Zejula · 4.5 Interaction with other medicinal products and other forms of interaction · 2

HOS-097943 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Adverse reactions of all grades occurring in ≥10% of the 851 patients receiving Zejula monotherapy in the pooled PRIMA (either 200 mg or 300 mg starting dose) and NOVA trials were nausea, anaemia, thrombocytopenia, fatigue, constipation, vomiting, headache, insomnia, platelet count decreased, neutropenia, abdominal pain, decreased appetite, diarrhoea, dyspnoea, hypertension, asthenia, dizziness, neutrophil count decreased, cough, arthralgia, back pain, white blood cell count decreased, and hot flush. The most common serious adverse reactions >1% (treatment-emergent frequencies) were thrombocytopenia and anaemia. Tabulated list of adverse reactions The following adverse reactions have been identified based on clinical trials and post-marketing surveillance in patients receiving Zejula monotherapy (see Table 4). 8 Frequencies of occurrence of undesirable effects are based on pooled adverse events data generated from the PRIMA and NOVA studies (fixed starting dose of 300 mg/day) where patient exposure is known and 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 Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 4: Tabulated list of adverse reactions System organ class Frequency of all CTCAE Frequency of CTCAE grades grade 3 or 4 Infections and infestations Very common Uncommon Urinary tract infection Urinary tract infection, Common bronchitis Bronchitis, conjunctivitis Neoplasms benign, malignant Common Common and unspecified (including Myelodysplastic syndrome/ Myelodysplastic syndrome/ cysts and polyps) acute myeloid leukaemiaa acute myeloid leukaemiaa Blood and lymphatic system Very common Very common disorders Thrombocytopenia, anaemia, Thrombocytopenia, anaemia, neutropenia, leukopenia neutropenia Uncommon Common

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HOS-097949 · has-adverse-reaction-information · PDF-Seite 30

Summary of the safety profile Adverse reactions of all grades occurring in ≥10% of the 851 patients receiving Zejula monotherapy in the pooled PRIMA (either 200 mg or 300 mg starting dose) and NOVA trials were nausea, anaemia, thrombocytopenia, fatigue, constipation, vomiting, headache, insomnia, platelet count decreased, neutropenia, abdominal pain, decreased appetite, diarrhoea, dyspnoea, hypertension, asthenia, dizziness, neutrophil count decreased, cough, arthralgia, back pain, white blood cell count decreased, and hot flush. The most common serious adverse reactions >1% (treatment-emergent frequencies) were thrombocytopenia and anaemia. Tabulated list of adverse reactions The following adverse reactions have been identified based on clinical trials and post-marketing surveillance in patients receiving Zejula monotherapy (see Table 4). Frequencies of occurrence of undesirable effects are based on pooled adverse events data generated from the PRIMA and NOVA studies (fixed starting dose of 300 mg/day) where patient exposure is known and 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 Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 30 Table 4: Tabulated list of adverse reactions System organ class Frequency of all CTCAE Frequency of CTCAE grades grade 3 or 4 Infections and infestations Very common Uncommon Urinary tract infection Urinary tract infection, Common bronchitis Bronchitis, conjunctivitis Neoplasms benign, malignant Common Common and unspecified (including Myelodysplastic syndrome/ Myelodysplastic syndrome/ cysts and polyps) acute myeloid leukaemiaa acute myeloid leukaemiaa Blood and lymphatic system Very common Very common disorders Thrombocytopenia, anaemia, Thrombocytopenia, anaemia, neutropenia, leukopenia neutropenia Uncommon Common Pancytopenia, febrile Leukopenia

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HOS-097945 · has-contraindication-information · PDF-Seite 27

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

HOS-097939 · has-contraindication-information · PDF-Seite 5

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

HOS-097944 · has-indication-information · PDF-Seite 24

Zejula is indicated: • as monotherapy for the maintenance treatment of adult patients with advanced epithelial (FIGO Stages III and IV) high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy. • as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

HOS-097938 · has-indication-information · PDF-Seite 2

Zejula is indicated: • as monotherapy for the maintenance treatment of adult patients with advanced epithelial (FIGO Stages III and IV) high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy. • as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

HOS-097941 · has-interaction-information · PDF-Seite 7

Pharmacodynamic interactions The combination of niraparib with vaccines or immunosuppressant agents has not been studied. The data on niraparib in combination with cytotoxic medicinal products are limited. Therefore, caution should be taken if niraparib is used in combination with vaccines, immunosuppressant agents or with other cytotoxic medicinal products. Pharmacokinetic interactions No clinical drug interaction studies have been performed with niraparib. Effect of niraparib on other medicinal products Induction of CYP1A2 In vitro, niraparib induces CYP1A2. Therefore, caution is recommended when niraparib is combined with active substances the metabolism of which is CYP1A2-dependent and, notably, those having a narrow therapeutic range (e.g. clozapine, theophylline, and ropinirole). Inhibition of efflux transporters [P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP) and MATE1/2K)] In vitro, niraparib is an inhibitor of P-gp. As no clinical data are available, it cannot be excluded that niraparib may increase the systemic exposure of other medicines transported by P-gp that are sensitive to intestinal P-gp inhibition (e.g., dabigatran etexilate). In vitro, niraparib is an inhibitor of BCRP. A clinically relevant interaction with BCRP substrates cannot be excluded. Caution is therefore recommended when niraparib is combined with substrates of BCRP (e.g., irinotecan, rosuvastatin, simvastatin, atorvastatin, and methotrexate) due to risk of increased systemic exposure. Niraparib is an inhibitor of MATE1 and -2K in vitro. Plasma concentrations of metformin may increase when concomitantly administered with niraparib. Close monitoring of glycaemia is recommended when starting or stopping niraparib in patients receiving metformin. A dose adjustment of metformin may be necessary. 7

HOS-097947 · has-interaction-information · PDF-Seite 29

Pharmacodynamic interactions The combination of niraparib with vaccines or immunosuppressant agents has not been studied. The data on niraparib in combination with cytotoxic medicinal products are limited. Therefore, caution should be taken if niraparib is used in combination with vaccines, immunosuppressant agents or with other cytotoxic medicinal products. Pharmacokinetic interactions No clinical drug interaction studies have been performed with niraparib. Effect of niraparib on other medicinal products Induction of CYP1A2 In vitro, niraparib induces CYP1A2. Therefore, caution is recommended when niraparib is combined with active substances the metabolism of which is CYP1A2-dependent and, notably, those having a narrow therapeutic range (e.g. clozapine, theophylline, and ropinirole). Inhibition of efflux transporters [P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP) and MATE1/2K)] In vitro, niraparib is an inhibitor of P-gp. As no clinical data are available, it cannot be excluded that niraparib may increase the systemic exposure of other medicines transported by P-gp that are sensitive to intestinal P-gp inhibition (e.g., dabigatran etexilate). In vitro, niraparib is an inhibitor of BCRP. A clinically relevant interaction with BCRP substrates cannot be excluded. Caution is therefore recommended when niraparib is combined with substrates of BCRP (e.g., irinotecan, rosuvastatin, simvastatin, atorvastatin, and methotrexate) due to risk of increased systemic exposure. Niraparib is an inhibitor of MATE1 and -2K in vitro. Plasma concentrations of metformin may increase when concomitantly administered with niraparib. Close monitoring of glycaemia is recommended when starting or stopping niraparib in patients receiving metformin. A dose adjustment of metformin may be necessary.

HOS-097948 · has-pregnancy-information · PDF-Seite 29

Women of childbearing potential/Contraception in females Women of childbearing potential should not become pregnant while on treatment and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment. Women of childbearing potential must use highly effective contraception during therapy and for 6 months after receiving the last dose of Zejula. 29 Pregnancy There are no or limited amount of data from the use of niraparib in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted. However, based on its mechanism of action, niraparib could cause embryonic or foetal harm, including embryo-lethal and teratogenic effects, when administered to a pregnant woman. Zejula should not be used during pregnancy. Breast-feeding It is unknown whether niraparib or its metabolites are excreted in human milk. Breast-feeding is contraindicated during administration of Zejula and for 1 month after receiving the last dose (see section 4.3). Fertility There are no clinical data on fertility. A reversible reduction of spermatogenesis was observed in rats and dogs (see section 5.3).

HOS-097942 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential/Contraception in females Women of childbearing potential should not become pregnant while on treatment and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment. Women of childbearing potential must use highly effective contraception during therapy and for 6 months after receiving the last dose of Zejula. Pregnancy There are no or limited amount of data from the use of niraparib in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted. However, based on its mechanism of action, niraparib could cause embryonic or foetal harm, including embryo-lethal and teratogenic effects, when administered to a pregnant woman. Zejula should not be used during pregnancy. Breast-feeding It is unknown whether niraparib or its metabolites are excreted in human milk. Breast-feeding is contraindicated during administration of Zejula and for 1 month after receiving the last dose (see section 4.3). Fertility There are no clinical data on fertility. A reversible reduction of spermatogenesis was observed in rats and dogs (see section 5.3).

HOS-097946 · has-warning-information · PDF-Seite 27

Haematologic adverse reactions Haematologic adverse reactions (thrombocytopenia, anaemia, neutropenia) have been reported in patients treated with Zejula (see section 4.8). Patients with lower body weight or lower baseline platelet count may be at increased risk of Grade 3+ thrombocytopenia (see section 4.2). Testing complete blood counts weekly for the first month, followed by monthly monitoring for the next 10 months of treatment and periodically after this time is recommended to monitor for clinically significant changes in any haematologic parameter during treatment (see section 4.2). If a patient develops severe persistent haematologic toxicity including pancytopenia that does not resolve within 28 days following interruption, Zejula should be discontinued. Due to the risk of thrombocytopenia, anticoagulants and medicinal products known to reduce the thrombocyte count should be used with caution (see section 4.8). 27 Myelodysplastic syndrome/acute myeloid leukaemia Cases of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including cases with fatal outcome, have been observed in patients treated with Zejula monotherapy or combination therapy in clinical trials and postmarketing (see section 4.8). In clinical trials, the duration of Zejula treatment in patients prior to developing MDS/AML varied from 0.5 months to >4.9 years. The cases were typical of secondary, cancer therapy-related MDS/AML. All patients had received platinum-containing chemotherapy regimens and many had also received other DNA damaging agents and radiotherapy. Some patients had a history of bone marrow suppression. In the NOVA trial, the incidence of MDS/AML was higher in the gBRCAmut cohort (7.4%) than in the non-gBRCAmut cohort (1.7%). For suspected MDS/AML or prolonged haematological toxicities, the patient should be referred to a haematologist for further evaluation. If MDS/AML is confirmed Zejula treatment should be discontinued and the patient treated appropriately. Hypertension, including hypertensive crisis Hypertension, including hypertensive crisis, has been reported with the use of Zejula (see section 4.8). Pre-existing hypertension should be adequately controlled before starting Zejula treatment. Blood pressure should be monitored at least weekly for two months, monitored monthly afterwards for the first year and periodically thereafter during treatment with Zejula. Home blood pressure monitoring

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HOS-097940 · has-warning-information · PDF-Seite 5

Haematologic adverse reactions Haematologic adverse reactions (thrombocytopenia, anaemia, neutropenia) have been reported in patients treated with Zejula (see section 4.8). Patients with lower body weight or lower baseline platelet count may be at increased risk of Grade 3+ thrombocytopenia (see section 4.2). Testing complete blood counts weekly for the first month, followed by monthly monitoring for the next 10 months of treatment and periodically after this time is recommended to monitor for clinically significant changes in any haematologic parameter during treatment (see section 4.2). If a patient develops severe persistent haematologic toxicity including pancytopenia that does not resolve within 28 days following interruption, Zejula should be discontinued. Due to the risk of thrombocytopenia, anticoagulants and medicinal products known to reduce the thrombocyte count should be used with caution (see section 4.8). 5 Myelodysplastic syndrome/acute myeloid leukaemia Cases of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including cases with fatal outcome, have been observed in patients treated with Zejula monotherapy or combination therapy in clinical trials and postmarketing (see section 4.8). In clinical trials, the duration of Zejula treatment in patients prior to developing MDS/AML varied from 0.5 months to >4.9 years. The cases were typical of secondary, cancer therapy-related MDS/AML. All patients had received platinum-containing chemotherapy regimens and many had also received other DNA damaging agents and radiotherapy. Some patients had a history of bone marrow suppression. In the NOVA trial, the incidence of MDS/AML was higher in the gBRCAmut cohort (7.4%) than in the non-gBRCAmut cohort (1.7%). For suspected MDS/AML or prolonged haematological toxicities, the patient should be referred to a haematologist for further evaluation. If MDS/AML is confirmed, Zejula treatment should be discontinued and the patient treated appropriately. Hypertension, including hypertensive crisis Hypertension, including hypertensive crisis, has been reported with the use of Zejula (see section 4.8). Pre-existing hypertension should be adequately controlled before starting Zejula treatment. Blood pressure should be monitored at least weekly for two months, monitored monthly afterwards for the first year and periodically thereafter during treatment with Zejula. Home blood pressure monitoring

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