Nubeqa

HOS-098759 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most frequently observed adverse reactions in patients with - nmCRPC or mHSPC receiving darolutamide are fatigue/asthenic conditions (13.7%) - mHSPC receiving darolutamide in combination with docetaxel are rash (16.6%) and hypertension (13.8%). For additional safety information when darolutamide is administered in combination, refer to the product information of the individual medicinal products. Tabulated list of adverse reactions The adverse reactions observed in patients with nmCRPC or mHSPC treated with darolutamide are listed in Table 1. The adverse reactions observed in patients with mHSPC treated with darolutamide in combination with docetaxel are listed in Table 2. Adverse reactions are classified according to System Organ Class. They are grouped according to their frequencies. Frequency groups are defined by the following convention: 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); not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are presented in order of decreasing seriousness. Table 1: Adverse reactions reported in nmCRPC and mHSPC patients treated with darolutamide in ARAMIS and ARANOTE studiesa System organ class Very common Common (MedDRA) Cardiac disorders Ischaemic heart diseaseb Heart failurec Skin and subcutaneous tissue disorders Rashd Musculoskeletal and connective tissue Pain in extremity disorders Fractures General disorders and administration Fatigue/asthenic conditionse site conditions Investigationsf Neutrophil count decreased Blood bilirubin increased ALT increased AST increased a The median duration of exposure in the ARAMIS and ARANOTE studies was 18.2 months (range: 0.0 to 44.3 months) in patients treated with darolutamide and 11.6 months (range: 0.0 to 40.5 months) in patients treated with placebo. b Includes arteriosclerosis coronary artery, coronary artery disease, coronary

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HOS-098755 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Women who are or may become pregnant (see section 4.6). 3

HOS-098754 · has-indication-information · PDF-Seite 2

NUBEQA is indicated for the treatment of adult men with - non-metastatic castration resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease (see section 5.1). - metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (see section 5.1). - metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel and androgen deprivation therapy (see section 5.1).

HOS-098757 · has-interaction-information · PDF-Seite 5

Effects of other medicinal products on darolutamide CYP3A4 and P-gp inducers Darolutamide is a substrate of CYP3A4 and P-glycoprotein (P-gp). Use of strong and moderate CYP3A4 inducers and P-gp inducers (e.g. carbamazepine, phenobarbital, St. John's Wort, phenytoin, and rifampicin) during treatment with darolutamide is not recommended, unless there is no therapeutic alternative. Selection of an alternate concomitant medicinal product, with no or weak potential to induce CYP3A4 or P-gp should be considered. Repeated administration of rifampicin (600 mg), a strong CYP3A4 and a P-gp inducer, with a single dose of darolutamide (600 mg) together with food, resulted in a decrease of 72% in mean exposure (AUC0-72) and a decrease of 52% in Cmax of darolutamide. CYP3A4, P-gp and BCRP inhibitors Darolutamide is a substrate of CYP3A4, P-gp and breast cancer resistance protein (BCRP). No clinically relevant drug-drug interaction is expected in case of CYP3A4, P-gp or BCRP inhibitor administration. Darolutamide may be given concomitantly with CYP3A4, P-gp or BCRP inhibitors. Concomitant use of darolutamide with a combined P-gp and strong CYP3A4 inhibitor increases darolutamide exposure which may increase the risk of darolutamide adverse reactions. It is recommended to monitor patients more frequently for darolutamide adverse reactions and modify darolutamide dose as needed. Administration of itraconazole (200 mg twice daily on day 1 and once daily on the following 7 days), a strong CYP3A4, P-gp and BCRP inhibitor, with a single dose of darolutamide (600 mg on day 5 together with food) resulted in a 1.7-fold increase in mean exposure (AUC0-72) and a 1.4-fold increase of Cmax of darolutamide. UGT1A9 inhibitors Darolutamide is a substrate of UGT1A9. No clinically relevant drug-drug interaction is expected in case of UGT1A9 inhibitor administration. Darolutamide may be given concomitantly with UGT1A9 inhibitors. A population pharmacokinetic analysis showed that co-administration of UGT1A9 inhibitors with darolutamide resulted in a 1.2-fold increase in exposure (AUC0-72) of darolutamide. Docetaxel Administration of darolutamide in combination with docetaxel resulted in no clinically relevant changes in the pharmacokinetics of darolutamide in mHSPC patients (see section 5.1). Effects of darolutamide on other medicinal products BCRP, OATP1B1 and OATP1B3 substrates Darolutamide is an inhibitor of breast cancer resistance protein (BCRP) and Organic Anion Transporting Poly

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HOS-098758 · has-pregnancy-information · PDF-Seite 6

This medicinal product is not indicated in women of childbearing potential. It is not to be used in women who are, or may be, pregnant or breast-feeding (see sections 4.1 and 4.3). Women of childbearing potential / contraception in males and females It is not known whether darolutamide or its metabolites are present in semen. If the patient is engaged in sexual activity with a woman of childbearing potential, a highly effective contraceptive method (< 1% failure rate per year) should be used during and for 1 week after completion of treatment with NUBEQA to prevent pregnancy. Pregnancy Based on its mechanism of action, darolutamide may cause foetal harm. No non-clinical reproductive toxicity studies have been conducted (see section 5.3). It is not known whether darolutamide or its metabolites are present in semen. If the patient is engaged in sexual activity with a pregnant woman, a condom should be used during and for 1 week after completion of treatment with NUBEQA. Exposure of the foetus to an androgen receptor inhibitor through seminal transfer to the pregnant woman has to be avoided, as this could affect development of the foetus. Breast-feeding It is unknown whether darolutamide or its metabolites are excreted in human milk. No studies in animals have been conducted to evaluate the excretion of darolutamide or its metabolites into milk (see section 5.3). A risk to the breast-fed child cannot be excluded. 6 Fertility There are no human data on the effect of darolutamide on fertility. Based on animal studies, NUBEQA may impair fertility in males of reproductive potential (see section 5.3).

HOS-098756 · has-warning-information · PDF-Seite 4

Renal impairment The available data in patients with severe renal impairment are limited. As exposure might be increased those patients should be closely monitored for adverse reactions (see sections 4.2 and 5.2). Hepatic impairment The available data in patients with moderate hepatic impairment are limited, and darolutamide has not been studied in patients with severe hepatic impairment. As exposure might be increased those patients should be closely monitored for adverse reactions (see sections 4.2 and 5.2). Recent cardiovascular disease Patients with clinically significant cardiovascular disease in the past 6 months including stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, and symptomatic congestive heart failure were excluded from the clinical studies. Therefore, the safety of darolutamide in these patients has not been established. If NUBEQA is prescribed, patients with clinically significant cardiovascular disease should be treated for these conditions according to established guidelines. Hepatotoxicity In case of liver function test abnormalities suggestive of idiosyncratic drug-induced liver injury, permanently discontinue treatment with darolutamide (see section 4.8). Concomitant use with other medicinal products Use of strong CYP3A4 and P-gp inducers during treatment with darolutamide may decrease the plasma concentration of darolutamide and is not recommended, unless there is no therapeutic alternative. Selection of an alternate concomitant medicinal product with less potential to induce CYP3A4 or P-gp should be considered (see section 4.5). Patients should be monitored for adverse reactions of BCRP, OATP1B1 and OATP1B3 substrates as co-administration with darolutamide may increase the plasma concentrations of these substrates. Co-administration with rosuvastatin should be avoided unless there is no therapeutic alternative (see section 4.5). Androgen deprivation therapy may prolong the QT interval In patients with a history of risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5), physicians should assess the benefit-risk ratio including the potential for Torsade de pointes prior to initiating NUBEQA. Information about excipients NUBEQA contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not

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