Dosing & Uses
Dosage Forms & Strengths
capsule
- 100mg
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
Dosage Modifications
Discontinue treatment if unable to tolerate 200 mg qDay
Coadministration of strong CYP3A4 inhibitors
- Reduce fedratinib dose to 200 mg qDay
- If strong CYP3A4 inhibitor is discontinued, increase fedratinib dose to 300 mg qDay during the first 2 weeks after discontinuing the CYP3A4 inhibitor, and then to 400 mg qDay thereafter as tolerated
Hematologic adverse reactions
-
Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding, or Grade 4 neutropenia
- Interrupt dose until resolved to Grade ≤2 or baseline
- Restart at 100 mg qDay below the last given dose
- Consider dose reduction in patients who become transfusion-dependent during treatment
Nausea, vomiting, diarrhea
- Grade ≥3 nausea, vomiting, diarrhea nonresponsive to supportive measure after 48 hr: Interrupt dose until resolved to Grade ≤1 or baseline
- Restart at 100 mg qDay below the last given dose
Hepatoxicity
- Grade ≥3 ALT, AST, bilirubin: Interrupt dose until resolved to Grade ≤1 or baseline
- Restart at 100 mg qDay below the last given dose
- Closely monitor ALT, AST, and bilirubin after dose reduction
- If Grade ≥3 recurs, discontinue treatment
Other nonhematologic toxicities
- Grade ≥3: Interrupt dose until resolved to Grade ≤2 or baseline
- Restart at 100 mg qDay below the last given 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
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
Dosing Considerations
Patients treated with ruxolitinib before initiating fedratinib must taper and discontinue according to the ruxolitinib prescribing information
Monitor parameters
-
Monitor the following before starting treatment, periodically during treatment, and as clinically indicated
- Thiamine (vitamin B-1) level
- Complete blood cell count
- Creatinine and BUN
- Hepatic panel
- Amylase and lipase
Management of thiamine levels and Wernicke encephalopathy
- Assess thiamine levels and nutritional status before starting treatment, periodically during treatment, and as clinically indicated
- Do not start in patients with thiamine deficiency; replete thiamine before initiating and during treatment if thiamine levels are low
- If Wernicke encephalopathy is suspected, immediately discontinue treatment and initiate parenteral thiamine treatment
- Monitor until symptoms resolve or improve and thiamine levels normalize
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>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%)
Grade 3 or 4
- Lipase increased (10%)
- Diarrhea (5%)
- Fatigue or asthenia (5%)
- Neutropenia (5%)
- Hyponatremia (5%)
- Vomiting (3.1%)
- Blood creatinine increased (1-3.1%)
- Hypertension (3%)
- Amylase increased (2.1%)
- ALT increased (1%)
Warnings
Encephalopathy
Serious and fatal encephalopathy, including Wernicke, has occurred
Wernicke encephalopathy is a neurologic emergency
Assess thiamine levels in all patients before starting treatment, periodically during treatment, and as clinically indicated
Do not start in patients with thiamine deficiency; replete thiamine before starting treatment
If encephalopathy suspected, immediately discontinue treatment and initiate parenteral thiamine
Monitor until symptoms resolve or improve and thiamine levels normalize
Contraindications
None
Cautions
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
Major adverse cardiac events (MACE)
- Another JAK-inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which this drug is not indicated
- Consider the benefits and risks for individual patients prior to initiating or continuing therapy, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors
- Patients should be informed about symptoms of serious cardiovascular events and steps to take if they occur
Thrombosis
- Another JAK-inhibitor has increased risk of thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which this drug is not indicated; in patients with MF treated with this drug in clinical trials, the rates of thromboembolic events were similar in drug-treated and placebo-treated patients
- Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately
Secondary malignancies
- Another JAK-inhibitor has increased risk of lymphoma and other malignancies excluding non-melanoma skin cancer (NMSC) (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which this drug is not indicated; patients who are current or past smokers are at additional increased risk
- Consider benefits and risks for the individual patient prior to initiating or continuing therapy, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers
Drug interaction overview
- Fedratinib is a CYP3A4 and CYP2C19 substrate; a moderate CYP3A4, CYP2C19, or CYP2D6 inhibitor
- In vitro studies showed that fedratinib is a P-gp substrate; it also inhibits P-gp, BCRP, OATP1B1, OATP1B3, organic cation transporter (OCT)2, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K
-
Strong CYP3A4 inhibitors
- Coadministration with a strong CYP3A4 inhibitor increases fedratinib exposure; increased exposure may increase risk of adverse reactions
- Consider other therapies that do not strongly inhibit CYP3A4
- If unable to avoid coadministration, reduce fedratinib dose
-
Strong and moderate CYP3A4 inducers
- Avoid coadministration
- Effect of concomitant use with a strong or moderate CYP3A4 inducer has not been studied
-
Dual CYP3A4 and CYP2C19 inhibitors
- Avoid coadministration
- Effect of concomitant use with a dual CYP3A4 and CYP2C19 inhibitor has not been studied
-
CYP3A4, CYP2C19, or CYP2D6 substrates
- Coadministration with CYP3A4, CYP2C19, or CYP2D6 substrates increases the concentrations of these drugs, which may increase the risk of adverse reactions of these drugs
- Monitor for adverse reactions and modify dose of these drugs as necessary
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.
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
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
Absorption
Peak plasma time: ~3 hr (steady-state)
Peak plasma concentration: 1,804 ng/mL
AUC: 26,870 ng⋅hr/mL
Steady-state reached within 15 days
Effect of food
- A low-fat, low-calorie or a high-fat, high-calorie meal increased AUC up to 24% and peak plasma concentration up to 14% of a single 500-mg dose
Distribution
Vd (steady-state): 1,770 L
Protein bound:≥92%
Metabolism
Primarily metabolized by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3 (FMO3)
Fedratinib accounts for ~80% of total circulating drug in plasma after oral administration
Elimination
Half-life: ~ 114 hr
Clearance: 13 L/hr
Excretion: Feces (77% [23% unchanged]); urine (5% [3% unchanged])
Administration
Oral Administration
Take orally with or without food
Administration with a high-fat meal may reduce incidence of nausea and vomiting
Missed dose
- Take the next scheduled dose the following day
Storage
Store <30ºC (86ºF)
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