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Clinicians have a legal and ethical responsibility to provide patients with adequate information that they can process and use to make appropriate decisions. During pregnancy, informed consent can be described as the process of decision-making between a patient and the health care provider regarding

The concept of medical futility is an ancient one. Hippocrates counseled clinicians not to treat patients who were “overmastered by their disease.” For centuries, most codes of medical ethics have stipulated that doctors should not recommend or provide treatments that, by their clinical judgment, wo

Glucagon-like peptide 1 (GLP-1)-based therapies (eg, dipeptidyl peptidase 4 [DPP-4] inhibitors, GLP-1 receptor agonists) affect glucose control through several mechanisms, including enhancement of glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon an

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. 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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

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. Long term follow-up of sulfur mustard related bronchiolitis obliterans treatment. Acta Med Iran. 2016;54(9):605-609. [PubMed 27832694]Adachi JA, Ericsson CD, Jiang ZD, et al. Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico. Clin Infect Dis. 2003;37(9):1165-1171. doi:10.1086/378746 [PubMed 14557959]Agha R, Goldberg MB. Shigella infection: treatment and prevention in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 16, 2021.Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD [published correction appears in N Engl J Med. 2012;366(14):1356]. N Engl J Med. 2011;365(8):689-698. [PubMed 21864166]Almalki ZS, Guo JJ. Cardiovascular events and safety outcomes associated with azithromycin therapy: a meta-analysis of randomized controlled trials. Am Health Drug Benefits. 2014;7(6):318-328. 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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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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

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

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 ac