fedratinib — Drug Monograph

Brand names: Inrebic

Drug class: JAK Inhibitor

Mechanism of Action

Fedratinib is a selective inhibitor of Janus kinase 2 (JAK2) and FLT3, with significantly less activity against JAK1 compared to ruxolitinib. By blocking JAK2 kinase activity, fedratinib inhibits STAT5 phosphorylation and downstream transcription of genes driving clonal myeloproliferation in myelofibrosis. Its JAK2 selectivity profile is hypothesized to reduce some off-target immunosuppression while maintaining robust antineoplastic activity against JAK2-driven disease.

FDA Indications

• Intermediate-2 or high-risk primary or secondary (post-PV or post-ET) myelofibrosis in adults — approved Aug 2019 (JAKARTA trial)
• Myelofibrosis in patients previously treated with ruxolitinib — approved Feb 2023 (JAKARTA2 trial)

Common Side Effects

• Diarrhea (~66%)
• Nausea (~62%)
• Vomiting (~39%)
• Anemia (~38%)
• Thrombocytopenia (~22%)
• Neutropenia
• Fatigue
• Muscle spasms
• Constipation
• Elevated creatinine
• Elevated amylase/lipase

Clinical Pearl

Fedratinib is the preferred agent in patients with myelofibrosis who have failed or are intolerant of ruxolitinib, demonstrating significant spleen volume reduction and symptom improvement in this difficult-to-treat population. The risk of Wernicke's encephalopathy is a unique class concern; clinicians should proactively check and supplement thiamine before starting therapy and educate patients about neurological warning signs. Antiemetic prophylaxis (e.g., ondansetron or prochlorperazine)…

Related Therapies & Mechanisms

• Ruxolitinib (Jakafi) — JAK Inhibitor · Leukemia
• Acalabrutinib (Calquence) — Leukemia
• Alemtuzumab (Campath) — Leukemia
• Arsenic Trioxide (Trisenox) — Leukemia