fedratinib (Rx)

Brand and Other Names:Inrebic
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Dosing & Uses

AdultPediatric

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

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Interactions

Interaction Checker

and fedratinib

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            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%)
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            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

            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
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            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.

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            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])

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            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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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.