Fedratinib

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What it isAn oral JAK2-selective inhibitor with FLT3 activity, for intermediate-2 and high-risk myelofibrosis.

Why this oneIt retains activity in patients who have failed or cannot tolerate ruxolitinib, which was the only prior option in that setting.

What limits itIt carries a boxed warning for encephalopathy including Wernicke encephalopathy — thiamine must be checked and repleted before and during treatment — and it causes anemia, thrombocytopenia and GI toxicity.

FDA-approved for

intermediate-2 or high-risk myelofibrosis

Off-label

post-polycythemia vera and post-essential thrombocythemia myelofibrosis

FDA label

Read the full label on DailyMed ↗

BOXED WARNING Serious and fatal encephalopathy including Wernicke's: assess thiamine before starting; do not start if thiamine-deficient (replete first); daily oral thiamine prophylaxis on treatment; if encephalopathy suspected, discontinue immediately and give parenteral thiamine

FDA dosing	Population	Start	Target	Max
Myelofibrosis (baseline platelets >=50 × 10^9/L)	Adults	400 mg QD	400 mg QD	400 mg QD

Renal Severe (CLcr 15–29 mL/min): reduce to 200 mg QD; mild-moderate (CLcr 30–89): no starting-dose change, but moderate impairment needs more intensive monitoring with dose modification as needed

Hepatic Undefined

Adverse-reaction dose modifications: Grade 4 thrombocytopenia/neutropenia or Grade >=3 GI toxicity/LFT elevation — interrupt, restart 100 mg below last dose; recurrent Grade >=3 LFT elevation — discontinue

Instructions

With or without food; high-fat meal may reduce nausea/vomiting
All patients: thiamine 100 mg PO daily prophylaxis; check thiamine at baseline and as indicated
Baseline and periodic: CBC with platelets, creatinine/BUN, hepatic panel, amylase/lipase
Missed dose: take next scheduled dose the following day
Swallowing difficulty/NG tube: disperse capsule contents in ~180 mL Ensure Plus; give within 2 h; flush NG tube with 60 mL water
Taper and discontinue ruxolitinib per its labeling before starting
Strong CYP3A4 inhibitor: reduce to 200 mg QD (on inhibitor stop: 300 mg QD ×2 weeks, then 400 mg QD)
Discontinue if unable to tolerate 200 mg QD

Cautions

Encephalopathy including Wernicke's (boxed): thiamine assessment/prophylaxis mandatory
Anemia (Grade 3 new/worsening in 34%) and thrombocytopenia: manage with dose reduction, interruption, or transfusion
GI toxicity (severe diarrhea/nausea/vomiting): antiemetic prophylaxis and antidiarrheals recommended
Hepatic toxicity: dose reduce/interrupt
Amylase/lipase elevation
Uveitis: refer for ophthalmological evaluation if symptoms
Major adverse cardiac events (MACE)
Thrombosis
Secondary malignancies (esp. current/past smokers)
Symptom exacerbation after interruption/discontinuation