Dosage & Administration
Inrebic Prescribing Information
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. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. While on treatment all patients should receive prophylaxis with daily oral thiamine and should have thiamine levels assessed as clinically indicated. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize [see Dosage and Administration (2.6), Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
INREBIC® is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).
Required Concomitant Medications
During treatment with INREBIC, all patients should receive prophylaxis with thiamine 100 mg orally daily [see Dosage and Administration (2.7) and Warnings and Precautions (5.1)].
Recommended Dosage
Conduct baseline testing of thiamine (Vitamin B1) levels prior to initiation of INREBIC [see Dosage and Administration (2.7), Warnings and Precautions (5.1)].
The recommended dosage of INREBIC is 400 mg taken orally once daily for patients with a baseline platelet count of greater than or equal to 50 × 109/L.
Modify the dose for patients using concomitant strong CYP3A4 inhibitors, and in patients with severe renal impairment (creatinine clearance (CLcr) 15 mL/min to 29 mL/min) [see Dosage and Administration (2.4, 2.5)].
Patients that are on treatment with ruxolitinib before the initiation of INREBIC must taper and discontinue according to the ruxolitinib prescribing information.
Administration Information:
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- INREBIC may be taken with or without food. Administration with a high fat meal may reduce the incidence of nausea and vomiting.
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- If a dose of INREBIC is missed, the next scheduled dose should be taken the following day.
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- For patients who have difficulty swallowing capsule(s) whole or those with a nasogastric tube:
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- Open the capsule(s).
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- In a glass container, mix the content of the capsule(s) with approximately 180 mL of Ensure® Plus liquid nutritional supplement [see Clinical Pharmacology (12.3)] at room temperature [between 20°C to 25°C (68°F to 77°F)].
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- Promptly administer the mixture orally or through a nasogastric tube (French size 14 or 16) within 2 hours of preparation.
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- If using a nasogastric tube, flush it with 60 mL of water after administering the mixture [see Clinical Pharmacology (12.3)].
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- Discard the prepared dose if not given within 2 hours.
Monitoring for Safety
Obtain the following blood tests prior to starting treatment with INREBIC, periodically during treatment, and as clinically indicated [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5)]:
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- Thiamine (Vitamin B1) level
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- Complete blood count with platelets
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- Creatinine and BUN
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- Hepatic panel
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- Amylase and lipase
Dose Modifications with Concomitant Use of Strong CYP3A4 Inhibitors
Reduce INREBIC dose when administering with strong CYP3A4 inhibitors to 200 mg once daily.
In cases where coadministration 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 [see Drug Interactions (7.1)].
Dose Modifications for Severe Renal Impairment
Reduce INREBIC dose to 200 mg once daily in patients with severe renal impairment (creatinine clearance (CLcr) 15 mL/min to 29 mL/min as estimated by Cockcroft-Gault (C-G) equation).
Dose Modifications for Adverse Reactions
Modify dose for hematologic and nonhematologic adverse reactions per Table 1 and Table 2. Discontinue INREBIC in patients unable to tolerate a dose of 200 mg daily. See Warnings and Precautions for other mitigating strategies.
Hematologic Adverse Reactions | Dose Reduction |
Grade 4 Thrombocytopenia or | Interrupt dose until resolved to Grade 2 or lower or baseline. Restart dose at 100 mg daily below the last given dose. |
Grade 4 Neutropenia | Interrupt dose until resolved to Grade 2 or lower or baseline. Restart dose at 100 mg daily below the last given dose. |
Consider dose reductions for patients who become transfusion-dependent during treatment with INREBIC.
Nonhematologic Adverse Reactions | Dose Reduction |
Grade 3 or higher Nausea, Vomiting, or Diarrhea not responding to supportive measures within 48 hours | Interrupt dose until resolved to Grade 1 or lower or baseline. Restart dose at 100 mg daily below the last given dose. |
Grade 3 or higher ALT, AST, or Bilirubin | Interrupt dose until resolved to Grade 1 or lower or baseline. Restart dose at 100 mg daily below the last given dose. |
Grade 3 or higher Other Nonhematologic Toxicities | Interrupt dose until resolved to Grade 1 or lower or baseline. Restart dose at 100 mg daily below the last given dose. |
Management of Thiamine Levels and Wernicke's Encephalopathy (WE)
Assess thiamine levels and nutritional status prior to starting INREBIC. Do not start INREBIC in patients with thiamine deficiency. However, if thiamine levels are low, replete thiamine prior to starting treatment. While on INREBIC treatment all patients should receive prophylaxis with daily 100 mg oral thiamine and should have thiamine levels assessed as clinically indicated. If Wernicke's encephalopathy is suspected, immediately discontinue treatment with INREBIC and initiate parenteral thiamine treatment. Monitor until symptoms resolve or improve and thiamine levels normalize [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
Capsules: 100 mg, reddish brown, opaque size 0, printed with "FEDR 100 mg" in white ink.
Pregnancy
Risk Summary
There are no available data on INREBIC use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. 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 (see Data). Consider the benefits and risks of INREBIC for the mother and possible risks to the fetus when prescribing INREBIC to a pregnant woman.
The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In an embryo-fetal development study in pregnant rats, fedratinib administration at a dose of 30 mg/kg/day during organogenesis (gestation days 6 to 17) was associated with adverse developmental outcomes including skeletal variations (such as additional ossification center of neuronal arches). These effects occurred in rats at approximately 0.1 times the clinical exposure based on AUC at the recommended daily dose. At lower doses of 10 mg/kg/day (0.01 times the clinical exposure at the recommended daily dose), fedratinib administered to pregnant rats resulted in maternal toxicity of decreased gestational weight gain.
In an embryo-fetal development study in pregnant rabbits, fedratinib administration during organogenesis (gestation Days 6 to 18) did not produce developmental or maternal toxicity at doses up to the highest dose level tested, 30 mg/kg/day (approximately 0.08 times the clinical exposure at the recommended daily dose). In a separate study, administration of 80 mg/kg/day fedratinib to rabbits resulted in maternal mortality.
In a pre- and postnatal study in rats, fedratinib was administered to pregnant female rats at doses of 3, 10, or 30 mg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on Day 21. A slight decrease in maternal body weight gain during gestation occurred at 30 mg/kg/day. The offspring from the high dose (30 mg/kg) had decreased body weight preweaning in both sexes and postweaning through the maturation phase in males. These effects occurred at exposures approximately 0.1 times the clinical exposure at the recommended daily dose.
Lactation
Risk Summary
There are no data on the presence of fedratinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with INREBIC, and for at least 1 month after the last dose.
Pediatric Use
The safety and effectiveness of INREBIC in pediatric patients have not been established.
Geriatric Use
Of the total number of patients with myelofibrosis who received an INREBIC dose of 400 mg in the clinical studies, 47.3% were greater than 65 years of age and 12.3% were greater than 75 years of age. No overall differences in safety or effectiveness of INREBIC were observed between these patients and younger patients.
Renal Impairment
Reduce INREBIC dose when administered to patients with severe renal impairment (CLcr 15 mL/min to 29 mL/min by Cockcroft-Gault) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. 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 Cockcroft-Gault). Due to potential increase of exposure, patients with preexisting moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions [see Dosage and Administration (2.6)].
None.