Akeega · 4.6 Fertility, pregnancy and lactation · 1

HOS-100295 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The overall safety profile of Akeega is based on pooled data from two clinical Phase 3 trials with 559 patients (AMPLITUDE [n=347] and MAGNITUDE cohort 1 [n=212]). The most common adverse reactions of all grades occurring in >10% in the niraparib plus AAP arm were anaemia (51.9%), hypertension (40.1%), fatigue (39.7%), musculoskeletal pain (35.8%), constipation (34.7%), nausea (28.6%), hypokalaemia (22.0%), thrombocytopenia (20.9%), neutropenia (19.7%), oedema (18.1%), respiratory tract infections (17.7%), dyspnoea (16.6%), vomiting (15.7%), decreased appetite (15.0%), leukopenia (14.5%), hot flush (14.1%), dizziness (14.0%), weight decreased (14.0%), abdominal pain (13.4%), hyperglycaemia (13.4%), insomnia (13.1%), diarrhoea (12.3%), lymphopenia (12.2%), headache (12.0%), blood creatinine increased (11.8%), urinary tract infection (11.8%), and cough (10.4%). The most frequently observed Grade 3-4 adverse reactions were anaemia (29.7%), hypertension (22.7%), hypokalaemia (9.3%), neutropenia (8.4%), thrombocytopenia (7.5%), and lymphopenia (5.2%). Tabulated list of adverse reactions Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: 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 (frequency cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 3: Adverse reactions identified in clinical studies System Organ Class Frequency Adverse reaction Infections and infestations very common respiratory tract infections1, urinary tract infection2 common pneumonia, gastrointestinal infection3, sepsis4 uncommon skin infection5, conjunctivitis Neoplasms benign, malignant uncommon myelodysplastic syndrome/acute myeloid and unspecified (including leukaemia cysts and polyps) Blood and lymphatic system very common anaemia, thrombocytopenia, neutropenia, disorders

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HOS-100291 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Women who are or may become pregnant (see section 4.6). Severe hepatic impairment [Child-Pugh Class C (see sections 4.2, 4.4 and 5.2)]. Akeega plus prednisone or prednisolone is contraindicated in combination with Ra-223 treatment.

HOS-100290 · has-indication-information · PDF-Seite 2

Akeega is indicated with prednisone or prednisolone:  in combination with androgen deprivation therapy (ADT) for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC) and BRCA 1/2 mutations (germline and/or somatic).  for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1/2 mutations (germline and/or somatic) in whom chemotherapy is not clinically indicated.

HOS-100293 · has-interaction-information · PDF-Seite 9

Pharmacokinetic interactions No clinical study evaluating drug interactions has been performed using Akeega. Interactions that have been identified in studies with individual components of Akeega (niraparib or abiraterone acetate) determine the interactions that may occur with Akeega. Effects of other medicinal products on niraparib or abiraterone acetate CYP3A4 inducers and inhibitors Abiraterone is a CYP3A4 substrate. In a clinical study in healthy subjects pretreated with the strong CYP3A4 inducer rifampicin, 600 mg daily for six days, followed by a single dose of abiraterone acetate 1 000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%. Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John’s 9 wort [Hypericum perforatum]) during treatment with Akeega should be avoided unless there is no therapeutic alternative (see section 4.4). In a separate clinical study in healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. Effects of niraparib or abiraterone acetate on other medicinal products CYP2D6 substrates Abiraterone is an inhibitor of CYP2D6. In a clinical study to determine the effects of abiraterone acetate plus prednisone (AAP) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased approximately 2.9-fold. The AUC24 for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%. Dose reduction of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6 should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol. CYP2C8 substrates Abiraterone is an inhibitor of CYP2C8. In a clinical study in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% and the AUCs for M-III and M-IV, the active metabolites of pioglitazone, each decreased by 10% when pioglitazone was given together with a single dose of 1 000 mg abiraterone acetate. Patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with Akeega because of the abiraterone acetate component. Exampl

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HOS-100294 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/Contraception in males and females It is not known whether components of Akeega or their metabolites are present in semen. During treatment and for four months after the last dose of Akeega:  A condom is required if the patient is engaged in sexual activity with a pregnant woman.  If the patient is engaged in sex with a woman of childbearing potential, a condom is required along with another effective contraceptive method. Studies in animals have shown reproductive toxicity (see section 5.3). Pregnancy Akeega is not for use in women (see section 4.3). 10 There are no data from the use of Akeega in pregnant women. Akeega has the potential to cause foetal harm based on the mechanism of action of both components and findings from animal studies with abiraterone acetate. Animal developmental and reproductive toxicology studies were not conducted with niraparib (see section 5.3). Breast-feeding Akeega is not for use in women. Fertility There are no clinical data on fertility with Akeega. In animal studies, male fertility was reduced with niraparib or abiraterone acetate but these effects were reversible following treatment cessation (see section 5.3).

HOS-100292 · has-warning-information · PDF-Seite 6

Haematological adverse reactions Haematological adverse reactions (thrombocytopenia, anaemia and neutropenia) have been reported in patients treated with Akeega (see section 4.2). Testing complete blood counts weekly for the first month, every two weeks for the next two months, followed by monthly monitoring for the first year and then every other month for the remainder of treatment is recommended to monitor for clinically significant changes in any haematological parameter while on treatment (see section 4.2). Based on individual laboratory values, weekly monitoring for the second month may be warranted. If a patient develops severe persistent haematological toxicity including pancytopenia that does not resolve within 28 days following interruption, Akeega should be discontinued. Due to the risk of thrombocytopenia, other medicinal products known to reduce platelet counts should be used with caution in patients taking Akeega (see section 4.8). When starting the lower strength dose of Akeega (two 50 mg/500 mg tablets) after dose interruption due to haematological adverse reactions, liver function should be monitored every two weeks for six weeks due to risk of increased abiraterone exposure (see section 5.2), before resuming regular monitoring (see section 4.2). Hypertension Akeega may cause hypertension and pre-existing hypertension should be adequately controlled before starting Akeega treatment. Blood pressure should be monitored at least weekly for two months, monitored monthly afterwards for the first year and every other month thereafter during treatment with Akeega. Hypokalaemia, fluid retention, & cardiovascular adverse reactions due to mineralocorticoid excess Akeega may cause hypokalaemia and fluid retention (see section 4.8) as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see section 5.1). Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in incidence and severity of these adverse reactions. Caution is required in treating patients whose underlying medical conditions might be compromised by hypokalaemia (e.g., those on cardiac glycosides), or fluid retention (e.g., those with heart failure, severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those with severe renal impairment). QT prolongation has been observed in patients experiencing hypokalaemia in association with Akeega treatment. Hypok

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