INREBIC

Small Molecule Antineoplastic Janus Associated Kinase (JAK) Inhibitors

Emetic Risk
Moderate/High
Administer routine antiemetic prophylaxis prior to treatment.

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]

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

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]

INREBIC

Rx

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

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]

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.

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; 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: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
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) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
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 CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. 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.
Adagrasib: (Major) Avoid coadministration of fedratinib with adagrasib 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 adagrasib 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 CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased fedratinib exposure by 3-fold.
Albuterol; 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.
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.
Alogliptin; Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
Alprazolam: (Major) Avoid coadministration of alprazolam and fedratinib due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with fedratinib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
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.
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; Celecoxib: (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; 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; Valsartan; 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.
Amobarbital: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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; 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. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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) Recommendations for managing aripiprazole and fedratinib vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; fedratinib is a moderate CYP2D6 and moderate CYP3A inhibitor.
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 barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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.
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.
Avapritinib: (Major) Avoid coadministration of avapritinib with fedratinib due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Barbiturates: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of fedratinib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and fedratinib is a CYP2C19 inhibitor.
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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
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; Phenylephrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
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.
Budesonide; Glycopyrrolate; 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 may 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 and 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 may 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 and 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 barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Butalbital; Acetaminophen: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%. (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.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%. (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.
Cabotegravir; 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.
Canagliflozin; Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
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. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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.
Celecoxib; 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.
Cenobamate: (Major) Avoid coadministration of fedratinib with cenobamate as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
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.
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.
Chlordiazepoxide; 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.
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) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
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; 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 CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. 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.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
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. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the AUC of cilostazol (single dose) by 73%; the AUC of 4-trans-hydroxycilostazol increased by 141%.
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; Guaifenesin; Pseudoephedrine: (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) Avoid concomitant use of colchicine and fedratinib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-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. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4. Fedratinib is a moderate CYP3A4 inhibitor.
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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
Dapagliflozin; Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with fedratinib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
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 i

s 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.
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.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Bupropion: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Quinidine: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
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.
Dihydroergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions including cerebral and peripheral ischemia during concomitant use of ergotamine and fedratinib. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate 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.
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: (Contraindicated) Concomitant use of dofetilide and fedratinib is contraindicated. This combination may increase dofetilide exposure and the risk of dofetilide-related adverse effects including drug-induced QT prolongation and torsade de pointes (TdP). Dofetilide is an OCT2 and CYP3A substrate; fedratinib is an OCT2 and 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 Liposomal: (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.
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. Coadministration of fedratinib with efavirenz decreased the overall exposure of fedratinib by 47%.
Efavirenz; Emtricitabine; 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. Coadministration of fedratinib with efavirenz decreased the overall exposure of fedratinib by 47%.
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. Coadministration of fedratinib with efavirenz decreased the overall exposure of fedratinib by 47%.
Elacestrant: (Major) Avoid concomitant use of elacestrant and fedratinib due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
Elagolix; Estradiol; Norethindrone acetate: (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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
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 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. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with fedratinib; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; fedratinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
Eliglustat: (Contraindicated) 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.
Empagliflozin; Linagliptin; Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
Empagliflozin; Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
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.
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. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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 CYP3A substrate. Fedratinib is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Ergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions including cerebral and peripheral ischemia during concomitant use of ergotamine and fedratinib. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
Ergotamine; Caffeine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions including cerebral and peripheral ischemia during concomitant use of ergotamine and fedratinib. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
Ertugliflozin; Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
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.
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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with fedratinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Fedratinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 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.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or fedratinib; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
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: (Contraindicated) 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: (Moderate) Closely monitor for an increase in fedratinib-related adverse effects if coadministered with fluconazole. Coadministration may increase fedratinib exposure. Fedratinib is a CYP3A and CYP2C19 substrate; fluconazole is an inhibitor of both CYP3A and CYP2C19. Coadministration is predicted to increase fedratinib exposure by approximately 1.5-fold at steady-state.
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.
Fluvoxamine: (Moderate) Closely monitor for an increase in fedratinib-related adverse effects if coadministered with fluvoxamine. Coadministration may increase fedratinib exposure. Fedratinib is a CYP3A and CYP2C19 substrate; fluvoxamine is an inhibitor of both CYP3A and CYP2C19. Coadministration with another dual CYP3A and CYP2C19 inhibitor increased fedratinib exposure by approximately 1.5-fold at steady-state.
Fosamprenavir: (Moderate) Monitor for increased fosamprenavir toxicity if coadministered with fedratinib. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
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. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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.
Glipizide; Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
Glyburide; Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
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 CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. 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 CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. 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: (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 CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. 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 CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. 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 CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. 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 ibrutinib is coadministered with fedratinib, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if fedratinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the CAUC value of ibrutinib was increased by 3-fold.
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.
Infigratinib: (Major) Avoid concomitant use of infigratinib and fedratinib. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor.
Isoniazid, INH; Pyrazinamide, PZA; 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. Coadministration of fedratinib with rifampin decreased the overall exposure of fedratinib by 81%.
Isoniazid, INH; 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. Coadministration of fedratinib with rifampin decreased the overall exposure of fedratinib by 81%.
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. Coadministration is not recommended in patients younger than 6 months. 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) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of fedratinib is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
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.
Lansoprazole; Amoxicillin; 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.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with fedratinib is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
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.
Lemborexant: (Major) Avoid coadministration of lemborexant and fedratinib as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Levamlodipine: (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.
Levoketoconazole: (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.
Linagliptin; Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
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: (Contraindicated) 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.
Lonafarnib: (Contraindicated) Concomitant use of lonafarnib and fedratinib is contraindicated and may increase the exposure and risk of adverse effects from both drugs. If concomitant use is necessary, reduce the dose of fedratinib to 200 mg PO once daily. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; fedratinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Lopinavir; 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.
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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
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.
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. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%. (Major) If fedratinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. 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. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of fedratinib is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
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%.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and fedratinib due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
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.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with fedratinib due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure and may decrease fedratinib exposure which may result in decreased therapeutic response. Mavacamten is a CYP2C19 substrate and substrate and moderate inducer of CYP3A and fedratinib is a CYP3A substrate and moderate CYP2C19 and CYP3A inhibitor. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%. Coadministration of fedratinib with another moderate CYP3A inducer decreased the overall exposure of fedratinib by 47%.
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. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4. Fedratinib is a moderate CYP3A4 inhibitor.
Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
Metformin; Repaglinide: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together. (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.
Metformin; Rosiglitazone: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
Metformin; Saxagliptin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
Metformin; Sitagliptin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administrat ion may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
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 barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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.
Metoprolol; Hydrochlorothiazide, HCTZ: (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.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with fedratinib and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-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. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and fedratinib; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions. Mobocertinib is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
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.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with fedratinib is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of fedratinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
Naproxen; 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.
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.
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.
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.
Nirmatrelvir; 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. (Major) Consider withholding fedratinib, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the fedratinib dose. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. When ritonavir-boosted nirmatrelvir 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. Coadministration may increase fedratinib exposure resulting in increased toxicity. Fedratinib is a CYP3A substrate and nirmatrelvir is a 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.
Olanzapine; 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.
Olaparib: (Major) Avoid coadministration of olaparib with fedratinib due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after fedratinib is discontinued. Olaparib is a CYP3A substrate and fedratinib is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and fedratinib is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and fedratinib may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects; these effects may be more pronounced with fedratinib as it can inhibit multiple CYP enzymes. If fedratinib is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 and CYP2D6 substrate and fedratinib is a moderate CYP3A4 and CYP2D6 inhibitor.
Olmesartan; 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.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and fedratinib. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-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; Amoxicillin; 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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%. (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.
Pacritinib: (Major) Avoid concurrent use of pacritinib with fedratinib due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
Palovarotene: (Major) Avoid concomitant use of palovarotene and fedratinib due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with fedratinib is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and fedratinib due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If fedratinib is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of fedratinib. Pemigatinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Pentobarbital: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and fedratinib due to the risk of increased pexidartinib exposure and decreased fedratinib exposure. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If fedratinib is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of fedratinib. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; fedratinib is a CYP3A substrate and moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%. Coadministration of fedratinib with another moderate CYP3A inducer decreased the overall exposure of fedratinib by 47%.
Phenobarbital: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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.
Pioglitazone; Metformin: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
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.
Pralsetinib: (Major) Avoid concomitant use of fedratinib with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of pralsetinib by 71%.
Primidone: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and fedratinib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Promethazine; Dextromethorphan: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
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.
Propranolol; Hydrochlorothiazide, HCTZ: (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. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
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. Coadministration of fedratinib with rifampin decreased the overall exposure of fedratinib by 81%.
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 strong CYP3A4 inducer. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
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.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with fedratinib; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and 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%.
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.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and fedratinib due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If fedratinib is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of fedratinib. Selpercatinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase selpercatinib exposure by 60% to 99%.
Selumetinib: (Major) Avoid coadministration of selumetinib and fedratinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If fedratinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of fedratinib. Selumetinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
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.
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.
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 concentrations and adjust sirolimus dosage as appropriate during concomitant use of fedratinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
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.
Sotorasib: (Major) Avoid coadministration of fedratinib with sotorasib as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with fedratinib is necessary. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%.
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. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Stiripentol: (Major) Avoid coadministration of fedratinib with stiripentol as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; stiripentol 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.
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.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with fedratinib as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If fedratinib is discontinued, wait at least 3 half-lives of fedratinib before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telmisartan; 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.
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. Coadministration is not recommended in patients younger than 6 months. 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: (Contraindicated) 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.
Tramadol; Acetaminophen: (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) Monitor for signs of triazolam toxicity during coadministration with fedratinib and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
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.
Tucatinib: (Major) Avoid coadministration of fedratinib with tucatinib 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 tucatinib 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; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with fedratinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with fedratinib due to increased vardenafil exposure; 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. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
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 an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with fedratinib is necessary. Vinblastine is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Enhanced vinblastine 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.
Voclosporin: (Major) Reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening if coadministered with fedratinib. Concomitant use may increase voclosporin exposure and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
Vonoprazan; Amoxicillin; 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.
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 as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fedratinib is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. 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.

INREBIC Oral Cap: 100mg

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.

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]

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.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C19, CYP2D6
Fedratinib is a substrate of CYP3A4 and CYP2C19 and a moderate inhibitor of CYP3A4, CYP2C19, and CYP2D6. 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 (OCT)-1, OCT2, multidrug and toxin extrusion (MATE) protein-1, and MATE-2K. In single-dose, drug-drug interaction evaluations, fedratinib (600 mg) did not inhibit P-gp (i.e., digoxin 0.25 mg), OATP1B1/OATP1B3 and BCRP (i.e., rosuvastatin 10 mg), or OCT2 and MATE1/MATE2-K (i.e., metformin 1,000 mg) substrates to a clinically meaningful degree; however, the renal clearance of OCT2 and MATE1/MATE2-K substrates may be decreased when fedratinib is coadministered with drugs that are renally excreted via OCT2 and MATE1/MATE2-K.[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]

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]