Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Pregnancy (see section 4.6).
Cases of serious and fatal encephalopathy, including Wernicke’s, were reported in patients taking Inrebic. Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (vitamin B1) deficiency. Signs and symptoms of Wernicke’s encephalopathy may include ataxia, mental status changes and ophthalmoplegia (e.g. nystagmus, diplopia). Any change in mental status, confusion or memory impairment should raise concern for potential encephalopathy, including Wernicke’s and prompt a full evaluation including a neurologic examination, assessment of thiamine levels and imaging (see sections 4.2 and 4.8).
Thiamine levels and nutritional status in patients should be assessed before starting treatment with Inrebic, periodically during treatment (e.g. monthly for the first 3 months and every 3 months thereafter) and as clinically indicated. Inrebic treatment should not be started in patients with thiamine deficiency. Before treatment initiation and during treatment, thiamine levels should be replenished if they are low. If encephalopathy is suspected, Inrebic treatment should be discontinued immediately and parenteral thiamine treatment should be initiated while evaluating for all possible causes. Patients should be monitored until symptoms have resolved or improved and thiamine levels have normalised (see sections 4.2 and 4.8).
Treatment with Inrebic may cause anaemia, thrombocytopenia and neutropenia. Complete blood counts should be obtained at baseline, periodically during treatment and as clinically indicated (see sections 4.2 and 4.8). Inrebic has not been studied in patients with a baseline platelet count <50 × 109/L and ANC <1.0 × 109/L.
Anaemia generally occurs within the first 3 months of treatment. Patients with a haemoglobin level below 10.0 g/dL at the start of therapy are more likely to develop anaemia of Grade 3 or above during treatment and should be carefully monitored (e.g. once weekly for the first month until haemoglobin levels improve). Patients developing anaemia may require blood transfusions. Consider dose reduction for patients developing anaemia particularly for those who become red blood cell transfusion dependent (see sections 4.2 and 4.8).
Thrombocytopenia generally occurs within the first 3 months of treatment. Patients with low platelet counts (<100 × 109/L) at the start of therapy are more likely to develop thrombocytopenia of Grade 3 or above during treatment and should be carefully monitored (e.g. once weekly for the first month until platelet count improves) (see sections 4.2 and 4.8). Thrombocytopenia is generally reversible and is usually managed by supportive treatment such as dose interruptions, dose reduction and/or platelet transfusions if necessary. Patients should be made aware of the increased risk of bleeding associated with thrombocytopenia.
Neutropenia was generally reversible and was managed by temporarily withholding Inrebic (see sections 4.2 and 4.8).
Nausea, vomiting and diarrhoea are among the most frequent adverse reactions in Inrebic-treated patients. Most of the adverse reactions are Grade 1 or 2 and typically occur within the first 2 weeks of treatment. Consider providing appropriate prophylactic anti-emetic therapy (e.g. 5-HT3 receptor antagonists) during Inrebic treatment. Treat diarrhoea with anti-diarrheal medicinal products promptly at the first onset of symptoms. For cases of Grade 3 or higher nausea, vomiting, and diarrhoea that are not responsive to supportive measures within 48 hours, the dose of Inrebic should be interrupted until resolved to Grade 1 or less/baseline. The dose should be restarted at 100 mg daily below the last given dose. Thiamine levels should be monitored and replenished as needed (see sections 4.2 and 4.8).
Elevations of ALT and AST have been reported with Inrebic treatment and one case of hepatic failure was reported. Patients should have their hepatic function monitored at baseline, at least monthly for the first 3 months, periodically during treatment and as clinically indicated. After observed toxicity, patients should be monitored at least every 2 weeks until resolution. ALT and AST elevations were generally reversible with dose modifications or permanent treatment discontinuation (see sections 4.2 and 4.8).
Elevations of amylase and/or lipase have been reported with Inrebic treatment and one case of pancreatitis was reported. Patients should have their amylase and lipase monitored at baseline, at least monthly for the first 3 months, periodically during treatment and as clinically indicated. After observed toxicity, patients should be monitored at least every 2 weeks until resolution. For Grade 3 or higher amylase and/or lipase, dose modifications are recommended (see sections 4.2 and 4.8).
Elevations of creatinine have been reported with Inrebic treatment (see section 4.8). Patients should have their creatinine levels monitored at baseline, at least monthly for the first 3 months, periodically during treatment and as clinically indicated. For severe renal impairment (CLcr 15 mL/min to 29 mL/min by C-G), dose modifications are recommended (see section 4.2).
Concomitant administration of Inrebic with strong CYP3A4 inhibitors increases Inrebic exposure. Increased exposure of Inrebic may increase the risk of adverse reactions. In place of strong CYP3A4 inhibitors, consider alternative therapies that do not strongly inhibit CYP3A4 activity. If strong CYP3A4 inhibitors cannot be replaced, the dose of Inrebic should be reduced when administering with strong CYP3A4 inhibitors, (e.g. ketoconazole, ritonavir). Patients should be carefully monitored (e.g. at least weekly) for safety. Prolonged co-administration of a moderate CYP3A4 inhibitor may require close safety monitoring and if necessary, dose modifications based on adverse reactions (see sections 4.2 and 4.5).
Agents that simultaneously inhibit CYP3A4 and CYP2C19 (e.g. fluconazole, fluvoxamine) or the combination of inhibitors of CYP3A4 and CYP2C19 may increase Inrebic exposure and should be avoided in patients receiving Inrebic (see section 4.5).
Agents that strongly or moderately induce CYP3A4 (e.g. phenytoin, rifampicin, efavirenz) can decrease Inrebic exposure and should be avoided in patients receiving Inrebic (see section 4.5).
If Inrebic 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 (see section 4.5).
If Inrebic 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).
The concomitant use of haematopoietic growth factors with Inrebic has not been studied. The safety and efficacy of these co-administrations are not known (see section 4.5 and 4.2).
The experience in the age group 75 years and older is limited. In clinical studies, 13.8% (28/203) of patients treated with Inrebic were 75 years and older and serious adverse reactions and adverse reactions leading to treatment discontinuation occurred more frequently.
Inrebic capsules contain less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium free’.
Fedratinib is metabolised by multiple CYPs in vitro with the predominant contribution from CYP3A4 and with a lesser contribution from CYP2C19, and flavin-containing monooxygenases (FMOs).
Co-administration of ketoconazole (strong CYP3A4 inhibitor: 200 mg twice daily) with a single dose of fedratinib (300 mg) increased the fedratinib area under the plasma concentration time curve from time zero to infinity (AUCinf) by approximately 3-fold. (see section 4.2).
Based on physiologically based pharmacokinetic (PBPK) simulations, co-administration of moderate CYP3A4 inhibitors, erythromycin (500 mg three times daily) or diltiazem (120 mg twice daily), with fedratinib 400 mg once daily is predicted to increase fedratinib AUC at steady state by 1.2 and 1.1-fold, respectively. Adverse reactions following prolonged co-administration of a moderate CYP3A4 inhibitor cannot be excluded.
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 AUCinf 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.
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 AUCinf of fedratinib by approximately 80% or 50%, respectively.
Co-administration of pantoprazole (proton pump inhibitor: 40 mg daily) with a single dose of fedratinib (500 mg) increased fedratinib AUCinf to a clinically insignificant extent (by 1.15-fold). Therefore, an increase in gastric pH is not expected to have clinically meaningful impact on fedratinib exposure and no dose adjustment is needed for concomitant administration of fedratinib with agents that increase gastric pH.
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 AUCinf by 3.8-, 2.8-, 1.8- fold and peak concentrations (Cmax) 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.
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 AUCinf 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 AUC0-3h 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.
The concurrent use of haematopoietic growth factors and fedratinib has not been studied. It is not known whether the JAK inhibition by fedratinib reduces the efficacy of haematopoietic growth factors or whether the haematopoietic growth factors affect the efficacy of fedratinib (see sections 4.2 and 4.4).
Females of reproductive potential should be advised to avoid becoming pregnant whilst receiving Inrebic and should use effective contraception during treatment with Inrebic and for at least 1 month after the last dose.
There are no data from the use of Inrebic in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3); exposure in these studies was lower than human exposure at the recommended dose. Based on its mechanism of action, Inrebic may cause foetal harm. Inrebic 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. Inrebic is contraindicated during pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception during treatment and for at least 1 month after the last dose. If Inrebic 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 Inrebic and for at least 1 month after the last dose of Inrebic.
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 (see section 5.3).
Inrebic has minor influence on the ability to drive and use machines. Patients who experience dizziness after taking Inrebic should refrain from driving or using machines.
The overall safety information of Inrebic was assessed in 608 patients who received continuous doses of Inrebic in Phase 1, 2 and 3 clinical studies.
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 Inrebic 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 Inrebic 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 (Table 2). 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 Inrebic.
Adverse reactions from clinical studies for entire treatment duration (Table 2) 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).
Table 2. All adverse reactions by system organ class and preferred term:
| System organ class | Adverse reaction | All grades frequency |
|---|---|---|
| Infections and infestations | Urinary tract infection | Very common |
| Blood and lymphatic system disorders | Anaemiaa | Very common |
| Thrombocytopeniaa | Very common | |
| Neutropeniaa | Very common | |
| Bleedingb | Very common | |
| Metabolism and nutrition disorders | Lipase increaseda | Very common |
| Amylase increaseda | Very common | |
| Nervous system disorders | Headache | Very common |
| Wernicke’s encephalopathy | Common | |
| Dizziness | Common | |
| Vascular disorders | Hypertension | Common |
| Gastrointestinal disorders | Diarrhoea | Very common |
| Vomiting | Very common | |
| Nausea | Very common | |
| Constipation | Very common | |
| Dyspepsia | Common | |
| Hepatobiliary disorders | Alanine aminotransferase increaseda | Very common |
| Aspartate aminotransferase increaseda | Very common | |
| Musculoskeletal and connective tissue disorders | Bone pain | Common |
| Muscle spasms | Very common | |
| Pain in extremity | Common | |
| Renal and urinary disorders | Blood creatinine increaseda | Very common |
| Dysuria | Common | |
| General disorders and administration site conditions | Fatigue/Asthenia | Very common |
| Investigations | Weight increased | Common |
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).
Serious cases of encephalopathy, including 1 established case of Wernicke’s, were reported in 1.3% (8/608) of patients treated with Inrebic in clinical studies; 7 patients were taking Inrebic 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 Inrebic 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 (see sections 4.2 and 4.4 for monitoring and management guidance and section 4.9).
Nausea, vomiting, and diarrhoea are among the most frequent adverse reactions in Inrebic-treated patients. In MF patients treated with 400 mg of Inrebic, 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 Inrebic occurred due to gastrointestinal toxicity in 4% of patients (see sections 4.2 and 4.4 for monitoring and management guidance).
In patients with primary or secondary myelofibrosis treated with 400 mg of Inrebic, 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 Inrebic treated patients and permanent discontinuation of 400 mg Inrebic occurred due to anaemia in 1.5% of patients (see sections 4.2 and 4.4 for monitoring and management guidance).
In patients with primary or secondary myelofibrosis treated with 400 mg of Inrebic, 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 Inrebic-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 (see sections 4.2 and 4.4 for monitoring and management guidance).
Grade 4 neutropenia occurred in 3.5% of patients and dose interruption due to neutropenia were reported in 0.5% of patients (see sections 4.2 and 4.4 for monitoring and management guidance).
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 Inrebic-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 (see sections 4.2 and 4.4 for monitoring and management guidance).
Elevations of amylase and/or lipase (all Grades) occurred in 24% and 40%, respectively, of Inrebic treated MF patients. Most of these events were Grade 1 or 2, with Grade ¾ in 2.5% and 12%, respectively (see section 4.2). 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 Inrebic (see sections 4.2 and 4.4 for monitoring and management guidance).
Elevations of creatinine (all Grades), occurred in 74% of MF patients taking 400 mg of Inrebic. 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 Inrebic-treated patients (see sections 4.2 and 4.4).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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