Fedratinib hydrochloride, a selective inhibitor of Janus kinase (JAK) 2 and fms-like tyrosine kinase (Flt) 3, is an antineoplastic agent.1, 2, 6, 8, 9, 10
Fedratinib hydrochloride is used for the treatment of adults with intermediate-2 or high-risk primary or secondary myelofibrosis, including post-polycythemia vera or post-essential thrombocythemia.1, 2 Fedratinib is designated an orphan drug by FDA for use in the treatment of these conditions.4 Fedratinib has been shown to substantially reduce splenomegaly and symptom burden compared to placebo in patients with myelofibrosis.1, 2
The current indication for fedratinib is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (JAKARTA) in 289 patients with myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis).1, 2 In this study, patients had palpable splenomegaly at least 5 cm below the left costal margin and a risk category of intermediate-2 (2 prognostic factors) or high risk (3 or more prognostic factors) based on the International Working Group (IWG) consensus criteria.1, 2, 6, 7 The International Prognostic Scoring System (IPSS) includes 5 risk factors for estimating survival from time of diagnosis, including age greater than 65 years, hemoglobin concentration less than 10 g/dL, leukocyte count greater than 25,000/mm3, circulating myeloblasts of 1% or greater, and presence of constitutional symptoms.6, 7 The presence of 0, 1, 2, or 3 or more risk factors indicates low, intermediate-1, intermediate-2, or high risk disease, respectively.6, 7
In this study, patients were randomized in a 1:1:1 ratio to receive fedratinib (400 mg once daily), fedratinib (500 mg once daily), or placebo for at least 6 consecutive 4-week cycles.1, 2 The median age of patients enrolled in the study was 65 years (range: 27-86 years); 59% of enrolled patients were male, median hemoglobin concentration was 10.2 g/dL, median platelet count was 214,000/mm3, median spleen volume (as measured by magnetic resonance imaging [MRI] or computed tomography [CT]) was 2568 cm3 (upper limit of normal is 300 cm3), and median palpable spleen length was 15 cm.1 Most patients (64%) had primary myelofibrosis, 26% had post-polycythemia vera myelofibrosis, and 10% had post-essential thrombocythemia myelofibrosis; 52 or 48% of patients had intermediate-2 or high-risk disease, respectively.1 The primary efficacy end point was the proportion of patients achieving a 35% or greater reduction from baseline in spleen volume (measured by MRI or CT) at 24 and 28 weeks.1, 2 An additional outcome measure included the proportion of patients achieving a 50% or greater reduction from baseline in total symptom score at 24 weeks (measured by the modified Myelofibrosis Symptom Assessment Form [MFSAF]); symptoms assessed included night sweats, itching, abdominal discomfort, early satiety, rib pain on left side, and bone or muscle pain.1, 2 A 35% or greater reduction in spleen volume from baseline was achieved in a substantially larger proportion of patients receiving fedratinib 400 mg once daily compared with those receiving placebo (37 versus 1%).1, 2 A reduction in total symptom score by at least 50% from baseline also was achieved in 40 or 9% of patients receiving fedratinib 400 mg once daily or placebo, respectively.1, 2
Fedratinib also has been studied in a multicenter, open-label, noncomparative phase 2 study (JAKARTA-2) in 97 patients with intermediate-2 or high-risk myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis) who were previously treated with ruxolitinib.16 Among 83 evaluable patients, 55% achieved a 35% or greater reduction in spleen volume from baseline.16 In an updated analysis of the study based on stringent criteria for relapsed or refractory myelofibrosis (defined as previous therapy with ruxolitinib for at least 3 months with an initial response) and intolerance to ruxolitinib therapy (defined as requiring red blood cell [RBC] transfusions or occurrence of grade 3 or greater cytopenia after at least 28 days of therapy), approximately 30% of these patients achieved a 35% or greater reduction in spleen volume from baseline.17
Myeloproliferative disorders, including myelofibrosis, frequently occur as the result of a driver mutation in the JAK 2 signal transducer and activator of transcription (STAT) 5 signaling pathway.18, 22 Patients with low- or intermediate-risk myelofibrosis who lack significant symptoms may be managed with observation alone.19 However, if cytoreductive therapy is indicated in low- to intermediate-risk patients, hydroxyurea is often recommended as first-line treatment.19, 22 There is no current consensus on the management of splenomegaly in patients with myelofibrosis before allogeneic stem cell transplantation.19 Historically, myelofibrosis-associated splenomegaly was treated with hydroxyurea; however, some experts currently recommend JAK inhibitors as first-line treatment in patients with intermediate or high-risk disease who are not eligible for allogeneic stem cell transplantation, in those who are unresponsive to or cannot tolerate hydroxyurea, and to reduce spleen size prior to allogeneic stem cell transplantation.19, 20, 21, 22
Fedratinib is administered orally once daily without regard to food; tolerability (i.e., reduced nausea or vomiting) of the drug may be increased when taken with a high-fat meal.1, 9
If a patient has difficulty swallowing a whole capsule or has a nasogastric (NG) tube, fedratinib capsules may be opened and the contents mixed with approximately 180 mL of Ensure® Plus at room temperature (20-25°C) in a glass container.1 Within 2 hours of preparation, the mixture should be administered orally or through the NG tube (French size 14 or 16).1 If administered via a NG tube, the tube should be flushed with 60 mL of water after mixture administration.1 The mixture should be discarded if not administered within 2 hours of preparation.1
If a dose of fedratinib is missed, the next scheduled dose should be administered the following day; an additional dose should not be administered to replace the missed dose.1
Do not initiate in patients receiving ruxolitinib until ruxolitinib has been discontinued by gradual taper.1
Fedratinib capsules should be stored at <30°C.1
Dosage of fedratinib hydrochloride is expressed in terms of fedratinib.1
For the treatment of intermediate-2 or high-risk primary or secondary myelofibrosis in patients with a baseline platelet count of 50,000/mm3 or greater, the recommended adult dosage of fedratinib is 400 mg once daily.1
Dosage Modification for Toxicity
Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of fedratinib may be necessary in patients experiencing certain adverse effects.1 Fedratinib should be discontinued in patients unable to tolerate a 200 mg daily dose.1
If grade 3 thrombocytopenia with active bleeding or grade 4 thrombocytopenia occurs, fedratinib therapy should be withheld; therapy may be resumed at 100 mg daily below the last given dose when thrombocytopenia resolves to grade 2 or less or baseline.1
If grade 4 neutropenia occurs, fedratinib therapy should be withheld; therapy may be resumed at 100 mg daily below the last given dose when neutropenia resolves to grade 2 or less or baseline.1
In patients who become transfusion-dependent during fedratinib therapy, consider dosage reduction of the drug.1
If grade 3 or greater nausea, vomiting, or diarrhea occurs and is unresponsive to supportive therapy within 48 hours, fedratinib therapy should be withheld; therapy may be resumed at 100 mg daily below the last given dose when the toxicity resolves to grade 1 or less or baseline.1
For grade 3 or greater elevations in serum aminotransferase (ALT and/or AST) or bilirubin concentrations, fedratinib therapy should be withheld until the toxicity resolves to grade 1 or less or baseline.1 Fedratinib therapy may then be resumed at 100 mg daily below the last given dose, and serum ALT, AST, and total and direct bilirubin concentrations should be monitored more frequently.1 If grade 3 or greater elevations in ALT, AST, or bilirubin concentrations recur, fedratinib therapy should be discontinued.1
If Wernicke encephalopathy is suspected, fedratinib therapy should be promptly discontinued and IV thiamine should be administered.1 Thiamine levels should be monitored until symptoms resolve or improve and thiamine levels reach normal limits.1
For grade 3 or greater elevations in serum amylase and/or lipase concentrations, fedratinib therapy should be withheld; therapy may then be resumed at 100 mg daily below the last given dose when serum amylase and/or lipase concentrations resolve to grade 1 or less or baseline.1
If grade 3 or greater adverse reactions occur, fedratinib therapy should be withheld; therapy may be resumed at 100 mg daily below the last given dose when the toxicity resolves to grade 1 or less or baseline.1
Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes
Because of the potential for strong CYP3A4 inhibitors (e.g., ketoconazole) to increase exposure to fedratinib, selection of an alternative drug with less CYP3A4 inhibition potential should be considered.1 Alternatively, the manufacturer recommends reducing the dosage of fedratinib to 200 mg once daily when coadministering a strong CYP3A4 inhibitor.1 If concomitant use of the strong CYP3A4 inhibitor is discontinued, the dosage of fedratinib should be gradually returned to the dosage used prior to initiation of the strong CYP3A4 inhibitor according to the following schedule: 300 mg once daily for 2 weeks followed by an increase to 400 mg once daily thereafter as tolerated.1
The manufacturer makes no specific dosage recommendations for patients with preexisting mild, moderate, or severe (Child-Pugh class A, B, or C) hepatic impairment; however, hepatic toxicity may occur with therapy requiring temporary interruption, dosage adjustment, or discontinuation.1
For patients with severe renal impairment (creatinine clearance 15-29 mL/minute), the manufacturer recommends a fedratinib dosage of 200 mg once daily.1
No initial dosage adjustment is necessary in patients with mild (creatinine clearance 60-89 mL/minute) to moderate (creatinine clearance 30-59 mL/minute) renal impairment; however, patients with preexisting moderate renal impairment should be closely monitored for signs of toxicity, and dosage of fedratinib should be adjusted as appropriate.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Serious encephalopathy, including Wernicke encephalopathy, has been reported in patients receiving fedratinib.1 The prescribing information for fedratinib contains a boxed warning regarding this risk.1 In clinical trials, serious encephalopathy was reported in 8 of 608 (1.3%) fedratinib-treated patients; fatal encephalopathy occurred in one of these patients.1
Wernicke encephalopathy, a neurologic disorder associated with thiamine deficiency, is an emergency characterized by ataxia, mental status changes, and ophthalmoplegia (e.g., nystagmus, diplopia).1, 14 It has been postulated that thiamine deficiency and Wernicke encephalopathy are adverse effects specific to fedratinib because of the similarity of a substructure of the drug to thiamine.14 Thiamine deficiency and Wernicke encephalopathy have not been observed with other Janus kinase (JAK) inhibitors (e.g., ruxolitinib, tofacitinib); in addition, no association between the JAK and signal transducers and activators of transcription (STAT) signaling pathway and thiamine uptake and/or function has been demonstrated.14 In vitro, fedratinib potently inhibited thiamine uptake, whereas no inhibition of thiamine uptake was observed with ruxolitinib and tofacitinib.14
Thiamine levels and nutritional status should be assessed prior to initiation of fedratinib therapy, periodically during therapy, and as clinically indicated.1 Fedratinib therapy should not be initiated in patients with thiamine deficiency.1 Thiamine levels should be corrected prior to initiation of fedratinib therapy.1 All patients should be administered prophylactic oral thiamine during fedratinib therapy.1
If changes in mental status, confusion, or memory impairment occur, fedratinib therapy should be interrupted and patients should be promptly evaluated for encephalopathy (i.e., neurologic examination, radiographic imaging, assessment of thiamine levels).1 If encephalopathy is suspected, fedratinib therapy should be promptly discontinued and IV thiamine should be administered.1 Thiamine levels should be monitored until symptoms resolve or improve and thiamine levels reach normal limits.1
Other Warnings and Precautions
Adverse hematologic effects (i.e., anemia, thrombocytopenia, neutropenia) have been reported in patients receiving fedratinib.1 In the JAKARTA study, grade 3 or greater anemia or thrombocytopenia occurred in 34 or 12%, respectively, of patients receiving fedratinib.1 The median time to initial onset of grade 3 anemia or thrombocytopenia was approximately 2 or 1 month(s), respectively; most cases of anemia or thrombocytopenia (75%) occurred within 3 or 4 months, respectively, of initiating fedratinib therapy.1 Nadir hemoglobin concentrations occurred after 12 to 16 weeks of fedratinib therapy and partial recovery and stabilization occurred after 16 weeks.1 Anemia was managed with red blood cell (RBC) transfusions in 51% of patients receiving fedratinib and permanent discontinuance of the drug was necessary in 1% of patients.1 Thrombocytopenia was managed with platelet transfusions in 3.1% of patients receiving fedratinib.1 In patients who developed thrombocytopenia or bleeding that required clinical intervention, permanent discontinuance of fedratinib therapy was required in 2.1 or 2.1% of patients, respectively.1 In the JAKARTA study, neutropenia also occurred in 23% of patients receiving fedratinib and was grade 3 or greater in 5% of patients.1
Complete blood cell counts (CBCs) should be monitored at baseline, periodically during therapy, and then as clinically indicated.1 If adverse hematologic effects resulting in transfusion dependence occur during fedratinib therapy, dosage reduction of the drug should be considered.1 Temporary interruption followed by dosage reduction or discontinuance of fedratinib may be necessary, depending on the severity of the hematologic toxicity.1
Diarrhea, nausea, and vomiting occur frequently in patients receiving fedratinib.1 In the JAKARTA study, diarrhea, nausea, or vomiting occurred in 66, 62, or 39% of patients, respectively; grade 3 diarrhea or vomiting occurred in 5 or 3.1% of patients, respectively.1 The median time to onset of nausea, vomiting, or diarrhea was 1 day; most cases (75%) occurred within 2 weeks of initiating fedratinib therapy.1
Prophylactic antiemetic therapy (e.g., 5-HT3 serotonin receptor antagonist) should be considered in patients receiving fedratinib.1 In patients experiencing diarrhea, antidiarrheal therapy should be promptly initiated at the onset of diarrhea.1 Temporary interruption of fedratinib therapy followed by dosage reduction or discontinuance of fedratinib may be necessary, depending on the severity of nausea, vomiting, or diarrhea.1 Thiamine levels also should be monitored and corrected as needed.1
Elevated serum aminotransferase (ALT and/or AST) concentrations have been reported in patients receiving fedratinib.1 In the JAKARTA study, elevated serum ALT or AST concentrations were reported in 43 or 40%, respectively, of patients receiving fedratinib; grade 3-4 elevated serum ALT or AST concentrations were reported in 1 or 0% of patients, respectively.1 The median time to onset of elevated ALT and/or AST concentrations was approximately 1 month; most cases (75%) occurred within 3 months of initiating fedratinib therapy.1
Liver function tests should be monitored at baseline, periodically during therapy, and as clinically indicated.1 Temporary interruption followed by dosage reduction or discontinuance of fedratinib may be necessary, depending on the severity of the ALT, AST, or bilirubin elevation.1
Elevated serum amylase and/or lipase concentrations have been reported in patients receiving fedratinib.1 In the JAKARTA study, grade 3 or greater elevated serum amylase or lipase concentrations were reported in 2 or 10%, respectively, of patients receiving fedratinib.1 The median time to onset of elevated serum amylase or lipase concentrations was 15 days; most cases (75%) occurred within 1 month of initiating fedratinib therapy.1 In clinical trials, 1 of 608 fedratinib-treated patients developed pancreatitis that resolved upon discontinuance of therapy.1
Serum amylase and lipase concentrations should be monitored at baseline, periodically during therapy, and as clinically indicated.1 Temporary interruption followed by dosage reduction or discontinuance of fedratinib may be necessary, depending on the severity of the amylase and/or lipase elevation.1
In post-approval studies, uveitis was seen in 11 (4%) of 251 patients; 55% of these cases were in Japanese patients.1 Uveitis occurred a median of 14 months (range: 8 to 22 months) after therapy initiation, with some patients experiencing recurrent uveitis with continued treatment.1 Sixty percent of uveitis episodes were grade 1/2 severity and 40% were grade 3/4 severity.1 Three quarters of the uveitis episodes were adequately treated with topical steroids; systemic steroids were required in 25% of episodes.1 Discontinuation of fedratinib due to uveitis occurred in 27% of patients.1 Patients should be advised on the risks of uveitis development with therapy and the common symptoms of the condition (e.g., eye pain, redness, photophobia, floaters, decreased vision).1 Prompt ophthalmologic evaluation is recommended if symptoms occur.1
Major Adverse Cardiac Events (MACE)
An increased risk of MACE, including cardiovascular death, myocardial infarction, and stroke, has been observed in patients with rheumatoid arthritis treated with another Janus Kinase inhibitor.1 Patients should be advised of the benefits and risks of initiating or continuing fedratinib therapy, particularly for those who are current or past smokers or have other cardiovascular risk factors.1 Inform patients about the symptoms of serious cardiovascular events and steps to take if such symptoms occur.1
An increased risk of thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, has been observed in patients with rheumatoid arthritis treated with another Janus Kinase inhibitor.1 The rates of thromboembolic events in patients treated with fedratinib in clinical trials were similar between fedratinib- and placebo-treated patients.1 Evaluate patients with thrombosis symptoms promptly and treat appropriately.1
An increased risk of lymphoma and other malignancies, excluding nonmelanoma skin cancer, has been observed in patients with rheumatoid arthritis treated with another Janus Kinase inhibitor.1 Current or past smokers are at an additional increased risk for secondary malignancy development.1 Patients should be advised of the benefits and risks of initiating or continuing fedratinib therapy, 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.1
Symptom Exacerbation Following Interruption or Discontinuation of Treatment
Following discontinuation of fedratinib, signs and symptoms from myeloproliferative neoplasms may flare including fever, respiratory distress, hypotension, disseminated intravascular coagulation, or multi-organ failure.1 If one or more of these signs and symptoms occur after fedratinib discontinuation, clinicians should evaluate for and treat any intercurrent illness and consider resumption of fedratinib.1 Patients should be advised not to interrupt or discontinue therapy without consulting their clinician.1 When discontinuing or interrupting therapy for reasons other than potentially life-threatening toxicities, clinicians should consider tapering fedratinib gradually rather than discontinuing abruptly.1
Fedratinib may cause fetal harm in humans based on animal findings.1 There are no available data regarding use of fedratinib in pregnant women to inform a drug-associated risk of adverse developmental outcomes.1 In animal reproduction studies, teratogenicity (e.g., skeletal variations) was demonstrated in rats receiving fedratinib at exposure levels approximately 0.1 times the human exposure at the recommended dosage.1 In a pre- and postnatal development study in pregnant rats, administration of fedratinib at exposure levels approximately 0.1 times the human exposure at the recommended dosage from gestation day 6 through lactation day 20 followed by weaning on day 21 resulted in decreased body weight in male and female pups up to day 21 of lactation and in male pups postweaning through maturation.1
If fedratinib therapy is necessary during pregnancy, the potential risks and benefits of the drug to the mother and the potential risk to the fetus should be considered prior to initiation of therapy.1
It is not known whether fedratinib or its metabolites are distributed into human milk or if the drug has any effect on milk production or the nursing infant.1 Because of the potential for serious adverse reactions to fedratinib in nursing infants, women should be advised to discontinue nursing during fedratinib therapy and for at least 1 month after discontinuance of the drug.1
Safety and efficacy of fedratinib have not been established in pediatric patients.1
In clinical trials, 47.3% of fedratinib-treated patients with myelofibrosis were 65 years of age or older, while 12.3% were 75 years of age or older.1 No overall differences in safety or efficacy were observed between geriatric patients and younger adults.1
Mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment do not have clinically meaningful effects on fedratinib pharmacokinetics.1
Following administration of a single 300-mg dose of fedratinib, systemic exposure of fedratinib in individuals with moderate (creatinine clearance of 30-59 mL/minute) or severe (creatinine clearance of 15-29 mL/minute) renal impairment increased by 1.5- or 1.9-fold, respectively, compared with individuals with normal renal function; dosage adjustment is required in patients with severe renal impairment.1, 9
Because grade 3 or 4 adverse effects requiring dosage modification were reported more frequently in patients with moderate renal impairment, patients with preexisting moderate renal impairment should be closely monitored for signs of toxicity during fedratinib therapy, and the dosage should be adjusted as appropriate.1, 6
Population pharmacokinetic analysis suggests that the pharmacokinetics of fedratinib are not substantially altered in patients with mild renal impairment (creatinine clearance of 60-89 mL/minute).1
Adverse effects reported in 20% or more of patients receiving fedratinib include diarrhea, nausea, anemia, and vomiting.1
Fedratinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2C19 and flavin-containing monooxygenase 3 (FMO3).1, 6
In vitro studies indicate that fedratinib 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;1 the drug is not an inhibitor of bile salt export pump (BSEP), multidrug resistance protein (MRP) 2, organic anion transporter (OAT) 1, and OAT3.1
In vitro studies indicate that fedratinib is a substrate of P-gp, but is not a substrate of BCRP, BSEP, OATP1B1, OATP1B3, MRP, or MRP2.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of fedratinib and strong inhibitors of CYP3A4 may result in increased systemic exposure to fedratinib and possible toxicity.1 When the strong CYP3A4 inhibitor ketoconazole (200 mg twice daily) was administered concomitantly with fedratinib (single 300-mg dose), area under the plasma concentration-time curve (AUC) of fedratinib increased 3-fold; simulations also suggest that concomitant use of fedratinib (400 mg once daily) and ketoconazole (400 mg once daily) may increase AUC of fedratinib 2-fold at steady state.1 Simulations suggest that concomitant use of fedratinib (400 mg once daily) and the moderate CYP3A4 inhibitors diltiazem (120 mg twice daily) or erythromycin (500 mg three times daily) may increase AUC of fedratinib 1.1- or 1.2- fold, respectively, at steady state.1
Because of the potential for strong CYP3A4 inhibitors (e.g., ketoconazole) to increase exposure to fedratinib, selection of an alternative drug with less CYP3A4 inhibition potential should be considered.1 If concomitant use of a strong CYP3A4 inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of fedratinib from 400 mg once daily to 200 mg once daily.1 When concomitant use of the strong CYP3A4 inhibitor is discontinued, the fedratinib dosage should be gradually returned to the dosage used prior to initiation of the strong CYP3A4 inhibitor according to the following schedule: 300 mg once daily for 2 weeks followed by an increase to 400 mg once daily, as tolerated.1
Concomitant use of fedratinib and a dual CYP3A4 and CYP2C19 inhibitor may result in increased systemic exposure to fedratinib and possible toxicity.1 Concomitant use of fedratinib with a dual CYP3A4 and CYP2C19 inhibitor requires more intensive safety monitoring and a potential dose modification if adverse reactions occur.1
Concomitant use of fedratinib and strong or moderate inducers of CYP3A4 may result in decreased systemic exposure to fedratinib and possible reduced effectiveness of the drug.1 Avoid concomitant use of fedratinib with strong and moderate CYP3A4 inducers.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP3A4, 2C19, or 2D6
Concomitant use of fedratinib and substrates of CYP3A4, 2C19, or 2D6 may result in increased systemic exposure to the CYP3A4, 2C19, or 2D6 substrate and possible toxicity of the substrate drug.1 When the CYP3A substrate midazolam (single 2-mg oral dose), CYP2C19 substrate omeprazole (single 20-mg dose), and CYP2D6 substrate metoprolol (single 100-mg dose) were administered concomitantly with fedratinib (500 mg once daily), AUC of midazolam, omeprazole, or metoprolol was increased 4-, 3-, or 2-fold, respectively.1, 6 Patients receiving fedratinib concomitantly with substrates of CYP3A4, 2C19, or 2D6 should be monitored for signs of toxicity of the substrate drug, and the dosage of the CYP3A4, 2C19, or 2D6 substrate should be adjusted as appropriate.1
Substrates of OCT2 and MATE1/2-K
Concomitant use of fedratinib and substrates of OCT2 and MATE1/2-K may result in reduced renal clearance of these substrates.1 Monitor for adverse reactions and consider dose modifications for drugs that are renally excreted via OCT2 or MATE1/2-K when administered concomitantly with fedratinib.1
Drugs Affecting Gastric Acidity
When the proton-pump inhibitor pantoprazole (40 mg once daily) was administered concomitantly with fedratinib (single 500-mg dose), AUC of fedratinib was increased 1.2-fold.1, 6
Fedratinib hydrochloride, a selective inhibitor of Janus kinase (JAK) 2 and fms-like tyrosine kinase (Flt) 3, is an antineoplastic agent.1, 2, 8, 9, 10 JAKs are a family of intracellular tyrosine kinases consisting of JAK1, JAK2, JAK3, and tyrosine kinase (TYK) 2 that mediate the signaling of cytokines and growth factors that are important for hematopoiesis and immune function.10, 11, 12 JAK signaling involves recruitment of signal transducers and activators of transcription (STAT) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression.11, 12 Myeloproliferative neoplasms, including myelofibrosis and polycythemia vera, are known to be associated with dysregulated JAK2 signaling.1, 2, 8 The majority of polycythemia vera myelofibrosis and 50-60% of primary myelofibrosis and essential thrombocythemia myelofibrosis carry the JAK2 V617F mutation, which results in constitutive activation of the JAK-STAT signaling pathway and subsequent abnormal hematopoiesis and dysregulation of inflammatory cytokines and chemokines.8, 9, 10, 15
Fedratinib functions through competitive inhibition at the ATP-binding site of wild-type JAK2 and JAK2 V617F, preventing the phosphorylation and activation of STATs.9 In vitro, fedratinib has greater inhibitory potency at JAK2 relative to JAK1, JAK3, and TYK2.1 In vitro, fedratinib demonstrated decreased phosphorylation of STAT3/5, inhibited cell proliferation, and induced apoptosis.1 In addition, fedratinib inhibited phosphorylation of STAT3/5 and improved survival, white blood cell counts, hematocrit, splenomegaly, and fibrosis in mouse models of myeloproliferative disease harboring JAK2 V617F.1
Fedratinib has been shown to cause dose-dependent inhibition of cytokine-induced STAT3 phosphorylation in whole blood of patients with myelofibrosis, with maximal inhibition observed approximately 2 hours after the initial dose of the drug and a return to near baseline activity by 24 hours.1, 13 Inhibition of cytokine-induced STAT3 phosphorylation at steady state was similar to the maximal inhibition observed following the initial dose.1
Following administration of fedratinib, systemic exposure to fedratinib increases in a dose-proportional manner over a dosage range of 300-500 mg once daily.1, 10 Following administration of fedratinib 400 mg once daily, peak plasma concentrations of the drug at steady state are achieved within 2-4 hours.1 Following repeated administration of once-daily dosing, steady-state concentrations of the drug are attained in 15 days, with a mean accumulation ratio of 3- to 4-fold.1, 8, 10 Administration of a single 500-mg dose of fedratinib with a low-fat or high-fat meal increased peak plasma concentrations and area under the concentration-time curve (AUC) of the drug by 14 or 24%, respectively.1 Fedratinib is at least 92% bound to plasma proteins.1 Fedratinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by 2C19 and flavin-containing monooxygenase 3 (FMO3).1, 6 Fedratinib circulates in plasma principally as the parent drug.1 Plasma concentrations decline in a biphasic manner with an effective half-life of 41 hours and a terminal half-life of approximately 114 hours.1 Following oral administration of a single radiolabeled dose of fedratinib, 77% of the dose was recovered in feces (23% as unchanged drug) and 5% was recovered in urine (3% as unchanged drug).1 The pharmacokinetics of fedratinib are not affected by age, sex, body weight, or race.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Fedratinib hydrochloride can only be obtained through designated specialty pharmacies and distributors.5 Contact manufacturer for additional information.5
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 100 mg (of fedratinib) | Celgene |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions August 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Celgene. Inrebic® (fedratinib hydrochloride) capsules prescribing information. Summit, NJ; 2026 Mar.
2. Pardanani A, Harrison C, Cortes JE et al. Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol . 2015; 1(15):643-51. [PubMed 26181658]
4. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
5. Celgene. Inrebic®: Access and support. From Inrebic® website. [Web]
6. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 212327Orig1s000: Multi-discipline review(s). From FDA website. [Web]
7. Cervantes F, Dupriez B, Pereira A et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood . 2009; 113:2895-901. [PubMed 18988864]
8. Pardanani A, Tefferi A, Jamieson C et al. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J . 2015; 5:e335. [PubMed 26252788]
9. Bewersdorf JP, Jaszczur SM, Afifi S et al. Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis. Cancer Manag Res . 2019; 11:10777-90. [PubMed 31920387]
10. Ogasawara K, Zhou S, Krishna G et al. Population pharmacokinetics of fedratinib in patients with myelofibrosis, polycythemia vera, and essential thrombocythemia.. Cancer Chemother Pharmacol . 2019; 84:891-98. [PubMed 31444617]
11. Furqan M, Mukhi N, Lee B et al. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark Res . 2013; 1:5. [PubMed 24252238]
12. Roskoski R. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res . 2016; 111:784-803. [PubMed 27473820]
13. Zhang M, Xu CR, Shamiyeh E et al. A randomized, placebo-controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK2 inhibitor fedratinib (SAR302503) in healthy volunteers. J Clin Pharmacol . 2014; 54:415-21. [PubMed 24165976]
14. Zhang Q, Zhang Y, Diamond S et al. The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke's encephalopathy. Drug Metab Dispos . 2014; 42:1656-62. [PubMed 25063672]
15. Pardanani A, Tefferi A. Targeting myeloproliferative neoplasms with JAK inhibitors. Curr Opin Hematol . 2011; 18:105-10. [PubMed 21245760]
16. Harrison CN, Schaap N, Vannucchi AM et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol . 2017; 4:e317-e324. [PubMed 28602585]
17. Harrison CN, Schaap N, Vannucchi AM et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol . 2020; [PubMed 32129512]
18. Shantzer L, Berger K, Pu JJ. Primary myelofibrosis and its targeted therapy. Ann Hematol. 2017; 96(4):531-535.
19. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from the European LeukemiaNet. Leukemia. 2018; 32(5):1057-1069.
20. Kröger N, Bacigalupo A, Barbui T, et al. Indication and management of allogeneic haematopoietic stem-cell transplantation in myelofibrosis: updated recommendations by the EMBT/ELN International Working Group. Lancet Haematol. 2024; 11(1):e62-e74.
21. Vannucchi AM, Barbui T, Cervantes F, et al; ESCO Guidelines Committee. Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5:v85-99.
22. Polverelli N, Hernández-Boluda JC, Czerw T, et al. Splenomegaly in patients with primary or secondary myelofibrosis who are candidates for allogeneic hematopoietic cell transplantation: a Position Paper on behalf of the Chronic Malignancies Working Party of the EBMT. Lancet Haematol. 2023; 10(1):e59-e70.