General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Pronunciation:
fed-ra-ti-nib

Trade Name(s)

• Inrebic

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

Intermediate-2 or high-risk primary or secondary (postpolycythemia vera or postessential thrombocythemia) myelofibrosis.

Action

Inhibits activated Janus-associated kinase 2 and FMS-like tyrosine kinase 3, which inhibits hematopoietic cell proliferation and causes apoptosis.

Therapeutic Effect(s):

Reduction in spleen size and symptoms.

Pharmacokinetics

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)

Contraindication/Precautions

Contraindicated in:

• Thiamine deficiency (correct before starting therapy);
• Severe hepatic impairment;
• OB:   Pregnancy;
• Lactation:  Lactation.

Use Cautiously in:

• Cardiovascular risk factors (↑ risk of cardiovascular death, MI, stroke);
• Current or past history of smoking (↑ risk of malignancy, cardiovascular death, MI, or stroke);
• Known malignancy;
• Severe renal impairment (↓ dose);
• Pedi:   Safety and efficacy not established in children.

Adverse Reactions/Side Effects

CV: ARTERIAL THROMBOSIS, CARDIOVASCULAR DEATH, DEEP VEIN THROMBOSIS, MI

F and E: hyponatremia

GI: constipation, diarrhea, ↑ amylase, ↑ lipase, ↑ liver enzymes, nausea, vomiting, HEPATOTOXICITY

GU: ↑ serum creatinine, dysuria

Hemat: anemia, NEUTROPENIA, thrombocytopenia

Metabolic: ↑ weight

MS: muscle spasm, pain

Neuro: fatigue, dizziness, ENCEPHALOPATHY, headache, STROKE

Resp: PULMONARY EMBOLISM

Misc: SECONDARY MALIGNANCY

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  Strong CYP3A4 inhibitors, including  ketoconazole, may ↑ levels and risk of toxicity; avoid concurrent use. If concurrent use unavoidable, ↓ fedratinib dose.
•  Dual CYP3A4 and CYP2C19 inhibitors, including  fluconazole, may ↑ levels and risk of toxicity.
•  Moderate or strong CYP3A4 inducers  may ↓ levels and effectiveness; avoid concurrent use.
• May ↑ levels of  CYP3A4 substrates,  CYP2C19 substrates, and  CYP2D6 substrates.

Route/Dosage

PO (Adults): Platelet count >50 × 10⁹ /L: 400 mg once daily.  Concurrent use of strong CYP3A4 inhibitor: 200 mg once daily.

Renal Impairment 
PO (Adults): CCr 15–29 mL/min and platelet count >50 × 10⁹ /L: 200 mg once daily.

Availability

Capsules: 100 mg

Assessment

• 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 hr,  hold fedratinib until resolved to ≤Grade 1 or baseline. Restart daily dose at 100 mg below dose last given.
• Monitor for signs and symptoms of anemia (fatigue, dizziness, pale conjunctiva), thrombocytopenia (easy bruising, bleeding gums or nose, petechiae, blood in urine), and neutropenia (fatigue, sore throat, lymphadenopathy); notify provider; may need to hold therapy and ↓ dose.

Lab Test Considerations:

Monitor thiamine (vitamin B1) levels at baseline and periodically during therapy. Do not start therapy if thiamine is deficient; replenish thiamine levels before starting therapy.

• CBC with platelet count, serum creatinine, BUN, hepatic function, amylase, and lipase levels to establish baseline and periodically during therapy
• 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, 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 ↓. If recurrence of a ≥Grade 3, discontinue fedratinib.
• 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.

Implementation

• Administer prophylactic oral thiamine 100 mg once daily during therapy for all patients.
• Prophylactic antiemetics may be used during therapy.
• PO Administer once daily without regard to food. Administering with a high-fat meal may ↓ nausea and vomiting.

Patient/Family Teaching

• Explain purpose and side effects of medication to patient. Advise patient to read  Patient Information  before starting therapy.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other medications.
• Explain need for continued medical follow-up to assess effectiveness and possible side effects of medication. Periodic lab tests will be needed.
• 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.
• Advise patient to report signs and symptoms of anemia (fatigue, dizziness, pale conjunctiva), thrombocytopenia (easy bruising, bleeding gums or nose, blood in urine), and neutropenia (fatigue, sore throat, swollen lymph nodes).
• Rep:  Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during therapy and for ≥1 mo after last dose.

Evaluation/Desired Outcomes

Reduction in spleen size and symptoms.