Inrebic - Drug Monograph

Introduction

Inrebic (fedratinib) is an oral kinase inhibitor approved for the treatment of myelofibrosis, a rare bone marrow disorder characterized by fibrosis, anemia, and splenomegaly. Developed by Celgene (now Bristol Myers Squibb), it represents an important therapeutic option for patients with this chronic myeloproliferative neoplasm.

Mechanism of Action

Fedratinib is a selective inhibitor of Janus-associated kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). It works by:

• Inhibiting JAK2-mediated signaling pathways
• Reducing phosphorylation of STAT proteins
• Decreasing production of inflammatory cytokines
• Modulating the bone marrow microenvironment
• Reducing splenomegaly and constitutional symptoms

The drug demonstrates greater selectivity for JAK2 over JAK1, JAK3, and TYK2, which may contribute to its distinct clinical profile compared to other JAK inhibitors.

Indications

Inrebic is FDA-approved for:

• Treatment of intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis in adults

Dosage and Administration

• Starting dose of 200 mg recommended for patients with platelet count 50-100 × 10⁹/L
• Treatment interruption and dose reduction to 200 mg or 100 mg for hematologic toxicity
• Hepatic impairment (Child-Pugh B): Reduce to 200 mg daily
• Hepatic impairment (Child-Pugh C): Not recommended
• Renal impairment (eGFR 15-89 mL/min): No adjustment needed
• Renal impairment (eGFR <15 mL/min): Use not recommended

• Swallow capsules whole with water
• Do not break, open, or chew capsules
• If vomiting occurs after dose administration, do not take an additional dose

Pharmacokinetics

• Median Tmax: 4 hours (range 2-6 hours)
• Food effect: None clinically significant
• Absolute bioavailability: Approximately 35%

• Volume of distribution: 1,110 L
• Protein binding: >99% primarily to albumin
• Blood-to-plasma ratio: 0.86

• Primarily metabolized by CYP3A4 and CYP2C19
• Forms multiple metabolites (M1, M2, M3a, M3b)
• M1 metabolite is pharmacologically active

• Half-life: Approximately 114 hours
• Clearance: 9.2 L/hour
• Excretion: Feces (76%, primarily as metabolites), urine (5%)

Contraindications

• Hypersensitivity to fedratinib or any component of the formulation
• Patients with thiamine deficiency (Wernicke's encephalopathy has been reported)
• Concomitant use with strong CYP3A4 inhibitors

Warnings and Precautions

• Encephalopathy, including Wernicke's encephalopathy
• Monitor thiamine levels before and during treatment
• Do not start Inrebic in patients with thiamine deficiency

• Anemia and thrombocytopenia: Monitor CBC weekly for first month, monthly thereafter
• Hepatotoxicity: Monitor liver function tests regularly
• Amylase and lipase elevation: Monitor periodically
• Gastrointestinal toxicity: Nausea, vomiting, and diarrhea may require supportive care
• Embryo-fetal toxicity: Can cause fetal harm; advise effective contraception

Drug Interactions

• Contraindicated (e.g., ketoconazole, itraconazole, clarithromycin)

• Avoid or reduce Inrebic dose to 200 mg (e.g., fluconazole, diltiazem)

• Avoid concomitant use (e.g., rifampin, carbamazepine, St. John's wort)

• PPIs: Separate administration by 2 hours
• H2-receptor antagonists: No significant interaction
• Antacids: No significant interaction

Adverse Effects

• Diarrhea (67%)
• Nausea (64%)
• Anemia (96%)
• Vomiting (38%)
• Fatigue (28%)
• Thrombocytopenia (23%)

• Increased ALT/AST
• Increased amylase/lipase
• Headache
• Dizziness
• Constipation
• Abdominal pain

• Wernicke's encephalopathy
• Severe hepatotoxicity
• Serious gastrointestinal toxicity
• Significant anemia and thrombocytopenia

Monitoring Parameters

• Complete blood count with differential
• Liver function tests
• Thiamine level
• Renal function
• Pregnancy test in women of childbearing potential

• CBC weekly for first month, then monthly
• LFTs monthly for first 3 months, then as clinically indicated
• Thiamine levels periodically
• Amylase and lipase as clinically indicated
• Nutritional status assessment
• Signs/symptoms of encephalopathy

• Spleen size reduction (palpation or imaging)
• Symptom improvement (MPN-SAF questionnaire)
• Hematologic parameters

Patient Education

• Take exactly as prescribed; do not adjust dose without medical supervision
• Report any neurological symptoms immediately (confusion, vision changes, coordination problems)
• Maintain adequate nutrition and report persistent nausea/vomiting
• Use effective contraception during treatment and for at least 1 month after final dose
• Inform all healthcare providers about Inrebic use
• Report signs of infection, unusual bleeding, or bruising
• Do not take with grapefruit or grapefruit juice
• Keep all follow-up appointments for monitoring

• Store at room temperature (20-25°C)
• Keep in original container with desiccant
• Keep out of reach of children

References

1. FDA Prescribing Information: Inrebic (fedratinib) capsules. August 2019. 2. Harrison CN, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol. 2020;95(6):594-603. 3. Pardanani A, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-651. 4. Talpaz M, et al. Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis. Leukemia. 2021;35(1):1-17. 5. Mesa RA, et al. Myelofibrosis-related anemia: current and emerging therapeutic strategies. Clin Lymphoma Myeloma Leuk. 2017;17S:S139-S144. 6. NCCN Guidelines: Myeloproliferative Neoplasms. Version 2.2023. 7. European Medicines Agency: Inrebic Assessment Report. 2021.