Jakavi · 4.8 Undesirable effects · 2

HOS-096224 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile Myelofibrosis The most frequently reported adverse drug reactions were thrombocytopenia and anaemia. Haematological adverse drug reactions (any Common Terminology Criteria for Adverse Events [CTCAE] grade) included anaemia (83.8%), thrombocytopenia (80.5%) and neutropenia (20.8%). Anaemia, thrombocytopenia and neutropenia are dose-related effects. The three most frequent non-haematological adverse drug reactions were bruising (33.3%), other bleeding (including epistaxis, post-procedural haemorrhage and haematuria) (24.3%) and dizziness (21.9%). The three most frequent non-haematological laboratory abnormalities identified as adverse reactions were increased alanine aminotransferase (40.7%), increased aspartate aminotransferase (31.5%) and hypertriglyceridaemia (25.2%). In phase 3 clinical studies in MF, neither CTCAE grade 3 or 4 12 hypertriglyceridaemia or increased aspartate aminotransferase, nor CTCAE grade 4 increased alanine aminotransferase or hypercholesterolaemia were observed. Discontinuation due to adverse events, regardless of causality, was observed in 30.0% of patients. Polycythaemia vera The most frequently reported adverse drug reactions were anaemia and increased alanine aminotransferase. Haematological adverse reactions (any CTCAE grade) included anaemia (61.8%), thrombocytopenia (25.0%) and neutropenia (5.3%). Anaemia and thrombocytopenia CTCAE grade 3 or 4 were reported in 2.9% and 2.6% of the patients, respectively. The three most frequent non-haematological adverse reactions were weight gain (20.3%), dizziness (19.4%) and headache (17.9%). The three most frequent non-haematological laboratory abnormalities (any CTCAE grade) identified as adverse reactions were increased alanine aminotransferase (45.3%), increased aspartate aminotransferase (42.6%), and hypercholesterolaemia (34.7%). No CTCAE grade 4 increased alanine aminotransferase or hypercholesterolaemia, and one CTCAE grade 4 increased aspartate aminotransferase were observed. Discontinuation due to adverse events, regardless of causality, was observed in 19.4% of patients. Acute GvHD The most frequently reported adverse drug reactions in REACH2 (adult and adolescent patients) were thrombocytopenia, anaemia, neutropenia, increased alanine aminotransferase and increased aspartate aminotransferase. The most frequently reported adverse drug reactions in the pool of paediatric patients (ad

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HOS-096230 · has-adverse-reaction-information · PDF-Seite 44

Summary of the safety profile Acute GvHD The most frequently reported adverse drug reactions in REACH2 (adult and adolescent patients) were thrombocytopenia, anaemia, neutropenia, increased alanine aminotransferase and increased aspartate aminotransferase. The most frequently reported adverse drug reactions in the pool of paediatric patients (adolescents from REACH2 and paediatric patients from REACH4) were anaemia, neutropenia, increased alanine aminotransferase, hypercholesterolaemia and thrombocytopenia. Haematological laboratory abnormalities identified as adverse drug reactions in REACH2 (adult and adolescent patients) and in the pool of paediatric patients (REACH2 and REACH4) included thrombocytopenia (85.2% and 55.1%), anaemia (75.0% and 70.8%) and neutropenia (65.1% and 70.0%), respectively. Grade 3 anaemia was reported in 47.7% of patients in REACH2 and in 45.8% of patients in the paediatric pool. Grade 3 and 4 thrombocytopenia were reported in 31.3% and 47.7% of patients in REACH2 and in 14.6% and 22.4% of patients in the paediatric pool, respectively. Grade 3 and 4 neutropenia were reported in 17.9% and 20.6% of patients in REACH2 and in 32.0% and 22.0% of patients in the paediatric pool, respectively. The most frequent non-haematological adverse drug reactions in REACH2 (adult and adolescent patients) and in the pool of paediatric patients (REACH2 and REACH4) were cytomegalovirus (CMV) infection (32.3% and 31.4%), sepsis (25.4% and 9.8%), urinary tract infections (17.9% and 9.8%), hypertension (13.4% and 17.6%) and nausea (16.4% and 3.9%), respectively. The most frequent non-haematological laboratory abnormalities identified as adverse drug reactions in REACH2 (adult and adolescent patients) and in the pool of paediatric patients (REACH2 and REACH4) were increased alanine aminotransferase (54.9% and 63.3%), increased aspartate aminotransferase (52.3% and 50.0%) and hypercholesterolaemia (49.2% and 61.2%), respectively. The majority were of grade 1 and 2, however grade 3 increased alanine aminotransferase was reported in 17.6% of patients in REACH2 and 27.3% of patients in the paediatric pool. 44 Discontinuation due to adverse events, regardless of causality, was observed in 29.4% of patients in REACH2 and in 21.6% of patients in the paediatric pool. Chronic GvHD The most frequently reported adverse drug reactions in REACH3 (adult and adolescent patients) were anaemia, hypercholesterole

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HOS-096220 · has-contraindication-information · PDF-Seite 7

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Pregnancy and lactation.

HOS-096226 · has-contraindication-information · PDF-Seite 39

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Pregnancy and lactation.

HOS-096219 · has-indication-information · PDF-Seite 3

Myelofibrosis (MF) Jakavi is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis. Polycythaemia vera (PV) Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Graft versus host disease (GvHD) Acute GvHD Jakavi is indicated for the treatment of adults and paediatric patients aged 28 days and older with acute graft versus host disease who have inadequate response to corticosteroids or other systemic therapies (see section 5.1). Chronic GvHD Jakavi is indicated for the treatment of adults and paediatric patients aged 6 months and older with chronic graft versus host disease who have inadequate response to corticosteroids or other systemic therapies (see section 5.1).

HOS-096225 · has-indication-information · PDF-Seite 36

Graft versus host disease (GvHD) Acute GvHD Jakavi is indicated for the treatment of adults and paediatric patients aged 28 days and older with acute graft versus host disease who have inadequate response to corticosteroids or other systemic therapies (see section 5.1). Chronic GvHD Jakavi is indicated for the treatment of adults and paediatric patients aged 6 months and older with chronic graft versus host disease who have inadequate response to corticosteroids or other systemic therapies (see section 5.1).

HOS-096222 · has-interaction-information · PDF-Seite 10

Interaction studies have only been performed in adults. Ruxolitinib is eliminated through metabolism catalysed by CYP3A4 and CYP2C9. Thus, medicinal products inhibiting these enzymes can give rise to increased ruxolitinib exposure. Interactions resulting in dose reduction of ruxolitinib CYP3A4 inhibitors Strong CYP3A4 inhibitors (such as, but not limited to, boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole) In healthy subjects co-administration of ruxolitinib (10 mg single dose) with a strong CYP3A4 inhibitor, ketoconazole, resulted in ruxolitinib Cmax and AUC that were higher by 33% and 91%, respectively, than with ruxolitinib alone. The half-life was prolonged from 3.7 to 6.0 hours with concurrent ketoconazole administration. When administering ruxolitinib with strong CYP3A4 inhibitors the unit dose of ruxolitinib should be reduced by approximately 50%, to be administered twice daily. Patients should be closely monitored (e.g. twice weekly) for cytopenias and dose titrated based on safety and efficacy (see section 4.2). 10 Dual CYP2C9 and CYP3A4 inhibitors In healthy subjects co-administration of ruxolitinib (10 mg single dose) with a dual CYP2C9 and CYP3A4 inhibitor, fluconazole, resulted in ruxolitinib Cmax and AUC that were higher by 47% and 232%, respectively, than with ruxolitinib alone. 50% dose reduction should be considered when using medicinal products which are dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid the concomitant use of ruxolitinib with fluconazole doses greater than 200 mg daily. Enzyme inducers CYP3A4 inducers (such as, but not limited to, avasimibe, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St.John’s wort (Hypericum perforatum)) Patients should be closely monitored and the dose titrated based on safety and efficacy (see section 4.2). In healthy subjects given ruxolitinib (50 mg single dose) following the potent CYP3A4 inducer rifampicin (600 mg daily dose for 10 days), ruxolitinib AUC was 70% lower than after administration of ruxolitinib alone. The exposure of ruxolitinib active metabolites was unchanged. Overall, the ruxolitinib pharmacodynamic activity was similar, suggesting the CYP3A4 induction resulted in minimal effect on the pharmacodynamics. However, thi

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HOS-096228 · has-interaction-information · PDF-Seite 42

Interaction studies have only been performed in adults. Ruxolitinib is eliminated through metabolism catalysed by CYP3A4 and CYP2C9. Thus, medicinal products inhibiting these enzymes can give rise to increased ruxolitinib exposure. Interactions resulting in dose reduction of ruxolitinib CYP3A4 inhibitors Strong CYP3A4 inhibitors (such as, but not limited to, boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole) In healthy subjects co-administration of ruxolitinib (10 mg single dose) with a strong CYP3A4 inhibitor, ketoconazole, resulted in ruxolitinib Cmax and AUC that were higher by 33% and 91%, respectively, than with ruxolitinib alone. The half-life was prolonged from 3.7 to 6.0 hours with concurrent ketoconazole administration. When administering ruxolitinib with strong CYP3A4 inhibitors the unit dose of ruxolitinib should be reduced by approximately 50%, to be administered twice daily. Patients should be closely monitored (e.g. twice weekly) for cytopenias and dose titrated based on safety and efficacy (see section 4.2). Dual CYP2C9 and CYP3A4 inhibitors In healthy subjects co-administration of ruxolitinib (10 mg single dose) with a dual CYP2C9 and CYP3A4 inhibitor, fluconazole, resulted in ruxolitinib Cmax and AUC that were higher by 47% and 232%, respectively, than with ruxolitinib alone. 50% dose reduction should be considered when using medicinal products which are dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid the concomitant use of ruxolitinib with fluconazole doses greater than 200 mg daily. 42 Enzyme inducers CYP3A4 inducers (such as, but not limited to, avasimibe, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St.John’s wort (Hypericum perforatum)) Patients should be closely monitored and the dose titrated based on safety and efficacy (see section 4.2). In healthy subjects given ruxolitinib (50 mg single dose) following the potent CYP3A4 inducer rifampicin (600 mg daily dose for 10 days), ruxolitinib AUC was 70% lower than after administration of ruxolitinib alone. The exposure of ruxolitinib active metabolites was unchanged. Overall, the ruxolitinib pharmacodynamic activity was similar, suggesting the CYP3A4 induction resulted in minimal effect on the pharmacodynamics. However, thi

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HOS-096229 · has-pregnancy-information · PDF-Seite 43

Pregnancy There are no data from the use of Jakavi in pregnant women. Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic. Teratogenicity was not observed in rats or rabbits. However, the exposure margins compared to the highest clinical dose were low and the results are therefore of limited relevance for humans (see section 5.3). The potential risk for humans is unknown. As a precautionary measure, the use of Jakavi during pregnancy is contraindicated (see section 4.3). 43 Women of childbearing potential/Contraception Women of child-bearing potential should use effective contraception during the treatment with Jakavi. In case pregnancy should occur during treatment with Jakavi, a risk/benefit evaluation must be carried out on an individual basis with careful counselling regarding potential risks to the foetus (see section 5.3). Breast-feeding Jakavi must not be used during breast-feeding (see section 4.3) and breast-feeding should therefore be discontinued when treatment is started. It is unknown whether ruxolitinib and/or its metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. Available pharmacodynamic/toxicological data in animals have shown excretion of ruxolitinib and its metabolites in milk (see section 5.3). Fertility There are no human data on the effect of ruxolitinib on fertility. In animal studies, no effect on fertility was observed.

HOS-096223 · has-pregnancy-information · PDF-Seite 12

Pregnancy There are no data from the use of Jakavi in pregnant women. Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic. Teratogenicity was not observed in rats or rabbits. However, the exposure margins compared to the highest clinical dose were low and the results are therefore of limited relevance for humans (see section 5.3). The potential risk for humans is unknown. As a precautionary measure, the use of Jakavi during pregnancy is contraindicated (see section 4.3). Women of childbearing potential/Contraception Women of child-bearing potential should use effective contraception during the treatment with Jakavi. In case pregnancy should occur during treatment with Jakavi, a risk/benefit evaluation must be carried out on an individual basis with careful counselling regarding potential risks to the foetus (see section 5.3). Breast-feeding Jakavi must not be used during breast-feeding (see section 4.3) and breast-feeding should therefore be discontinued when treatment is started. It is unknown whether ruxolitinib and/or its metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. Available pharmacodynamic/toxicological data in animals have shown excretion of ruxolitinib and its metabolites in milk (see section 5.3). Fertility There are no human data on the effect of ruxolitinib on fertility. In animal studies, no effect on fertility was observed.

HOS-096227 · has-warning-information · PDF-Seite 39

Myelosuppression Treatment with Jakavi can cause haematological adverse drug reactions, including thrombocytopenia, anaemia and neutropenia. A complete blood count, including a white blood cell count differential, must be performed before initiating therapy with Jakavi. Thrombocytopenia is generally reversible and is usually managed by reducing the dose or temporarily withholding Jakavi (see sections 4.2 and 4.8). However, platelet transfusions may be required as clinically indicated. Patients developing anaemia may require blood transfusions. Dose modifications or interruption for patients developing anaemia may also need to be considered. Patients with a haemoglobin level below 10.0 g/dl at the beginning of the treatment have a higher risk of developing a haemoglobin level below 8.0 g/dl during treatment compared to patients with a higher baseline haemoglobin level (79.3% versus 30.1%). More frequent monitoring of haematology parameters and of clinical signs and symptoms of Jakavi-related adverse drug reactions is recommended for patients with baseline haemoglobin below 10.0 g/dl. 39 Neutropenia (absolute neutrophil count <500) was generally reversible and was managed by temporarily withholding Jakavi (see sections 4.2 and 4.8). Complete blood counts should be monitored as clinically indicated and dose adjusted as required (see sections 4.2 and 4.8). Infections Serious bacterial, mycobacterial, fungal, viral and other opportunistic infections have occurred in patients treated with Jakavi. Patients should be assessed for the risk of developing serious infections. Physicians should carefully observe patients receiving Jakavi for signs and symptoms of infections and initiate appropriate treatment promptly. Treatment with Jakavi should not be started until active serious infections have resolved. Tuberculosis has been reported in patients receiving Jakavi. Before starting treatment, patients should be evaluated for active and inactive (“latent”) tuberculosis, as per local recommendations. This can include medical history, possible previous contact with tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-gamma release assay, as applicable. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised. Hepatitis B viral load (HBV-DNA titre) increases, with and with

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HOS-096221 · has-warning-information · PDF-Seite 7

Myelosuppression Treatment with Jakavi can cause haematological adverse drug reactions, including thrombocytopenia, anaemia and neutropenia. A complete blood count, including a white blood cell count differential, must be performed before initiating therapy with Jakavi. Treatment should be discontinued in MF patients with platelet count less than 50 000/mm3 or absoute neutrophil count less than 500/mm3 (see section 4.2). It has been observed that MF patients with low platelet counts (<200 000/mm3) at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia is generally reversible and is usually managed by reducing the dose or temporarily withholding Jakavi (see sections 4.2 and 4.8). However, platelet transfusions may be required as clinically indicated. Patients developing anaemia may require blood transfusions. Dose modifications or interruption for patients developing anaemia may also need to be considered. Patients with a haemoglobin level below 10.0 g/dl at the beginning of the treatment have a higher risk of developing a haemoglobin level below 8.0 g/dl during treatment compared to patients with a higher baseline haemoglobin level (79.3% versus 30.1%). More frequent monitoring of haematology parameters and of clinical signs and symptoms of Jakavi-related adverse drug reactions is recommended for patients with baseline haemoglobin below 10.0 g/dl. Neutropenia (absolute neutrophil count <500) was generally reversible and was managed by temporarily withholding Jakavi (see sections 4.2 and 4.8). 7 Complete blood counts should be monitored as clinically indicated and dose adjusted as required (see sections 4.2 and 4.8). Infections Serious bacterial, mycobacterial, fungal, viral and other opportunistic infections have occurred in patients treated with Jakavi. Patients should be assessed for the risk of developing serious infections. Physicians should carefully observe patients receiving Jakavi for signs and symptoms of infections and initiate appropriate treatment promptly. Treatment with Jakavi should not be started until active serious infections have resolved. Tuberculosis has been reported in patients receiving Jakavi. Before starting treatment, patients should be evaluated for active and inactive (“latent”) tuberculosis, as per local recommendations. This can include medical history, possible previous contact with tuberculosis, and/or appropria

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