Lynparza · 4.6 Fertility, pregnancy and lactation · 1

HOS-096938 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile Lynparza has been associated with adverse reactions generally of mild or moderate severity (CTCAE grade 1 or 2) and generally not requiring treatment discontinuation. The most frequently observed adverse reactions across clinical trials in patients receiving Lynparza monotherapy (≥10%) were nausea, fatigue/asthenia, anaemia, vomiting, diarrhoea, decreased appetite, headache, neutropenia, dysgeusia, cough, leukopenia, dizziness, dyspnoea and dyspepsia. The Grade ≥3 adverse reactions occurring in > 2% of patients were anaemia (14%), neutropenia (5%), fatigue/asthenia (4%), leukopenia (2%) and thrombocytopenia (2%). 11 Adverse reactions that most commonly led to dose interruptions and/ or reductions in monotherapy were anaemia (16%), nausea (7%), fatigue/asthenia (6%), neutropenia (6%) and vomiting (6%). Adverse reactions that most commonly led to permanent discontinuation were anaemia (1.7%), nausea (0.9%), fatigue/asthenia (0.8%), thrombocytopenia (0.7%), neutropenia (0.6%) and vomiting (0.5%). When Lynparza is used in combination with bevacizumab for ovarian cancer, in combination with abiraterone and prednisone or prednisolone for prostate cancer, or in combination with durvalumab following treatment with durvalumab in combination with platinum-based chemotherapy for endometrial cancer, the safety profile is generally consistent with that of the individual therapies. When used in combination with bevacizumab, adverse events led to dose interruption and/ or reduction of olaparib in 57% of patients and led to permanent discontinuation of treatment with olaparib and placebo in 21% and 6% of patients, respectively. The adverse reactions that most commonly led to dose interruption and/or reduction of olaparib were anaemia (21.7%), nausea (9.5%), fatigue/asthenia (5.4%), vomiting (3.7%), neutropenia (3.6%), thrombocytopenia (3.0%) and diarrhoea (2.6%). The adverse reactions that most commonly led to permanent discontinuation were anaemia (3.7%), nausea (3.6%) and fatigue/asthenia (1.5%). When used in combination with abiraterone, adverse events led to dose interruption and/or reduction of olaparib in 50.7% of patients and led to permanent discontinuation of treatment with olaparib and placebo in 19.0% and 8.8% of patients, respectively. The adverse reactions that most commonly led to dose interruption and/or reduction of olaparib were anaemia (17.1%), fatigue/asthenia (5.5%)

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HOS-096934 · has-contraindication-information · PDF-Seite 7

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Breast-feeding during treatment and for 1 month after the last dose (see section 4.6). 7

HOS-096933 · has-indication-information · PDF-Seite 2

Ovarian cancer Lynparza is indicated as monotherapy for the: • maintenance treatment of adult patients with advanced (FIGO stages III and IV) BRCA1/2- mutated (germline and/or somatic) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy. • maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. Lynparza in combination with bevacizumab is indicated for the: • maintenance treatment of adult patients with advanced (FIGO stages III and IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with homologous recombination deficiency 2  (HRD) positive status defined by either a BRCA1/2 mutation and/or genomic instability (see section 5.1). Breast cancer Lynparza is indicated as: • monotherapy or in combination with endocrine therapy for the adjuvant treatment of adult patients with germline BRCA1/2-mutations who have HER2-negative, high risk early breast cancer previously treated with neoadjuvant or adjuvant chemotherapy (see sections 4.2 and 5.1). • monotherapy for the treatment of adult patients with germline BRCA1/2-mutations, who have HER2 negative locally advanced or metastatic breast cancer. Patients should have previously been treated with an anthracycline and a taxane in the (neo)adjuvant or metastatic setting unless patients were not suitable for these treatments (see section 5.1). Patients with hormone receptor (HR)-positive breast cancer should also have progressed on or after prior endocrine therapy, or be considered unsuitable for endocrine therapy. Adenocarcinoma of the pancreas Lynparza is indicated as monotherapy for the maintenance treatment of adult patients with germline BRCA1/2-mutations who have metastatic adenocarcinoma of the pancreas and have not progressed after a minimum of 16 weeks of platinum treatment within a first-line chemotherapy regimen. Pr

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HOS-096936 · has-interaction-information · PDF-Seite 9

Pharmacodynamic interactions Clinical studies of olaparib in combination with other anticancer medicinal products, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. The recommended Lynparza monotherapy dose is not suitable for combination with myelosuppressive anticancer medicinal products. Combination of olaparib with vaccines or immunosuppressant agents has not been studied. Therefore, caution should be taken if these medicinal products are co-administered with Lynparza and patients should be closely monitored. Pharmacokinetic interactions Effect of other medicinal products on olaparib CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of olaparib. A clinical study to evaluate the impact of itraconazole, a known CYP3A inhibitor, has shown that co-administration with olaparib increased mean olaparib Cmax by 42% (90% CI: 33-52%) and mean AUC by 170% (90% CI: 144-197%). Therefore, known strong (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, boceprevir, telaprevir) or moderate (e.g. erythromycin, diltiazem, fluconazole, verapamil) inhibitors of this isozyme are not recommended with Lynparza (see section 4.4). If strong or moderate CYP3A inhibitors must be co-administered, the dose of Lynparza should be reduced. The recommended Lynparza dose reduction 9 is to 100 mg taken twice daily (equivalent to a total daily dose of 200 mg) with a strong CYP3A inhibitor or 150 mg taken twice daily (equivalent to a total daily dose of 300 mg) with a moderate CYP3A inhibitor (see sections 4.2 and 4.4). It is also not recommended to consume grapefruit juice while on Lynparza therapy as it is a CYP3A inhibitor. A clinical study to evaluate the impact of rifampicin, a known CYP3A inducer, has shown that co-administration with olaparib decreased olaparib mean Cmax by 71% (90% CI: 76-67%) and mean AUC by 87% (90% CI: 89-84%). Therefore, known strong inducers of this isozyme (e.g. phenytoin, rifampicin, rifapentine, carbamazepine, nevirapine, phenobarbital and St John’s Wort) are not recommended with Lynparza, as it is possible that the efficacy of Lynparza could be substantially reduced. The magnitude of the effect of moderate to strong inducers (e.g. efavirenz, rifabutin) on olaparib exposure is not established, therefore the co-administration of Lynparza with these medicinal products

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HOS-096937 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/contraception in females Women of childbearing potential should not become pregnant while on Lynparza and not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment and considered regularly throughout treatment. Women of childbearing potential must use two forms of reliable contraception before starting Lynparza therapy, during therapy and for 6 months after receiving the last dose of Lynparza, unless 10 abstinence is the chosen method of contraception (see section 4.4). Two highly effective and complementary forms of contraception are recommended. Since it cannot be excluded that olaparib may reduce exposure to substrates of CYP2C9 through enzyme induction, the efficacy of some hormonal contraceptives may be reduced if co-administered with olaparib. Therefore, an additional non-hormonal contraceptive method should be considered during treatment (see section 4.5). For women with hormone dependent cancer, two non-hormonal contraceptive methods should be considered. Contraception in males It is not known whether olaparib or its metabolites are found in seminal fluid. Male patients must use a condom during therapy and for 3 months after receiving the last dose of Lynparza when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients must also use highly effective contraception if they are of childbearing potential (see section 4.4). Male patients should not donate sperm during therapy and for 3 months after receiving the last dose of Lynparza. Pregnancy Studies in animals have shown reproductive toxicity including serious teratogenic effects and effects on embryofoetal survival in the rat at maternal systemic exposures lower than those in humans at therapeutic doses (see section 5.3). There are no data from the use of olaparib in pregnant women, however, based on the mode of action of olaparib, Lynparza should not be used during pregnancy and in women of childbearing potential not using reliable contraception during therapy and for 6 months after receiving the last dose of Lynparza. (See previous paragraph: “Women of childbearing potential/contraception in females” for further information about birth control and pregnancy testing.) Breast-feeding There are no animal studies on the excretion of olaparib in breast milk. It i

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HOS-096935 · has-warning-information · PDF-Seite 8

Haematological toxicity Haematological toxicity has been reported in patients treated with Lynparza, including clinical diagnoses and/or laboratory findings of generally mild or moderate (CTCAE grade 1 or 2) anaemia, neutropenia, thrombocytopenia and lymphopenia. Pure red cell aplasia (PRCA) (see Section 4.8) and/or autoimmune haemolytic anaemia (AIHA) have been reported when Lynparza has been used in combination with durvalumab. Patients should not start treatment with Lynparza until they have recovered from haematological toxicity caused by previous anticancer therapy (haemoglobin, platelet and neutrophil levels should be ≤CTCAE grade 1). Baseline testing, followed by monthly monitoring, of complete blood counts is recommended for the first 12 months of treatment and periodically after this time to monitor for clinically significant changes in any parameter during treatment (see section 4.8). If a patient develops severe haematological toxicity or blood transfusion dependence, treatment with Lynparza should be interrupted and appropriate haematological testing should be initiated. If the blood parameters remain clinically abnormal after 4 weeks of Lynparza dose interruption, bone marrow analysis and/or blood cytogenetic analysis are recommended. If PRCA or AIHA are confirmed, treatment with Lynparza and durvalumab should be discontinued. Myelodysplastic syndrome/Acute myeloid leukaemia Myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) has occurred in patients treated with Lynparza (see section 4.8). The majority of events had a fatal outcome. Patients with BRCAm platinum-sensitive relapsed ovarian cancer who had received at least two prior lines of platinum chemotherapy were at higher risk to experience MDS/AML. The duration of therapy with olaparib in patients who developed MDS/AML varied from < 6 months to > 4 years. If MDS/AML is suspected, the patient should be referred to a haematologist for further investigations, including bone marrow analysis and blood sampling for cytogenetics. If, following investigation for prolonged haematological toxicity, MDS/AML is confirmed, Lynparza should be discontinued and the patient treated appropriately. Venous Thromboembolic Events Venous thromboembolic events, predominantly events of pulmonary embolism, have occurred in patients treated with Lynparza and had no consistent clinical pattern. A higher incidence was observed in patients with metastatic castration-resistant prostate cancer, who also re

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