ZYTIGA 250mg tablets medication leaflet

ZYTIGA 250 mg tablets

Each tablet contains 250 mg of abiraterone acetate equivalent to 223 mg of abiraterone.

Each tablet contains 198.65 mg of lactose monohydrate and 6.8 mg of sodium.

For the full list of excipients, see section 6.1.

Tablet

White to off-white oval tablets (15.9 mm long x 9.5 mm wide), debossed with AA250 on one side.

ZYTIGA 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 section5.1)

- the treatment of metastatic castration resistant prostate cancer (mCRPC) in adult men who areasymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whomchemotherapy is not yet clinically indicated (see section 5.1)

- the treatment of mCRPC in adult men whose disease has progressed on or after adocetaxel-based chemotherapy regimen.

This medicinal product should be prescribed by an appropriate healthcare professional.

The recommended dose is 1 000 mg (four 250 mg tablets) as a single daily dose that must not be takenwith food (see “Method of administration” below). Taking the tablets with food increases systemicexposure to abiraterone (see sections 4.5 and 5.2).

For mHSPC, ZYTIGA is used with 5 mg prednisone or prednisolone daily.

For mCRPC, ZYTIGA is used with 10 mg prednisone or prednisolone daily.

Medical castration with luteinising hormone releasing hormone (LHRH) analogue should be continuedduring treatment in patients not surgically castrated.

Serum transaminases should be measured prior to starting treatment, every two weeks for the firstthree months of treatment and monthly thereafter. Blood pressure, serum potassium and fluid retentionshould be monitored monthly. However, patients with a significant risk for congestive heart failureshould be monitored every 2 weeks for the first three months of treatment and monthly thereafter (seesection 4.4).

In patients with pre-existing hypokalaemia or those that develop hypokalaemia whilst being treatedwith ZYTIGA, consider maintaining the patient’s potassium level at ≥ 4.0 mM.

For patients who develop Grade ≥ 3 toxicities including hypertension, hypokalaemia, oedema andother non-mineralocorticoid toxicities, treatment should be withheld and appropriate medicalmanagement should be instituted. Treatment with ZYTIGA should not be reinitiated until symptomsof the toxicity have resolved to Grade 1 or baseline.

In the event of a missed daily dose of either ZYTIGA, prednisone or prednisolone, treatment should beresumed the following day with the usual daily dose.

For patients who develop hepatotoxicity during treatment (alanine aminotransferase [ALT] increasesor aspartate aminotransferase [AST] increases above 5 times the upper limit of normal [ULN]),treatment should be withheld immediately (see section 4.4). Re-treatment following return of liverfunction tests to the patient’s baseline may be given at a reduced dose of 500 mg (two tablets) oncedaily. For patients being re-treated, serum transaminases should be monitored at a minimum of everytwo weeks for three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of500 mg daily, treatment should be discontinued.

If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy,treatment should be discontinued and patients should not be re-treated.

No dose adjustment is necessary for patients with pre-existing mild hepatic impairment, Child-Pugh

Class A.

Moderate hepatic impairment (Child-Pugh Class B) has been shown to increase the systemic exposureto abiraterone by approximately four-fold following single oral doses of abiraterone acetate 1 000 mg(see section 5.2). There are no data on the clinical safety and efficacy of multiple doses of abirateroneacetate when administered to patients with moderate or severe hepatic impairment (Child-Pugh

Class B or C). No dose adjustment can be predicted. The use of ZYTIGA should be cautiouslyassessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweighthe possible risk (see sections 4.2 and 5.2). ZYTIGA should not be used in patients with severe hepaticimpairment (see sections pct. 4.3, pct. 4.4 and 5.2).

No dose adjustment is necessary for patients with renal impairment (see section 5.2). However, thereis no clinical experience in patients with prostate cancer and severe renal impairment. Caution isadvised in these patients (see section 4.4).

There is no relevant use of ZYTIGA in the paediatric population.

ZYTIGA is for oral use.

The tablets must be taken as a single dose once daily on an empty stomach. ZYTIGA must be taken atleast two hours after eating and food must not be eaten for at least one hour after taking ZYTIGA.

ZYTIGA tablets must be swallowed whole with water.

- 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, pct. 4.4 and 5.2)].

- ZYTIGA with prednisone or prednisolone is contraindicated in combination with Ra-223.

ZYTIGA may cause hypertension, hypokalaemia and fluid retention (see section 4.8) as aconsequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see section 5.1).

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resultingin a reduction in incidence and severity of these adverse reactions. Caution is required in treatingpatients 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 thosewith severe renal impairment).

ZYTIGA should be used with caution in patients with a history of cardiovascular disease. The Phase 3studies conducted with ZYTIGA excluded patients with uncontrolled hypertension, clinicallysignificant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in thepast 6 months, severe or unstable angina, or New York Heart Association Class (NYHA) III or IVheart failure (study 301) or Class II to IV heart failure (studies 3011 and 302) or cardiac ejectionfraction measurement of < 50%. In studies 3011 and 302, patients with atrial fibrillation, or othercardiac arrhythmia requiring medical therapy were excluded. Safety in patients with left ventricularejection 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 cardiacfailure, uncontrolled hypertension, or cardiac events such as ischaemic heart disease), considerobtaining an assessment of cardiac function (e.g. echocardiogram). Before treatment with ZYTIGA,cardiac failure should be treated and cardiac function optimised. Hypertension, hypokalaemia andfluid 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 heartfailure should be monitored every 2 weeks for 3 months, then monthly thereafter and abnormalitiescorrected. QT prolongation has been observed in patients experiencing hypokalaemia in associationwith ZYTIGA treatment. Assess cardiac function as clinically indicated, institute appropriatemanagement and consider discontinuation of this treatment if there is a clinically significant decreasein cardiac function (see section 4.2).

Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurredin controlled clinical studies (see section 4.8). Serum transaminase levels should be measured prior tostarting treatment, every two weeks for the first three months of treatment, and monthly thereafter. Ifclinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should bemeasured immediately. If at any time the ALT or AST rises above 5 times the ULN, treatment shouldbe interrupted immediately and liver function closely monitored. Re-treatment may take place onlyafter return of liver function tests to the patient’s baseline and at a reduced dose level (see section 4.2).

If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy,treatment should be discontinued and patients should not be re-treated.

Patients with active or symptomatic viral hepatitis were excluded from clinical trials; thus, there are nodata to support the use of ZYTIGA in this population.

There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate whenadministered to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). Theuse of ZYTIGA should be cautiously assessed in patients with moderate hepatic impairment, in whomthe benefit clearly should outweigh the possible risk (see sections 4.2 and 5.2). ZYTIGA should not beused in patients with severe hepatic impairment (see sections 4.2, pct. 4.3 and 5.2).

There have been rare post-marketing reports of acute liver failure and hepatitis fulminant, some withfatal outcome (see section 4.8).

Caution is advised and monitoring for adrenocortical insufficiency should occur if patients arewithdrawn from prednisone or prednisolone. If ZYTIGA is continued after corticosteroids arewithdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see informationabove).

In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose ofcorticosteroids may be indicated before, during and after the stressful situation.

Decreased bone density may occur in men with metastatic advanced prostate cancer. The use of

ZYTIGA in combination with a glucocorticoid could increase this effect.

Lower rates of response might be expected in patients previously treated with ketoconazole forprostate cancer.

The use of glucocorticoids could increase hyperglycaemia, therefore blood sugar should be measuredfrequently in patients with diabetes.

Cases of hypoglycaemia have been reported when ZYTIGA plus prednisone/prednisolone wasadministered to patients with pre-existing diabetes receiving pioglitazone or repaglinide (seesection 4.5); therefore, blood sugar should be monitored in patients with diabetes.

The safety and efficacy of concomitant use of ZYTIGA with cytotoxic chemotherapy has not beenestablished (see section 5.1).

Intolerance to excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains 27.2 mg (1.18 mmol) sodium per dose of four tablets, equivalent to1.36% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Anaemia and sexual dysfunction may occur in men with metastatic prostate cancer including thoseundergoing treatment with ZYTIGA.

Cases of myopathy and rhabdomyolysis have been reported in patients treated with ZYTIGA. Mostcases developed within the first 6 months of treatment and recovered after ZYTIGA withdrawal.

Caution is recommended in patients concomitantly treated with medicinal products known to beassociated with myopathy/rhabdomyolysis.

Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeuticalternative, due to risk of decreased exposure to abiraterone (see section 4.5).

Treatment with abiraterone and prednisone/prednisolone in combination with Ra-223 iscontraindicated (see section 4.3) due to an increased risk of fractures and a trend for increasedmortality among asymptomatic or mildly symptomatic prostate cancer patients as observed in clinicaltrials.

It is recommended that subsequent treatment with Ra-223 is not initiated for at least 5 days after thelast administration of ZYTIGA in combination with prednisone/prednisolone.

Administration with food significantly increases the absorption of abiraterone. The efficacy and safetywhen given with food have not been established therefore this medicinal product must not be takenwith food (see sections 4.2 and 5.2).

In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4inducer rifampicin, 600 mg daily for 6 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 wort [Hypericum perforatum]) during treatment are to be avoided, unlessthere is no therapeutic alternative.

In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration ofketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on thepharmacokinetics of abiraterone.

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 wasincreased approximately 2.9 fold. The AUC24 for dextrorphan, the active metabolite ofdextromethorphan, 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 ofmedicinal products with a narrow therapeutic index that are metabolised by CYP2D6 should beconsidered. Examples of medicinal products metabolised by CYP2D6 include metoprolol,propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine,oxycodone and tramadol (the latter three medicinal products requiring CYP2D6 to form their activeanalgesic metabolites).

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by46% 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. Patientsshould be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeuticindex if used concomitantly. Examples of medicinal products metabolised by CYP2C8 includepioglitazone and repaglinide (see section 4.4).

In vitro, the major metabolites abiraterone sulphate and N-oxide abiraterone sulphate were shown toinhibit the hepatic uptake transporter OATP1B1 and as a consequence it may increase theconcentrations of medicinal products eliminated by OATP1B1. There are no clinical data available toconfirm transporter based interaction.

Since androgen deprivation treatment may prolong the QT interval, caution is advised whenadministering ZYTIGA with medicinal products known to prolong the QT interval or medicinalproducts able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III(e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone,moxifloxacin, antipsychotics, etc.

Use with Spironolactone

Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels.

Use with ZYTIGA is not recommended (see section 5.1).

There are no human data on the use of ZYTIGA in pregnancy and this medicinal product is not for usein women of childbearing potential.

It is not known whether abiraterone or its metabolites are present in semen. A condom is required ifthe patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sex with awoman of childbearing potential, a condom is required along with another effective contraceptivemethod. Studies in animals have shown reproductive toxicity (see section 5.3).

ZYTIGA is not for use in women and is contraindicated in women who are or may potentially bepregnant (see section 4.3 and 5.3).

ZYTIGA is not for use in women.

Abiraterone acetate affected fertility in male and female rats, but these effects were fully reversible(see section 5.3).

ZYTIGA has no or negligible influence on the ability to drive and use machines.

In an analysis of adverse reactions of composite Phase 3 studies with ZYTIGA, adverse reactions thatwere observed in ≥10% of patients were peripheral oedema, hypokalaemia, hypertension, urinary tractinfection, and alanine aminotransferase increased and/or aspartate aminotransferase increased. Otherimportant adverse reactions include, cardiac disorders, hepatotoxicity, fractures, and allergic alveolitis.

ZYTIGA may cause hypertension, hypokalaemia and fluid retention as a pharmacodynamicconsequence of its mechanism of action. In Phase 3 studies, anticipated mineralocorticoid adversereactions were seen more commonly in patients treated with abiraterone acetate than in patients treatedwith placebo: hypokalaemia 18% vs. 8%, hypertension 22% vs. 16% and fluid retention (peripheraloedema) 23% vs. 17%, respectively. In patients treated with abiraterone acetate versus patients treatedwith placebo: CTCAE (version 4.0) Grades 3 and 4 hypokalaemia were observed in 6% versus 1%,

CTCAE (version 4.0) Grades 3 and 4 hypertension were observed in 7% versus 5%, and fluidretention (peripheral oedema) Grades 3 and 4 were observed in 1% versus 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 (seesection 4.4).

In studies of patients with metastatic advanced prostate cancer who were using an LHRH analogue, orwere previously treated with orchiectomy, ZYTIGA was administered at a dose of 1 000 mg daily incombination with low dose prednisone or prednisolone (either 5 or 10 mg daily depending on theindication).

Adverse reactions observed during clinical studies and post-marketing experience are listed below byfrequency 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 very common: urinary tract infectioncommon: sepsis

Immune system disorders not known: anaphylactic reactions

Endocrine disorders uncommon: adrenal insufficiency

Metabolism and nutrition disorders very common: hypokalaemiacommon: hypertriglyceridaemia

Cardiac disorders common: cardiac failure*, angina pectoris,atrial fibrillation, tachycardiauncommon: other arrhythmiasnot known: myocardial infarction,

QT prolongation (see sections 4.4 and 4.5)

Vascular disorders very common: hypertension

Respiratory, thoracic and mediastinal rare: allergic alveolitisadisorders

Gastrointestinal disorders very common: diarrhoeacommon: dyspepsia

Hepatobiliary disorders very common: alanine aminotransferaseincreased and/or aspartate aminotransferaseincreased brare: hepatitis fulminant, acute hepatic failure

Skin and subcutaneous tissue disorders common: rash

Musculoskeletal and connective tissue uncommon: myopathy, rhabdomyolysisdisorders

Renal and urinary disorders common: haematuria

General disorders and administration site very common: oedema peripheralconditions

Injury, poisoning and procedural common: fractures**complications

* Cardiac failure also includes congestive heart failure, left ventricular dysfunction and ejection fraction decreased

** Fractures includes osteoporosis and all fractures with the exception of pathological fracturesa Spontaneous reports from post-marketing experienceb Alanine aminotransferase increased and/or aspartate aminotransferase increased includes ALT increased, ASTincreased, and hepatic function abnormal.

The following CTCAE (version 4.0) Grade 3 adverse reactions occurred in patients treated withabiraterone acetate: hypokalaemia 5%; urinary tract infection 2%; alanine aminotransferase increasedand/or aspartate aminotransferase increased 4%; hypertension 6%; fractures 2%; peripheral oedema,cardiac failure, and atrial fibrillation 1% each. CTCAE (version 4.0) Grade 3 hypertriglyceridaemiaand angina pectoris occurred in < 1% of patients. CTCAE (version 4.0) Grade 4 urinary tract infection,alanine aminotransferase increased and/or aspartate aminotransferase increased, hypokalaemia, cardiacfailure, atrial fibrillation, and fractures occurred in < 1% of patients.

A higher incidence of hypertension and hypokalaemia was observed in the hormone sensitivepopulation (study 3011). Hypertension was reported in 36.7% of patients in the hormone sensitivepopulation (study 3011) compared to 11.8% and 20.2% in studies 301 and 302, respectively.

Hypokalaemia was observed in 20.4% of patients in the hormone sensitive population (study 3011)compared to 19.2% and 14.9% in 301 and 302, respectively).

The incidence and severity of adverse events was higher in the subgroup of patients with baseline

ECOG2 performance status grade and also in elderly patients (≥75 years).

The three Phase 3 studies excluded patients with uncontrolled hypertension, clinically significant heartdisease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months,severe or unstable angina, or NYHA Class III or IV heart failure (study 301) or Class II to IV heartfailure (studies 3011 and 302) or cardiac ejection fraction measurement of < 50%. All patients enrolled(both active and placebo-treated patients) were concomitantly treated with androgen deprivationtherapy, predominantly with the use of LHRH analogues, which has been associated with diabetes,myocardial infarction, cerebrovascular accident and sudden cardiac death. The incidence ofcardiovascular adverse reactions in the Phase 3 studies in patients taking abiraterone acetate versuspatients taking placebo were as follows: atrial fibrillation 2.6% vs. 2.0%, tachycardia 1.9% vs. 1.0%,angina pectoris 1.7% vs. 0.8%, cardiac failure 0.7% vs. 0.2%, and arrhythmia 0.7% vs. 0.5%.

Hepatotoxicity with elevated ALT, AST and total bilirubin has been reported in patients treated withabiraterone acetate. Across Phase 3 clinical studies, hepatotoxicity grades 3 and 4 (e.g., ALT or ASTincreases of > 5 x ULN or bilirubin increases > 1.5 x ULN) were reported in approximately 6% ofpatients who received abiraterone acetate, typically during the first 3 months after starting treatment.

In Study 3011, grade 3 or 4 hepatotoxicity was observed in 8.4% of patients treated with ZYTIGA.

Ten patients who received ZYTIGA were discontinued because of hepatotoxicity; two had Grade 2hepatotoxicity, six had Grade 3 hepatotoxicity, and two had Grade 4 hepatotoxicity. No patient died ofhepatotoxicity in Study 3011. In the Phase 3 clinical studies, patients whose baseline ALT or ASTwere elevated were more likely to experience liver function test elevations than those beginning withnormal values. When elevations of either ALT or AST > 5 x ULN, or elevations in bilirubin> 3 x ULN were observed, abiraterone acetate was withheld or discontinued. In two instances markedincreases in liver function tests occurred (see section 4.4). These two patients with normal baselinehepatic function, experienced ALT or AST elevations 15 to 40 x ULN and bilirubin elevations 2 to6 x ULN. Upon discontinuation of treatment, both patients had normalisation of their liver functiontests and one patient was re-treated without recurrence of the elevations. In study 302, Grade 3 or 4

ALT or AST elevations were observed in 35 (6.5%) patients treated with abiraterone acetate.

Aminotransferase elevations resolved in all but 3 patients (2 with new multiple liver metastases and 1with AST elevation approximately 3 weeks after the last dose of abiraterone acetate). In Phase 3clinical studies, treatment discontinuations due to ALT and AST increases or abnormal hepaticfunction were reported in 1.1% of patients treated with abiraterone acetate and 0.6% of patients treatedwith placebo; no deaths were reported due to hepatotoxicity events.

In clinical trials, the risk for hepatotoxicity was mitigated by exclusion of patients with baselinehepatitis or significant abnormalities of liver function tests. In the 3011 trial, patients with baseline

ALT and AST > 2.5 X ULN, bilirubin > 1.5 X ULN or those with active or symptomatic viralhepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction wereexcluded. In the 301 trial, patients with baseline ALT and AST ≥ 2.5 x ULN in the absence of livermetastases and > 5 x ULN in the presence of liver metastases were excluded. In the 302 trial, patientswith liver metastases were not eligible and patients with baseline ALT and AST ≥ 2.5 x ULN wereexcluded. Abnormal liver function tests developing in patients participating in clinical trials werevigorously managed by requiring treatment interruption and permitting re-treatment only after returnof liver function tests to the patient’s baseline (see section 4.2). Patients with elevations of ALT or

AST > 20 x ULN were not re-treated. The safety of re-treatment in such patients is unknown. Themechanism for hepatotoxicity is not understood.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, administration should be withheld andgeneral supportive measures undertaken, including monitoring for arrhythmias, hypokalaemia and forsigns and symptoms of fluid retention. Liver function also should be assessed.

Pharmacotherapeutic group: endocrine therapy, other hormone antagonists and related agents, ATCcode: L02BX03

Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor.

Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). Thisenzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatictumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosteroneprecursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the

C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals(see section 4.4).

Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels.

Androgen deprivation therapies, such as treatment with LHRH analogues or orchiectomy, decreaseandrogen production in the testes but do not affect androgen production by the adrenals or in thetumour. Treatment with ZYTIGA decreases serum testosterone to undetectable levels (usingcommercial assays) when given with LHRH analogues (or orchiectomy).

ZYTIGA decreases serum testosterone and other androgens to levels lower than those achieved by theuse of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the

CYP17 enzyme required for androgen biosynthesis. PSA serves as a biomarker in patients withprostate cancer. In a Phase 3 clinical study of patients who failed prior chemotherapy with taxanes,38% of patients treated with abiraterone acetate, versus 10% of patients treated with placebo, had atleast a 50% decline from baseline in PSA levels.

Efficacy was established in three randomised placebo-controlled multicentre Phase 3 clinical studies(studies 3011, 302 and 301) of patients with mHSPC and mCRPC. Study 3011 enrolled patients whowere newly diagnosed (within 3 months of randomisation) mHSPC who had high-risk prognosticfactors. High-risk prognosis was defined as having at least 2 of the following 3 risk factors: (1)

Gleason score of ≥8; (2) presence of 3 or more lesions on bone scan; (3) presence of measurablevisceral (excluding lymph node disease) metastasis. In the active arm, ZYTIGA was administered at adose of 1 000 mg daily in combination with low dose prednisone 5 mg once daily in addition to ADT(LHRH agonist or orchiectomy), which was the standard of care treatment. Patients in the control armreceived ADT and placebos for both ZYTIGA and prednisone. Study 302 enrolled docetaxel naïvepatients; whereas, study 301 enrolled patients who had received prior docetaxel. Patients were usingan LHRH analogue or were previously treated with orchiectomy. In the active treatment arm,

ZYTIGA was administered at a dose of 1 000 mg daily in combination with low dose prednisone orprednisolone 5 mg twice daily. Control patients received placebo and low dose prednisone orprednisolone 5 mg twice daily.

Changes in PSA serum concentration independently do not always predict clinical benefit. Therefore,in all studies it was recommended that patients be maintained on their study treatments untildiscontinuation criteria were met as specified below for each study.

In all studies spironolactone use was not allowed as spironolactone binds to the androgen receptor andmay increase PSA levels.

In Study 3011, (n=1199) the median age of enrolled patients was 67 years. The number of patientstreated with ZYTIGA by racial group was Caucasian 832 (69.4%), Asian 246 (20.5%), Black or

African American 25 (2.1%), other 80 (6.7%), unknown/not reported 13 (1.1%), and American Indianor Alaska Native 3 (0.3%). The ECOG performance status was 0 or 1 for 97% of patients. Patientswith known brain metastasis, uncontrolled hypertension, significant heart disease, or NYHA Class II-

IV heart failure were excluded. Patients that were treated with prior pharmacotherapy, radiationtherapy, or surgery for metastatic prostate cancer were excluded with the exception of up to 3 monthsof ADT or 1 course of palliative radiation or surgical therapy to treat symptoms resulting frommetastatic disease. Co-primary efficacy endpoints were overall survival (OS) and radiographicprogression-free survival (rPFS). The median baseline pain score, as measured by the Brief Pain

Inventory Short Form (BPI-SF) was 2.0 in both the treatment and Placebo groups. In addition to theco-primary endpoint measures, benefit was also assessed using time to skeletal-related event (SRE),time to subsequent therapy for prostate cancer, time to initiation of chemotherapy, time to painprogression, and time to PSA progression. Treatment continued until disease progression, withdrawalof consent, the occurrence of unacceptable toxicity, or death.

Radiographic progression-free survival was defined as the time from randomisation to the occurrenceof radiographic progression or death from any cause. Radiographic progression included progressionby bone scan (according to modified PCWG2) or progression of soft tissue lesions by CT or MRI(according to RECIST 1.1).

A significant difference in rPFS between treatment groups was observed (see Table 2 and Figure 1).

Table 2: Radiographic Progression-Free Survival - Stratified Analysis; Intent-to-treat Population(Study PCR3011)

AA-P Placebo

Subjects randomised 597 602

Event 239 (40.0%) 354 (58.8%)

Censored 358 (60.0%) 248 (41.2%)

Time to Event (months)

Median (95% CI) 33.02 (29.57, NE) 14.78 (14.69, 18.27)

Range (0.0+, 41.0+) (0.0+, 40.6+)p valuea < 0.0001

Hazard ratio (95% CI)b 0.466 (0.394, 0.550)

Note: += censored observation, NE=not estimable. The radiographic progression and death are considered indefining the rPFS event. AA-P= subjects who received abiraterone acetate and prednisone.a p value is from a log-rank test stratified by ECOG PS score (0/1 or 2) and visceral lesion (absent or present).b Hazard ratio is from stratified proportional hazards model. Hazard ratio <1 favours AA-P.

Figure 1: Kaplan-Meier Plot of Radiographic Progression-free Survival; Intent-to-treat Population (Study

PCR3011)

A statistically significant improvement in OS in favour of AA-P plus ADT was observed with a 34%reduction in the risk of death compared to Placebo plus ADT (HR=0.66; 95% CI: 0.56, 0.78;p<0.0001), (see Table 3 and Figure 2).

Table 3: Overall Survival of Patients Treated with Either ZYTIGA or Placebos in Study PCR3011(Intent-to-Treat Analysis)

Overall Survival ZYTIGA with Prednisone Placebos(N=597) (N=602)

Deaths (%) 275 (46%) 343 (57%)

Median survival (months) 53.3 36.5(95% CI) (48.2, NE) (33.5, 40.0)

Hazard ratio (95% CI)1 0.66 (0.56, 0.78)

NE=Not estimable1 Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio 1 favours ZYTIGA withprednisone.

Figure 2: Kaplan-Meier Plot of Overall Survival; Intent-to-treat Population in Study PCR3011 Analysis

Subgroup analyses consistently favour treatment with ZYTIGA. The treatment effect of AA-P on rPFSand OS across the pre-specified subgroups was favourable and consistent with the overall studypopulation, except for the subgroup of ECOG score of 2 where no trend towards benefit was observed,however the small sample size (n=40) limits drawing any meaningful conclusion.

In addition to the observed improvements in overall survival and rPFS, benefit was demonstrated for

ZYTIGA vs. placebo treatment in all prospectively-defined secondary endpoints.

This study enrolled chemotherapy naïve patients who were asymptomatic or mildly symptomatic andfor whom chemotherapy was not yet clinically indicated. A score of 0-1 on Brief Pain Inventory-Short

Form (BPI-SF) worst pain in last 24 hours was considered asymptomatic, and a score of 2-3 wasconsidered mildly symptomatic.

In study 302, (n = 1 088) the median age of enrolled patients was 71 years for patients treated with

ZYTIGA plus prednisone or prednisolone and 70 years for patients treated with placebo plusprednisone or prednisolone. The number of patients treated with ZYTIGA by racial group was

Caucasian 520 (95.4%), Black 15 (2.8%), Asian 4 (0.7%) and other 6 (1.1%). The Eastern Cooperative

Oncology Group (ECOG) performance status was 0 for 76% of patients, and 1 for 24% of patients inboth arms. Fifty percent of patients had only bone metastases, an additional 31% of patients had boneand soft tissue or lymph node metastases and 19% of patients had only soft tissue or lymph nodemetastases. Patients with visceral metastases were excluded. Co-primary efficacy endpoints wereoverall survival and radiographic progression-free survival (rPFS). In addition to the co-primaryendpoint measures, benefit was also assessed using time to opiate use for cancer pain, time to initiationof cytotoxic chemotherapy, time to deterioration in ECOG performance score by ≥ 1 point and time to

PSA progression based on Prostate Cancer Working Group-2 (PCWG2) criteria. Study treatmentswere discontinued at the time of unequivocal clinical progression. Treatments could also bediscontinued at the time of confirmed radiographic progression at the discretion of the investigator.

Radiographic progression free survival (rPFS) was assessed with the use of sequential imaging studiesas defined by PCWG2 criteria (for bone lesions) and modified Response Evaluation Criteria In Solid

Tumours (RECIST) criteria (for soft tissue lesions). Analysis of rPFS utilised centrally-reviewedradiographic assessment of progression.

At the planned rPFS analysis there were 401 events, 150 (28%) of patients treated with ZYTIGA and251 (46%) of patients treated with placebo had radiographic evidence of progression or had died. Asignificant difference in rPFS between treatment groups was observed (see Table 4 and Figure 3).

Table 4: Study 302: Radiographic progression-free survival of patients treated with either

ZYTIGA or placebo in combination with prednisone or prednisolone plus LHRHanalogues or prior orchiectomy

ZYTIGA Placebo(N = 546) (N = 542)

Radiographic

Progression-free Survival(rPFS)

Progression or death 150 (28%) 251 (46%)

Median rPFS in months Not reached 8.3(95% CI) (11.66; NE) (8.12; 8.54)p-value* < 0.0001

Hazard ratio** (95% CI) 0.425 (0.347; 0.522)

NE = Not estimated

* p-value is derived from a log-rank test stratified by baseline ECOG score (0 or 1)

** Hazard ratio < 1 favours ZYTIGA

Figure 3: Kaplan Meier curves of radiographic progression-free survival in patients treatedwith either ZYTIGA or placebo in combination with prednisone or prednisoloneplus LHRH analogues or prior orchiectomy

AA = ZYTIGA

However, subject data continued to be collected through the date of the second interim analysis of

Overall survival (OS). The investigator radiographic review of rPFS performed as a follow upsensitivity analysis is presented in Table 5 and Figure 4.

Six hundred and seven (607) subjects had radiographic progression or died: 271 (50%) in theabiraterone acetate group and 336 (62%) in the placebo group. Treatment with abiraterone acetatedecreased the risk of radiographic progression or death by 47% compared with placebo(HR = 0.530; 95% CI: [0.451; 0.623], p < 0.0001). The median rPFS was 16.5 months in theabiraterone acetate group and 8.3 months in the placebo group.

Table 5: Study 302: Radiographic progression-free survival of patients treated with either

ZYTIGA or placebo in combination with prednisone or prednisolone plus LHRHanalogues or prior orchiectomy (At second interim analysis of OS-Investigator

Review)

ZYTIGA Placebo(N = 546) (N = 542)

Radiographic

Progression-free Survival(rPFS)

Progression or death 271 (50%) 336 (62%)

Median rPFS in months 16.5 8.3(95% CI) (13.80; 16.79) (8.05; 9.43)p-value* < 0.0001

Hazard ratio**0.530 (0.451; 0.623)(95% CI)

* p-value is derived from a log-rank test stratified by baseline ECOG score (0 or 1)

** Hazard ratio < 1 favours ZYTIGA

Figure 4: Kaplan Meier curves of radiographic progression-free survival in patients treatedwith either ZYTIGA or placebo in combination with prednisone or prednisoloneplus LHRH analogues or prior orchiectomy (At second interim analysis of

OS-Investigator Review)

AA = ZYTIGA

A planned interim analysis (IA) for OS was conducted after 333 deaths were observed. The study wasunblinded based on the magnitude of clinical benefit observed and patients in the placebo group wereoffered treatment with ZYTIGA. Overall survival was longer for ZYTIGA than placebo with a 25%reduction in risk of death (HR = 0.752; 95% CI: [0.606; 0.934], p = 0.0097), but OS was not matureand interim results did not meet the pre-specified stopping boundary for statistical significance (see

Table 4). Survival continued to be followed after this IA.

The planned final analysis for OS was conducted after 741 deaths were observed (median follow up of49 months). Sixty-five percent (354 of 546) of patients treated with ZYTIGA, compared with 71%(387 of 542) of patients treated with placebo, had died. A statistically significant OS benefit in favourof the ZYTIGA-treated group was demonstrated with a 19.4% reduction in risk of death(HR = 0.806; 95% CI: [0.697; 0.931], p = 0.0033) and an improvement in median OS of 4.4 months(ZYTIGA 34.7 months, placebo 30.3 months) (see Table 6 and Figure 5). This improvement wasdemonstrated even though 44% of patients in the placebo arm received ZYTIGA as subsequenttherapy.

Table 6: Study 302: Overall survival of patients treated with either ZYTIGA or placebo incombination with prednisone or prednisolone plus LHRH analogues or priororchiectomy

ZYTIGA Placebo(N = 546) (N = 542)

Interim survival analysis

Deaths (%) 147 (27%) 186 (34%)

Median survival (months) Not reached 27.2(95% CI) (NE; NE) (25.95; NE)p-value* 0.0097

Hazard ratio** (95% CI) 0.752 (0.606; 0.934)

Final survival analysis

Deaths 354 (65%) 387 (71%)

Median overall survival in34.7 (32.7; 36.8) 30.3 (28.7; 33.3)months (95% CI)p-value* 0.0033

Hazard ratio** (95% CI) 0.806 (0.697; 0.931)

NE = Not Estimated

* p-value is derived from a log-rank test stratified by baseline ECOG score (0 or 1)

** Hazard ratio < 1 favours ZYTIGA

Figure 5: Kaplan Meier survival curves of patients treated with either ZYTIGA or placebo incombination with prednisone or prednisolone plus LHRH analogues or priororchiectomy, final analysis

AA = ZYTIGA

In addition to the observed improvements in overall survival and rPFS, benefit was demonstrated for

ZYTIGA vs. placebo treatment in all secondary endpoint measures as follows:

Time to PSA progression based on PCWG2 criteria: The median time to PSA progression was11.1 months for patients receiving ZYTIGA and 5.6 months for patients receiving placebo(HR = 0.488; 95% CI: [0.420; 0.568], p < 0.0001). The time to PSA progression was approximatelydoubled with ZYTIGA treatment (HR = 0.488). The proportion of subjects with a confirmed PSAresponse was greater in the ZYTIGA group than in the placebo group (62% vs. 24%; p < 0.0001). Insubjects with measurable soft tissue disease, significantly increased numbers of complete and partialtumour responses were seen with ZYTIGA treatment.

Time to opiate use for cancer pain: The median time to opiate use for prostate cancer pain at the timeof final analysis was 33.4 months for patients receiving ZYTIGA and was 23.4 months for patientsreceiving placebo (HR = 0.721; 95% CI: [0.614; 0.846], p < 0.0001).

Time to initiation of cytotoxic chemotherapy: The median time to initiation of cytotoxic chemotherapywas 25.2 months for patients receiving ZYTIGA and 16.8 months for patients receiving placebo(HR = 0.580; 95% CI: [0.487; 0.691], p < 0.0001).

Time to deterioration in ECOG performance score by ≥ 1 point: The median time to deterioration in

ECOG performance score by ≥ 1 point was 12.3 months for patients receiving ZYTIGA and10.9 months for patients receiving placebo (HR = 0.821; 95% CI: [0.714; 0.943], p = 0.0053).

The following study endpoints demonstrated a statistically significant advantage in favour of ZYTIGAtreatment:

Objective response: Objective response was defined as the proportion of subjects with measurabledisease achieving a complete or partial response according to RECIST criteria (baseline lymph nodesize was required to be ≥ 2 cm to be considered a target lesion). The proportion of subjects withmeasurable disease at baseline who had an objective response was 36% in the ZYTIGA group and16% in the placebo group (p < 0.0001).

Pain: Treatment with ZYTIGA significantly reduced the risk of average pain intensity progression by18% compared with placebo (p = 0.0490). The median time to progression was 26.7 months in the

ZYTIGA group and 18.4 months in the placebo group.

Time to degradation in the FACT-P (Total Score): Treatment with ZYTIGA decreased the risk of

FACT-P (Total Score) degradation by 22% compared with placebo (p = 0.0028). The median time todegradation in FACT-P (Total Score) was 12.7 months in the ZYTIGA group and 8.3 months in theplacebo group.

Study 301 enrolled patients who had received prior docetaxel. Patients were not required to showdisease progression on docetaxel, as toxicity from this chemotherapy may have led to discontinuation.

Patients were maintained on study treatments until there was PSA progression (confirmed 25%increase over the patient’s baseline/nadir) together with protocol-defined radiographic progression andsymptomatic or clinical progression. Patients with prior ketoconazole treatment for prostate cancerwere excluded from this study. The primary efficacy endpoint was overall survival.

The median age of enrolled patients was 69 years (range 39-95). The number of patients treated with

ZYTIGA by racial group was Caucasian 737 (93.2%), Black 28 (3.5%), Asian 11 (1.4%) and other 14(1.8%). Eleven percent of patients enrolled had an ECOG performance score of 2; 70% hadradiographic evidence of disease progression with or without PSA progression; 70% had received oneprior cytotoxic chemotherapy and 30% received two. Liver metastasis was present in 11% of patientstreated with ZYTIGA.

In a planned analysis conducted after 552 deaths were observed, 42% (333 of 797) of patients treatedwith ZYTIGA compared with 55% (219 of 398) of patients treated with placebo, had died. Astatistically significant improvement in median overall survival was seen in patients treated with

ZYTIGA (see Table 7).

Table 7: Overall survival of patients treated with either ZYTIGA or placebo incombination with prednisone or prednisolone plus LHRH analogues or priororchiectomy

ZYTIGA Placebo(N = 797) (N = 398)

Primary Survival Analysis

Deaths (%) 333 (42%) 219 (55%)

Median survival (months) 14.8 (14.1; 15.4) 10.9 (10.2; 12.0)(95% CI)p-valuea < 0.0001

Hazard ratio (95% CI)b 0.646 (0.543; 0.768)

Updated Survival Analysis

Deaths (%) 501 (63%) 274 (69%)

Median survival (months)15.8 (14.8; 17.0) 11.2 (10.4; 13.1)(95% CI)

Hazard ratio (95% CI)b 0.740 (0.638; 0.859)a p-value is derived from a log-rank test stratified by ECOG performance status score (0-1 vs. 2), pain score (absent vs.

present), number of prior chemotherapy regimens (1 vs. 2), and type of disease progression (PSA only vs.radiographic).

b Hazard ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favours ZYTIGA

At all evaluation time points after the initial few months of treatment, a higher proportion of patientstreated with ZYTIGA remained alive, compared with the proportion of patients treated with placebo(see Figure 6).

Figure 6: Kaplan Meier survival curves of patients treated with either ZYTIGA or placebo incombination with prednisone or prednisolone plus LHRH analogues or priororchiectomy

AA = ZYTIGA

Subgroup survival analyses showed a consistent survival benefit for treatment with ZYTIGA (see

Figure 7).

Figure 7: Overall survival by subgroup: hazard ratio and 95% confidence interval

AA = ZYTIGA; BPI = Brief Pain Inventory; C.I. = confidence interval; ECOG = Eastern Cooperative Oncology Groupperformance score; HR = hazard ratio; NE = not evaluable

In addition to the observed improvement in overall survival, all secondary study endpoints favoured

ZYTIGA and were statistically significant after adjusting for multiple testing as follows:

Patients receiving ZYTIGA demonstrated a significantly higher total PSA response rate (defined as a≥ 50% reduction from baseline), compared with patients receiving placebo, 38% vs. 10%, p < 0.0001.

The median time to PSA progression was 10.2 months for patients treated with ZYTIGA and6.6 months for patients treated with placebo (HR = 0.580; 95% CI: [0.462; 0.728], p < 0.0001).

The median radiographic progression-free survival was 5.6 months for patients treated with ZYTIGAand 3.6 months for patients who received placebo (HR = 0.673; 95% CI: [0.585; 0.776], p < 0.0001).

The proportion of patients with pain palliation was statistically significantly higher in the ZYTIGAgroup than in the placebo group (44% vs. 27%, p = 0.0002). A responder for pain palliation wasdefined as a patient who experienced at least a 30% reduction from baseline in the BPI-SF worst painintensity score over the last 24 hours without any increase in analgesic usage score observed attwo consecutive evaluations four weeks apart. Only patients with a baseline pain score of ≥ 4 and atleast one post-baseline pain score were analysed (N = 512) for pain palliation.

A lower proportion of patients treated with ZYTIGA had pain progression compared to patients takingplacebo at 6 (22% vs. 28%), 12 (30% vs. 38%) and 18 months (35% vs. 46%). Pain progression wasdefined as an increase from baseline of ≥ 30% in the BPI-SF worst pain intensity score over theprevious 24 hours without a decrease in analgesic usage score observed at two consecutive visits, or anincrease of ≥ 30% in analgesic usage score observed at two consecutive visits. The time to painprogression at the 25th percentile was 7.4 months in the ZYTIGA group, versus 4.7 months in theplacebo group.

A lower proportion of patients in the ZYTIGA group had skeletal-related events compared with theplacebo group at 6 months (18% vs. 28%), 12 months (30% vs. 40%), and 18 months (35% vs. 40%).

The time to first skeletal-related event at the 25th percentile in the ZYTIGA group was twice that of thecontrol group at 9.9 months versus 4.9 months. A skeletal-related event was defined as a pathologicalfracture, spinal cord compression, palliative radiation to bone, or surgery to bone.

The European Medicines Agency has waived the obligation to submit the results of studies with

ZYTIGA in all subsets of the paediatric population in advanced prostate cancer. See section 4.2 forinformation on paediatric use.

Following administration of abiraterone acetate, the pharmacokinetics of abiraterone has been studiedin healthy subjects, patients with metastatic advanced prostate cancer and subjects without cancer withhepatic or renal impairment. Abiraterone acetate is rapidly converted in vivo to abiraterone, anandrogen biosynthesis inhibitor (see section 5.1).

Following oral administration of abiraterone acetate in the fasting state, the time to reach maximumplasma abiraterone concentration is approximately 2 hours.

Administration of abiraterone acetate with food, compared with administration in a fasted state, resultsin up to a 10-fold (AUC) and up to a 17-fold (Cmax) increase in mean systemic exposure of abiraterone,depending on the fat content of the meal. Given the normal variation in the content and composition ofmeals, taking ZYTIGA with meals has the potential to result in highly variable exposures. Therefore,

ZYTIGA must not be taken with food. ZYTIGA tablets must be taken as a single dose once daily onan empty stomach. ZYTIGA must be taken at least two hours after eating and food must not be eatenfor at least one hour after taking ZYTIGA. The tablets must be swallowed whole with water (seesection 4.2).

The plasma protein binding of 14C-abiraterone in human plasma is 99.8%. The apparent volume ofdistribution is approximately 5 630 L, suggesting that abiraterone extensively distributes to peripheraltissues.

Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolysedto abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidationprimarily in the liver. The majority of circulating radioactivity (approximately 92%) is found in theform of metabolites of abiraterone. Of 15 detectable metabolites, 2 main metabolites, abirateronesulphate and N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity.

The mean half-life of abiraterone in plasma is approximately 15 hours based on data from healthysubjects. Following oral administration of 14C-abiraterone acetate 1 000 mg, approximately 88% of theradioactive dose is recovered in faeces and approximately 5% in urine. The major compounds presentin faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of theadministered dose, respectively).

The pharmacokinetics of abiraterone acetate was examined in subjects with pre-existing mild ormoderate hepatic impairment (Child-Pugh Class A and B, respectively) and in healthy controlsubjects. Systemic exposure to abiraterone after a single oral 1 000 mg dose increased byapproximately 11% and 260% in subjects with mild and moderate pre-existing hepatic impairment,respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects withmild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with pre-existingsevere (n = 8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normalhepatic function. The AUC to abiraterone increased by approximately 600% and the fraction of freedrug increased by 80% in subjects with severe hepatic impairment compared to subjects with normalhepatic function.

No dose adjustment is necessary for patients with pre-existing mild hepatic impairment. The use ofabiraterone acetate should be cautiously assessed in patients with moderate hepatic impairment inwhom the benefit clearly should outweigh the possible risk (see sections 4.2 and 4.4). abirateroneacetate should not be used in patients with severe hepatic impairment (see sections 4.2, pct. 4.3 and 4.4).

For patients who develop hepatotoxicity during treatment, suspension of treatment and doseadjustment may be required (see sections 4.2 and 4.4).

The pharmacokinetics of abiraterone acetate was compared in patients with end-stage renal disease ona stable haemodialysis schedule versus matched control subjects with normal renal function. Systemicexposure to abiraterone after a single oral 1 000 mg dose did not increase in subjects with end-stagerenal disease on dialysis. Administration in patients with renal impairment, including severe renalimpairment, does not require dose reduction (see section 4.2). However, there is no clinical experiencein patients with prostate cancer and severe renal impairment. Caution is advised in these patients.

In all animal toxicity studies, circulating testosterone levels were significantly reduced. As a result,reduction in organ weights and morphological and/or histopathological changes in the reproductiveorgans, and the adrenal, pituitary and mammary glands were observed. All changes showed completeor partial reversibility. The changes in the reproductive organs and androgen-sensitive organs areconsistent with the pharmacology of abiraterone. All treatment-related hormonal changes reversed orwere shown to be resolving after a 4-week recovery period.

In fertility studies in both male and female rats, abiraterone acetate reduced fertility, which wascompletely reversible in 4 to 16 weeks after abiraterone acetate was stopped.

In a developmental toxicity study in the rat, abiraterone acetate affected pregnancy including reducedfoetal weight and survival. Effects on the external genitalia were observed though abiraterone acetatewas not teratogenic.

In these fertility and developmental toxicity studies performed in the rat, all effects were related to thepharmacological activity of abiraterone.

Aside from reproductive organ changes seen in all animal toxicology studies, non-clinical data revealno special hazard for humans based on conventional studies of safety pharmacology, repeated dosetoxicity, genotoxicity and carcinogenic potential. Abiraterone acetate was not carcinogenic in a6-month study in the transgenic (Tg.rasH2) mouse. In a 24-month carcinogenicity study in the rat,abiraterone acetate increased the incidence of interstitial cell neoplasms in the testes. This finding isconsidered related to the pharmacological action of abiraterone and rat specific. Abiraterone acetatewas not carcinogenic in female rats.

The active substance, abiraterone, shows an environmental risk for the aquatic environment, especiallyto fish.

Microcrystalline cellulose

Croscarmellose sodium

Lactose monohydrate

Magnesium stearate

Povidone (K29/K32)

Colloidal anhydrous silica

Sodium laurilsulfate

Not applicable.

2 years.

This medicinal product does not require any special storage conditions.

Round white HDPE bottles fitted with a polypropylene child-resistant closure containing 120 tablets.

Each pack contains one bottle.

Based on its mechanism of action, this medicinal product may harm a developing foetus; therefore,women who are pregnant or may be pregnant should not handle it without protection, e.g., gloves.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements. This medicinal product may pose a risk to the aquatic environment (see section 5.3).

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/11/714/001

Date of first authorisation: 05 September 2011

Date of latest renewal: 26 May 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.