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Introduction

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

Uses for Fedratinib (Systemic)

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 (Systemic) Dosage and Administration

General

Pretreatment Screening

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

• CBCs, serum amylase and lipase concentrations, and hepatic and renal function at baseline.

Patient Monitoring

• Monitor thiamine levels and nutritional status periodically during therapy and as clinically indicated.

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

• Monitor for the development of major adverse cardiac events (MACE), thrombosis, and secondary malignancies during therapy.

Premedication and Prophylaxis

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

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), fedratinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Other General Considerations

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

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.

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

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

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

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

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

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

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.

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 (Cl_cr 15–29 mL/minute): Reduce dosage to 200 mg once daily.

Moderate renal impairment (Cl_cr 60–89 mL/minute): No initial dosage adjustment required. Closely monitor for signs of toxicity and adjust dosage as appropriate .

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

Geriatric Patients

No specific dosage recommendations at this time.

Contraindications

• None.

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.

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. 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.

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.

Major Adverse Cardiac Events (MACE)

An increased risk of MACE observed in patients with rheumatoid arthritis treated with another Janus Kinase inhibitor. Advise patients of benefits and risks of initiating or continuing fedratinib, particularly for current or past smokers or those who have other cardiovascular risk factors. Inform patients about symptoms of serious cardiovascular events and steps to take if such symptoms occur.

Thrombosis

An increased risk of thrombosis observed in patients with rheumatoid arthritis treated with another Janus Kinase inhibitor. Evaluate patients with thrombosis symptoms promptly and treat appropriately.

Secondary Malignancies

An increased risk of lymphoma and other malignancies, excluding nonmelanoma skin cancer, observed in patients with rheumatoid arthritis treated with another Janus Kinase inhibitor. Current or past smokers are at an additional increased risk for secondary malignancy development. Advise patients of benefits and risks of initiating or continuing fedratinib, particularly for those with a known malignancy (other than nonmelanoma skin cancer), those who develop a malignancy, and those who are current or past smokers.

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 (Cl_cr 60–89 mL/minute).

Increased systemic exposure in individuals with moderate or severe renal impairment (Cl_cr 15–59 mL/minute). Reduce dosage in patients with preexisting severe renal impairment.

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.

Common Adverse Effects

Adverse effects reported in ≥20% of patients: Diarrhea, nausea, anemia, vomiting.

General

Pretreatment Screening

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

• CBCs, serum amylase and lipase concentrations, and hepatic and renal function at baseline.

Patient Monitoring

• Monitor thiamine levels and nutritional status periodically during therapy and as clinically indicated.

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

• Monitor for the development of major adverse cardiac events (MACE), thrombosis, and secondary malignancies during therapy.

Premedication and Prophylaxis

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

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), fedratinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Other General Considerations

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

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.

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

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

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

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

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

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

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.

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 (Cl_cr 15–29 mL/minute): Reduce dosage to 200 mg once daily.

Moderate renal impairment (Cl_cr 60–89 mL/minute): No initial dosage adjustment required. Closely monitor for signs of toxicity and adjust dosage as appropriate .

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

Geriatric Patients

No specific dosage recommendations at this time.

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 may result in increased systemic exposure to fedratinib and possible toxicity. May require more intensive safety monitoring and a potential dose modification if adverse reactions occur.

Moderate and potent CYP3A4 inducers: Concomitant use may result in decreased systemic exposure to fedratinib and possible reduced effectiveness of the drug. 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.

Substrates of OCT2 and MATE1/2-K: Possible reduced renal clearance of the substrate drug. If fedratinib used concomitantly with a OCT2 or MATE1/2-K substrate, monitor for adverse reactions and consider dose modifications.

Specific Drugs