Abiraterone Mylan · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-099571 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile In an analysis of adverse reactions of composite Phase 3 studies with abiraterone acetate, adverse 7 reactions that were observed in ≥ 10 % of patients were peripheral oedema, hypokalaemia, hypertension, urinary tract infection, and alanine aminotransferase increased and/or aspartate aminotransferase increased. Other important adverse reactions include, cardiac disorders, hepatotoxicity, fractures, and allergic alveolitis. Abiraterone may cause hypertension, hypokalaemia and fluid retention as a pharmacodynamic consequence of its mechanism of action. In Phase 3 studies, anticipated mineralocorticoid adverse reactions were seen more commonly in patients treated with abiraterone acetate than in patients treated with placebo: hypokalaemia 18% vs. 8%, hypertension 22% vs. 16% and fluid retention (peripheral oedema) 23% vs. 17%, respectively. In patients treated with abiraterone acetate versus patients treated with placebo: CTCAE (version 4.0) Grades 3 and 4 hypokalaemia were observed in 6% vs. 1%, CTCAE (version 4.0) Grades 3 and 4 hypertension were observed in 7% vs. 5%, and fluid retention (peripheral oedema) Grades 3 and 4 were observed in 1% vs. 1% of patients, respectively. Mineralocorticoid reactions generally were able to be successfully managed medically. Concomitant use of a corticosteroid reduces the incidence and severity of these adverse reactions (see section 4.4). Tabulated list of adverse reactions In studies of patients with metastatic advanced prostate cancer who were using a LHRH analogue, or were previously treated with orchiectomy, abiraterone was administered at a dose of 1000 mg daily in combination with low dose prednisone or prednisolone (either 5 or 10 mg daily depending on the indication). Adverse reactions observed during clinical studies and post-marketing experience 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 1: Adverse reactions identified in clinical studies and post-marketing System Organ Class Adverse reaction and frequency Infections and infestations

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HOS-099567 · has-contraindication-information · PDF-Seite 4

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

HOS-099566 · has-indication-information · PDF-Seite 2

Abiraterone Mylan is indicated with prednisone or prednisolone for: • the treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT) (see section 5.1).the treatment of metastatic castration resistant prostate cancer (mCRPC) in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated (see section 5.1). • the treatment of mCRPC in adult men whose disease has progressed on or after a docetaxel based chemotherapy regimen.

HOS-099569 · has-interaction-information · PDF-Seite 6

Effect of food on abiraterone Administration with food significantly increases the absorption of abiraterone. The efficacy and safety when given with food have not been established therefore this medicinal product must not be taken with food (see sections 4.2 and 5.2). Interactions with other medicinal products Potential for other medicinal products to affect abiraterone exposures In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer rifampicin, 600 mg daily for 6 days followed by a single dose of abiraterone acetate 1000 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 wort [Hypericum perforatum]) during treatment are to be avoided, unless there is no therapeutic alternative. In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. Potential to affect exposures to other medicinal products Abiraterone is an inhibitor of the hepatic drug-metabolising enzymes CYP2D6 and CYP2C8. In a study to determine the effects of abiraterone acetate (plus prednisone) 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%. Caution is advised when administering with medicinal products activated by or metabolised by CYP2D6, particularly with medicinal products that have a narrow therapeutic index. 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 6 tramadol (the latter three medicinal products requiring CYP2D6 to form their active analgesic metabolites). In a CYP2C8 drug-drug interaction study in healthy subjects, the AUC of pioglitazone 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 1000 mg abiraterone acetate. Pat

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HOS-099570 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential There are no human data on the use of abiraterone in pregnancy and this medicinal product is not for use in women of childbearing potential. Contraception in males and females It is not known whether abiraterone or its metabolites are present in semen. 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 Abiraterone Mylan is not for use in women and is contraindicated in women who are or may potentially be pregnant (see section 4.3 and 5.3). Breastfeeding Abiraterone Mylan is not for use in women. Fertility Abiraterone acetate affected fertility in male and female rats, but these effects were fully reversible (see section 5.3).

HOS-099568 · has-warning-information · PDF-Seite 4

Hypertension, hypokalaemia, fluid retention and cardiac failure due to mineralocorticoid excess Abiraterone Mylan may cause hypertension, 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 increases in blood pressure, 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). Abiraterone Mylan should be used with caution in patients with a history of cardiovascular disease. The phase 3 studies conducted with abiraterone excluded patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association Class (NYHA) III or IV heart failure (study 301) or Class II to IV heart failure (studies 3011 and 302) or cardiac ejection fraction measurement of < 50%. In studies 3011 and 302, patients with atrial fibrillation, or other cardiac arrhythmia requiring medical therapy were excluded. Safety in patients with left ventricular ejection fraction (LVEF) < 50% or NYHA Class III or IV heart failure (in study 301) or NYHA Class II to IV heart failure (in studies 3011 and 302) was not established (see sections 4.8 and 5.1). Before treating patients with a significant risk for congestive heart failure (e.g. a history of cardiac failure, uncontrolled hypertension, or cardiac events such as ischaemic heart disease), consider obtaining an assessment of cardiac function (e.g. echocardiogram). Before treatment with Abiraterone Mylan, cardiac failure should be treated and cardiac function optimised. Hypertension, hypokalaemia and fluid retention should be corrected and controlled. During treatment, blood pressure, serum potassium, fluid retention (weight gain, peripheral oedema), and other signs and symptoms of congestive heart failure should be monitored every 2 weeks for 3 months, then monthly thereafter and abnormalities corrected. QT prolongation has been observed in patients exper

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