FDA Approves INREBIC (fedratinib) for Myelofibrosis

FDA Approves INREBIC (fedratinib) for Myelofibrosis

On August 16, 2019, the U.S. Food and Drug Administration (FDA) approved INREBIC (fedratinib) for the treatment of adult patients with intermediate-2 or high-risk primary or secondary [post-polycythemia vera (PV) or post-essential thrombocythemia (ET)] myelofibrosis (MF). Fedratinib was granted priority review and orphan drug designation. The approved recommended dosage of INREBIC is 400 mg orally once daily with or without food, for patients with a baseline platelet count greater than or equal to 50 x 10⁹/L. Administration with a high fat meal may reduce the incidence of nausea and vomiting.

Patients on ruxolitinib before the initiation of INREBIC must taper and discontinue according to the ruxolitinib prescribing information. Monitor patients for the following blood tests: baseline testing of thiamine (vitamin B1) level, complete blood count with platelets, creatinine and BUN, hepatic panel, and amylase and lipase levels prior to initiating INREBIC, periodically during treatment, and as clinically indicated.

Serious and fatal encephalopathy, including Wernicke’s, has occurred in patients treated with INREBIC. Wernicke’s encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency, replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

Additional information regarding dosage and administration as well as important warnings and precautions about encephalopathy, including Wernicke’s, anemia and thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, and amylase and lipase elevation can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

• MOA: Fedratinib is a kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3).
• General PK: INREBIC at 300 mg to 500 mg once daily (0.75 to 1.25 times the recommended dose) results in a dose proportional increase in geometric mean fedratinib peak concentrations (C_max) and the area under the plasma concentration time curve over the dosing interval (AUC_tau). Mean steady-state plasma levels are reached by 15 days of daily dosing. The accumulation ratio of fedratinib ranged from 3 to 4. At the dose of 400 mg once daily, the geometric mean (coefficient of variation, %CV) of fedratinib C_max is 1804 ng/mL (49%) and AUC_tau is 26870 ng•hr/mL (43%) in patients with MF.
• Absorption: Following 400 mg once daily, fedratinib median time to peak concentrations (T_max) at steady-state was 3 hours (range: 2 to 4 hours).
• Distribution: The apparent volume of distribution of fedratinib at steady-state is 1770 L in patients with MF at 400 mg once daily dose. Fedratinib is 92% or greater bound to human plasma proteins.
• Elimination: Fedratinib pharmacokinetics is characterized by a biphasic disposition with an effective half-life of 41 hours, a terminal half-life of approximately 114 hours, and apparent clearance (CL/F) (%CV) of 13 L/h (51%) in patients with MF.
• Metabolism: Fedratinib is metabolized by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3 (FMO3). Fedratinib accounts for approximately 80% of the total circulating drug in plasma after oral administration.
• Excretion: Following a single oral dose of radiolabeled fedratinib, 77% (23% unchanged) of the administered dose was excreted in the feces and 5% (3% unchanged) was eliminated in urine.
• Pharmacodynamics: Fedratinib inhibited cytokine-induced STAT3 phosphorylation in whole blood from patients with MF. The inhibition of STAT3 phosphorylation was maximal approximately 2 hours after the first dose, with values returning to near baseline at 24 hours. After daily administration of fedratinib, levels of inhibition at steady state PK were similar to the maximal inhibition reached after the first dose of 300 (0.75 times the recommended dose), 400, or 500 mg (1.25 times the recommended dose) of fedratinib.

Drug Interactions

• Strong CYP3A4 Inhibitors: Consider alternative therapies that do not strongly inhibit CYP3A4 activity. Alternatively, reduce dose of INREBIC to 200 mg once daily with strong CYP3A4 inhibitors. In cases where co-administration with a strong CYP3A4 inhibitor is discontinued, INREBIC dosage should be increased to 300 mg once daily during the first two weeks after discontinuation of the CYP3A4 inhibitor, and then to 400 mg once daily thereafter as tolerated. Co-administration of INREBIC with a strong CYP3A4 inhibitor increases fedratinib exposure and may increase the risk of adverse reactions.
• Strong and Moderate CYP3A4 Inducers: Avoid INREBIC with strong and moderate CYP3A4 inducers. The effect of co-administration of a strong or moderate CYP3A4 inducer with INREBIC has not been studied.
• Dual CYP3A4 and CYP2C19 Inhibitors: Avoid INREBIC with dual CYP3A4 and CYP2C19 inhibitors. The effect of co-administration of a dual CYP3A4 and CYP2C19 inhibitor with INREBIC has not been studied.
• CYP3A4, CYP2C19, or CYP2D6 Substrates: Monitor for adverse reactions and adjust the dose of drugs that are CYP3A4, CYP2C19, or CYP2D6 substrates as necessary when co-administered with INREBIC. Co-administration of INREBIC with drugs that are CYP3A4 substrates, CYP2C19 substrates, or CYP2D6 substrates increases the concentrations of these drugs, which may increase the risk of adverse reactions of these drugs.

Use in Specific Populations

Age (20 to 95 years), sex, race/ethnicity (White, Asian), body weight (40 to 135 kg), mild (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1-1.5 times ULN and any AST) or moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment, and mild to moderate renal impairment (creatinine clearance [CLcr] 30 mL/min to 89 mL/min as estimated by Cockcroft-Gault (C-G) equation) did not have clinically meaningful effects on the pharmacokinetics of fedratinib.

Renal Impairment: Reduce INREBIC dose to 200 mg when administered to patients with severe renal impairment (CLcr 15 mL/min to 29 mL/min by C-G). No modification of the starting dose is recommended for patients with mild to moderate renal impairment (CLcr 30 mL/min to 89 mL/min by C-G). Due to potential increase of exposure, patients with pre-existing moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions. Refer to the full prescribing information linked below for dose modifications for specific adverse reactions.

Hepatic Impairment: Avoid INREBIC use in patients with severe hepatic impairment (total bilirubin > 3 times ULN and any AST), as fedratinib pharmacokinetics has not been evaluated in this population.

Efficacy and Safety

Efficacy of INREBIC was demonstrated in a double-blind, randomized, placebo-controlled trial that enrolled adult patients with intermediate-2 or high-risk primary MF, post-PV MF or post-ET MF with splenomegaly. Patients were randomized to receive either INREBIC 500 mg, 400 mg, or placebo once daily for at least 6 cycles. The primary efficacy outcome was the proportion of patients achieving ≥ 35% reduction from baseline in spleen volume at the end of cycle 6 measured by MRI or CT with a follow-up scan 4 weeks later. Additional information regarding this efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (incidence ≥ 20%) are diarrhea, nausea, anemia, and vomiting.

Full prescribing information is available at https://go.usa.gov/xVTW7.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.