INREBIC Capsule (2020)
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Celgene Corporation
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BOXED WARNING SECTION
<b>WARNING: ENCEPHALOPATHY INCLUDING WERNICKES</b> <b>Serious and fatal encephalopathy, including Wernickes, has occurred in patients treated with INREBIC. Wernickes encephalopathy is a neurologic emergency. ...
1. Indications and Usage
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).
2. Dosage and Administration
2.1 Recommended Dosage Conduct baseline testing of thiamine (Vitamin B1) levels prior to initiation of INREBIC <em>[see Dosage and Administration (2.2), Warnings and Precautions (5.1)]</em>. The recommended ...
3. Dosage Forms and Strengths
Capsules: 100 mg, reddish brown, opaque size 0, printed with FEDR 100 mg in white ink.
4. Contraindications
None.
5. Warnings and Precautions
5.1 Encephalopathy, Including Wernickes Serious and fatal encephalopathy, including Wernickes encephalopathy, has occurred in INREBIC-treated patients. Serious cases were reported in 1.3% (8/608) of patients ...
6. Adverse Reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: Encephalopathy, including Wernickes <em>[see Warnings and Precautions (5.1)]</em> Anemia and Thrombocytopenia ...
6.1. Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another ...
7. Drug Interactions
7.1 Effect of Other Drugs on INREBIC Strong CYP3A4 Inhibitors Coadministration of INREBIC with a strong CYP3A4 inhibitor increases fedratinib exposure <em>[see Clinical Pharmacology (12.3)]</em>. Increased ...
8.1. 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 ...
8.2. 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 ...
8.4. Pediatric Use
The safety and effectiveness of INREBIC in pediatric patients have not been established.
8.5. 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 ...
8.6. Renal Impairment
Reduce INREBIC dose when administered to patients with severe renal impairment (CL<sub>cr</sub> 15 mL/min to 29 mL/min by Cockcroft-Gault) <em>[see Dosage and Administration (2.4) and Clinical Pharmacology ...
8.7. Hepatic Impairment
INREBIC pharmacokinetics has not been evaluated in patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST). Avoid use of INREBIC in patients with severe hepatic impairment <em> ...
11. Description
INREBIC (fedratinib) is a kinase inhibitor with the chemical name N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate. ...
12.1. 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). Fedratinib is a JAK2-selective ...
12.2. Pharmacodynamics
Fedratinib inhibited cytokine-induced STAT3 phosphorylation in whole blood from patients with myelofibrosis. The inhibition of STAT3 phosphorylation was maximal approximately 2 hours after the first dose, ...
12.3. Pharmacokinetics
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<sub>max</sub>) and the area ...
13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility
Fedratinib was not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model. Fedratinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration ...
13.2. Animal Toxicology and/or Pharmacology
The JAK/STAT pathway has been implicated in bone formation and metabolism, and its inhibition may cause bone abnormalities, e.g. in developing bone. There is currently no evidence of bone abnormalities ...
14. Clinical Studies
JAKARTA JAKARTA (NCT01437787) was a double-blind, randomized, placebo-controlled trial in patients with intermediate-2 or high-risk myelofibrosis, post-polycythemia vera myelofibrosis or post-essential ...
16.1. How Supplied
INREBIC (fedratinib) 100 mg capsules: Reddish brown, opaque, size 0 capsule, printed with FEDR 100 mg in white ink. Bottles of 120 capsules (NDC 59572-720-12)
16.2. Storage and Handling
Store below 86°F (30°C).
17. Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Discuss the following with patients prior to and during treatment with INREBIC. Encephalopathy, including Wernickes Advise ...