Intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.
Inhibits activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3) which inhibits hematopoietic cell proliferation and causes apoptosis.
Reduction in spleen size and symptoms.
Absorption: Well absorbed following oral administration.
Distribution: Extensively distributed to tissues.
Protein Binding: ≥92%.
Metabolism and Excretion: Mostly metabolized in the liver via the CYP3A4 and CYP2C19 isoenzymes. Primarily excreted in feces (77%, 23% as unchanged drug), with 5% excreted in urine (3% as unchanged drug).
Half-life: 114 hr.
TIME/ACTION PROFILE (plasma concentrations)
|PO||unknown||2–4 hr||24 hr|
- Severe hepatic impairment
- OB: Pregnancy (may cause fetal harm)
- Lactation: Lactation.
Use Cautiously in:
- Thiamine deficiency (correct before starting therapy)
- Severe renal impairment (↓ dose)
- Pedi: Safety and efficacy not established in children.
Adverse Reactions/Side Effects
F and E: hyponatremia
GI: HEPATOTOXICITY, constipation, diarrhea, ↑ amylase, ↑ lipase, ↑ liver enzymes, nausea, vomiting
GU: ↑ serum creatinine, dysuria
Hemat: NEUTROPENIA, anemia, thrombocytopenia
Metabolic: ↑ weight
MS: muscle spasms, pain
Neuro: ENCEPHALOPATHY, fatigue, dizziness, headache
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- Strong CYP3A4 inhibitors, including ketoconazole , may ↑ levels and risk of toxicity; avoid concurrent use. If unable to avoid use of strong CYP3A4 inhibitor, ↓ fedratinib dose.
- Dual CYP3A4 and CYP2C19 inhibitors may ↑ levels and risk of toxicity; avoid concurrent use.
- Moderate or strong CYP3A4 inducers may ↓ levels and effectiveness; avoid concurrent use.
- May ↑ levels of CYP3A4 substrates, CYP2C19 substrates, and CYP2D6 substrates.
PO (Adults): Platelet count >50 × 109 /L– 400 mg once daily. Concurrent use of strong CYP3A4 inhibitor– 200 mg once daily.
PO (Adults): CCr 15–29 mL/min and platelet count >50 × 109 /L– 200 mg once daily.
Capsules: 100 mg
- Monitor for signs and symptoms of encephalopathy (ataxia, mental status changes, nystagmus, diplopia, mental status change, confusion, memory impairment) during therapy. If encephalopathy is suspected, discontinue fedratinib and begin IV thiamine.
- Monitor for signs and symptoms of GI toxicity (nausea, vomiting, diarrhea) periodically during therapy. Nausea can be prophylactically treated with antiemetics. Use antidiarrheal agents at onset of diarrhea. For ≥Grade 3 nausea, vomiting, or diarrhea unresponsive to treatments within 48 hours, hold fedratinib until resolved to ≤Grade 1 or baseline. Restart dose at 100 mg daily below dose last given.
Lab Test Considerations:
Monitor thiamine (Vitamin B1) levels, CBC with platelet count, creatinine, BUN, hepatic function, amylase and lipase levels to establish baseline before starting therapy and periodically during therapy. Do not start therapy if thiamine is deficient.
- May cause anemia, thrombocytopenia, and neutropenia. For Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with active bleeding, hold dose until resolved to ≤Grade 2 or baseline. Restart dose at 100 mg daily below last dose given. For Grade 4 neutropenia, hold dose until resolved to ≤Grade 2 or baseline. Restart dose at 100 mg daily below last dose given.
- May cause hepatotoxicty. For ≥Grade 3 ALT, AST, (>5 × ULN) or bilirubin, hold fedratinib until ≤Grade 1 or baseline. Restart dose at 100 mg daily below last dose given. Monitor ALT, AST, and bilirubin (total and direct) more frequently following dose reduction. If re-occurrence of a ≥Grade 3, discontinue fedratrinib.
- If ≥Grade 3 amylase and/or lipase levels, hold fedratinib until resolved to ≤Grade 1 or baseline. Restart dose at 100 mg daily below last dose given.
- Deficient knowledge, related to medication regimen (Patient/Family/Teaching)
- Prophylactic antiemetics may be used during therapy.
- PO Administer once daily without regard to food. Administering with a high fat meal may reduce nausea and vomiting.
- Instruct patient to take fedratinib as directed. If a dose is missed, omit and that the next scheduled dose the next day. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
- Advise patient to notify health care professional immediately if signs and symptoms of encephalopathy (confusion, memory problems, drowsiness, problems with balance and movement, difficulty walking, double or blurred vision, abnormal eye movements) or GI toxicity (diarrhea, nausea, or vomiting that does not respond to treatment, rapid weight loss or weight loss that does not get better with treatment) occur.
- Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
- Rep: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during and for at least 1 mo after last dose.
Reduction in spleen size and symptoms.
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