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
Adverse 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%)
Mechanism 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