Fedratinib

Indications

Fedratinib is used for: Myelofibrosis

Adult Dose

Myelofibrosis Indicated for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF) Baseline platelet count >50 x 109/L: 400 mg PO qDay Hepatic impairment Mild-to-moderate (total bilirubin ?3x ULN and any AST): No dosage adjustment necessary Severe (total bilirubin >3x ULN and any AST): Avoid use; pharmacokinetics not evaluated

Child Dose

Renal Dose

Renal impairment Mild-to-moderate (CrCl 30 to <90 mL/min): No dosage adjustment necessary; patients with preexisting moderate renal impairment require close monitoring and dosage modifications based on adverse reactions if necessary Severe (CrCl 15 to <30 mL/min): Reduce to 200 mg qDay

Administration

Oral Administration Take orally with or without food Administration with a high-fat meal may reduce incidence of nausea and vomiting

Contra Indications

Precautions

Serious cases of encephalopathy, including Wernicke encephalopathy, reported in clinical trials May cause anemia and thrombocytopenia; manage by dose reduction, interruption, or transfusion Elevations of ALT and AST during the randomized treatment period occurred; monitor hepatic function at baseline and periodically during treatment; dose reduction may be needed for hepatoxicity Grade >3 Grade >3 amylase and/or lipase elevations developed; one patient developed pancreatitis in the clinical development program, which resolved once treatment was discontinued Gastrointestinal toxicities Gastrointestinal toxicities are the most frequent adverse reactions reported Manage by dose reduction or interruption if patient develops severe diarrhea, nausea, or vomiting Consider prophylaxis with antiemetics and treatment with antidiarrheals

Pregnancy-Lactation

Pregnancy No data available on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes Animal data In animal reproduction studies, oral administration of fedratinib to pregnant rats during organogenesis at doses of 400 mg/day resulted in adverse developmental outcomes Consider the benefits and risks for the mother and possible risks to the fetus when prescribing to a pregnant woman Lactation 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 Owing to the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment, and for at least 1 month after the last dose.

Interactions

Side Effects

Side effects of Fedratinib : >10% All grades Diarrhea (66%) Nausea (62%) Anemia (40-74%) Blood creatinine increased (10-59%) Thrombocytopenia (47%) ALT increased (9-43%) AST increased (5-40%) Vomiting (39%) Lipase increased (35%) Hyponatremia (26%) Amylase increased (24%) Neutropenia (23%) Fatigue or asthenia (19%) Muscle spasms (12%) Grade 3 or 4 Anemia (30-34%) Thrombocytopenia (12%) 1-10% All grades Pain in extremity (10%) Headache (9%) Weight increased (9%) Dizziness (8%) Bone pain (8%) Urinary tract infection (6%) Dysuria (6%) Hypertension (5%)

Mode of Action

Kinase inhibitor; inhibits Janus-associated kinase-2 (JAK2), which mediates signaling of cytokines and growth factors that are important for hematopoiesis and immune function JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus, leading to modulation of gene expression Myelofibrosis is a myeloproliferative neoplasm known to be associated with dysregulated JAK signaling