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Fedratinib

Class: Antineoplastic Agents
- Fms-like Tyrosine Kinase-3 Inhibitor
- Flt-3 Inhibitor
- Janus Kinase Inhibitor
- JAK Inhibitor
VA Class: AN900
Chemical Name: N-tert-Butyl-3-[(5-methyl-2-{4-[2-(pyrrolidin-1-yl)ethoxy]anilino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate
Molecular Formula: C27H36N6O3S•2HCL•H2O
CAS Number: 1374744-69-0
Brands: Inrebic

Medically reviewed by Drugs.com on Aug 24, 2020. Written by ASHP.

Warning

    Encephalopathy
  • Serious, sometimes fatal, encephalopathy reported. Wernicke encephalopathy, a neurologic emergency caused by thiamine deficiency, also reported. (See Encephalopathy under Cautions.)

  • If changes in mental status, confusion, or memory impairment occur, interrupt fedratinib therapy and promptly evaluate for encephalopathy (i.e., neurologic examination, radiographic imaging, assess thiamine levels).

  • Do not initiate fedratinib therapy in patients with thiamine deficiency. Correct thiamine levels prior to initiating and during therapy.

Introduction

Antineoplastic agent; selective inhibitor of Janus kinase (JAK) 2 and fms-like tyrosine kinase (Flt) 3.

Uses for Fedratinib

Myelofibrosis

Treatment of intermediate-2 or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis (designated an orphan drug by FDA for these conditions). Substantially reduces splenomegaly and symptom burden compared with placebo.

Fedratinib Dosage and Administration

General

  • Monitor thiamine levels and nutritional status prior to initiating therapy, periodically during therapy, and as clinically indicated. Do not initiate fedratinib in patients with thiamine deficiency. Correct thiamine levels prior to initiating and during fedratinib therapy. (See Encephalopathy under Cautions.)

  • Monitor CBCs, serum amylase and lipase concentrations, and hepatic and renal function at baseline, periodically during therapy, and as clinically indicated.

  • Do not initiate in patients receiving ruxolitinib until ruxolitinib has been discontinued by gradual taper of the ruxolitinib dosage.

  • Consider prophylactic antiemetic therapy (e.g., 5-HT3 serotonin receptor antagonist).

Restricted Distribution

  • Obtain fedratinib through designated specialty pharmacies and distributors.

Administration

Oral Administration

Administer once daily without regard to food; tolerability (i.e., reduced nausea or vomiting) increased with a high-fat meal.

Dosage

Available as fedratinib hydrochloride; dosage expressed in terms of fedratinib.

Adults

Myelofibrosis
Oral

400 mg once daily in those with baseline platelet count ≥50,000/mm3.

Do not initiate if baseline platelet count <50,000/mm3.

If concomitant use with potent CYP3A4 inhibitors cannot be avoided, adjust fedratinib dosage. (See Interactions.)

Dosage Modification for Toxicity
Oral

Adverse effects may require temporary interruption, dosage reduction, and/or permanent discontinuance.

If dosage reduction from 400 mg once daily is necessary, reduce dosage to 300 mg once daily.

If dosage reduction from 300 mg once daily is necessary, reduce dosage to 200 mg once daily.

If further dosage reduction is necessary, discontinue fedratinib.

Hematologic Toxicity
Oral

If grade 3 thrombocytopenia with active bleeding or grade 4 thrombocytopenia occurs, interrupt fedratinib therapy. If thrombocytopenia resolves to grade 2 or less or baseline, resume fedratinib at next lower dosage.

If grade 4 neutropenia occurs, interrupt fedratinib therapy. If neutropenia resolves to grade 2 or less or baseline, resume fedratinib at next lower dosage.

In patients who become transfusion-dependent, consider dosage reduction.

GI Effects
Oral

If grade 3 or greater nausea, vomiting, or diarrhea occurs and is not responsive to supportive therapy within 48 hours, interrupt fedratinib therapy. When toxicity resolves to grade 1 or less or baseline, resume fedratinib at next lower dosage.

Hepatic Toxicity
Oral

For grade 3 or greater ALT, AST, or bilirubin concentration elevations, interrupt fedratinib therapy. If toxicity resolves to grade 1 or less or baseline, resume fedratinib at next lower dosage and monitor serum ALT, AST, and total and direct bilirubin concentrations more frequently.

If grade 3 or greater ALT, AST, or bilirubin concentration elevations recur, discontinue fedratinib therapy.

Wernicke Encephalopathy
Oral

If Wernicke encephalopathy suspected, promptly discontinue fedratinib and administer IV thiamine. Monitor thiamine levels until symptoms resolve or improve and thiamine levels reach normal limits.

Pancreatic Enzyme Elevation
Oral

For grade 3 or greater serum amylase and/or lipase concentration elevations, interrupt fedratinib therapy. If toxicity resolves to grade 1 or less or baseline, resume fedratinib at next lower dosage.

Other Toxicity
Oral

If grade 3 or greater adverse reactions occur, interrupt fedratinib therapy. If toxicity resolves to grade 1 or less or baseline, resume fedratinib at next lower dosage.

Prescribing Limits

Adults

Myelofibrosis
Oral

Dosage <200 mg once daily not recommended.

Special Populations

Hepatic Impairment

Severe hepatic impairment (total bilirubin concentration >3 times ULN with any AST): Avoid use. (See Hepatic Impairment under Cautions.)

Mild hepatic impairment (total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN, or total bilirubin concentration >1 times ULN, but not >1.5 times ULN, with any AST concentration): No specific dosage recommendations at this time.

Moderate (total bilirubin concentration >1.5 times ULN, but not >3 times ULN, with any AST concentration): No specific dosage recommendations at this time.

Renal Impairment

Severe renal impairment (Clcr 15–29 mL/minute): Reduce dosage to 200 mg once daily. (See Renal Impairment under Cautions.)

Moderate renal impairment (Clcr 60–89 mL/minute): No initial dosage adjustment required. Closely monitor for signs of toxicity and adjust dosage as appropriate (see Dosage Modification for Toxicity under Dosage and Administration).

Mild renal impairment (Clcr 30–59 mL/minute): No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations at this time. (See Geriatric Uses under Cautions.)

Cautions for Fedratinib

Contraindications

  • Manufacturer states none known.

Warnings/Precautions

Warnings

Encephalopathy

Serious, sometimes fatal, encephalopathy reported. Wernicke encephalopathy, a neurologic emergency caused by thiamine deficiency, also reported.

If changes in mental status, confusion, or memory impairment occur, interrupt fedratinib therapy and promptly evaluate for encephalopathy (i.e., neurologic examination, radiographic imaging, assessment of thiamine levels). If encephalopathy is suspected, promptly discontinue fedratinib and administer IV thiamine. Monitor thiamine levels until symptoms resolve or improve and thiamine levels reach normal limits.

Assess thiamine levels and nutritional status prior to initiating therapy, periodically during therapy, and as clinically indicated. Do not initiate fedratinib therapy in patients with thiamine deficiency. Correct thiamine levels prior to initiating and during therapy.

Other Warnings and Precautions

Hematologic Effects

Adverse hematologic effects (i.e., anemia, thrombocytopenia, neutropenia) reported. Median time to initial onset of grade 3 anemia or thrombocytopenia is approximately 2 or 1 month(s), respectively. Nadir hemoglobin concentrations occur after 12–16 weeks of fedratinib therapy; partial recovery and stabilization occurs after 16 weeks. Approximately one-half of patients who developed anemia required RBC transfusions and 3.1% of patients who developed thrombocytopenia required platelet transfusions.

Monitor CBCs at baseline, periodically during therapy, and then as clinically indicated. Temporary interruption of therapy, dosage reduction, or treatment discontinuance may be necessary based on severity of the toxicity. (See Hematologic Toxicity under Dosage and Administration.)

GI Effects

Diarrhea, nausea, and vomiting occur frequently, generally within 2 weeks of initiating therapy.

Consider prophylactic antiemetic therapy (e.g., 5-HT3 serotonin receptor antagonist). If diarrhea occurs, promptly initiate antidiarrheal therapy at onset of diarrhea.

Temporary interruption of therapy, dosage reduction, or treatment discontinuance may be necessary based on severity of the toxicity. (See GI Effects under Dosage and Administration.) Monitor thiamine levels and correct as needed.

Hepatic Toxicity

Serum ALT and/or AST elevations, generally within 3 months of initiating therapy, reported.

Monitor liver function tests at baseline, periodically during therapy, and as clinically indicated. Temporary interruption followed by dosage reduction or treatment discontinuance may be necessary based on severity of the toxicity. (See Hepatic Toxicity under Dosage and Administration.)

Pancreatic Enzyme Elevation

Serum amylase and/or lipase elevations, generally within 1 month of initiating therapy, reported. Pancreatitis also reported.

Monitor serum amylase and lipase concentrations at baseline, periodically during therapy, and as clinically indicated. Temporary interruption followed by dosage reduction or treatment discontinuance may be necessary based on severity of the toxicity. (See Pancreatic Enzyme Elevation under Dosage and Administration.)

Specific Populations

Pregnancy

May cause fetal harm; teratogenicity demonstrated in animals.

Consider potential risks and benefits of drug to mother and potential risk to fetus prior to initiating therapy in pregnant women.

Lactation

Not known whether fedratinib or its metabolites are distributed into human milk or affect nursing infants or milk production. Discontinue nursing during therapy and for ≥1 month after discontinuance of the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety or efficacy relative to younger adults.

Hepatic Impairment

Pharmacokinetics of fedratinib not altered in patients with mild (total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN, or total bilirubin concentration >1 times ULN, but not >1.5 times ULN, with any AST concentration) or moderate (total bilirubin concentration >1.5 times ULN, but not >3 times ULN, with any AST concentration) hepatic impairment.

Effect of severe hepatic impairment (total bilirubin concentration >3 times ULN with any AST concentration) on pharmacokinetics not established. Avoid use in patients with severe hepatic impairment.

Renal Impairment

Pharmacokinetics of fedratinib not altered in patients with mild renal impairment (Clcr 60–89 mL/minute).

Increased systemic exposure in individuals with moderate or severe renal impairment (Clcr 15–59 mL/minute). Reduce dosage in patients with preexisting severe renal impairment. (See Renal Impairment under Dosage and Administration.)

Grade 3 or 4 adverse effects requiring dosage modification reported more frequently in patients with moderate renal impairment; closely monitor patients with preexisting moderate renal impairment for signs of fedratinib toxicity and adjust dosage as appropriate. (See Dosage Modification for Toxicity under Dosage and Administration.)

Common Adverse Effects

Diarrhea, nausea, anemia, vomiting.

Interactions for Fedratinib

Metabolized principally by CYP3A4 and, to a lesser extent, by CYP2C19 and flavin-containing monooxygenase 3 (FMO3).

In vitro, inhibits P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, multidrug and toxin extrusion (MATE) transporter 1, and MATE2K; not an inhibitor of bile salt export pump (BSEP), multidrug resistance protein (MRP) 2, organic anion transporter (OAT) 1, and OAT3.

Substrate of P-gp, but not a substrate of BCRP, BSEP, OATP1B1, OATP1B3, MRP, or MRP2.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible increased systemic exposure to, and increased toxicity of, fedratinib. Consider alternative drug with less CYP3A4 inhibition potential. If concomitant use of a potent CYP3A4 inhibitor cannot be avoided, reduce fedratinib dosage to 200 mg once daily. If the potent CYP3A4 inhibitor is discontinued, increase fedratinib dosage to 300 mg once daily for 2 weeks followed by an increase to 400 mg once daily, as tolerated.

Combined CYP3A4 and 2C19 inhibitors: Concomitant use not evaluated. Avoid concomitant use.

Moderate and potent CYP3A4 inducers: Concomitant use not evaluated. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4, 2C19, or 2D6: Possible increased systemic exposure to, and increased toxicity of, the substrate drug. If fedratinib used concomitantly with a CYP3A4, 2C19, or 2D6 substrate, monitor for toxicity of substrate drug and adjust dosage of substrate drug as appropriate.

Specific Drugs

Drug

Interaction

Comments

Diltiazem

No substantial effect on fedratinib AUC

Erythromycin

No substantial effect on fedratinib AUC

Ketoconazole

Increased fedratinib AUC (2-fold at steady state)

Consider alternative drug with less CYP3A4 inhibition potential; if concomitant use cannot be avoided, reduce fedratinib dosage to 200 mg once daily

If ketoconazole is discontinued, increase fedratinib dosage to 300 mg once daily for 2 weeks followed by an increase to 400 mg once daily, as tolerated

Metoprolol

Increased metoprolol AUC (2-fold)

Monitor for metoprolol toxicity and adjust metoprolol dosage as appropriate

Midazolam

Increased midazolam AUC (4-fold)

Monitor for midazolam toxicity and adjust midazolam dosage as appropriate

Omeprazole

Increased omeprazole AUC (3-fold)

Monitor for omeprazole toxicity and adjust omeprazole dosage as appropriate

Pantoprazole

No substantial effect on fedratinib AUC

Fedratinib Pharmacokinetics

Absorption

Bioavailability

Systemic exposure increases in a dose-proportional manner over a dosage range of 300–500 mg once daily.

Peak plasma concentrations achieved within 2–4 hours following administration of fedratinib 400 mg once daily.

Steady-state concentrations achieved in 15 days. Mean accumulation ratio is 3- to 4-fold.

Food

Administration with a low-fat or high-fat meal increased peak plasma concentrations and AUC by 14 and 24%, respectively.

Special Populations

Mild (total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN, or total bilirubin concentration >1 times ULN, but not >1.5 times ULN, with any AST concentration) or moderate (total bilirubin concentration >1.5 times ULN, but not >3 times ULN, with any AST concentration) hepatic impairment: No effect on pharmacokinetics of fedratinib.

Severe hepatic impairment (total bilirubin concentration >3 times ULN with any AST concentration): Pharmacokinetics not studied.

Mild renal impairment (Clcr 60–89 mL/minute): No effect on pharmacokinetics of fedratinib.

Moderate (Clcr 30–59 mL/minute) or severe renal impairment (Clcr15–29 mL/minute): Systemic exposure increased by 1.5- or 1.9-fold, respectively.

Age (20–95 years), sex, body weight, and race: No substantial effect on pharmacokinetics.

Distribution

Extent

Not known whether fedratinib is distributed into human milk.

Plasma Protein Binding

≥92%.

Elimination

Metabolism

Metabolized principally by CYP3A4 and, to a lesser extent, by 2C19 and FMO3.

Elimination Route

Eliminated primarily in feces (77%; 23% as unchanged drug) and to a lesser extent in urine (5%; 3% as unchanged drug).

Half-life

Effective half-life: 41 hours.

Terminal half-life: Approximately 114 hours.

Stability

Storage

Oral

Capsules

<30°C.

Actions

  • Selectively inhibits JAK2 and Flt 3.

  • Myeloproliferative neoplasms, including myelofibrosis and polycythemia vera, associated with dysregulated JAK2 signaling. Majority of polycythemia vera myelofibrosis and 50–60% of primary myelofibrosis and essential thrombocythemia myelofibrosis carry JAK2V617F mutation, which results in constitutive activation of JAK-STAT signaling pathway and subsequent abnormal hematopoiesis and dysregulation of inflammatory cytokines and chemokines.

  • Competitively inhibits at ATP-binding site of wild-type JAK2 and JAK2V617F, preventing phosphorylation and activation of STATs.

  • In vitro, greater inhibitory potency at JAK2 relative to JAK1, JAK3, and TYK2.

  • In vitro, decreased phosphorylation of STAT3/5, inhibited cell proliferation, and induced apoptosis.

  • Inhibits phosphorylation of STAT3/5 and improves survival, WBCs, hematocrit, splenomegaly, and fibrosis in mouse models of myeloproliferative disease harboring JAK2V617F.

  • Causes dose-dependent inhibition of cytokine-induced STAT3 phosphorylation in whole blood of patients with myelofibrosis. Maximal inhibition observed approximately 2 hours after initial dose of drug; activity returns to near baseline by 24 hours. Inhibition at steady state similar to maximal inhibition observed following the initial dose.

Advice to Patients

  • Importance of advising patients to read the manufacturer's patient information (medication guide).

  • Importance of advising patients that if they miss a dose of fedratinib, they should take their prescribed dose at the next scheduled time; an additional dose should not be administered to replace the missed dose.

  • Risk of encephalopathy, including Wernicke encephalopathy. Importance of monitoring of thiamine levels. Importance of seeking emergency medical attention if changes in mental status (e.g., confusion, drowsiness, memory impairment), cerebellar abnormalities (e.g., ataxia), or ophthalmic abnormalities (e.g., diplopia, nystagmus) occur. Importance of promptly informing clinician if nausea, vomiting, diarrhea, and weight loss unresponsive to appropriate treatment and resulting in malnutrition and low thiamine levels occur.

  • Risk of thrombocytopenia or anemia and importance of monitoring CBCs prior to and during fedratinib therapy. Importance of informing clinician if bleeding or bruising occurs.

  • Risk of diarrhea, nausea, or vomiting unresponsive to appropriate treatment.

  • Risk of hepatotoxicity and importance of liver function test monitoring prior to and during fedratinib therapy.

  • Risk of elevated amylase or lipase concentrations and importance of pancreatic enzyme monitoring prior to and during fedratinib therapy.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of advising women not to breast-feed during and for ≥1 month after discontinuance of therapy.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution is restricted. (See Restricted Distribution under Dosage and Administration.)

Fedratinib Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

100 mg (of fedratinib)

Inrebic

Celgene

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 24, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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