PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Small Molecule Antineoplastic Janus Associated Kinase (JAKs) Inhibitors

    BOXED WARNING

    Encephalopathy, thiamine deficiency

    Serious and fatal encephalopathy including Wernicke encephalopathy, a neurologic emergency, has been reported with fedratinib therapy. Obtain thiamine levels prior to starting therapy, periodically during therapy, and as clinically indicated thereafter. Replete thiamine with supplementation as indicated. Patients with thiamine deficiency may be at increased risk for developing encephalopathy; therefore, do not start fedratinib in patients with thiamine deficiency until after thiamine levels are repleted. Patients may develop neurological symptoms (e.g., confusion, mental status changes, memory impairment, ataxia, and visual symptoms such as nystagmus or diplopia) during fedratinib therapy; evaluate patients with a neurologic exam and imaging tests if neurological symptoms occur. Immediately discontinue fedratinib if Wernicke encephalopathy is suspected and initiate IV thiamine treatment; monitor patients until symptoms resolve or improve and thiamine levels normalize.[64568]

    DEA CLASS

    Rx

    DESCRIPTION

    JAK2 and FLT3 kinase inhibitor
    Used for adults with intermediate-2 or high-risk primary or secondary myelofibrosis
    Boxed warning regarding encephalopathy risk; evaluate for thiamine deficiency and replete thiamine levels prior to treatment

    COMMON BRAND NAMES

    INREBIC

    HOW SUPPLIED

    INREBIC Oral Cap: 100mg

    DOSAGE & INDICATIONS

    For the treatment of intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.
    NOTE: The FDA has designated fedratinib as an orphan drug for the treatment of primary or secondary myelofibrosis.
    Oral dosage
    Adults

    400 mg orally once daily in patients with a baseline platelet count of 50 X 109 cells/L or greater. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Consider prophylactic anti-emetic therapy (e.g., 5-HT3 receptor antagonists) during fedratinib therapy. If applicable, taper and discontinue treatment with ruxolitinib prior to starting fedratinib. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop severe toxicity. The proportion of patients achieving a 35% reduction from baseline or greater in spleen volume after 6 cycles of therapy was significantly higher in patients (median age, 65 years; range, 27 to 86 years) with intermediate-2 or high-risk primary or secondary myelofibrosis who received fedratinib 400 mg/day compared with placebo (37% vs. 1%; p less than 0.0001) in a multinational, randomized (1:1:1), double-blind, 3-arm, phase 3 trial (n = 289). The median duration of spleen response was 18.2 months in the fedratinib 400 mg/day arm. Additionally, patients who received fedratinib 400 mg/day had reduced myelofibrosis symptoms at the end of cycle 6 compared with placebo as measured by the modified Myelofibrosis Symptom Assessment Form. The proportion of patients who had 50% or greater reduction in the total symptom score was 40% in the fedratinib 400 mg/day arm and 9% in the placebo arm (p less than 0.0001).[64568]

    MAXIMUM DOSAGE

    Adults

    400 mg/day PO.

    Geriatric

    400 mg/day PO.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Severe hepatic impairment at baseline (total bilirubin level greater than 3-times the upper limit of normal (ULN) and any AST level): Avoid use.
    Treatment-Related Toxicity
    Grade 3 or higher increased ALT or AST levels (greater than 5-times the ULN) or bilirubin levels: Hold therapy until the toxicity resolves to baseline or grade 1 or less; resume fedratinib at a reduced dose that is 100 mg/day below the previous dose. Monitor liver function tests more frequently after the dose reduction. If grade 3 or higher increased ALT or AST levels recur, discontinue fedratinib.[64568]

    Renal Impairment

    Severe renal impairment at baseline (creatinine clearance of 15 to 29 mL/min): Reduce the fedratinib dose to 200 mg PO once daily.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Take fedratinib with or without food.
    If nausea or vomiting occurs after a dose, taking subsequent doses with a high-fat meal may reduce these side effects.
    If a dose is missed, skip the dose and take the next dose at the regular time.[64568]

    STORAGE

    INREBIC:
    - Store below 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Encephalopathy, thiamine deficiency

    Serious and fatal encephalopathy including Wernicke encephalopathy, a neurologic emergency, has been reported with fedratinib therapy. Obtain thiamine levels prior to starting therapy, periodically during therapy, and as clinically indicated thereafter. Replete thiamine with supplementation as indicated. Patients with thiamine deficiency may be at increased risk for developing encephalopathy; therefore, do not start fedratinib in patients with thiamine deficiency until after thiamine levels are repleted. Patients may develop neurological symptoms (e.g., confusion, mental status changes, memory impairment, ataxia, and visual symptoms such as nystagmus or diplopia) during fedratinib therapy; evaluate patients with a neurologic exam and imaging tests if neurological symptoms occur. Immediately discontinue fedratinib if Wernicke encephalopathy is suspected and initiate IV thiamine treatment; monitor patients until symptoms resolve or improve and thiamine levels normalize.[64568]

    Anemia, neutropenia, thrombocytopenia

    New or worsening hematologic toxicity (e.g., anemia, neutropenia, thrombocytopenia) has been reported with fedratinib therapy. Obtain complete blood counts at baseline, periodically during therapy, and as clinically indicated. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop severe myelosuppression or active bleeding. Consider a fedratinib dose reduction in patients who become red blood cell transfusion dependent.[64568]

    Diarrhea, nausea/vomiting

    Gastrointestinal toxicity (e.g., diarrhea, nausea/vomiting) has been reported with fedratinib therapy. Consider administering a prophylactic anti-emetic agent (e.g., 5-HT3 receptor antagonists) during fedratinib therapy. Treat diarrhea with anti-diarrheal medications at the first onset of symptoms. Therapy interruption and a dose reduction may be necessary in patients who develop severe nausea, vomiting, or diarrhea not responding to supportive measures within 48 hours.[64568]

    Hepatic disease, hepatotoxicity

    Hepatotoxicity (e.g., elevated hepatic enzymes) has been reported with fedratinib therapy; use is not recommended in patients with severe hepatic disease/impairment [total bilirubin level greater than 3-times the upper limit of normal (ULN), regardless of AST level]. Obtain liver function tests (LFTs) at baseline, periodically during therapy, and as clinically indicated. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop severe ALT and/or AST elevations or hepatotoxicity. Monitor LFTs more frequently after the dose reduction.[64568]

    Pancreatitis

    Elevated pancreatic enzymes (e.g., hyperamylasemia) have been reported in patients who received fedratinib therapy; 1 case of pancreatitis was reported. Obtain amylase and lipase levels at baseline, periodically during therapy, and as clinically indicated. Therapy interruption may be necessary in patients who develop elevated pancreatic enzymes or pancreatitis.[64568]

    Renal failure, renal impairment

    Reduce the fedratinib dose in patients with severe renal impairment [creatinine clearance (CrCl) of 15 to 29 mL/minute]. Obtain renal function tests (e.g., serum creatinine level/BUN) at baseline, periodically during therapy, and as clinically indicated in these patients. No modification of the starting dose is recommended for patients with mild to moderate renal impairment (CrCl 30 to 89 mL/minute). Due to the potential increase of exposure, patients with pre-existing moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions. No specific recommendations are available for patients with end-stage renal disease (renal failure, CrCl less than 15 mL/minute).[64568]

    Pregnancy

    Consider the benefits versus the risk of therapy prior to administering fedratinib during pregnancy. No well-controlled studies have been conducted evaluating the use of fedratinib in pregnant women. In animal reproduction studies, oral administration of fedratinib to pregnant rats during organogenesis at doses considerably lower than the recommended human daily dose of 400 mg/day resulted in adverse developmental outcomes. Adverse developmental outcomes (e.g., skeletal variations, specifically additional ossification center of neuronal arches) were observed in the offspring of pregnant rats who received fedratinib doses (30 mg/kg/day) that resulted in about 0.1-times the clinical exposure based on AUC values at the recommended human dose. In pregnant rabbits, fedratinib doses of 30 mg/kg/day resulted in no developmental or maternal toxicity; however, doses of 80 mg/kg per day led to maternal death in another study in rabbits.[64568]

    Breast-feeding

    It is not known if fedratinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for serious adverse reactions in a nursing child, women should discontinue breast-feeding during fedratinib therapy and for at least 1 month after the last dose.[64568]

    Children, infants

    The safety and effectiveness of fedratinib in pediatric patients have not been established; there are no data available for infants, children or adolescents.

    ADVERSE REACTIONS

    Severe

    anemia / Delayed / 0-34.0
    neutropenia / Delayed / 5.0-5.0
    diarrhea / Early / 0-5.0
    heart failure / Delayed / 5.0-5.0
    asthenia / Delayed / 5.0-5.0
    fatigue / Early / 5.0-5.0
    hyponatremia / Delayed / 5.0-5.0
    vomiting / Early / 0-3.1
    nephrotoxicity / Delayed / 0-3.1
    hypertension / Early / 3.0-3.0
    hyperamylasemia / Delayed / 2.1-2.1
    encephalopathy / Delayed / 1.3-1.3
    elevated hepatic enzymes / Delayed / 0-1.0
    pancreatitis / Delayed / 0-0.2
    hepatotoxicity / Delayed / Incidence not known

    Moderate

    bone pain / Delayed / 8.0-8.0
    cystitis / Delayed / 6.0-6.0
    dysuria / Early / 6.0-6.0
    angina / Early / 2.0-2.0
    thrombocytopenia / Delayed / 35.0
    constipation / Delayed / 20.0
    nystagmus / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    confusion / Early / Incidence not known
    bleeding / Early / Incidence not known

    Mild

    muscle cramps / Delayed / 12.0-12.0
    musculoskeletal pain / Early / 10.0-10.0
    headache / Early / 9.0-9.0
    weight gain / Delayed / 9.0-9.0
    dizziness / Early / 8.0-8.0
    infection / Delayed / 0-6.0
    nausea / Early / 62.0
    diplopia / Early / Incidence not known
    ecchymosis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with fedratinib. Coadministration may increase the exposure of dolutegravir. Dolutegravir is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
    Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with fedratinib is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with fedratinib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Acetaminophen; Butalbital: (Major) Avoid coadministration of fedratinib with butalbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid coadministration of fedratinib with butalbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of fedratinib with butalbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated. (Moderate) Concomitant use of codeine with fedratinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with fedratinib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with fedratinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Acetaminophen; Dextromethorphan: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. If fedratinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like fedratinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fedratinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetaminophen; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with fedratinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of fedratinib, a moderate CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. If fedratinib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If fedratinib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Alfuzosin: (Moderate) Monitor for evidence of alfuzosin-related adverse effects including hypotension and QT prolongation if coadministered with fedratinib. Increased alfuzosin exposure may occur. Alfuzosin is a CYP3A4 substrate. Fedratinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the alfuzosin AUC by 1.3-fold.
    Aliskiren; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Alprazolam: (Moderate) Monitor for an increase in alprazolam-related adverse reactions including sedation and respiratory depression if coadministration with fedratinib is necessary; consider reducing the dose of alprazolam as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and alprazolam is a CYP3A substrate. Drugs inhibiting this metabolic pathway may have a profound effect on the clearance of alprazolam.
    Amiodarone: (Moderate) If concomitant use of fedratinib with amiodarone is necessary, consider serial measurement of amiodarone serum concentrations. Coadministration may increase amiodarone concentrations resulting in amiodarone-related adverse events. Fedratinib is a moderate CYP3A4 inhibitor and amiodarone is a CYP3A substrate.
    Amitriptyline: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of amitriptyline may be necessary. Amitriptyline is a CYP2D6 and CYP2C19 substrate and fedratinib is a moderate inhibitor of CYP2D6 and CYP2C19.
    Amitriptyline; Chlordiazepoxide: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of amitriptyline may be necessary. Amitriptyline is a CYP2D6 and CYP2C19 substrate and fedratinib is a moderate inhibitor of CYP2D6 and CYP2C19.
    Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Atorvastatin: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Telmisartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amobarbital: (Major) Avoid coadministration of fedratinib with amobarbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; amobarbital is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Amoxapine: (Moderate) Monitor for increased toxicity of amoxapine, such as increased anticholinergic effects, if coadministered with fedratinib. Coadministration may increase serum concentrations of amoxapine. Amoxapine is a CYP2D6 substrate; fedratinib is a moderate CYP2D6 inhibitor.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of fedratinib with clarithromycin as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If clarithromycin is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of fedratinib with clarithromycin as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If clarithromycin is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold. (Moderate) Monitor for increased omeprazole adverse effects as coadministration of omeprazole and fedratinib increased omeprazole exposure by 3-fold in a drug interaction study. Although dose adjustments are not generally needed, patients with Zollinger-Ellison's syndrome who often require higher omeprazole doses may require an adjustment in omeprazole dose. Omeprazole is metabolized primarily by CYP2C19 and secondarily by CYP3A4; fedratinib is an inhibitor of CYP2C19 and CYP3A4.
    Apalutamide: (Major) Avoid coadministration of fedratinib with apalutamide as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of fedratinib and aprepitant/fosaprepitant due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Aprepitant is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Administration of a moderate CYP3A4 inhibitor increased the aprepitant AUC by 2-fold.
    Aripiprazole: (Major) Reduce the oral aripiprazole dose to one-quarter (25%) of the usual dose in patients receiving fedratinib as aripiprazole exposure and adverse effects may be increased. Adults receiving this combination for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during concurrent use. Aripiprazole is a CYP3A4 and CYP2D6 substrate; fedratinib is a moderate inhibitor of both CYP3A4 and CYP2D6.
    Artemether; Lumefantrine: (Moderate) Caution and close monitoring are advised if these drugs are used together. Concomitant use of fedratinib with artemether; lumefantrine may result in increased serum concentrations of artemether; lumefantrine. Artemether and lumefantrine are substrates of the hepatic isoenzyme CYP3A4; fedratinib is a moderate inhibitor of this enzyme.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of fedratinib with butalbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of fedratinib with butalbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated. (Moderate) Concomitant use of codeine with fedratinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with fedratinib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Aspirin, ASA; Carisoprodol: (Moderate) Monitor for an altered clinical response to carisoprodol if coadministration with fedratinib is necessary. Carisoprodol is metabolized by CYP2C19 to form meprobamate. Fedratinib is a moderate CYP2C19 inhibitor. Coadministration could increase exposure to carisoprodol and decrease exposure to meprobamate. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with fedratinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Monitor for an altered clinical response to carisoprodol if coadministration with fedratinib is necessary. Carisoprodol is metabolized by CYP2C19 to form meprobamate. Fedratinib is a moderate CYP2C19 inhibitor. Coadministration could increase exposure to carisoprodol and decrease exposure to meprobamate. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Aspirin, ASA; Omeprazole: (Moderate) Monitor for increased omeprazole adverse effects as coadministration of omeprazole and fedratinib increased omeprazole exposure by 3-fold in a drug interaction study. Although dose adjustments are not generally needed, patients with Zollinger-Ellison's syndrome who often require higher omeprazole doses may require an adjustment in omeprazole dose. Omeprazole is metabolized primarily by CYP2C19 and secondarily by CYP3A4; fedratinib is an inhibitor of CYP2C19 and CYP3A4.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. If fedratinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like fedratinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fedratinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atazanavir: (Major) Avoid coadministration of fedratinib with atazanavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If atazanavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of fedratinib with atazanavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If atazanavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold. (Major) Avoid coadministration of fedratinib with cobicistat as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If cobicistat is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Atovaquone; Proguanil: (Moderate) Monitor for increased proguanil adverse reactions if administered with fedratinib. Proguanil is primarily metabolized by CYP2C19 and fedratinib is a moderate CYP2C19 inhibitor. Potential pharmacokinetic interactions between proguanil and CYP2C19 inhibitors are unknown.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of fedratinib with phenobarbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Avanafil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving fedratinib. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of fedratinib with phenobarbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated. (Moderate) Use caution if coadministration of fedratinib, a moderate CYP3A4 inhibitor, with ergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of ergotamine may be increased resulting in an increase in ergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of ergotamine if necessary.
    Benzhydrocodone; Acetaminophen: (Moderate) Monitor patients for respiratory depression and sedation at frequent intervals if benzhydrocodone is administered with fedratinib. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Concurrent use may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Discontinuation of fedratinib in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If fedratinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Fedratinib is an inhibitor of CYP3A4.
    Bexarotene: (Major) Avoid coadministration of fedratinib with bexarotene as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Bosentan: (Major) Avoid coadministration of fedratinib with bosentan as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. The systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions. Fedratinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor; bosentan is a CYP3A4 substrate and moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and fedratinib as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
    Brexpiprazole: (Major) Reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose if brexpiprazole and fedratinib are coadministered. If fedratinib is discontinued, adjust the brexpiprazole dosage to its original level. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. Brexpiprazole is a CYP3A4 and CYP2D6 substrate. Concomitant use of moderate CYP3A4 inhibitors with a strong or moderate CYP2D6 inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
    Brigatinib: (Major) Avoid coadministration of brigatinib with fedratinib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of fedratinib, resume the brigatinib dose that was tolerated prior to initiation of fedratinib. Brigatinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of fedratinib. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; fedratinib is a moderate inhibitor of CYP3A4. Coadministration with another moderate CYP3A4 inhibitor increased bromocriptine exposure by 2.8-fold.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Budesonide: (Moderate) Avoid coadministration of systemic budesonide with fedratinib due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor.
    Budesonide; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with fedratinib due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor.
    Buprenorphine: (Moderate) Concomitant use of buprenorphine and fedratinib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when fedratinib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping fedratinib, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If fedratinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. fedratinib is a moderate CYP3A4 inhibitor.
    Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and fedratinib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when fedratinib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping fedratinib, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If fedratinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. fedratinib is a moderate CYP3A4 inhibitor.
    Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse reactions if coadministration with fedratinib is necessary; the effect may be more pronounced if the patient has been titrated to a stable dose of buspirone and fedratinib is added or removed from therapy. Buspirone is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased buspirone exposure by 3.4 to 6-fold and was accompanied by increased buspirone-related adverse reactions.
    Butabarbital: (Major) Avoid coadministration of fedratinib with butabarbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; butabarbital is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Caffeine; Ergotamine: (Moderate) Use caution if coadministration of fedratinib, a moderate CYP3A4 inhibitor, with ergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of ergotamine may be increased resulting in an increase in ergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of ergotamine if necessary.
    Cannabidiol: (Moderate) Consider a dose reduction of cannabidiol if coadministered with fedratinib. Coadministration may increase cannabidiol plasma concentrations increasing the risk of adverse reactions. Cannabidiol is metabolized by CYP3A4 and CYP2C19; fedratinib is a moderate inhibitor of CYP3A4 and CYP2C19.
    Carbamazepine: (Major) Avoid coadministration of fedratinib with carbamazepine as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carisoprodol: (Moderate) Monitor for an altered clinical response to carisoprodol if coadministration with fedratinib is necessary. Carisoprodol is metabolized by CYP2C19 to form meprobamate. Fedratinib is a moderate CYP2C19 inhibitor. Coadministration could increase exposure to carisoprodol and decrease exposure to meprobamate. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Ceritinib: (Major) Avoid coadministration of fedratinib with ceritinib as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ceritinib is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Cevimeline: (Moderate) Coadministration of fedratinib may increase systemic exposure of cevimeline resulting in an increase in cevimeline-related adverse reactions. Use caution if coadministration is necessary. Individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, may be at a higher risk of adverse events. Cevimeline is a CYP3A4 and CYP2D6 substrate; fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6.
    Chloramphenicol: (Major) Avoid coadministration of fedratinib with chloramphenicol as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If chloramphenicol is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with fedratinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Dextromethorphan: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with fedratinib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with fedratinib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with fedratinib, and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate. fedratinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%.
    Cimetidine: (Major) Avoid coadministration of fedratinib with cimetidine as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; cimetidine is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    Cisapride: (Major) Avoid the use of fedratinib and cisapride concurrently. Coadministration of fedratinib, a moderate inhibitor of CYP3A4, with cisapride, a CYP3A4 substrate, can increase cisapride exposure leading to toxicity, specifically an increased risk for QT prolongation.
    Citalopram: (Major) Because citalopram causes dose-dependent QT prolongation, the maximum daily dose of citalopram should not exceed 20 mg per day in patients receiving fedratinib. The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with fedratinib, a moderate CYP2C19 inhibitor.
    Clarithromycin: (Major) Avoid coadministration of fedratinib with clarithromycin as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If clarithromycin is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Clobazam: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of omeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fedratinib is a moderate inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam.
    Clomipramine: (Moderate) Monitor for an increase in clomipramine-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of clomipramine may be necessary. Clomipramine is a CYP2D6 and CYP2C19 substrate and fedratinib is a moderate CYP2D6 and CYP2C19 inhibitor.
    Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with fedratinib; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Fedratinib is a moderate CYP3A4 inhibitor and clonazepam is a CYP3A4 substrate.
    Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of fedratinib. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; fedratinib is a moderate CYP2C19 inhibitor.
    Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with fedratinib and monitor for adverse reactions. If fedratinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4 and CYP2D6. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6.
    Cobicistat: (Major) Avoid coadministration of fedratinib with cobicistat as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If cobicistat is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with fedratinib due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate and fedratinib is a moderate inhibitor of CYP3A.
    Codeine: (Moderate) Concomitant use of codeine with fedratinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with fedratinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with fedratinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with fedratinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and fedratinib in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. fedratinib can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a moderate CYP3A4 inhibitor like fedratinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
    Colchicine; Probenecid: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and fedratinib in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. fedratinib can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a moderate CYP3A4 inhibitor like fedratinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
    Conivaptan: (Major) Avoid use of fedratinib during and for 1 week after conivaptan as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If conivaptan is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Use caution if coadministration of fedratinib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. fedratinib is a moderate CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
    Crizotinib: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with fedratinib is necessary; crizotinib exposure may increase. Crizotinib is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
    Cyclosporine: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with fedratinib. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Fedratinib is a moderate inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
    Dabrafenib: (Major) Avoid coadministration of fedratinib with dabrafenib as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; dabrafenib is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Darifenacin: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with fedratinib. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
    Darunavir: (Major) Avoid coadministration of fedratinib with darunavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If darunavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Darunavir; Cobicistat: (Major) Avoid coadministration of fedratinib with cobicistat as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If cobicistat is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold. (Major) Avoid coadministration of fedratinib with darunavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If darunavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of fedratinib with cobicistat as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If cobicistat is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold. (Major) Avoid coadministration of fedratinib with darunavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If darunavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of fedratinib with ritonavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ritonavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Deflazacort: (Major) Decrease deflazacort dose to one-third of the recommended dosage when coadministered with fedratinib. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; fedratinib is a moderate inhibitor of CYP3A4.
    Delavirdine: (Major) Avoid coadministration of fedratinib with delavirdine as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If delavirdine is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Desipramine: (Moderate) Monitor for an increase in desipramine-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of desipramine may be necessary. Desipramine is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor.
    Dexamethasone: (Major) Avoid coadministration of fedratinib with dexamethasone as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; dexamethasone is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Dexlansoprazole: (Minor) The plasma concentrations of dexlansoprazole may be elevated when administered concurrently with fedratinib. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. fedratinib is a moderate CYP3A4 and CYP2C19 inhibitor, while dexlansoprazole is a CYP3A4 and CYP2C19 substrate.
    Dextromethorphan: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Dextromethorphan; Guaifenesin: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Dextromethorphan; Promethazine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Dextromethorphan; Quinidine: (Moderate) Exposure of dextromethorphan may be increased when administered with fedratinib. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Dextromethorphan is primarily metabolized by CYP2D6; fedratinib is a moderate CYP2D6 inhibitor.
    Diazepam: (Moderate) Monitor for increased diazepam-related adverse reactions including sedation and respiratory depression if coadministration with fedratinib is necessary. Diazepam is a CYP3A4 and CYP2C19 substrate and fedratinib is a moderate CYP3A and CYP2C19 inhibitor. Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with fedratinib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. If fedratinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Dihydroergotamine: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with fedratinib is necessary. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and fedratinib is a moderate CYP3A inhibitor.
    Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with fedratinib is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Disopyramide: (Major) Monitor for increased toxicity of disopyramide if coadministered with fedratinib. Coadministration may increase the exposure of disopyramide. Disopyramide is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor. Cases of life-threatening interactions have been reported for disopyramide when given with other moderate CYP3A4 inhibitors.
    Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse effects, including QT prolongation and torsade de pointes (TdP), if coadministered with fedratinib. Coadministration may increase the exposure of dofetilide. Dofetilide is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
    Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with fedratinib. Coadministration may increase the exposure of dolutegravir. Dolutegravir is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
    Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with fedratinib. Coadministration may increase the exposure of dolutegravir. Dolutegravir is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
    Dolutegravir; Rilpivirine: (Moderate) Monitor for increased rilpivirine adverse effects if administered with fedratinib. Coadministration may increase rilpivirine exposure. Rilpivirine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with fedratinib. Coadministration may increase the exposure of dolutegravir. Dolutegravir is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
    Doxepin: (Moderate) Monitor for an increase in doxepin-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of doxepin may be necessary. Doxepin is a CYP2D6 and CYP2C19 substrate and fedratinib is a moderate CYP2D6 and CYP2C19 inhibitor.
    Doxorubicin: (Major) Avoid coadministration of fedratinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Fedratinib is a moderate CYP3A4 and CYP2D6 inhibitor and doxorubicin is a major substrate of CYP3A4 and CYP2D6. Concurrent use of CYP3A4/CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronabinol: (Moderate) Monitor for increased toxicity (e.g., feeling high, dizziness, confusion, somnolence) of dronabinol if coadministered with fedratinib. Coadministration may increase the exposure of dronabinol. Dronabinol is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
    Dronedarone: (Moderate) Monitor for increased toxicity of dronedarone during coadministration. Coadministration may increase the exposure of dronedarone. Fedratinib is a moderate inhibitor of CYP3A; dronedarone is a sensitive substrate of CYP3A.
    Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of fedratinib with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A4 and CYP2D6 substrate and fedratinib is a moderate CYP3A4 and CYP2D6 inhibitor. The effects of concomitant administration of moderate CYP3A4 and moderate CYP2D6 inhibitors on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 and CYP2D6 inhibition.
    Duvelisib: (Moderate) Monitor for increased toxicity if duvelisib is coadministered with fedratinib. Coadministration may increase the exposure of duvelisib, increasing the risk of toxicity. Duvelisib is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
    Efavirenz: (Major) Avoid coadministration of fedratinib with efavirenz as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of fedratinib with efavirenz as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of fedratinib with efavirenz as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Elagolix: (Major) Avoid coadministration of fedratinib with elagolix as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; elagolix is a weak to moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with fedratinib. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and fedratinib is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the elexacaftor; tezacaftor; ivacaftor dosing schedule when coadministered with fedratinib; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor; tezacaftor; ivacaftor combination tablets every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., elexacaftor/tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive substrate); fedratinib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased ivacaftor exposure by 3-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2-fold, respectively. (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with fedratinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); fedratinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If fedratinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Eliglustat: (Severe) Coadministration of fedratinib and eliglustat is contraindicated in extensive or intermediate CYP2D6 metabolizers (EMs or IMs). Avoid coadministration in poor CYP2D6 metabolizers (PMs). In PMs also receiving a strong CYP3A4 inhibitor, coadministration is contraindicated. Eliglustat is a CYP3A and CYP2D6 substrate. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6. Concurrent use may result in unexpectedly high plasma concentrations of eliglustat, further increasing the risk of serious adverse events (e.g., cardiac arrhythmias).
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of fedratinib with cobicistat as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If cobicistat is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of fedratinib with cobicistat as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If cobicistat is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for increased rilpivirine adverse effects if administered with fedratinib. Coadministration may increase rilpivirine exposure. Rilpivirine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Monitor for increased rilpivirine adverse effects if administered with fedratinib. Coadministration may increase rilpivirine exposure. Rilpivirine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
    Enalapril; Felodipine: (Moderate) Concurrent use of felodipine and fedratinib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Concurrent use of another moderate CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
    Encorafenib: (Major) Avoid coadministration of encorafenib and fedratinib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fedratinib. If fedratinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fedratinib. Encorafenib is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Entrectinib: (Major) Avoid coadministration of entrectinib with fedratinib due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If fedratinib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of fedratinib. Entrectinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Enzalutamide: (Major) Avoid coadministration of fedratinib with enzalutamide as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with fedratinib in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving fedratinib, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating fedratinib and periodically thereafter. Eplerenone is a CYP3A4 substrate. fedratinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Ergotamine: (Moderate) Use caution if coadministration of fedratinib, a moderate CYP3A4 inhibitor, with ergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of ergotamine may be increased resulting in an increase in ergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of ergotamine if necessary.
    Eslicarbazepine: (Major) Avoid coadministration of fedratinib with eslicarbazepine as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Esomeprazole: (Moderate) Monitor for increased esomeprazole adverse effects as coadministration of esomeprazole and fedratinib may result in increased concentrations of esomeprazole. Although dose adjustments are not generally needed, patients with Zollinger-Ellison's syndrome who often require higher esomeprazole doses (up to 240 mg/day) may require an adjustment in esomeprazole dose. Esomeprazole is metabolized primarily by CYP2C19 and secondarily by CYP3A4; fedratinib is an inhibitor of CYP2C19 and CYP3A4.
    Esomeprazole; Naproxen: (Moderate) Monitor for increased esomeprazole adverse effects as coadministration of esomeprazole and fedratinib may result in increased concentrations of esomeprazole. Although dose adjustments are not generally needed, patients with Zollinger-Ellison's syndrome who often require higher esomeprazole doses (up to 240 mg/day) may require an adjustment in esomeprazole dose. Esomeprazole is metabolized primarily by CYP2C19 and secondarily by CYP3A4; fedratinib is an inhibitor of CYP2C19 and CYP3A4.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Use caution if coadministration of fedratinib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. fedratinib is a moderate CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
    Etravirine: (Major) Avoid coadministration of fedratinib with etravirine as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; etravirine is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Everolimus: (Major) A dose adjustment of everolimus is necessary if coadministered with fedratinib due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If fedratinib is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If fedratinib is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased everolimus exposure by 4.4-fold.
    Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fedratinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor.
    Felodipine: (Moderate) Concurrent use of felodipine and fedratinib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Concurrent use of another moderate CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. If fedratinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If fedratinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Flecainide: (Moderate) Monitor for an increase in flecainide-related adverse reactions, including QT prolongation, if coadministration with fedratinib is necessary. Plasma concentrations of flecainide may increase, especially in extensive CYP2D6 metabolizers. Flecainide is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor.
    Flibanserin: (Severe) The concomitant use of flibanserin and fedratinib is contraindicated due to increased flibanserin exposure, which can result in severe hypotension and syncope. If initiating flibanserin following use of fedratinib, start flibanserin at least 2 weeks after the last dose of fedratinib. If initiating fedratinib following flibanserin use, start fedratinib at least 2 days after the last dose of flibanserin. Flibanserin is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor.
    Fluconazole: (Major) Avoid coadministration of fedratinib with fluconazole as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; fluconazole is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    Fluoxetine: (Major) Avoid coadministration of fedratinib with fluoxetine as concurrent use may increase fedratinib exposure; fluoxetine exposure may also increase. Fedratinib is a substrate of both CYP3A4 and CYP2C19 and a moderate CYP2D6 inhibitor; fluoxetine is an inhibitor of both CYP3A4 and CYP2C19 and a CYP2D6 substrate. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of fedratinib with fluoxetine as concurrent use may increase fedratinib exposure; fluoxetine exposure may also increase. Fedratinib is a substrate of both CYP3A4 and CYP2C19 and a moderate CYP2D6 inhibitor; fluoxetine is an inhibitor of both CYP3A4 and CYP2C19 and a CYP2D6 substrate. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    Fluvoxamine: (Major) Avoid coadministration of fedratinib with fluvoxamine as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; fluvoxamine is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    Fosamprenavir: (Major) Avoid coadministration of fedratinib with fosamprenavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If fosamprenavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Fosphenytoin: (Major) Avoid coadministration of fedratinib with fosphenytoin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response; phenytoin exposure may also increase. Monitoring of serum phenytoin concentrations is advised. Fedratinib is a CYP3A4 substrate and moderate CYP2C19 inhibitor; fosphenytoin is a strong CYP3A4 inducer and CYP2C19 substrate. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with fedratinib is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and fedratinib is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit/grapefruit juice while taking fedratinib as fedratinib exposure may increase leading to increased adverse effects. Fedratinib is a CYP3A4 substrate; Grapefruit/grapefruit juice is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guanfacine: (Major) Decrease the dose of extended-release guanfacine by 50% if coadministration with fedratinib is necessary; if fedratinib is discontinued, the dose of extended-release guanfacine may be increased to the recommended level. Monitor patients closely for adverse effects including hypotension, drowsiness, lethargy, and bradycardia. Recommendations for immediate-release guanfacine are not available. Guanfacine is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
    Haloperidol: (Moderate) Monitor for an increase in haloperidol-related adverse reactions if coadministration with fedratinib is necessary. Haloperidol is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor. In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterized as inhibitors of CYP2D6.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration of fedratinib. A dosage reduction for metoprolol may be needed based on response. Coadministration with fedratinib, a moderate CYP2D6 inhibitor, increased metoprolol, a sensitive CYP2D6 substrate, exposure by 2-fold.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Monitor for increased propranolol adverse reactions including bradycardia and hypotension during coadministration of fedratinib. Propranolol exposure may increase. Fedratinib is a moderate CYP2D6 and CYP2C19 inhibitor and propranolol is a CYP2D6 and CYP2C19 substrate.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If fedratinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ibrutinib: (Major) If coadministered with fedratinib, reduce the ibrutinib dose to 280 mg/day PO for the treatment of B-cell malignancies. Resume ibrutinib at the previous dose if fedratinib is discontinued. Initiate ibrutinib at the recommended dose of 420 mg/day PO for the treatment of chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interruption of ibrutinib therapy or a dose reduction may be necessary in patients who develop severe toxicity. Ibrutinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. If fedratinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like fedratinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fedratinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Idelalisib: (Major) Avoid coadministration of fedratinib with idelalisib as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If idelalisib is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with fedratinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Fedratinib is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Imipramine: (Moderate) Monitor for an increase in imipramine-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of imipramine may be necessary. Imipramine is a CYP2D6 and CYP2C19 substrate and fedratinib is a moderate CYP2D6 and CYP2C19 inhibitor.
    Indinavir: (Major) Avoid coadministration of fedratinib with indinavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If indinavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Isoniazid, INH: (Major) Avoid coadministration of fedratinib with isoniazid as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; isoniazid is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of fedratinib with isoniazid as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; isoniazid is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated. (Major) Avoid coadministration of fedratinib with rifampin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of fedratinib with isoniazid as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; isoniazid is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated. (Major) Avoid coadministration of fedratinib with rifampin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Isradipine: (Moderate) Caution and close monitoring are advised if these drugs are used together. Concomitant use of fedratinib with isradipine may result in increased serum concentrations of isradipine. Isradipine is a substrate of the hepatic isoenzyme CYP3A4; fedratinib, is a moderate inhibitor of this enzyme.
    Itraconazole: (Major) Avoid coadministration of fedratinib with itraconazole as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If itraconazole is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Ivabradine: (Major) Avoid coadministration of ivabradine and fedratinib as increased concentrations of ivabradine are possible, which may result in bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4 and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased the AUC of ivabradine by 2- to 3-fold.
    Ivacaftor: (Major) If fedratinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with fedratinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
    Ixabepilone: (Moderate) Frequently monitor peripheral blood counts between cycles of ixabepilone, and for other acute ixabepilone-related adverse reactions if coadministration with fedratinib is necessary; consider the use of an alternative agent to fedratinib that does not inhibit CYP3A4. Ixabepilone is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibitors on exposure to ixabepilone has not been studied.
    Ketoconazole: (Major) Avoid coadministration of fedratinib with ketoconazole as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ketoconazole is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of ketoconazole 200 mg twice daily with a single 300-mg dose of fedratinib increased the fedratinib AUC(inf) by 3-fold. The expected steady-state fedratinib AUC increase is 2-fold when fedratinib 400 mg/day is coadministered with ketoconazole 400 mg/day based on pharmacokinetic modeling and simulations.
    Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with fedratinib as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. The effect of moderate inhibitors on lefamulin has not been studied; however, use of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
    Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and fedratinib. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; fedratinib is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
    Lomitapide: (Severe) Concomitant use of fedratinib and lomitapide is contraindicated due to increased lomitapide exposure. If treatment with fedratinib is unavoidable, lomitapide should be stopped during the course of treatment. Lomitapide is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use based on the 27-fold increase in exposure observed with coadministration of a strong CYP3A4 inhibitor.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with fedratinib, a CYP3A4 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with fedratinib, a CYP3A4 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) Avoid coadministration of fedratinib with lopinavir; ritonavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If lopinavir; ritonavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; lopinavir; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold. (Major) Avoid coadministration of fedratinib with ritonavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ritonavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Lorlatinib: (Major) Avoid coadministration of fedratinib with lorlatinib as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fedratinib is necessary. Coadministration may increase the exposure of lovastatin. Lovastatin is a sensitive substrate of CYP3A4 and fedratinib is a moderate CYP3A4 inhibitor.
    Lovastatin; Niacin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fedratinib is necessary. Coadministration may increase the exposure of lovastatin. Lovastatin is a sensitive substrate of CYP3A4 and fedratinib is a moderate CYP3A4 inhibitor.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of fedratinib with lumacaftor; ivacaftor as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated. (Major) If fedratinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of fedratinib with lumacaftor; ivacaftor as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Lurasidone: (Major) The recommended starting dose of lurasidone is 20 mg daily (maximum, 80 mg daily) if coadministration with fedratinib is necessary. Reduce the lurasidone dose to half of its original dose level if fedratinib is added to existing lurasidone therapy. Lurasidone is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased lurasidone exposure by 116%.
    Maprotiline: (Moderate) Monitor for an increase in maprotiline-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of maprotiline may be necessary. Fedratinib is a moderate CYP2D6 inhibitor. Because of the pharmacologic similarity of maprotiline hydrochloride to the tricyclic antidepressants, the plasma concentration of maprotiline may be increased when the drug is given concomitantly with hepatic enzyme inhibitors.
    Medroxyprogesterone: (Moderate) Use caution if coadministration of fedratinib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. fedratinib is a moderate CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
    Metformin; Repaglinide: (Moderate) Monitor blood sugar if coadministration of repaglinide with fedratinib is necessary; an increase in repaglinide-related adverse reactions may occur. Repaglinide is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor.
    Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. If fedratinib is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP3A4, CYP2D6, and CYP2C19 substrate, and coadministration with moderate inhibitors of CYP3A4, CYP2D6, and CYP2C19 like fedratinib can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If fedratinib is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Methohexital: (Major) Avoid coadministration of fedratinib with methohexital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; methohexital is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration of fedratinib. A dosage reduction for metoprolol may be needed based on response. Coadministration with fedratinib, a moderate CYP2D6 inhibitor, increased metoprolol, a sensitive CYP2D6 substrate, exposure by 2-fold.
    Mexiletine: (Moderate) Monitor for an increase in mexiletine-related adverse reactions if coadministration with fedratinib is necessary. Mexiletine is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor. In a drug interaction study, coadministration of another moderate CYP2D6 inhibitor did not alter the kinetics of mexiletine in CYP2D6 poor metabolizers. However, in extensive metabolizers, the metabolic clearance of mexiletine decreased by about 70% making the poor and extensive metabolizer groups indistinguishable.
    Midazolam: (Moderate) Consider reducing the dose of midazolam and monitor for signs of toxicity during coadministration with fedratinib. Coadministration may increase the exposure of midazolam. Fedratinib is a moderate CYP3A inhibitor and midazolam is a sensitive CYP3A substrate. In drug interaction studies, coadministration of fedratinib and midazolam increased the AUC of midazolam by 4-fold.
    Mifepristone: (Major) Avoid coadministration of fedratinib with mifepristone as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If mifepristone is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor. The significance of the interaction when mifepristone is used for pregnancy termination is unknown. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Mitotane: (Major) Avoid coadministration of fedratinib with mitotane as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Modafinil: (Major) Avoid coadministration of fedratinib with modafinil as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Nafcillin: (Major) Avoid coadministration of fedratinib with nafcillin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with fedratinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
    Naloxegol: (Major) Avoid concomitant administration of naloxegol and fedratinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
    Nebivolol: (Moderate) Monitor for increased nebivolol adverse reactions including bradycardia and hypotension during coadministration of fedratinib. Fedratinib is a moderate CYP2D6 inhibitor and nebivolol is a sensitive CYP2D6 substrate.
    Nebivolol; Valsartan: (Moderate) Monitor for increased nebivolol adverse reactions including bradycardia and hypotension during coadministration of fedratinib. Fedratinib is a moderate CYP2D6 inhibitor and nebivolol is a sensitive CYP2D6 substrate.
    Nefazodone: (Major) Avoid coadministration of fedratinib with nefazodone as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If nefazodone is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Nelfinavir: (Major) Avoid coadministration of fedratinib with nelfinavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If nelfinavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Neratinib: (Major) Avoid concomitant use of fedratinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Nevirapine: (Major) Avoid coadministration of fedratinib with nevirapine as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; nevirapine is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fedratinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor.
    Nicardipine: (Major) Avoid coadministration of fedratinib with nicardipine as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; nicardipine is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    Nifedipine: (Moderate) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with fedratinib as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
    Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with fedratinib is necessary. Nimodipine is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with fedratinib due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and fedratinib is a CYP3A4 inhibitor
    Nortriptyline: (Moderate) Monitor for an increase in nortriptyline-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of nortriptyline may be necessary. nortriptyline is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor.
    Olaparib: (Major) Avoid coadministration of olaparib with fedratinib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the AUC of olaparib by 121%.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of fedratinib with ritonavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ritonavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Omeprazole: (Moderate) Monitor for increased omeprazole adverse effects as coadministration of omeprazole and fedratinib increased omeprazole exposure by 3-fold in a drug interaction study. Although dose adjustments are not generally needed, patients with Zollinger-Ellison's syndrome who often require higher omeprazole doses may require an adjustment in omeprazole dose. Omeprazole is metabolized primarily by CYP2C19 and secondarily by CYP3A4; fedratinib is an inhibitor of CYP2C19 and CYP3A4.
    Omeprazole; Sodium Bicarbonate: (Moderate) Monitor for increased omeprazole adverse effects as coadministration of omeprazole and fedratinib increased omeprazole exposure by 3-fold in a drug interaction study. Although dose adjustments are not generally needed, patients with Zollinger-Ellison's syndrome who often require higher omeprazole doses may require an adjustment in omeprazole dose. Omeprazole is metabolized primarily by CYP2C19 and secondarily by CYP3A4; fedratinib is an inhibitor of CYP2C19 and CYP3A4.
    Oxybutynin: (Minor) Monitor for oxybutynin-related adverse reactions if coadministration with fedratinib is necessary. Oxybutynin is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use with moderate CYP3A4 inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. If fedratinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like fedratinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fedratinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with fedratinib is necessary. Coadministration may increase the exposure of paclitaxel. Paclitaxel is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor.
    Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Perphenazine: (Moderate) Monitor for an increase in perphenazine-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of perphenazine may be necessary. perphenazine is a sensitive CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor.
    Perphenazine; Amitriptyline: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of amitriptyline may be necessary. Amitriptyline is a CYP2D6 and CYP2C19 substrate and fedratinib is a moderate inhibitor of CYP2D6 and CYP2C19. (Moderate) Monitor for an increase in perphenazine-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of perphenazine may be necessary. perphenazine is a sensitive CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor.
    Phenobarbital: (Major) Avoid coadministration of fedratinib with phenobarbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Phenytoin: (Major) Avoid coadministration of fedratinib with phenytoin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response; phenytoin exposure may also increase. Monitoring of serum phenytoin concentrations is advised. Fedratinib is a CYP3A4 substrate and moderate CYP2C19 inhibitor; phenytoin is a strong CYP3A4 inducer and CYP2C19 substrate. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Pimozide: (Major) Concurrent use of pimozide and fedratinib should be avoided. Pimozide is metabolized primarily through CYP3A4, and fedratinib is a CYP3A4 inhibitor. Elevated pimozide concentrations occurring through inhibition of CYP3A4 can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Posaconazole: (Major) Avoid coadministration of fedratinib with posaconazole as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If posaconazole is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Primidone: (Major) Avoid coadministration of fedratinib with primidone as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Propafenone: (Major) Avoid coadministration of fedratinib and propafenone as propafenone exposure and adverse effects may be increased. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Propafenone is a CYP3A4 and CYP2D6 substrate; fedratinib is a moderate inhibitor of both CYP3A4 and CYP2D6. The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous.
    Propranolol: (Moderate) Monitor for increased propranolol adverse reactions including bradycardia and hypotension during coadministration of fedratinib. Propranolol exposure may increase. Fedratinib is a moderate CYP2D6 and CYP2C19 inhibitor and propranolol is a CYP2D6 and CYP2C19 substrate.
    Protriptyline: (Moderate) Monitor for an increase in protriptyline-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of protriptyline may be necessary. Protriptyline is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor.
    Quinine: (Moderate) Monitor for increased adverse events of quinine if administered with fedratinib. Concurrent use may increase quinine exposure. Fedratinib is a moderate CYP3A4 inhibitor and quinine is a CYP3A4 substrate.
    Ranolazine: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with fedratinib is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased plasma levels of ranolazine by 50% to 130%.
    Repaglinide: (Moderate) Monitor blood sugar if coadministration of repaglinide with fedratinib is necessary; an increase in repaglinide-related adverse reactions may occur. Repaglinide is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor.
    Ribociclib: (Major) Avoid coadministration of fedratinib with ribociclib as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ribociclib is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Ribociclib; Letrozole: (Major) Avoid coadministration of fedratinib with ribociclib as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ribociclib is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Rifabutin: (Major) Avoid coadministration of fedratinib with rifabutin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Rifampin: (Major) Avoid coadministration of fedratinib with rifampin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Rifapentine: (Major) Avoid coadministration of fedratinib with rifapentine as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; rifapentine is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Rifaximin: (Moderate) Avoid coadministration of fedratinib with rifaximin in patients with hepatic dysfunction as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate. In patients with normal hepatic function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with hepatic dysfunction who have elevated rifaximin concentrations. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Rilpivirine: (Moderate) Monitor for increased rilpivirine adverse effects if administered with fedratinib. Coadministration may increase rilpivirine exposure. Rilpivirine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
    Ritonavir: (Major) Avoid coadministration of fedratinib with ritonavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ritonavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with fedratinib is necessary; carefully weigh the risks and benefits of treatment. Roflumilast is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of roflumilast by 70%.
    Rucaparib: (Major) Avoid coadministration of fedratinib with rucaparib as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; rucaparib is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    Saquinavir: (Major) Avoid coadministration of fedratinib with saquinavir as concurrent use may increase fedratinib exposure; saquinavir exposure may also increase. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If saquinavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor; saquinavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Secobarbital: (Major) Avoid coadministration of fedratinib with secobarbital as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; secobarbital is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with fedratinib is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
    Silodosin: (Moderate) Monitor for silodosin-related adverse reactions if coadministration with fedratinib is necessary. Silodosin is a substrate of CYP3A4. Fedratinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibitors has not been evaluated; however, plasma concentrations of silodosin may increase based on its interaction with strong CYP3A4 inhibitors.
    Simeprevir: (Major) Concurrent use of fedratinib with simeprevir is not recommended due to increased plasma concentrations of simeprevir. Simeprevir is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
    Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fedratinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor.
    Simvastatin; Sitagliptin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fedratinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor.
    Siponimod: (Moderate) Concomitant use of siponimod and fedratinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the AUC of siponimod.
    Sirolimus: (Moderate) Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions if coadministration with fedratinib is necessary. The dose of sirolimus may need to be reduced. Sirolimus is a CYP3A4 substrate with a narrow therapeutic range. fedratinib is a moderate CYP3A inhibitor.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and fedratinib; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of fedratinib with St. John's Wort as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if fedratinib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. If fedratinib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a CYP3A4 inhibitor like fedratinib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If fedratinib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with fedratinib. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
    Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with fedratinib is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range. Fedratinib is a moderate CYP3A inhibitor.
    Tamsulosin: (Moderate) Use caution if coadministration of fedratinib with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A4 and CYP2D6 substrate and fedratinib is a moderate CYP3A4 and CYP2D6 inhibitor. The effects of concomitant administration of moderate CYP3A4 and moderate CYP2D6 inhibitors on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 and CYP2D6 inhibition.
    Telithromycin: (Major) Avoid coadministration of fedratinib with telithromycin as concurrent use may increase fedratinib exposure; telithromycin exposure may also increase. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If telithromycin is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor; telithromycin is a strong CYP3A4 inhibitor and CYP 3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Terbinafine: (Moderate) Monitor for increased terbinafine adverse effects if administered with fedratinib as terbinafine exposure may increase. Fedratinib is a moderate inhibitor of CYP2C9 and CYP3A enzymes. Coadministration of another CYP3A4 and CYP2d6 inhibitor increased terbinafine exposure by 69%. Based on this finding, it is likely that other inhibitors of both CYP2C9 and CYP3A4 may also lead to a substantial increase in the systemic exposure (Cmax and AUC) of terbinafine when concomitantly administered.
    Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with fedratinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); fedratinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If fedratinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Thioridazine: (Severe) Concomitant use of thioridazine and fedratinib is contraindicated due to the risk of QT prolongation and torsade de pointes (TdP) from elevated plasma concentrations of thioridazine. Thioridazine is a CYP2D6 substrate; fedratinib is an inhibitor of this enzyme.
    Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with fedratinib. Coadministration may increase the exposure of ticagrelor. Ticagrelor is a sensitive substrate of CYP3A; fedratinib is a moderate inhibitor of CYP3A.
    Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with fedratinib is necessary. Concurrent use may prolong the half-life and decrease the plasma clearance of tinidazole, increasing the plasma concentrations of tinidazole. Tinidazole is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor.
    Tipranavir: (Major) Avoid coadministration of fedratinib with tipranavir as concurrent use may increase fedratinib exposure; tipranavir exposure may also increase. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If tipranavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor; tipranavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Tolvaptan: (Major) Avoid coadministration of fedratinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with fedratinib. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with fedratinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of fedratinib, a moderate CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Trandolapril; Verapamil: (Moderate) Monitor for increased toxicity of verapamil during coadministration as fedratinib may increase verapamil exposure. Fedratinib is a moderate inhibitor of CYP3A; verapamil is a substrate of CYP3A.
    Triazolam: (Moderate) Consider reducing the dose of triazolam and monitor for signs of toxicity during coadministration with fedratinib. Coadministration may increase the exposure of triazolam. Fedratinib is a moderate CYP3A inhibitor and triazolam is a sensitive CYP3A substrate.
    Trimipramine: (Moderate) Monitor for an increase in trimipramine-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of trimipramine may be necessary. Trimipramine is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor.
    Vardenafil: (Major) Due to increased vardenafil exposure, do not use vardenafil orally disintegrating tablets with fedratinib; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5. Fedratinib is a moderate CYP3A4 inhibitor. Moderate CYP3A4 inhibitors, increased the Cmax and AUC of vardenafil by 3-fold and 4-fold, respectively.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with fedratinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of fedratinib. Venetoclax is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
    Venlafaxine: (Moderate) Although no dosage adjustment of venlafaxine is required during concomitant use of fedratinib, venlafaxine exposure may increase resulting in increased adverse effects. Venlafaxine is a sensitive CYP2D6 substrate and venlafaxine is a moderate CYP2D6 inhibitor.
    Verapamil: (Moderate) Monitor for increased toxicity of verapamil during coadministration as fedratinib may increase verapamil exposure. Fedratinib is a moderate inhibitor of CYP3A; verapamil is a substrate of CYP3A.
    Vinblastine: (Moderate) Monitor for increased severity or earlier onset of vinblastine-related adverse reactions if coadministration with fedratinib is necessary. Vinblastine is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor. Enhanced toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fedratinib is necessary. Vinorelbine is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor.
    Voriconazole: (Major) Avoid coadministration of fedratinib with voriconazole as concurrent use may increase fedratinib exposure; voriconazole exposure may also increase. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If voriconazole is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Monitor for increased voriconazole adverse effects and adjust the dose as necessary. Fedratinib is a CYP3A4 substrate and moderate CYP3A4 and CYP2C19 inhibitor; voriconazole is a strong CYP3A4 inhibitor and CYP3A4 and CYP2C19 substrate. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with fedratinib is necessary. Fedratinib is a moderate CYP3A inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. Concomitant use of warfarin with CYP3A4 inhibitors may increase the INR. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with fedratinib. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of fedratinib, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
    Zolpidem: (Moderate) Monitor for an increase in zolpidem-related adverse reactions, including excess sedation, if coadministration with fedratinib is necessary. A dose reduction of zolpidem may be necessary. Zolpidem is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem during coadministration with some potent inhibitors of CYP3A4.

    PREGNANCY AND LACTATION

    Pregnancy

    Consider the benefits versus the risk of therapy prior to administering fedratinib during pregnancy. No well-controlled studies have been conducted evaluating the use of fedratinib in pregnant women. In animal reproduction studies, oral administration of fedratinib to pregnant rats during organogenesis at doses considerably lower than the recommended human daily dose of 400 mg/day resulted in adverse developmental outcomes. Adverse developmental outcomes (e.g., skeletal variations, specifically additional ossification center of neuronal arches) were observed in the offspring of pregnant rats who received fedratinib doses (30 mg/kg/day) that resulted in about 0.1-times the clinical exposure based on AUC values at the recommended human dose. In pregnant rabbits, fedratinib doses of 30 mg/kg/day resulted in no developmental or maternal toxicity; however, doses of 80 mg/kg per day led to maternal death in another study in rabbits.[64568]

    It is not known if fedratinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for serious adverse reactions in a nursing child, women should discontinue breast-feeding during fedratinib therapy and for at least 1 month after the last dose.[64568]

    MECHANISM OF ACTION

    Fedratinib is a kinase inhibitor that inhibits wild-type and mutation-positive Janus Associated Kinase-2 (JAK2) and FMS-like tyrosine kinase-3 (FLT3). Fedratinib has higher inhibitory activity for JAK2 than for JAK1, JAK3, and TYK2. Abnormal JAK2 activation is associated with myeloproliferative neoplasms, including myelofibrosis and polycythemia vera. Fedratinib reduced phosphorylation of signal transducer and activator of transcription (STAT)-3/5 proteins, inhibited cell proliferation, and induced apoptotic cell death in cell models that expressed JAK2V617F or FLT3ITD mutations. Improvements in survival, white blood cell counts, hematocrit, splenomegaly, and fibrosis were observed in mouse models of JAK2V617F-driven myeloproliferative disease.[64568]

    PHARMACOKINETICS

    Fedratinib is administered orally. It is 92% or greater bound to human plasma proteins. Following treatment with fedratinib 400 mg/day, the apparent steady-state Vd in patients with myelofibrosis is 1,770 L. The apparent fedratinib clearance is 13 L/hour (coefficient of variation, 51%) in myelofibrosis patients. Fedratinib is metabolized by CYP3A4, CYP2C19, and flavin-containing monooxygenase-3 (FMO3); the parent drug accounts for about 80% of the total circulating drug in the plasma after oral dosing. After a single oral radiolabeled dose, 77% of the dose was excreted in the feces (23% unchanged) and 5% of the dose was eliminated in the urine (3% unchanged). Elimination exhibits a biphasic disposition with an effective half-life of 41 hours and a terminal half-life of about 114 hours.[64568]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C19, CYP2D6
    Fedratinib is a substrate of CYP3A4 and CYP2C19. Avoid coadministration with strong CYP3A4 inducers or inhibitors, moderate CYP3A4 inducers, and dual CYP3A4 and CYP2C19 inhibitors; reduce the fedratinib dosage if use with a strong CYP3A4 inhibitor is required. Fedratinib is a moderate inhibitor of CYP3A4, CYP2C19, and CYP2D6; therefore, monitor for adverse drug reactions and dose reduce the CYP3A4, CYP2C19, or CYP2D6 substrates if necessary. A clinically insignificant increase in steady-state exposure is anticipated when fedratinib is given with moderate CYP3A4 inhibitors (erythromycin, increased AUC by 1.2-fold; diltiazem, increased AUC by 1.1-fold) based on pharmacokinetic modeling and simulation. In vitro, fedratinib is a substrate of P-glycoprotein (P-gp) and inhibits P-gp, breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1 and OATP1B3, organic cation transporter-2 (OCT2), multidrug and toxin extrusion (MATE) protein-1, and MATE-2K.[64568]

    Oral Route

    Following multiple oral doses of fedratinib 400 mg once daily, the geometric mean Cmax level was 1,804 ng/mL (coefficient of variation (CV), 49%) and the geometric mean AUC(tau) value was 26,870 ng x hour/mL (CV, 43%) in patients with myelofibrosis. A dose-proportional increase in the geometric mean Cmax and AUC values was observed following multiple oral doses of fedratinib 300 mg to 500 mg once daily (0.75- to 1.25-times the recommended dose). The mean accumulation ratio ranged between 3-fold and 4-fold; mean steady-state levels were achieved within 15 days. Compared with the fasted state, AUC and Cmax values were increased by 24% and 14%, respectively, when a single, 500-mg dose of fedratinib was administered with a low-fat, low-calorie (162 calories: 6% from fat; 78% from carbohydrate; and 16% from protein) or high-fat, high-calorie meal (815 calories: 52% from fat; 33% from carbohydrate; and 15% from protein). Fedratinib may be taken with or without food. Concurrent administration of a single, 500-mg oral dose of fedratinib with a gastric acid reducing agent, pantoprazole 40 mg/day, resulted in an increased fedratinib AUC by 1.2-fold.[64568]