Fedratinib

If fedratinib is to be co-administered with agents that are renally excreted via organic cation transporter (OCT)2 and multidrug and toxin extrusion (MATE)1/2-K (e.g. metformin), caution should be exercised and dose modifications should be made as needed (see section 4.5).

In in vitro studies, fedratinib inhibits P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), MATE1, MATE2-K, organic anion transporting polypeptide (OATP)1B1, OATP1B3 and OCT2. Coadministration of a single dose of fedratinib (600 mg) with a single dose of digoxin (P-gp substrate: 0.25 mg), rosuvastatin (OATP1B1/1B3 and BCRP substrate: 10 mg), and metformin (OCT2 and MATE1/2-K substrate: 1000 mg) had no clinically meaningful effect on the AUC_inf of digoxin, rosuvastatin, and metformin. Renal clearance of metformin was decreased by 36% in the presence of fedratinib. The glucose-lowering pharmacodynamic effect of metformin in the presence of fedratinib appears reduced, with the glucose AUC_0-3h being 17% higher. Caution should be exercised and dose modifications should be made as needed for agents that are renally excreted via OCT2 and MATE1/2-K.

Agents that strongly or moderately induce CYP3A4 (e.g. phenytoin, rifampicin, efavirenz) can decrease fedratinib exposure and should be avoided in patients receiving fedratinib.

Co-administration of rifampicin (strong CYP3A4 inducer: 600 mg once daily) or efavirenz (moderate CYP3A4 inducer: 600 mg once daily) with a single dose of fedratinib (500 mg) decreased AUC_inf of fedratinib by approximately 80% or 50%, respectively.

The effect of concomitant administration of a dual or combination of CYP3A4 and CYP2C19 inhibitors on fedratinib pharmacokinetics has not been studied. The PBPK simulations suggest that co-administration of a dual CYP3A4 and CYP2C19 inhibitor with a single dose of fedratinib can increase the AUC_inf of fedratinib by approximately 4-fold and the situation may change with multiple-dose fedratinib administration due to complex interplay of CYP enzyme autoinhibition and autoinduction. Agents that simultaneously inhibit CYP3A4 and CYP2C19 (e.g. fluconazole, fluvoxamine) or the combination of inhibitors of CYP3A4 and CYP2C19 may increase fedratinib exposure and should be avoided in patients receiving fedratinib.

If fedratinib is to be co-administered with substrate of CYP3A4 (e.g. midazolam, simvastatin), CYP2C19 (e.g. omeprazole, S-mephenytoin) or CYP2D6 (e.g. metoprolol, dextromethorphan), dose modifications of co-administered medicines should be made as needed with close monitoring of safety and efficacy.

Concomitant administration of fedratinib with the CYP3A4 substrate, midazolam (2 mg), the CYP2C19 substrate, omeprazole (20 mg), and the CYP2D6 substrate, metoprolol (100 mg), increases midazolam, omeprazole, and metoprolol AUC_inf by 3.8-, 2.8-, 1.8- fold and peak concentrations (C_max) by 1.8-, 1.1- and 1.6-fold, respectively. Therefore, dose modifications of medicinal products that are CYP3A4, CYP2C19, or CYP2D6 substrates should be made as needed with close monitoring of safety and efficacy.

If concomitant strong CYP3A4 inhibitors cannot be avoided, the dose of fedratinib should be reduced to 200 mg. Patients should be carefully monitored (e.g. at least weekly) for safety.

In cases where co-administration with a strong CYP3A4 inhibitor is discontinued, the fedratinib dose should be increased to 300 mg once daily during the first two weeks after discontinuation of the CYP3A4 inhibitor and then 400 mg once daily thereafter as tolerated. Additional dose adjustments should be made as needed, based upon monitoring of fedratinib-related safety and efficacy.

Due to potential increase of exposure, patients with pre-existing moderate renal impairment may require at least weekly safety monitoring and if necessary, dose modifications based on adverse reactions.

For patients with severe renal impairment (creatinine clearance [CLcr] 15 mL/min to 29 mL/min by Cockcroft-Gault [C-G]), the dose should be reduced to 200 mg.

Fedratinib pharmacokinetics have not been evaluated in patients with severe hepatic impairment. Use of fedratinib in patients with severe hepatic impairment (Child-Pugh class C or total bilirubin >3 times ULN and any AST increase) should be avoided.

There are no data from the use of fedratinib in pregnant women. Studies in animals have shown reproductive toxicity; exposure in these studies was lower than human exposure at the recommended dose. Based on its mechanism of action, fedratinib may cause foetal harm. Fedratinib belongs to a class of drugs, JAK inhibitors, that has been shown in pregnant rats and rabbits to cause embryo-foetal mortality and teratogenicity at clinically-relevant exposures. Fedratinib is contraindicated during pregnancy. Women of childbearing potential have to use effective contraception during treatment and for at least 1 month after the last dose. If fedratinib is used during pregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient should be advised of the potential hazard to the foetus.

It is unknown whether fedratinib/metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded.

Women should not breastfeed during treatment with fedratinib and for at least 1 month after the last dose of fedratinib.

Fertility

There are no human data on the effect of fedratinib on fertility. There are no data on effects on fertility in animals at clinically-relevant exposure levels.

Summary of the safety profile

The overall safety information of fedratinib was assessed in 608 patients who received continuous doses of fedratinib in Phase 1, 2 and 3 clinical studies.

Primary or secondary myelofibrosis (JAKARTA, JAKARTA2, ARD11936)

In clinical studies of patients with primary myelofibrosis (MF), post polycythaemia vera myelofibrosis (post-PV MF), or post essential thrombocythemia myelofibrosis (post-ET MF), treated with fedratinib 400 mg (N=203), including patients previously exposed to ruxolitinib (N=97; JAKARTA2), the median exposure was 35.6 weeks (range 0.7 to 114.6 weeks) and the median number of cycles (1 cycle = 28 days) initiated was 9 cycles. Sixty-three percent of 203 patients were exposed for 6 months or longer and 38% were exposed for 12 months or longer.

Among the 203 patients with MF treated with a 400 mg dose of fedratinib in the clinical studies, the most frequent non-haematologic adverse reactions were diarrhoea (67.5%), nausea (61.6%), and vomiting (44.8%). The most frequent haematologic adverse reactions were anaemia (99.0%) and thrombocytopenia (68.5%) based on laboratory values. The most frequent serious adverse reactions in MF patients treated with 400 mg were anaemia (2.5% based on reported adverse events and not laboratory values) and diarrhoea (1.5%). Permanent discontinuation due to adverse event regardless of causality occurred in 24% of patients receiving 400 mg of fedratinib.

Tabulated list of adverse reactions

Adverse reactions from clinical studies for entire treatment duration are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from available data).

All adverse reactions by system organ class and preferred term:

MedDRA = Medical dictionary of regulatory activities
SMQ = Standardized MedDRA Query (a grouping of several MedDRA preferred terms to capture a medical concept).
^a requency is based on laboratory value.
^b Bleeding includes any type associated with thrombocytopenia requiring clinical intervention.Bleeding is evaluated using the MedDRA SMQ haemorrhage terms (broad scope).

Description of selected adverse reactions

Encephalopathy, including Wernicke’s

Serious cases of encephalopathy, including 1 established case of Wernicke’s, were reported in 1.3% (8/608) of patients treated with fedratinib in clinical studies; 7 patients were taking fedratinib at 500 mg daily prior to the onset of neurologic findings and had predisposing factors such as malnutrition, gastrointestinal adverse events, and other risk factors that could lead to thiamine deficiency. One patient treated with fedratinib at 400 mg was determined to have hepatic encephalopathy. Most events resolved with some residual neurological symptoms including memory loss, cognitive impairment and dizziness, except for one fatal case (1/608; 0.16%). This was a patient with head and neck cancer, brain metastasis, difficulty eating, and weight loss who received fedratinib 500 mg in a study for another indication.

Gastrointestinal toxicity

Nausea, vomiting, and diarrhoea are among the most frequent adverse reactions in fedratinib-treated patients. In MF patients treated with 400 mg of fedratinib, diarrhoea occurred in 68% of patients, nausea in 62% of patients, and vomiting in 45% of patients. Grade 3 diarrhoea, nausea, and vomiting occurred in 5%, 0.5% and 2% of patients, respectively. The median time to onset of any grade nausea, vomiting, and diarrhoea was 2 days, with 75% of cases occurring within 3 weeks of starting treatment. Dose interruptions and reductions due to gastrointestinal toxicity were reported in 11% and 9% of patients, respectively. Permanent discontinuation of 400 mg fedratinib occurred due to gastrointestinal toxicity in 4% of patients.

Anaemia

In patients with primary or secondary myelofibrosis treated with 400 mg of fedratinib, 52% of patients developed Grade 3 anaemia. The median time to first onset of Grade 3 anaemia event was approximately 60 days with 75% of cases occurring within 4 months of starting treatment. Red blood cell transfusions were received by 58% of 400 mg fedratinib treated patients and permanent discontinuation of 400 mg fedratinib occurred due to anaemia in 1.5% of patients.

Thrombocytopenia

In patients with primary or secondary myelofibrosis treated with 400 mg of fedratinib, 14% and 9% of patients developed Grade 3 and Grade 4 thrombocytopenia, respectively. The median time to first onset of Grade 3 or 4 thrombocytopenia was approximately 70 days with 75% of cases occurring within 7 months of starting treatment. Platelet transfusions were received by 9% of 400 mg fedratinib-treated patients. Bleeding (associated with thrombocytopenia), that required clinical intervention occurred in 11% of patients. Permanent discontinuation of treatment due to thrombocytopenia occurred in 3% of patients.

Neutropenia

Grade 4 neutropenia occurred in 3.5% of patients and dose interruption due to neutropenia were reported in 0.5% of patients.

Hepatic toxicity

Elevations of ALT and AST (all Grades) occurred in 52% and 59%, respectively, with Grade 3 or 4 in 3% and 2%, respectively, of 400 mg fedratinib-treated patients. The median time to onset of any Grade transaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months of starting treatment.

Elevated amylase / lipase

Elevations of amylase and/or lipase (all Grades) occurred in 24% and 40%, respectively, of fedratinib treated MF patients. Most of these events were Grade 1 or 2, with Grade ¾ in 2.5% and 12%, respectively. The median time to onset of any Grade amylase or lipase elevation was 16 days, with 75% of cases occurring within 3 months of starting treatment. Permanent discontinuation of treatment due to elevated amylase and/or lipase occurred in 1.0% of patients receiving 400 mg of fedratinib.

Elevated creatinine

Elevations of creatinine (all Grades), occurred in 74% of MF patients taking 400 mg of fedratinib. These elevations were generally asymptomatic Grade 1 or 2 events, with Grade 3 elevations observed in 3% of patients. The median time to onset of any Grade creatinine elevation was 27 days, with 75% of cases occurring within 3 months of starting treatment. Dose interruptions and reductions due to elevated creatinine were reported in 1% and 0.5% of patients, respectively. Permanent discontinuation of treatment due to elevated creatinine occurred in 1.5% of 400 mg fedratinib-treated patients.