney injury is reversible in most cases after dosage reduction or discontinuation, although in some instances, a full return to baseline may not occur (Ref).Mechanism: Dose-related; formation of acyclovir crystals is the most commonly noted cause of kidney injury, resulting in intrarenal obstruction and nephropathy (Ref). Less commonly, an immune reaction may contribute to interstitial nephritis (Ref). In addition, a major metabolite of acyclovir (9-carboxymethoxymethylguanine [CMMG]) may be directly cytotoxic to cells of the renal tubule (Ref).Onset: Rapid; typically occurred within 48 hours of initiation in adult and pediatric patients (Ref). May occur after a single dose (Ref).Risk factors:Adult patients:• Rapid infusion of high dose (Ref)• Intravenous administration (due to higher bioavailability of acyclovir/valacyclovir), although cases during oral therapy have been noted (Ref)• Volume depletion (Ref)• Preexisting kidney impairment (Ref)• Hypertension (Ref)• Diabetes (Ref)• Concurrent use of nephrotoxic agents (eg, nonsteroidal anti-inflammatory drugs, vancomycin) (Ref)• Obesity (Ref)Pediatric patients:• Doses >500 mg/m2 (Ref)• Doses >15 mg/kg (associated with a 25% to 49% reduction in eGFR) (Ref)• Age >8 years (Ref)• Weight >20 kg (Ref)• BMI >19 kg/m2 (Ref)• Concomitant ceftriaxone with or without gadolinium (Ref)NeurotoxicityAcyclovir-induced neuropsychiatric symptoms are a spectrum of neurologic disturbances, including confusion, agitation, lethargy, hallucination, and impaired consciousness, representing cognitive, psychiatric, or motor disturbances (Ref). Rare features may include aphasia and ataxia. Myoclonus, tremor, and seizure (including status epilepticus) have also been reported (Ref).Mechanism: Dose-related; indirect, via metabolite 9-carboxymethoxymethylguanine (CMMG) accumulation (Ref).Onset: Varied; within 1 to 5 days of dose administration in most patients (Ref); however, some cases have occurred after 30 days or more (Ref).Risk factors:• Higher doses (on a mg/kg basis) (Ref)()• Kidney impairment (Ref); however, some cases reported in normal kidney function (Ref)• Patient weight (presumably also associated with dose) (Ref)• Increased CSF: Albumin ratio (indicating blood-brain barrier passage) (Ref)Thrombotic microangiopathyThrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS), manifestations of thrombotic microangiopathy, have been reported with acyclovir/valacyclovir (Ref). TTP/HUS may result in damage to the brain, kidney, liver, heart, and pancreas (Ref). In one trial, valacyclovir was associated more frequently than acyclovir (14 cases vs a total of 4 in 2 acyclovir arms) and the symptoms were noted to be less severe than in classical TTP/HUS (Ref). Resolution has been noted with drug discontinuation and appropriate therapy (Ref).Mechanism: Idiosyncratic; leading to intravascular platelet-fibrin microthrombi, vascular damage, hemolysis, and thrombocytopenia (Ref). In HUS, this injury is believed to be initiated by uncontrolled activity of the alternative complement pathway, while TTP features a reduction in activity of ADAMTS13, the metalloprotease responsible for cleaving ultra-large von Willebrand factor multimers (Ref). Medications that cause direct injury to endothelial cells may result in HUS (Ref). Alternatively, some medications can trigger TTP by causing an immune reaction leading to development of drug-induced auto-antibodies against ADAMTS13 (Ref).Onset: Variable; may occur within a few days of initiation (Ref) or be delayed (ie, after a year in one case with valacyclovir) (Ref).Risk factors:Largely unknown:• Genetic susceptibility may play a role for drug-induced HUS (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported with IV administration, unless otherwise noted.>10%:Hematologic & oncologic: Decreased hemoglobin (neonates: 13%), decrease in absolute neutrophil count (neonates: 3% to 16%)Nervous system: Malaise (oral: 12%)1% to 10%:Dermatologic: Pruritus (≤2%), skin rash (≤2%), urticaria (≤2%)Gastrointestinal: Diarrhea (oral: 2% to 3%; IV: <1%), nausea (oral and IV: ≤7%), vomiting (oral and IV: ≤7%)Hematologic & oncologic: Thrombocytopenia (neonates: 5% to 10%; children, adolescents, and adults: <1%)Hepatic: Increased serum bilirubin (neonates, grades 3/4: 4%), increased serum transaminases (1% to 2%)Local: Inflammation at injection site (≤9%), injection site phlebitis (≤9%)Nervous system: Headache (≤2%)Renal: Increased blood urea nitrogen (5% to 10%), increased serum creatinine (5% to 10%)<1%: Hematologic & oncologic: Anemia, leukocytosis, neutropenia, neutrophilia, thrombocythemiaFrequency not defined: Gastrointestinal: AnorexiaPostmarketing:Cardiovascular: Hypersensitivity angiitis, hypotension, peripheral edemaDermatologic: Acute generalized exanthematous pustulosis (Kubin 2016), alopecia (Sharma 2016), bullous rash (Gurkan 2012), contact dermatitis (topical) (Vernassiere 2003), erythema multiforme, skin photosensitivity (topical) (Rodriguez-Serna 1999), Stevens-Johnson syndrome (Fazal 1995), toxic epidermal necrolysisGenitourinary: Hematuria (Meng 2011)Hematologic & oncologic: Disseminated intravascular coagulation, hemolysis, hemolytic-uremic syndrome (Bell 1997), leukopenia, lymphadenopathy, thrombotic thrombocytopenic purpura (Bukhari 2020)Hepatic: Hepatitis, hyperbilirubinemia, jaundiceHypersensitivity: Anaphylaxis, angioedema (Jen 2011), fixed drug eruption (Lee 2016)Nervous system: Aggressive behavior, agitation (Rashiq 1993), aphasia (Patel 2019), ataxia (Patel 2019), coma, confusion (Rashiq 1993), delirium (Rashiq 1993), dizziness, drowsiness, dysarthria, encephalopathy, fatigue, hallucination (Berry 2014), impaired consciousness (Adair 1994), myoclonus (Adair 1994), obtundation (Adair 1994), pain, paresthesia, psychosis, seizure (Hoskote 2016)Neuromuscular & skeletal: Myalgia, tremor (Rashiq 1993)Renal: Acute kidney injury (common: >10%) (Lee 2018), interstitial nephritis (Rashed 1990), renal disease (obstructive nephropathy) (Fleischer 2010), renal tubular necrosis (Chavez-Iniguez)Miscellaneous: FeverContraindicationsHypersensitivity to acyclovir, valacyclovir, or any component of the formulationWarnings/PrecautionsConcerns related to adverse effects:• Extravasation: Acyclovir IV is an irritant (depending on concentration); avoid extravasation.Disease-related concerns:• Varicella: Appropriate use: For maximum benefit, treatment should begin within 24 hours of appearance of rash; oral route not recommended for routine use in otherwise healthy children with varicella but may be effective in patients at increased risk of moderate to severe infection (>12 years of age, chronic cutaneous or pulmonary disorders, long-term salicylate therapy, corticosteroid therapy).Dosage form specific issues:• Injection: Use IV preparation with caution in patients with underlying neurologic abnormalities, serious hepatic or electrolyte abnormalities, or substantial hypoxia. Encephalopathic changes characterized by lethargy, obtundation, confusion, hallucination, tremors, agitation, seizure, or coma have been observed in patients receiving IV acyclovir.Metabolism/Transport EffectsSubstrate of OAT1/3, OCT1; Inhibits CYP1A2 (weak)Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programCladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine.Risk X: Avoid combinationCloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine.Risk C: Monitor therapyFoscarnet: May enhance the nephrotoxic effect of Acyclovir-Valacyclovir. Risk X: Avoid combinationMycophenolate: Acyclovir-Valacyclovir may increase the serum concentration of Mycophenolate. Mycophenolate may increase the serum concentration of Acyclovir-Valacyclovir.Risk C: Monitor therapyNetilmicin (Systemic): Acyclovir (Systemic) may enhance the nephrotoxic effect of Netilmicin (Systemic). Acyclovir (Systemic) may enhance the neurotoxic effect of Netilmicin (Systemic).Risk X: Avoid combinationTalimogene Laherparepvec: Antiherpetic Antivirals may diminish the therapeutic effect of Talimogene Laherparepvec.Risk C: Monitor therapyTenofovir Products: Acyclovir-Valacyclovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir.Risk C: Monitor therapyTheophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives.Risk C: Monitor therapyTiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine.Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modificationVaricella Virus Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Varicella Virus Vaccine.Management: When possible, avoid use of acyclovir or valacyclovir within the 24 hours prior to administration of the varicella vaccine, and avoid use of these antiviral agents for 14 days after vaccination. Risk X: Avoid combinationZidovudine: Acyclovir-Valacyclovir may enhance the CNS depressant effect of Zidovudine.Risk C: Monitor therapyZoster Vaccine (Live/Attenuated): Acyclovir-Valacyclovir may diminish the therapeutic effect of Zoster Vaccine (Live/Attenuated).Risk X: Avoid combinationDietary ConsiderationsSome products may contain sodium.Pregnancy ConsiderationsAcyclovir crosses the placenta (Frenkel 1991; Henderson 1992; Kimberlin 1998).A pregnancy registry established in 1984 and closed in 1999 included 749 pregnancies with 756 known outcomes following first trimester acyclovir exposure. Data from the registry did not find an increase in the number of birth defects with exposure to acyclovir when compared to those expected in the general population. In addition, no pattern of birth defects was observed (Stone 2004). A population-based registry study conducted in Denmark had similar results. The study used data from 1996 to 2008 and included 1,561 pregnancies with first trimester acyclovir exposure; an increased risk of birth defects was not observed (Pasternak 2010). One study observed an increased risk of gastroschisis following use of antiherpetic medications such as acyclovir during the first trimester to treat maternal genital herpes; this risk was also increased in offspring of women with genital herpes not receiving treatment (Ahrens 2013).Due to pregnancy-induced physiologic changes, the pharmaco*kinetic properties of acyclovir may be altered in some women (Brocklehurst 1998; Frenkel 1991; Kimberlin 1998; Leung 2009). Dose adjustments are required for suppressive therapy and recurrent infections during pregnancy due to increased renal clearance (ACOG 2020). Acyclovir is associated with adverse effects on renal function; this risk may be increased with IV administration to patients during the third trimester of pregnancy (Boujenah 2020).Acyclovir is recommended for the treatment of genital herpes simplex virus (HSV) in pregnant patients (ACOG 2020; CDC [Workowski 2021]). Primary HSV infection during the first trimester may be associated with neonatal chorioretinitis, microcephaly, and skin lesions. The risk of perinatal transmission is greater when the primary infection occurs during pregnancy. Maternal treatment decreases duration and severity of disease and duration of viral shedding (ACOG 2020). Suppressive therapy is recommended for patients beginning at 36 weeks' gestation who have a history of genital lesions (ACOG 2020; CDC [Workowski 2021]).Acyclovir is also recommended for the treatment of varicella (chickenpox) in pregnant patients. When treatment is started within 24 hours of rash development, acyclovir reduces the duration and total number of maternal lesions; however, it does not prevent congenital varicella syndrome (ACOG 2015).Monitoring ParametersUrine output, volume status, BUN, SCr, urinalysis; liver enzymes; CBC (including neutrophil count at least twice weekly in neonates receiving 60 mg/kg/day [Kimberlin 2001]). When using high doses, monitor for signs and symptoms of neurotoxicity (eg, lethargy, confusion, hallucinations, tremors, myoclonus, seizures, extrapyramidal signs, changes in state of consciousness) (Whitley 2012).Mechanism of ActionAcyclovir is converted to acyclovir monophosphate by virus-specific thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.Pharmaco*kinetics (Adult data unless noted)Absorption: Oral: Poorly absorbed; absorption improves with multiple small doses compared to one large daily dose (de Miranda 1983).Distribution: Widely (eg, brain, kidney, lungs, liver, spleen, muscle, uterus, vagin*, CSF) (de Miranda 1983; Laskin 1983); CSF acyclovir concentration is ~50% of plasma concentrations.Vd:Neonates (Sampson 2014; manufacturer's labeling):PMA <30 weeks: Median: 2.88 L/kg (range: 0.646 to 5.3 L/kg).PMA 30 to <36 weeks: Median: 4.49 L/kg (range: 1.87 to 10.85 L/kg).PMA 36 to 41 weeks: Median: 2.55 L/kg (range: 0.293 to 4.09 L/kg).Infants <3 months: 1.08 ± 0.35 L/kg (manufacturer's labeling).Infants ≥3 months and Children: 1.01 ± 0.28 L/kg (manufacturer's labeling).Adults: 0.8 ± 0.18 L/kg (Spector 1981).Protein binding: 9% to 33%.Metabolism: Converted by viral enzymes to acyclovir monophosphate, and further converted to diphosphate then triphosphate (active form) by cellular enzymes.Bioavailability: Oral: 10% to 20% with normal renal function (bioavailability decreases with increased dose).Half-life elimination:Neonates (Sampson 2014):PMA <30 weeks: Median: 10.2 hours (range: 4.73 to 13.2 hours).PMA 30 to 35 weeks: Median: 6.55 hours (range: 4.28 to 9.26 hours).PMA 36 to 41 weeks: Median: 3 hours (range: 1.61 to 3.69 hours).Infants ≤3 months: 3.8 ± 1.19 hours (manufacturer's labeling).Infants >3 months and Children: 2.36 ± 0.97 hours (manufacturer's labeling).Adults: ~2.5 hours (with normal renal function); 20 hours (ESRD) (Gorlitsky 2017); Hemodialysis: ~5 hours.Excretion: Urine (62% to 91% as unchanged drug and metabolite).Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: Total body clearance and half-life are dependent on renal function.Additional InformationSodium content of 1 g: 5.1 mEqPricing: USCapsules (Acyclovir Oral)200 mg (per each): $0.13 - $1.53Solution (Acyclovir Sodium Intravenous)50 mg/mL (per mL): $0.52 - $2.26Suspension (Acyclovir Oral)200 mg/5 mL (per mL): $0.46 - $0.94Suspension (Zovirax Oral)200 mg/5 mL (per mL): $1.24Tablets (Acyclovir Oral)400 mg (per each): $0.21 - $2.17800 mg (per each): $0.36 - $4.22Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAcic (AE, BH, EE, KW, LV, QA);Aciclodan (DK);Aciclor (VE);Aciclosina (PT);Acicvir (NZ);Aciherpin (PH);Acirax (LK, VN);Acivir (BD, EG, ET, LV);Acivir Eye (IN);Acivirex (GT, HN, NI, SV);Aclovir (FI, TH, TW);Acovir (ZW);ACS (KR);Activir (FR);Acyclo (TW);Acyclo-V (AU, BH);Acyclovenir (IL);Acylene (MY);Acyrax (FI);Acyvir (EC, IT, VN);Aisike (CN);Aisile (CN);Alovir (ZW);Alvoles (TH);Antix (NO);Avir (VE);Avorax (HK);Azost (PH);Bangna (CN);Bearax (SG);Biraxin (PH);Ciclevir (VN);Cicloferon (CR, DO, GT, HN, MX, NI, PA, SV);Cicloviral (CO);Ciclox (PH);Clinovir (ID, TH);Clopes (ID);Clovika (ID);Clovir (KR, PH, PY, QA);Clovirex (LK);Covelay (PH);Cusiviral (MY, QA, SG);Cyclivex (ZA);Cycloherp (HK);Cyclostad (PH);Cyclovax (TR, ZW);Cyclovex (LB);Cyclovir (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);Cyllanvir (PH);Deherp (TH, TW);Dravyr (MY, SG);Duvimex (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);Ecuvir (EC);Entir (SG, TH);Erlvirax (SG);Euroclovir (HK);Eurovir (PY);Expit (UY);Gantai (CN);Geavir (DK, SE);Helvevir (CH);Herax (ID);Herpavir (JO);Herperax (ZW);Herpesin (CZ, SK);Herpevex (MY);Herpevir (FR);Herpex (BH, ET, IN, PH, ZW);Herpirax (NL);Herpizyg (TH);Heviran (PL);Isavir (CR, DO, GT, HN, NI, PA, SV);Lermex (TH);Licovir (ID);Lisovyr (AR, CL);Lovir (AE, AU, EG, KW, NZ, PH, QA);Lovire (ZA);Marvir (TH);Matrovir (ID);Medovir (AE, BF, BG, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, MY, NE, NG, OM, QA, SA, SC, SD, SG, SL, SN, SY, TN, TW, TZ, UG, YE, ZM, ZW);Mibeviru (VN);Molavir (ID);Norum (TH);Noviral (QA);Ozvir (AU);Poviral (AR);Qualiclovir (HK);Ranvir (TH);Reclovax (TH);Remex (FR);Skirax (TW);Supraviran (JO, LB);Vacrax (MY);Vermis (TH);Vialesel (ET);Vilerm (SG);Viralex-DS (PH);Viramed (ZW);Viratak (ZW);Viratop (BE);Virax (KR);Virest (HK, SG);Virex (CO);Virherpes (ES);Virless (LK, MY, SG, TW);Viroclear (HK);Virogon (TH);Virolex (HU, RO);Virolox (HR);Viromed (TH);Virpes (AE, JO);Virucid (MT, TR, VN);Virustat (JO);Virzin (DE);Vivir (KR);Wariviron (LB, QA);Xinvir (TW);Xovir (BD);Zevin (TH);Ziverone (MX);Zodiac (KR);Zoral (HK, MY, SG);Zorax (MY, SG);Zorexin (MY);Zoter (ID);Zovir (DK, IS);Zovirax (AE, AR, AT, AU, BB, BD, BE, BF, BG, BH, BJ, BM, BO, BR, BS, CH, CI, CU, CY, CZ, EC, EE, EG, ET, FI, FR, GB, GH, GM, GN, GR, GY, HK, HU, ID, IE, IL, IN, IQ, IR, IT, JM, JO, JP, KE, KR, KW, LB, LR, LU, LV, LY, MA, ML, MR, MT, MU, MW, MY, NE, NG, NL, NO, NZ, OM, PE, PH, PK, PL, PR, PT, PY, QA, RU, SA, SC, SD, SE, SK, SL, SN, SY, TN, TR, TT, TW, TZ, UA, UG, UY, YE, ZA, ZM, ZW);Zoylex (PE);Zyvir (KE)For country code abbreviations (show table)Acyclovir capsule, tablet [prescribing information]. Fort Lee, NJ: DAVA Pharmaceuticals, Inc; April 2014.Acyclovir Sodium injection [prescribing information]. Pennington, NJ: Zydus Pharmaceuticals (USA) Inc: May 2020.Acyclovir Sodium injection [prescribing information]. Pennington, NJ: Zydus Pharmaceuticals (USA) Inc: June 2021.Acyclovir oral [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2014.Adair JC, Gold M, Bond RE. Acyclovir neurotoxicity: clinical experience and review of the literature. South Med J. 1994;87(12):1227-1231. doi: 10.1097/00007611-199412000-00006. [PubMed 7973922]Adour KK, Ruboyianes JM, Von Doersten PG, et al. Bell's palsy treatment with acyclovir and prednisone compared with prednisone alone: a double-blind, randomized, controlled trial. Ann Otol Rhinol Laryngol. 1996;105(5):371-378. doi: 10.1177/000348949610500508. [PubMed 8651631]Ahrens KA, Anderka MT, Feldkamp ML, Canfield MA, Mitchell AA, Werler MM; National Birth Defects Prevention Study. Antiherpetic medication use and the risk of gastroschisis: findings from the National Birth Defects Prevention Study, 1997-2007. Paediatr Perinat Epidemiol. 2013;27(4):340-345. doi:10.1111/ppe.12064 [PubMed 23772935]Albrecht MA. Treatment of herpes zoster in the immunocompetent host. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed February 4, 2020a.Albrecht MA. Treatment of varicella (chickenpox) infection. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 29, 2022b.Almond MK, Fan S, Dhillon S, Pollock AM, Raftery MJ. Avoiding acyclovir neurotoxicity in patients with chronic renal failure undergoing haemodialysis. Nephron. 1995;69(4):428-432. doi:10.1159/000188514 [PubMed 7777108]American Academy of Pediatrics (AAP). In: Kimberlin DW, Brady MT, Jackson MA, Long SA, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. 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A case of chronic renal dysfunction following treatment with oral acyclovir. Scand J Infect Dis. 2003;35(10):770-772. doi: 10.1080/00365540310016574-1. [PubMed 14606623]Spector SA, Connor JD, Hintz M, Quinn RP, Blum MR, Keeney RE. Single-dose pharmaco*kinetics of acyclovir. Antimicrob Agents Chemother. 1981;19(4):608-612. [PubMed 7247383]Spruance SL, Hamill ML, Hoge WS, Davis LG, Mills J. Acyclovir prevents reactivation of herpes simplex labialis in skiers. JAMA. 1988;260(11):1597-1599. [PubMed 3411740]Spruance SL, Stewart JC, Rowe NH, McKeough MB, Wenerstrom G, Freeman DJ. Treatment of recurrent herpes simplex labialis with oral acyclovir. J Infect Dis. 1990;161(2):185-190. [PubMed 2153735]Stathoulopoulou F, Almond MK, Dhillon S, Raftery MJ. Clinical pharmaco*kinetics of oral acyclovir in patients on continuous ambulatory peritoneal dialysis. Nephron. 1996;74(2):337-341. doi:10.1159/000189332 [PubMed 8893152]Stevens DL, Bisno AL, Chambers HF, et al. 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Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 27, 2020.Turner RB, Cumpston A, Sweet M, et al. Prospective, controlled study of acyclovir pharmaco*kinetics in obese patients. Antimicrob Agents Chemother. 2016;60(3):1830-3. doi:10.1128/AAC.02010-15 [PubMed 26824940]Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmaco*kinet. 2010;49(1):1-16. doi:10.2165/11318140-000000000-00000 [PubMed 20000886]US Department of Health and Human Services (HHS) Panel on Adult and Adolescent Opportunistic Infection. 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A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med. 1994;330(13):896-900. doi: 10.1056/NEJM199403313301304. [PubMed 8114860]Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. doi:10.15585/mmwr.rr7004a1 [PubMed 34292926]Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137. [PubMed 26042815 ]World Health Organization (WHO). Breastfeeding and maternal medication, recommendations for drugs in the eleventh WHO model list of essential drugs. http://www.who.int/maternal_child_adolescent/documents/55732/en. Published 2002.Zovirax (acyclovir) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; January 2019.Zovirax (acyclovir 200 mg, USP) oral suspension [prescribing information]. Morgantown, WV: Mylan Pharmaceuticals Inc; April 2018. [PubMed Mylan.1]Topic 15938 Version 550.0

CloseAcyclovir (systemic): Drug informationAcyclovir (systemic): Drug information(For additional information see "Acyclovir (systemic): Patient drug information" and see "Acyclovir (systemic): Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USZoviraxBrand Names: CanadaAPO-Acyclovir;MINT-Acyclovir;MYLAN-Acyclovir;TEVA-Acyclovir;ZoviraxPharmacologic CategoryAntiviral AgentDosing: AdultNote: Use ideal body weight or adjusted body weight for weight-based dosing in patients with obesity to avoid overdosing and subsequent toxicity (eg, acute renal failure) (Ref).Bell palsy, new onsetBell palsy, new onset (adjunctive therapy) (alternative agent) (off-label use): Oral: 400 mg 5 times daily for 10 days in combination with corticosteroids; begin within 3 days of symptom onset. Note: Antiviral therapy alone is not recommended (Ref); some experts only recommend addition of an antiviral to steroid therapy in patients with severe Bell palsy (Ref).Cytomegalovirus, prevention in low-risk allogeneic hematopoietic cell transplant recipientsCytomegalovirus, prevention in low-risk allogeneic hematopoietic cell transplant recipients (alternative agent) (off-label use): Note: Begin at engraftment and continue to day 100; requires close monitoring for cytomegalovirus (CMV) reactivation (due to weak activity); not for use in patients at high risk for CMV disease (Ref):IV: 500 mg/m2/dose every 8 hours for up to 4 weeks or until hospital discharge, followed by oral therapy (Ref).Oral: Following initial IV therapy: 800 mg 4 times daily (Ref).Herpes simplex virus, central nervous system infectionHerpes simplex virus, central nervous system infection (encephalitis or meningitis): IV: 10 mg/kg/dose every 8 hours. Duration for encephalitis is 14 to 21 days and for meningitis is 10 to 14 days; treatment of encephalitis requires IV therapy while treatment of meningitis may include step-down oral antiviral therapy. Note: Empiric herpes simplex virus (HSV) therapy should be initiated in all patients with suspected encephalitis (Ref).Herpes simplex virus, mucocutaneous infectionHerpes simplex virus, mucocutaneous infection:Esophagitis (off-label use):Immunocompetent patients: Oral: 400 mg 3 times daily or 200 mg 5 times daily for 7 to 10 days (Ref).Immunocompromised patients: Oral: 400 mg 5 times daily for 14 to 21 days (Ref).Patients with severe odynophagia or dysphagia: IV: 5 mg/kg/dose every 8 hours; patients who rapidly improve can be switched to an oral antiviral to complete a total of 7 to 14 days of therapy (Ref).Genital:Immunocompetent patients:Treatment, initial episode:Oral: 400 mg 3 times daily for 7 to 10 days; extend duration if lesions have not healed completely after 10 days (Ref).IV (for severe disease): 5 to 10 mg/kg/dose every 8 hours; once clinically improved, may switch to oral antiviral therapy to complete >10 days of therapy total (Ref).Treatment, recurrent episode: Oral: 800 mg twice daily for 5 days or 800 mg 3 times daily for 2 days. Note: Treatment is most effective when initiated during the prodrome or within 1 day of lesion onset (Ref).Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 400 mg twice daily. Note: Reassess need periodically (eg, annually) (Ref).Immunocompromised patients (including patients with HIV):Treatment, initial or recurrent episode:Oral: 400 mg 3 times daily for 5 to 10 days (7 to 10 days for initial episode in patients with HIV); extend treatment duration if lesions have not healed completely after 10 days (Ref).IV (for severe disease): 5 to 10 mg/kg/dose every 8 hours; may transition to oral antiviral therapy once lesions begin to regress and continue for >10 days of therapy and until complete resolution (Ref).Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 400 to 800 mg 2 to 3 times daily. Note: Reassess need periodically (eg, annually) (Ref).Pregnant patients:Treatment, initial episode: Oral: 400 mg 3 times daily for 7 to 10 days; extend treatment duration if lesion has not healed completely after 10 days (Ref).Treatment, recurrent episode (symptomatic): Oral: 400 mg 3 times daily or 800 mg twice daily for 5 days (Ref). Note: Some experts reserve treatment of recurrent episodes for patients with severe and/or frequent symptoms (Ref).Treatment, severe or disseminated disease: IV: 5 to 10 mg/kg every 8 hours for 2 to 7 days, then change to oral therapy for primary infection to complete 10 days of therapy (Ref).Suppressive therapy, for patients with a genital HSV lesion anytime during pregnancy: Oral: 400 mg 3 times daily, beginning at 36 weeks gestation and continued until delivery (Ref); some experts recommend discontinuing suppressive therapy at the onset of labor (Ref). Note: For patients with a primary infection during the third trimester, may consider suppressive therapy earlier than 36 weeks' gestation (Ref).Orolabial: Note: Initiate therapy at earliest symptom.Immunocompetent and immunocompromised patients (including patients with HIV):Treatment, initial or recurrent episode:Oral: 400 mg 3 times daily for 5 to 10 days and until complete lesion resolution in immunocompromised patients (Ref)IV (for severe disease in immunocompromised patients): 5 mg/kg/dose every 8 hours; switch to oral acyclovir (or similar antiviral) once lesions begin to regress and continue until complete resolution (Ref).Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 400 mg twice daily (Ref). Note: Reassess need periodically (eg, annually) (Ref).Herpes simplex virus, prevention in immunocompromised patientsHerpes simplex virus, prevention in immunocompromised patients (off-label use):Seropositive hematopoietic cell transplant recipients (allogeneic or autologous) or seropositive patients undergoing leukemia induction chemotherapy:IV: 250 mg/m2/dose every 12 hours (Ref)Oral: 400 to 800 mg twice daily (Ref)Note: Initiate with the chemotherapeutic or conditioning regimen and continue until recovery of WBC count and resolution of mucositis; duration may be extended in patients with frequent recurrences or graft-vs-host disease (Ref).Solid organ transplant recipients (HSV-seropositive patients who do not require CMV prophylaxis): Oral: 400 to 800 mg twice daily for ≥1 month (Ref); some experts recommend continuing for 3 to 6 months after transplantation and during periods of lymphodepletion associated with treatment of rejection (Ref).Herpes zoster, treatmentHerpes zoster (shingles), treatment: Note: Initiate at earliest sign or symptom. Antiviral treatment is most effective ≤72 hours after rash onset but may be initiated >72 hours in certain situations (eg, new lesions continue to appear); for immunocompromised patients, initiate treatment even if >72 hours after symptom onset unless all lesions have crusted (Ref).Acute localized dermatomal lesion(s): Oral: 800 mg 5 times daily for 7 to 10 days; for slowly improving lesions, may extend therapy until resolution (Ref). For select immunocompromised patients at high risk of dissemination (eg, recent transplant, graft-versus-host disease), some experts suggest regimens used for disseminated zoster (Ref).Disseminated zoster (extensive cutaneous lesions or visceral involvement): IV: 10 mg/kg/dose every 8 hours (Ref). When formation of new lesions has ceased and signs/symptoms of visceral infection are improving, switch to an oral antiviral to complete a total of 10 to 14 days of therapy (Ref).Herpes zoster ophthalmicusHerpes zoster ophthalmicus (off-label use): Immunocompromised patients or patients who require hospitalization for sight-threatening disease: IV: 10 mg/kg/dose every 8 hours for 7 days (Ref)Varicella, treatmentVaricella (chickenpox), treatment: Ideally initiate therapy within 24 hours of symptom onset, but may start later if the patient still has active lesions:Immunocompetent patients with uncomplicated infection: Oral: 800 mg 5 times daily for ≥5 to 7 days and until all lesions have crusted (Ref)Immunocompromised patients (including patients with HIV):Severe or complicated infection: IV: 10 mg/kg/dose every 8 hours for 7 to 10 days (Ref). May switch to oral antiviral after defervescence if no evidence of visceral involvement; continue until all lesions have crusted (Ref).Uncomplicated infection: Oral: 800 mg 5 times daily for 5 to 7 days (Ref); some experts recommend a minimum duration of 7 days, extending the course until all lesions have crusted (Ref).Varicella zoster virus, acute retinal necrosisVaricella zoster virus, acute retinal necrosis (off-label use): IV: 10 mg/kg/dose every 8 hours for 10 to 14 days, followed by ~6 weeks of valacyclovir (Ref); in patients with HIV, intravitreal ganciclovir should be added (Ref).Varicella zoster virus, encephalitisVaricella zoster virus, encephalitis (off-label use): IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days (Ref)Varicella zoster virus, prevention in immunocompromised patientsVaricella zoster virus, prevention in immunocompromised patients (off-label use):Seropositive hematopoietic cell transplant recipients (allogeneic and autologous): Oral: 800 mg twice daily (Ref). Note: Initiate with the chemotherapeutic or conditioning regimen and continue for 1 year; may extend duration in patients requiring ongoing immunosuppression (some experts continue prophylaxis in these patients until 6 months after discontinuation of all systemic immunosuppression) (Ref).Solid organ transplant recipients (VZV-seropositive patients who do not require CMV prophylaxis): Oral: 200 mg 3 to 5 times daily for 3 to 6 months after transplantation and during periods of lymphodepletion associated with treatment of rejection (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Note: Monitor closely for neurotoxicity (Ref). For usual recommended doses not described in the following sections, a comparable reduction in the dose and/or frequency may be considered based on CrCl or the type of dialysis, taking into consideration the goals of therapy and the anticipated duration of treatment (Ref).Altered kidney function:Acyclovir Dose Adjustments for Kidney Impairment aCrClbOralIVIf the usual dose is 400 mg every 12 hoursIf the usual dose is 200 mg 5 times daily If the usual dose is 800 mg 5 times dailyIf the usual dose is 5 mg/kg/dose every 8 hoursIf the usual dose is 10 mg/kg/dose every 8 hoursaRecommendations are from manufacturer’s labeling unless otherwise noted.bThe manufacturer's labeling dosing adjustments are reported as mL/minute/1.73 m2 based on data using CrCl adjusted for BSA (Blum 1982; de Miranda 1983).cWhile toxicity is not likely to occur with an unadjusted dose in patients with a CrCl of 10 to 25 mL/minute/1.73 m2 (as recommended in the manufacturer’s labeling), the exposure from the reduced dose is expected to be comparable to exposure achieved in patients receiving the usual recommended dose with normal kidney function (ie, CrCl >50 mL/minute/1.73 m2) (expert opinion).dManufacturer’s labeling recommends 800 mg every 12 hours. However, due to reports of neurotoxicity in patients with end-stage kidney disease (Almond 1995; Beales 1994; Davenport 1992), a reduced dose is preferred (expert opinion).>50 mL/minute/1.73 m2No dosage adjustment necessary.No dosage adjustment necessary.No dosage adjustment necessary.No dosage adjustment necessary.No dosage adjustment necessary.25 to 50 mL/minute/1.73 m2No dosage adjustment necessary.No dosage adjustment necessary.No dosage adjustment necessary.5 mg/kg/dose every 12 hours10 mg/kg/dose every 12 hours10 to <25 mL/minute/1.73 m2No dosage adjustment necessary or reduce to 200 mg every 12 hourscNo dosage adjustment necessary or reduce to 200 mg every 8 hoursc800 mg every 8 hours5 mg/kg/dose every 24 hours10 mg/kg/dose every 24 hours<10 mL/minute/1.73 m2 (not on dialysis)200 mg every 12 hours200 mg every 12 hours200 mg every 12 hours or 400 mg every 12 hours (severe infections)d2.5 mg/kg/dose every 24 hours5 mg/kg/dose every 24 hoursAugmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): IV, Oral: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).Use the indication-specific maximum allowable dose along with therapeutic drug monitoring when available (Ref).Hemodialysis, intermittent (thrice weekly): Dialyzable (60% reduction following a 6-hour session (Ref)). Therapeutic drug monitoring of acyclovir is recommended when available (Ref).Oral:If the usual recommended dose is 200 mg 5 times daily or 400 mg every 12 hours: Administer 200 mg every 12 hours. Administer after dialysis when given on a dialysis day or administer an additional dose after each dialysis (Ref).If the usual recommended dose is 800 mg 5 times daily: Administer a loading dose of 400 mg, followed by a maintenance dose of 200 mg every 12 hours, plus an additional 400 mg dose after each dialysis session (Ref). Note: Dose based on pharmaco*kinetic data and computer modeling.IV: 2.5 to 5 mg/kg/dose every 24 hours. Administer after dialysis when given on a dialysis day (Ref). Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.Peritoneal dialysis: Dialyzable (12% reduction during continuous ambulatory peritoneal dialysis (Ref)): Therapeutic drug monitoring of acyclovir is recommended when available (Ref).Oral:If the usual recommended dose is 200 mg 5 times daily or 400 mg every 12 hours: Administer 200 mg every 12 hours (Ref).If the usual recommended dose is 800 mg 5 times daily: Administer 600 to 800 mg every 24 hours (Ref).IV: 2.5 to 5 mg/kg/dose every 24 hours, no supplemental dose needed (Ref). Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important. Therapeutic drug monitoring of acyclovir is recommended when available (Ref).IV: 5 to 10 mg/kg/dose every 12 to 24 hours (Ref). Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important. Therapeutic drug monitoring of acyclovir is recommended when available (Ref).IV: 5 to 10 mg/kg/dose every 12 to 24 hours (Ref). On non-PIRRT days, dose as for CrCl <10 mL/minute/1.73 m2. Note: Use the higher end of dosing range for viral meningoencephalitis and varicella-zoster infections.Dosing: Hepatic Impairment: AdultOral, IV: There are no dosage adjustments provided in the manufacturer's labeling; use caution in patients with severe impairment.Dosing: Pediatric(For additional information see "Acyclovir (systemic): Pediatric drug information")Note: Obese patients should be dosed using ideal body weight. Parenteral IV doses >15 mg/kg/dose or 500 mg/m2 may be associated with an increased risk of nephrotoxicity; close monitoring of renal function is recommended (Ref).Cytomegalovirus prophylaxisCytomegalovirus (CMV) prophylaxis: Low-risk allogeneic hematopoietic stem cell transplant (HSCT) in seropositive recipient. Note: Begin at engraftment and continue to day 100; requires close monitoring for CMV reactivation (due to weak activity); not for use in patients at high risk for CMV disease (Ref):Oral:Infants, Children, and Adolescents <40 kg: 600 mg/m2/dose 4 times daily; maximum dose: 800 mg/dose.Children and Adolescents ≥40 kg: 800 mg 4 times daily.IV: Infants, Children, and Adolescents: 500 mg/m2/dose every 8 hours.Varicella zoster virus, acute retinal necrosis, treatment, HIV-exposed/-infectedVaricella zoster virus, acute retinal necrosis, treatment, HIV-exposed/-infected:Initial treatment: Note: Follow up IV therapy with oral valacyclovir or acyclovir therapy (valacyclovir preferred) (Ref).Infants and Children: IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days (Ref).Adolescents: IV: 10 mg/kg/dose every 8 hours for 10 to 14 days; recommended to be used in combination with 1 to 2 doses of intravitreal ganciclovir (Ref).Maintenance treatment (alternative to valacyclovir): Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 4 to 6 weeks to begin after 10- to 14-day course of IV acyclovir (Ref).Herpes zoster, treatmentHerpes zoster (shingles), treatment:Immunocompetent host: Ambulatory therapy: Children ≥12 years and Adolescents: Oral: 800 mg every 4 hours (5 doses per day) for 5 to 7 days (Ref).Hospitalized patient:Infants and Children <2 years: IV: 10 mg/kg/dose every 8 hours for 7 to 10 days (Ref).Children ≥2 years and Adolescents: IV: 500 mg/m2/dose every 8 hours for 7 to 10 days; some experts recommend 10 mg/kg/dose every 8 hours (Ref).Immunocompromised host, non-HIV-exposed/-infected: IV: Infants, Children, and Adolescents: 10 mg/kg/dose every 8 hours for 7 to 10 days (Ref).HIV-exposed/-infected:Mild, uncomplicated disease and no or moderate immune suppression:Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 to 10 days; maximum dose: 800 mg/dose; consider longer course if resolution of lesions is slow (Ref).Adolescents (alternative therapy): Oral: 800 mg 5 times daily for 7 to 10 days, longer if lesions resolve slowly (Ref).Severe immune suppression or complicated disease; trigeminal nerve involvement, extensive multidermatomal zoster or extensive cutaneous lesions or visceral involvement:Infants: IV: 10 mg/kg/dose every 8 hours until resolution of cutaneous lesions and visceral disease clearly begins, then convert to oral therapy to complete a 10- to 14-day total course of therapy (Ref).Children: IV: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours until resolution of cutaneous lesions and visceral disease clearly begins, then convert to oral therapy to complete a 10- to 14-day total course of therapy (Ref).Adolescents: IV: 10 mg/kg/dose every 8 hours until clinical improvement is evident, then convert to oral therapy to complete a 10- to 14-day total course of therapy (Ref).Herpes simplex virus neonatal infection, treatment and suppressive therapy in very young infantsHerpes simplex virus (HSV) neonatal infection, treatment and suppressive therapy in very young infants (independent of HIV status):Treatment (disseminated, CNS, or skin, eye, or mouth disease): Infants 1 to 3 months: IV: 20 mg/kg/dose every 8 hours; treatment duration: For cutaneous and mucous membrane infections (skin, eye, or mouth): 14 days; for CNS or disseminated infection: 21 days (Ref).Chronic suppressive therapy following any neonatal HSV infection: Infants: Oral: 300 mg/m2/dose every 8 hours for 6 months; begin after completion of a 14- to 21-day-course of IV therapy dependent upon type of infection (Ref).HSV encephalitis, treatmentHSV encephalitis, treatment:Independent of HIV status:Infants and Children 3 months to <12 years: IV: 10 to 15 mg/kg/dose every 8 hours for 14 to 21 days. Note: Due to increased risk of neurotoxicity and nephrotoxicity, higher doses (20 mg/kg) are not routinely recommended (Ref).Children ≥12 years and Adolescents: IV: 10 mg/kg/dose every 8 hours for 14 to 21 days (Ref).HSV genital infectionHSV genital infection: First infection, mild to moderate:Non-HIV-exposed/-infected:Children <12 years: Oral: 40 to 80 mg/kg/day divided in 3 to 4 doses per day for 7 to 10 days; maximum daily dose: 1,200 mg/day (Ref).Children and Adolescents ≥12 years: Oral: 200 mg every 4 hours while awake (5 times daily) or 400 mg 3 times daily for 7 to 10 days; treatment can be extended beyond 10 days if healing is not complete (Ref).HIV-exposed/-infected:Children: Oral: 20 mg/kg/dose 3 times daily for 7 to 10 days; maximum dose: 400 mg/dose (Ref).Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days (Ref).First infection, severe (independent of HIV status): IV: Children and Adolescents ≥12 years: 5 mg/kg/dose every 8 hours for 5 to 7 days or 5 to 10 mg/kg/dose every 8 hours for 2 to 7 days, followed with oral therapy to complete at least 10 days of therapy (Ref).Recurrent infection:Children <12 years (independent of HIV status): Oral: 20 mg/kg/dose 3 times daily for 5 days; maximum dose: 400 mg/dose (Ref).Children and Adolescents ≥12 years:Non-HIV-exposed/-infected: Oral: 200 mg every 4 hours while awake (5 times daily) for 5 days, or 400 mg 3 times daily for 5 days, or 800 mg twice daily for 5 days or 800 mg 3 times daily for 2 days (Ref).HIV-exposed/-infected: Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days (Ref).Suppression, chronic:Non-HIV-exposed/-infected:Children <12 years: Limited data available: Oral: 20 mg/kg/dose twice daily; maximum dose: 400 mg/dose (Ref).Children and Adolescents ≥12 years: Oral: 400 mg twice daily; reassess therapy after 12 months (Ref).HIV-exposed/-infected: Infants and Children: Oral: 20 mg/kg/dose twice daily; maximum dose: 800 mg/dose (Ref).Adolescents: Oral: 400 mg twice daily (Ref).HSV orolabial diseaseHSV orolabial disease (ie, gingivostomatitis, herpes labialis):Non-HIV-exposed/-infected: Primary infection: Infants, Children, and Adolescents: Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; usual maximum dose: 800 mg/dose (Ref).HIV-exposed/-infected (Ref):Mild, symptomatic:Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 to 10 days; maximum dose: 400 mg/dose.Adolescents: Oral: 400 mg 3 times daily for 5 to 10 days (Ref).Moderate to severe, symptomatic: Note: Switch to oral therapy once lesions begin to regress and continue oral therapy until lesions completely healed.Infants and Children: IV: 5 to 10 mg/kg/dose every 8 hours.Adolescents: IV: 5 mg/kg/dose every 8 hours.HSV mucocutaneous infectionHSV mucocutaneous infection: Immunocompetent host: Infants, Children, and Adolescents:Treatment:IV: 5 mg/kg/dose every 8 hours (Ref).Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; maximum dose: 800 mg/dose (Ref).Suppression, chronic: Limited data available; no pediatric data; some experts recommend oral 20 mg/kg/dose 2 to 3 times daily for 6 to 12 months, then reevaluate need; maximum dose: 400 mg/dose (Ref).Immunocompromised host: Treatment:IV:Infants and Children: IV: 10 mg/kg/dose every 8 hours for 7 to 14 days (Ref).Adolescents: IV: 5 to 10 mg/kg/dose every 8 hours; change to oral therapy after lesions begin to regress (Ref).Oral: Children ≥2 years and Adolescents: 1,000 mg/day in 3 to 5 divided doses for 7 to 14 days (Ref).Suppression, chronic (cutaneous, ocular) episodes:Non-HIV-exposed/-infected:Children ≥12 years and Adolescents: Oral: 400 mg twice daily; reassess at 12 months (Ref).HIV-exposed/-infected:Infants and Children: Oral: 20 mg/kg/dose twice daily; maximum dose: 800 mg/dose; reassess after 12 months (Ref).Adolescents: Oral: 400 mg twice daily; reassess at 12 months (Ref).HSV progressive or disseminated infection, treatmentHSV progressive or disseminated infection, treatment (immunocompromised host):Non-HIV-exposed/-infected: Infants, Children, and Adolescents: IV: 10 mg/kg/dose every 8 hours for 7 to 14 days (Ref).HIV-exposed/-infected: Infants, Children, and Adolescents: IV: 10 mg/kg/dose every 8 hours for 21 days; higher doses (up to 20 mg/kg/dose) may be used in children <12 years of age (Ref).HSV, acute retinal necrosis, treatment, HIV-exposed/-infectedHSV, acute retinal necrosis, treatment, HIV-exposed/-infected: Infants and Children (Ref):Initial treatment: IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14 days. Note: Follow up IV therapy with oral acyclovir or valacyclovir maintenance therapy.Maintenance treatment (alternative to valacyclovir): Begin after 10- to 14-day course of IV acyclovir: Oral: 20 mg/kg/dose 4 times daily for 4 to 6 weeks.HSV prophylaxis; immunocompromised hosts, seropositiveHSV prophylaxis; immunocompromised hosts, seropositive:HSCT in seropositive recipient (Ref):Prevention of early reactivation: Note: Begin at conditioning and continue until engraftment or resolution of mucositis; whichever is longer (~30 days post-HSCT)Infants, Children, and Adolescents <40 kg:IV: 250 mg/m2/dose every 8 hours or 125 mg/m2/dose every 6 hours; maximum daily dose: 80 mg/kg/dayOral: 60 to 90 mg/kg/day in 2 to 3 divided doses; maximum dose: 800 mg/dose twice dailyChildren and Adolescents ≥40 kg:IV: 250 mg/m2/dose every 12 hoursOral: 400 to 800 mg twice dailyPrevention of late reactivation: Note: Treatment during first year after HSCT.Infants, Children, and Adolescents <40 kg: Oral: 60 to 90 mg/kg/day in 2 to 3 divided doses; maximum daily dose: 800 mg twice dailyChildren and Adolescents ≥40 kg: Oral: 800 mg twice dailyOther immunocompromised hosts who are HSV seropositive: IV: Infants, Children, and Adolescents: 5 mg/kg/dose every 8 hours during period of risk (Ref).Oral: Children ≥2 years and Adolescents: 200 mg every 4 hours while awake (5 doses daily) or 200 mg every 8 hours; administer during periods of risk (Ref).Varicella or herpes zoster, prophylaxisVaricella (chickenpox) or herpes zoster (shingles), prophylaxisHSCT: Prophylaxis of disease reactivation: Note: Continue therapy for 1 year after HSCT (Ref):Infants, Children, and Adolescents <40 kg: Oral: 60 to 80 mg/kg/day in 2 to 3 divided dosesChildren and Adolescents ≥40 kg: Oral: 800 mg twice dailyHIV-exposed/-infected: Limited data available: Note: Consider use if >96 hours postexposure or if VZV-immune globulin is not available; begin therapy 7 to 10 days after exposure; some experts begin therapy at first appearance of rash (Ref).Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 days; maximum dose: 800 mg/dose (Ref).Adolescents: Oral: 800 mg 5 times daily for 5 to 7 days (Ref).Other immunocompromised hosts: Infants, Children, and Adolescents: Oral: 20 mg/kg/dose 4 times daily for 7 days; maximum dose: 800 mg/dose. Note: Consider use if VZV-immune globulin or IVIG is not available; begin therapy 7 to 10 days after exposure (Ref).Varicella, treatmentVaricella (chickenpox), treatment: Begin treatment within the first 24 hours of rash onset:Immunocompetent host: Ambulatory therapy: Oral: Infants, Children, and Adolescents: 20 mg/kg/dose 4 times daily for 5 days; maximum daily dose: 3,200 mg/day (Ref).Hospitalized patient: IV: Infants, Children, and Adolescents: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 to 14 days (Ref); some experts recommend 15 to 20 mg/kg/dose for severe disseminated or CNS infection (Ref).Immunocompromised host, non-HIV-exposed/-infected:Infants and Children <2 years: IV: 10 mg/kg/dose every 8 hours; duration dependent upon clinical response, typically 7 to 14 days (Ref).Children ≥2 years and Adolescents: IV: 500 mg/m2/dose every 8 hours duration dependent upon clinical response, typically 7 to 14 days; some experts recommend 10 mg/kg/dose every 8 hours (Ref).HIV-exposed/-infected: Mild, uncomplicated disease and no or moderate immune suppression:Infants and Children: Oral: 20 mg/kg/dose 4 times daily for 7 to 10 days and until no new lesions for 48 hours; maximum dose: 800 mg/dose (Ref).Adolescents (alternative therapy): Oral: 800 mg 5 times daily for 5 to 7 days (Ref).Severe, complicated disease or severe immune suppression:Infants: IV: 10 mg/kg/dose every 8 hours for 7 to 10 days and until no new lesions for 48 hours (Ref).Children: IV: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 to 10 days or until no new lesions for 48 hours (Ref).Adolescents: IV: 10 mg/kg/dose every 8 hours for 7 to 10 days; may convert to oral therapy after defervescence and if no evidence of visceral involvement is evident (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricMonitor closely for neurotoxicity (Ref).Infants, Children and Adolescents: IV:CrCl >50 mL/minute/1.73 m2: No dosage adjustment necessaryCrCl 25 to 50 mL/minute/1.73 m2: Administer the usual recommended dose every 12 hoursCrCl 10 to <25 mL/minute/1.73 m2: Administer the usual recommended dose every 24 hoursCrCl <10 mL/minute/1.73 m2: Administer 50% of the usual recommended dose every 24 hours (eg, if the usual recommended dose is 10 mg/kg/dose every 8 hours, then administer 5 mg/kg/dose every 24 hours)Intermittent hemodialysis (IHD): Dialyzable (60% reduction following a 6-hour session): 5 mg/kg/dose every 24 hours; administer after hemodialysis on dialysis days (Ref)Peritoneal dialysis (PD): 5 mg/kg/dose every 24 hours; no supplemental dose needed (Ref)Continuous renal replacement therapy (CRRT): 10 mg/kg/dose every 12 hours (Ref)Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Older AdultRefer to adult dosing; use with caution.Dosing: Obesity: AdultThe recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.Class 1, 2, or 3 obesity (BMI ≥30 kg/m2): IV: Use ideal body weight (IBW) for weight-based dosing to avoid overdosing and subsequent toxicity (eg, acute renal failure). In patients with class 3 obesity (BMI ≥40 kg/m2) who are severely ill (eg, herpes simplex virus [HSV] encephalitis), consider using adjusted body weight for dose calculations (Ref).Rationale for recommendations:In patients with obesity, IBW has been used for weight-based dosing of acyclovir to avoid overdosing and subsequent toxicity (Ref). However, a pharmaco*kinetic study evaluating a single IBW-based dose of IV acyclovir in subjects with BMI ≥40 kg/m2 demonstrated lower systemic exposures compared to subjects who were not obese dosed using actual body weight (Ref). To avoid potentially underdosing severely ill patients (eg, HSV encephalitis) with class 3 obesity (eg, BMI ≥40 kg/m2), consider using adjusted body weight to calculate the weight-based IV dose (Ref), although this approach has not been evaluated in clinical outcome studies. Acyclovir is primarily excreted unchanged in urine, and careful attention to estimated kidney function is also essential in patients with obesity (Ref).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productCapsule, Oral: Zovirax: 200 mg [DSC] [contains fd&c blue #2 (indigotine), parabens]Generic: 200 mgSolution, Intravenous, as sodium [strength expressed as base]: Generic: 50 mg/mL (20 mL)Solution, Intravenous, as sodium [strength expressed as base, preservative free]: Generic: 50 mg/mL (10 mL, 20 mL)Suspension, Oral: Zovirax: 200 mg/5 mL (473 mL [DSC]) [contains methylparaben, propylparaben]Zovirax: 200 mg/5 mL (473 mL) [contains methylparaben, propylparaben; banana flavor]Generic: 200 mg/5 mL (473 mL)Tablet, Oral: Zovirax: 400 mg [DSC]Zovirax: 800 mg [DSC] [contains fd&c blue #2 (indigotine)]Generic: 400 mg, 800 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution, Intravenous: Generic: 25 mg/mL (20 mL)Solution, Intravenous, as sodium [strength expressed as base]: Generic: 50 mg/mL (10 mL, 20 mL)Suspension, Oral: Zovirax: 200 mg/5 mL (125 mL) [contains methylparaben, propylparaben]Tablet, Oral: Generic: 200 mg, 400 mg, 800 mgAdministration: AdultOral: Administer with or without food.IV: Avoid rapid infusion; infuse over 1 hour to prevent renal damage; maintain adequate hydration of patient; check for phlebitis and rotate infusion sites. Do not administer IM or SubQ. Acyclovir IV is an irritant (depending on concentration); avoid extravasation.Administration: PediatricOral: May administer with or without food; shake suspension well before use. Maintain adequate hydration during therapy.Parenteral: Administer by slow IV infusion over at least 1 hour; rapid infusion is associated with nephrotoxicity due to crystalluria and renal tubular damage and should be avoided. Maintain adequate hydration during therapy. Do not administer IV push, IM, or SubQ.Acyclovir IV is an irritant (depending on concentration); avoid extravasation. If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Apply dry warm compresses. Intradermal hyaluronidase may be considered for refractory cases (Ref).Use: Labeled IndicationsOral:Herpes simplex virus (HSV), genital: Treatment of initial episodes and the management of recurrent episodes of genital herpes.Herpes zoster (shingles): Acute treatment of herpes zoster (shingles).Varicella (chickenpox): Treatment of varicella (chickenpox).Injection:Herpes simplex encephalitis: Treatment of herpes simplex encephalitis.Herpes simplex virus (HSV), genital infection (severe): Treatment of severe initial clinical episodes of genital herpes in immunocompetent patients.Herpes simplex virus (HSV), mucocutaneous infection in immunocompromised patients: Treatment of initial and recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) in immunocompromised patients.Herpes simplex virus (HSV), neonatal: Treatment of neonatal herpes infections.Herpes zoster (shingles) in immunocompromised patients: Treatment of herpes zoster (shingles) in immunocompromised patients.Use: Off-Label: AdultBell palsy, new onset; Cytomegalovirus prevention in low-risk allogeneic hematopoietic cell transplant recipients; Herpes simplex virus, esophagitis; Herpes simplex virus, prevention in immunocompromised patients; Herpes zoster ophthalmicus; Varicella zoster virus, acute retinal necrosis; Varicella zoster virus, encephalitis; Varicella zoster virus, prevention in immunocompromised patientsMedication Safety IssuesSound-alike/look-alike issues:Acyclovir may be confused with famciclovir, ganciclovir, Retrovir, valacyclovir, valganciclovirZovirax may be confused with Doribax, Valtrex, Zithromax, Zostrix, Zyloprim, ZyvoxAdverse Reactions (Significant): ConsiderationsAcute kidney injuryAcyclovir may cause acute kidney injury, resulting most often from obstructive nephropathy but may also be due to interstitial nephritis or renal tubular necrosis in adult and pediatric patients (Ref). Kidney injury is reversible in most cases after dosage reduction or discontinuation, although in some instances, a full return to baseline may not occur (Ref).Mechanism: Dose-related; formation of acyclovir crystals is the most commonly noted cause of kidney injury, resulting in intrarenal obstruction and nephropathy (Ref). Less commonly, an immune reaction may contribute to interstitial nephritis (Ref). In addition, a major metabolite of acyclovir (9-carboxymethoxymethylguanine [CMMG]) may be directly cytotoxic to cells of the renal tubule (Ref).Onset: Rapid; typically occurred within 48 hours of initiation in adult and pediatric patients (Ref). May occur after a single dose (Ref).Risk factors:Adult patients:• Rapid infusion of high dose (Ref)• Intravenous administration (due to higher bioavailability of acyclovir/valacyclovir), although cases during oral therapy have been noted (Ref)• Volume depletion (Ref)• Preexisting kidney impairment (Ref)• Hypertension (Ref)• Diabetes (Ref)• Concurrent use of nephrotoxic agents (eg, nonsteroidal anti-inflammatory drugs, vancomycin) (Ref)• Obesity (Ref)Pediatric patients:• Doses >500 mg/m2 (Ref)• Doses >15 mg/kg (associated with a 25% to 49% reduction in eGFR) (Ref)• Age >8 years (Ref)• Weight >20 kg (Ref)• BMI >19 kg/m2 (Ref)• Concomitant ceftriaxone with or without gadolinium (Ref)NeurotoxicityAcyclovir-induced neuropsychiatric symptoms are a spectrum of neurologic disturbances, including confusion, agitation, lethargy, hallucination, and impaired consciousness, representing cognitive, psychiatric, or motor disturbances (Ref). Rare features may include aphasia and ataxia. Myoclonus, tremor, and seizure (including status epilepticus) have also been reported (Ref).Mechanism: Dose-related; indirect, via metabolite 9-carboxymethoxymethylguanine (CMMG) accumulation (Ref).Onset: Varied; within 1 to 5 days of dose administration in most patients (Ref); however, some cases have occurred after 30 days or more (Ref).Risk factors:• Higher doses (on a mg/kg basis) (Ref)()• Kidney impairment (Ref); however, some cases reported in normal kidney function (Ref)• Patient weight (presumably also associated with dose) (Ref)• Increased CSF: Albumin ratio (indicating blood-brain barrier passage) (Ref)Thrombotic microangiopathyThrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS), manifestations of thrombotic microangiopathy, have been reported with acyclovir/valacyclovir (Ref). TTP/HUS may result in damage to the brain, kidney, liver, heart, and pancreas (Ref). In one trial, valacyclovir was associated more frequently than acyclovir (14 cases vs a total of 4 in 2 acyclovir arms) and the symptoms were noted to be less severe than in classical TTP/HUS (Ref). Resolution has been noted with drug discontinuation and appropriate therapy (Ref).Mechanism: Idiosyncratic; leading to intravascular platelet-fibrin microthrombi, vascular damage, hemolysis, and thrombocytopenia (Ref). In HUS, this injury is believed to be initiated by uncontrolled activity of the alternative complement pathway, while TTP features a reduction in activity of ADAMTS13, the metalloprotease responsible for cleaving ultra-large von Willebrand factor multimers (Ref). Medications that cause direct injury to endothelial cells may result in HUS (Ref). Alternatively, some medications can trigger TTP by causing an immune reaction leading to development of drug-induced auto-antibodies against ADAMTS13 (Ref).Onset: Variable; may occur within a few days of initiation (Ref) or be delayed (ie, after a year in one case with valacyclovir) (Ref).Risk factors:Largely unknown:• Genetic susceptibility may play a role for drug-induced HUS (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported with IV administration, unless otherwise noted.>10%:Hematologic & oncologic: Decreased hemoglobin (neonates: 13%), decrease in absolute neutrophil count (neonates: 3% to 16%)Nervous system: Malaise (oral: 12%)1% to 10%:Dermatologic: Pruritus (≤2%), skin rash (≤2%), urticaria (≤2%)Gastrointestinal: Diarrhea (oral: 2% to 3%; IV: <1%), nausea (oral and IV: ≤7%), vomiting (oral and IV: ≤7%)Hematologic & oncologic: Thrombocytopenia (neonates: 5% to 10%; children, adolescents, and adults: <1%)Hepatic: Increased serum bilirubin (neonates, grades 3/4: 4%), increased serum transaminases (1% to 2%)Local: Inflammation at injection site (≤9%), injection site phlebitis (≤9%)Nervous system: Headache (≤2%)Renal: Increased blood urea nitrogen (5% to 10%), increased serum creatinine (5% to 10%)<1%: Hematologic & oncologic: Anemia, leukocytosis, neutropenia, neutrophilia, thrombocythemiaFrequency not defined: Gastrointestinal: AnorexiaPostmarketing:Cardiovascular: Hypersensitivity angiitis, hypotension, peripheral edemaDermatologic: Acute generalized exanthematous pustulosis (Kubin 2016), alopecia (Sharma 2016), bullous rash (Gurkan 2012), contact dermatitis (topical) (Vernassiere 2003), erythema multiforme, skin photosensitivity (topical) (Rodriguez-Serna 1999), Stevens-Johnson syndrome (Fazal 1995), toxic epidermal necrolysisGenitourinary: Hematuria (Meng 2011)Hematologic & oncologic: Disseminated intravascular coagulation, hemolysis, hemolytic-uremic syndrome (Bell 1997), leukopenia, lymphadenopathy, thrombotic thrombocytopenic purpura (Bukhari 2020)Hepatic: Hepatitis, hyperbilirubinemia, jaundiceHypersensitivity: Anaphylaxis, angioedema (Jen 2011), fixed drug eruption (Lee 2016)Nervous system: Aggressive behavior, agitation (Rashiq 1993), aphasia (Patel 2019), ataxia (Patel 2019), coma, confusion (Rashiq 1993), delirium (Rashiq 1993), dizziness, drowsiness, dysarthria, encephalopathy, fatigue, hallucination (Berry 2014), impaired consciousness (Adair 1994), myoclonus (Adair 1994), obtundation (Adair 1994), pain, paresthesia, psychosis, seizure (Hoskote 2016)Neuromuscular & skeletal: Myalgia, tremor (Rashiq 1993)Renal: Acute kidney injury (common: >10%) (Lee 2018), interstitial nephritis (Rashed 1990), renal disease (obstructive nephropathy) (Fleischer 2010), renal tubular necrosis (Chavez-Iniguez)Miscellaneous: FeverContraindicationsHypersensitivity to acyclovir, valacyclovir, or any component of the formulationWarnings/PrecautionsConcerns related to adverse effects:• Extravasation: Acyclovir IV is an irritant (depending on concentration); avoid extravasation.Disease-related concerns:• Varicella: Appropriate use: For maximum benefit, treatment should begin within 24 hours of appearance of rash; oral route not recommended for routine use in otherwise healthy children with varicella but may be effective in patients at increased risk of moderate to severe infection (>12 years of age, chronic cutaneous or pulmonary disorders, long-term salicylate therapy, corticosteroid therapy).Dosage form specific issues:• Injection: Use IV preparation with caution in patients with underlying neurologic abnormalities, serious hepatic or electrolyte abnormalities, or substantial hypoxia. Encephalopathic changes characterized by lethargy, obtundation, confusion, hallucination, tremors, agitation, seizure, or coma have been observed in patients receiving IV acyclovir.Metabolism/Transport EffectsSubstrate of OAT1/3, OCT1; Inhibits CYP1A2 (weak)Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine.Risk X: Avoid combinationCloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine.Risk C: Monitor therapyFoscarnet: May enhance the nephrotoxic effect of Acyclovir-Valacyclovir. Risk X: Avoid combinationMycophenolate: Acyclovir-Valacyclovir may increase the serum concentration of Mycophenolate. Mycophenolate may increase the serum concentration of Acyclovir-Valacyclovir.Risk C: Monitor therapyNetilmicin (Systemic): Acyclovir (Systemic) may enhance the nephrotoxic effect of Netilmicin (Systemic). Acyclovir (Systemic) may enhance the neurotoxic effect of Netilmicin (Systemic).Risk X: Avoid combinationTalimogene Laherparepvec: Antiherpetic Antivirals may diminish the therapeutic effect of Talimogene Laherparepvec.Risk C: Monitor therapyTenofovir Products: Acyclovir-Valacyclovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir.Risk C: Monitor therapyTheophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives.Risk C: Monitor therapyTiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine.Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modificationVaricella Virus Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Varicella Virus Vaccine.Management: When possible, avoid use of acyclovir or valacyclovir within the 24 hours prior to administration of the varicella vaccine, and avoid use of these antiviral agents for 14 days after vaccination. Risk X: Avoid combinationZidovudine: Acyclovir-Valacyclovir may enhance the CNS depressant effect of Zidovudine.Risk C: Monitor therapyZoster Vaccine (Live/Attenuated): Acyclovir-Valacyclovir may diminish the therapeutic effect of Zoster Vaccine (Live/Attenuated).Risk X: Avoid combinationPregnancy ConsiderationsAcyclovir crosses the placenta (Frenkel 1991; Henderson 1992; Kimberlin 1998).A pregnancy registry established in 1984 and closed in 1999 included 749 pregnancies with 756 known outcomes following first trimester acyclovir exposure. Data from the registry did not find an increase in the number of birth defects with exposure to acyclovir when compared to those expected in the general population. In addition, no pattern of birth defects was observed (Stone 2004). A population-based registry study conducted in Denmark had similar results. The study used data from 1996 to 2008 and included 1,561 pregnancies with first trimester acyclovir exposure; an increased risk of birth defects was not observed (Pasternak 2010). One study observed an increased risk of gastroschisis following use of antiherpetic medications such as acyclovir during the first trimester to treat maternal genital herpes; this risk was also increased in offspring of women with genital herpes not receiving treatment (Ahrens 2013).Due to pregnancy-induced physiologic changes, the pharmaco*kinetic properties of acyclovir may be altered in some women (Brocklehurst 1998; Frenkel 1991; Kimberlin 1998; Leung 2009). Dose adjustments are required for suppressive therapy and recurrent infections during pregnancy due to increased renal clearance (ACOG 2020). Acyclovir is associated with adverse effects on renal function; this risk may be increased with IV administration to patients during the third trimester of pregnancy (Boujenah 2020).Acyclovir is recommended for the treatment of genital herpes simplex virus (HSV) in pregnant patients (ACOG 2020; CDC [Workowski 2021]). Primary HSV infection during the first trimester may be associated with neonatal chorioretinitis, microcephaly, and skin lesions. The risk of perinatal transmission is greater when the primary infection occurs during pregnancy. Maternal treatment decreases duration and severity of disease and duration of viral shedding (ACOG 2020). Suppressive therapy is recommended for patients beginning at 36 weeks' gestation who have a history of genital lesions (ACOG 2020; CDC [Workowski 2021]).Acyclovir is also recommended for the treatment of varicella (chickenpox) in pregnant patients. When treatment is started within 24 hours of rash development, acyclovir reduces the duration and total number of maternal lesions; however, it does not prevent congenital varicella syndrome (ACOG 2015).Breastfeeding ConsiderationsAcyclovir is present in breast milk.Information related to the presence of acyclovir in breast milk is available from multiple sources:• Acyclovir use for the treatment of labial herpes simplex in a lactating patient 6 weeks postpartum was described in a case report. Acyclovir 900 mg IV was administered daily for 5 days and breast milk was sampled every 6 hours after the last dose. The maximum breast milk concentration was 7.3 mcg/mL observed within the first 72 hours of sampling (Bork 1995). Using a milk concentration of 7.3 mcg/mL, the relative infant dose (RID) of acyclovir is 1.83% to 3.65% compared to an IV infant therapeutic dose of 30 to 60 mg/kg/day, providing an estimated infant dose via breast milk of 1.095 mg/kg/day. In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).• The mean half-life of acyclovir in breast milk was 3.2 hours in one study (Lau 1987).• Low/negligible concentrations of acyclovir appear in breast milk for up to 5 days after the last maternal dose (Bork 1995; Frenkel 1991).In one case report, the mother reported no adverse events in her exclusively breastfed infant following a maternal dose of acyclovir 800 mg orally 5 times daily for 7 days (Taddio 1994). Acyclovir has been detected in the urine of breastfeeding infants (Frenkel 1991; Lau 1987).Although the manufacturer recommends that caution be exercised when administering acyclovir to patients who are breastfeeding, acyclovir is considered compatible with breastfeeding (ACOG 2020; WHO 2002). Patients with HSV infection taking acyclovir may breastfeed as long as there are not lesions on the breast, body lesions are covered, and strict hand hygiene is practiced; patients with herpetic lesions near or on the breast should not breastfeed (ACOG 2020). Patients with breast lesions can pump and discard milk to maintain milk supply until lesions are healed and breastfeeding can be resumed (D’Andrea 2019).Dietary ConsiderationsSome products may contain sodium.Monitoring ParametersHydration status, urinalysis, BUN, serum creatinine, urine output; liver enzymes, CBC; signs and symptoms of neurotoxicity, monitor for nephrotoxicity in pediatric patients when using high-dose therapy; neutrophil count at least twice weekly in neonates receiving acyclovir 60 mg/kg/day IV. Monitor infusion site.Mechanism of ActionAcyclovir is converted to acyclovir monophosphate by virus-specific thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.Pharmaco*kineticsAbsorption: Oral: Poorly absorbed; absorption improves with multiple small doses compared to one large daily dose (de Miranda 1983).Distribution: Widely (eg, brain, kidney, lungs, liver, spleen, muscle, uterus, vagin*, CSF) (de Miranda 1983; Laskin 1983); CSF acyclovir concentration is ~50% of plasma concentrations.Vd:Neonates (Sampson 2014; manufacturer's labeling):PMA <30 weeks: Median: 2.88 L/kg (range: 0.646 to 5.3 L/kg).PMA 30 to <36 weeks: Median: 4.49 L/kg (range: 1.87 to 10.85 L/kg).PMA 36 to 41 weeks: Median: 2.55 L/kg (range: 0.293 to 4.09 L/kg).Infants <3 months: 1.08 ± 0.35 L/kg (manufacturer's labeling).Infants ≥3 months and Children: 1.01 ± 0.28 L/kg (manufacturer's labeling).Adults: 0.8 ± 0.18 L/kg (Spector 1981).Protein binding: 9% to 33%.Metabolism: Converted by viral enzymes to acyclovir monophosphate, and further converted to diphosphate then triphosphate (active form) by cellular enzymes.Bioavailability: Oral: 10% to 20% with normal renal function (bioavailability decreases with increased dose).Half-life elimination:Neonates (Sampson 2014):PMA <30 weeks: Median: 10.2 hours (range: 4.73 to 13.2 hours).PMA 30 to 35 weeks: Median: 6.55 hours (range: 4.28 to 9.26 hours).PMA 36 to 41 weeks: Median: 3 hours (range: 1.61 to 3.69 hours).Infants ≤3 months: 3.8 ± 1.19 hours (manufacturer's labeling).Infants >3 months and Children: 2.36 ± 0.97 hours (manufacturer's labeling).Adults: ~2.5 hours (with normal renal function); 20 hours (ESRD) (Gorlitsky 2017); Hemodialysis: ~5 hours.Excretion: Urine (62% to 91% as unchanged drug and metabolite).Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: Total body clearance and half-life are dependent on renal function.Pricing: USCapsules (Acyclovir Oral)200 mg (per each): $0.13 - $1.53Solution (Acyclovir Sodium Intravenous)50 mg/mL (per mL): $0.52 - $2.26Suspension (Acyclovir Oral)200 mg/5 mL (per mL): $0.46 - $0.94Suspension (Zovirax Oral)200 mg/5 mL (per mL): $1.24Tablets (Acyclovir Oral)400 mg (per each): $0.21 - $2.17800 mg (per each): $0.36 - $4.22Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAcic (AE, BH, EE, KW, LV, QA);Aciclodan (DK);Aciclor (VE);Aciclosina (PT);Acicvir (NZ);Aciherpin (PH);Acirax (LK, VN);Acivir (BD, EG, ET, LV);Acivir Eye (IN);Acivirex (GT, HN, NI, SV);Aclovir (FI, TH, TW);Acovir (ZW);ACS (KR);Activir (FR);Acyclo (TW);Acyclo-V (AU, BH);Acyclovenir (IL);Acylene (MY);Acyrax (FI);Acyvir (EC, IT, VN);Aisike (CN);Aisile (CN);Alovir (ZW);Alvoles (TH);Antix (NO);Avir (VE);Avorax (HK);Azost (PH);Bangna (CN);Bearax (SG);Biraxin (PH);Ciclevir (VN);Cicloferon (CR, DO, GT, HN, MX, NI, PA, SV);Cicloviral (CO);Ciclox (PH);Clinovir (ID, TH);Clopes (ID);Clovika (ID);Clovir (KR, PH, PY, QA);Clovirex (LK);Covelay (PH);Cusiviral (MY, QA, SG);Cyclivex (ZA);Cycloherp (HK);Cyclostad (PH);Cyclovax (TR, ZW);Cyclovex (LB);Cyclovir (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);Cyllanvir (PH);Deherp (TH, TW);Dravyr (MY, SG);Duvimex (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);Ecuvir (EC);Entir (SG, TH);Erlvirax (SG);Euroclovir (HK);Eurovir (PY);Expit (UY);Gantai (CN);Geavir (DK, SE);Helvevir (CH);Herax (ID);Herpavir (JO);Herperax (ZW);Herpesin (CZ, SK);Herpevex (MY);Herpevir (FR);Herpex (BH, ET, IN, PH, ZW);Herpirax (NL);Herpizyg (TH);Heviran (PL);Isavir (CR, DO, GT, HN, NI, PA, SV);Lermex (TH);Licovir (ID);Lisovyr (AR, CL);Lovir (AE, AU, EG, KW, NZ, PH, QA);Lovire (ZA);Marvir (TH);Matrovir (ID);Medovir (AE, BF, BG, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, MY, NE, NG, OM, QA, SA, SC, SD, SG, SL, SN, SY, TN, TW, TZ, UG, YE, ZM, ZW);Mibeviru (VN);Molavir (ID);Norum (TH);Noviral (QA);Ozvir (AU);Poviral (AR);Qualiclovir (HK);Ranvir (TH);Reclovax (TH);Remex (FR);Skirax (TW);Supraviran (JO, LB);Vacrax (MY);Vermis (TH);Vialesel (ET);Vilerm (SG);Viralex-DS (PH);Viramed (ZW);Viratak (ZW);Viratop (BE);Virax (KR);Virest (HK, SG);Virex (CO);Virherpes (ES);Virless (LK, MY, SG, TW);Viroclear (HK);Virogon (TH);Virolex (HU, RO);Virolox (HR);Viromed (TH);Virpes (AE, JO);Virucid (MT, TR, VN);Virustat (JO);Virzin (DE);Vivir (KR);Wariviron (LB, QA);Xinvir (TW);Xovir (BD);Zevin (TH);Ziverone (MX);Zodiac (KR);Zoral (HK, MY, SG);Zorax (MY, SG);Zorexin (MY);Zoter (ID);Zovir (DK, IS);Zovirax (AE, AR, AT, AU, BB, BD, BE, BF, BG, BH, BJ, BM, BO, BR, BS, CH, CI, CU, CY, CZ, EC, EE, EG, ET, FI, FR, GB, GH, GM, GN, GR, GY, HK, HU, ID, IE, IL, IN, IQ, IR, IT, JM, JO, JP, KE, KR, KW, LB, LR, LU, LV, LY, MA, ML, MR, MT, MU, MW, MY, NE, NG, NL, NO, NZ, OM, PE, PH, PK, PL, PR, PT, PY, QA, RU, SA, SC, SD, SE, SK, SL, SN, SY, TN, TR, TT, TW, TZ, UA, UG, UY, YE, ZA, ZM, ZW);Zoylex (PE);Zyvir (KE)For country code abbreviations (show table)Acyclovir capsule, tablet [prescribing information]. 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CloseDexamethasone (systemic): Pediatric drug informationDexamethasone (systemic): Pediatric drug information(For additional information see "Dexamethasone (systemic): Drug information" and see "Dexamethasone (systemic): Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USActive Injection D [DSC];Decadron [DSC];Dexabliss;Dexamethasone Intensol;DexPak 10 Day [DSC];DexPak 13 Day [DSC];DexPak 6 Day [DSC];DoubleDex;Dxevo 11-Day;Hemady;HiDex 6-Day;MAS Care-Pak;ReadySharp Dexamethasone [DSC];TaperDex 12-Day;TaperDex 6-Day;TaperDex 7-Day;TopiDex;ZCORT 7-Day [DSC]Brand Names: CanadaAPO-Dexamethasone;Dexamethasone Omega Unidose;Dexamethasone-Omega;Odan-Dexamethasone;PMS-Dexamethasone;PMS-Dexamethasone Sod Phosphat [DSC];PRO-Dexamethasone-4 [DSC]Therapeutic CategoryAdrenal Corticosteroid;Anti-inflammatory Agent;Antiemetic;Corticosteroid, Systemic;GlucocorticoidDosing: NeonatalAirway edema or extubationAirway edema or extubation: Limited data available: IV: 0.25 mg/kg/dose given ~4 hours prior to scheduled extubation then every 8 hours for a total of 3 doses (Ref); others have used 0.5 mg/kg/dose every 8 hours for 3 doses with last dose administered 1 hour prior to scheduled extubation (Ref); range: 0.25 to 0.5 mg/kg/dose for 1 to 3 doses; maximum daily dose: 1.5 mg/kg/day. Note: A longer duration of therapy may be needed with more severe cases. A recent meta-analysis concluded that future neonatal clinical trials should study a multiple dose strategy with initiation of dexamethasone at least 12 hours before extubation (Ref).Bronchopulmonary dysplasia, facilitation of ventilator weanBronchopulmonary dysplasia, facilitation of ventilator wean: Limited data available: PNA ≥7 days: Oral, IV: Initial: 0.15 mg/kg/day in divided doses every 12 hours for 3 days, followed by a taper of: 0.1 mg/kg/day for 3 days, then 0.05 mg/kg/day for 2 days, and 0.02 mg/kg/day for 2 days for a total dexamethasone dose of 0.89 mg/kg given over 10 days; tapering doses were administered in divided doses every 12 hours (Ref). Note: Multiple regimens have been described. Optimal regimen has not been defined. High doses (~0.5 mg/kg/day) are associated with higher incidence of adverse effects (including adverse neurodevelopmental outcomes) and are not recommended for use (Ref). However, a meta-analysis reported total cumulative doses >4 mg/kg initiated after the first week of life produced a greater reduction in the relative risk compared to lower cumulative doses for the combined outcome, mortality, or bronchopulmonary dysplasia without increasing the risk of neurodevelopmental sequelae in ventilated preterm infants (Ref).Dosing: PediatricCOVID-19, treatmentCOVID-19, treatment: Very limited data available:Note: Safety and effectiveness of dexamethasone or other corticosteroids for COVID-19 treatment have not been sufficiently evaluated in pediatric patients; use is extrapolated from adult patients; use caution. Reserve use for hospitalized patients who require high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO); not routinely recommended for pediatric patients requiring low levels of oxygen support (ie, nasal canula only). Use in profoundly immunocompromised pediatric patients should be considered only on a case-by-case basis as it has not been evaluated and may be harmful. Pediatric patients with COVID-19 should be enrolled in clinical trials whenever possible (Ref).Infants, Children, and Adolescents: IV, Oral: 0.15 to 0.3 mg/kg/dose once daily for up to 10 days; maximum dose: 6 mg/dose (Ref). Note: An equivalent dose of an alternative glucocorticoid may be substituted if dexamethasone is unavailable (Ref).Acute mountain sickness/high altitude cerebral edema; treatmentAcute mountain sickness (AMS) (moderate)/high altitude cerebral edema (HACE); treatment: Limited data available: Note: Dexamethasone does not facilitate acclimatization; further ascent should be delayed until patient is asymptomatic off medication (Ref).Infants, Children, and Adolescents: Oral, IM, IV: 0.15 mg/kg/dose every 6 hours; maximum dose: 4 mg/dose (Ref).Airway edema or extubationAirway edema or extubation: Limited data available: Infants, Children, and Adolescents: Oral, IM, IV: 0.5 mg/kg/dose (maximum dose: 10 mg/dose) administered 6 to 12 hours prior to extubation then every 6 hours for 6 doses (total dexamethasone dose: 3 mg/kg) (Ref).Anti-inflammatoryAnti-inflammatory: Infants, Children, and Adolescents: Oral, IM, IV: Initial dose range: 0.02 to 0.3 mg/kg/day or 0.6 to 9 mg/m2/day in divided doses every 6 to 12 hours; dose depends upon condition being treated and response of patient; dosage for infants and children should be based on disease severity and patient response; usual adult initial daily dose range: 0.75 to 9 mg/day.Asthma exacerbationAsthma exacerbation: Limited data available: Infants, Children, and Adolescents: Oral, IM, IV: 0.6 mg/kg once daily as a single dose or once daily for 2 days; maximum dose: 16 mg/dose (Ref); single dose regimens as low as 0.3 mg/kg/dose and as high as 1.7 mg/kg/dose have also been reported (Ref). Note:Duration >2 days is not recommended due to increased risk of metabolic effects (Ref).Bacterial meningitisBacterial meningitis (Haemophilus influenzae type b): Limited data available:Infants >6 weeks and Children: IV: 0.15 mg/kg/dose every 6 hours for the first 2 to 4 days of antibiotic treatment; start dexamethasone 10 to 20 minutes before or with the first dose of antibiotic; if antibiotics have already been administered, dexamethasone use has not been shown to improve patient outcome and is not recommended (Ref). Note: For pneumococcal meningitis, efficacy results are variable and use is controversial; risk and benefits should be considered prior to use (Ref).Cerebral edemaCerebral edema: Limited data available: Note: Dose, route, and duration may vary due to underlying cause of edema; tapering may be required. Infants, Children, and Adolescents: Oral, IM, IV: Loading dose: 1 to 2 mg/kg/dose as a single dose; maintenance: 1 to 2 mg/kg/day in divided doses every 4 to 6 hours; maximum daily dose: 16 mg/day (Ref).Chemotherapy-induced nausea and vomiting, preventionChemotherapy-induced nausea and vomiting, prevention: Reported regimens variable; optimal dose not established (Ref). Refer to individual protocols and emetogenic potential:Infants, Children, and Adolescents:POGO recommendations (Ref): Note: Reduce dose by 50% if administered concomitantly with aprepitant:Highly/severely emetogenic chemotherapy: Oral, IV: 6 mg/m2/dose every 6 hours.Moderately emetogenic chemotherapy: Oral, IV:BSA ≤0.6 m2: 2 mg every 12 hours.BSA >0.6 m2: 4 mg every 12 hours.Alternate dosing: Highly/severely emetogenic chemotherapy: IV: Usual: 10 mg/m2/dose once daily on days of chemotherapy; some patients may require every 12-hour dosing; usual range: 8 to 14 mg/m2/dose (Ref).Congenital adrenal hyperplasia, maintenanceCongenital adrenal hyperplasia, maintenance: Adolescents (fully grown): Oral: 0.25 to 0.5 mg once daily; use of a liquid dosage form may be preferable to allow for better dose titration (Ref). Note: For younger patients who are still growing, hydrocortisone or fludrocortisone are preferred.CroupCroup (laryngotracheobronchitis): Limited data available; dosing regimens variable:Infants and Children: Oral, IM, IV: 0.6 mg/kg once; reported maximum dose highly variable; usual maximum dose: 16 mg/dose (Ref); in trials, maximum doses of 10 to 20 mg/dose have been reported with similar efficacy findings for mild to moderate croup. The majority of reported experience in infants are those ≥3 months of age; data available in <3 months of age is very limited (Ref). In one evaluation of 22 children >2 years of age, a maximum dose of 12 mg/dose (at 0.6 mg/kg/dose) did not decrease endogenous glucocorticoid levels (Ref). A single oral dose of 0.15 mg/kg has also been shown effective in infants ≥3 months and children with mild to moderate croup (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricInfants, Children, and Adolescents: IM, IV, Oral:Kidney impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.Hemodialysis or peritoneal dialysis: Based on adult data, supplemental dose is not necessary (Ref).Dosing: Hepatic Impairment: PediatricInfants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling.Dosing: Adult(For additional information see "Dexamethasone (systemic): Drug information")Note: Dosing: Evidence to support an optimal dose and duration is lacking for most indications; recommendations provided are general guidelines only and primarily based on expert opinion. In general, glucocorticoid dosing should be individualized and the minimum effective dose/duration should be used. Hypothalamic-pituitary-adrenal (HPA) suppression: Although some patients may become hypothalamic-pituitary-adrenal (HPA) suppressed with lower doses or briefer exposure, some experts consider HPA-axis suppression likely in any adult receiving >3 mg/day (daytime dosing) or ≥0.75 mg per 24 hours (evening or night dosing) for >2 weeks or with Cushingoid appearance (Ref); do not abruptly discontinue treatment in these patients; dose tapering may be necessary (Ref).Usual dosage range:Oral, IV, IM: 4 to 20 mg/day given in a single daily dose or in 2 to 4 divided doses; High dose: 0.4 to 0.8 mg/kg/day (usually not to exceed 40 mg/day).Indication-specific dosing:Acute mountain sickness/high-altitude cerebral edemaAcute mountain sickness/high-altitude cerebral edema (off-label use):Prevention, moderate- to high-risk situations(alternative agent): Note: Use in addition to gradual ascent and start the day of ascent.Oral: 2 mg every 6 hours or 4 mg every 12 hours; may be discontinued after staying at the same elevation for 2 to 4 days or if descent is initiated. Due to adverse effects, limit duration to ≤10 days (Ref); some experts limit to ≤7 days (Ref). In situations of rapid ascent to altitudes >3,500 meters (eg, rescue or military operations), 4 mg every 6 hours may be considered (Ref).Treatment:Acute mountain sickness (moderate to severe): Note: Dexamethasone does not facilitate acclimatization; further ascent should be delayed until patient is asymptomatic off medication (Ref).Oral, IM, IV: 4 mg every 6 hours, continue until 24 hours after symptoms resolve or descent completed (not longer than 7 days total) (Ref).High-altitude cerebral edema: Oral, IM, IV: 8 mg as a single dose, followed by 4 mg every 6 hours until descent is complete and symptoms resolve (Ref).Acute respiratory distress syndrome, moderate to severeAcute respiratory distress syndrome, moderate to severe (off-label use): Note: May consider in most patients with persistent or refractory moderate to severe acute respiratory distress syndrome who are relatively early in the disease course (within 14 days) (Ref). Do not abruptly discontinue since this may cause deterioration due to inflammatory response (Ref).IV: 20 mg once daily from days 1 to 5, then 10 mg once daily from days 6 to 10 (Ref).Adrenal insufficiency, adrenal crisisAdrenal insufficiency, adrenal crisis (alternative agent): Note: Dexamethasone should only be used if hydrocortisone is unavailable. Corticosteroid therapy should be combined with adequate fluid resuscitation in patients with primary adrenal insufficiency (Ref).IV: 4 mg every 12 hours; transition to hydrocortisone as soon as possible (Ref).Adrenal insufficiency, primary chronicAdrenal insufficiency, primary chronic (alternative agent): Note: For use in patients who are unable to tolerate treatment with other glucocorticoids (hydrocortisone is preferred); risk of overreplacement may be higher with dexamethasone (Ref). Use in conjunction with fludrocortisone. Dose is based on prednisolone equivalency.Chronic maintenance dosing:Oral: Usual dosage range: 0.25 to 0.75 mg once daily (Ref).Stress dosing:Note: Patients who are unable to tolerate oral medication (eg, due to vomiting or diarrhea), are in active labor, or are under surgical stress may require parenteral corticosteroid therapy (preferably with hydrocortisone) to prevent adrenal crisis (Ref).Patients with febrile illness: Oral: Double the chronic maintenance dose until recovery for fever 38°C (100.4°F) to 39°C (102.2°F) or triple the chronic maintenance dose until recovery for fever >39°C (102.2°F), then return to baseline dose within 1 to 3 days (Ref).Minor surgical stress (eg, hernia repair, procedures with local anesthetic): Oral: Continue chronic maintenance dose (no additional supplementation needed) (Ref); may give an additional 0.75 mg (equivalent to ~20 mg hydrocortisone) postoperatively if signs or symptoms of adrenal insufficiency are present (Ref).Antiemetic regimens: Chemotherapy-associated nausea and vomiting, preventionAntiemetic regimens: Chemotherapy-associated nausea and vomiting, prevention (off-label use): Note: When dexamethasone is given with rolapitant in a prechemotherapy regimen, the oral route for both is generally used. When checkpoint inhibitor therapy is administered in combination with emetogenic chemotherapy, there is no evidence to omit dexamethasone from the prophylactic antiemetic regimen (Ref).Single-day IV chemotherapy regimens: Highly emetogenic chemotherapy (>90% risk of emesis): Cisplatin and other highly emetogenic single agents: Dexamethasone dose depends on specific neurokinin 1 (NK1) receptor antagonist: Day of chemotherapy: Administer prior to chemotherapy and in combination with an NK1 receptor antagonist, and a 5-HT3 receptor antagonist, with or without olanzapine (Ref).In combination with aprepitant, fosaprepitant, netupitant/palonosetron (NEPA), or fosnetupitant/palonosetron: Oral, IV: 12 mg.In combination with rolapitant: Oral, IV: 20 mg.If NK1 receptor antagonist not used: Oral, IV: 20 mg.Postchemotherapy days:If aprepitant given: Oral, IV: 8 mg once daily on days 2 to 4 (Ref).If fosaprepitant given: Oral, IV: 8 mg once on day 2, followed by 8 mg twice daily on days 3 and 4 (Ref).If NEPA or fosnetupitant/palonosetron given: Prophylaxis with dexamethasone on subsequent days is not needed unless regimen contained cisplatin: Oral, IV: 8 mg once daily on days 2 to 4 (Ref).If rolapitant given: Oral, IV: 8 mg twice daily on days 2 to 4 (Ref).If NK1 receptor antagonist not used: Oral, IV: 8 mg twice daily on days 2 to 4 (Ref).Highly emetogenic chemotherapy (>90% risk of emesis): Breast cancer regimens that include an anthracycline combined with cyclophosphamide:Dexamethasone dose depends on specific NK1 receptor antagonist: Day of chemotherapy: Administer prior to chemotherapy and in combination with an NK1 receptor antagonist, and a 5-HT3 receptor antagonist, with or without olanzapine (Ref).In combination with aprepitant, fosaprepitant, NEPA, fosnetupitant/palonosetron: Oral, IV: 12 mg (Ref).In combination with rolapitant: Oral, IV: 20 mg (Ref).If NK1 receptor antagonist not used: Oral, IV: 20 mg (Ref).Postchemotherapy days: Dexamethasone use is not recommended (an alternative agent or agents is/are recommended) (Ref).Moderately emetogenic chemotherapy (30% to 90% risk of emesis): Carboplatin-based regimens: Dexamethasone dose depends on specific NK1 receptor antagonist (Ref):Day of chemotherapy: Administer prior to chemotherapy and in combination with an NK1 receptor antagonist and a 5-HT3 receptor antagonist (Ref).In combination with aprepitant, fosaprepitant, NEPA, or fosnetupitant/palonosetron: Oral, IV: 12 mg (Ref).In combination with rolapitant: Oral, IV: 20 mg (Ref).Postchemotherapy days: Prophylaxis is not necessary on subsequent days (Ref).Moderately emetogenic chemotherapy (30% to 90% risk of emesis): Non-carboplatin-based regimens: Day of chemotherapy: Administer prior to chemotherapy and in combination with a 5-HT3 receptor antagonist: Oral, IV: 8 mg (Ref).Postchemotherapy days: Note: Consider single-agent dexamethasone use for regimens containing agents with known potential to induce delayed emesis (eg, oxaliplatin, cyclophosphamide, doxorubicin) (Ref); a single-day dexamethasone regimen may be employed when utilizing palonosetron (Ref); however, if a first-generation 5-HT3 antagonist was used on day 1 rather than palonosetron, some experts suggest the first-generation 5-HT3 receptor antagonist be continued for postchemotherapy emetic prophylaxis on days 2 and 3 (Ref).Oral, IV: 8 mg on days 2 and 3 (Ref).Low emetogenic risk (10% to 30% risk of emesis): Oral, IV: 4 to 8 mg administered as a single agent in a single dose prior to chemotherapy; prophylaxis is not necessary on subsequent days (Ref).Antiemetic regimens: Postoperative nausea and vomiting, preventionAntiemetic regimens: Postoperative nausea and vomiting, prevention (off-label use): Note: May be used alone or in combination with one or more other prophylactic interventions depending on risk factors (Ref).IV: 4 to 10 mg once, before or after induction of anesthesia. Dose depends on risk and type of surgery (Ref).Antiemetic regimens: Radiation therapy-associated nausea and vomiting, preventionAntiemetic regimens: Radiation therapy-associated nausea and vomiting, prevention (off-label use): High emetogenic risk radiation therapy (total body irradiation): Radiation day(s): Oral, IV: 4 mg once daily prior to each fraction of radiation; give in combination with a 5-HT3 receptor antagonist (Ref).Postradiation days: Oral, IV: The appropriate duration of therapy following radiotherapy days is not well defined; ASCO guidelines recommend continuing dexamethasone 4 mg once on the day after each day of radiation if radiation is not planned for that day (Ref).Moderate emetogenic risk radiation therapy (upper abdomen, craniospinal irradiation):Radiation day(s): Oral, IV: 4 mg once daily prior to each of the first 5 fractions of radiation; give in combination with a 5-HT3 receptor antagonist (Ref).Asthma, acute exacerbationAsthma, acute exacerbation (alternative agent) (off-label use): Note: Alternative to a longer course of other corticosteroids in mild to moderate exacerbations or in patients who do not respond promptly and completely to short-acting beta-agonists; administer within 1 hour of presentation to emergency department (Ref).Oral: 12 to 16 mg daily for 1 to 2 days only (Ref); longer treatment at this dose may be associated with metabolic adverse effects (Ref).Cancer-related cachexiaCancer-related cachexia (off-label use): Oral: 3 to 4 mg once daily; short-term therapy (weeks) is recommended, although duration of treatment depends on treatment goals and risk/benefit assessment (Ref) or 3 to 6 mg/day for up to 4 weeks (Ref).Cancer-related pain, advanced cancer, adjuvant therapyCancer-related pain, advanced cancer, adjuvant therapy (off-label use): Note: Although available data are limited and with mixed results, dexamethasone may provide clinical benefit in the management of a variety of types of pain in patients with advanced cancer (Ref). Due to the risk for potential toxicity, carefully consider the risks and benefits of glucocorticoid use for treating cancer-related pain, including the availability of other treatments, duration of treatment, other symptoms, and life expectancy.Low-dose regimen for pain and other symptoms in the context of advanced cancer and short prognosis: Oral, IV: Initial: 0.75 to 1.5 mg once or twice daily; usual effective dose range: 1 to 2 mg IV or orally twice daily (Ref).Higher-dose regimen for pain crisis that is poorly responsive to initial opioid therapy: Oral, IV: Initial: 8 to 10 mg once; if responsive, then may consider 4 mg twice daily or 8 mg once daily; use the lowest dose that maintains pain relief while other analgesic treatments are added, if indicated (Ref).Cerebral edema associated with brain tumorCerebral (vasogenic) edema associated with brain tumor: Moderate to severe symptoms (eg, lowered consciousness/brainstem dysfunction):Initial: IV: 10 mg once followed by maintenance dosing (Ref).Maintenance: IV, Oral: 4 mg every 6 hours (Ref). Note: Consider taper after 7 days of therapy; taper slowly over several weeks (Ref).Mild symptoms: IV, Oral: 4 to 8 mg/day in 1 to 4 divided doses (Ref). Note: Consider taper after 7 days of therapy; taper slowly over several weeks (Ref).COVID-19, hospitalized patientsCOVID-19, hospitalized patients (off-label use): Note: Dexamethasone is recommended for treatment of COVID-19 in hospitalized patients requiring supplemental oxygen or ventilatory support (Ref). An equivalent dose of an alternative glucocorticoid may be substituted if dexamethasone is unavailable (Ref).IV, Oral: 6 mg once daily for up to 10 days (or until discharge if sooner) as part of an appropriate combination regimen (Ref).Cushing syndrome, diagnosisCushing syndrome, diagnosis: Note: Interpretation requires evaluation of one or more of the following: serum cortisol concentration, serum dexamethasone concentration, urinary cortisol excretion, or 17-hydroxycorticosteroid excretion; consultation with a clinical endocrinologist is recommended (Ref).Initial testing:Overnight 1 mg dexamethasone suppression test: Oral: 1 mg given once between 11 PM and 12 AM (Ref).Longer low-dose dexamethasone suppression test (2 mg/day for 48 hours): Note: May be preferred in patients with depression, anxiety, obsessive-compulsive disorder, morbid obesity, alcoholism, or diabetes mellitus (Ref).Oral: 0.5 mg every 6 hours for 48 hours for a total of 8 doses; start time varies (eg, 9 AM or12 PM) (Ref).Fetal lung maturation, acceleration ofFetal lung maturation, acceleration of (maternal administration) (off-label use): Note: Generally, for patients between 24 and 34 weeks of gestation, including those with ruptured membranes or multiple gestations, who are at risk of delivering within 7 days. A single course may be appropriate in some pregnant patients beginning at 23 weeks' gestation or late preterm (between 34 0/7 weeks' and 36 6/7 weeks' gestation) who are at risk of delivering within 7 days.IM: 6 mg every 12 hours for a total of 4 doses. May repeat course in select patients (eg, patients with pregnancies up to 34 weeks' gestation at risk for delivery within 7 days and >14 days have elapsed since initial course of antenatal corticosteroids) (Ref).Immune thrombocytopeniaImmune thrombocytopenia (initial therapy): Note: Goal of therapy is to provide a safe platelet count to prevent clinically important bleeding rather than normalization of the platelet count (Ref).Oral, IV: 40 mg once daily for 4 days and then stop (no taper); may be repeated up to 3 times if inadequate response (Ref). For severe bleeding with thrombocytopenia, give in combination with other therapies (Ref).Iodinated contrast media allergic-like reaction, preventionIodinated contrast media allergic-like reaction, prevention (alternative agent): Note: Generally for patients with a prior allergic-like or unknown-type iodinated contrast reaction who will be receiving another iodinated contrast agent. Nonurgent premedication with an oral corticosteroid (eg, prednisone) is generally preferred when contrast administration is scheduled to begin in ≥12 hours; however, consider an urgent (accelerated) regimen with an IV corticosteroid for those requiring contrast in <12 hours. Efficacy of premedication regimens starting <4 to 5 hours before the use of contrast has not been demonstrated (Ref).Urgent (accelerated) regimen: IV: 7.5 mg every 4 hours until contrast medium administration in combination with diphenhydramine (Ref).Meningitis, prevention of neurologic complicationsMeningitis (bacterial), prevention of neurologic complications (off-label use): Note: Administer first dose of dexamethasone shortly before or at the same time as the first dose of antibacterials. If antibacterials have already been administered, do not administer dexamethasone. In patients with pneumococcal meningitis who receive dexamethasone, some experts recommend adding rifampin to the standard initial antibacterial regimen or adding rifampin if susceptibility tests, once available, show intermediate susceptibility (MIC ≥2 mcg/mL) to ceftriaxone and cefotaxime (Ref).Developed world (suspected or confirmed pneumococcal meningitis): IV: 0.15 mg/kg/dose or 10 mg every 6 hours for 4 days; discontinue if culture data reveal non-pneumococcal etiology (Ref).Developing world (strongly suspected or confirmed bacterial meningitis): IV: 0.4 mg/kg/dose every 12 hours for 4 days; discontinue if culture data reveal non-pneumococcal etiology; not recommended in regions with high rates of HIV infection and/or malnutrition or in cases of delayed clinical presentation (Ref).Migraine, recurrence preventionMigraine, recurrence prevention (off-label use): IM, IV: 10 to 24 mg once in combination with standard migraine abortive therapy (Ref).Multiple myelomaMultiple myeloma: Note: Multiple dexamethasone-containing regimens are available. Refer to literature/guidelines for additional details. For many regimens, dexamethasone is continued until disease progression or unacceptable toxicity. Dexamethasone total weekly dose may be split over 2 days when combination therapies are administered on successive days (refer to protocol) (Ref).Frail patients (eg, >75 years of age, BMI <18.5 kg/m2, poorly controlled diabetes, corticosteroid intolerance): When administered weekly, dexamethasone is usually reduced to 20 mg once weekly for frail patients (Ref). May consider lower initial dexamethasone doses (8 to 20 mg once weekly) in patients >75 years of age or those with comorbidities, with subsequent titration based on response/tolerance (Ref).Combination regimens that do not include a monoclonal antibody:Oral:40 mg once weekly on days 1, 8, 15, and 22 every 28 days in combination with lenalidomide (Ref), pomalidomide (Ref), ixazomib and lenalidomide (Ref), ixazomib and lenalidomide for 18 cycles (Ref), carfilzomib and lenalidomide (Ref), or bortezomib and lenalidomide (Ref) or 40 mg once weekly on days 1, 8, 15, and 22 every 28 days in cycles 1 to 9, and then 40 mg once weekly on days 1, 8, and 15 every 28 days beginning at cycle 10 (in combination with carfilzomib) (Ref).or20 mg on days 1, 8, 15, and 22 every 28 days (in combination with lenalidomide) for 9 cycles, followed by lenalidomide maintenance (Ref) or 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days (in combination with bortezomib and lenalidomide) for 8 cycles (induction), followed by 40 mg on days 1, 8, 15, and 22 every 28 days (in combination with lenalidomide) for maintenance (Ref) or 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 every 28 days (in combination with carfilzomib) (Ref) or 20 mg on days 1 and 3 of each week (in combination with selinexor) (Ref) or 20 mg on days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 every 35 days (in combination with selinexor and bortezomib) (Ref).or40 mg once daily on days 1 to 4 and 9 to 12 every 28 days in combination with bortezomib and lenalidomide for 6 cycles followed by transplant (Ref) or 40 mg once daily on days 1 to 4, 9 to 12, and 17 to 20 every 28 days in combination with bortezomib and doxorubicin for 3 cycles as induction (Ref). Note: Some experts reserve this dosing (for 1 cycle, followed by 40 mg once weekly thereafter) for patients with an aggressive disease presentation or acute renal failure from light chain cast nephropathy (Ref).Combination regimens that include a monoclonal antibody:Oral, IV:40 mg weekly in combination with daratumumab and pomalidomide (Ref) or daratumumab/hyaluronidase and pomalidomide (Ref) or daratumumab and lenalidomide (Ref) or daratumumab/hyaluronidase and lenalidomide (Ref) or daratumumab and carfilzomib (Ref) or isatuximab and pomalidomide (Ref) or 20 mg once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days in combination with daratumumab and bortezomib (Ref) or 20 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 every 28 days in combination with isatuximab and carfilzomib (Ref). Note: In some studies, the dexamethasone dose is split over 2 days (20 mg before daratumumab and 20 mg the day after daratumumab infusion).or40 mg weekly, except on days elotuzumab is administered (administer dexamethasone 28 mg orally [8 mg orally in patients >75 years of age] plus 8 mg IV prior to elotuzumab) in combination with elotuzumab and pomalidomide (Ref) or elotuzumab and lenalidomide (Ref).Neoplastic epidural spinal cord compression, symptomaticNeoplastic epidural spinal cord compression, symptomatic: Note: As an adjunct to definitive treatment (radiotherapy or surgery), particularly in patients with neurologic deficits (Ref).IV (initial dose): 10 or 16 mg followed by oral dosing (Ref).Oral (after IV dose): 16 mg/day (usually given in 2 to 4 divided doses). Once definitive treatment is underway, taper gradually over 1 to 2 weeks until discontinuation (Ref).Tuberculosis, central nervous systemTuberculosis, central nervous system: Note: In general, steroids are indicated for patients with established or suspected tuberculous meningitis, regardless of HIV status (Ref).IV: Initial dose: 0.3 to 0.4 mg/kg/day for 2 weeks, then 0.2 mg/kg/day for week 3, then 0.1 mg/kg/day for week 4, followed by oral therapy (Ref).Oral: Starting week 5 of treatment: 4 mg/day, then taper by 1 mg of the daily dose each week; total combined IV/oral therapy duration: ~8 weeks (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Note: The pharmaco*kinetics and pharmacodynamics of corticosteroids in kidney impairment are not well understood (Ref). Dexamethasone half-life is decreased in patients with severe kidney impairment (Ref), potentially due to decreased protein binding (Ref); however, the clinical implications of these findings are unclear.Oral, parenteral:Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (Ref).Hemodialysis, intermittent (thrice weekly): No supplemental dose or dosage adjustment necessary (Ref).Peritoneal dialysis: No dosage adjustment necessary (Ref).CRRT: No dosage adjustment necessary (Ref).PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productConcentrate, Oral: Dexamethasone Intensol: 1 mg/mL (30 mL) [contains alcohol, usp; unflavored flavor]Elixir, Oral: Decadron: 0.5 mg/5 mL (237 mL [DSC]) [contains alcohol, usp, benzoic acid, fd&c red #40 (allura red ac dye), propylene glycol]Generic: 0.5 mg/5 mL (237 mL)Kit, Injection, as sodium phosphate: ReadySharp Dexamethasone: 10 mg/mL [DSC] [contains benzyl alcohol, sodium sulfite]TopiDex: 10 mg/mL [contains benzyl alcohol]Kit, Injection, as sodium phosphate [preservative free]: Active Injection D: 10 mg/mL [DSC]DoubleDex: 10 mg/mLMAS Care-Pak: 10 mg/mLSolution, Oral: Generic: 0.5 mg/5 mL (240 mL, 500 mL)Solution, Injection, as sodium phosphate: Generic: 4 mg/mL (1 mL); 20 mg/5 mL (5 mL); 120 mg/30 mL (30 mL); 10 mg/mL (1 mL); 100 mg/10 mL (10 mL)Solution, Injection, as sodium phosphate [preservative free]: Generic: 4 mg/mL (1 mL); 10 mg/mL (1 mL)Solution Prefilled Syringe, Injection, as sodium phosphate [preservative free]: Generic: 10 mg/mL (1 mL)Tablet, Oral: Decadron: 0.5 mg [DSC] [scored; contains fd&c yellow #5 (tartrazine), quinoline yellow (d&c yellow #10)]Decadron: 0.75 mg [DSC] [scored; contains fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]Decadron: 4 mg [DSC], 6 mg [DSC] [scored]Hemady: 20 mg [contains corn starch]Generic: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, 6 mgTablet Therapy Pack, Oral: Dexabliss: 1.5 MG (39) (39 ea)DexPak 10 Day: 1.5 mg (35 ea [DSC]) [scored; contains fd&c red #40(allura red ac)aluminum lake]DexPak 13 Day: 1.5 mg (51 ea [DSC]) [scored; contains fd&c red #40(allura red ac)aluminum lake]DexPak 6 Day: 1.5 mg (21 ea [DSC]) [scored; contains fd&c red #40(allura red ac)aluminum lake]Dxevo 11-Day: 1.5 mg (39 ea)Dxevo 11-Day: 1.5 mg (39 ea) [scored]HiDex 6-Day: 1.5 mg (21 ea) [scored; contains fd&c red #40 (allura red ac dye)]TaperDex 12-Day: 1.5 mg (49 ea) [contains fd&c red #40 (allura red ac dye)]TaperDex 6-Day: 1.5 mg (21 ea) [scored; contains fd&c red #40 (allura red ac dye)]TaperDex 6-Day: 1.5 mg (21 ea) [scored; contains fd&c red #40(allura red ac)aluminum lake]TaperDex 7-Day: 1.5 mg (27 ea) [scored; contains fd&c red #40 (allura red ac dye)]ZCORT 7-Day: 1.5 mg (25 ea [DSC]) [scored]Generic: 1.5 mg (21 ea, 35 ea, 51 ea)Generic Equivalent Available: USMay be product dependentDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Elixir, Oral: Generic: 0.5 mg/5 mL (100 ea, 100 mL)Solution, Injection, as sodium phosphate: Generic: 4 mg/mL (5 mL); 10 mg/mL (1 mL, 10 mL)Tablet, Oral: Generic: 0.5 mg, 0.75 mg, 2 mg, 4 mgAdministration: PediatricOral: May administer with food or milk to decrease GI adverse effects.Parenteral: Use preservative-free dosage forms in neonates.IM: May administer 4 mg/mL or 10 mg/mL undiluted.IV: May administer as undiluted solution (4 mg/mL or 10 mg/mL) slow IV push, usually over 1 to 4 minutes; rapid administration is associated with perineal discomfort (burning, tingling) (Ref); may consider further dilution of high doses and administration by IV intermittent infusion over 15 to 30 minutes (Ref).Administration: AdultOral: Administer with meals to help prevent GI upset. If appropriate, may administer antacids between meals to help prevent peptic ulcers.Oral concentrate: Use only the calibrated dropper provided. Draw dose into dropper; squeeze dropper contents into a liquid or semi-solid food (water, juice, soda or soda-like beverage, applesauce, pudding). Gently stir for a few seconds. Administer the entire mixture immediately. Do not store for future use.IV: May administer 4 mg/mL or 10 mg/mL concentration undiluted over ≥1 minute (Ref) or infuse by IVPB over 5 to 30 minutes (Ref). Rapid administration of dexamethasone may be associated with perineal irritation (especially with higher doses); consider further dilution and slower administration by IVPB to avoid perineal irritation (Ref).IM: Administer 4 mg/mL or 10 mg/mL concentration by deep IM injection.Intra-articular or soft tissue injection: Note: Dexamethasone sodium phosphate (a short-acting solution) is the only formulation available for intra-articular or soft tissue injections in the United States or Canada. Other glucocorticoids, such as triamcinolone acetonide or methylprednisolone acetate, are used more commonly for intra-articular or soft tissue injection (Ref). Refer to product-specific labeling for further details.Intra-articular: Administer into affected joint.Soft tissue: Administer into affected tissue.Intralesional injection: Note: Dexamethasone sodium phosphate (a short-acting solution) is the only formulation available for intralesional injections in the United States or Canada. Another glucocorticoid, triamcinolone acetonide, is used more commonly for intralesional injection (Ref). Refer to product-specific labeling for further details.Intralesional: Administer into affected area.Storage/StabilityElixir: Store at 15°C to 30°C (59°F to 86°F); avoid freezing.Injection: Store intact vials at 20°C to 25°C (68°F to 77°F). Protect from light, heat, and freezing. Do not autoclave. Diluted solutions should be used within 24 hours.Oral concentrated solution (Intensol): Store at 20°C to 25°C (68°F to 77°F); do not freeze; do not use if precipitate is present; dispense only in original bottle and only with manufacturer-supplied calibrated dropper; discard open bottle after 90 days.Oral solution, tablets: Store at 20°C to 25°C (68°F to 77°F); protect from moisture.Hemady (tablets): Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Dispense in a tight, light-resistant, child-resistant container.UseOral, parenteral: Primarily as an anti-inflammatory or immunosuppressant agent in the treatment of a variety of diseases, including those of allergic, hematologic, dermatologic, neoplastic, rheumatic, autoimmune, nervous system, renal, and respiratory origin (FDA approved in pediatric patients [age not specified] and adults); primary or secondary adrenocorticoid deficiency (not first line) (FDA approved in pediatric patients [age not specified] and adults); management of cerebral edema, shock, and as a diagnostic agent (FDA approved in pediatric patients [age not specified] and adults). Has also been used as adjunctive antiemetic agent in the treatment of chemotherapy-induced emesis, treatment of croup (laryngotracheobronchitis), treatment of airway edema prior to extubation, treatment of acute mountain sickness (AMS) and high altitude cerebral edema (HACE), and in neonates with bronchopulmonary dysplasia to facilitate ventilator weaning.Medication Safety IssuesSound-alike/look-alike issues:DexAMETHasone may be confused with desoximetasone, dexmedeTOMIDine, dextroamphetamineDecadron may be confused with PercodanAdverse Reactions (Significant): ConsiderationsAdrenal suppression (tertiary adrenal insufficiency)Adrenal suppression (tertiary adrenal insufficiency) may occur with glucocorticoids, including dexamethasone, and results from inadequate stimulation of the adrenal glands (Ref). Glucocorticoid-induced adrenal insufficiency usually resolves with discontinuation of dexamethasone, but symptoms may persist for 6 to 12 months (Ref). Adrenal insufficiency may lead to adrenal crisis, a life-threatening emergency that may present like a hypotensive shock state (Ref).Mechanism: Dose- and time-related; occurs due to lack of or diminished cortisol production by the adrenal gland (Ref). Exogenous glucocorticoids produce a similar negative feedback mechanism as endogenous cortisol, causing a subsequent decrease in adrenocorticotrophic hormone (ACTH) secretion; thus, cortisol production is suppressed resulting in adrenal atrophy and subsequent insufficiency (ie, hypothalamic-pituitary-adrenal-axis [HPA-axis] suppression) (Ref). In times of stress (eg, critical illness, trauma, surgery), the body requires stress doses in patients taking dexamethasone chronically (Ref). Primary adrenal insufficiency can be caused by dexamethasone alone (without fludrocortisone) because of its lack of mineralocorticoid activity (Ref).Onset: Varied; acute (minutes after administration) and/or chronic (2 to 20 hours to days) (Ref). Chronic dexamethasone use does not allow for the HPA axis to recover quickly (Ref).Risk factors: • High doses for prolonged periods: Although some patients may become HPA suppressed with lower doses or briefer exposure, some experts consider HPA axis-suppression likely in any adult receiving a dose comparable to prednisone >20 mg/day (daytime dosing) or a dose comparable to prednisone ≥5 mg per 24 hours (evening or night dosing) for >3 weeks or with cushingoid appearance (Ref)• Potency of glucocorticoids (Ref); dexamethasone is the most potent glucocorticoid for suppressing the HPA axis (Ref).• Abrupt withdrawal (Ref)• Concurrent interacting medications (eg, carbamazepine, St John's wort, mitotane, rifampicin, itraconazole, diltiazem, thyroid replacement therapy) (Ref)• History of previous adrenal crisis (Ref)• Use of glucocorticoid therapy delivered by various routes of administration (oral and inhaled greater risk than topical or intra-articular) (Ref)CNS and psychiatric/behavioral effectsGlucocorticoids, including dexamethasone, may cause a myriad of CNS and psychiatric/behavioral adverse reactions (Ref). Patients may develop apathy or depression. More commonly, patients develop excitatory psychiatric disturbances (including agitation, anxiety, distractibility, fear, hypomania, insomnia, irritability, lethargy, labile mood, mania, pressured speech, restlessness, and tearfulness) (Ref). Exact incidences are unclear but range from 1.8% to 57% (Ref). Severe psychiatric effects have been reported in 6% of adults receiving high-dose regimens, while depression or mania have been reported in 36% (Ref). Discontinuation or dose reductions generally resolve symptoms over days to weeks (Ref).Mechanism: Dose-related; not clearly established. Dexamethasone and other glucocorticoids may alter feedback on the hypothalamic-pituitary-adrenal axis, which may lead to mood changes (Ref). Glucocorticoids may induce glutamate release, which may be responsible for neuronal toxicity (Ref). Exogenous glucocorticoids may also impact GABAergic steroids (Ref).Onset: Varied; most cases occur early in treatment (within the first 5 days), average of 11.5 days. The majority develop within 6 weeks of initiation (Ref).Risk factors:• Higher doses (comparable to ≥80 mg prednisone) (Ref)Possible additional risk factors:• Age >30 years (Ref)• Females (Ref)• History of neuropsychiatric disorders (Ref)Cushingoid features/Cushing syndromeGlucocorticoids may cause a cushingoid appearance (truncal obesity, facial adipose tissue, dorsocervical adipose tissue), which are adverse reactions related to patient's physical features (Ref). Reactions are more metabolic than weight gain, which is related to fluid retention (edema) (Ref). Iatrogenic Cushing syndrome resulting from glucocorticoid therapy increases morbidity and mortality and decreases quality of life (Ref).Mechanism: Dose- and time-related; excess cortisol from exogenous source (dexamethasone) results in suppression of adrenocorticotrophic hormone (ACTH), commonly called iatrogenic Cushing syndrome (Ref).Onset: Delayed; may develop within the first 2 months of dexamethasone therapy, with the risk dependent on the dose and duration of treatment (Ref).Risk factors:• Higher doses (Ref)• Longer duration of use (Ref)• Drug interactions prolonging the half-life of glucocorticoids via cytochrome P450 (Ref)• BMI (high) (Ref)• Daily caloric intake (>30 kcal/kg/day) (Ref)GI effectsGlucocorticoids, including dexamethasone, may cause GI effects, including peptic ulcer (with possible perforation and hemorrhage), dyspepsia, gastritis, abdominal distention, and ulcerative esophagitis (Ref). Meta-analyses suggest that glucocorticoid monotherapy carries little to no risk of peptic ulcer disease in the general population (Ref). Studies have demonstrated an increased risk of focal small bowel perforation in infants with low birth weight receiving dexamethasone (Ref).Mechanism: Dose-related; glucocorticoids inhibit gastroprotective prostaglandin synthesis and reduce gastric mucus and bicarbonate secretion (Ref). Glucocorticoid immunosuppressive effects may prevent wound healing as well as mask GI signs and symptoms (Ref). Focal small bowel perforation is thought to be due to segmental degeneration of the muscularis externa (Ref).Risk factors:• Higher doses (equivalent to methylprednisolone ≥4 mg/day) (Ref)• Concurrent aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) (Ref)• Hospitalized (but not ambulatory) patients (Ref)• Infants with low birth weight (Ref)• Recent glucocorticoid users (7 to 28 days) versus remote or nonusers (Ref)HyperglycemiaGlucocorticoids, including dexamethasone, may provoke new-onset hyperglycemia in patients without a history of diabetes and may cause an exacerbation of diabetes mellitus (Ref). Glucose levels have been noted to increase 68% above baseline (Ref). Certain patient populations (eg, transplant, cancer, chronic rheumatologic conditions) are at particular risk due to medication combinations (Ref). Resolution may occur within 24 to 36 hours after dexamethasone discontinuation (Ref).Mechanism: Dose- and time-related; increased insulin resistance (Ref). May also interfere with insulin signaling by direct effects on the insulin receptor and the glucose transporter and may promote gluconeogenesis via liver stimulation (Ref).Onset: Rapid; 4 hours (Ref). Rapid onset of steroid-induced hyperglycemia occurred within 2 days after initiation of glucocorticoids with a peak in the late afternoon following daily dosing in the morning (Ref).Risk factors:• Dose and type of glucocorticoid (Ref)• Duration of use (Ref)• Divided versus once-daily dosing (Ref)• IV and oral routes of administration (Ref)• Older age (Ref)• Males (Ref)• BMI >25 kg/m2 (Ref)• African American or Hispanic (Ref)• eGFR <40 mL/minute/1.73 m2 (Ref)• HbA1c ≥6% (Ref)• History of gestational diabetes (Ref)• Family history of diabetes mellitus (Ref)• Concurrent use of mycophenolate mofetil and calcineurin inhibitors (Ref)• Previous history of impaired fasting glucose or impaired glucose tolerance (Ref)• Patients receiving palliative care (Ref)InfectionGlucocorticoids, including dexamethasone, have immunosuppressive and anti-inflammatory effects that are reversible with discontinuation. Infection may occur after prolonged use, including Pneumocystis jirovecii pneumonia (PJP), herpes zoster, tuberculosis, and other more common bacterial infections (Ref).Mechanism: Dose- and time-related; related to pharmacologic action (ie, multiple activities on cell macrophage production and differentiation, inhibition of T-cell activation, and effects on dendritic cells) (Ref).Onset: Varied; in one study, the median duration of glucocorticoid use prior to PJP diagnosis was 12 weeks but also occurred earlier or later in some cases (Ref).Risk factors:• Higher dose and longer duration of glucocorticoid (Ref); however, may also increase risk at lower doses (eg, ≤5 mg/day of prednisone or equivalent) (Ref).• Immunocompromised state (Ref)• Concurrent medications (immunosuppressive) (Ref)• Rheumatoid arthritis (Ref)• Interstitial lung disease (Ref)• Older adults (Ref)• Male (Ref)• Low performance status (Ref)Neuromuscular and skeletal effectsGlucocorticoid (including dexamethasone)-induced neuromuscular and skeletal effects can take the form of various pathologies in patients ranging from osteoporosis and vertebral compression fracture to myopathy to osteonecrosis in adult and pediatric patients (Ref). Glucocorticoid use is the most common cause of secondary osteoporosis; may be underrecognized and undertreated due to underestimation of risk in this patient population (Ref). Vertebral fractures are the most common glucocorticoid-related fracture (Ref). Myopathies can also occur secondary to direct skeletal muscle catabolism (Ref). Acute steroid myopathy is rare (Ref).Mechanism: Dose- and time-related; glucocorticoids have direct/indirect effects on bone remodeling with osteoblast recruitment decreasing and apoptosis increasing (Ref). Myopathies or myasthenia result from reductions in protein synthesis and protein catabolism, which can manifest as proximal muscle weakness and atrophy in the upper and lower extremities (Ref).Onset: Delayed; vertebral fracture risk is increased within 3 months of initiation and peaks at 12 months (Ref).Risk factors:Drug-related risks:• Cumulative dose of glucocorticoids prednisone >5 g or equivalent (Ref)• Children receiving ≥4 courses of glucocorticoids (Ref)• Prednisone ≥2.5 mg to 7.5 mg daily or equivalent for ≥3 months (Ref)• Myopathy may occur at prednisone doses ≥10 mg daily or equivalent, with higher doses potentiating more of a rapid onset (Ref)• Fluorinated glucocorticoid preparations (eg, dexamethasone, betamethasone, triamcinolone) have a higher risk of myopathies (Ref)General fracture risks:• Age >55 years (Ref)• BMI <18.5 kg/m2 (Ref)• Bone mineral T score below -1.5 (Ref)• Endocrine disorders (eg, hypogonadism, hyper- or hypoparathyroidism) (Ref)• Excess alcohol use (>2 units/day) (Ref)• Females (Ref)• History of falls (Ref)• Malabsorption (Ref)• Menopause and duration of menopause (Ref)• White race (Ref)• Patients with cancer (Ref)• Previous fracture (Ref)• Smoking (Ref)• Underlying inflammatory condition in all ages (eg, inflammatory bowel disease, rheumatoid arthritis) (Ref)Ocular effectsGlucocorticoid (including dexamethasone)-induced ocular effects may include increased intraocular pressure (IOP), glaucoma (open-angle), and subcapsular posterior cataract in adult and pediatric patients (Ref). Cataracts may persist after discontinuation of glucocorticoid therapy (Ref).Mechanism: Dose- and time-related; Glucocorticoids can induce cataracts by covalently bonding to lens proteins, causing destabilization of the protein structure, and oxidative changes leading to cataracts formation (Ref). There are various proposed mechanisms of IOP contributing to glaucoma, including accumulation of polymerized glycosaminoglycans in the trabecular meshwork, producing edema and increasing outflow resistance (Ref). Another mechanism may include inhibition of phagocytic endothelial cells, leading to accumulation of aqueous debris (Ref). Glucocorticoids can also alter the trabecular meshwork causing an increase in nuclear size and DNA content (Ref). In addition, they can decrease the synthesis of prostaglandins which regulate the aqueous outflow (Ref).Onset: Delayed; cataracts may occur at least 1 year after initiation of chronic glucocorticoid therapy (Ref). IOP may occur at 4 years or more after initiation (Ref).Risk factors:• Dose (Ref)• Topical > Systemic (Ref)• Duration of use in all ages (Ref)• Family history of open-angle glaucoma (Ref)• Type I diabetes mellitus (Ref)• High myopia (Ref)• Pseudophakia (Ref)• Prior vitrectomies (Ref)• Connective tissue disease and sex (eg, rheumatoid arthritis in males) (Ref)• Older patients or age <6 years (Ref)• Genetics (Ref)• Angle recessive glaucoma (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Some reactions listed are based on reports for other agents in this same pharmacologic class and may not be specifically reported for dexamethasone.Frequency not defined:Cardiovascular: Bradycardia, cardiac arrhythmia, cardiomegaly, circulatory shock, edema, embolism (fat), heart failure (in susceptible patients), hypertension, myocardial rupture (after recent myocardial infarction), syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitisDermatologic: Acne vulgaris, allergic dermatitis, alopecia, atrophic striae, diaphoresis, ecchymoses, erythema of skin, facial erythema, fragile skin, hyperpigmentation, hypertrichosis, hypopigmentation, inadvertent suppression of skin test reaction, perianal skin irritation (itching, burning, tingling; following rapid IV injection; more common in females, with higher doses; sudden onset with resolution in <1 minute) (Allan 1986; Neff 2002; Perron 2003; Singh 2011), skin atrophy, skin rash, subcutaneous atrophy, urticaria, xerodermaEndocrine & metabolic: Decreased serum potassium, fluid retention, growth suppression (children), hirsutism, hypokalemic alkalosis, menstrual disease, negative nitrogen balance (due to protein catabolism), sodium retention, weight gainGastrointestinal: Hiccups, increased appetite, nausea, pancreatitis, pruritus ani (following IV injection)Genitourinary: Defective spermatogenesis (increased or decreased), glycosuriaHematologic & oncologic: Kaposi sarcoma (Goedert 2002), petechiaHepatic: Hepatomegaly, increased serum transaminasesHypersensitivity: Anaphylaxis, angioedema, nonimmune anaphylaxisInfection: Sterile abscessLocal: Postinjection flare (intra-articular use)Nervous system: Amyotrophy, emotional lability, euphoria, headache, increased intracranial pressure, intracranial hypertension (idiopathic; usually following discontinuation), malaise, myasthenia, neuritis, neuropathy, paresthesia, personality changes, seizure, vertigoNeuromuscular & skeletal: Charcot arthropathy, rupture of tendonOphthalmic: ExophthalmosRespiratory: Pulmonary edemaMiscellaneous: Wound healing impairmentPostmarketing:Cardiovascular: Hypertrophic cardiomyopathy (premature infants) (Kale 2015)Endocrine & metabolic: Adrenal suppression (tertiary) (Dineen 2019), Cushing syndrome (iatrogenic) (Hopkins 2005), cushingoid appearance (Hopkins 2005), exacerbation of diabetes mellitus (Tamez-Pérez 2015), hyperglycemia (Tamez-Pérez 2015), impaired glucose tolerance (Tamez-Pérez 2015), moon face (Hopkins 2005), redistribution of body fat (Hopkins 2005)Gastrointestinal: Abdominal distention (Liu 2013), intestinal perforation (Gordon 1999, Gordon 2001), peptic ulcer (with possible perforation and hemorrhage) (Liu 2013), ulcerative esophagitis (Liu 2013)Hematologic & oncologic: Tumor lysis syndrome (Chanimov 2006)Infection: Infection (Youssef 2016)Nervous system: Apathy (Ciriaco 2013, Warrington 2006), depression (Ciriaco 2013, Warrington 2006), psychiatric disturbance (including agitation, anxiety, distractibility, euphoria, fear, hypomania, insomnia, irritability, labile mood, lethargy, pressured speech, restlessness, tearfulness) (Ciriaco 2013, Warrington 2006)Neuromuscular & skeletal: Bone fracture (Buckley 2018), myopathy (Liu 2013), osteonecrosis (femoral and humoral heads) (Liu 2013), osteoporosis (Buckley 2018), steroid myopathy (Haran 2018), vertebral compression fracture (Buckley 2018)Ophthalmic: Glaucoma (Phulke 2017), increased intraocular pressure (Phulke 2017), subcapsular posterior cataract (Urban 1986)ContraindicationsHypersensitivity to dexamethasone or any component of the formulation; systemic fungal infectionsDocumentation of allergenic cross-reactivity for corticosteroids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.Warnings/PrecautionsConcerns related to adverse effects:• Adrenal suppression: May cause hypercortisolism or suppression of hypothalamic-pituitary-adrenal axis, particularly in younger children.Disease-related concerns:• Adrenal insufficiency: Dexamethasone does not provide any mineralocorticoid activity in adrenal insufficiency (may be employed as a single dose while cortisol assays are performed). Hydrocortisone is the preferred treatment of chronic primary adrenal insufficiency and adrenal crisis (ES [Bornstein 2016]).• Cardiovascular disease: Use with caution in patients with heart failure and/or hypertension; use has been associated with fluid retention, electrolyte disturbances, and hypertension. Monitor BP. Use with caution following acute myocardial infarction; corticosteroids have been associated with myocardial rupture.• GI disease: Use with caution in patients with GI diseases (diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, ulcerative colitis, abscess, or other pyogenic infection) due to GI perforation risk. Signs of GI perforation may be masked in patients receiving corticosteroid therapy.• Head injury: Increased mortality was observed in patients receiving high-dose IV methylprednisolone. High-dose corticosteroids should not be used for the management of head injury (BTF [Carney 2016]).• Hepatic impairment: Use with caution in patients with hepatic impairment, including cirrhosis; long-term use has been associated with fluid retention.• Hepatitis B: Reactivation may occur.• Myasthenia gravis: Use may cause transient worsening of myasthenia gravis (MG) (eg, within first 2 weeks of treatment); monitor for worsening MG (AAN [Narayanaswami 2021]).• Ocular disease: Use with caution in patients with a history of ocular herpes simplex; corneal perforation has occurred; do not use in active ocular herpes simplex. Not recommended for the treatment of optic neuritis; may increase frequency of new episodes.• Pheochromocytoma: Pheochromocytoma crisis (may be fatal) has been reported after administration of systemic corticosteroids. Consider the risk of pheochromocytoma crisis in patients with suspected or confirmed pheochromocytoma.• Renal impairment: Use with caution in patients with renal impairment; fluid retention may occur.• Seizure disorders: Use corticosteroids with caution in patients with a history of seizure disorder; seizures have been reported with adrenal crisis.• Systemic sclerosis: Use with caution in patients with systemic sclerosis; an increase in scleroderma renal crisis incidence has been observed with corticosteroid use. Monitor BP and renal function in patients with systemic sclerosis treated with corticosteroids (EULAR [Kowal-Bielecka 2017]).• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of corticosteroids increases in hyperthyroid patients and decreases in hypothyroid patients.Concurrent drug therapy issues:• Immunizations: Avoid administration of live or live attenuated vaccines in patients receiving immunosuppressive doses of corticosteroids. Non-live or inactivated vaccines may be administered, although the response cannot be predicted.Special populations:• Older adult: Use with caution in elderly patients with the smallest possible effective dose for the shortest duration.• Pediatric: May affect growth velocity; growth should be routinely monitored in pediatric patients.Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP ["Inactive" 1997]; Zar 2007).• Sulfite: Some products may contain sodium sulfite, a sulfite that may cause allergic-type reactions including anaphylaxis and life-threatening or less severe asthmatic episodes in susceptible patients.Other warnings/precautions:• Discontinuation of therapy: Withdraw therapy with gradual tapering of dose.• Epidural injection: Corticosteroids are not approved for epidural injection. Serious neurologic events (eg, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, stroke), some resulting in death, have been reported with epidural injection of corticosteroids, with and without use of fluoroscopy.• Intra-articular injection: May produce systemic as well as local effects. Appropriate examination of any joint fluid present is necessary to exclude a septic process. Avoid injection into an infected site. Do not inject into unstable joints. Patients should not overuse joints in which symptomatic benefit has been obtained as long as the inflammatory process remains active. Frequent intra-articular injection may result in damage to joint tissues.Warnings: Additional Pediatric ConsiderationsIn premature neonates, the use of high-dose dexamethasone (approximately >0.5 mg/kg/day) for the prevention or treatment of bronchopulmonary dysplasia has been associated with adverse neurodevelopmental outcomes, including higher rates of cerebral palsy without additional clinical benefit over lower doses; current data do not support use of high doses; further studies are needed (Watterberg 2010).Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities, which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults, including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).Metabolism/Transport EffectsSubstrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP3A4 (weak)Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAbrocitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Abrocitinib.Management: The use of abrocitinib in combination with other immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationAcetylcholinesterase Inhibitors: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur.Risk C: Monitor therapyAldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin.Risk X: Avoid combinationAmphotericin B: Corticosteroids (Systemic) may enhance the hypokalemic effect of Amphotericin B.Risk C: Monitor therapyAndrogens: Corticosteroids (Systemic) may enhance the fluid-retaining effect of Androgens.Risk C: Monitor therapyAntacids: May decrease the bioavailability of Corticosteroids (Oral). Management: Consider separating doses by 2 or more hours. Budesonide enteric coated tablets could dissolve prematurely if given with drugs that lower gastric acid, with unknown impact on budesonide therapeutic effects. Risk D: Consider therapy modificationAntidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.Risk C: Monitor therapyAprepitant: May increase the serum concentration of DexAMETHasone (Systemic). Management: Reduce dexamethasone dose 50% with aprepitant. Aprepitant labeling incorporates this recommendation into the dose provided for dexamethasone; further reduction is not necessary. No dose adjustment may be needed with single, low-dose aprepitant for PONV. Risk D: Consider therapy modificationBaricitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Baricitinib.Management: The use of baricitinib in combination with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationBCG Products: Corticosteroids (Systemic) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of BCG Products.Risk X: Avoid combinationBile Acid Sequestrants: May decrease the absorption of Corticosteroids (Oral). Risk C: Monitor therapyBrincidofovir: Corticosteroids (Systemic) may diminish the therapeutic effect of Brincidofovir.Risk C: Monitor therapyCalcitriol (Systemic): Corticosteroids (Systemic) may diminish the therapeutic effect of Calcitriol (Systemic).Risk C: Monitor therapyCAR-T Cell Immunotherapy: Corticosteroids (Systemic) may enhance the adverse/toxic effect of CAR-T Cell Immunotherapy. Specifically, the severity and duration of neurologic toxicities may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of CAR-T Cell Immunotherapy.Management: Avoid use of corticosteroids as premedication before treatment with CAR-T cell immunotherapy agents. Corticosteroids are indicated and may be required for treatment of toxicities such as cytokine release syndrome or neurologic toxicity. Risk D: Consider therapy modificationCaspofungin: Inducers of Drug Clearance may decrease the serum concentration of Caspofungin.Management: Consider using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m2, up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance. Risk D: Consider therapy modificationCladribine: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Cladribine.Risk X: Avoid combinationClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyCloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine.Risk C: Monitor therapyCobicistat: May increase the serum concentration of DexAMETHasone (Systemic). Dexamethasone (Systemic) may also counteract the boosting effects of Cobicistat on some agents. DexAMETHasone (Systemic) may increase the serum concentration of Cobicistat. Management: Consider an alternative corticosteroid. Monitor patients receiving this combination closely for evidence of diminished response to the antiviral regimen. Risk D: Consider therapy modificationCoccidioides immitis Skin Test: Corticosteroids (Systemic) may diminish the diagnostic effect of Coccidioides immitis Skin Test.Management: Consider discontinuing systemic corticosteroids (dosed at 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks) several weeks prior to coccidioides immitis skin antigen testing. Risk D: Consider therapy modificationCorticorelin: Corticosteroids (Systemic) may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response to corticorelin may be blunted by recent or current corticosteroid therapy.Risk C: Monitor therapyCosyntropin: Corticosteroids (Systemic) may diminish the diagnostic effect of Cosyntropin.Risk C: Monitor therapyCOVID-19 Vaccine (Adenovirus Vector): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector).Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters) Risk D: Consider therapy modificationCOVID-19 Vaccine (Inactivated Virus): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus).Risk C: Monitor therapyCOVID-19 Vaccine (mRNA): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA).Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modificationCOVID-19 Vaccine (Subunit): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit).Risk C: Monitor therapyCOVID-19 Vaccine (Virus-like Particles): Corticosteroids (Systemic) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles).Risk C: Monitor therapyCYP3A4 Inducers (Moderate): May decrease the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of DexAMETHasone (Systemic). Management: Consider dexamethasone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced dexamethasone efficacy. Consider avoiding this combination when treating life threatening conditions (ie, multiple myeloma). Risk D: Consider therapy modificationCYP3A4 Inhibitors (Moderate): May increase the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapyCYP3A4 Inhibitors (Strong): May increase the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapyDeferasirox: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapyDelavirdine: DexAMETHasone (Systemic) may decrease the serum concentration of Delavirdine.Risk C: Monitor therapyDengue Tetravalent Vaccine (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live).Risk X: Avoid combinationDenosumab: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and systemic corticosteroids. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modificationDesirudin: Corticosteroids (Systemic) may enhance the anticoagulant effect of Desirudin. More specifically, corticosteroids may increase hemorrhagic risk during desirudin treatment.Management: Discontinue treatment with systemic corticosteroids prior to desirudin initiation.If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: Consider therapy modificationDesmopressin: Corticosteroids (Systemic) may enhance the hyponatremic effect of Desmopressin.Risk X: Avoid combinationDeucravacitinib: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Management: The use of deucravacitinib in combination with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationDisulfiram: May enhance the adverse/toxic effect of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid combinationElvitegravir: DexAMETHasone (Systemic) may decrease the serum concentration of Elvitegravir.Management: Consider using an alternative corticosteroid.Monitor patients receiving these agents in combination for diminished antiviral response. Risk D: Consider therapy modificationEPHEDrine (Systemic): May decrease the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapyEstrogen Derivatives: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapyFexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFilgotinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Filgotinib.Management: Coadministration of filgotinib with systemic corticosteroids at doses equivalent to greater than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks is not recommended. Risk D: Consider therapy modificationFosamprenavir: DexAMETHasone (Systemic) may decrease the serum concentration of Fosamprenavir. Fosamprenavir may increase the serum concentration of DexAMETHasone (Systemic).Risk C: Monitor therapyFosaprepitant: May increase the serum concentration of DexAMETHasone (Systemic). Management: Reduce the dexamethasone dose 50% when coadministered with aprepitant. Aprepitant prescribing information incorporates this recommendation into the dose provided for dexamethasone; further reduction is not necessary. Risk D: Consider therapy modificationFosnetupitant: May increase the serum concentration of DexAMETHasone (Systemic). Management: Decrease dexamethasone doses to 12 mg on day 1, and if needed based on the emetic potential of the regimen, 8 mg daily on days 2 to 4 of chemotherapy when administered with fosnetupitant. Risk D: Consider therapy modificationFosphenytoin: May decrease the serum concentration of DexAMETHasone (Systemic). DexAMETHasone (Systemic) may decrease the serum concentration of Fosphenytoin. DexAMETHasone (Systemic) may increase the serum concentration of Fosphenytoin. Management: Consider dexamethasone dose increases when combined with fosphenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely, both increased and decreased phenytoin levels have been reported. Risk D: Consider therapy modificationFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationGallium Ga 68 Dotatate: Corticosteroids (Systemic) may diminish the diagnostic effect of Gallium Ga 68 Dotatate.Risk C: Monitor therapyGrowth Hormone Analogs: Corticosteroids (Systemic) may diminish the therapeutic effect of Growth Hormone Analogs. Growth Hormone Analogs may decrease serum concentrations of the active metabolite(s) of Corticosteroids (Systemic).Risk C: Monitor therapyHormonal Contraceptives: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hormonal Contraceptives.Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modificationHyaluronidase: Corticosteroids (Systemic) may diminish the therapeutic effect of Hyaluronidase.Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider therapy modificationImatinib: DexAMETHasone (Systemic) may decrease the serum concentration of Imatinib.Management: Avoid concurrent use of imatinib with dexamethasone when possible.If such a combination must be used, increase imatinib dose by at least 50% and monitor clinical response closely. Risk D: Consider therapy modificationImmune Checkpoint Inhibitors: Corticosteroids (Systemic) may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Management: Carefully consider the need for corticosteroids, at doses of a prednisone-equivalent of 10 mg or more per day, during the initiation of immune checkpoint inhibitor therapy. Use of corticosteroids to treat immune related adverse events is still recommended Risk D: Consider therapy modificationIndium 111 Capromab Pendetide: Corticosteroids (Systemic) may diminish the diagnostic effect of Indium 111 Capromab Pendetide.Risk X: Avoid combinationInebilizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Inebilizumab.Risk C: Monitor therapyInfluenza Virus Vaccines: Corticosteroids (Systemic) may diminish the therapeutic effect of Influenza Virus Vaccines.Management: Administer influenza vaccines at least 2 weeks prior to initiation of systemic corticosteroids at immunosuppressive doses. Influenza vaccines administered less than 14 days prior to or during such therapy should be repeated 3 months after therapy. Risk D: Consider therapy modificationIsoniazid: Corticosteroids (Systemic) may decrease the serum concentration of Isoniazid.Risk C: Monitor therapyLapatinib: DexAMETHasone (Systemic) may decrease the serum concentration of Lapatinib.Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Risk X: Avoid combinationLeflunomide: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Leflunomide.Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as systemic corticosteroids. Risk D: Consider therapy modificationLenalidomide: DexAMETHasone (Systemic) may enhance the thrombogenic effect of Lenalidomide.Management: Consider using venous thromboembolism prophylaxis (eg, low-molecular weight heparin or warfarin [INR 2.0-3.0]) in patients with multiple myeloma who are receiving lenalidomide and dexamethasone. Risk D: Consider therapy modificationLicorice: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapyLoop Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Loop Diuretics.Risk C: Monitor therapyLopinavir: DexAMETHasone (Systemic) may decrease the serum concentration of Lopinavir.Management: Consider alternative corticosteroids for coadministration with lopinavir/ritonavir due to the potential for dexamethasone to decrease lopinavir/ritonavir efficacy and result in the development of resistance. Risk D: Consider therapy modificationLutetium Lu 177 Dotatate: Corticosteroids (Systemic) may diminish the therapeutic effect of Lutetium Lu 177 Dotatate.Management: Avoid repeated use of high-doses of corticosteroids during treatment with lutetium Lu 177 dotatate. Use of corticosteroids is still permitted for the treatment of neuroendocrine hormonal crisis. The effects of lower corticosteroid doses is unknown. Risk D: Consider therapy modificationMacimorelin: Corticosteroids (Systemic) may diminish the diagnostic effect of Macimorelin.Risk X: Avoid combinationMethotrimeprazine: Products Containing Ethanol may enhance the adverse/toxic effect of Methotrimeprazine. Specifically, CNS depressant effects may be increased.Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid combinationMetyraPONE: Corticosteroids (Systemic) may diminish the diagnostic effect of MetyraPONE.Management: Consider alternatives to the use of the metyrapone test in patients taking systemic corticosteroids. Risk D: Consider therapy modificationMifamurtide: Corticosteroids (Systemic) may diminish the therapeutic effect of Mifamurtide.Risk X: Avoid combinationMiFEPRIStone: May diminish the therapeutic effect of Corticosteroids (Systemic). MiFEPRIStone may increase the serum concentration of Corticosteroids (Systemic). Management: Avoid mifepristone in patients who require long-term corticosteroid treatment of serious illnesses or conditions (eg, for immunosuppression following transplantation). Corticosteroid effects may be reduced by mifepristone treatment. Risk X: Avoid combinationNatalizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Natalizumab.Risk X: Avoid combinationNetupitant: May increase the serum concentration of DexAMETHasone (Systemic). Management: Decrease dexamethasone doses to 12 mg on day 1, and if needed based on the emetic potential of the regimen, 8 mg daily on days 2 to 4 of chemotherapy when administered with netupitant. Risk D: Consider therapy modificationNeuromuscular-Blocking Agents (Nondepolarizing): May enhance the adverse neuromuscular effect of Corticosteroids (Systemic). Increased muscle weakness, possibly progressing to polyneuropathies and myopathies, may occur. Management: If concomitant therapy is required, use the lowest dose for the shortest duration to limit the risk of myopathy or neuropathy. Monitor for new onset or worsening muscle weakness, reduction or loss of deep tendon reflexes, and peripheral sensory decriments Risk D: Consider therapy modificationNicorandil: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nicorandil. Gastrointestinal perforation has been reported in association with this combination.Risk C: Monitor therapyNiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine.Risk C: Monitor therapyNirmatrelvir and Ritonavir: May increase the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective).Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (Nonselective): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective).Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (Topical): May enhance the adverse/toxic effect of Corticosteroids (Systemic). Specifically, the risk of gastrointestinal bleeding, ulceration, and perforation may be increased. Risk C: Monitor therapyOcrelizumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ocrelizumab.Risk C: Monitor therapyOfatumumab: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ofatumumab.Risk C: Monitor therapyOrnidazole: May enhance the adverse/toxic effect of Products Containing Ethanol. Specifically, a disulfiram-like reaction may occur. Risk X: Avoid combinationPhenytoin: May decrease the serum concentration of DexAMETHasone (Systemic). DexAMETHasone (Systemic) may decrease the serum concentration of Phenytoin. DexAMETHasone (Systemic) may increase the serum concentration of Phenytoin. Management: Consider dexamethasone dose increases when combined with phenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely when combined with dexamethasone, both increased and decreased phenytoin levels have been reported. Risk D: Consider therapy modificationPidotimod: Corticosteroids (Systemic) may diminish the therapeutic effect of Pidotimod.Risk C: Monitor therapyPimecrolimus: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Risk X: Avoid combinationPneumococcal Vaccines: Corticosteroids (Systemic) may diminish the therapeutic effect of Pneumococcal Vaccines.Risk C: Monitor therapyPoliovirus Vaccine (Live/Trivalent/Oral): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral).Risk X: Avoid combinationPolymethylmethacrylate: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Polymethylmethacrylate. Specifically, the risk for hypersensitivity or implant clearance may be increased.Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modificationQuinolones: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Quinolones. Specifically, the risk of tendonitis and tendon rupture may be increased.Risk C: Monitor therapyRabies Vaccine: Corticosteroids (Systemic) may diminish the therapeutic effect of Rabies Vaccine.Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modificationRilpivirine: DexAMETHasone (Systemic) may decrease the serum concentration of Rilpivirine.Risk X: Avoid combinationRitodrine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Ritodrine.Risk C: Monitor therapyRubella- or Varicella-Containing Live Vaccines: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines.Risk X: Avoid combinationRuxolitinib (Topical): Corticosteroids (Systemic) may enhance the immunosuppressive effect of Ruxolitinib (Topical).Risk X: Avoid combinationSalicylates: May enhance the adverse/toxic effect of Corticosteroids (Systemic). These specifically include gastrointestinal ulceration and bleeding. Corticosteroids (Systemic) may decrease the serum concentration of Salicylates. Withdrawal of corticosteroids may result in salicylate toxicity. Risk C: Monitor therapySaquinavir: DexAMETHasone (Systemic) may decrease the serum concentration of Saquinavir.Management: Consider alternatives to this combination if possible, due to the potential for decreased saquinavir/ritonavir therapeutic effect and the potential development of resistance. Risk D: Consider therapy modificationSargramostim: Corticosteroids (Systemic) may enhance the therapeutic effect of Sargramostim. Specifically, corticosteroids may enhance the myeloproliferative effects of sargramostim.Risk C: Monitor therapySecnidazole: Products Containing Ethanol may enhance the adverse/toxic effect of Secnidazole.Risk X: Avoid combinationSelpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib.Risk C: Monitor therapySimeprevir: DexAMETHasone (Systemic) may decrease the serum concentration of Simeprevir.Risk X: Avoid combinationSipuleucel-T: Corticosteroids (Systemic) may diminish the therapeutic effect of Sipuleucel-T.Management: Consider reducing the dose or discontinuing immunosuppressants, such as systemic corticosteroids, prior to initiating sipuleucel-T therapy. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone given for 2 or more weeks are immunosuppressive. Risk D: Consider therapy modificationSirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Conventional).Risk C: Monitor therapySirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Protein Bound).Risk C: Monitor therapySodium Benzoate: Corticosteroids (Systemic) may diminish the therapeutic effect of Sodium Benzoate.Risk C: Monitor therapySphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Corticosteroids (Systemic). Risk C: Monitor therapySuccinylcholine: Corticosteroids (Systemic) may enhance the neuromuscular-blocking effect of Succinylcholine.Risk C: Monitor therapyTacrolimus (Systemic): Corticosteroids (Systemic) may decrease the serum concentration of Tacrolimus (Systemic). Conversely, when discontinuing corticosteroid therapy, tacrolimus concentrations may increase.Risk C: Monitor therapyTacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic).Risk C: Monitor therapyTacrolimus (Topical): Corticosteroids (Systemic) may enhance the immunosuppressive effect of Tacrolimus (Topical).Risk X: Avoid combinationTalimogene Laherparepvec: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased.Risk X: Avoid combinationTemsirolimus: DexAMETHasone (Systemic) may decrease serum concentrations of the active metabolite(s) of Temsirolimus.Risk C: Monitor therapyTertomotide: Corticosteroids (Systemic) may diminish the therapeutic effect of Tertomotide.Risk X: Avoid combinationThalidomide: DexAMETHasone (Systemic) may enhance the dermatologic adverse effect of Thalidomide. DexAMETHasone (Systemic) may enhance the thrombogenic effect of Thalidomide.Management: Consider using venous thromboembolism prophylaxis (eg, low-molecular-weight heparin or warfarin [INR 2.0 to 3.0]) in patients with multiple myeloma receiving both thalidomide and dexamethasone. Monitor for increased dermatologic adverse effects (eg, rash) Risk D: Consider therapy modificationThiazide and Thiazide-Like Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics.Risk C: Monitor therapyTofacitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Tofacitinib.Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modificationTyphoid Vaccine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Typhoid Vaccine.Risk X: Avoid combinationUbrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant.Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Risk D: Consider therapy modificationUpadacitinib: Corticosteroids (Systemic) may enhance the immunosuppressive effect of Upadacitinib.Management: Coadministration of upadacitinib with systemic corticosteroids at doses equivalent to greater than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks is not recommended. Risk D: Consider therapy modificationUrea Cycle Disorder Agents: Corticosteroids (Systemic) may diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Corticosteroids (Systemic) may increase protein catabolism and plasma ammonia concentrations, thereby increasing the doses of Urea Cycle Disorder Agents needed to maintain these concentrations in the target range.Risk C: Monitor therapyVaccines (Inactivated/Non-Replicating): Corticosteroids (Systemic) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating).Management: Administer vaccines at least 2 weeks prior to immunosuppressive corticosteroids if possible. If patients are vaccinated less than 14 days prior to or during such therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationVaccines (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Vaccines (Live).Management: Avoid live vaccines during and for 1 month after therapy with immunosuppressive doses of corticosteroids (equivalent to prednisone > 2 mg/kg or 20 mg/day in persons over 10 kg for at least 2 weeks). Give live vaccines prior to therapy whenever possible. Risk D: Consider therapy modificationVitamin K Antagonists (eg, warfarin): Corticosteroids (Systemic) may enhance the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapyVoriconazole: DexAMETHasone (Systemic) may decrease the serum concentration of Voriconazole.Risk C: Monitor therapyYellow Fever Vaccine: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Yellow Fever Vaccine.Risk X: Avoid combinationDietary ConsiderationsMay be taken with meals to decrease GI upset. May need diet with increased potassium, pyridoxine, vitamin C, vitamin D, folate, calcium, and phosphorus.Reproductive ConsiderationsThe manufacturer’s labeling for use of dexamethasone as part of combination therapy for multiple myeloma recommends pregnancy testing prior to use in patients who may become pregnant. Patients who may become pregnant should use effective contraception during therapy and for at least 1 month after the last dexamethasone dose. Consult individual monographs for additional information related to pregnancy testing and contraception when combination therapy is used for multiple myeloma.Dexamethasone may alter the motility of and number of spermatozoa.Pregnancy ConsiderationsDexamethasone crosses the placenta (Brownfoot 2013); and is partially metabolized by placental enzymes to an inactive metabolite (Murphy 2007).Some studies have shown an association between first trimester systemic corticosteroid use and oral clefts or decreased birth weight; however, information is conflicting and may be influenced by maternal dose/indication for use (Lunghi 2010; Park-Wyllie 2000; Pradat 2003). Hypoadrenalism may occur in newborns following maternal use of corticosteroids during pregnancy; monitor.Dexamethasone is classified as a fluorinated corticosteroid. When systemic corticosteroids are needed in pregnancy for rheumatic disorders, nonfluorinated corticosteroids (eg, prednisone) are preferred. Chronic high doses should be avoided for the treatment of maternal disease (ACR [Sammaritano 2020]).Use of the overnight dexamethasone 1 mg suppression test for Cushing syndrome is not recommended during pregnancy due to the increased risk of false positives. In addition, dexamethasone is generally avoided for the treatment of pregnant patients with adrenal insufficiency (ES [Nieman 2008]; ESE [Luger 2021]).Antenatal corticosteroid administration promotes fetal lung maturity and is associated with the reduction of intraventricular hemorrhage, necrotizing enterocolitis, neonatal mortality, and respiratory distress syndrome. A single course of dexamethasone is recommended for patients between 24 0/7 and 33 6/7 weeks' gestation who are at risk of delivering within 7 days. This recommendation includes those with ruptured membranes or multiple gestations. A single course of dexamethasone may be considered for patients beginning at 23 0/7 weeks' gestation who are at risk of delivering within 7 days, in consultation with the family regarding resuscitation. In addition, a single course of dexamethasone may be given to patients between 34 0/7 weeks and 36 6/7 weeks who are at risk of preterm delivery within 7 days and who have not previously received corticosteroids if induction or delivery will proceed ≥24 hours and ≤7 days; delivery should not be delayed for administration of antenatal corticosteroids. Use of concomitant tocolytics is not currently recommended and administration of late preterm corticosteroids has not been evaluated in patients with intrauterine infection, multiple gestations, pregestational diabetes, or patients who delivered previously by cesarean section at term. Multiple repeat courses are not recommended. However, in patients with pregnancies less than 34 weeks' gestation at risk for delivery within 7 days and who had a course of antenatal corticosteroids >14 days prior, a single repeat course may be considered; use of a repeat course in patients with preterm prelabor rupture of membranes is controversial (ACOG 2016; ACOG 2017; ACOG 2020).Dexamethasone is used off label in the management of COVID-19. Use is recommended for hospitalized pregnant patients with COVID-19 who require mechanical ventilation, or who require supplemental oxygen without mechanical ventilation (NIH 2022). In patients who do not require dexamethasone for fetal lung maturity, or in those who have already completed a course of dexamethasone to enhance fetal lung development, treatment recommendations are available using alternative corticosteroids which have more limited placental transfer and may provide less fetal risk. A treatment algorithm is available for pregnant patients with severe or critical COVID-19 requiring corticosteroids for fetal lung maturation and those who do not (Saad 2020). The risk of severe illness from COVID-19 infection is increased in symptomatic pregnant patients compared to nonpregnant patients (ACOG 2022). Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.Some products contain alcohol, benzyl alcohol or sodium sulfite; use of preservative-free or alternative formulations in pregnancy is recommended.Monitoring ParametersHemoglobin, occult blood loss, blood pressure, serum potassium and glucose; intraocular pressure with systemic use >6 weeks; weight and height in children.Mechanism of ActionDexamethasone is a long-acting corticosteroid with minimal sodium-retaining potential. It decreases inflammation by suppression of neutrophil migration, decreased production of inflammatory mediators, and reversal of increased capillary permeability; suppresses normal immune response. Dexamethasone induces apoptosis in multiple myeloma cells. Dexamethasone's mechanism of antiemetic activity is unknown.Pharmaco*kinetics (Adult data unless noted)Onset of action: IV: Rapid.Immune thrombocytopenia: Oral: Initial response: 2 to 14 days; Peak response: 4 to 28 days (Neunert 2011).Duration: IV: Short.Absorption: Oral: 61% to 86% (Czock 2005).Metabolism: Hepatic.Half-life elimination:Extremely low birth-weight infants with BPD: 9.26 ± 3.34 hours (range: 5.85 to 16.1 hours) (Charles 1993).Children 4 months to 16 years: 4.34 ± 4.14 hours (range: 2.33 to 9.54 hours) (Richter 1983).Adults: Oral: 4 ± 0.9 hours (Czock 2005); IV: ~1 to 5 hours (Hochhaus 2001; Miyabo 1981; Rohdewald 1987; Tóth 1999).Time to peak, serum: Oral: 1 to 2 hours (Czock 2005); IM: ~30 to 120 minutes (Egerman 1997; Hochhaus 2001); IV: 5 to 10 minutes (free dexamethasone) (Miyabo 1981; Rohdewald 1987).Excretion: Urine (~10%) (Duggan 1975; Miyabo 1981).Pricing: USConcentrate (Dexamethasone Intensol Oral)1 mg/mL (per mL): $1.07Elixir (Dexamethasone Oral)0.5 mg/5 mL (per mL): $0.11 - $0.27Kit (DoubleDex Injection)10 mg/mL (per each): $598.00Kit (MAS Care-Pak Injection)10 mg/mL (per each): $605.00Solution (Dexamethasone Oral)0.5 mg/5 mL (per mL): $0.27Solution (Dexamethasone Sod Phosphate PF Injection)10 mg/mL (per mL): $2.10 - $8.22Solution (Dexamethasone Sodium Phosphate Injection)4 mg/mL (per mL): $0.93 - $3.4710 mg/mL (per mL): $1.49 - $1.7220 mg/5 mL (per mL): $0.21 - $1.51100 mg/10 mL (per mL): $0.48 - $1.70120 mg/30 mL (per mL): $0.39 - $1.63Tablet Therapy Pack (Dexamethasone Oral)1.5MG (21) (per each): $8.06 - $8.541.5MG (35) (per each): $8.551.5MG (51) (per each): $8.54Tablet Therapy Pack (Dxevo 11-Day Oral)1.5 mg (per each): $17.79Tablet Therapy Pack (HiDex 6-Day Oral)1.5MG (21) (per each): $33.29Tablet Therapy Pack (TaperDex 12-Day Oral)1.5MG (49) (per each): $5.68Tablet Therapy Pack (TaperDex 6-Day Oral)1.5 mg (per each): $10.801.5MG (21) (per each): $10.80Tablet Therapy Pack (TaperDex 7-Day Oral)1.5MG (27) (per each): $8.66Tablets (Dexamethasone Oral)0.5 mg (per each): $0.14 - $0.210.75 mg (per each): $0.25 - $0.271 mg (per each): $0.30 - $0.371.5 mg (per each): $0.48 - $3.702 mg (per each): $0.59 - $0.744 mg (per each): $1.19 - $1.206 mg (per each): $1.78 - $1.90Tablets (Hemady Oral)20 mg (per each): $31.31Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAacidexam (BE);Alin (CR, DO, GT, HN, NI, PA, SV);Asiadexa (VN);Camidexon (ID);Corodex (UY);Cortyk (CL);D Cort (BD);Decadron (AE, BH, CO, CY, EC, IT, JO, KW, LB, PY, QA, SA);Decan (PH, SG);Decasone (ZA);Decdan (IN);Dectancyl (VN);Deltasone (EG);Desalark (IT);Dexa-Sine (BE);Dexacor (BD);Dexacort Forte (IL);Dexaflam (DE);Dexafree (CH, FR, PL, PT);Dexamax (PH);Dexamed (CZ, JO, RO, SG, TR);Dexamed Elixir (LK);Dexamet Solution for Injection (HK);Dexanocorten (EG);Dexasone (EG, MY);Dexazone (QA);Dexcor (BD);Dexmethsone (AU, NZ);Dexo (ET);Dexona (ET, IN);Dexona-E (LK);Dexone (ZW);Dexovit (LK);Dexsol (IE);Fortecortin (AT, BG, CH, DE, ES);Lenadex (JP);Lodexa (TH);Lodexa-5 (TH);Maradex (VE);Martapan (GB);Medicort (PE);Meradexone (BD);Metacort (PH);Methodex (LK);Millicorten (QA);Naxidex (LK);Nexadron Oftal (AR);Odeson (BD);Oftan Dexa (EE);Opnol (SE);Oradexon (CL, FI, ID, NL, PT, SA);Ordex (BD);Ronic (ET);Sonexa (BD);Spersadex (CH, DE, HK, NO, ZA);Sterodex (IL);Steron (BD);Vedex (LK);Vextasone (MY);Vherdex (PH);Visumetazone (IT);Wymesone (IN)For country code abbreviations (show table)Abouir K, Gosselin P, Guerrier S, et al. 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Statement of endorsem*nt-congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. Pediatrics. 2010; 126(5):151. Accessed October 27, 2014. http://pediatrics.aappublications.org/content/126/5/1051.extract.American Academy of Pediatrics Committee on Infectious Diseases. Dexamethasone Therapy for Bacterial Meningitis in Infants and Children. Pediatrics. 1990;86(1):130-133. [PubMed 2193301]American College of Obstetricians and Gynecologists (ACOG) Committee on Obstetric Practice. ACOG Committee Opinion No. 713: Antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol. 2017;130(2):e102-e109. doi:10.1097/AOG.0000000000002237 [PubMed 28742678]American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins–Obstetrics. ACOG Practice Bulletin No. 171: Management of preterm labor. 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[PubMed 17555487]Topic 15964 Version 623.0

CloseIsotretinoin: Pediatric drug informationIsotretinoin: Pediatric drug information(For additional information see "Isotretinoin: Drug information" and see "Isotretinoin: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Special AlertsREMS Drugs COVID-19 Safety AlertMarch 2020Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.ALERT: US Boxed WarningPregnancy:Isotretinoin can cause severe, life-threatening birth defects and is contraindicated in pregnancy. Isotretinoin must not be used by patients who are or may become pregnant. There is an extremely high risk that life-threatening birth defects will result if pregnancy occurs while taking isotretinoin in any amount, even for short periods of time. Potentially, any fetus exposed during pregnancy can be affected. There are no accurate means of determining prenatally whether an exposed fetus has been affected.Birth defects that have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, CNS, cardiovascular system, and thymus and parathyroid glands. Cases of intelligence quotient (IQ) scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported.Documented external abnormalities include skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases, death has occurred with some of the abnormalities previously noted.If pregnancy does occur during treatment of a patient who is taking isotretinoin, isotretinoin must be discontinued immediately and the patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling.Special prescribing requirements:Because of isotretinoin's teratogenicity and to minimize fetal exposure, isotretinoin is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This REMS is called iPLEDGE. Isotretinoin must only be prescribed by prescribers who are enrolled and activated with the iPLEDGE REMS. Isotretinoin must only be dispensed by a pharmacy enrolled and activated with iPLEDGE, and must only be dispensed to patients who are enrolled and meet all the requirements of iPLEDGE.Brand Names: USAbsorica;Absorica LD;Accutane;Amnesteem;Claravis;Myorisan;ZenataneBrand Names: CanadaAccutane Roche;ALTI-Isotretinoin;Clarus;EpurisTherapeutic CategoryAcne Products;Antineoplastic Agent, Retinoic Acid Derivatives;Retinoic Acid Derivative;Vitamin A DerivativeDosing: PediatricNote: The product formulation of Absorica LD (micronized) is not bioequivalent to other capsule formulations of isotretinoin (eg, Absorica, or softgel formulations: generics, Amnesteem, Claravis, Myorisan, Zenatane) and should not be substituted on a mg:mg basis.Acne vulgaris, severe recalcitrant nodularAcne vulgaris, severe recalcitrant nodular: Children ≥12 years and Adolescents:Softgel capsule (eg, generics, Amnesteem, Claravis, Myorisan, Zenatane) or hard-gelatin capsule (Absorica):Initial: Oral: 0.5 mg/kg/day in 2 divided doses for 4 weeks, then increase dose to 1 mg/kg/day in 2 divided doses (AAD [Zaenglein 2016]; AAP [Eichenfield 2013]); for severe extensive cases (involving trunk, nuchal region, lower back, buttocks, thighs) may require higher doses up to 2 mg/kg/day in 2 divided doses (manufacturer labeling).Duration of therapy: Typically 15 to 20 weeks depending upon daily dose; a target cumulative dose range of 120 to 150 mg/kg has been recommended based on observed lower relapse rates with courses ≥120 mg/kg and the plateau effect observed with higher cumulative total doses of >150 mg/kg (AAD [Zaenglein 2016]).Repeat course: In older adolescents who have completed skeletal growth, a second course of isotretinoin may be repeated after a period of ≥2 months off therapy for persistent or recurring severe nodular acne; for younger patients who have not completed skeletal growth, the optimal interval before retreatment has not been defined.Micronized hard-gelatin capsule (eg, Absorica LD): Oral: 0.4 to 0.8 mg/kg/day in 2 divided doses. In adults with severe, extensive cases (involving trunk, nuchal region, lower back, buttocks, thighs), higher doses up to 1.6 mg/kg/day in 2 divided doses have been used; pediatric data specific to the micronized dosage form is lacking. Duration of therapy is typically 15 to 20 weeks, until the total cyst count decreased by 70%, whichever is sooner. Based on experience with other isotretinoin dosage forms, in older adolescents who have completed skeletal growth, a second course of isotretinoin may be repeated after a period of ≥2 months off therapy for persistent or recurring severe nodular acne; for younger patients who have not completed skeletal growth, the optimal interval before retreatment has not been defined.Acne vulgaris, moderateAcne vulgaris, moderate: Limited data available: Children ≥12 years and Adolescents: Softgel capsule (eg, generics, Amnesteem, Claravis, Myorisan, Zenatane) and hard-gelatin capsule (Absorica): Oral: 0.25 to 0.4 mg/kg/day continued for 6 to 12 months (AAD [Zaenglein 2016]; Amichai 2006).Neuroblastoma, maintenanceNeuroblastoma, maintenance: Limited data available: Infants, Children, and Adolescents: Softgel capsule (eg, generics, Amnesteem, Claravis, Myorisan, Zenatane) and hard-gelatin capsule (Absorica): Oral: 80 mg/m2/dose every 12 hours for the last 2 weeks (14 consecutive days) of a 4-week cycle for 6 cycles; dinutuximab therapy is administered during the first week of the 4-week cycle (Yu 2010); begin after continuation chemotherapy or transplantation (Matthay 1999).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: PediatricChildren and Adolescents:Baseline hepatic impairment: There are no dosage adjustments provided in the manufacturer's labeling.Hepatotoxicity during treatment: Mild liver enzymes may occur, and generally normalize with dosage reduction or with continued treatment; discontinue if normalization does not readily occur or if hepatitis (eg, transaminases >3 times baseline) is suspected (Brelsford 2008).Dosing: Adult(For additional information see "Isotretinoin: Drug information")Note: Isotretinoin products are available in different formulations: a standard formulation (eg, Amnesteem, Claravis, Myorisan, Zenatane) that requires administration with food and lidose (Absorica) and micronized (Absorica LD) formulations that may be administered with or without food. Standard formulations are not bioequivalent to lidose or micronized formulations. Lidose and micronized formulations are not substitutable with one another due to differences in bioavailability.Note: All dosing is based on use of a standard or lidose formulation unless otherwise indicated.Acne vulgaris, moderate to severeAcne vulgaris, moderate to severe: Oral: Standard or lidose formulation: 0.5 mg/kg/day in 2 divided doses for 1 month, then increase to 1 mg/kg/day in 2 divided doses as tolerated; alternatively, may administer the total daily dose once daily to increase adherence to therapy (Owen 2022). For patients with severe inflammatory acne (eg, acne conglobata) or deep comedonal acne, consider initial doses <0.5 mg/kg/day (eg, 0.1 mg/kg/day) in combination with an oral glucocorticoid given before or at isotretinoin initiation and continued for the first 2 to 4 weeks of therapy to reduce the risk of severe acne flares (AAD [Zaenglein 2016]; Greywal 2017; Owen 2022). Continue until a total cumulative dose of 120 to 150 mg/kg is reached (AAD [Zaenglein 2016]).Micronized formulation: 0.4 to 0.8 mg/kg/day in 2 divided doses. Adults with very severe disease/scarring or primarily involving the trunk may require dosage adjustment up to 1.6 mg/kg/day in divided doses, as tolerated. Continue therapy until nodule count has been reduced by at least 70% or for up to 15 to 20 weeks.Alternative low-dose regimen for moderate acne (off-label use): Standard or lidose formulation: 0.3 to 0.5 mg/kg once daily (AAD [Zaenglein 2016]; Amichai 2006; Lee 2011; Owen 2022). Continue until a total cumulative dose of 120 to 150 mg/kg is reached (AAD [Zaenglein 2016]).Cutaneous T-cell lymphomasCutaneous T-cell lymphomas (off-label use): Oral: Induction: 1 mg/kg/day (in 2 divided doses and in combination with interferon alfa-2b) for 3 to 4 months (Duvic 2003; Knobler 1991). If response occurs, may continue therapy for an additional 3 months; if response continues after 6 months of therapy, may administer isotretinoin and interferon alfa-2b at a 50% reduced dose for an additional 3 months, followed by interferon alfa-2b maintenance therapy (Knobler 1991). Additional trials may be necessary to further define the role of isotretinoin in the management of this condition.Squamous cell skin cancer, prevention in high-risk patientsSquamous cell skin cancer, prevention in high-risk patients (off-label use): Oral: Initial: 0.25 mg/kg every other day for 1 month, then 0.25 mg/kg daily for one month, then 0.5 mg/kg daily. Adjust dose as needed based on tolerance; higher doses may be more effective for severe skin cancer (Otley 2006). Additional data may be necessary to further define the role of isotretinoin in this setting.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: AdultHepatic impairment prior to treatment: There are no dosage adjustments provided in the manufacturer's labeling.Hepatotoxicity during treatment: Liver enzymes may normalize with dosage reduction or with continued treatment; discontinue if normalization does not readily occur or if hepatitis is suspected.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Capsule, Oral: Absorica: 10 mg, 20 mg [contains soybean oil]Absorica: 25 mg [contains fd&c blue #1 (brilliant blue), fd&c yellow #5 (tartrazine), fd&c yellow #6 (sunset yellow), soybean oil]Absorica: 30 mg [contains soybean oil]Absorica: 35 mg [contains fd&c blue #2 (indigotine), soybean oil]Absorica: 40 mg [contains soybean oil]Absorica LD: 8 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10), soybean oil]Absorica LD: 16 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), soybean oil]Absorica LD: 24 mg [contains fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10), soybean oil]Absorica LD: 32 mg [contains soybean oil]Accutane: 10 mg [contains edetate (edta) disodium, fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigotine), methylparaben, propylparaben, quinoline (d&c yellow #10) aluminum lake, soybean oil]Accutane: 10 mg [contains edetate (edta) disodium, fd&c blue #1 (brilliant blue), fd&c blue #2 (indigotine), methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]Accutane: 20 mg [contains disodium edta, fd&c blue #2 (indigotine), fd&c red #40(allura red ac)aluminum lake, soybean oil]Accutane: 20 mg [contains edetate (edta) disodium, fd&c blue #2 (indigotine), methylparaben, propylparaben, soybean oil]Accutane: 30 mg [contains disodium edta, fd&c blue #2 (indigotine), soybean oil]Accutane: 30 mg [contains edetate (edta) disodium, fd&c blue #2 (indigo carm) aluminum lake, methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]Accutane: 40 mg [contains disodium edta, fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigotine), quinoline (d&c yellow #10) aluminum lake, soybean oil]Accutane: 40 mg [contains edetate (edta) disodium, fd&c blue #1 (brilliant blue), fd&c blue #2 (indigotine), methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]Amnesteem: 10 mg, 20 mg, 40 mg [contains soybean oil]Claravis: 10 mg [contains fd&c yellow #6 (sunset yellow), soybean oil]Claravis: 20 mg, 30 mg [contains edetate (edta) disodium, soybean oil]Claravis: 40 mg [contains edetate (edta) disodium, fd&c yellow #6 (sunset yellow), soybean oil]Myorisan: 10 mg, 20 mg [contains soybean oil]Myorisan: 30 mgMyorisan: 40 mg [contains fd&c yellow #6 (sunset yellow), soybean oil]Zenatane: 10 mg [contains edetate (edta) disodium, fd&c blue #1 (brilliant blue), methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]Zenatane: 20 mg [contains edetate (edta) disodium, methylparaben, propylparaben, soybean oil]Zenatane: 30 mg [contains edetate (edta) disodium, fd&c blue #2 (indigo carm) aluminum lake, methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]Zenatane: 40 mg [contains edetate (edta) disodium, fd&c blue #1 (brilliant blue), fd&c blue #2 (indigotine), methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]Generic: 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Capsule, Oral: Accutane Roche: 10 mg [contains soybean oil]Accutane Roche: 40 mg [contains fd&c yellow #6 (sunset yellow), methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]Clarus: 10 mg, 40 mg [contains soybean oil]Epuris: 10 mg, 20 mg, 30 mg, 40 mg [contains soybean oil]Generic: 10 mg, 40 mgMedication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Absorica: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021951s013lbl.pdf#page=32Accutane: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018662s061MedGuide.pdfSotret: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/Sotret.pdfAdministration: PediatricOral:Softgel (eg, generics, Amnesteem, Claravis, Myorisan, Zenatane): Administer orally with a meal. According to the manufacturers’ labeling, capsules should be swallowed whole with a full glass of liquid. For patients unable to swallow capsule whole, an oral liquid may be prepared (see Extemporaneous Preparations). Contents removed from capsules may irritate esophagus.Neuroblastoma: In pediatric neuroblastoma trials when patient was unable to swallow capsule, the end of capsule was punctured/cut and capsule's contents extruded into ice cream or yogurt (high-fat food); if capsule is opened, contents must be consumed immediately to avoid degradation of the drug (Matthay 1999; Veal 2007).Hard-gelatin capsules (Absorica, Absorica LD [micronized]): May be taken without regard to meals.Administration: AdultOral: Administer standard formulation with a meal; lidose (Absorica) or micronized (Absorica LD) formulations may be taken without regard to meals. According to the manufacturer's labeling, capsules should be swallowed whole with a full glass of liquid; do not chew or suck on the capsule. For patients unable to swallow capsule whole, an oral liquid may be prepared (see "Extemporaneously Prepared"); may irritate esophagus if contents are removed from the capsule. Safety of once-daily dosing of isotretinoin has not been established and is not recommended.Neuroblastoma (off-label use): In a pharmaco*kinetic study, the end of the capsule was punctured/cut and capsule contents extruded into ice cream or yogurt if patients were unable to swallow capsules whole; if capsule is opened, contents must be consumed immediately to avoid degradation (Veal 2007). Refer to "Extemporaneously Prepared" for additional information.Hazardous Drugs Handling ConsiderationsThis medication is not on the NIOSH (2016) list; however, it meets the criteria for a hazardous drug. Isotretinoin may cause teratogenicity and has a structural or toxicity profile similar to existing hazardous agents.Use appropriate precautions for receiving, handling, storage, preparation, dispensing, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).Use appropriate precautions for receiving, handling, storage, preparation, dispensing, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).Storage/StabilityStore at 20°C to 25°C (68°F to 77° F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from light.UseTreatment of severe recalcitrant nodular acne unresponsive to conventional therapy, including systemic antibiotics (FDA approved in ages ≥12 years and adults); has also been used for the treatment of moderate acne and high-risk neuroblastoma.Medication Safety IssuesSound-alike/look-alike issues:Accutane may be confused with Accolate, Accupril.Claravis may be confused with Cleviprex.ISOtretinoin may be confused with tretinoin.High alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.Other safety concerns:Isotretinoin may be confused with tretinoin (which is also called all-trans retinoic acid, or ATRA); while both products may have uses in cancer treatment, they are not interchangeable.Adverse Reactions (Significant): ConsiderationsBone and growth effectsData are conflicting, but decreased bone mineral density (Ref), osteopenia, osteoporosis, bone fracture, and delayed healing of bone fractures have been reported (Ref). Premature epiphyseal closure has been reported (Ref).Mechanism: Possibly dose-related; related to pharmacologic action (ie, retinoids may lead to impaired bone growth) (Ref).Onset: Delayed; noted on imaging 6 months after initiation (Ref). Premature epiphyseal closure may occur months to years after initiation (Ref).Risk factors:• Higher doses for prolonged durations may be associated with premature epiphyseal closure (Ref)• Genetic predisposition for bone loss (eg, age-related osteoporosis, history of childhood osteoporosis conditions, osteomalacia, other disorders of bone metabolism)• Concurrent use of oral contraceptives (Ref)Cutaneous/hypersensitivity reactionsCutaneous adverse reactions associated with isotretinoin range from mucocutaneous effects such as cheilitis, xeroderma, dry eye syndrome, conjunctivitis, blepharitis, and episcleritis (Ref) to cases of erythema nodosum (Ref), pityriasis rosea-like eruptions (Ref), pyogenic granuloma (Ref), acne fulminans (Ref), skin photosensitivity (Ref), and pyoderma gangrenosum (Ref). Hypersensitivity reactions have also been reported, including immediate (anaphylaxis, angioedema) (Ref) and delayed reactions (Stevens-Johnson syndrome [SJS] (Ref), toxic epidermal necrolysis, erythema multiforme-like drug eruption, acute generalized exanthematous pustulosis [AGEP], allergic vasculitis, allergic myocardial infarction) (Ref). Inflammatory sacroiliitis has also been described with isotretinoin, in association with a HLA-B27 negative antigen (Ref).Mechanism:• Immediate hypersensitivity reactions: Non–dose-related; immunologic (ie, IgE-mediated, with specific antibodies formed against a drug allergen following initial exposure) (Ref).• Delayed hypersensitivity reactions: Non–dose-related, immunologic. SJS and AGEP are T-cell mediated (Ref). Allergic myocardial infarction occurs due to mast cell degranulation following an allergic insult (Ref).• Cheilitis: Dose-related (Ref). Isotretinoin and its major metabolite, 4-oxo-isotretinoin, have been shown to have a phototoxic potential (Ref).Onset:• Immediate hypersensitivity reactions: Rapid; generally occurs within 1 hour of administration but may occur several hours after exposure (Ref).• Delayed hypersensitivity reactions: Varied. Severe cutaneous adverse reactions, including SJS and AGEP, usually occur 1 to 8 weeks after initiation (Ref). Allergic vasculitis usually occurs 6 weeks to 5 months after isotretinoin initiation (Ref) and has been reported to occur up to 6 weeks after discontinuation of isotretinoin (Ref). Allergic myocardial infarction can occur within 5 minutes of isotretinoin administration (Ref).• Cutaneous reactions: Varied, with most reactions occurring 2 to 6 weeks after isotretinoin initiation (Ref).• Sacroiliitis: Delayed; occurs months to years after initiation of isotretinoin (Ref).Hepatic effectsClinical hepatitis and mild to moderate increased liver enzymes have been reported in ~15% of patients receiving isotretinoin (Ref). Reversibility back to baseline has been demonstrated within 4 weeks of discontinuation (Ref).Mechanism: Unknown; may be related to other comorbidities, concurrent drug therapy, or idiosyncratic (Ref).Onset: Delayed; occurring 1 to 3 months after initiation (Ref).Risk factors:• Concurrent hepatotoxic medications, including alcoholHypertriglyceridemia and pancreatitisIncreased serum triglycerides occur in ~5% to 25% of patients receiving isotretinoin (Ref). Rare and potentially fatal acute pancreatitis may occur in patients with normal or elevated triglyceride levels (Ref). Case reports in adolescents (Ref) and adults (Ref) have demonstrated reversibility upon discontinuation.Mechanism: Retinoids increase apolipoproteins (Ref).Onset: Varied; seen within 2 weeks to 15 months of initiation (Ref)Risk factors:• Elevated baseline triglycerides (Ref)• Weight >89 kg males or >73 kg females (Ref)Musculoskeletal effectsCommon and potentially fatal (Ref) musculoskeletal symptoms (arthralgia, myalgia, rhabdomyolysis) have been reported in pediatric and adult patients; generally, symptoms were mild to moderate but occasionally required discontinuation of therapy (Ref). Children may experience a higher frequency of myalgia, arthralgia, and back pain. Myalgia symptom resolution occurred with dose reduction, cessation of therapy, or treatment with a non-steroidal anti-inflammatory medication (Ref).Mechanism: Dose-related; not clearly established. Hypothesized to cause cell membrane damage (Ref).Onset: Varied; onset can be 1 week to 3 months following initiation (Ref).Risk factors:• High cumulative dose (>1,800 mg) (Ref).• Females (Ref).Ocular effectsVisual disturbance, night blindness, dry eye syndrome, eye irritation, and conjunctivitis have been reported in 10% to 70% of patients (Ref). Cessation in therapy may reverse ocular effects; however, permanent damage may occur (Ref).Mechanism: Causes changes in the cornea, tear film composition, and visual process in the retina (Ref).Onset: Delayed; seen after 3 months of therapy (Ref).Risk factors:• Males (Ref)• Weight <70 kg (Ref)• Hypovitaminosis A (Ref)Pseudotumor cerebriRare and reversible pseudotumor cerebri (idiopathic intracranial hypertension) has been documented in case reports (Ref) and in large scale adverse drug reporting systems (Ref). Symptoms are reversible with cessation of isotretinoin (Ref).Mechanism: Unclear (Ref).Onset: Delayed; onset is typically 2 months (Ref).Risk factors:• Concurrent use with tetracyclines (Ref)Psychiatric effectsWhile data are conflicting, isotretinoin may cause depression, psychosis, mood disturbance (Ref), and rarely, suicidal ideation, suicidal tendencies, death by suicide, aggressive behavior, and/or violent behavior (Ref). Symptoms often resolve with therapy discontinuation (Ref).Mechanism: Dose-related; the fat solubility of isotretinoin allows for passage through the blood brain barrier, possibly affecting the dopamine and serotonin or hypothalamic regulation (Ref).Onset: Delayed; occurs between 1 to 4 months after initiation (Ref).Risk factors:• Higher doses (Ref)• Underlying psychiatric diagnosis, in particular bipolar disorder (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions are for adults and adolescents unless otherwise indicated.>10%:Endocrine & metabolic: Decreased HDL cholesterol (15%), increased serum triglycerides (25%; including cases reported >800 mg/dL)Hepatic: Increased liver enzymes (15%, including increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, increased serum bilirubin)Neuromuscular & skeletal: Arthralgia (≤22%; severe arthralgia: adolescents: 2%), back pain (adolescents: 29%)1% to 10%:Endocrine & metabolic: Increased serum cholesterol (7%)Neuromuscular & skeletal: Decreased bone mineral density (adolescents: 9%)Frequency not defined:Cardiovascular: Cerebrovascular accident, chest pain (transient), edema, flushing, palpitations, syncope, tachycardia, thrombosis, vasculitis (ten Holder 2002)Dermatologic: Acne fulminans (Fakih 2020), alopecia (Vallerand 2018), cheilitis (Vallerand 2018), cheilosis (Vallerand 2018), contact dermatitis, dermatitis (Vallerand 2018), diaphoresis, eczema (Vallerand 2018), erythema of skin, facial erythema, fragile skin, hair disease, hyperpigmentation, hypopigmentation, nail disease, paronychia, pruritus (Vallerand 2018), pyogenic granuloma (Simmons 2016), scaling of skin of feet, seborrhea, skin photosensitivity (Vallerand 2018), skin rash, sunburn, superficial peeling of palms, urticaria (Saray 2006), xeroderma (Vallerand 2018)Endocrine & metabolic: Altered serum glucose, decreased libido, eruptive xanthoma, hirsutism, hyperuricemia, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased LDL cholesterol, increased serum glucose, menstrual disease, weight lossGastrointestinal: Abdominal pain, colitis, constipation, decreased appetite, diarrhea (Vallerand 2018), esophageal ulcer, esophagitis, gingival hemorrhage, gingivitis, ileitis, inflammatory bowel disease (Papageorgiou 2009, Passier 2006), nausea (Vallerand 2018), pancreatitis (Opel 2017), vomiting (Vallerand 2018), xerostomia (Vallerand 2018)Genitourinary: Erectile dysfunction, gross hematuria, microscopic hematuria, proteinuria, pyuria, sexual disorderHematologic & oncologic: Anemia, bruise, decreased white blood cell count, increased erythrocyte sedimentation rate, lymphadenopathy, severe neutropenia, thrombocythemia, thrombocytopeniaInfection: Herpes simplex infection (disseminated), infectionNervous system: Aggressive behavior (Bremner 2012), anxiety, auditory hallucinations (Vallerand 2018), depression (Vallerand 2018), dizziness, drowsiness, emotional lability, euphoria, fatigue (Vallerand 2018), headache (Vallerand 2018), insomnia (Vallerand 2018), irritability, lethargy (Vallerand 2018), malaise, nervousness, outbursts of anger, pain, panic attack, paresthesia, psychosis, seizure, suicidal ideation (Bremner 2012), suicidal tendencies (Bremner 2012), violent behavior, voice disorderNeuromuscular & skeletal: Arthritis, asthenia, bone fracture (Miziolek 2019), calcification of ligament, calcification of tendon, granulomatosis with polyangiitis (ten Holder 2002), increased creatine phosphokinase in blood specimen, limb pain, musculoskeletal pain (Vallerand 2018), myalgia, neck pain, osteopenia (Miziolek 2019), osteoporosis (Miziolek 2019), premature epiphyseal closure (Alazawi 2011), skeletal hyperostosis, stiffness, tendinopathyOphthalmic: Asthenopia, blepharitis, blurred vision (Vallerand 2018), cataract, conjunctivitis (Vallerand 2018), corneal opacity, decreased visual acuity, eye irritation (Vallerand 2018), eye pruritus, hordeolum, increased lacrimation, keratitis, ocular hyperemia, optic neuritis, photophobia (Vallerand 2018), vision color changes, visual disturbance (Vallerand 2018)Otic: Tinnitus (Rosende 2011)Renal: GlomerulonephritisRespiratory: Bronchospasm, dry nose (Vallerand 2018), epistaxis (Vallerand 2018), nasopharyngitis, respiratory tract infection, upper respiratory tract infectionMiscellaneous: Wound healing impairmentPostmarketing:Cardiovascular: Hypersensitivity angiitis (Vallerand 2018)Dermatologic: Acute generalized exanthematous pustulosis (da Cunha Filho 2010), allergic skin reaction, erythema multiforme, erythema nodosum (Pasmatzi 2020), pityriasis rosea (Gurel 2018), pyoderma gangrenosum (Wang 2018), Stevens-Johnson syndrome (Vallerand 2018), toxic epidermal necrolysisHematologic & oncologic: Agranulocytosis (Ozdemir 2007)Hepatic: Hepatitis (Kizilyel 2014)Hypersensitivity: Anaphylaxis (Bamidis 2021), angioedema (Saray 2006)Nervous system: Idiopathic intracranial hypertension (pseudotumor cerebri) (Tan 2019, Varoglu 2018)Neuromuscular & skeletal: Rhabdomyolysis (Gutman-Yassky 2003)Ophthalmic: Dry eye syndrome (Vallerand 2018), eyelid disease (meibomian gland dysfunction/atrophy) (Neudorfer 2012), night blindness (Teo 2014)Otic: Auditory impairment (Gainville 2021)ContraindicationsHypersensitivity to isotretinoin or any component of the formulation; pregnancy. Note: Based on the chemical similarity of vitamin A to isotretinoin, the prescribing information of some products (eg, Absorica) lists sensitivity to vitamin A as a contraindication to isotretinoin therapy.Canadian labeling: Additional contraindications not in the US labeling: Breastfeeding, hepatic or renal insufficiency, hypervitaminosis A, excessive hyperlipidemia, concurrent tetracycline therapy.Documentation of allergenic cross-reactivity for retinoids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.Warnings/PrecautionsConcerns related to adverse effects:• Inflammatory bowel disease: Inflammatory bowel disease (IBD), including regional ileitis, has been reported in patients without a prior history of intestinal disorders; discontinue treatment immediately if abdominal pain, rectal bleeding, or severe diarrhea occurs. Of note, a position statement from the American Academy of Dermatology states that based on currently available data, there is insufficient evidence to prove either an association or a causal relationship between IBD and isotretinoin use (AAD 2016).• Photosensitivity: Avoid prolonged exposure to UV rays or sunlight.Disease-related concerns:• Diabetes: Use with caution in patients with diabetes mellitus; impaired glucose control has been reported.Dosage form specific issues:• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.• Product interchange: Isotretinoin and tretinoin (which is also known as all-trans retinoic acid, or ATRA) may be confused, while both products may be used in cancer treatment, they are not interchangeable; verify product prior to dispensing and administration to prevent medication errors.• Tartrazine: Some products may contain tartrazine (FD&C yellow no. 5), which may cause allergic reactions, including bronchial asthma, in certain individuals. Allergy is frequently seen in patients who also have an aspirin hypersensitivity.Other warnings/precautions:• Blood donation: Patients should be instructed not to donate blood during therapy and for 1 month following discontinuation of therapy due to risk of donated blood being given to a pregnant patient.• Experienced health care provider: This medication should only be prescribed by health care providers competent in treating severe recalcitrant nodular acne and experienced with the use of systemic retinoids.• Long-term use: Safety of long-term use is not established and is not recommended; the effect on bone loss is unknown.• Skin resurfacing procedures: Avoid skin resurfacing procedures (eg, dermabrasion, laser) and wax epilation during therapy and for ≥6 months after discontinuation of isotretinoin due to the risk of scarring.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAlcohol (Ethyl): May enhance the adverse/toxic effect of ISOtretinoin (Systemic). Specifically, the risk for elevated triglyceride concentrations may be increased. Risk C: Monitor therapyAminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).Risk X: Avoid combinationAminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).Risk C: Monitor therapyMethoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic).Risk C: Monitor therapyMipomersen: ISOtretinoin (Systemic) may enhance the hepatotoxic effect of Mipomersen.Risk C: Monitor therapyMultivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combinationMultivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combinationMultivitamins/Minerals (with AE, No Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combinationPorfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer.Risk C: Monitor therapyProgestins (Contraceptive): Retinoic Acid Derivatives may diminish the therapeutic effect of Progestins (Contraceptive). Retinoic Acid Derivatives may decrease the serum concentration of Progestins (Contraceptive).Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Microdosed progesterone-only preparations (ie, minipills that do not contain estrogen) are considered an inadequate method of contraception. Risk D: Consider therapy modificationTetracyclines: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Risk X: Avoid combinationVerteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin.Risk C: Monitor therapyVitamin A: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combinationFood InteractionsStandard formulation isotretinoin bioavailability increased if taken with food or milk. Management: Administer orally with a meal. Note: Also available as lidose (Absorica) and micronized (Absorica LD) formulations that may be administered with or without food.Dietary ConsiderationsStandard formulation should be taken with food; lidose (Absorica) or micronized formulations (Absorica LD) may be taken without regard to meals. Limit intake of vitamin A; avoid use of other vitamin A products. Some formulations may contain soybean oil.Reproductive Considerations[US Boxed Warning]: Isotretinoin must not be used by patients who may become pregnant.Patients of childbearing potential must be able to comply with the guidelines of the iPLEDGE™ pregnancy prevention program. Females of childbearing potential must have 2 negative pregnancy tests with a sensitivity of ≥25 milliunits/mL prior to beginning therapy, and testing should continue monthly during therapy. Patients of childbearing potential should not become pregnant during therapy or for 1 month following discontinuation of isotretinoin. Upon discontinuation of treatment, patients of childbearing potential should have a pregnancy test after their last dose and again 1 month after their last dose.All patients (male and female) must be enrolled in the iPLEDGE™ risk management program. Patients of childbearing potential must receive oral and written information reviewing the hazards of therapy and the effects that isotretinoin can have on a fetus. Therapy should not begin without 2 negative pregnancy tests ≥19 days apart. Two forms of contraception (a primary and secondary form as described in the iPLEDGE™ program materials) must be used simultaneously beginning 1 month prior to treatment, during treatment, and for 1 month after therapy is discontinued; limitations to their use must be explained. Micro-dosed progesterone products that do not contain an estrogen ("mini-pills") are not an acceptable form of contraception during isotretinoin treatment. Prescriptions should be written for no more than a 30-day supply, and pregnancy testing and counseling should be repeated monthly. During therapy, pregnancy tests must be conducted by a CLIA-certified laboratory. Prescriptions must be filled and picked up from the pharmacy within 7 days of specimen collection for pregnancy test for patients of childbearing potential. Prescriptions for patients of nonchildbearing potential (male and female) must be filled and picked up within 30 days of prescribing.Any cases of accidental pregnancy should be reported to the iPLEDGE™ program or FDA MedWatch. All patients (male and female) must read and sign the informed consent material provided in the pregnancy prevention program.Pregnancy ConsiderationsIsotretinoin and its metabolites can be detected in fetal tissue following maternal use during pregnancy (Benifla 1995; Kraft 1989).Use is contraindicated in pregnant women. [US Boxed Warning]: Isotretinoin must not be used by patients who are pregnant. There is an extremely high risk that life-threatening birth defects can result if pregnancy occurs while taking isotretinoin in any amount, even for short periods of time. Potentially, any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected. Birth defects that have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, CNS, cardiovascular system, and thymus and parathyroid glands. Cases of intelligence quotient (IQ) scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported. Documented external abnormalities include skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases, death has occurred with some of the abnormalities previously noted.If pregnancy does occur during treatment of a patient who is taking isotretinoin, isotretinoin must be discontinued immediately and the patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling.Any pregnancies should be reported to the iPLEDGE™ program (www.ipledgeprogram.com or 866-495-0654) and the FDA through MedWatch (800-FDA-1088).Monitoring ParametersCBC with differential and platelet count, baseline sedimentation rate, glucose, CPK; signs of depression, mood alteration, psychosis, aggression, severe skin reactionsPregnancy test (for all female patients of childbearing potential): Two negative tests with a sensitivity of at least 25 mIU/mL prior to beginning therapy (the second performed at least 19 days after the first test and performed during the first 5 days of the menstrual period immediately preceding the start of therapy); monthly tests to rule out pregnancy prior to refilling prescriptionLipids: Prior to treatment and at weekly or biweekly intervals until response to treatment is established. Test should not be performed <36 hours after consumption of ethanol.Liver function tests: Prior to treatment and at weekly or biweekly intervals until response to treatment is established.Mechanism of ActionReduces sebaceous gland size and reduces sebum production in acne treatment; in neuroblastoma, decreases cell proliferation and induces differentiationPharmaco*kinetics (Adult data unless noted)Note: Pharmaco*kinetic parameters in adolescents (12 to 15 years) are similar to adults.Absorption:Standard formulation: Enhanced with a high-fat meal.Lidose formulation (Absorica): AUC0-t and Cmax increased 50% and 26%, respectively, under fed compared to fasting conditions.Micronized formulation (Absorica LD): AUC0-t and Cmax increased 20% and 6%, respectively, under fed compared to fasting conditions.Protein binding: 99% to 100%; primarily albumin.Metabolism: Hepatic via CYP2B6, 2C8, 2C9, 3A4; forms metabolites; major metabolite: 4-oxo-isotretinoin (active).Half-life elimination:Standard formulation: Parent drug: 21 ± 8.2 hours; Metabolite: 24 ± 5.3 hours.Lidose formulation (Absorica): Parent drug: 18 hours; Metabolite: 38 hours.Micronized formulation (Absorica LD): Parent drug: ~24 hours; Metabolite: ~38 hours.Time to peak, serum:Standard formulation: 5.3 hours (fed); 3.2 hours (fasting).Lidose formulation (Absorica): 6.4 hours (fed); 2.9 hours (fasting).Micronized formulation (Absorica LD): Median: 5 hours (fed); 3.5 hours (fasting).Excretion: Urine and feces (equal amounts).Extemporaneous PreparationsFor patients unable to swallow the capsules whole, an oral liquid may be prepared with softgel capsules (not recommended by the manufacturers) by one of the following methods:Place capsules (softgel formulations only) in small container and add warm (~37°C [97°F]) water or milk to cover capsule(s); wait 2 to 3 minutes until capsule is softened and then drink the milk or water with the softened capsule, or swallow softened capsule.Puncture capsule (softgel formulations only) with needle or cut with scissors; squeeze capsule contents into 5 to 10 mL of milk or tube feed formula; draw mixture up into oral syringe and administer via feeding tube; flush feeding tube with ≥30 mL additional milk or tube feeding formula.Puncture capsule (softgel formulations only) with needle or cut with scissors and draw contents into oral syringe; add 1 to 5 mL of medium chain triglyceride, soybean, or safflower oil to the oral syringe; mix gently and administer via feeding tube; flush feeding tube with ≥30 mL milk or tube feeding formula.Lam MS. Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. Pharmacotherapy. 2011;31(2):164-192.21275495Pricing: USCapsules (Absorica LD Oral)8 mg (per each): $46.8916 mg (per each): $46.8924 mg (per each): $50.4532 mg (per each): $50.45Capsules (Absorica Oral)10 mg (per each): $44.6520 mg (per each): $44.6525 mg (per each): $48.0430 mg (per each): $48.0435 mg (per each): $48.0440 mg (per each): $48.04Capsules (Accutane Oral)10 mg (per each): $7.9920 mg (per each): $7.9930 mg (per each): $7.9940 mg (per each): $7.99Capsules (Amnesteem Oral)10 mg (per each): $18.0220 mg (per each): $21.3740 mg (per each): $24.83Capsules (Claravis Oral)10 mg (per each): $20.5020 mg (per each): $24.3130 mg (per each): $20.5640 mg (per each): $28.25Capsules (ISOtretinoin Oral)10 mg (per each): $20.50 - $42.4220 mg (per each): $24.31 - $42.4225 mg (per each): $36.61 - $45.6430 mg (per each): $20.56 - $45.6435 mg (per each): $36.61 - $45.6440 mg (per each): $28.25 - $45.64Capsules (Myorisan Oral)10 mg (per each): $18.0220 mg (per each): $21.3730 mg (per each): $12.3340 mg (per each): $24.82Capsules (Zenatane Oral)10 mg (per each): $18.0220 mg (per each): $21.3730 mg (per each): $24.8340 mg (per each): $24.83Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAccotin (DK);Acnal SC (KR);Acnecur (PY);Acnelar (EG);Acnemin (ES);Acnetrex (LK, PH);Acnotin (CL, EC, HK, PE, SG, TH, VN);Acnova (BR);Akinol (KR);Aknenormin (DE);Aknetin (UA);Aknil Gel (BD);Atlacne (AR);Atretin (CO);Ciscutan (AT);Claravis (BM);Contracne (FR);Cosmin (PK);Curacne (AE, JO, KW, LB, QA);Curacne Ge (FR);Curakne (CH);Curatane (IL);Dercutane (ES);Dermatane (AU);Hyndriax (CR, DO, GT, HN, NI, PA, SV);Isocural (BE);Isocutan (AR);Isoface (CO, CR, DO, EC, GT, HN, MX, NI, PA, PE, PY, SV, VE);Isolve (CR, DO, GT, HN, NI, PA, SV);Isosupra (BE);Isotane (NZ, TH);Isotina (KR);Isotinon (KR);Isotren (KR);Isotret-Hexal (DE);Isotrex (AE, BH, BR, CL, CR, CY, DK, DO, GB, GT, HN, HU, ID, IE, LU, MX, NI, PA, PK, SA, SG, SV);Isotrex Gel (DE, ES, FR, HK, IL, IT, MY, PH, PL, TH);Isotroin (IN, LB);LOAC SC (KR);Neotrex (MX);Netlook (EG);Nimegen (MY, SG);Oratane (AE, AU, MY, NZ, SG);Procuta Ge (FR);Reducar (BH, HK);Reticap-5 (BD);Retigel (BD);Roaccutan (AR, CO, FI, HU, IT, MX, PE, PT, PY, UY, VE);Roaccutane (AE, AU, BB, BE, BG, BH, BS, BZ, CH, CU, CY, CZ, EE, EG, GB, GH, GR, GY, HK, HR, IE, IL, IQ, IR, JM, JO, KE, KR, KW, LB, LK, LT, LU, LV, LY, NL, OM, PH, PK, PR, QA, RO, SA, SI, SK, SR, SY, TR, TT, TW, TZ, UA, UG, YE, ZM);Roacnetan (CN);Roacta (TH);Roacutan (BR);Rocta (AU);Sotret (IN, TH);Sotrexe (MX);Tretinex (EC)For country code abbreviations (show table)<800> Hazardous Drugs–Handling in Healthcare Settings. 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Cutaneous and systemic manifestations of drug-induced vasculitis. Ann Pharmacother. 2002;36(1):130-147. doi:10.1345/aph.1A124 [PubMed 11816242]Teo K, Yazdabadi A. Isotretinoin and night blindness. Australas J Dermatol. 2014;55(3):222-224. doi:10.1111/ajd.12107 [PubMed 25117163]Trautinger F, Eder J, Assaf C, et al. European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2017. Eur J Cancer. 2017;77:57-74. [PubMed 28365528]Türel A, Oztürkcan S, Sahin MT, Türkdogan P. A rare side-effect of systemic isotretinoin treatment: pyogenic granuloma. J Eur Acad Dermatol Venereol. 2003;17(5):609-611. doi:10.1046/j.1468-3083.2003.00620.x [PubMed 12941114]US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed October 5, 2016.Vallerand IA, Lewinson RT, Farris MS, et al. Efficacy and adverse events of oral isotretinoin for acne: a systematic review. Br J Dermatol. 2018;178(1):76-85. doi:10.1111/bjd.15668 [PubMed 28542914]Varoglu AO, Aksoy A. Herpes simplex encephalitis and pseudotumour cerebri due to ısotretinoin. J Pak Med Assoc. 2018;68(12):1833-11835. [PubMed 30504951]Veal GJ, Cole M, Errington J, et al. Pharmaco*kinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma - a study of the United Kingdom Children's Cancer Study Group. Br J Cancer. 2007;96(3):424-431. [PubMed 17224928]Vieira AS, Beijamini V, Melchiors AC. The effect of isotretinoin on triglycerides and liver aminotransferases. An Bras Dermatol. 2012;87(3):382-387. doi:10.1590/s0365-05962012000300005 [PubMed 22714752]Wang JY, French LE, Shear NH, Amiri A, Alavi A. Drug-induced pyoderma gangrenosum: a review. Am J Clin Dermatol. 2018;19(1):67-77. doi:10.1007/s40257-017-0308-7 [PubMed 28624960]Warrington R, Silviu-Dan F, Wong T. Drug allergy. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):60. doi:10.1186/s13223-018-0289-y [PubMed 30275849]Yu AL, Gilman AL, Ozkaynak MF, et al, “Anti-GD2 Antibody With GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma,” N Engl J Med, 2010, 363(14):1324-34. [PubMed 20879881]Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945-973.e33. http://www.jaad.org/article/S0190-9622(15)02614-6/pdf. Accessed March 3, 2022. [PubMed 26897386]Zane LT, Leyden WA, Marqueling AL, Manos MM. A population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. Arch Dermatol. 2006;142(8):1016-1022. doi:10.1001/archderm.142.8.1016 [PubMed 16924051]Zenatane (isotretinoin) [prescribing information]. Princeton, NJ: Dr. Reddy's Laboratories Inc; February 2022.Zhang C and Duvic M, “Treatment of Cutaneous T-Cell Lymphoma With Retinoids,” Dermatol Ther, 2006, 19(5):264-71. [PubMed 17014481]Topic 13395 Version 303.0

CloseTenofovir disoproxil fumarate and emtricitabine: Drug informationTenofovir disoproxil fumarate and emtricitabine: Drug information(For additional information see "Tenofovir disoproxil fumarate and emtricitabine: Patient drug information" and see "Tenofovir disoproxil fumarate and emtricitabine: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningPosttreatment acute exacerbation of hepatitis B:Severe, acute exacerbations of hepatitis B virus (HBV) have been reported in HBV-infected individuals who have discontinued emtricitabine/tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in individuals who are infected with HBV and discontinue emtricitabine/tenofovir disoproxil fumarate. If appropriate, initiation of antihepatitis B therapy may be warranted.Risk of drug resistance with use for preexposure prophylaxis:Emtricitabine/tenofovir disoproxil fumarate used for HIV-1 preexposure prophylaxis must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and at least every 3 months during use. Drug-resistant HIV-1 variants have been identified with use of emtricitabine/tenofovir disoproxil fumarate for HIV-1 preexposure prophylaxis following undetected acute HIV-1 infection. Do not initiate emtricitabine/tenofovir disoproxil fumarate for HIV-1 preexposure prophylaxis if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed.Brand Names: USTruvadaBrand Names: CanadaAG-Emtricitabine/Tenofovir;APO-Emtricitabine-Tenofovir;AURO-Emtricitabine-Tenofovir;JAMP Emtricitabine/Tenofovir;MINT-Emtricitabine/Tenofovir;MYLAN-Emtricitabine/Tenofov DF;PMS-Emtricitabine-Tenofovir;TEVA-Emtricitabine/Tenofovir;TruvadaPharmacologic CategoryAntiretroviral, Reverse Transcriptase Inhibitor, Nucleoside (Anti-HIV);Antiretroviral, Reverse Transcriptase Inhibitor, Nucleotide (Anti-HIV)Dosing: AdultHIV-1 infection, preexposure prophylaxisHIV-1 infection, preexposure prophylaxis:Persons who inject drugs (off-label use): Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily (CDC 2021).HIV-uninfected individuals at high-risk for sexual acquisition:Daily dosing schedule: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily in combination with safe sex practices (CDC 2021). In men who have sex with men, some experts recommend initiating with a double dose (2 tablets [emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg per tablet]) on day 1, followed by 1 tablet once daily to reduce time to anticipated maximal protection (IAS-USA [Saag 2020]).On demand (2-1-1) dosing schedule (for use in men who have sex with men only) (off label): Oral: Two tablets (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg per tablet) taken 2 to 24 hours (as close to 24 hours as possible) prior to sexual activity, 1 tablet 24 hours later, and 1 tablet 24 hours after that. In patients who initiate on demand therapy more than once within a week, only 1 tablet should be used for a loading dose (CDC 2021; IAS-USA [Saag 2020]; Molina 2015).HIV-1 infection, postexposure prophylaxisHIV-1 infection, postexposure prophylaxis (off-label use):Nonoccupational exposure: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily for 28 days in combination with other antiretroviral agents. Initiate therapy within 72 hours of exposure (HHS [nPEP 2016]).Occupational exposure: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily for 4 weeks with concomitant raltegravir. Initiate therapy as soon as possible after occupational exposure (and within 72 hours) (Kuhar 2013).HIV-1 infection, treatmentHIV-1 infection, treatment: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily in combination with other antiretroviral agents.HIV-1/hepatitis B co-infection, treatmentHIV-1/hepatitis B co-infection, treatment (off-label use): Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily in combination with other antiretroviral agents (HHS [adult 2019]).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultHIV-1 infection, treatment:Manufacturer's labeling: CrCl ≥50 mL/minute: No dosage adjustment necessaryCrCl 30 to 49 mL/minute: Increase interval to every 48 hours.CrCl <30 mL/minute: Not recommended.Hemodialysis: Not recommended.Alternate recommendations (IDSA [Lucas 2014]):CrCl <50 mL/minute (and not on hemodialysis) or GFR <60 mL/minute/1.73 m2: Avoid use of tenofovirPrEP:CrCl ≥60 mL/minute: No dosage adjustment necessaryCrCl <60 mL/minute: Not recommended.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Pediatric(For additional information see "Tenofovir disoproxil fumarate and emtricitabine: Pediatric drug information")Note: Multiple tablet strengths exist and contain different amounts of emtricitabine and tenofovir. International Considerations: Tenofovir doses are expressed as tenofovir disoproxil fumarate, consistent with US labeling; in some other countries, dosing may be expressed as tenofovir disoproxil base. Tenofovir disoproxil fumarate 300 mg is equivalent to tenofovir disoproxil base 245 mg.HIV-1 infection, treatmentHIV-1 infection, treatment: Use in combination with another antiretroviral agent. Gene mutation and antiretroviral resistance patterns should be evaluated (refer to https://www.iasusa.org for more information) when necessary.Children and Adolescents weighing ≥17 kg:17 to <22 kg: Oral: One tablet (emtricitabine 100 mg/tenofovir disoproxil fumarate 150 mg) once daily.22 to <28 kg: Oral: One tablet (emtricitabine 133 mg/tenofovir disoproxil fumarate 200 mg) once daily.28 to <35 kg: Oral: One tablet (emtricitabine 167 mg/tenofovir disoproxil fumarate 250 mg) once daily.≥35 kg: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily.HIV infection, postexposure prophylaxis, nonoccupationalHIV infection, postexposure prophylaxis, nonoccupational (nPEP) (HHS [nPEP] 2016): Limited data available:Adolescents: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily for 28 days in combination with other antiretroviral agents. Initiate therapy within 72 hours of exposure.HIV-1 infection, preexposure prophylaxis in uninfected high-risk individualsHIV-1 infection, preexposure prophylaxis (PrEP) in uninfected high-risk individuals: Note: Patients should be confirmed HIV-negative immediately prior to initiation of therapy and screened again at least once every 3 months and upon diagnosis of any other sexually transmitted infections (CDC/USPHS 2021; manufacturer's labeling).Adolescents weighing ≥35 kg: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricHIV-1 infection, treatment: Children and Adolescents weighing ≥17 kg: Oral:CrCl ≥50 mL/minute: No dosage adjustment necessary.CrCl <50 mL/minute: There are no pediatric-specific recommendations; based on experience in adult patients, dosage adjustment suggested; use in hemodialysis is not recommended.Preexposure prophylaxis: Adolescents weighing ≥35 kg:CrCl ≥60 mL/minute: No dosage adjustment necessary.CrCl <60 mL/minute: Use is not recommended.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling; however, no dosing adjustments are necessary for tenofovir in hepatic impairment. No specific data is available on emtricitabine in hepatic impairment, but given its limited hepatic metabolism, the impact of liver impairment should be minimal; need for dose adjustment is unlikely.Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Truvada: Emtricitabine 100 mg and tenofovir disoproxil fumarate 150 mg, Emtricitabine 133 mg and tenofovir disoproxil fumarate 200 mg, Emtricitabine 167 mg and tenofovir disoproxil fumarate 250 mg, Emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg [contains fd&c blue #2 (indigo carm) aluminum lake]Generic: Emtricitabine 100 mg and tenofovir disoproxil fumarate 150 mg, Emtricitabine 133 mg and tenofovir disoproxil fumarate 200 mg, Emtricitabine 167 mg and tenofovir disoproxil fumarate 250 mg, Emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Truvada: Emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg [contains fd&c blue #2 (indigo carm) aluminum lake]Generic: Emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mgMedication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021752s061lbl.pdf#page=35, must be dispensed with this medication.Administration: AdultOral: May be administered with or without food.Administration: PediatricOral: May be administered without regard to foodUse: Labeled IndicationsHIV-1 infection, treatment: Treatment of HIV-1 infection in combination with other antiretroviral agents in adults and pediatric patients weighing ≥17 kgHIV-1 infection, preexposure prophylaxis: Preexposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in at-risk adults and adolescents weighing ≥35 kg.Use: Off-Label: AdultHIV-1/hepatitis B co-infection, treatment; HIV-1 nonoccupational postexposure prophylaxis; HIV-1 occupational postexposure prophylaxisAdverse Reactions (Significant): ConsiderationsBone effectsTenofovir disoproxil fumarate (TDF) is associated with a larger decreased bone mineral density (BMD) in HIV-1 infected adults than in those not taking TDF (Ref). The rate of bone loss slows after 1 to 2 years following initiation (Ref). TDF may be associated with in increased risk of bone fracture (Ref). When used as preexposure prophylaxis (PrEP), there is a smaller reduction in BMD (Ref). Mean BMD returns to baseline levels within 12 to18 months after TDF-based PrEP discontinuation in both hip and spine (Ref). TDF is also associated with bone loss (both absolute BMD and reduced Z-score) in children and adolescents (Ref). Adolescents with HIV aged ≥12 years treated with TDF are more likely to experience a >4% decline in lumber spine BMD than those treated with placebo (Ref). Those with sexual maturity ratings (SMR [formerly Tanner staging]) 1 to 2 may be at greater risk (Ref). Bone loss partially recovers after discontinuation in children and adolescents (Ref).Mechanism: Time-related; not clearly established. Tenofovir inhibition of calcium-sensing receptors in the parathyroid (Ref) may increase PTH levels (Ref). It has been proposed that PTH levels accelerate bone remodeling which, combined with persistent HIV-associated demineralization in persons with HIV, results in increased osteoid volume (Ref).Onset: Varied; markers of bone resorption are apparent within 12 weeks after beginning TDF (Ref). Reductions in BMD are observed during the first 1 to 2 years following initiation (Ref).Risk factors (for bone loss and/or fracture):• Treatment duration (Ref)• Females (especially postmenopausal) (Ref)• Transgender (Ref)• White race (Ref)• Prior fracture (and patients at risk for recurrent falls) (Ref)• Prolonged systemic corticosteroid use (Ref)• Medroxyprogesterone use (Ref)• Smoking (Ref)• Early stages of puberty (Ref)• Older age (Ref)• Vitamin D insufficiency/deficiency (Ref)• Low BMI (Ref)• Lack of weight-bearing exercise (Ref)• Cardiovascular disease (Ref)• Longer duration and greater severity of HIV disease (Ref)• CD4+ cell count <350 cells/mm3 (Ref)• Pharmacologic boosters (cobicistat or ritonavir) (Ref)• IV Drug use (Ref)• Lipodystrophy (Ref)• Recent non-AIDS cancer (Ref)Kidney injuryThe tenofovir disoproxil fumarate (TDF) component is associated with multiple renal syndromes. Toxic acute tubular necroses manifest as acute kidney injury, chronic interstitial nephritis as chronic kidney disease, and renal tubulopathies as Fanconi syndrome and rarely nephrogenic diabetes insipidus (Ref).Acute kidney injury (AKI): TDF is associated with AKI, with the majority of cases meeting the risk definition according to the RIFLE classification or AKIN Stage I (Ref). Kidney function improves over months after TDF discontinuation but does not reverse completely in all cases (Ref). It is reported to recur on rechallenge (Ref).Chronic kidney disease (CKD): TDF reduces estimated glomerular filtration rate (eGFR) by ~4 mL/minute compared with non–TDF-containing regimens (Ref) and this may progress to CKD (Ref). A smaller reduction in eGFR occurs when used for preexposure prophylaxis (PrEP) compared with placebo (eg, 1.59 mL/minute in PARTNERS) (Ref). When used for PrEP, eGFR returns to baseline 4 to 8 weeks after discontinuation (Ref) but may not return to baseline in some cases (Ref).Fanconi syndrome (FS): TDF is associated with partial or, more rarely, complete FS (proximal renal tubular acidosis with a normal anion gap metabolic acidosis, hypophosphatemia and osteomalacia with renal phosphate wasting, hypokalemia, hypouricemia, glycosuria with normal blood glucose, and aminoaciduria) (Ref). FS has resulted in fatal cases (Ref). In most patients, proximal tubulopathy resolves within 2 months of TDF discontinuation, but CrCl takes longer to recover and may not return to baseline (Ref). Osteomalacia resolved within 14 weeks of discontinuing TDF in one case report (Ref). FS may present as bone pain as a manifestation of osteomalacia (Ref). FS occurs less frequently when used for PrEP (Ref).Mechanism: Dose- and time-related; inhibition of DNA polymerase gamma results in mitochondrial DNA (mtDNA) depletion, mitochondrial dysfunction, and cell toxicity (Ref). Proximal tubule epithelial cells are particularly susceptible (Ref).Onset:AKI: Varied; mean of 6 months (range, 3 to 16.5 months) (Ref).CKD: Varied; an eGFR decline is seen within 1 month of initiation (Ref). Significant (stage 3 or greater) CKD has occurred at a median of 45 weeks (interquartile range, 11 to 137 weeks) (Ref).FS: Varied; diagnosis ranged from 3.9 months to 11 years in a representative case series (Ref).Risk factors:AKI:• Lower baseline SCr (Ref)• Higher baseline eGFR (Ref)• Concurrent protease inhibitor (Ref)• Concurrent sulfamethoxazole/trimethoprim (Ref)• Concurrent non-steroidal anti-inflammatory drugs (NSAIDs), particularly diclofenac (Ref)• Lower baseline CD4 cell count (Ref)• Higher baseline viral load (Ref)CKD:• Cumulative TDF exposure (Ref)• Higher preexisting risk of CKD (Ref)• Preexisting kidney disease (Ref)• Lower eGFR at initiation (Ref)• Prior AKI (Ref)• Concurrent atazanavir/lopinavir or ritonavir (Ref)• Concurrent NSAIDs, particularly diclofenac (Ref)• Hypertension (Ref)• Older age (Ref)• Hepatitis C coinfection (Ref)• Lower CD4 (Ref)• Higher viral load (Ref)FS:• Longer TDF treatment duration (Ref)• Reduced CrCl before TDF initiation (Ref)• Concurrent cobicistat or ritonavir (Ref)• Previous or concurrent lopinavir/ritonavir (Ref)• Coronary artery disease (Ref)• Diabetes (Ref)• Low body weight (Ref)• Older age (Ref)• Hepatitis C coinfection (Ref)• Hypertension (Ref)• White race (Ref)• Longer HIV duration (Ref)• Lower nadir CD4 counts (Ref)• Prior AIDS diagnosis (Ref)• ABCC2 & ABCC10 polymorphism (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adult monotherapy studies for HIV-1 pre-exposure prophylaxis. Also see individual agents.>10%: Neuromuscular & skeletal: Decreased bone mineral density (13%)Emtricitabine and Tenofovir Disoproxil Fumarate: Adverse Reaction: Decreased Bone Mineral DensityDrug (Emtricitabine and Tenofovir Disoproxil Fumarate)Placebo Comments13%6%≥5% bone mineral density loss at the spine during treatment1% to 10%:Endocrine & metabolic: Abnormal phosphorus levels (<2.0 mg/dL: 10%), weight loss (3%)Gastrointestinal: Abdominal pain (4%)Hematologic & oncologic: Decreased neutrophils (5%)Nervous system: Headache (7%)Neuromuscular & skeletal: Bone fracture (2%) (table 1)Bone FractureEmtricitabine and Tenofovir Disoproxil Fumarate: Adverse Reaction: Bone FractureDrug (Emtricitabine and Tenofovir Disoproxil Fumarate)Placebo 2%1%<1%: Genitourinary: Glycosuria, proteinuriaFrequency not defined: Hepatic: Exacerbation of hepatitis B (following discontinuation)Postmarketing:Immunologic: Immune reconstitution syndromeRenal: Fanconi syndrome (Rao 2021)ContraindicationsAs preexposure prophylaxis in patients with unknown or HIV-1 positive statusCanadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to emtricitabine, tenofovir, or any component of the formulationWarnings/PrecautionsConcerns related to adverse effects:• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) later in therapy; further evaluation and treatment may be required.• Lactic acidosis/hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with use of nucleoside analogues, alone or in combination with other antiretrovirals. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (marked transaminase elevation may/may not accompany hepatomegaly and steatosis).Disease-related concerns:• Comprehensive prevention program: Preexposure prophylaxis (PrEP) should be accompanied by a comprehensive HIV-1 prevention program (eg, risk reduction counseling, access to condoms), with particular emphasis on medication adherence. In addition, regular monitoring (eg, HIV status of patient and partner(s), risk behavior, adherence, adverse effects, sexually transmitted infections that facilitate HIV-1 transmission) is highly recommended. Time from initiation of therapy to maximal protection against HIV-1 is unknown.• Renal impairment: Use with caution in patients with renal impairment; see "Dosing in Altered Kidney Function" for additional information.Concurrent drug therapy issues:• Duplicate therapy: Do not use concurrently with emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, or any combination of these drugs.Warnings: Additional Pediatric ConsiderationsEmtricitabine-associated hyperpigmentation may occur at a higher frequency in pediatric patients compared to adults (children: 32%; adults: 2% to 6%).Tenofovir disoproxil fumarate (TDF) disrupts vitamin D metabolism and has been associated with decreased bone mineral density (BMD) in adults and children. Plasma concentrations of the TDF metabolite tenofovir (TFV) have been associated with endocrine disruption and low BMD; tenofovir alafenamide (TAF) is associated with lower plasma TFV concentrations and less decline in BMD than TDF. Data suggest the impact may be greater in children who are less mature (eg, sexual maturity ratings [SMRs] 1 to 2 [previously Tanner stages]) than in those with more advanced pubertal development (SMR ≥3). The potential for BMD loss during the important period of rapid bone accrual in childhood and early adolescence is concerning and favors use of abacavir or TAF in children with SMRs 1 to 3 (children with perinatally acquired HIV are already at risk for low peak bone mass). Prior to initiation of therapy, assessment of benefits versus potential risks should be assessed; with TDF therapy, monitor plasma vitamin D concentrations; supplement with vitamin D as needed; calcium carbonate supplementation may also be considered. Monitoring of BMD may be considered in patients with additional risk factors for decreased bone density (HHS [pediatric] 2022).Metabolism/Transport EffectsRefer to individual components.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Acyclovir-Valacyclovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir. Risk C: Monitor therapyAdefovir: May diminish the therapeutic effect of Tenofovir Products. Adefovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Adefovir. Risk X: Avoid combinationAminoglycosides: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Aminoglycosides. Risk C: Monitor therapyAminosalicylic Acid: May decrease the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapyAtazanavir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Tenofovir Disoproxil Fumarate.Management: Use boosted atazanavir in adults; give combo (atazanavir/ritonavir or atazanavir/cobicistat with tenofovir) as a single daily dose with food. Pediatric patients, pregnant patients, and use of H2-blockers require dose changes. See Lexi Interact monograph. Risk D: Consider therapy modificationBetibeglogene Autotemcel: Antiretroviral Agents may diminish the therapeutic effect of Betibeglogene Autotemcel.Risk X: Avoid combinationCabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib.Risk C: Monitor therapyCidofovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Cidofovir. Risk C: Monitor therapyCladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine.Risk X: Avoid combinationCobicistat: Tenofovir Disoproxil Fumarate may enhance the adverse/toxic effect of Cobicistat. More specifically, cobicistat may impair proper tenofovir disoproxil fumarate monitoring and dosing.Risk C: Monitor therapyDarolutamide: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyDarunavir: Tenofovir Disoproxil Fumarate may increase the serum concentration of Darunavir. Darunavir may increase the serum concentration of Tenofovir Disoproxil Fumarate.Risk C: Monitor therapyDidanosine: Tenofovir Disoproxil Fumarate may diminish the therapeutic effect of Didanosine. Tenofovir Disoproxil Fumarate may increase the serum concentration of Didanosine.Management: Avoid use of tenofovir disoproxil fumarate and didanosine when possible. If combined in adults with CrCL greater than 60 mL/min, decrease didanosine to 250 mg daily if 60 kg or more or to 200 mg if less than 60 kg. Avoid if CrCL is less than 60 mL/min. Risk D: Consider therapy modificationElivaldogene Autotemcel: Antiretroviral Agents may diminish the therapeutic effect of Elivaldogene Autotemcel.Management: Avoid use of antiretroviral medications for at least one month, or for the amount of time required for elimination of the retroviral medication, prior to stem cell mobilization and until the all apheresis cycles are finished Risk X: Avoid combinationEltrombopag: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyEncorafenib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyFutibatinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyGanciclovir-Valganciclovir: Tenofovir Products may increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Tenofovir Products.Risk C: Monitor therapyGilteritinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyLedipasvir: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Avoid this combination if TDF is used as part of the elvitegravir/cobicistat/emtricitabine/TDF product. Consider alternatives when TDF is used with a ritonavir or cobicistat boosted protease inhibitor. Monitor for increased TDF toxicities if combined. Risk D: Consider therapy modificationLeflunomide: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyLopinavir: May enhance the nephrotoxic effect of Tenofovir Disoproxil Fumarate. Lopinavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapyLumacaftor and Ivacaftor: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose due to a potential risk of acute renal failure. Diclofenac appears to confer the most risk. Risk D: Consider therapy modificationNonsteroidal Anti-Inflammatory Agents (Topical): May enhance the nephrotoxic effect of Tenofovir Products. Risk C: Monitor therapyOrlistat: May decrease the serum concentration of Antiretroviral Agents. Risk C: Monitor therapyOsimertinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyOteseconazole: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyPacritinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combinationP-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapyRegorafenib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyRolapitant: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Management: Monitor patients receiving rolapitant for increased exposure to and/or effects of BCRP/ABCG2 substrates.Use the lowest effective rosuvastatin dose when used in combination with rolapitant. Risk C: Monitor therapyTafamidis: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyTaurursodiol: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combinationTedizolid: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyTeriflunomide: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyTipranavir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Tenofovir Disoproxil Fumarate.Risk C: Monitor therapyVoxilaprevir: Tenofovir Disoproxil Fumarate may increase the serum concentration of Voxilaprevir. Voxilaprevir may increase the serum concentration of Tenofovir Disoproxil Fumarate.Risk C: Monitor therapyFood InteractionsSee individual agents.Reproductive ConsiderationsThe Health and Human Services (HHS) perinatal HIV guidelines consider this a preferred combination for patients with HIV infection who are not yet pregnant but are trying to conceive.This combination is recommended for pre-exposure prophylaxis (PrEP) in patients at risk for HIV infection who are planning a pregnancy. The partner without HIV should begin therapy 20 days prior to attempting conception. Up to 20 days of therapy are required to achieve protective drug concentrations in cervicovagin*l tissue, therefore continued use of condoms to prevent HIV exposure is recommended during this time. PrEP should continue for 28 days after attempting conception or condomless sex exposure. Episodic or on demand dosing is not effective for prevention of HIV via vagin*l exposure (HHS [perinatal] 2021).Refer to individual monographs for additional information.Pregnancy ConsiderationsThe Health and Human Services (HHS) perinatal HIV guidelines consider emtricitabine with tenofovir disoproxil fumarate to be a preferred nucleoside reverse transcriptase inhibitor backbone for initial therapy in antiretroviral-naive pregnant patients. In addition, this combination is preferred for use in pregnant patients with HIV infection who have had antiretroviral therapy (ART) in the past but are restarting, or who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen). Patients who become pregnant while taking this combination may continue if viral suppression is effective and the regimen is well tolerated.This combination is recommended for pre-exposure prophylaxis (PrEP) in uninfected patients at risk for HIV infection who are pregnant; if started prior to conception, it may be continued during pregnancy. Emtricitabine and tenofovir disoproxil fumarate are recommended as part of a preferred regimen when acute HIV infection is detected during pregnancy.The HHS perinatal guidelines also recommend emtricitabine plus tenofovir disoproxil fumarate as a component of regimens for HIV/hepatitis B virus–coinfected patients who are pregnant (HHS [perinatal] 2021).Refer to individual monographs for additional information.Breastfeeding ConsiderationsEmtricitabine and tenofovir are present in breast milk.Emtricitabine and tenofovir disoproxil are recommended for pre-exposure prophylaxis (PrEP) in uninfected patients at risk for HIV infection who are breastfeeding (HHS [perinatal] 2021).Refer to individual monographs for additional information.Dietary ConsiderationsConsider calcium and vitamin D supplementation in patients with history of bone fracture or osteopenia.Monitoring ParametersCBC with differential, reticulocyte count, creatine kinase, CD4 count, HIV RNA plasma levels, serum phosphorus (individuals with chronic kidney disease) or at risk of kidney dysfunction with persistent or worsening bone or muscle symptoms); serum creatinine, urine glucose and urine protein (prior to initiation and as clinically indicated during therapy), hepatic function tests, bone density (patients with a history of bone fracture or have risk factors for bone loss or kidney dysfunction with persistent or worsening bone or muscle symptoms); testing for hepatitis B virus (HBV) is recommended prior to the initiation of antiretroviral therapy; weight (children).Patients with HIV and HBV coinfection should be monitored for several months following tenofovir discontinuation.HIV-1 preexposure prophylaxis (PrEP) (CDC 2021): Documented negative HIV test (≤1 week before initiating or reinitiating PrEP, at least every 3 months while taking PrEP, and following discontinuation of PrEP). Screen for acute viral infections and potential exposure events (eg, condomless sex/condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, or a recent STI) within 1 month of starting PrEP; if infections or events exist, reconfirm HIV-1 negative status. Assess symptoms of side effects and acute HIV infection (every 3 months); renal function (prior to initiation, then every 6 to 12 months); testing for HBV (prior to initiation).HIV occupational postexposure prophylaxis (PEP) (Kuhar 2013): Documented HIV test (at baseline and 6 weeks, 12 weeks, and 6 months after exposure); if confirmation that a fourth generation HIV p2 antigen-HIV antibody test is being used, monitor at baseline, 6 weeks and 4 months after exposure. CBC, renal and hepatic function assessments at baseline and 2 weeks after exposure (minimum recommendations, others dictated by clinical assessment).Mechanism of ActionNucleoside and nucleotide reverse transcriptase inhibitor combination; emtricitabine is a cytidine analogue while tenofovir is an analog of adenosine 5'-monophosphate. Each drug interferes with HIV viral RNA dependent DNA polymerase resulting in inhibition of viral replication.Pharmaco*kineticsRefer to individual monographs.Pricing: USTablets (Emtricitabine-Tenofovir DF Oral)100-150 mg (per each): $70.01133-200 mg (per each): $70.01167-250 mg (per each): $70.01200-300 mg (per each): $2.34 - $70.01Tablets (Truvada Oral)100-150 mg (per each): $73.69133-200 mg (per each): $73.69167-250 mg (per each): $73.69200-300 mg (per each): $73.69Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAgifovir-E (VN);Emtifovir (BD);Emzavir (LB);Fovirem (CO);Recovir-Em (TH);Teno-Em (TH);Tenof-Em (TH);Tenofence Plus (EG);Tenvir EM (UY);Tenvir-EM (IN);Tenvor-Em (LB);Tolak E (CO);Truvada (AE, AR, AT, AU, BB, BE, BG, CH, CL, CN, CR, CY, CZ, DE, DK, DO, EE, EG, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, IE, IL, IS, IT, JO, JP, KR, LB, LT, LU, LV, MT, MX, NI, NL, NO, NZ, PA, PL, PT, RO, RU, SE, SG, SI, SK, SV, TH, TR, TW)For country code abbreviations (show table)Ascher SB, Scherzer R, Estrella MM, et al. HIV preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and changes in kidney function and tubular health. AIDS. 2020;34(5):699-706. doi:10.1097/QAD.0000000000002456 [PubMed 31794523]Atencio P, Conesa-Buendía FM, Cabello-Ubeda A, et al. Bone deleterious effects of different NRTIs in treatment-naïve HIV patients after 12 and 48 weeks of treatment. Curr HIV Res. 2021;19(5):434-447. doi:10.2174/1570162X19666210805094434 [PubMed 34353266]Aurpibul L, Cressey TR, Sricharoenchai S, et al. Efficacy, safety and pharmaco*kinetics of tenofovir disoproxil fumarate in virologic-suppressed HIV-infected children using weight-band dosing. Pediatr Infect Dis J. 2015;34(4):392-397. doi:10.1097/INF.0000000000000633 [PubMed 25760566]Baeten JM, Donnell D, Ndase P, et al. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med. 2012;367(5):399-410. [PubMed 22784037]Baranek B, Wang S, Cheung AM, Mishra S, Tan DH. The effect of tenofovir disoproxil fumarate on bone mineral density: a systematic review and meta-analysis. Antivir Ther. 2020;25(1):21-32. doi:10.3851/IMP3346 [PubMed 32077867]Bickel M, Khaykin P, Stephan C, et al. Acute kidney injury caused by tenofovir disoproxil fumarate and diclofenac co-administration. HIV Med. 2013;14(10):633-638. doi:10.1111/hiv.12072 [PubMed 23980564]Borges ÁH, Hoy J, Florence E, et al. Antiretrovirals, fractures, and osteonecrosis in a large international HIV cohort. Clin Infect Dis. 2017;64(10):1413-1421. doi:10.1093/cid/cix167 [PubMed 28329090]Cahn P, Madero JS, Arribas JR, et al. Durable efficacy of dolutegravir plus lamivudine in antiretroviral treatment-naive adults with HIV-1 infection: 96-week results from the GEMINI-1 and GEMINI-2 randomized clinical trials. J Acquir Immune Defic Syndr. 2020;83(3):310-318. doi:10.1097/QAI.0000000000002275 [PubMed 31834000]Carr A, Grund B, Schwartz AV, et al. 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[PubMed 25234519]McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203(12):1791-1801. doi:10.1093/infdis/jir188 [PubMed 21606537]Medland NA, Chow EP, Walker RG, Chen M, Read TR, Fairley CK. Incidence of renal Fanconi syndrome in patients taking antiretroviral therapy including tenofovir disoproxil fumarate. Int J STD AIDS. 2018;29(3):227-236. doi:10.1177/0956462417722133 [PubMed 28764611]Microbicide Trials Network (MTN). MTN Statement on Decision to Discontinue Use of Oral Tenofovir Tablets in VOICE, a Major HIV Prevention Study in Women. Microbicide Trials Network. 2011. http://www.mtnstopshiv.org/node/3619.Mingione A, Maruca K, Chiappori F, et al. 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Int J STD AIDS. 2022;33(4):391-396. doi:10.1177/09564624221076632 [PubMed 35143730]Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana. N Engl J Med. 2012;367(5):423-434. [PubMed 22784038]Truvada (emtricitabine/tenofovir disoproxil fumarate) [prescribing information]. Foster City, CA: Gilead Sciences; June 2020.Truvada (emtricitabine/tenofovir) [product monograph]. Mississauga, Ontario, Canada: Gilead Sciences Canada Inc; July 2018.US Department of Health and Human Services (HHS). Updated Guidelines for Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV - United States, 2016. https://stacks.cdc.gov/view/cdc/38856US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. HIV.gov. Updated January 20, 2022. Accessed May 9, 2022. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-new-guidelinesUS Department of Health and Human Services (HHS) Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the use of antiretroviral agents in pediatric HIV infection. HIV.gov. Updated April 11, 2022. Accessed May 9, 2022. https://clinicalinfo.hiv.gov/en/guidelines/pediatric-arv/whats-new-guidelinesUS Department of Health and Human Services (HHS) Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission. Recommendations for the use of antiretroviral drugs during pregnancy and interventions to reduce perinatal HIV transmission in the United States. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/Perinatal_GL.pdf. Updated December 30, 2021. Accessed January 3, 2022.Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411-422. [PubMed 22784040]Wever K, van Agtmael MA, Carr A. Incomplete reversibility of tenofovir-related renal toxicity in HIV-infected men. J Acquir Immune Defic Syndr. 2010;55(1):78-81. doi:10.1097/QAI.0b013e3181d05579 [PubMed 20173649]Wikman P, Safont P, Del Palacio M, Moreno A, Moreno S, Casado JL. The significance of antiretroviral-associated acute kidney injury in a cohort of ambulatory human immunodeficiency virus-infected patients. Nephrol Dial Transplant. 2013;28(8):2073-2081. doi:10.1093/ndt/gft210 [PubMed 23739150]Zaidan M, Lescure FX, Brochériou I, et al. Tubulointerstitial nephropathies in HIV-infected patients over the past 15 years: a clinico-pathological study. Clin J Am Soc Nephrol. 2013;8(6):930-938. doi:10.2215/CJN.10051012 [PubMed 23430209]Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis. 2006;42(2):283-290. doi:10.1086/499048 [PubMed 16355343]Topic 8527 Version 409.0

CloseTenofovir disoproxil fumarate and emtricitabine: Pediatric drug informationTenofovir disoproxil fumarate and emtricitabine: Pediatric drug information(For additional information see "Tenofovir disoproxil fumarate and emtricitabine: Drug information" and see "Tenofovir disoproxil fumarate and emtricitabine: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningPosttreatment acute exacerbation of hepatitis B:Severe, acute exacerbations of hepatitis B virus (HBV) have been reported in HBV-infected individuals who have discontinued emtricitabine/tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in individuals who are infected with HBV and discontinue emtricitabine/tenofovir disoproxil fumarate. If appropriate, initiation of antihepatitis B therapy may be warranted.Risk of drug resistance with use for preexposure prophylaxis:Emtricitabine/tenofovir disoproxil fumarate used for HIV-1 preexposure prophylaxis must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and at least every 3 months during use. Drug-resistant HIV-1 variants have been identified with use of emtricitabine/tenofovir disoproxil fumarate for HIV-1 preexposure prophylaxis following undetected acute HIV-1 infection. Do not initiate emtricitabine/tenofovir disoproxil fumarate for HIV-1 preexposure prophylaxis if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed.Brand Names: USTruvadaBrand Names: CanadaAG-Emtricitabine/Tenofovir;APO-Emtricitabine-Tenofovir;AURO-Emtricitabine-Tenofovir;JAMP Emtricitabine/Tenofovir;MINT-Emtricitabine/Tenofovir;MYLAN-Emtricitabine/Tenofov DF;PMS-Emtricitabine-Tenofovir;TEVA-Emtricitabine/Tenofovir;TruvadaTherapeutic CategoryAntiretroviral Agent;HIV Agents (Anti-HIV Agents);Nucleoside Reverse Transcriptase Inhibitor (NRTI);Nucleotide Reverse Transcriptase Inhibitor (NRTI)Dosing: PediatricNote: Multiple tablet strengths exist and contain different amounts of emtricitabine and tenofovir. International Considerations: Tenofovir doses are expressed as tenofovir disoproxil fumarate, consistent with US labeling; in some other countries, dosing may be expressed as tenofovir disoproxil base. Tenofovir disoproxil fumarate 300 mg is equivalent to tenofovir disoproxil base 245 mg.HIV-1 infection, treatmentHIV-1 infection, treatment: Use in combination with another antiretroviral agent. Gene mutation and antiretroviral resistance patterns should be evaluated (refer to https://www.iasusa.org for more information) when necessary.Children and Adolescents weighing ≥17 kg:17 to <22 kg: Oral: One tablet (emtricitabine 100 mg/tenofovir disoproxil fumarate 150 mg) once daily.22 to <28 kg: Oral: One tablet (emtricitabine 133 mg/tenofovir disoproxil fumarate 200 mg) once daily.28 to <35 kg: Oral: One tablet (emtricitabine 167 mg/tenofovir disoproxil fumarate 250 mg) once daily.≥35 kg: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily.HIV infection, postexposure prophylaxis, nonoccupationalHIV infection, postexposure prophylaxis, nonoccupational (nPEP) (HHS [nPEP] 2016): Limited data available:Adolescents: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily for 28 days in combination with other antiretroviral agents. Initiate therapy within 72 hours of exposure.HIV-1 infection, preexposure prophylaxis in uninfected high-risk individualsHIV-1 infection, preexposure prophylaxis (PrEP) in uninfected high-risk individuals: Note: Patients should be confirmed HIV-negative immediately prior to initiation of therapy and screened again at least once every 3 months and upon diagnosis of any other sexually transmitted infections (CDC/USPHS 2021; manufacturer's labeling).Adolescents weighing ≥35 kg: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricHIV-1 infection, treatment: Children and Adolescents weighing ≥17 kg: Oral:CrCl ≥50 mL/minute: No dosage adjustment necessary.CrCl <50 mL/minute: There are no pediatric-specific recommendations; based on experience in adult patients, dosage adjustment suggested; use in hemodialysis is not recommended.Preexposure prophylaxis: Adolescents weighing ≥35 kg:CrCl ≥60 mL/minute: No dosage adjustment necessary.CrCl <60 mL/minute: Use is not recommended.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling; however, no dosing adjustments are necessary for tenofovir in hepatic impairment. No specific data is available on emtricitabine in hepatic impairment, but given its limited hepatic metabolism, the impact of liver impairment should be minimal; need for dose adjustment is unlikely.Dosing: Adult(For additional information see "Tenofovir disoproxil fumarate and emtricitabine: Drug information")HIV-1 infection, preexposure prophylaxisHIV-1 infection, preexposure prophylaxis:Persons who inject drugs (off-label use): Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily (CDC 2021).HIV-uninfected individuals at high-risk for sexual acquisition:Daily dosing schedule: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily in combination with safe sex practices (CDC 2021). In men who have sex with men, some experts recommend initiating with a double dose (2 tablets [emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg per tablet]) on day 1, followed by 1 tablet once daily to reduce time to anticipated maximal protection (IAS-USA [Saag 2020]).On demand (2-1-1) dosing schedule (for use in men who have sex with men only) (off label): Oral: Two tablets (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg per tablet) taken 2 to 24 hours (as close to 24 hours as possible) prior to sexual activity, 1 tablet 24 hours later, and 1 tablet 24 hours after that. In patients who initiate on demand therapy more than once within a week, only 1 tablet should be used for a loading dose (CDC 2021; IAS-USA [Saag 2020]; Molina 2015).HIV-1 infection, postexposure prophylaxisHIV-1 infection, postexposure prophylaxis (off-label use):Nonoccupational exposure: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily for 28 days in combination with other antiretroviral agents. Initiate therapy within 72 hours of exposure (HHS [nPEP 2016]).Occupational exposure: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily for 4 weeks with concomitant raltegravir. Initiate therapy as soon as possible after occupational exposure (and within 72 hours) (Kuhar 2013).HIV-1 infection, treatmentHIV-1 infection, treatment: Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily in combination with other antiretroviral agents.HIV-1/hepatitis B co-infection, treatmentHIV-1/hepatitis B co-infection, treatment (off-label use): Oral: One tablet (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once daily in combination with other antiretroviral agents (HHS [adult 2019]).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultHIV-1 infection, treatment:Manufacturer's labeling: CrCl ≥50 mL/minute: No dosage adjustment necessaryCrCl 30 to 49 mL/minute: Increase interval to every 48 hours.CrCl <30 mL/minute: Not recommended.Hemodialysis: Not recommended.Alternate recommendations (IDSA [Lucas 2014]):CrCl <50 mL/minute (and not on hemodialysis) or GFR <60 mL/minute/1.73 m2: Avoid use of tenofovirPrEP:CrCl ≥60 mL/minute: No dosage adjustment necessaryCrCl <60 mL/minute: Not recommended.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Truvada: Emtricitabine 100 mg and tenofovir disoproxil fumarate 150 mg, Emtricitabine 133 mg and tenofovir disoproxil fumarate 200 mg, Emtricitabine 167 mg and tenofovir disoproxil fumarate 250 mg, Emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg [contains fd&c blue #2 (indigo carm) aluminum lake]Generic: Emtricitabine 100 mg and tenofovir disoproxil fumarate 150 mg, Emtricitabine 133 mg and tenofovir disoproxil fumarate 200 mg, Emtricitabine 167 mg and tenofovir disoproxil fumarate 250 mg, Emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Truvada: Emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg [contains fd&c blue #2 (indigo carm) aluminum lake]Generic: Emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mgMedication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021752s061lbl.pdf#page=35, must be dispensed with this medication.Administration: PediatricOral: May be administered without regard to foodAdministration: AdultOral: May be administered with or without food.Storage/StabilityStore tablets at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Dispense only in original container. Once bottle is opened, discard any remaining tablets after 6 weeks (Gilead 2022).UseTreatment of HIV-1 infection in combination with other antiretroviral agents (FDA approved in pediatric patients weighing ≥17 kg and adults); Note: HIV regimens consisting of 3 antiretroviral agents from at least 2 classes are strongly recommended; preexposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in at-risk individuals (FDA approved in adolescents weighing ≥35 kg and adults); has also been used for HIV-1 nonoccupational postexposure prophylaxis (nPEP).Adverse Reactions (Significant): ConsiderationsBone effectsTenofovir disoproxil fumarate (TDF) is associated with a larger decreased bone mineral density (BMD) in HIV-1 infected adults than in those not taking TDF (Ref). The rate of bone loss slows after 1 to 2 years following initiation (Ref). TDF may be associated with in increased risk of bone fracture (Ref). When used as preexposure prophylaxis (PrEP), there is a smaller reduction in BMD (Ref). Mean BMD returns to baseline levels within 12 to18 months after TDF-based PrEP discontinuation in both hip and spine (Ref). TDF is also associated with bone loss (both absolute BMD and reduced Z-score) in children and adolescents (Ref). Adolescents with HIV aged ≥12 years treated with TDF are more likely to experience a >4% decline in lumber spine BMD than those treated with placebo (Ref). Those with sexual maturity ratings (SMR [formerly Tanner staging]) 1 to 2 may be at greater risk (Ref). Bone loss partially recovers after discontinuation in children and adolescents (Ref).Mechanism: Time-related; not clearly established. Tenofovir inhibition of calcium-sensing receptors in the parathyroid (Ref) may increase PTH levels (Ref). It has been proposed that PTH levels accelerate bone remodeling which, combined with persistent HIV-associated demineralization in persons with HIV, results in increased osteoid volume (Ref).Onset: Varied; markers of bone resorption are apparent within 12 weeks after beginning TDF (Ref). Reductions in BMD are observed during the first 1 to 2 years following initiation (Ref).Risk factors (for bone loss and/or fracture):• Treatment duration (Ref)• Females (especially postmenopausal) (Ref)• Transgender (Ref)• White race (Ref)• Prior fracture (and patients at risk for recurrent falls) (Ref)• Prolonged systemic corticosteroid use (Ref)• Medroxyprogesterone use (Ref)• Smoking (Ref)• Early stages of puberty (Ref)• Older age (Ref)• Vitamin D insufficiency/deficiency (Ref)• Low BMI (Ref)• Lack of weight-bearing exercise (Ref)• Cardiovascular disease (Ref)• Longer duration and greater severity of HIV disease (Ref)• CD4+ cell count <350 cells/mm3 (Ref)• Pharmacologic boosters (cobicistat or ritonavir) (Ref)• IV Drug use (Ref)• Lipodystrophy (Ref)• Recent non-AIDS cancer (Ref)Kidney injuryThe tenofovir disoproxil fumarate (TDF) component is associated with multiple renal syndromes. Toxic acute tubular necroses manifest as acute kidney injury, chronic interstitial nephritis as chronic kidney disease, and renal tubulopathies as Fanconi syndrome and rarely nephrogenic diabetes insipidus (Ref).Acute kidney injury (AKI): TDF is associated with AKI, with the majority of cases meeting the risk definition according to the RIFLE classification or AKIN Stage I (Ref). Kidney function improves over months after TDF discontinuation but does not reverse completely in all cases (Ref). It is reported to recur on rechallenge (Ref).Chronic kidney disease (CKD): TDF reduces estimated glomerular filtration rate (eGFR) by ~4 mL/minute compared with non–TDF-containing regimens (Ref) and this may progress to CKD (Ref). A smaller reduction in eGFR occurs when used for preexposure prophylaxis (PrEP) compared with placebo (eg, 1.59 mL/minute in PARTNERS) (Ref). When used for PrEP, eGFR returns to baseline 4 to 8 weeks after discontinuation (Ref) but may not return to baseline in some cases (Ref).Fanconi syndrome (FS): TDF is associated with partial or, more rarely, complete FS (proximal renal tubular acidosis with a normal anion gap metabolic acidosis, hypophosphatemia and osteomalacia with renal phosphate wasting, hypokalemia, hypouricemia, glycosuria with normal blood glucose, and aminoaciduria) (Ref). FS has resulted in fatal cases (Ref). In most patients, proximal tubulopathy resolves within 2 months of TDF discontinuation, but CrCl takes longer to recover and may not return to baseline (Ref). Osteomalacia resolved within 14 weeks of discontinuing TDF in one case report (Ref). FS may present as bone pain as a manifestation of osteomalacia (Ref). FS occurs less frequently when used for PrEP (Ref).Mechanism: Dose- and time-related; inhibition of DNA polymerase gamma results in mitochondrial DNA (mtDNA) depletion, mitochondrial dysfunction, and cell toxicity (Ref). Proximal tubule epithelial cells are particularly susceptible (Ref).Onset:AKI: Varied; mean of 6 months (range, 3 to 16.5 months) (Ref).CKD: Varied; an eGFR decline is seen within 1 month of initiation (Ref). Significant (stage 3 or greater) CKD has occurred at a median of 45 weeks (interquartile range, 11 to 137 weeks) (Ref).FS: Varied; diagnosis ranged from 3.9 months to 11 years in a representative case series (Ref).Risk factors:AKI:• Lower baseline SCr (Ref)• Higher baseline eGFR (Ref)• Concurrent protease inhibitor (Ref)• Concurrent sulfamethoxazole/trimethoprim (Ref)• Concurrent non-steroidal anti-inflammatory drugs (NSAIDs), particularly diclofenac (Ref)• Lower baseline CD4 cell count (Ref)• Higher baseline viral load (Ref)CKD:• Cumulative TDF exposure (Ref)• Higher preexisting risk of CKD (Ref)• Preexisting kidney disease (Ref)• Lower eGFR at initiation (Ref)• Prior AKI (Ref)• Concurrent atazanavir/lopinavir or ritonavir (Ref)• Concurrent NSAIDs, particularly diclofenac (Ref)• Hypertension (Ref)• Older age (Ref)• Hepatitis C coinfection (Ref)• Lower CD4 (Ref)• Higher viral load (Ref)FS:• Longer TDF treatment duration (Ref)• Reduced CrCl before TDF initiation (Ref)• Concurrent cobicistat or ritonavir (Ref)• Previous or concurrent lopinavir/ritonavir (Ref)• Coronary artery disease (Ref)• Diabetes (Ref)• Low body weight (Ref)• Older age (Ref)• Hepatitis C coinfection (Ref)• Hypertension (Ref)• White race (Ref)• Longer HIV duration (Ref)• Lower nadir CD4 counts (Ref)• Prior AIDS diagnosis (Ref)• ABCC2 & ABCC10 polymorphism (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adult monotherapy studies for HIV-1 pre-exposure prophylaxis. Also see individual agents.>10%: Neuromuscular & skeletal: Decreased bone mineral density (13%)Emtricitabine and Tenofovir Disoproxil Fumarate: Adverse Reaction: Decreased Bone Mineral DensityDrug (Emtricitabine and Tenofovir Disoproxil Fumarate)Placebo Comments13%6%≥5% bone mineral density loss at the spine during treatment1% to 10%:Endocrine & metabolic: Abnormal phosphorus levels (<2.0 mg/dL: 10%), weight loss (3%)Gastrointestinal: Abdominal pain (4%)Hematologic & oncologic: Decreased neutrophils (5%)Nervous system: Headache (7%)Neuromuscular & skeletal: Bone fracture (2%) (table 1)Bone FractureEmtricitabine and Tenofovir Disoproxil Fumarate: Adverse Reaction: Bone FractureDrug (Emtricitabine and Tenofovir Disoproxil Fumarate)Placebo 2%1%<1%: Genitourinary: Glycosuria, proteinuriaFrequency not defined: Hepatic: Exacerbation of hepatitis B (following discontinuation)Postmarketing:Immunologic: Immune reconstitution syndromeRenal: Fanconi syndrome (Rao 2021)ContraindicationsAs preexposure prophylaxis in patients with unknown or HIV-1 positive statusCanadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to emtricitabine, tenofovir, or any component of the formulationWarnings/PrecautionsConcerns related to adverse effects:• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) later in therapy; further evaluation and treatment may be required.• Lactic acidosis/hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with use of nucleoside analogues, alone or in combination with other antiretrovirals. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (marked transaminase elevation may/may not accompany hepatomegaly and steatosis).Disease-related concerns:• Comprehensive prevention program: Preexposure prophylaxis (PrEP) should be accompanied by a comprehensive HIV-1 prevention program (eg, risk reduction counseling, access to condoms), with particular emphasis on medication adherence. In addition, regular monitoring (eg, HIV status of patient and partner(s), risk behavior, adherence, adverse effects, sexually transmitted infections that facilitate HIV-1 transmission) is highly recommended. Time from initiation of therapy to maximal protection against HIV-1 is unknown.• Renal impairment: Use with caution in patients with renal impairment; see "Dosing in Altered Kidney Function" for additional information.Concurrent drug therapy issues:• Duplicate therapy: Do not use concurrently with emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, or any combination of these drugs.Warnings: Additional Pediatric ConsiderationsEmtricitabine-associated hyperpigmentation may occur at a higher frequency in pediatric patients compared to adults (children: 32%; adults: 2% to 6%).Tenofovir disoproxil fumarate (TDF) disrupts vitamin D metabolism and has been associated with decreased bone mineral density (BMD) in adults and children. Plasma concentrations of the TDF metabolite tenofovir (TFV) have been associated with endocrine disruption and low BMD; tenofovir alafenamide (TAF) is associated with lower plasma TFV concentrations and less decline in BMD than TDF. Data suggest the impact may be greater in children who are less mature (eg, sexual maturity ratings [SMRs] 1 to 2 [previously Tanner stages]) than in those with more advanced pubertal development (SMR ≥3). The potential for BMD loss during the important period of rapid bone accrual in childhood and early adolescence is concerning and favors use of abacavir or TAF in children with SMRs 1 to 3 (children with perinatally acquired HIV are already at risk for low peak bone mass). Prior to initiation of therapy, assessment of benefits versus potential risks should be assessed; with TDF therapy, monitor plasma vitamin D concentrations; supplement with vitamin D as needed; calcium carbonate supplementation may also be considered. Monitoring of BMD may be considered in patients with additional risk factors for decreased bone density (HHS [pediatric] 2022).Metabolism/Transport EffectsRefer to individual components.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAcyclovir-Valacyclovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir. Risk C: Monitor therapyAdefovir: May diminish the therapeutic effect of Tenofovir Products. Adefovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Adefovir. Risk X: Avoid combinationAminoglycosides: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Aminoglycosides. Risk C: Monitor therapyAminosalicylic Acid: May decrease the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapyAtazanavir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Tenofovir Disoproxil Fumarate.Management: Use boosted atazanavir in adults; give combo (atazanavir/ritonavir or atazanavir/cobicistat with tenofovir) as a single daily dose with food. Pediatric patients, pregnant patients, and use of H2-blockers require dose changes. See Lexi Interact monograph. Risk D: Consider therapy modificationBetibeglogene Autotemcel: Antiretroviral Agents may diminish the therapeutic effect of Betibeglogene Autotemcel.Risk X: Avoid combinationCabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib.Risk C: Monitor therapyCidofovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Cidofovir. Risk C: Monitor therapyCladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine.Risk X: Avoid combinationCobicistat: Tenofovir Disoproxil Fumarate may enhance the adverse/toxic effect of Cobicistat. More specifically, cobicistat may impair proper tenofovir disoproxil fumarate monitoring and dosing.Risk C: Monitor therapyDarolutamide: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyDarunavir: Tenofovir Disoproxil Fumarate may increase the serum concentration of Darunavir. Darunavir may increase the serum concentration of Tenofovir Disoproxil Fumarate.Risk C: Monitor therapyDidanosine: Tenofovir Disoproxil Fumarate may diminish the therapeutic effect of Didanosine. Tenofovir Disoproxil Fumarate may increase the serum concentration of Didanosine.Management: Avoid use of tenofovir disoproxil fumarate and didanosine when possible. If combined in adults with CrCL greater than 60 mL/min, decrease didanosine to 250 mg daily if 60 kg or more or to 200 mg if less than 60 kg. Avoid if CrCL is less than 60 mL/min. Risk D: Consider therapy modificationElivaldogene Autotemcel: Antiretroviral Agents may diminish the therapeutic effect of Elivaldogene Autotemcel.Management: Avoid use of antiretroviral medications for at least one month, or for the amount of time required for elimination of the retroviral medication, prior to stem cell mobilization and until the all apheresis cycles are finished Risk X: Avoid combinationEltrombopag: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyEncorafenib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyFutibatinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyGanciclovir-Valganciclovir: Tenofovir Products may increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Tenofovir Products.Risk C: Monitor therapyGilteritinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyLedipasvir: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Avoid this combination if TDF is used as part of the elvitegravir/cobicistat/emtricitabine/TDF product. Consider alternatives when TDF is used with a ritonavir or cobicistat boosted protease inhibitor. Monitor for increased TDF toxicities if combined. Risk D: Consider therapy modificationLeflunomide: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyLopinavir: May enhance the nephrotoxic effect of Tenofovir Disoproxil Fumarate. Lopinavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapyLumacaftor and Ivacaftor: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose due to a potential risk of acute renal failure. Diclofenac appears to confer the most risk. Risk D: Consider therapy modificationNonsteroidal Anti-Inflammatory Agents (Topical): May enhance the nephrotoxic effect of Tenofovir Products. Risk C: Monitor therapyOrlistat: May decrease the serum concentration of Antiretroviral Agents. Risk C: Monitor therapyOsimertinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyOteseconazole: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyPacritinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combinationP-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapyRegorafenib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyRolapitant: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Management: Monitor patients receiving rolapitant for increased exposure to and/or effects of BCRP/ABCG2 substrates.Use the lowest effective rosuvastatin dose when used in combination with rolapitant. Risk C: Monitor therapyTafamidis: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyTaurursodiol: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combinationTedizolid: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyTeriflunomide: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyTipranavir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Tenofovir Disoproxil Fumarate.Risk C: Monitor therapyVoxilaprevir: Tenofovir Disoproxil Fumarate may increase the serum concentration of Voxilaprevir. Voxilaprevir may increase the serum concentration of Tenofovir Disoproxil Fumarate.Risk C: Monitor therapyFood InteractionsSee individual agents.Dietary ConsiderationsConsider calcium and vitamin D supplementation in patients with history of bone fracture or osteopenia.Reproductive ConsiderationsThe Health and Human Services (HHS) perinatal HIV guidelines consider this a preferred combination for patients with HIV infection who are not yet pregnant but are trying to conceive.This combination is recommended for pre-exposure prophylaxis (PrEP) in patients at risk for HIV infection who are planning a pregnancy. The partner without HIV should begin therapy 20 days prior to attempting conception. Up to 20 days of therapy are required to achieve protective drug concentrations in cervicovagin*l tissue, therefore continued use of condoms to prevent HIV exposure is recommended during this time. PrEP should continue for 28 days after attempting conception or condomless sex exposure. Episodic or on demand dosing is not effective for prevention of HIV via vagin*l exposure (HHS [perinatal] 2021).Refer to individual monographs for additional information.Pregnancy ConsiderationsThe Health and Human Services (HHS) perinatal HIV guidelines consider emtricitabine with tenofovir disoproxil fumarate to be a preferred nucleoside reverse transcriptase inhibitor backbone for initial therapy in antiretroviral-naive pregnant patients. In addition, this combination is preferred for use in pregnant patients with HIV infection who have had antiretroviral therapy (ART) in the past but are restarting, or who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen). Patients who become pregnant while taking this combination may continue if viral suppression is effective and the regimen is well tolerated.This combination is recommended for pre-exposure prophylaxis (PrEP) in uninfected patients at risk for HIV infection who are pregnant; if started prior to conception, it may be continued during pregnancy. Emtricitabine and tenofovir disoproxil fumarate are recommended as part of a preferred regimen when acute HIV infection is detected during pregnancy.The HHS perinatal guidelines also recommend emtricitabine plus tenofovir disoproxil fumarate as a component of regimens for HIV/hepatitis B virus–coinfected patients who are pregnant (HHS [perinatal] 2021).Refer to individual monographs for additional information.Monitoring ParametersHIV: Preexposure prophylaxis (PrEP): General recommendations: Refer to current guidelines for complete monitoring recommendations for patients receiving PrEP. Assessment should include risk behaviors and HIV testing (prior to initiation, every 3 months, if recent exposures are suspected, upon diagnosis of other sexually transmitted infections, and if clinical symptoms consistent with acute HIV infection are present). Monitor CrCl every 12 months, or more frequently in some patients as clinically appropriate.HIV: Treatment: General recommendations: Management of HIV infection requires extensive monitoring; refer to current guidelines (https://clinicalinfo.hiv.gov/en/guidelines) for additional guidance. Antiretroviral (ARV) drug-resistance testing is recommended before initiation of therapy in treatment-naive patients. After initiation of or change in ARV therapy regimen, pediatric patients should be evaluated for clinical adverse effects and treatment adherence at 1 to 2 weeks, and laboratory testing for drug toxicity should occur at 2 to 4 weeks; monitor for therapy adherence, effectiveness, and toxicities every 3 to 4 months.Drug-specific monitoring: Frequency may vary based on several factors including age, concomitant therapy, and clinical response; refer to current guidelines for additional information.Screen for hepatitis B prior to starting therapy (in patients who previously demonstrated no immunity to hepatitis B). For patients with hepatitis B coinfection, monitor hepatic function and hepatitis B viral load for several months after therapy with tenofovir is stopped. Serum electrolytes (including anion gap), 25-OH-vitamin D levels, serum phosphate, SCr, lipid profiles, urine protein and glucose and/or urinalysis, serum lactate (if clinical presentation indicates need).Urine albumin to protein ratio may be helpful in identifying the nonalbumin proteinuria seen in tenofovir disoproxil fumarate-associated nephrotoxicity. Consider obtaining a dual-energy x-ray absorptiometry scan in patients with additional risk factors for decreased bone density (eg, cerebral palsy, additional medications) (HHS [pediatric] 2022).HIV-1 preexposure prophylaxis (PrEP): Pregnancy test for women receiving PrEP (every 3 months); documented negative HIV test (immediately prior to use, every 3 months, and following discontinuation of PrEP); assess risk behaviors and symptoms of sexually transmitted infections (STIs) or acute HIV-1 infection and provide condoms (immediately prior to use, then every 3 months during therapy); BUN and serum creatinine (prior to initiation, 3 months after initiation, then every 6 months); testing for HBV (prior to initiation) and STIs (prior to initiation, then at least every 6 months, even if asymptomatic) (CDC 2018)Mechanism of ActionNucleoside and nucleotide reverse transcriptase inhibitor combination; emtricitabine is a cytidine analogue while tenofovir is an analog of adenosine 5'-monophosphate. Each drug interferes with HIV viral RNA dependent DNA polymerase resulting in inhibition of viral replication.Pharmaco*kinetics (Adult data unless noted)Refer to individual monographs.Additional InformationEmtricitabine is the (-) enantiomer of 2', 3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), a fluorinated derivative of lamivudine.Mutation in the HIV reverse transcriptase gene at codon 184, M184V/I (ie, substitution of methionine by valine or isoleucine) is associated with resistance to emtricitabine. Emtricitabine-resistant isolates (M184V/I) are cross-resistant to lamivudine and zalcitabine. HIV-1 isolates containing the K65R mutation show reduced susceptibility to emtricitabine.Pricing: USTablets (Emtricitabine-Tenofovir DF Oral)100-150 mg (per each): $70.01133-200 mg (per each): $70.01167-250 mg (per each): $70.01200-300 mg (per each): $2.34 - $70.01Tablets (Truvada Oral)100-150 mg (per each): $73.69133-200 mg (per each): $73.69167-250 mg (per each): $73.69200-300 mg (per each): $73.69Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAgifovir-E (VN);Emtifovir (BD);Emzavir (LB);Fovirem (CO);Recovir-Em (TH);Teno-Em (TH);Tenof-Em (TH);Tenofence Plus (EG);Tenvir EM (UY);Tenvir-EM (IN);Tenvor-Em (LB);Tolak E (CO);Truvada (AE, AR, AT, AU, BB, BE, BG, CH, CL, CN, CR, CY, CZ, DE, DK, DO, EE, EG, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, IE, IL, IS, IT, JO, JP, KR, LB, LT, LU, LV, MT, MX, NI, NL, NO, NZ, PA, PL, PT, RO, RU, SE, SG, SI, SK, SV, TH, TR, TW)For country code abbreviations (show table)Ascher SB, Scherzer R, Estrella MM, et al. HIV preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and changes in kidney function and tubular health. AIDS. 2020;34(5):699-706. doi:10.1097/QAD.0000000000002456 [PubMed 31794523]Atencio P, Conesa-Buendía FM, Cabello-Ubeda A, et al. Bone deleterious effects of different NRTIs in treatment-naïve HIV patients after 12 and 48 weeks of treatment. Curr HIV Res. 2021;19(5):434-447. doi:10.2174/1570162X19666210805094434 [PubMed 34353266]Aurpibul L, Cressey TR, Sricharoenchai S, et al. Efficacy, safety and pharmaco*kinetics of tenofovir disoproxil fumarate in virologic-suppressed HIV-infected children using weight-band dosing. Pediatr Infect Dis J. 2015;34(4):392-397. doi:10.1097/INF.0000000000000633 [PubMed 25760566]Baeten JM, Donnell D, Ndase P, et al. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med. 2012;367(5):399-410. [PubMed 22784037]Baranek B, Wang S, Cheung AM, Mishra S, Tan DH. The effect of tenofovir disoproxil fumarate on bone mineral density: a systematic review and meta-analysis. Antivir Ther. 2020;25(1):21-32. doi:10.3851/IMP3346 [PubMed 32077867]Bickel M, Khaykin P, Stephan C, et al. Acute kidney injury caused by tenofovir disoproxil fumarate and diclofenac co-administration. HIV Med. 2013;14(10):633-638. doi:10.1111/hiv.12072 [PubMed 23980564]Borges ÁH, Hoy J, Florence E, et al. Antiretrovirals, fractures, and osteonecrosis in a large international HIV cohort. Clin Infect Dis. 2017;64(10):1413-1421. doi:10.1093/cid/cix167 [PubMed 28329090]Cahn P, Madero JS, Arribas JR, et al. Durable efficacy of dolutegravir plus lamivudine in antiretroviral treatment-naive adults with HIV-1 infection: 96-week results from the GEMINI-1 and GEMINI-2 randomized clinical trials. J Acquir Immune Defic Syndr. 2020;83(3):310-318. doi:10.1097/QAI.0000000000002275 [PubMed 31834000]Carr A, Grund B, Schwartz AV, et al. The rate of bone loss slows after 1-2 years of initial antiretroviral therapy: final results of the Strategic Timing of Antiretroviral Therapy (START) bone mineral density substudy. HIV Med. 2020;21(1):64-70. doi:10.1111/hiv.12796 [PubMed 31642586]Centers for Disease Control and Prevention (CDC), US Department of Health and Human Services (HHS). Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV—United States, 2016. https://stacks.cdc.gov/view/cdc/38856. Published April 18, 2016. Accessed July 11, 2016.Centers for Disease Control and Prevention (CDC), US Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States—2017 Update: a clinical practice guideline. https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf. Published March 2, 2018. Accessed June 4, 2018.Centers for Disease Control and Prevention (CDC), US Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States—2021 update: a clinical practice guideline. https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf. Published December 2021. Accessed June 14, 2022.Cheli S, Baldelli S, De Silvestri A, et al. ABCC4 single-nucleotide polymorphisms as markers of tenofovir disoproxil fumarate-induced kidney impairment. Pharmacogenomics J. 2021;21(5):586-593. doi:10.1038/s41397-021-00235-7 [PubMed 33850298]Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis. 2010;51(5):496-505. doi:10.1086/655681 [PubMed 20673002]Della Negra M, de Carvalho AP, de Aquino MZ, et al. A randomized study of tenofovir disoproxil fumarate in treatment-experienced HIV-1 infected adolescents. Pediatr Infect Dis J. 2012;31(5):469-473. doi:10.1097/INF.0b013e31824bf239 [PubMed 22301477]Flandre P, Pugliese P, Cuzin L, et al. Risk factors of chronic kidney disease in HIV-infected patients. Clin J Am Soc Nephrol. 2011;6(7):1700-1707. doi:10.2215/CJN.09191010 [PubMed 21566114]Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292(2):191-201. doi:10.1001/jama.292.2.191 [PubMed 15249568]Gilead medical information. Truvada storage and stability. https://www.askgileadmedical.com/docs/truvada-prep/truvada-storage-and-stability. Published April 2022. Accessed November 8, 2022.Glidden DV, Mulligan K, McMahan V, et al. Brief report: recovery of bone mineral density after discontinuation of tenofovir-based HIV pre-exposure prophylaxis. J Acquir Immune Defic Syndr. 2017;76(2):177-182. doi:10.1097/QAI.0000000000001475 [PubMed 28639995]Grant RM, Lama JR, Anderson PL, et a. Pre-exposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex With Men. N Engl J Med. 2010;363(27):2587-2599. [PubMed 21091279]Gupta SK, Anderson AM, Ebrahimi R, et al. Fanconi syndrome accompanied by renal function decline with tenofovir disoproxil fumarate: a prospective, case-control study of predictors and resolution in HIV-infected patients. PLoS One. 2014;9(3):e92717. doi:10.1371/journal.pone.0092717 [PubMed 24651857]Gupta SK. Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. AIDS Patient Care STDS. 2008;22(2):99-103. doi:10.1089/apc.2007.0052 [PubMed 18260800]Hamzah L, Jose S, Booth JW, et al. Treatment-limiting renal tubulopathy in patients treated with tenofovir disoproxil fumarate. J Infect. 2017;74(5):492-500. doi:10.1016/j.jinf.2017.01.010 [PubMed 28130143]Han WM, Wattanachanya L, Ap*rnpong T, et al. Bone mineral density changes among people living with HIV who have started with TDF-containing regimen: a five-year prospective study. PLoS One. 2020;15(3):e0230368. doi:10.1371/journal.pone.0230368 [PubMed 32210458]Havens PL, Perumean-Chaney SE, Patki A, et al. Changes in bone mass after discontinuation of preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine in young men who have sex with men: extension phase results of adolescent trials network protocols 110 and 113. Clin Infect Dis. 2020;70(4):687-691. doi:10.1093/cid/ciz486 [PubMed 31179503]Hazra R, Gafni RI, Maldarelli F, et al. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection. Pediatrics. 2005;116(6):e846-e854. [PubMed 16291735]Herlitz LC, Mohan S, Stokes MB, Radhakrishnan J, D'Agati VD, Markowitz GS. Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities. Kidney Int. 2010;78(11):1171-1177. doi:10.1038/ki.2010.318 [PubMed 20811330]Hsu R, Brunet L, Fusco J, et al. Risk of chronic kidney disease in people living with HIV by tenofovir disoproxil fumarate (TDF) use and baseline D:A:D chronic kidney disease risk score. HIV Med. 2021;22(5):325-333. doi:10.1111/hiv.13019 [PubMed 33247876]Izzedine H, Hulot JS, Villard E, et al. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis. 2006;194(11):1481-1491. doi:10.1086/508546 [PubMed 17083032]Jose S, Hamzah L, Campbell LJ, et al. Incomplete reversibility of estimated glomerular filtration rate decline following tenofovir disoproxil fumarate exposure. J Infect Dis. 2014;210(3):363-373. doi:10.1093/infdis/jiu107 [PubMed 24585896]Kalayjian RC, Lau B, Mechekano RN, et al. Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care. AIDS. 2012;26(15):1907-1915. doi:10.1097/QAD.0b013e328357f5ed [PubMed 22824630]Kuhar DT, Henderson DK, Struble KA, et al. Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis. Infect Control Hosp Epidemiol. 2013;34(9):875-892. [PubMed 23917901]Linn BS, Vandiver JW, Ren D, Shassetz J. Fanconi syndrome induced by concomitant HIV PrEP and tacrolimus. J Investig Med High Impact Case Rep. 2021;9:23247096211050207. doi:10.1177/23247096211050207 [PubMed 34608820]Lucas GM, Ross MJ, Stock PG, et al. Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(9): e96-e138. [PubMed 25234519]McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203(12):1791-1801. doi:10.1093/infdis/jir188 [PubMed 21606537]Medland NA, Chow EP, Walker RG, Chen M, Read TR, Fairley CK. Incidence of renal Fanconi syndrome in patients taking antiretroviral therapy including tenofovir disoproxil fumarate. Int J STD AIDS. 2018;29(3):227-236. doi:10.1177/0956462417722133 [PubMed 28764611]Microbicide Trials Network (MTN). MTN Statement on Decision to Discontinue Use of Oral Tenofovir Tablets in VOICE, a Major HIV Prevention Study in Women. Microbicide Trials Network. 2011. http://www.mtnstopshiv.org/node/3619.Mingione A, Maruca K, Chiappori F, et al. High parathyroid hormone concentration in tenofovir-treated patients are due to inhibition of calcium-sensing receptor activity. Biomed Pharmacother. 2018;97:969-974. doi:10.1016/j.biopha.2017.11.037 [PubMed 29136775]Mirembe BG, Kelly CW, Mgodi N, et al. Bone mineral density changes among young, healthy African women receiving oral tenofovir for HIV preexposure prophylaxis. J Acquir Immune Defic Syndr. 2016;71(3):287-294. doi:10.1097/QAI.0000000000000858 [PubMed 26866954]Mocroft A, Kirk O, Reiss P, et al. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS. 2010;24(11):1667-1678. doi:10.1097/QAD.0b013e328339fe53 [PubMed 20523203]Molina JM, Capitant C, Spire B, et al; ANRS IPERGAY Study Group. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015;373(23):2237-2246. doi:10.1056/NEJMoa1506273 [PubMed 26624850]Mugwanya KK, Wyatt C, Celum C, et al. Changes in glomerular kidney function among HIV-1-uninfected men and women receiving emtricitabine-tenofovir disoproxil fumarate preexposure prophylaxis: a randomized clinical trial. JAMA Intern Med. 2015;175(2):246-254. doi:10.1001/jamainternmed.2014.6786 [PubMed 25531343]Mugwanya KK, Wyatt C, Celum C, et al. Reversibility of glomerular renal function decline in HIV-uninfected men and women discontinuing emtricitabine-tenofovir disoproxil fumarate pre-exposure prophylaxis. J Acquir Immune Defic Syndr. 2016;71(4):374-380. doi:10.1097/QAI.0000000000000868 [PubMed 26914909]Ozcan SN, Sevgi DY, Oncul A, et al. The prevalence and associated factors of reduced bone mineral density (BMD) among men with suppressed viral load taking antiretroviral therapy. Curr HIV Res. 2022;20(1):74-81. doi:10.2174/1570162X19666211202100308 [PubMed 34856908]Patel KK, Patel AK, Ranjan RR, Patel AR, Patel JK. Tenofovir-associated renal dysfunction in clinical practice: an observational cohort from western India. Indian J Sex Transm Dis AIDS. 2010;31(1):30-34. doi:10.4103/0253-7184.68998 [PubMed 21808434]Perazella MA. Tenofovir-induced kidney disease: an acquired renal tubular mitochondriopathy. Kidney Int. 2010;78(11):1060-1063. doi:10.1038/ki.2010.344 [PubMed 21076445]Purdy JB, Gafni RI, Reynolds JC, Zeichner S, Hazra R. Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr. 2008;152(4):582-584. [PubMed 18346519]Ramalho J, Martins CSW, Galvão J, et al. Treatment of human immunodeficiency virus infection with tenofovir disoproxil fumarate-containing antiretrovirals maintains low bone formation rate, but increases osteoid volume on bone histomorphometry. J Bone Miner Res. 2019;34(9):1574-1584. doi:10.1002/jbmr.3751 [PubMed 31269294]Rao M, Dadey L, Glowa T, Veldkamp P. Fanconi syndrome leading to hypophosphatemic osteomalacia related to tenofovir use. Infect Dis Rep. 2021;13(2):448-453. doi:10.3390/idr13020044 [PubMed 34073672]Rokx C, Alshangi H, Verbon A, Zietse R, Hoorn EJ, Rijnders BJ. Renal toxicity of concomitant exposure to tenofovir and inhibitors of tenofovir's renal efflux transporters in patients infected with HIV type 1. J Infect Dis. 2016;213(4):561-568. doi:10.1093/infdis/jiv466 [PubMed 26401025]Rukuni R, Rehman AM, Mukwasi-Kahari C, et al. Effect of HIV infection on growth and bone density in peripubertal children in the era of antiretroviral therapy: a cross-sectional study in Zimbabwe. Lancet Child Adolesc Health. 2021;5(8):569-581. doi:10.1016/S2352-4642(21)00133-4 [PubMed 34139202]Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the International Antiviral Society-USA Panel. JAMA. 2020;324(16):1651-1669. doi:10.1001/jama.2020.17025 [PubMed 33052386]Sahoo RR, Wakhlu A. Clinical images: tenofovir-induced Fanconi syndrome: an uncommon cause of hypophosphatemic osteomalacia. ACR Open Rheumatol. 2022;10.1002/acr2.11415. doi:10.1002/acr2.11415 [PubMed 35132821]Scherzer R, Estrella M, Li Y, et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012;26(7):867-875. doi:10.1097/QAD.0b013e328351f68f [PubMed 22313955]Stray KM, Bam RA, Birkus G, et al. Evaluation of the effect of cobicistat on the in vitro renal transport and cytotoxicity potential of tenofovir. Antimicrob Agents Chemother. 2013;57(10):4982-4989. doi:10.1128/AAC.00712-13 [PubMed 23896476]Suppadungsuk S, Janepiriyaprayoon P, Sungkanuparph S. Recovery of renal function after early versus late switching of tenofovir disoproxil fumarate in people living with HIV with renal insufficiency. Int J STD AIDS. 2022;33(4):391-396. doi:10.1177/09564624221076632 [PubMed 35143730]Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana. N Engl J Med. 2012;367(5):423-434. [PubMed 22784038]Truvada (emtricitabine/tenofovir disoproxil fumarate) [prescribing information]. Foster City, CA: Gilead Sciences; June 2020.Truvada (emtricitabine/tenofovir) [product monograph]. Mississauga, Ontario, Canada: Gilead Sciences Canada Inc; July 2018.US Department of Health and Human Services (HHS). Updated Guidelines for Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV - United States, 2016. https://stacks.cdc.gov/view/cdc/38856US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. HIV.gov. Updated January 20, 2022. Accessed May 9, 2022. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-new-guidelinesUS Department of Health and Human Services (HHS) Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the use of antiretroviral agents in pediatric HIV infection. HIV.gov. Updated April 11, 2022. Accessed May 9, 2022. https://clinicalinfo.hiv.gov/en/guidelines/pediatric-arv/whats-new-guidelinesUS Department of Health and Human Services (HHS) Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission. Recommendations for the use of antiretroviral drugs during pregnancy and interventions to reduce perinatal HIV transmission in the United States. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/Perinatal_GL.pdf. Updated December 30, 2021. Accessed January 3, 2022.Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411-422. [PubMed 22784040]Wever K, van Agtmael MA, Carr A. Incomplete reversibility of tenofovir-related renal toxicity in HIV-infected men. J Acquir Immune Defic Syndr. 2010;55(1):78-81. doi:10.1097/QAI.0b013e3181d05579 [PubMed 20173649]Wikman P, Safont P, Del Palacio M, Moreno A, Moreno S, Casado JL. The significance of antiretroviral-associated acute kidney injury in a cohort of ambulatory human immunodeficiency virus-infected patients. Nephrol Dial Transplant. 2013;28(8):2073-2081. doi:10.1093/ndt/gft210 [PubMed 23739150]Zaidan M, Lescure FX, Brochériou I, et al. Tubulointerstitial nephropathies in HIV-infected patients over the past 15 years: a clinico-pathological study. Clin J Am Soc Nephrol. 2013;8(6):930-938. doi:10.2215/CJN.10051012 [PubMed 23430209]Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis. 2006;42(2):283-290. doi:10.1086/499048 [PubMed 16355343]Topic 13013 Version 375.0

CloseLithium: Drug informationLithium: Drug information(For additional information see "Lithium: Patient drug information" and see "Lithium: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningMonitoring:Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to therapeutic levels. Facilities for prompt and accurate serum lithium determinations should be available before initiating therapy.Brand Names: USLithobidBrand Names: CanadaAPO-Lithium Carbonate;Carbolith;DOM-Lithium Carbonate;Lithane;Lithmax;PMS-Lithium CarbonatePharmacologic CategoryAntimanic AgentDosing: AdultNote: Lithium oral solution has been discontinued in the United States for >1 year.Note: Safety: Only prescribe in settings where serum concentration monitoring is available. Toxic effects occur with serum concentrations ≥1.5 mEq/L and may be seen in some patients with serum concentrations as low as 1.2 mEq/L (Janicak 2021). Formulations: Available formulations include oral IR tablets and capsules as carbonate salt (initially dosed 2 to 3 times daily), ER carbonate tablets (initially dosed 2 times daily), and oral solution as citrate salt (initially dosed 2 to 3 times daily); if initial dose is ≤300 mg/day, may initiate as once daily regardless of formulation (Gitlin 2021). Lithium citrate 5 mL (8 mEq) oral solution is equivalent to carbonate 300 mg tablets/capsules. Lithium oral solution has been discontinued in the United States for >1 year. All doses in this monograph are expressed as the equivalent amounts of lithium carbonate salt. To convert between formulations, see Dosing Conversion below. Conversion to once-daily dosing: To improve tolerability, initiate total daily doses >300 mg/day with 2 or 3 divided daily doses. After several weeks at an established dose and stable serum concentrations, may consolidate schedule to a single dose of immediate release or extended release at bedtime (Carter 2013).Bipolar disorderBipolar disorder (monotherapy or combination therapy):Acute mania, acute episodes with mixed features (labeled use), acute hypomania (off-label use), or acute bipolar major depression (alternative agent) (off-label use): For most patients, a therapeutic response occurs with serum concentrations between 0.8 and 1.2 mEq/L; some respond to lower levels (eg, 0.6 mEq/L). For treatment of acute severe mania, typically given in combination with an antipsychotic or antiseizure drug (CANMAT/ISBD [Yatham 2018]; Janicak 2021; Stovall 2020).Oral: Immediate release or extended release: Initial: 600 to 900 mg/day in 2 to 3 divided doses based on chosen formulation; increase based on response and tolerability by 300 to 600 mg every 1 to 5 days to usual therapeutic dose range of 900 mg/day to 1.8 g/day in 1 to 3 divided doses based on tolerability or chosen formulation. After 5 to 7 days at a stable therapeutic dose, further adjust as needed based on clinical response, tolerability, and serum concentration (Calabrese 2005; Janicak 2021; manufacturer's labeling). Also see “Note: Formulations” and “Note: Conversion to Once-Daily Dosing” above.Maintenance treatment to prevent manic or depressed episodes: Note: Continue regimen (ie, monotherapy or combination) that was used to achieve control of the acute episode; a lower dose and serum concentration at the lower end of the therapeutic range may suffice for some patients. (CANMAT/ISBD [Yatham 2018]).Major depressive disorder, unipolarMajor depressive disorder, unipolar (alternative agent; adjunctive therapy) (off-label use): For most patients, a therapeutic response occurs with serum concentrations between 0.6 and 1.2 mEq/L; some respond to lower serum concentrations (Gitlin 2021; Nierenberg 2006). Peak clinical improvement may take up to 6 weeks when lithium is used for antidepressant augmentation for acute depression (APA 2010; Stein 1993).Oral: Immediate release or extended release: Initial: 300 to 600 mg/day in 1 to 2 divided doses; may increase based on response and tolerability every 1 to 5 days to a target dose of 600 mg to 1.2 g/day in 1 to 3 divided doses based on tolerability or chosen formulation (Bauer 2003; Gitlin 2021). Also see “Note: Formulations” and “Note: Conversion to Once-Daily Dosing” above.Dosing conversion: To convert between IR and ER capsules/tablets, administer the same total daily dose. Initially administer IR daily dose in 2 to 3 divided doses and ER daily dose in 2 divided doses. If initial dose is ≤300 mg/day, may initiate as once daily regardless of formulation (Gitlin 2021). After several weeks at an established dose, may consolidate schedule to a single dose of immediate release or extended release at bedtime (Carter 2013; Janicak 2021). When taken as a single dose per day, serum trough concentrations are 10% to 26% higher compared to serum trough concentrations with divided doses, due to changes in renal excretion (Mitchell 2001; Singh 2011). Individual dosage adjustments may be necessary.Discontinuation of therapy: Gradual dose reduction is advised to avoid disease recurrence unless discontinuation is due to significant adverse effects. If it is necessary to switch to a different drug during acute treatment, decrease the lithium dose over 1 to 2 weeks (eg, by 300 mg each day or every other day) (Kupka 2021; Stovall 2021). In order to detect disease recurrence when discontinuing maintenance treatment for bipolar disorder, decrease lithium over several weeks to months when feasible (Post 2021).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MSNote: Lithium is primarily excreted via the kidneys and clearance correlates directly with glomerular filtration rate (Clericetti 1991; Kamper 1989). Because of the risk of lithium-related nephrotoxicity, routine monitoring of serum lithium levels and kidney function are recommended in patients with reduced kidney function (Rej 2015).Altered kidney function: Oral: CrCl ≥60 mL/minute: No dosage adjustment necessary (expert opinion).CrCl 30 to <60 mL/minute: Initiate at low doses (eg, 150 to 300 mg/day) in 1 to 2 divided doses, titrate slowly based on clinical response and tolerability, monitor levels frequently (expert opinion).CrCl <30 mL/minute: Avoid use (manufacturer's labeling; expert opinion).Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Bilbao-Meseguer 2018; Udy 2010).Oral: No data available. Consider dose adjustments based on serum lithium levels (expert opinion).Hemodialysis, intermittent (thrice weekly): Dialyzable (80%) (Engels 2019); lithium levels drawn immediately post hemodialysis may be inaccurate/falsely low as equilibration of lithium from tissue compartments into the blood stream occurs (also known as "rebound"):Oral: Avoid use when possible. Consider use of an alternative therapy, especially in patients with significant residual kidney function due to risk of lithium-induced kidney damage. If necessary, initiate therapy at 300 mg 3 times weekly after dialysis; gradually titrate based on clinical response, tolerability, and serum lithium levels (Engels 2019; McGrane 2021; expert opinion). In some patients, daily dosing may be required to achieve targeted lithium serum levels (Engels 2019; McGrane 2021).Peritoneal dialysis: Dialyzable (less than hemodialysis) (Brown 1981; Wilson 1971):Oral: Avoid use when possible. Consider use of an alternative therapy, especially in patients with significant residual kidney function due to risk of lithium-induced kidney damage. If necessary, start at low dose (eg, 150 mg daily); gradually titrate based on clinical response, tolerability, and serum lithium levels (expert opinion).CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) and minimal residual kidney function unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.Oral: Avoid use (expert opinion).PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.Oral: Avoid use (expert opinion).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling.Dosing: Pediatric(For additional information see "Lithium: Pediatric drug information")Note: Lithium oral solution has been discontinued in the United States for >1 year. Monitor serum concentrations and clinical response (efficacy and toxicity) to determine proper dose. Each 5 mL of lithium oral solution contains 8 mEq of lithium ion, equivalent to the amount of lithium in 300 mg of lithium carbonate immediate-release capsules/tablets.Bipolar disorderBipolar disorder: Oral:Immediate release: Children ≥7 years and Adolescents: Limited data available in weight <20 kg: Note: Dosing in weight <20 kg extrapolated from clinical experience (Gal 2007).Lithium carbonate capsule or tablet:Patient weight <30 kg: Initial: 300 mg twice daily, increase dose at weekly intervals in 300 mg/day increments as tolerated to clinical response and goals based on type of therapy (acute or maintenance).Acute therapy: Titrate dose to 600 to 1,500 mg/day in divided doses and target serum lithium concentration of 0.8 to 1.2 mEq/L; a maximum dose is not described in the manufacturer labeling; in trials, weight-dependent maximum daily doses were reported: Patients <23 kg: 900 mg/day; patients ≥23 kg: 40 mg/kg/day and doses were not further increased if serum lithium concentration was ≥1.4 mEq/L. In a multicenter, double-blind, placebo-controlled efficacy trial for treatment of acute mania, the mean effective daily dose was 956 ± 225 mg/day. For all patients in the trial (regardless of weight) the mean final dose was: 30.5 ± 8.7 mg/kg/day (Findling 2011; Findling 2013; Findling 2015).Maintenance therapy: Titrate dose to 600 to 1,200 mg/day in divided doses and target serum trough concentration of 0.8 to 1 mEq/L as tolerated.Patient weight ≥30 kg: Initial: 300 mg 3 times daily, increase dose in 300 mg/day increments every 3 days as tolerated to clinical response and goals based on type of therapy (acute or maintenance).Acute therapy: Titrate dose to 600 mg twice or 3 times daily and target serum lithium concentration of 0.8 to 1.2 mEq/L; a maximum dose is not described in the manufacturer labeling; in trials, reported doses did not exceed a maximum daily dose of 40 mg/kg/day and doses were not further increased if serum lithium concentration was ≥1.4 mEq/L. In a multicenter, double-blind, placebo-controlled efficacy trial for treatment of acute mania, the mean effective daily dose was 1,583 ± 524 mg/day. For all patients in the trial (regardless of weight) the mean final dose was 30.5 ± 8.7 mg/kg/day (Findling 2011; Findling 2013; Findling 2015).Maintenance therapy: Titrate dose to 300 to 600 mg twice or 3 times daily and target serum trough concentration of 0.8 to 1 mEq/L as tolerated; in a long-term trial, doses were not further increased if serum lithium concentration was ≥1.4 mEq/L (Findling 2013).Lithium oral solution:Patient weight <30 kg: Initial: 8 mEq twice daily, increase dose at weekly intervals in 8 mEq increments as tolerated to clinical response and goals based on type of therapy (acute or maintenance).Acute therapy: Titrate dose to 16 to 40 mEq/day in divided doses and target serum lithium concentration of 0.8 to 1.2 mEq/L; a maximum dose is not described in the manufacturer labeling; in trials, weight-dependent maximum daily doses were reported: Patients <23 kg: 900 mg of lithium carbonate/day; patients ≥23 kg: 40 mg of lithium carbonate/kg/day and doses were not further increased if serum lithium concentration was ≥1.4 mEq/L (Findling 2011; Findling 2013; Findling 2015).Maintenance therapy: Titrate dose to 16 to 32 mEq/day in divided doses and target serum trough concentration of 0.8 to 1 mEq/L as tolerated and doses were not further increased if serum lithium concentration was ≥1.4 mEq/L (Findling 2011; Findling 2013; Findling 2015).Patient weight ≥30 kg: Initial: 8 mEq 3 times daily, increase dose in 8 mEq increments every 3 days as tolerated to clinical response and goals based on type of therapy (acute or maintenance).Acute therapy: Titrate dose to 16 mEq twice or 3 times daily and target serum lithium concentration of 0.8 to 1.2 mEq/L; maximum doses are not described in the manufacturer labeling; in trials, reported doses did not exceed a maximum daily dose of: 40 mg of lithium carbonate/kg/day and doses were not further increased if serum lithium concentration was ≥1.4 mEq/L (Findling 2011; Findling 2013; Findling 2015).Maintenance therapy: Titrate dose to 8 to 16 mEq twice or 3 times daily and target serum trough concentration of 0.8 to 1 mEq/L as tolerated; in a long-term trial, doses were not further increased if serum lithium concentration was ≥1.4 mEq/L (Findling 2013).Extended release: Children ≥12 years and Adolescents: Weight-based usual daily dosing administered in 2 divided doses: <22 kg: 600 mg/day; 22 to 41 kg: 900 mg/day, and >41 kg: 1,200 mg/day (Kliegman 2016). In an open-label trial of 27 subjects (age range: 12 to 18 years), an initial dose of 15 mg/kg/dose twice daily, maximum initial dose: 600 mg/dose, with dose titration at weekly intervals as tolerated to target serum lithium concentration of 1 to 1.2 mEq/L was used (Patel 2006). In adults, therapy is initiated at a low dose (eg, 450 mg 2 times daily or less); increased gradually based on response and tolerability (APA 2002); the usual adult dosage is 900 to 1,800 mg/day in 2 divided doses.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricImmediate release: Children ≥7 years and Adolescents:CrCl >89 mL/minute: No dosage adjustment required.CrCl 30 to 89 mL/minute: Initiate therapy with low dose; titrate slowly with frequent monitoring.CrCl <30 mL/minute: Avoid use.Extended release: Children ≥12 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; monitor renal function closely during therapy and re-evaluate treatment with any changes in renal function.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Older AdultBipolar disorder: Initiate therapy with lower doses; refer to adult dosing. Some guidelines recommend lower target serum concentrations (eg, 0.4 to 0.8 mEq/L for older adults) (CANMAT/ISBD [Yatham 2018]).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productCapsule, Oral, as carbonate: Generic: 150 mg, 300 mg, 600 mgSolution, Oral, as citrate: Generic: 8 mEq/5 mL (500 mL [DSC])Tablet, Oral, as carbonate: Generic: 300 mgTablet Extended Release, Oral, as carbonate: Lithobid: 300 mg [contains fd&c blue #2 (indigo carm) aluminum lake, fd&c red #40(allura red ac)aluminum lake, fd&c yellow #6(sunset yellow)alumin lake]Generic: 300 mg, 450 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Capsule, Oral, as carbonate: Carbolith: 150 mg, 300 mg [contains fd&c yellow #6 (sunset yellow)]Carbolith: 600 mg [contains fd&c blue #1 (brilliant blue)]Lithane: 150 mg, 300 mgGeneric: 150 mg, 300 mg, 600 mgTablet Extended Release, Oral, as carbonate: Lithmax: 300 mgProduct AvailabilityLithium oral solution has been discontinued in the United States for >1 year.Medication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Lithium: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/017812s036,018421s035,018558s030lbl.pdf#page=19Administration: AdultOral: Administer with meals to decrease GI upset. ER tablets must be swallowed whole; do not crush or chew.Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. If tablet is scored, may cut in half. Options include to switch to IR capsule or tablet; be aware that the peak serum concentration is reached much faster than the extended release and if capsules are opened or tablets crushed, this could be reached even faster and patient may experience stomach upset or nausea. Alternatively, switch to oral solution but be aware of appropriate dose conversion since the liquid form is a different lithium salt. Of note, lithium clearance is impacted by body weight, so as patient loses weight after bariatric surgery, dose adjustments may be necessary. Therapeutic drug monitoring recommended.Administration: PediatricOral: Administer with meals to decrease GI upset. Do not crush or chew extended release dosage form; swallow wholeUse: Labeled IndicationsBipolar disorder:Immediate release: Treatment of acute mania, acute episodes with mixed features, and maintenance treatment in patients ≥7 years of age with a diagnosis of bipolar disorder.Extended release: Treatment of manic episodes and maintenance treatment in patients ≥12 years of age with a diagnosis of bipolar disorder.Use: Off-Label: AdultBipolar disorder, hypomania; Bipolar major depression; Major depressive disorder, unipolarMedication Safety IssuesSound-alike/look-alike issues:Eskalith may be confused with Estratest.Lithium may be confused with lanthanum, Ultram.Lithobid may be confused with Levbid, Lithostat.Other safety concerns:Do not confuse mEq (milliequivalent) with mg (milligram). Note: 300 mg lithium carbonate or citrate contain 8 mEq lithium. Dosage should be written in mg (milligrams) to avoid confusion.Check prescriptions for unusually high volumes of the syrup for dosing errors.Adverse Reactions (Significant): ConsiderationsCardiac effectsLithium may cause cardiac arrhythmia, including bradycardia, sinoatrial dysfunction (SA block), abnormal T waves on ECG (T-wave inversion), and ST-segment depression (Ref). Additional cardiovascular affects have occurred, including peripheral edema, hypotension, and cardiovascular collapse (Ref). Brugada syndrome (Brugada ECG pattern) may be unmasked with lithium therapy (Ref). In a scientific statement from the American Heart Association, lithium has been determined to be an agent that may cause direct myocardial toxicity that is reversible upon discontinuation (magnitude: major) (Ref).Mechanism: Serum concentration-related; affects various ion channels in the myocardium, in particular Na/K channels, and leads to decreased intracellular potassium levels. These changes alter the normal functioning of the myocardium, leading to conduction disturbances and ECG abnormalities (Ref).Onset: Varied; may occur within days of initiation of medication, dose increase, or addition of interacting medication or be delayed (Ref).Risk factors:• Higher serum levels, particularly toxic levels (>1.5 mEq/L) (Ref)• Concurrent medications that either inhibit the excretion of lithium via the kidneys or have additive effects on the myocardium (Ref)• Kidney impairment (Ref)• Brugada syndrome: Family history of Brugada syndrome, family history of sudden death at a young age (Ref)CNS effectsLithium may cause a variety of CNS effects in adult and pediatric patients including drowsiness, sedated state, ataxia, abnormal gait, confusion, decreased alertness, disorientation, lethargy, memory impairment, slurred speech, headache, and others (Ref) . More significant manifestations may occur with elevated serum lithium levels or toxicity, such as coma, seizure (including tonic-clonic twitching), hallucination, agitation, abnormal electroencephalogram (EEG), and may proceed to death without intervention (Ref). Of note, some patients may describe decreased creativity and cognitive dulling as an adverse reaction, when it could also be a result of effective treatment of their manic episode and resultant decreased manic symptoms. CNS effects may persist indefinitely during treatment. Tolerance may or may not occur over time (Ref). Cognitive adverse reactions may be a reason for medication nonadherence, but it is unclear whether these adverse reactions are associated with lithium or bipolar disorder (Ref).Mechanism: Dose-related; may be related to neuronal cell membrane polarization/depolarization, alterations in glutamate functioning, increases in serotonin release, inhibition of inositol monophosphatase, and alteration of CNS catecholamine levels (Ref).Onset: Varied; may begin soon after initiation. Effects may be exacerbated with dose increases (or increased serum levels) or intentional or unintentional overdoses (Ref).Risk factors: • Higher doses/serum levels (Ref)• Concurrent use of medications reducing the clearance of lithium (eg, angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs, diuretics) (Ref)• Concurrent use of other CNS depressant medications (eg, sedative-hypnotics, antipsychotics, antiseizure medications, etc.) (Ref)• Older adults (Ref)• Preexisting neurocognitive impairment (Ref)• Current episode of depression (Ref)Dermatologic effectsLithium may cause acne vulgaris and/or psoriasis (including exacerbation of acne and exacerbation of psoriasis) in patients with and without either condition at baseline. May vary from mild to severe, and occur on the face, scalp, trunk, and extremities (Ref). Plaque-type psoriasis is the most common presentation, but others may occur (Ref).Mechanism: Dose-related; may exert toxic effects on the follicular epithelium, producing acne through neutrophilic chemotaxis and degranulation. In addition, the inflammatory cascade may become activated, leading to psoriasis. Follicular plugging may also contribute to these effects (Ref).Onset: Varied; typically takes several months to develop, although exacerbations of existing acne or psoriasis may occur sooner (Ref).Risk factors:• Males (Ref)• Preexisting moderate to severe psoriasis (Ref)GI effectsA variety of adverse GI effects have been reported with lithium in adult and pediatric patients, including dyspepsia, diarrhea, nausea, vomiting, dysgeusia (metallic or salty taste), gastritis, and abdominal pain (Ref). Some effects (eg, nausea) my subside over time. Vomiting is typically associated with toxicity (Ref). Supratherapeutic lithium concentrations should be suspected with severe nausea, vomiting, and diarrhea (Ref).Mechanism: Dose-related; may be related to direct irritation on the stomach lining or related to other physiological processes in the body after absorption. Potential effects of increased serotonin release may play a role in nausea, as well as general electrolyte changes (Ref).Onset: Varied; some effects (eg, nausea, diarrhea) may occur early in treatment. Other effects may take longer to develop (Ref).Risk factors:• Earlier in treatment (Ref)• Higher doses/serum levels (Ref)• Peak lithium levels (possible association) (Ref)• Controlled-release preparations may be associated with less upper GI cramping and nausea, but increased diarrhea compared to immediate-release formulations (Ref)Hyperparathyroidism and hypercalcemiaHypercalcemia has been reported with lithium treatment, which may or may not be related to drug-induced hyperparathyroidism. Symptoms may include weakness, fatigue, development of renal stones (calculi), osteoporosis, GI distress, and others. Psychiatric disturbances, including depression, may also develop, and potentially be misinterpreted as a new episode of the underlying mood disorder (Ref). Changes are usually reversible if lithium is discontinued; however, sustained hypercalcemia and parathyroid gland enlargement have been reported (Ref).Mechanism: While unclear, lithium is thought to inhibit calcium receptors in the parathyroid gland, preventing inhibition of parathyroid hormone (PTH) release. As PTH levels rise, this alters calcium homeostasis leading to hypercalcemia (Ref).Onset: Varied; while lithium has been observed to affect PTH levels after a single dose, more long-term exposure (ie, years) is likely required to observe clinically relevant alterations in calcium homeostasis. Progression to osteoporosis would likely take a significant exposure time as well (Ref).Risk factors:Exact risk factors unclear, but may include:• Longer duration of treatment (Ref)• Females (Ref)HypothyroidismLithium treatment has been associated with various thyroid function abnormalities, but most commonly hypothyroidism in adult and pediatric patients (Ref). Patients may present with typical hypothyroidism signs and symptoms, including lethargy, impaired cognition, weight gain, dry skin, and cold intolerance. Additionally, depressive symptoms may worsen/emerge and be misinterpreted as a component of the underlying mood disorder (Ref).Mechanism: While unclear, it is thought that lithium has varied effects on thyroid hormone production and regulation, including inhibition of iodine uptake in the thyroid, inhibition of thyroid hormone synthesis and release, and hepatic conversion of free thyroxine (Ref).Onset: Hypothyroid features, either symptomatic or lab-value based, generally occur after years of lithium treatment. While acute changes have been noted within the first month of treatment, it is much more likely after several years of use (Ref).Risk factors:• Females (Ref)• Older adults (Ref)• Family history of hypothyroidism (Ref)• Presence of antithyroid antibodies (Ref)Lithium toxicityLithium is classified as a narrow-therapeutic index drug, requiring close monitoring to ensure patients’ serum levels are maintained within the therapeutic range. Supratherapeutic levels, even slight elevations above 1.5 mEq/L, may lead to increased adverse reactions and toxicity. Notably, toxicity can occur at any level (Ref). General symptoms of low-grade lithium toxicity may include weakness, tremor (new-onset or worsening), mild ataxia, poor concentration, tinnitus, nausea, and diarrhea. More significant toxicity may result in vomiting, gross/coarse tremor, slurred speech, confusion, nystagmus disorder, dysarthria, and lethargy. If not treated, it may lead to seizure (tonic-clonic), coma, neurological damage, and death (Ref). Permanent neurotoxicity, described as the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT), has been reported with acute and chronic lithium toxicity (Ref).Mechanism: Lithium toxicity is an augmented presentation of the various adverse reactions seen with treatment (Ref).Onset: Varied; may occur within minutes of ingestion (mostly GI effects), but more significant symptoms may take over an hour or more to manifest. There are also reports of delayed symptom onset several days after ingestion (Ref).Risk factors:• Higher doses/serum levels (Ref)• Concurrent use of drugs or medications (eg, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists) that increase serum levels (Ref)• Acute alterations in serum electrolytes or dehydration (Ref)• Older adults (may manifest symptoms at lower comparative serum levels) (Ref)• Kidney impairment (Ref)Nephrogenic diabetes insipidusNephrogenic diabetes insipidus may occur (Ref). The ability of the kidney to retain free water may become impaired, leading to dehydration and electrolyte disturbances, most notably hypernatremia. Additionally, serum lithium levels may increase due to the decreased dilutional effect from decreased whole body water. Symptoms of nephrogenic diabetes insipidus and its related hypernatremia may include polyuria, polydipsia, lethargy, and irritability. More severe cases may progress to muscle twitching, coma, seizures, and death. Nephrogenic diabetes insipidus may persist after prolonged lithium therapy despite discontinuation (Ref).Mechanism: Dose- and duration-related. Lithium-related changes in the collecting tubules of the kidney decrease sensitivity to antidiuretic hormone, leading to decreased concentrating ability and increased production of dilute urine. Lithium may reduce aquaporin-2 water channels within the collecting duct, causing reduction of water reabsorption (Ref). As total body stores of free water decrease, the sensation of thirst increases to compensate (Ref).Onset: Varied; typical onset within 2 to 4 months of initiation but may occur earlier or later (Ref).Risk factors:• Longer duration of treatment (Ref)• Higher doses/serum levels (Ref)• Any episodes of lithium toxicity (Ref)• Extended release or multiple-daily dose regimens (Ref)• Nonresponse to lithium (may be a risk factor) (Ref)• Infection (Ref)• Dehydration (Ref)• Alcohol intoxication (Ref)Polydipsia and polyuriaCommon adverse reactions associated with lithium are polyuria and polydipsia. These reactions may vary in intensity from mild to more significant effects on overall quality of life. Patients may notice increased urinary frequency (>3 L in 24 hours) due to poor urine concentration. As a result of decreased body water stores, patients may also report increased thirst, which is independent of any dry mouth effects of the drug. May decrease in intensity over time in some patients as the kidneys compensate for this effect (Ref). Refer to "nephrogenic diabetes insipidus" for long-term complications.Mechanism: Lithium-related changes in the collecting tubules of the kidney decrease sensitivity to antidiuretic hormone, leading to decreased concentrating ability and increased production of dilute urine. As total body stores of free water are decreased, the sensation of thirst increases to compensate (Ref).Onset: Varied; may occur early in treatment (within days) or later in treatment (Ref).Risk factors:• Longer duration of treatment (Ref)• Higher doses/serum levels episodes (Ref)• Any episodes of lithium toxicity (Ref)• Concurrent use of other psychotropic medications, especially antipsychotics (Ref)• Multiple-daily dose regimens (conflicting data) (Ref)Renal effectsUp to one-third of patients may develop some degree of decreased kidney function over the course of lithium treatment, with a smaller percentage (~5%) developing significant kidney impairment/failure (eGFR <30 mL/minute). Changes in eGFR (decreased creatinine clearance), renal concentrating defect, and other parameters have been observed in these patients. The development of polyuria/polydipsia may or may not be an early marker for later development of kidney insufficiency. Progression of kidney impairment may continue after discontinuation of lithium in some patients (Ref). Chronic kidney disease will develop in 17% to 21% of long-term users (Ref).Mechanism: Duration-related; related to various changes in kidney morphology, including interstitial nephritis and fibrosis, nephron atrophy, and possibly glomerular damage. Hypothesized to be related to acute decreases in kidney sensitivity to antidiuretic hormone, causing gradual change in kidney function over time (Ref). Time from lithium initiation to progression to chronic kidney disease and end stage renal disease is 16.5 to 31 years, and 23 years, respectively (Ref).Onset: Typically delayed, although acute changes may occur with acute toxicity. As lithium exposure continues over years, the rate of more significant kidney impairment increases as the alternations in kidney structure become more severe (Ref).Risk factors:• Longer duration of treatment (Ref)• Older adults (Ref)• Any episodes of lithium toxicity (Ref)• Higher doses/serum concentrations (probable risk factor) (Ref)• Concurrent use of other psychotropic medications, especially antipsychotics (Ref)Sexual dysfunctionVarious types of sexual dysfunction have been reported with lithium treatment, in both females and males. While the rates of the various effects are not clear (anywhere from <5% to nearly 40% in studies), they may include decreased libido, impaired sexual arousal, erectile dysfunction, and general decreased sexual satisfaction. Negative effects on org*sm are unclear. Sexual dysfunction can negatively impact patients’ quality of life (Ref).Mechanism: Exact mechanism is unclear. Effects on promoting serotonin release may play a role, similar to the serotonin-augmenting effects of antidepressants (Ref).Onset: Varied; may take days to weeks or longer (Ref).Risk factors:No clear risk factors have been described. Possible risk factors include:• Concurrent use of benzodiazepines (Ref)• Concurrent use of other medications that cause sexual dysfunction (eg, antidepressants) (probable risk factor) (Ref)TremorLithium may cause tremor in nearly one-quarter of patients, making it one of the most common adverse reactions. Most commonly seen as a bilateral, symmetrical hand tremor, similar to essential tremor; although, this may vary to other limbs and in symmetry (Ref). May spontaneously decrease over time as compensatory mechanisms develop within the patient (Ref). Course tremor and muscle twitching may be observed in lithium toxicity (Ref).Mechanism: Exact mechanism is unclear; thought to be related to CNS depressant effects, leading to dysregulation of fine muscle control (Ref).Onset: Varied; commonly begins early in treatment but can develop later in treatment (with or without a dose increase) (Ref).Risk factors:• Higher doses/serum levels (Ref)• Concurrent use of medications reducing the clearance of lithium (eg, angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs, diuretics) (Ref)• Concurrent use of other medications known to induce tremor (eg, antipsychotics, antidepressants) (Ref)• Concurrent use of caffeine (Ref)• Concurrent anxiety disorder (Ref)• Personal or family history of essential tremor (Ref)• Older adults (Ref)• Concurrent substance withdrawal (especially alcohol) (Ref)Weight gainWeight gain is reported as one of the more common and bothersome adverse reactions of lithium. May include weight gain of 10 kg or more over time with an average increase in body weight of 6 kg (Ref). This can lead to other medical comorbidities and negative effects on mood and adherence to treatment (Ref). Many pediatric studies suggest that lithium has a low risk for weight gain (not statistically different than placebo), with many demonstrating that it is weight neutral (Ref).Mechanism: Exact mechanism is unclear. Effects on central mechanisms related to weight gain, satiety, and metabolism are possible. In addition, increased consumption of high-calorie, sugary beverages from increased thirst due to lithium could play a role, as well as any drug-induced hypothyroidism and fluid retention (Ref).Onset: Varied; may occur within the first few weeks of initiation, with more significant increases over time. Increases of 4 to 7 kg within the first year have been reported in the literature. While the most significant weight gain typically occurs within the first 1 to 2 years of treatment, it may continue (Ref).Risk factors:Unclear, but may include:• Concurrent use of other medications that can cause weight gain (particularly other psychotropic medications) (Ref)• Early weight gain after treatment initiation (Ref)• Overweight/obese prior to initiation (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.Frequency not defined:Cardiovascular: Abnormal T waves on ECG (including inversion T wave on ECG and flattened T wave of ECG), bradycardia (Ataallah 2020), cardiac arrhythmia (including unmasking of Brugada Syndrome) (Ravi 2020), chest tightness, circulatory shock, cold extremities, edema, hypotension, myxedema (Ahmad Mir 2013), peripheral vascular disease (resembling Raynaud’s syndrome), prolonged QT interval on ECG, sinus node dysfunction, syncope, ventricular tachyarrhythmiaDermatologic: Acne vulgaris (Scarfi 2013), alopecia, dermal ulcer, dermatitis, dry and/or thinning hair, exacerbation of acne (Gitlin 2016), exacerbation of psoriasis, folliculitis, pruritus, psoriasis, skin rash, xerodermaEndocrine & metabolic: Albuminuria, dehydration, diabetes insipidus, euthyroid goiter, glycosuria, hypercalcemia (including secondary to hyperparathyroidism [McKnight 2012]), hyperglycemia, hypermagnesemia, hyperparathyroidism, hyperthyroidism, hyponatremia, weight lossGastrointestinal: Abdominal pain, anorexia, decreased appetite, dental caries, dysgeusia (including metallic taste and salty taste), dyspepsia, fecal incontinence, flatulence, gastritis, salivary gland disease (swelling), sialorrhea, swelling of lips, tongue changes (movement), vomiting, xerostomiaGenitourinary: Glomerulopathy (fibrosis), impotence, nephron atrophy, nephrotic syndrome (Bear 1985), oliguria, sexual disorder, urinary incontinenceHematologic & oncologic: LeukocytosisHypersensitivity: AngioedemaImmunologic: Drug reaction with eosinophilia and systemic symptoms (Shreedhar 2010)Local: Local pain (fingers and toes), local skin discoloration (fingers and toes), localized edema (ankles and wrists)Nervous system: Abnormal electroencephalogram (diffuse slowing, potentiation, disorganization of background rhythm), abnormal gait, ataxia, bradyphrenia, cogwheel rigidity, coma, confusion, decreased mental acuity (worsening of organic brain syndromes), disorientation, dizziness, drowsiness, dystonic reaction, epileptiform seizure, extrapyramidal reaction, fatigue, hallucination, headache, hyperactive behavior (startled response), hyperactive deep tendon reflex, hyperirritability (muscle), hypertonia, idiopathic intracranial hypertension, involuntary choreoathetoid movements, lethargy, local anesthesia (skin), memory impairment, myasthenia, psychom*otor impairment, reduced intellectual ability, restlessness, sedated state, seizure, slurred speech, stupor, tic disorder, vertigoNeuromuscular & skeletal: Arthralgia, joint swelling, polyarthralgia, tremorOphthalmic: Blurred vision, exophthalmos, nystagmus disorder, transient scotomaOtic: TinnitusRenal: Decreased creatinine clearance, interstitial nephritis, renal concentrating defectMiscellaneous: Fever, interstitial fibrosis, iodism (elevated iodine uptake)Postmarketing:Endocrine & metabolic: Hypothyroidism (common: ≥10%) (Lieber 2020), nephrogenic diabetes insipidus (common: ≥10%) (Ott 2019, Rauf 2020, Schoot 2020), polydipsia (common in long-term patients: ≥10%) (Gitlin 2016), weight gain (common: ≥10%) (Gitlin 2016)Gastrointestinal: Diarrhea (common: ≥10%) (Gitlin 2016), nausea (common: ≥10%) (Gitlin 2016)Nervous system: Intracranial hypertension (Tan 2020)Neuromuscular & skeletal: Lupus-like syndrome (Shukla 1982)Renal: Polyuria (common in long-term patients: ≥10%) (Gitlin 2016)ContraindicationsHypersensitivity to lithium or any component of the formulation.Immediate-release capsule, solution and tablet: Severe cardiovascular or renal disease, severe debilitation, dehydration, sodium depletion, concurrent use with diuretics.Canadian labeling: Additional contraindications (not in US manufacturer’s labeling): Brain damage; conditions requiring low sodium intake.Warnings/PrecautionsConcerns related to adverse effects:• Pseudotumor cerebri: Pseudotumor cerebri (increased intracranial pressure and papilledema) has rarely been reported with use; undetected cases may result in blind spot enlargement, visual field constriction, and blindness secondary to optic atrophy. Discontinue therapy, if clinically possible, if syndrome occurs.• Serotonin syndrome: Lithium can precipitate a potentially life-threatening serotonin syndrome, particularly when used in combination with other serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants, fentanyl, tramadol, buspirone, St. John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, monoamine oxidase inhibitors). Monitor patients closely for signs of serotonin syndrome, such as mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), GI symptoms (eg, nausea, vomiting, diarrhea), and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise and initiate supportive therapy.Disease-related concerns:• Cardiovascular disease: Generally avoid use in patients with significant cardiovascular disease due to risk of precipitation of cardiac arrhythmia; if use is unavoidable, use with extreme caution and monitor serum lithium levels and EKG closely.• Depression/suicidal ideation: Use with caution in patients at risk of suicide (suicidal thoughts or behavior) by drug overdose; lithium has a narrow therapeutic index (Nelson 2017).• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Mehrizi 2012).Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyAlosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyAmphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapyAngiotensin II Receptor Blockers: May increase the serum concentration of Lithium. Management: Initiate lithium at lower doses in patients receiving an angiotensin II receptor blocker (ARB). Consider lithium dose reductions in patients stable on lithium therapy who are initiating an ARB. Monitor lithium concentrations closely when combined. Risk D: Consider therapy modificationAngiotensin-Converting Enzyme Inhibitors: May increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor.Monitor for increased concentrations/toxic effects of lithium if an ACE inhibitor is initiated/dose increased, or if switching between ACE inhibitors. Risk D: Consider therapy modificationAntiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyAntipsychotic Agents: Lithium may enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine.Risk C: Monitor therapyBusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyCaffeine and Caffeine Containing Products: May decrease the serum concentration of Lithium. Risk C: Monitor therapyCalcitonin: May decrease the serum concentration of Lithium. Risk C: Monitor therapyCalcium Channel Blockers (Nondihydropyridine): May enhance the neurotoxic effect of Lithium. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Lithium. Decreased or unaltered lithium concentrations have also been reported with this combination. Risk C: Monitor therapyCalcium Polystyrene Sulfonate: May decrease the serum concentration of Lithium. Management: Consider separating administration of lithium from administration of oral calcium polystyrene sulfonate by at least 6 hours. Risk D: Consider therapy modificationCarBAMazepine: May enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapyCarbonic Anhydrase Inhibitors: May decrease the serum concentration of Lithium. Risk C: Monitor therapyCyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyDapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combinationDesmopressin: Lithium may diminish the therapeutic effect of Desmopressin. Desmopressin may increase the serum concentration of Lithium.Risk C: Monitor therapyDexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyDextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyEletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyEplerenone: May increase the serum concentration of Lithium. Risk C: Monitor therapyErgot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyFenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapyFosphenytoin-Phenytoin: May enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapyHaloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol.Risk C: Monitor therapyLasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyLevomethadone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyLinezolid: May enhance the serotonergic effect of Lithium. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modificationLoop Diuretics: May decrease the serum concentration of Lithium. Loop Diuretics may increase the serum concentration of Lithium. Risk C: Monitor therapyLorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyMetaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyMethadone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyMethyldopa: May enhance the adverse/toxic effect of Lithium. This may occur without notable changes in serum lithium concentrations. Risk C: Monitor therapyMethylene Blue: May enhance the serotonergic effect of Lithium. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modificationMetoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyMetroNIDAZOLE (Systemic): May enhance the adverse/toxic effect of Lithium. MetroNIDAZOLE (Systemic) may increase the serum concentration of Lithium. Risk C: Monitor therapyMonoamine Oxidase Inhibitors (Antidepressant): May enhance the serotonergic effect of Lithium. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modificationMonoamine Oxidase Inhibitors (Type B): May enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Risk X: Avoid combinationNefazodone: May enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyNeuromuscular-Blocking Agents: Lithium may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents.Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Lithium. Management: Consider reducing the lithium dose when initiating a NSAID. Monitor for increased lithium therapeutic/toxic effects if a NSAID is initiated/dose increased, or decreased effects if a NSAID is discontinued/dose decreased. Risk D: Consider therapy modificationNonsteroidal Anti-Inflammatory Agents (Topical): May increase the serum concentration of Lithium. Risk C: Monitor therapyOndansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyOpioid Agonists: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyOpioid Agonists (metabolized by CYP3A4 and CYP2D6): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyOpioid Agonists (metabolized by CYP3A4): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyOrnidazole: May enhance the adverse/toxic effect of Lithium. Ornidazole may increase the serum concentration of Lithium. Risk C: Monitor therapyOxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyOzanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapyPotassium Iodate: Lithium may enhance the hypothyroid effect of Potassium Iodate.Risk C: Monitor therapyPotassium Iodide: May enhance the hypothyroid effect of Lithium. Risk C: Monitor therapyQT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyRamosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySargramostim: May enhance the adverse/toxic effect of Lithium. Specifically, the myeloproliferative effects may be increased. Risk C: Monitor therapySelective Serotonin Reuptake Inhibitors: Serotonergic Agents (High Risk, Miscellaneous) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySerotonergic Non-Opioid CNS Depressants: Serotonergic Agents (High Risk, Miscellaneous) may enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySerotonergic Opioids (High Risk): May enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapySerotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySerotonin/Norepinephrine Reuptake Inhibitors: May enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySertindole: Lithium may enhance the QTc-prolonging effect of Sertindole.Risk X: Avoid combinationSodium Bicarbonate: May increase the excretion of Lithium. Risk C: Monitor therapySodium Chloride: May increase the excretion of Lithium. Risk C: Monitor therapySodium Polystyrene Sulfonate: May decrease the serum concentration of Lithium. Management: Consider separating administration of lithium from administration of oral sodium polystyrene sulfonate by at least 6 hours. Risk D: Consider therapy modificationSodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: May decrease the serum concentration of Lithium. Risk C: Monitor therapySt John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySyrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyTetracyclines: May increase the serum concentration of Lithium. Risk C: Monitor therapyTheophylline Derivatives: May decrease the serum concentration of Lithium. Risk C: Monitor therapyThiazide and Thiazide-Like Diuretics: May decrease the excretion of Lithium. Management: Reduce the lithium dose if coadministered with thiazide or thiazide-like diuretics. Monitor serum lithium levels during coadministration with thiazide and thiazide-like diuretics. Risk D: Consider therapy modificationTopiramate: May increase the serum concentration of Lithium. Risk C: Monitor therapyTricyclic Antidepressants: May enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyTryptophan: Lithium may enhance the serotonergic effect of Tryptophan. This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyValproate Products: Lithium may increase the serum concentration of Valproate Products.Risk C: Monitor therapyVasopressin: Drugs Suspected of Causing Diabetes Insipidus may diminish the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic hormone effects of vasopressin may be decreased.Risk C: Monitor therapyPregnancy ConsiderationsLithium crosses the placenta in concentrations similar to those in the maternal plasma (Newport 2005).Cardiac malformations in the infant, including Ebstein anomaly, are associated with use of lithium during the first trimester of pregnancy. Other adverse events including polyhydramnios, fetal/neonatal cardiac arrhythmias, hypoglycemia, diabetes insipidus, changes in thyroid function, premature delivery, floppy infant syndrome, or neonatal lithium toxicity are associated with lithium exposure when used later in pregnancy (ACOG 2008). The incidence of adverse events may be associated with higher maternal doses (Newport 2005). Fetal echocardiography should be considered if first trimester exposure occurs (ACOG 2008).Due to pregnancy-induced physiologic changes, women who are pregnant may require dose adjustments of lithium to achieve euthymia and avoid toxicity (ACOG 2008; Grandjean 2009; Yonkers 2011).For planned pregnancies, use of lithium during the first trimester should be avoided if possible (Grandjean 2009). However, the absolute risk of Ebstein anomaly is small and treatment for bipolar disorder should not be withheld when clinically indicated (Larsen 2015). If lithium is needed during pregnancy, the minimum effective dose should be used, maternal serum concentrations should be monitored, and consideration should be given to start therapy after the period of organogenesis; lithium should be suspended 24 to 48 hours prior to delivery or at the onset of labor when delivery is spontaneous, then restarted when the patient is medically stable after delivery (ACOG 2008; Grandjean 2009; Newport 2005).Breastfeeding ConsiderationsLithium is present in breast milk.Serum concentrations of breastfeeding infants may be 10% to 50% of the maternal serum concentration (Grandjean 2009). Hypotonia, hypothermia, cyanosis, electrocardiogram changes, and lethargy have been reported in breastfed infants (ACOG 2008). It is generally recommended that breastfeeding be avoided during maternal use of lithium; however, treatment may be continued in appropriately selected patients (Grandjean 2009; Larsen 2015; Sharma 2009; Viguera 2007). The hydration status of the breastfed infant and maternal serum concentrations of lithium should be monitored (ACOG 2008). In addition, monitor the infant for lethargy, growth, and feeding problems; obtain infant serum concentrations only if clinical concerns arise (Bogen 2012; Yonkers 2011). Long-term effects on development and behavior have not been studied (ACOG 2008; Grandjean 2009).Dietary ConsiderationsMay be taken with meals to avoid GI upset; maintain adequate salt and fluid intake.Monitoring ParametersRenal function including BUN and SCr (baseline, every 2 to 3 months during the first 6 months of treatment, then once a year in stable patients or as clinically indicated); fluid status; pediatric patients may require more frequent checks); serum electrolytes (baseline, then periodically), serum calcium (baseline, 2 to 6 weeks after initiation, then every 6 to 12 months; repeat as clinically indicated; if discontinued due to hypercalcemia, monitor weekly for 1 month for return to baseline) (Broome 2011); signs and symptoms of hypercalcemia (eg, fatigue, weakness, abdominal pain, constipation, nephrolithiasis, bone pain); thyroid (baseline, 1 to 2 times with in the first 6 months of treatment, then once a year in stable patients or as clinically indicated); PTH as clinically indicated; beta-hCG pregnancy test for all females not known to be sterile (baseline); ECG with rhythm strip (baseline for all patients >40 years of age or if underlying cardiac risk factors, repeat as clinical indicated), CBC with differential (baseline, repeat as clinically indicated); serum lithium levels (twice weekly until both patient's clinical status and levels are stable, then repeat levels every 1 to 3 months or as clinically indicated; closely monitor in patients with significant renal or cardiovascular disease, debilitation, dehydration, sodium depletion, or those taking concomitant medications that impact renal function); weight (baseline, then periodically) (APA 2002; Mehta 2017); polyuria; signs of lithium toxicity (eg, diarrhea, vomiting, tremor, mild ataxia, drowsiness, muscular weakness).Reference RangeMonitor symptom improvement in conjunction with serum concentrations to guide dose adjustments. Obtain 2 consecutive serum concentrations in the therapeutic range during the acute phase, then monitor regularly (ie, every 3 to 6 months).Timing of serum samples: A 12-hour trough level is preferred, but in some circ*mstances (eg, 3 times a day dosing, limited lab hours) it may be drawn 8 to 12 hours post dose. Check levels ~5 days after a dosage adjustment (CANMAT [Yatham 2018]; manufacturer's labeling).Therapeutic concentrations:Bipolar disorder:Acute mania: 0.8 to 1.2 mEq/L (SI: 0.8 to 1.2 mmol/L); some guidelines recommend lower target serum concentrations (eg, 0.4 to 0.8 mEq//L [SI: 0.4 to 0.8 mmol/L]) for older adults.Maintenance: 0.6 to 1 mEq/L (SI: 0.6 to 1.0 mmol/L); a higher rate of relapse is described in subjects who are maintained at <0.6 mEq/L (SI: 0.6 mmol/L). Some guidelines recommend targeting the lower end of the range for older adults (CANMAT [Yatham 2018]).Major depressive disorder: 0.6 to 1.2 mEq/L (SE: 0.6 to 1.2 mEq/L) (Gitlin 2020).Toxic concentrations>1.5 mEq/L (SI: >1.5 mmol/L): Early signs and symptoms of intoxication may include marked tremor, nausea, diarrhea, blurred vision, vertigo, confusion, and decreased deep tendon reflexes (APA 2002).>2.5 mEq/L (SI: >2.5 mmol/L): Intoxication symptoms may progress to include severe neurological complications, seizures, coma, cardiac dysrhythmia, and permanent neurological impairment (APA 2002).>3.5 mEq/L (SI: >3.5 mmol/L): Potentially lethal toxicity (Mitchell 2001).Note: A 10% to 26% increase of a 12-hour serum concentration can be expected with once-daily dosing compared to a 12-hour serum concentration checked of an equal dose that is given twice daily (Mitchell 2001; Singh 2011).Mechanism of ActionThe precise mechanism of action in mood disorders is unknown. Traditionally thought to alter cation transport across cell membranes in nerve and muscle cells, influence the reuptake of serotonin and/or norepinephrine, and inhibit second messenger systems involving the phosphatidylinositol cycle (Ward 1994). May also provide neuroprotective effects by increasing glutamate clearance, inhibiting apoptotic glycogen synthase kinase activity, increasing the levels of antiapoptotic protein Bcl-2 and, enhancing the expression of neurotropic factors, including brain-derived neurotrophic factor (Sanacora 2008).Pharmaco*kineticsAbsorption: Rapid and completeDistribution: Vd: Initial: 0.307 L/kg; Vdss: 0.7 to 1 L/kg; decreased in elderly patients (Ward 1994)Protein binding: Not protein boundMetabolism: Not metabolized (Ward 1994)Bioavailability: 80% to 100% (Ward 1994)Half-life elimination:Pediatric patients 7 to 17 years: t1/2(beta): 27 hours (Findling 2010)Adults: 18 to 36 hours; prolonged in elderly patients (~28.5 hours) (Ward 1994)Time to peak, serum: Immediate release: ~0.5 to 3 hours; Extended release: 2 to 6 hours; Solution: 15 to 60 minutesExcretion: Urine (primarily; unchanged drug); sweat, saliva, and feces (negligible amounts)Clearance: 80% of filtered lithium is reabsorbed in the proximal convoluted tubules; decreased in elderly patients secondary to age-related decreases in renal function (Ward 1994)Pharmaco*kinetics: Additional ConsiderationsPediatric: In pediatric patients, great variability in clearance was found across subjects with linear pharmaco*kinetics correlated to fat-free mass (Findling 2010).Older adult: Elderly patients receiving lithium may have a decreased glomerular filtration rate and decrease in renal plasma clearance (13.7 mL/minute) (Ward 1994).Pricing: USCapsules (Lithium Carbonate Oral)150 mg (per each): $0.14 - $0.19300 mg (per each): $0.17 - $0.21600 mg (per each): $0.36 - $0.44Tablet, controlled release (Lithium Carbonate ER Oral)300 mg (per each): $0.25 - $0.47450 mg (per each): $0.46 - $0.76Tablet, controlled release (Lithobid Oral)300 mg (per each): $15.08Tablets (Lithium Carbonate Oral)300 mg (per each): $0.21 - $0.26Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalCalith (TW);Camcolit (BE, BH, CY, GB, IE, IQ, IR, KW, LB, LU, LY, MT, NL, OM, PK, QA, SA, SG, SY, TW, YE, ZA);Camcolite (AE, JO);Carbolim (BR);Carbolit (CL, CO, CR, DO, GT, HN, MX, NI, PA, SV);Carbolithium (IT);Carlit (PY);Ceglution (AR);Contemnol (CZ);Eskalit (AR);Eskalith (BB, BM, BS, BZ, GY, JM, SR, TT);Frimania (ID);Hynorex Retard (DE);Hypnolith (LK);Licab (IN);Licarb (HK, TH);Licarbium (IL);Liconate (MY);Limas (JP);Limed (TH);Liskonum (AE, BH, CY, GB, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);Litarex (SA);Litcab (PH);Lithan (KR);Litheum 300 (MX);Lithicarb (AU);Lithicarb FC (NZ);Lithin SR (BD);Lithioderm (FR);Lithionit (NO, SE);Lithium Carbonicum (PL);Lithiumkarbonat ”Oba” (DK);Lithocap (IN);Lithosun SR (BD);Lithuril (TR);Litiam ER (BD);Liticarb (HN, HU);Litij-karbonat (HR);Litiumkarbonat ”Dak” (DK);Lito (FI);Litocarb (PE);Manicarb SR (LK);Maniprex (BE, LU);Microlit (PH);Milithin (GR);Neurolepsin (AT);Plenur (ES);Priadel (BE, GB, IE, LU, NL, NZ, PT);Priadel Retard (CH);Prianil C.R. (EG);Quilonium (ZA);Quilonium-R (PH);Quilonorm (AT);Quilonorm Retardtabletten (CH);Quilonum (AU);Quilonum Retard (DE);Quilonum retard (LU);Sicolitio (UY);Teralithe (FR);Theralite (CO)For country code abbreviations (show table)ACOG Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists number 92, April 2008 (replaces practice bulletin number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol. 2008;111:1001-1020. [PubMed 18378767]Adityanjee, Munshi KR, Thampy A. The syndrome of irreversible lithium-effectuated neurotoxicity. Clin Neuropharmacol. 2005;28(1):38-49. doi:10.1097/01.wnf.0000150871.52253.b7 [PubMed 15714160]Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]Altshuler LL, Sugar CA, McElroy SL, et al. Switch rates during acute treatment for bipolar II depression with lithium, sertraline, or the two combined: a randomized double-blind comparison. Am J Psychiatry. 2017;174(3):266-276. doi:10.1176/appi.ajp.2016.15040558. [PubMed 28135846]American Psychiatric Association (APA). Practice guideline for the treatment of patients with bipolar disorder. American Journal of Psychiatry. 2002;159(4 Suppl):1-50. [PubMed 11958165]American Psychiatric Association (APA). Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Published October 2010. Accessed March 2020.Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007.Ataallah B, Al-Zakhari R, Sharma A, Tofano M, Haggerty G. A rare but reversible cause of lithium-induced bradycardia. Cureus. 2020;12(6):e8600. doi:10.7759/cureus.8600 [PubMed 32676239]Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord. 2006;8(5, pt 2):625-639. doi:10.1111/j.1399-5618.2006.00344.x [PubMed 17042835]Bauer M, Adli M, Baethge C, et al. Lithium augmentation therapy in refractory depression: clinical evidence and neurobiological mechanisms. Can J Psychiatry. 2003;48(7):440-448. doi:10.1177/070674370304800703. [PubMed 12971013]Bear RA, Sugar L, Paul M. Nephrotic syndrome and renal failure secondary to lithium carbonate therapy. Can Med Assoc J. 1985;132(7):735-737. [PubMed 3919911]Bilbao-Meseguer I, Rodríguez-Gascón A, Barrasa H, Isla A, Solinís MÁ. Augmented renal clearance in critically ill patients: a systematic review. Clin Pharmaco*kinet. 2018;57(9):1107-1121. doi:10.1007/s40262-018-0636-7 [PubMed 29441476]Bogen DL, Sit D, Genovese A, Wisner KL. Three cases of lithium exposure and exclusive breastfeeding. Arch Womens Ment Health. 2012;15:69-72. [PubMed 22277970]Broome JT, Solorzano CC. Lithium use and primary hyperparathyroidism. Endocrine Practice. 2011;17:31-35. [PubMed 21247849]Brown EA, Pawlikowski TR. Lithium intoxication treated by peritoneal dialysis. Br J Clin Pract. 1981;35(2):90-91. [PubMed 7259950]Calabrese JR, Shelton MD, Rapport DJ, et al. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Am J Psychiatry. 2005;162(11):2152-2161. doi:10.1176/appi.ajp.162.11.2152. [PubMed 16263857]Carbolith (lithium carbonate) [product monograph]. Laval, Quebec, Canada: Bausch Health Canada Inc; May 2019.Carter L, Zolezzi M, Lewczyk A. An updated review of the optimal lithium dosage regimen for renal protection. Can J Psychiatry. 2013;58(10):595-600. doi:10.1177/070674371305801009. [PubMed 24165107]Centers for Disease Control (CDC). 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Front Psychiatry. 2020;11:377. doi:10.3389/fpsyt.2020.00377 [PubMed 32457664]Ward ME, Musa MN, Bailey L. Clinical pharmaco*kinetics of lithium. J Clin Pharmacol. 1994;34:280-285. [PubMed 8006194]Wilson JH, Donker AJ, van der Hem GK, Wientjes J. Peritoneal dialysis for lithium poisoning. Br Med J. 1971;2(5764):749-750. doi:10.1136/bmj.2.5764.749 [PubMed 5090765]Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. doi:10.1111/bdi.12609. [PubMed 29536616]Yonkers KA, Vigod S, Ross LE. Diagnosis, pathophysiology, and management of mood disorders in pregnant and postpartum women. Obstet Gynecol. 2011;117:961-977. [PubMed 21422871]Zar T, Graeber C, Perazella MA. Recognition, treatment, and prevention of propylene glycol toxicity. Semin Dial. 2007;20(3):217-219. [PubMed 17555487]Topic 9566 Version 396.0

ClosePravastatin: Pediatric drug informationPravastatin: Pediatric drug information(For additional information see "Pravastatin: Drug information" and see "Pravastatin: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Special AlertsStatin Pregnancy Contraindication UpdateJuly 2021After a comprehensive review of all available data, the FDA is requesting all statin manufacturers to remove the contraindication in the prescribing information against using statins in pregnant patients. Although statin therapy should be discontinued in most pregnant patients, health care providers should consider the ongoing therapeutic needs of the individual patient, especially patients at very high risk of cardiovascular events during pregnancy, such as patients with hom*ozygous familial hypercholesterolemia or those with established cardiovascular disease. Additionally, breastfeeding is still not recommended in patients taking a statin; health care providers should determine whether it is better to temporarily stop statin therapy while breastfeeding or to continue statin therapy and not have the patient breastfeed. If ongoing statin treatment is necessary, infant formula and other alternatives are available. The FDA expects that removing the contraindication will enable health care providers and patients to make individual decisions about benefit and risk, especially for those at very high risk of heart attack or stroke.Further information is available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-removal-strongest-warning-against-using-cholesterol-lowering-statins-during-pregnancy.Brand Names: USPravachol [DSC]Brand Names: CanadaACH-Pravastatin;AG-Pravastatin;APO-Pravastatin;AURO-Pravastatin;BIO-Pravastatin;DOM-Pravastatin;JAMP-Pravastatin;M-Pravastatin;MAR-Pravastatin;MINT-Pravastatin;PMS-Pravastatin;Pravachol [DSC];Priva-Pravastatin [DSC];RIVA-Pravastatin [DSC];SANDOZ Pravastatin;TARO-Pravastatin;TEVA-PravastatinTherapeutic CategoryAntilipemic Agent;HMG-CoA Reductase InhibitorDosing: PediatricNote: Dosage should be individualized according to the baseline LDL-C level, the recommended goal of therapy, and patient response; adjustments should be made at intervals of 4 weeks.Hyperlipidemia or heterozygous familial and nonfamilial hypercholesterolemiaHyperlipidemia or heterozygous familial and nonfamilial hypercholesterolemia:Note: Begin treatment if, after adequate trial (6 to 12 months) of intensive lifestyle modification emphasizing body weight normalization and diet, the following are present (AACE [Jellinger 2017]):LDL-C ≥190 mg/dL orLDL-C remains ≥160 mg/dL and two or more cardiovascular risk factors: Family history of premature atherosclerotic cardiovascular disease (<55 years of age), overweight, obesity, or other elements of insulin resistance syndrome orLDL-C ≥130 mg/dL and diabetes mellitus (Daniels 2008; NHLBI 2011).Therapy may also be considered for children 8 to 9 years of age meeting the above criteria or for children with diabetes mellitus and LDL-C ≥130 mg/dL (Daniels 2008).Children and Adolescents 8 to 13 years: Oral: 20 mg once daily; lower doses (5 and 10 mg/day) have been evaluated and less efficacy observed compared to 20 mg doses (NHLBI 2011; Vuorio 2017); doses >20 mg have not been studied (Vuorio 2017).Adolescents 14 to 18 years: Oral: 40 mg once daily; lower doses have been evaluated and less efficacy observed; doses >40 mg have not been studied (NHLBI 2011; Vuorio 2017).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing adjustment for toxicity: Muscle symptoms (potential myopathy): Children ≥8 years and Adolescents: Discontinue use until symptoms can be evaluated; check CPK level; based on experience in adult patients, also evaluate patient for conditions that may increase the risk for muscle symptoms (eg, hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases). Upon resolution (symptoms and any associated CPK abnormalities), resume the original or consider a lower dose of pravastatin and retitrate. If muscle symptoms recur, discontinue pravastatin use. After muscle symptom resolution, may then reinitiate a different statin at an initial low dose; gradually increase if tolerated. Based on experience in adult patients, if muscle symptoms or elevated CPK persists for 2 months in the absence of continued statin use, consider other causes of muscle symptoms. If determined to be due to another condition aside from statin use, may resume statin therapy at the original dose (NHLBI 2011; Stone 2013).Dosing: Kidney Impairment: PediatricThere are no pediatric specific recommendations; based on experience in adult patients, dosing adjustment suggestedDosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer labeling; contraindicated in active liver disease or in patients with unexplained persistent elevations of serum transaminases.Dosing: Adult(For additional information see "Pravastatin: Drug information")Note: Use in conjunction with lifestyle modification (eg, diet and exercise). When choosing to initiate therapy and selecting dose intensity, consider the following: age, baseline LDL-C, 10-year atherosclerotic cardiovascular disease (ASCVD) risk, risk-enhancing factors, potential adverse effects, and drug interactions. Pravastatin is considered a moderate-intensity statin at doses of 40 to 80 mg/day (generally reduces LDL-C by ~30% to 49%). If LDL-C must be lowered ≥50%, select an alternative high-intensity statin (atorvastatin or rosuvastatin). Assess response ~1 to 3 months after initiation of therapy or dose adjustment and every 3 to 12 months thereafter (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).Heterozygous familial hypercholesterolemiaHeterozygous familial hypercholesterolemia (alternative agent):Note: Use of pravastatin should be limited to patients unable to tolerate a high-intensity statin. Multiple lipid-lowering therapies may be needed if statin monotherapy is not effective. Referral to a lipid specialist should be considered if treatment goals are not met (ACC/AHA [Grundy 2019]; Rosenson 2020a).Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):Moderate-intensity therapy: Oral: 40 to 80 mg once daily (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).hom*ozygous familial hypercholesterolemiahom*ozygous familial hypercholesterolemia (alternative agent):Note: Use of pravastatin should be limited to patients unable to tolerate a high-intensity statin. Multiple lipid-lowering therapies may be needed if statin monotherapy is not effective. Referral to a lipid specialist should be considered if treatment goals are not met (ACC/AHA [Grundy 2019]; Rosenson 2020a).Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):Moderate-intensity therapy: Oral: 40 to 80 mg once daily (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).Prevention of atherosclerotic cardiovascular diseasePrevention of atherosclerotic cardiovascular disease:Note: If LDL-C goal (eg, percent reduction or absolute goal) is not met with the initial dose, may consider up-titration based on estimated 10-year ASCVD risk (see ACC/AHA ASCVD Risk Estimator Plus online), LDL-C response, and tolerability. If LDL-C goal is not met with maximally tolerated dose, consider switching to a high-intensity statin (atorvastatin or rosuvastatin); additional lipid-lowering therapy may be warranted (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).Primary prevention:Patients without diabetes, 40 to 75 years of age, and LDL-C 70 to 189 mg/dL:ASCVD 10-year risk 5% to <7.5%:Note: Depending on baseline LDL-C and presence of risk-enhancing factors, consider statin therapy after shared decision-making with patient. Some experts suggest shared decision-making if ASCVD 10-year risk is 5% to 10%; however, in patients with a baseline LDL-C ≥160 mg/dL, statin therapy is usually recommended (Pignone 2020).Moderate-intensity therapy: Oral: 40 to 80 mg once daily to reduce LDL-C by 30% to 49% (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).ASCVD 10-year risk ≥7.5% to <20%:Note: Depending on baseline LDL-C and presence of risk-enhancing factors, consider statin therapy after shared decision-making with patient. Some experts suggest initiating moderate-intensity statin therapy in most patients if ASCVD 10-year risk is >10% to <20% and LDL-C is >100 mg/dL (Pignone 2020).Moderate-intensity therapy: Oral: 40 to 80 mg once daily to reduce LDL-C by 30% to 49%; higher-risk patients with multiple risk-enhancing factors may benefit from high-intensity statin therapy (ie, with atorvastatin or rosuvastatin) to reduce LDL-C by ≥50% (ACC/AHA [Grundy 2019]).ASCVD 10-year risk ≥20% (alternative agent):Note: Use of pravastatin should be limited to patients unable to tolerate a high-intensity statin (ACC/AHA [Grundy 2019]; Rosenson 2020a).Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):Moderate-intensity therapy: Oral: 40 to 80 mg once daily (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).Patients with diabetes:Age 40 to 75 years without additional ASCVD risk factors:Moderate-intensity therapy: Oral: 40 to 80 mg once daily to reduce LDL-C by 30% to 49% (ACC/AHA [Grundy 2019; ACC/AHA [Stone 2014]).ASCVD 10-year risk ≥20% or multiple ASCVD risk factors (alternative agent):Note: Use of pravastatin should be limited to patients unable to tolerate a high-intensity statin (ACC/AHA [Grundy 2019]; Rosenson 2020a).Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):Moderate-intensity therapy: Oral: 40 to 80 mg once daily (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).Patients with LDL-C ≥190 mg/dL and 20 to 75 years of age (regardless of ASCVD risk estimate or coexisting diabetes mellitus) (alternative agent): Note: Use of pravastatin should be limited to patients unable to tolerate a high-intensity statin (ACC/AHA [Grundy 2019]; Rosenson 2020a).Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):Moderate-intensity therapy: Oral: 40 to 80 mg once daily (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).Secondary prevention in patients with established atherosclerotic cardiovascular disease (eg, coronary heart disease, cerebrovascular disease [ischemic stroke or transient ischemic attack], peripheral arterial disease) (alternative agent):Note: Use of pravastatin should be limited to patients unable to tolerate a high-intensity statin (ACC/AHA [Grundy 2019]; Rosenson 2020a). Patients with high-risk ASCVD may require additional therapies to achieve LDL-C goal (eg, <70 mg/dL or <50 mg/dL if very high risk) (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]; Rosenson 2020b).Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):Moderate-intensity therapy: Oral: 40 to 80 mg once daily (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]).TransplantationTransplantation:Note: Certain immunosuppressive drugs can induce or exacerbate hypercholesterolemia. Significant drug interactions between statins and immunosuppressant drugs are frequent; some interactions can increase statin serum concentrations and risk of toxicity (eg, myopathy) (AHA [Wiggins 2016]; Eisen 2022; ISHLT [Costanzo 2010]; KDIGO [Tonelli 2014]; Lentine 2022). Consult drug interactions database for more detailed information.Transplantation, post heart (off-label use): Oral: Initial: 20 mg once daily starting 1 to 2 weeks after transplant, regardless of baseline cholesterol levels; increase to the maximum tolerated dose within 4 to 8 weeks of transplantation based on response and concomitant drugs up to 40 mg once daily (AHA [Wiggins 2016]; Eisen 2022; ISHLT [Costanzo 2010]).Transplantation, post kidney (off-label use):Note: The decision to initiate therapy for primary or secondary prevention is similar to the nontransplant population (see "Use: Prevention of atherosclerotic cardiovascular disease"). However, in patients who are 30 to 39 years of age, some experts suggest statin therapy post-kidney transplantation for primary prevention of ASCVD. For primary prevention of ASCVD in patients 18 to 29 years of age, use shared decision making while considering risks and benefits (Lentine 2022).Oral: Initial: 20 mg once daily; increase dose based on response, tolerability, and concomitant drugs up to 40 mg once daily (AHA [Wiggins 2016]; Lentine 2022).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MSAltered kidney function: Oral:CrCl >30 mL/minute: No dosage adjustment necessary (Halstenson 1992).CrCl ≤30 mL/minute: Initial: 10 mg once daily. May increase based on efficacy and tolerability up to the indication-specific usual recommended dose (Launay-Vachar 2005; manufacturer's labeling).Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (Gehr 1997):Note: Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend not initiating a statin in dialysis patients due to lack of benefits shown in this population; however, patients initiated on a statin before progressing to dialysis may continue to receive therapy (KDIGO [Tonelli 2014]).Oral: Dose as for CrCl ≤30 mL/minute (Gehr 1997; Nishizawa 1995; expert opinion).Peritoneal dialysis: Unlikely to be significantly dialyzed (expert opinion):Note: KDIGO guidelines recommend not initiating a statin in dialysis patients due to lack of benefits shown in this population; however, patients initiated on a statin before progressing to dialysis may continue to receive therapy (KDIGO [Tonelli 2014]).Oral: Dose as for CrCl ≤30 mL/minute (Nishizawa 1995; expert opinion).CRRT: Dose as for CrCl ≤30 mL/minute (expert opinion).PIRRT (eg, sustained, low-efficiency diafiltration): Oral: Dose as for CrCl ≤30 mL/minute (expert opinion).Dosing: Hepatic Impairment: AdultActive hepatic disease or unexplained persistent elevations of serum transaminases: Use is contraindicated.Chronic liver disease: Some experts suggest starting at a low dose (eg, 10 mg once daily) and adjusting gradually based on monitoring of aminotransferase levels (Rosenson 2018).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productTablet, Oral, as sodium: Pravachol: 20 mg [DSC]Pravachol: 40 mg [DSC] [contains fd&c blue #1 (brill blue) aluminum lake, quinoline (d&c yellow #10) aluminum lake]Pravachol: 80 mg [DSC]Generic: 10 mg, 20 mg, 40 mg, 80 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productTablet, Oral, as sodium: Pravachol: 20 mg [DSC]Pravachol: 40 mg [DSC] [contains fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]Generic: 10 mg, 20 mg, 40 mgAdministration: PediatricOral: May be taken without regard to meals or time of day; administer at least 1 hour before or 4 hours after bile acid resins.Administration: AdultOral: Administer without regard to meals.Storage/StabilityStore at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.UseAdjunct to dietary therapy in patients with heterozygous familial hypercholesterolemia (HFH) hypercholesterolemia if LDL-C remains ≥190 mg/dL or if ≥160 mg/dL with family history of premature cardiovascular (CVD) or presence of ≥2 cardiovascular risk (FDA approved in children ≥8 years of age and adolescents). Adjunct to dietary therapy to decrease elevated serum total and low density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo-B), and triglyceride levels, and to increase high density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia (heterozygous, familial, and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb; FDA approved in adults); adjunct to dietary therapy in patients with isolated hypertriglyceridemia (Fredrickson type IV; FDA approved in adults); treatment of primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet (FDA approved in adults); primary and secondary prevention of cardiovascular disease in high risk patients (FDA approved in adults); primary prevention of cardiovascular disease in high-risk patients (FDA approved in adults).Medication Safety IssuesSound-alike/look-alike issues:Pravachol may be confused with Prevacid, Prinivil, propranololPravastatin may be confused with atorvastatin, nystatin, pitavastatin, prasugrelAdverse Reactions (Significant): ConsiderationsHepatic effectsStatins are associated with increased serum transaminases and hepatotoxicity (Ref). Asymptomatic transient or persistent increases both <3 or >3 times the ULN in serum transaminases may occur with all statins; the increased serum alanine aminotransferase (ALT) is typically greater than the increased serum aspartate aminotransferase (AST) (Ref). Acute hepatotoxicity has been documented (Ref).Upon dose reduction or discontinuation, transaminase levels return to or near pretreatment levels; although, mild elevations resolve with continued use in some cases (Ref). In patients with acute hepatotoxicity, resolution of symptoms usually occurs within 1 to 2 months; however, some cases may not normalize until 5 months after discontinuation (Ref). Chronic liver injury (defined as liver biochemical or histological abnormalities that persisted for 6 months or more after onset) have been reported (Ref).Mechanism: Unknown; pravastatin undergoes minimal hepatic metabolism. Minor toxic intermediate metabolites may cause mild increases in ALT (Ref). Pravastatin can induce liver mitochondrial redox imbalance, which may contribute to hepatotoxicity (Ref). Acute liver injury may be idiosyncratic or via immune-mediated mechanisms (Ref).Onset: Varied; duration of therapy prior to hepatotoxicity ranges from 1 month to several years (Ref). Most cases occur within the first 3 months of initiation or dose escalation (Ref).Risk factors:• Higher doses may increase the risk of liver injury (Ref).• Concurrent medications with statin drug-drug interactions or hepatotoxic properties (Ref)• Hepatotoxicity is more commonly associated with atorvastatin than pravastatin, rosuvastatin, and simvastatin (Ref). Fluvastatin is associated with the greatest risk of developing hepatotoxicity (Ref).• Cross-reactivity between different statins and the susceptibility to hepatotoxicity is unknown, as data have shown conflicting results (Ref).• Chronic hepatitis B and alcohol consumption are independent risk factors for hepatic aminotransferase elevation associated with statins in patients 80 years of age or older (Ref).Muscle-related effectsStatins are associated with several muscle-related effects, including:• Myalgia (muscle symptoms without significant creatine kinase [CK] elevations; also known as statin-associated muscle symptoms) (Ref)• Myopathy (defined as unexplained muscle pain or weakness accompanied by a CK >10 times the ULN) (Ref)• Rhabdomyolysis (CK >40 times the ULN) (Ref) often with acute renal failure secondary to myoglobinuria (Ref)• Immune-mediated necrotizing myopathy (IMNM) (elevated CK plus the presence of autoantibodies against HMG-CoA reductase) (Ref)Mechanism: Uncertain; alterations in the mevalonate pathway and changes in the electrical and structural characteristics of the sarcolemma related to calcium ion flux possibly contribute (Ref). Decreased ubiquinone, which is essential for energy production in skeletal muscle, may also contribute (Ref). Myopathy/rhabdomyolysis risk is related to circulating active drug concentrations (Ref). IMNM is considered an immune-mediated process; autoantibodies against HMG-CoA reductase (anti-HMG-CoA) have been identified (Ref).Onset: Delayed; often presents within a few months after starting therapy (highest risk within first year of use), when the dose of the statin is increased, or when introducing an interacting drug (Ref). Muscle symptoms often appear more promptly when patients are reexposed to the same statin (Ref). Duration of statin use prior to development of IMNM is ~2 to 3.5 years (Ref).Risk factors:• First year of therapy (Ref)• Dose increase (for myopathy and rhabdomyolysis, but not IMNM) (Ref)• Addition of an interacting drug (eg, concurrent use of medications associated with myopathy [eg, gemfibrozil]) (Ref). Since there is minimal metabolism of pravastatin by CYP3A4, low risk for clinically significant drug interactions with CYP3A4 inhibitors; however, concomitant use of inhibitors of OATP1B1 (eg, cyclosporine) or OATP1B3 may result in increased pravastatin plasma levels (Ref)• Older patients (Ref)• Hypothyroidism (Ref)• Preexisting muscle disease (Ref)• Kidney impairment (Ref)• Females (Ref)• Low body mass index (Ref)• Heavy exercise (Ref)• Surgery (Ref)• Higher HMG-COA reductase inhibitory activity (Ref), rosuvastatin > atorvastatin > simvastatin > pravastatin ≈ lovastatin (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.>10%:Neuromuscular & skeletal: Musculoskeletal pain (25%) (table 1)Pravastatin: Adverse Reaction: Musculoskeletal PainPravastatin: Adverse Reaction: Musculoskeletal PainDrug (Pravastatin)Placebo DoseNumber of Patients (Pravastatin)Number of Patients (Placebo)25%24%40 mg once daily10,76410,719Respiratory: Upper respiratory tract infection (21%)1% to 10%: Respiratory: Cough (8%)<1%: Neuromuscular & skeletal: MyopathyFrequency not defined: Cardiovascular: Increased serum creatine kinasePostmarketing:Cardiovascular: VasculitisDermatologic: Erythema multiforme, lichen planus, skin changes (including changes to hair/nails, discoloration, dryness of mucous membranes, nodules), skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysisEndocrine & metabolic: Decreased libido (de Graaf 2004), diabetes mellitus (including exacerbation of diabetes mellitus) (Ohmura 2005), elevated glycosylated hemoglobin (Ohmura 2005), gynecomastia, increased in fasting plasma glucose, thyroid dysfunctionGastrointestinal: Abdominal pain, constipation, pancreatitis (Tarar 2021; Tsigrelis 2006)Genitourinary: Cystitis (interstitial) (Huang 2015), dysuria, nocturia, urinary frequencyHematologic & oncologic: Eosinophilia, hemolytic anemia, increased erythrocyte sedimentation rate, positive ANA titer, purpuric diseaseHepatic: Acute hepatotoxicity (Hartleb 1999), cholestatic jaundice, fulminant hepatic necrosis, hepatic cirrhosis, hepatic failure, hepatic neoplasm, hepatitis, increased serum transaminases, liver steatosisHypersensitivity: Anaphylaxis, angioedemaImmunologic: DermatomyositisNervous system: Asthenia, chills, cranial nerve disorder (including dysgeusia, facial paresis, impairment of extraocular movement), malaise, myasthenia (Purvin 2006), nightmares, peripheral nerve palsyNeuromuscular & skeletal: Arthralgia, arthritis, immune-mediated necrotizing myopathy (Essers 2019), lupus-like syndrome, myalgia (Selva-O’Callaghan 2018, Stroes 2015), polymyalgia rheumatica, polymyositis, rhabdomyolysis (Takei 1999), tendinopathyRespiratory: Dyspnea, interstitial pulmonary disease, pleural effusion (Kalomenidis 2007)ContraindicationsHypersensitivity to pravastatin or any component of the formulation; active liver disease or decompensated cirrhosis.Warnings/PrecautionsConcerns related to adverse effects:• Diabetes mellitus: Increases in HbA1c and fasting blood glucose have been reported with HMG-CoA reductase inhibitors; however, the benefits of statin therapy far outweigh the risk of dysglycemia.• Myopathy/rhabdomyolysis: Discontinue therapy in any patient in which CPK levels are markedly elevated (>10 times ULN) or if myopathy is suspected/diagnosed.Disease-related concerns:• Hepatic impairment: Use with caution in patients who consume large amounts of ethanol and/or have a history of liver disease. May require dosage adjustment in some patients with hepatic impairment.• Myasthenia gravis: May rarely worsen or precipitate myasthenia gravis (MG); monitor for worsening MG if treatment is initiated (AAN [Narayanaswami 2021]).Special Populations:• Older adult: Use with caution in patients with advanced age, these patients are predisposed to myopathy.• Surgical patients: Based on current research and clinical guidelines, HMG-CoA reductase inhibitors should be continued in the perioperative period for noncardiac and cardiac surgery (ACC/AHA [Fleisher 2014]; ACC/AHA [Hillis 2011]). Perioperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.Metabolism/Transport EffectsSubstrate of CYP3A4 (minor), OAT1/3, OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAcipimox: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapyAntihepaciviral Combination Products: May increase the serum concentration of Pravastatin. Management: Limit the pravastatin dose to a maximum of 40 mg per day when used with antihepaciviral combination products and monitor patients for evidence of pravastatin toxicities (eg, myopathy). Risk D: Consider therapy modificationAsunaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapyBempedoic Acid: May increase the serum concentration of Pravastatin. Management: Avoid coadministration of bempedoic acid with pravastatin doses greater than 40 mg due to the potential for increased pravastatin concentrations and pravastatin-related myopathy. Risk D: Consider therapy modificationBezafibrate: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Bezafibrate may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). More specifically, bezafibrate may increase the serum concentration of fluvastatin Management: Avoid use of bezafibrate and HMG-CoA reductase inhibitors (statins) unless strictly indicated due to the increased of muscle toxicity (including rhabdomyolysis). In patients who may be predisposed to myopathy, concomitant use is contraindicated. Risk D: Consider therapy modificationBile Acid Sequestrants: May decrease the serum concentration of Pravastatin. Management: Administer pravastatin at least 1 hour before or 4 hours after administration of bile-acid resins (eg, cholestyramine, colestipol, colesevelam) to minimize the risk for any significant interaction. Risk D: Consider therapy modificationCarBAMazepine: May decrease the serum concentration of Pravastatin. Risk C: Monitor therapyCiprofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Management: Avoid the use of HMG-CoA reductase inhibitors and ciprofibrate if possible. If concomitant therapy is considered, benefits should be carefully weighed against the risks, and patients should be monitored closely for signs/symptoms of muscle toxicity. Risk D: Consider therapy modificationClarithromycin: May increase the serum concentration of Pravastatin. Management: Limit pravastatin to a maximum of 40 mg/day when used in combination with clarithromycin. If this combination is used, monitor patients more closely for evidence of pravastatin toxicity. Risk D: Consider therapy modificationColchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). HMG-CoA Reductase Inhibitors (Statins) may increase the serum concentration of Colchicine. Risk C: Monitor therapyCycloSPORINE (Systemic): May increase the serum concentration of Pravastatin. Pravastatin may increase the serum concentration of CycloSPORINE (Systemic). Management: Initiate pravastatin dose at 10 mg daily and limit the maximum pravastatin dose to 20 mg daily in patients who are also receiving cyclosporine. Monitor for pravastatin toxicities (eg, myalgia, myopathy, rhabdomyolysis) if combined. Risk D: Consider therapy modificationDaclatasvir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapyDAPTOmycin: HMG-CoA Reductase Inhibitors (Statins) may enhance the adverse/toxic effect of DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased.Management: Consider temporarily stopping statin (HMG-CoA reductase inhibitor) therapy prior to daptomycin. If daptomycin is used with a statin, creatine phosphokinase (CPK) monitoring could be considered. Risk D: Consider therapy modificationDarolutamide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyDarunavir: May increase the serum concentration of Pravastatin. This effect has been demonstrated with darunavir/ritonavir and may occur with darunavir/cobicistat. The individual contributions of darunavir, ritonavir, and cobicistat are unknown. Risk C: Monitor therapyEfavirenz: May decrease the serum concentration of Pravastatin. Risk C: Monitor therapyEltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyEncorafenib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyErythromycin (Systemic): May increase the serum concentration of Pravastatin. Management: Limit pravastatin dose to a maximum of 40 mg/day when used in combination with erythromycin. If this combination is used, monitor patients more closely for evidence of pravastatin toxicity. Risk D: Consider therapy modificationFenofibrate and Derivatives: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapyFostemsavir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest possible starting statin dose and monitor patients closely for statin-related adverse effects (eg, muscle aches and pains) during coadministration with fostemsavir. Risk D: Consider therapy modificationFusidic Acid (Systemic): May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for muscle toxicities, including rhabdomyolysis may be significantly increased. Management: Avoid concurrent use whenever possible. Use is listed as contraindicated in product characteristic summaries in several countries, although UK labeling suggests that use could be considered under exceptional circ*mstances and with close supervision. Risk X: Avoid combinationGemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of Pravastatin. Gemfibrozil may increase the serum concentration of Pravastatin. Risk X: Avoid combinationGlecaprevir and Pibrentasvir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest statin dose possible if combined with glecaprevir/pibrentasvir and monitor for increased statin effects/toxicities. Avoid concomitant use with atorva-, simva-, or lovastatin. Limit rosuvastatin to 10 mg daily and reduce pravastatin dose 50% Risk D: Consider therapy modificationItraconazole: May increase the serum concentration of Pravastatin. Risk C: Monitor therapyLanthanum: HMG-CoA Reductase Inhibitors (Statins) may decrease the serum concentration of Lanthanum.Management: Administer HMG-CoA reductase inhibitors (eg, statins) at least two hours before or after lanthanum. Risk D: Consider therapy modificationLeflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyLetermovir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapyNelfinavir: May decrease the serum concentration of Pravastatin. Risk C: Monitor therapyNiacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapyPARoxetine: Pravastatin may enhance the adverse/toxic effect of PARoxetine. Specifically, blood glucose elevations may occur with the combination.Risk C: Monitor therapyRaltegravir: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapyRed Yeast Rice: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Risk X: Avoid combinationRepaglinide: HMG-CoA Reductase Inhibitors (Statins) may increase the serum concentration of Repaglinide.Risk C: Monitor therapyRifAMPin: May decrease the serum concentration of Pravastatin. Risk C: Monitor therapyRoxadustat: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapyRupatadine: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for increased CPK and/or other muscle toxicities may be increased. Risk C: Monitor therapySaquinavir: May decrease the serum concentration of Pravastatin. This effect has only been demonstrated with saquinavir/ritonavir. The individual contributions of saquinavir and ritonavir are unknown. Risk C: Monitor therapySimeprevir: May increase the serum concentration of Pravastatin. Risk C: Monitor therapyTelithromycin: May increase the serum concentration of Pravastatin. Risk C: Monitor therapyTeriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyTrabectedin: HMG-CoA Reductase Inhibitors (Statins) may enhance the myopathic (rhabdomyolysis) effect of Trabectedin.Risk C: Monitor therapyVitamin K Antagonists (eg, warfarin): HMG-CoA Reductase Inhibitors (Statins) may enhance the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapyVoclosporin: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyVoxilaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest statin dose possible if combined with voxilaprevir and monitor patients for increased statin effects/toxicities. Avoid concomitant use of voxilaprevir with rosuvastatin or pitavastatin, and limit pravastatin doses to 40 mg daily. Risk D: Consider therapy modificationDietary ConsiderationsBefore initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 6 weeks and the diet should be continued during drug therapy.Red yeast rice contains variable amounts of several compounds that are structurally similar to HMG-CoA reductase inhibitors, primarily monacolin K (or mevinolin) which is structurally identical to lovastatin; concurrent use of red yeast rice with HMG-CoA reductase inhibitors may increase the incidence of adverse and toxic effects (Lapi 2008; Smith 2003). Reproductive ConsiderationsAdequate contraception is recommended if an HMG-CoA reductase inhibitor (statin) is required in patients who may become pregnant (AHA/ACC [Grundy 2019]; CCS [Pearson 2021]). Patients planning to become pregnant should discuss their lifetime risk of cardiovascular disease, as well as risks and benefits of statin therapy with their health care team (CCS [Pearson 2021]). When appropriate, statins can be discontinued 1 to 2 months prior to conception (AHA/ACC [Grundy 2019]).When a statin is needed in a patient of reproductive potential, a more hydrophilic option (eg, pravastatin, rosuvastatin) may be preferred to limit placental transfer (CCS [Pearson 2021]).Pregnancy ConsiderationsPravastatin crosses the placenta (Ahmed 2020; Costantine 2016; Costantine 2021; Nanovskaya 2013).Cord blood concentrations were near or below the limit of quantification (<0.1 ng/mL) in 10 women administered pravastatin 10 mg once daily (Costantine 2016). Following administration of pravastatin 10 mg once daily to 1 patient during pregnancy, the estimated placental transfer was 25.5%; pravastatin was not detected in the infant serum 4 days after delivery. In a second patient administered pravastatin 10 mg once daily during pregnancy, the estimated placental transfer was 23.8% of the maternal dose, and pravastatin was not detected in infant serum when measured 1 day after birth (Saito 2021).In healthy pregnancies, changes in lipid synthesis occur that are required for normal placental and fetal growth. Low-density lipoprotein cholesterol and triglycerides increase as pregnancy progresses and decline postpartum. HMG-CoA reductase inhibitors (statins) decrease the synthesis of cholesterol and substances derived from cholesterol. Therefore, based on the mechanism of action, in utero exposure may cause fetal harm (Lecarpentier 2012); however, data from available studies have not shown an increased risk of major congenital anomalies following first trimester exposure (Bateman 2015; Chang 2021; Vahedian-Azimi 2021a). Additional data are needed to evaluate other pregnancy outcomes, such as miscarriage (Vahedian-Azimi 2021b).Due to pregnancy-induced physiologic changes, some pharmaco*kinetic properties of pravastatin may be altered (limited data) (Costantine 2016; Costantine 2021).Because there is potential for fetal harm, statins should be discontinued once pregnancy is recognized (AHA/ACC [Grundy 2019]; Brunham 2018). If lipid-lowering therapy during pregnancy is required, it should be individualized based on the therapeutic needs of the patient, considering the lifetime risk of untreated disease, use of nonstatin therapies, as well as the known risks and benefits of statins. Based on limited data, when a statin is needed in a pregnant patient, a more hydrophilic option (eg, pravastatin, rosuvastatin) may be preferred. Lipophilic statins (eg, atorvastatin, fluvastatin, lovastatin, simvastatin, pitavastatin) may be more likely to cross the placenta and increase the risk of congenital malformations (AHA/ACC [Grundy 2019]; CCS [Pearson 2021]; Lecarpentier 2012).Additional data are needed to clarify the role of statins for the prevention of atherosclerotic cardiovascular disease in at-risk pregnant patients (AHA/ACC [Grundy 2019]; AHA [Parikh 2021]; CCS [Pearson 2021]).Monitoring ParametersManufacturer's labeling: Consider neuromuscular and serologic testing if immune-mediated necrotizing myopathy is suspected.​Pediatric patients: Baseline: ALT, AST, and creatine phosphokinase levels (CPK); fasting lipid panel (FLP) and repeat ALT and AST should be checked after 4 weeks of therapy; if no myopathy symptoms or laboratory abnormalities, then monitor FLP, ALT, and AST every 3 to 4 months during the first year and then every 6 months thereafter (NHLBI 2011).Adults:2013 ACC/AHA Blood Cholesterol Guideline recommendations (Stone 2013):Lipid panel (total cholesterol, HDL, LDL, triglycerides): Baseline lipid panel; fasting lipid profile within 4 to 12 weeks after initiation or dose adjustment and every 3 to 12 months (as clinically indicated) thereafter. If 2 consecutive LDL levels are <40 mg/dL, consider decreasing the dose.Hepatic transaminase levels: Baseline measurement of hepatic transaminase levels (ie, ALT); measure hepatic function if symptoms suggest hepatotoxicity (eg, unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of skin or sclera) during therapy.CPK: CPK should not be routinely measured. Baseline CPK measurement is reasonable for some individuals (eg, family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy). May measure CPK in any patient with symptoms suggestive of myopathy (pain, tenderness, stiffness, cramping, weakness, or generalized fatigue).Evaluate for new-onset diabetes mellitus during therapy; if diabetes develops, continue statin therapy and encourage adherence to a heart-healthy diet, physical activity, a healthy body weight, and tobacco cessation.If patient develops a confusional state or memory impairment, may evaluate patient for nonstatin causes (eg, exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy.Manufacturer recommendations: Liver enzyme tests at baseline and repeated when clinically indicated. Upon initiation or titration, lipid panel should be analyzed at intervals of 4 weeks or more. Mechanism of ActionPravastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is the rate-limiting enzyme involved in de novo cholesterol synthesis. In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity C-reactive protein (hsCRP), they also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects (de Denus 2002; Ray 2005).Pharmaco*kinetics (Adult data unless noted)Onset of action: Several daysPeak effect: 4 weeksLDL-reduction: 40 mg/day: 34% (for each doubling of this dose, LDL-C is lowered by ~6%)Absorption: Rapidly absorbed; average absorption 34%Distribution: Vd: 0.46 L/kg Protein binding: ~50%Metabolism: Hepatic multiple metabolites; primary metabolite is 3 alpha-hydroxy-iso-pravastatin (2.5% to 10% activity of parent drug); extensive first-pass metabolismBioavailability: 17%Half-life elimination:Children and Adolescents (4.9 to 15.6 years): 1.6 hours; range: 0.85 to 4.2 hours (Hedman 2003)Adults: 77 hours (including all metabolites); Pravastatin: ~2 to 3 hours (Pan 1990); 3 alpha-hydroxy-iso-pravastatin: ~1.5 hours (Gustavson 2005) Time to peak, serum: 1 to 1.5 hours Excretion: Feces (70%); urine (~20%, 8% as unchanged drug)Pharmaco*kinetics: Additional ConsiderationsOlder adult: Mean AUC was approximately 27% greater and mean cumulative urinary excretion was approximately 19% lower in elderly men. Mean AUC was approximately 46% higher and mean cumulative urinary excretion was approximately 18% lower in elderly women.Pricing: USTablets (Pravastatin Sodium Oral)10 mg (per each): $2.61 - $3.2220 mg (per each): $2.83 - $3.2740 mg (per each): $4.17 - $4.7980 mg (per each): $4.79Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAgivastar (VN);Astin (MX);Brakhor (MX);Bristacol (ES);Brufincol (CR, DO, GT, HN, MX, NI, PA, SV);Cholespar (ID);Cholestate (EG);Cholstat (AU);Cholvastin (NZ);Col-Alphar (MX);Colite (ZA);Colpradin (CR, DO, GT, HN, MX, NI, PA, SV);Elisor (FR);Emipastin (CR, DO, GT, HN, MX, NI, PA, SV);Geastatin (FI);Genoestatina (MX);Kenstatin (MX);Koloskol (ID);Lipemol (ES);Lipista (VN);Lipizad (EG);Liplat (ES);Lipostat (AE, AU, BG, BH, EE, EG, GB, IE, JO, KW, LB, PL, QA, SA);Loretsin (MX);Lowchol (JO);Mechol (TW);Mevachol (ID);Mevalotin (BR, CH, CN, JP, KR, TW, VE);Mevalotin Protect (TH);Mevatorte (JP);Nikron (HU);Novales (ID);Novina (MX);Panchol (AT);Pitaduce (KR);Pixeta (ZA);Prastan (KR);Pratin (MY, TW);Pravachol (AU, BB, BM, BS, BZ, GR, GY, HK, JM, NO, NZ, PE, PK, SR, TR, TT, VE);Pravacol (AR, BR, CL, EC, MX, PE, PT);Pravalip (IL);Pravamel (IE);Pravaselect (IT);Pravasin (DE, LU);Pravasine (BE);Pravastax (CH);Pravat (IE);Pravator (IN, PL, RO, VE);Pravaz (PH);Pravinat (HK);Pravitin (IE);Pravyl (CO);Prereduct (BE);Pritanol (PT);Pu Hui Zhi (CN);Ronstatin (AR);Sanapran (PT);Sanaprav (AT);Selectin (IT);Selektine (NL);Selipran (AT, CH);Setac (IT);Stavacor (LB);Stavenir (IL);Tissulest (MX);Vasten (FR)For country code abbreviations (show table)Ahmed A, Williams DJ, Cheed V, et al; StAmP trial Collaborative Group. 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