Fedratinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omid Afkhami-Ardakani
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Black Box Warning
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Encephalopathy Including Wernicke’s
See full prescribing information for complete Boxed Warning.
Serious and fatal encephalopathy, including Wernicke’s encephalopathy, has occurred in patients treated with Fedratinib. Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Assess thiamine levels in all patients prior to starting Fedratinib, periodically during treatment, and as clinically indicated. Do not start Fedratinib in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue Fedratinib and initiate parenteral thiamine.
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Overview
Fedratinib is a Janus Kinase 2 (JAK2) Inhibitor that is FDA approved for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Diarrhea, Nausea, Vomiting, Fatigue, Anemia, Thrombocytopenia, Elevated liver enzymes (ALT/AST), and Elevated serum creatinine..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Intermediate-2 or High-Risk Primary or Secondary Myelofibrosis (MF): Dose: 400 mg orally once daily. Administration: Take with or without food. Duration: Continue until disease progression or unacceptable toxicity.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy have not been established in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fedratinib in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fedratinib in pediatric patients.
Contraindications
Patients with known serious hypersensitivity to Fedratinib or any of its components.
Warnings
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Encephalopathy Including Wernicke’s
See full prescribing information for complete Boxed Warning.
Serious and fatal encephalopathy, including Wernicke’s encephalopathy, has occurred in patients treated with Fedratinib. Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Assess thiamine levels in all patients prior to starting Fedratinib, periodically during treatment, and as clinically indicated. Do not start Fedratinib in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue Fedratinib and initiate parenteral thiamine.
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Encephalopathy Including Wernicke’s: Serious and fatal cases have occurred. Assess thiamine levels before and during treatment.
Anemia and Thrombocytopenia: Fedratinib can cause severe anemia and thrombocytopenia. Monitor complete blood counts regularly.
Gastrointestinal Toxicity: Diarrhea, nausea, and vomiting are common. Provide supportive care as necessary.
Hepatic Toxicity: Elevations in liver enzymes have been observed. Monitor liver function tests periodically.
Renal Toxicity: Elevations in serum creatinine and decreased renal function have occurred. Monitor renal function tests periodically.
Adverse Reactions
Clinical Trials Experience
Diarrhea, Nausea, Vomiting, Fatigue, Anemia, Thrombocytopenia, Elevated liver enzymes (ALT/AST), and Elevated serum creatinine.
Postmarketing Experience
Specific postmarketing adverse reactions have not been detailed in available reports.
Drug Interactions
CYP3A Inhibitors: Strong CYP3A inhibitors can increase Fedratinib exposure, potentially leading to toxicity. Dose adjustment may be necessary. CYP3A Inducers: Strong CYP3A inducers can decrease Fedratinib exposure, potentially reducing efficacy. Avoid concomitant use if possible.
CYP3A Substrates: Fedratinib may increase plasma concentrations of drugs metabolized by CYP3A. Monitor for adverse reactions of concomitant CYP3A substrates.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There are no studies with the use of Fedratinib in pregnant women to inform drug-associated risks. Based on animal studies, Fedratinib may cause fetal harm. Advise pregnant women of the potential risk to a fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fedratinib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Fedratinib during labor and delivery.
Nursing Mothers
It is unknown if Fedratinib is excreted in human milk. Advise against breastfeeding during treatment and for at least one month after the final dose.
Pediatric Use
There is no FDA guidance on the use of Fedratinib in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Fedratinib in geriatric settings.
Gender
There is no FDA guidance on the use of Fedratinib with respect to specific gender populations.
Race
There is no FDA guidance on the use of Fedratinib with respect to specific racial populations.
Renal Impairment
Moderate to severe renal impairment increases drug exposure. Reduce dose to 200 mg once daily in patients with severe renal impairment (eGFR <30 mL/min/1.73m²).
Hepatic Impairment
Contraindicated in patients with severe hepatic impairment (Child-Pugh Class C).
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fedratinib in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Fedratinib in patients who are immunocompromised.
Administration and Monitoring
Administration
Take 400 mg orally once daily. May be taken with or without food, though food may help with GI tolerability.
Monitoring
Monitor thiamine levels before starting and during treatment. Check CBCs regularly to monitor for anemia and thrombocytopenia. Assess liver function tests (LFTs) periodically.
IV Compatibility
There is limited information regarding the compatibility of Fedratinib and IV administrations.
Overdosage
There is limited information regarding Fedratinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Fedratinib Pharmacology in the drug label.
Mechanism of Action
Fedratinib is an oral kinase inhibitor with activity against wild-type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). It selectively inhibits JAK2 over other family members, disrupting the JAK-STAT signaling pathway, which is often aberrantly activated in myeloproliferative neoplasms, including myelofibrosis.
Structure
There is limited information regarding Fedratinib Structure in the drug label.
Pharmacodynamics
Fedratinib inhibits STAT3 phosphorylation, with maximal inhibition occurring approximately 2 hours after dosing. This leads to suppression of cellular proliferation and induction of apoptosis in affected cells.
Pharmacokinetics
Absorption: Peak plasma concentrations (C_max) are reached approximately 2-4 hours after oral administration. Distribution: Fedratinib is extensively distributed in tissues, with a volume of distribution (V_d) of approximately 1770 L. Metabolism: Primarily metabolized by CYP3A4, with minor contributions from CYP2C19 and CYP2D6. Elimination: The terminal half-life is approximately 41 hours. About 77% is excreted in feces and 5% in urine.
Nonclinical Toxicology
There is limited information regarding Fedratinib Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Fedratinib Clinical Studies in the drug label.
How Supplied
Fedratinib is supplied as 100 mg hard gelatin capsules for oral administration. Each capsule contains 100 mg of fedratinib (equivalent to 117.3 mg of fedratinib dihydrochloride monohydrate).
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Keep the bottle tightly closed to protect from moisture.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Risk of Encephalopathy: Inform patients about the risk of serious and potentially fatal encephalopathy, including Wernicke’s encephalopathy. Advise them to report symptoms such as confusion, memory impairment, or vision changes immediately. Gastrointestinal Symptoms: Advise patients that diarrhea, nausea, and vomiting are common side effects. They should maintain hydration and seek medical attention if symptoms are severe or persistent. Myelosuppression: Inform patients about the risk of anemia and thrombocytopenia. Regular blood tests will be necessary to monitor blood counts. Pregnancy and Lactation: Discuss potential risks to the fetus and advise against breastfeeding during treatment and for at least one month after the final dose.
Precautions with Alcohol
Alcohol can exacerbate certain side effects, such as dizziness and liver enzyme elevations. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Fedratinib is marketed under the brand name INREBIC.
Look-Alike Drug Names
There is limited information regarding Fedratinib Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.