Inrebic

HOS-287627 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The safety data is pooled for 486 patients (at 400 mg daily dose) previously treated with ruxolitinib. This analysis combines data from six studies: three pre-approval trials (JAKARTA, JAKARTA2, ARD11936) and three post-approval trials (FEDR-MF-001, FEDR-MF-002, FEDR-MF-003). 10 Primary or secondary myelofibrosis (JAKARTA, JAKARTA2, ARD11936, FEDR-MF-001, FEDR-MF-002, FEDR-MF-003) 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 = 486), including patients previously exposed to ruxolitinib (N = 97; JAKARTA2, N = 38; FEDR-MF-001, N = 182; FEDR-MF-002). The median exposure was 43.9 weeks (range 0.1 to 264.0 weeks). The median number of cycles (1 cycle = 28 days) initiated was 11 cycles (range 1 to 66 cycles). Among the 486 patients with MF treated with a 400 mg dose of Inrebic in the clinical studies, the most frequent non-haematologic adverse reactions were diarrhoea (55.3%), nausea (49.6%), and vomiting (32.5%). The most frequent haematologic adverse reactions were anaemia (51.4%) and thrombocytopenia (28.8%) based on laboratory values (Table 2). The most frequent serious adverse reactions in MF patients treated with 400 mg were anaemia (2.3%) and neutropenia (0.4%) based on reported adverse events and not laboratory values. Permanent discontinuation due to adverse event regardless of causality occurred in 20.2% of patients receiving 400 mg of Inrebic. Tabulated list of adverse reactions 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 Urinary tract infection Very common infestations Blood and lymphatic Anaemiaa

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HOS-287623 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Pregnancy (see section 4.6).

HOS-287622 · has-indication-information · PDF-Seite 2

Inrebic is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis who are Janus Associated Kinase (JAK) inhibitor naïve or have been treated with ruxolitinib.

HOS-287625 · has-interaction-information · PDF-Seite 9

Effect of other medicinal products on fedratinib 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). Strong and moderate CYP3A4 inhibitors 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 1.1-fold. Adverse reactions following prolonged co-administration of a moderate CYP3A4 inhibitor cannot be excluded. Simultaneous inhibition of CYP3A4 and CYP2C19 Co-administration of fluconazole (dual inhibitor of CYP3A4 and CYP2C19, 200 mg once daily) with a single dose of fedratinib (100 mg) increased AUCinf of fedratinib by 1.7-fold. Based on PBPK simulations, co-administration of fluconazole (200 mg once daily) with fedratinib 400 mg once daily is predicted to increase fedratinib AUC at steady state by 1.5-fold. Due to potential increase in exposure of fedratinib, patients taking concomitant dual inhibitors of CYP3A4 and CYP2C19 may require more intensive safety monitoring and if necessary, dose modifications of Inrebic based on adverse reactions (see section 4.2). Strong and moderate CYP3A4 inducers 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. Proton pump inhibitors 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. Effect of fedratinib on other medicinal products Effects on enzymes: CYP3A4, CYP2C19 or CYP2D6 substrates Concomitant administration of fedratinib

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HOS-287626 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/Contraception 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. Pregnancy 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. Breast-feeding 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. 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 (see section 5.3).

HOS-287624 · has-warning-information · PDF-Seite 5

Encephalopathy, including Wernicke’s encephalopathy In the absence of thiamine supplementation, 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. Inrebic treatment should not be started in patients with thiamine deficiency. Before treatment initiation, thiamine levels should be replenished if they are low. While on treatment, all patients should receive prophylaxis with oral thiamine and should have thiamine levels assessed as clinically indicated. 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). Anaemia, thrombocytopenia and neutropenia 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 x 109/L and ANC < 1.0 x 109/L. 5 Anaemia 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 Thrombocytopenia generally occurs within the first 3 months of treatme

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