▼This medicinal product is subject to additional monitoring. Adverse events should be reported. Please report any suspected adverse reaction to HPRA Pharmacovigilance; Website: www.hpra.ie NUBEQA 300 mg film coated tablets (darolutamide)

Refer to full SmPC before prescribing. Composition: Active ingredient: film-coated tablet containing 300 mg darolutamide. Contains lactose. Indication: Treatment of adult men with non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease. Dosage and Administration: Treatment should be initiated and supervised by a specialist physician experienced in treatment of prostate cancer. The maximum recommended dose is 600 mg darolutamide taken orally twice daily with food, equivalent to a total daily dose of 1200 mg. Medical castration with a luteinising hormone-releasing hormone (LHRH) analogue should be continued during treatment of patients not surgically castrated. Missed dose: If a dose is missed, the dose should be taken as soon as the patient remembers prior to the next scheduled dose. The patient should not take two doses together to make up for a missed dose. Dose modification: If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction, withhold dosing or reduce to 300 mg twice daily until symptoms improve. Treatment may then be resumed at a dose of 600 mg twice daily. Dose reduction below 300 mg twice daily is not recommended, because efficacy has not been established. Elderly: No dose adjustment is necessary. Renal impairment: No dose adjustment is necessary for patients with mild or moderate renal impairment. For patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2), the recommended starting dose is 300 mg twice daily. Hepatic impairment: No dose adjustment is necessary for patients with mild hepatic impairment. The available data on darolutamide pharmacokinetics in moderate hepatic impairment is limited. Darolutamide has not been studied in patients with severe hepatic impairment. For patients with moderate and severe hepatic impairment (Child-Pugh Classes B and C), the recommended starting dose is 300 mg twice daily. Paediatric population: There is no relevant use of darolutamide in the paediatric population for the indication of treatment of nmCRPC. Contraindications: hypersensitivity to the active substance or to any of the excipients. Women who are or may become pregnant. Warnings and Precautions: The available data in patients with severe renal impairment are limited. Monitor those patients closely for adverse reactions. The available data in patients with moderate hepatic impairment are limited, and darolutamide has not been studied in patients with severe hepatic impairment. Monitor those patients closely for adverse reactions. 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. 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. 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. In patients with a history of risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval, physicians should assess the benefit-risk ratio including the potential for Torsade de pointes prior to initiating NUBEQA. NUBEQA contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take this medicinal product. Interactions: Darolutamide is a substrate of CYP3A4 and P-glycoprotein (P-gp). Use of strong 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. 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. Darolutamide is an inhibitor of breast cancer resistance protein (BCRP) and Organic Anion Transporting Polypeptides (OATP) 1B1 and 1B3. Co-administration of rosuvastatin should be avoided unless there is no therapeutic alternative. Selection of an alternative concomitant medicinal product with less potential to inhibit BCRP, OATP1B1 and OATP1B3 should be considered. Co-administration of darolutamide may increase the plasma concentrations of other concomitant BCRP, OATP1B1 and OATP1B3 substrates (e.g. methotrexate, sulfasalazine, fluvastatin, atorvastatin, pitavastatin). Therefore, it is recommended to monitor patients for adverse reactions of BCRP, OATP1B1 and OATP1B3 substrates. No clinically relevant drug-drug interaction is expected in case of P-gp substrate administration. Darolutamide may be given concomitantly with P-gp substrates (e.g. digoxin, verapamil or nifedipine). Darolutamide is a mild inducer of CYP3A4. No clinically relevant drug-drug interaction is expected in case of CYP substrate administration. Darolutamide may be given concomitantly with CYP substrates (e.g. warfarin, L-thyroxine, omeprazole). Since androgen deprivation treatment may prolong the QT interval, the co-administration with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes should be carefully evaluated. These include medicinal products such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, and antipsychotics (e.g. haloperidol). Fertility, pregnancy and lactation: This medicine 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. 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 4 weeks 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. It is not known whether darolutamide or its metabolites are present in semen. 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. A risk to the breast-fed child cannot be excluded. Fertility: There are no human data on the effect of darolutamide on fertility. Animal studies showed that darolutamide affected the reproductive system in male rats and dogs. The clinical relevance of these effects is unknown. Effects on ability to drive and use machines: NUBEQA has no or negligible influence on the ability to drive and use machines. Undesirable effects: Very common: fatigue/asthenic conditions (incl. fatigue and asthenia, lethargy and malaise), neutrophil count decreased, bilirubin increased, AST increased; Common: ischaemic heart disease (incl. arteriosclerosis coronary artery, coronary artery disease, coronary artery occlusion, coronary artery stenosis, acute coronary syndrome, acute myocardial infarction, angina pectoris, angina unstable, myocardial infarction, myocardial ischaemia., heart failure (incl. cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiogenic shock), rash, pain in extremity, musculoskeletal pain, fractures. On prescription only. Marketing Authorisation Holder: Bayer AG. 51368 Leverkusen. Germany. MA numbers: EU/1/20/1432/001 Further information available from: Bayer Ltd., The Atrium, Blackthorn Road, Dublin 18. Tel: 01 2163300. Date of Preparation: March 2020

PP-M_DAR-IE-0002-1. March 2021