ABIRATERONA MYLAN 1000mg tablets medication leaflet

Each film-coated tablet contains 500 mg of abiraterone acetate equivalent to 446 mg abiraterone.

Each film-coated tablet contains 1000 mg of abiraterone acetate equivalent to 893 mg abiraterone.

Each 500 mg film-coated tablet contains 68 mg lactose monohydrate (see section 4.4).

Each 1000 mg film-coated tablet contains 136 mg lactose monohydrate (see section 4.4).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Brown, oval-shaped film-coated tablet, debossed with “500” on one side, with dimensions 19 mmlong x 10 mm wide.

White to off-white, oval-shaped film-coated tablet, with a break line on one side and plain on the otherside, with dimensions 23 mm long x 11 mm wide. The score line is only to facilitate breaking for easeof swallowing and not to divide into equal doses.

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 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 a docetaxelbased chemotherapy regimen.

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

The recommended dose is 1000 mg (two 500 mg tablets or one 1000 mg tablet) as a single daily dosethat must not be taken with food (see “Method of administration” below). Taking the tablets with foodincreases the systemic exposure of abiraterone (see sections 4.5 and 5.2).

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

For mCRPC, Abiraterone Mylan 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 Abiraterone Mylan, 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 Abiraterone Mylan should not be reinitiated untilsymptoms of the toxicity have resolved to Grade 1 or baseline.

In the event of a missed daily dose of either Abiraterone Mylan, prednisone or prednisolone, treatmentshould be resumed 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 (one tablet) 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 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).

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 1000 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 Abiraterone Mylan should be cautiouslyassessed in patients with moderate hepatic impairment, in whom the benefit clearly outweighs thepossible risk (see sections 4.2 and 5.2). Abiraterone Mylan should not be used in patients with severehepatic impairment (see sections pct. 4.3, pct. 4.4 and 5.2).

There is no relevant use of Abiraterone Mylan in the paediatric population.

Abiraterone Mylan is for oral use.

The tablet(s) must be taken as a single dose once daily on an empty stomach. Abiraterone Mylan mustbe taken at least two hours after eating and food must not be eaten for least one hour after taking thetablets. The 500 mg tablet(s) must be swallowed whole with water.

Abiraterone Mylan 1000 mg film-coated tablets can be divided to make it easier for the patient toswallow. The 1000 mg tablet(s) should be swallowed 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)].

 Abiraterone Mylan with prednisone or prednisolone is contraindicated in combination with

Ra-223.

Abiraterone Mylan 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, severeor unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those withsevere 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 eventsin 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 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 Abiraterone

Mylan, cardiac failure should be treated and cardiac function optimised. Hypertension, hypokalaemiaand fluid retention should be corrected and controlled. During treatment, blood pressure, serumpotassium, fluid retention (weight gain, peripheral oedema), and other signs and symptoms ofcongestive heart failure should be monitored every 2 weeks for 3 months, then monthly thereafter andabnormalities corrected. QT prolongation has been observed in patients experiencing hypokalaemia inassociation with abiraterone treatment. Assess cardiac function as clinically indicated, instituteappropriate management and consider discontinuation of this treatment if there is a clinicallysignificant decrease in 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 studies; thus, there areno data to support the use of abiraterone 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 Abiraterone Mylan should be cautiously assessed in patients with moderate hepatic impairment,in whom the benefit clearly should outweigh the possible risk (see sections 4.2 and 5.2). Abiraterone

Mylan should not be used 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 Abiraterone Mylan is continued after corticosteroidsare withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (seeinformation above).

In patients on prednisone or prednisolone who are subjected to unusual stress, an increased doseofcorticosteroids 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

Abiraterone Mylan 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 abiraterone acetate plus prednisone/prednisolonewas administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide (seesection 4.5); therefore, blood sugar should be measured frequently in patients with diabetes.

The safety and efficacy of the concomitant use of abiraterone acetate with cytotoxic chemotherapy hasnot been established (see section 5.1).

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

Cases of myopathy and rhabdomyolysis have been reported in patients treated with abirateroneacetate. Most cases developed within the first 6 months of treatment and recovered after abirateroneacetate withdrawal. Caution is recommended in patients concomitantly treated with medicinalproducts known to be associated 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 clinicalstudies.

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

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

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

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 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, 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 study in healthy subjects, the AUC of pioglitazone was increasedby 46% and the AUCs for M-III and M-IV, the active metabolites of pioglitazone, each decreased by10% when pioglitazone was given together with a single dose of 1000 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 Abiraterone Mylan with medicinal products known to prolong the QT interval ormedicinal products 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.

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

Use with Abiraterone Mylan is not recommended (see section 5.1).

There are no human data on the use of abiraterone in pregnancy and this medicinal product is not foruse in 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).

Abiraterone Mylan is not for use in women and is contraindicated in women who are or maypotentially be pregnant (see section 4.3 and 5.3).

Abiraterone Mylan 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).

Abiraterone Mylan 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 abiraterone acetate, adversereactions that were observed in ≥ 10 % of patients were peripheral oedema, hypokalaemia,hypertension, urinary tract infection, and alanine aminotransferase increased and/or aspartateaminotransferase increased. Other important adverse reactions include, cardiac disorders,hepatotoxicity, fractures, and allergic alveolitis.

Abiraterone 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% 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. Concomitantuse of a corticosteroid reduces the incidence and severity of these adverse reactions (see section 4.4).

In studies of patients with metastatic advanced prostate cancer who were using a LHRH analogue, orwere previously treated with orchiectomy, abiraterone was administered at a dose of 1000 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, atrialfibrillation, tachycardiauncommon: other arrhythmiasnot known: myocardial infarction, QTprolongation (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 aminotransferase increasedand/or aspartate aminotransferase increasedbrare: 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 ejectionfraction 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 ALTincreased, AST increased, 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, severeor unstable angina, or NYHA Class 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%. All patients enrolled (bothactive and placebo-treated patients) were concomitantly treated with androgen deprivation therapy,predominantly with the use of LHRH analogues, which has been associated with diabetes, myocardialinfarction, cerebrovascular accident and sudden cardiac death. The incidence of cardiovascular adversereactions in the Phase 3 studies in patients taking abiraterone acetate versus patients taking placebowere 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 abiraterone.

Ten patients who received abiraterone 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 to 6 x

ULN. Upon discontinuation of treatment, both patients had normalisation of their liver function testsand 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 studies, the risk for hepatotoxicity was mitigated by exclusion of patients with baselinehepatitis or significant abnormalities of liver function tests. In the 3011 study, patients with baseline

ALT and AST > 2.5 x ULN, bilirubin > 1.5 x ULN or those with active or symptomatic viral hepatitisor chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction were excluded.

In the 301 study, patients with baseline ALT and AST ≥ 2.5 x ULN in the absence of liver metastasesand > 5 x ULN in the presence of liver metastases were excluded. In the 302 study, patients with livermetastases were not eligible and patients with baseline ALT and AST ≥ 2.5 x ULN were excluded.

Abnormal liver function tests developing in patients participating in clinical studies were vigorouslymanaged by requiring treatment interruption and permitting re-treatment only after return of liverfunction 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 abiraterone 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 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 abiraterone decreases serum testosterone to undetectable levels (usingcommercial assays) when given with LHRH analogues (or orchiectomy).

Abiraterone acetate decreases serum testosterone and other androgens to levels lower than thoseachieved by the use of LHRH analogues alone or by orchiectomy. This results from the selectiveinhibition of the CYP17 enzyme required for androgen biosynthesis. PSA serves as a biomarker inpatients with prostate cancer. In a Phase 3 clinical study of patients who failed prior chemotherapywith taxanes, 38% of patients treated with abiraterone acetate, versus 10% of patients treated withplacebo, had at least 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, abiraterone acetate wasadministered at a dose of 1000 mg daily in combination with low dose prednisone 5 mg once daily inaddition to ADT (LHRH agonist or orchiectomy), which was the standard of care treatment. Patientsin the control arm received ADT and placebos for both abiraterone acetate and prednisone. Study 302enrolled docetaxel naïve patients; whereas, study 301 enrolled patients who had received priordocetaxel. Patients were using an LHRH analogue or were previously treated with orchiectomy. In theactive treatment arm, abiraterone acetate was administered at a dose of 1000 mg daily in combinationwith low dose prednisone or prednisolone 5 mg twice daily. Control patients received placebo and lowdose prednisone or prednisolone 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 abiraterone acetate by racial group was Caucasian 832 (69.4%), Asian 246 (20.5%), Blackor African American 25 (2.1%), other 80 (6.7%), unknown/not reported 13 (1.1%), and American

Indian or Alaska Native 3 (0.3%). The ECOG performance status was 0 or 1 for 97% of patients.

Patients with known brain metastasis, uncontrolled hypertension, significant heart disease, or NYHA

Class II to IV heart failure were excluded. Patients that were treated with prior pharmacotherapy,radiation therapy, or surgery for metastatic prostate cancer were excluded with the exception of up to3 months of ADT or 1 course of palliative radiation or surgical therapy to treat symptoms resultingfrom metastatic 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 treatpopulation (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)b0.466 (0.394, 0.550)

Note: += censored observation, NE=not estimable. The radiographic progression and death areconsidered in defining the rPFS event. AA-P= subjects who received abiraterone acetate andprednisone.a p value is from a log-rank test stratified by ECOG PS score (0/1 or 2) and visceral lesion (absentor 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-treatpopulation (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 abiraterone acetate or placebos instudy PCR3011 (intent-to-treat analysis)

Overall Survival Abiraterone acetate Placeboswith Prednisone (N=602)(N=597)

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)10.66 (0.56, 0.78)

NE=Not estimable1 Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio  1 favoursabiraterone acetate with prednisone.

Figure 2: Kaplan-Meier plot of overall survival; intent-to-treat population in study

PCR3011 analysis

Subgroup analyses consistently favour treatment with abiraterone acetate. The treatment effect of AA-

P on rPFS and OS across the pre-specified subgroups was favourable and consistent with the overallstudy population, except for the subgroup of ECOG score of 2 where no trend towards benefit wasobserved, 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 forabiraterone acetate 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 withabiraterone acetate plus prednisone or prednisolone and 70 years for patients treated with placebo plusprednisone or prednisolone. The number of patients treated with abiraterone acetate by racial groupwas 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% ofpatients in both arms. Fifty percent of patients had only bone metastases, an additional 31% of patientshad bone and soft tissue or lymph node metastases and 19% of patients had only soft tissue or lymphnode metastases. 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

Tumors (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 abirateroneacetate and 251 (46%) of patients treated with placebo had radiographic evidence of progression orhad died. A significant 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 eitherabiraterone acetate or placebo in combination with prednisone or prednisoloneplus LHRH analogues or prior orchiectomy.

Abiraterone Placeboacetate (N = 542)(N = 546)

Radiographicprogression-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 abiraterone acetate

Figure 3: Kaplan Meier curves of radiographic progression-free survival in patientstreated with either abiraterone acetate or placebo in combination withprednisone or prednisolone plus LHRH analogues or prior orchiectomy

AA = Abiraterone acetate

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 the abiraterone acetategroup and 8.3 months in the placebo group.

Table 5: Study 302: Radiographic progression-free survival of patients treated with eitherabiraterone acetate or placebo in combination with prednisone or prednisoloneplus LHRH analogues or prior orchiectomy (at second interim analysis of OS-investigator review)

Abiraterone Placeboacetate (N = 542)(N = 546)

Radiographicprogression-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 abiraterone acetate

Figure 4: Kaplan Meier curves of radiographic progression-free survival in patientstreated with either abiraterone acetate or placebo in combination withprednisone or prednisolone plus LHRH analogues or prior orchiectomy (atsecond interim analysis of OS-investigator review)

AA = Abiraterone acetate

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 abiraterone acetate. Overall survival was longer for abiraterone acetate thanplacebo with a 25% reduction in risk of death (HR = 0.752; 95% CI: [0.606; 0.934], p = 0.0097), but

OS was not mature and interim results did not meet the pre-specified stopping boundary for statisticalsignificance (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 abiraterone acetate, compared with71% (387 of 542) of patients treated with placebo, had died. A statistically significant OS benefit infavour of the abiraterone-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(abiraterone acetate 34.7 months, placebo 30.3 months) (see Table 6 and Figure 5). This improvementwas demonstrated even though 44% of patients in the placebo arm received abiraterone acetate assubsequent therapy.

Table 6: Study 302: Overall survival of patients treated with either abiraterone acetate orplacebo in combination with prednisone or prednisolone plus LHRH analoguesor prior orchiectomy

Abiraterone acetate 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 in 34.7 (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 abiraterone acetate

Figure 5: Kaplan Meier survival curves of patients treated with either abiraterone acetateor placebo in combination with prednisone or prednisolone plus LHRHanalogues or prior orchiectomy, final analysis

AA = Abiraterone acetate

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

Abiraterone acetate 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 abiraterone acetate 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 abiraterone acetate treatment (HR = 0.488). The proportion of subjects with a confirmed

PSA response was greater in the abiraterone group than in the placebo group (62% vs. 24%;p < 0.0001). In subjects with measurable soft tissue disease, significantly increased numbers ofcomplete and partial tumour responses were seen with abiraterone acetate 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 abiraterone acetate and was 23.4 months forpatients receiving 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 abiraterone acetate and 16.8 months for patients receivingplacebo (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 abiraterone acetate 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 ofabiraterone acetate treatment:

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 abiraterone group and16% in the placebo group (p < 0.0001).

Pain: Treatment with abiraterone acetate significantly reduced the risk of average pain intensityprogression by 18% compared with placebo (p = 0.0490). The median time to progression was26.7 months in the abiraterone group and 18.4 months in the placebo group.

Time to degradation in the FACT-P (total score): Treatment with abiraterone acetate decreased the riskof 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 abiraterone 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 withabiraterone acetate by racial group was Caucasian 737 (93.2%), Black 28 (3.5%), Asian 11 (1.4%) andother 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 abiraterone acetate.

In a planned analysis conducted after 552 deaths were observed, 42% (333 of 797) of patients treatedwith abiraterone acetate 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 withabiraterone acetate (see Table 7).

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

Abiraterone acetate 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)b0.646 (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)b0.740 (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 ofdisease progression (PSA only vs. radiographic).b Hazard ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favoursabiraterone acetate

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

Figure 6: Kaplan Meier survival curves of patients treated with either abiraterone acetateor placebo in combination with prednisone or prednisolone plus LHRHanalogues or prior orchiectomy

AA = Abiraterone acetate

Subgroup survival analyses showed a consistent survival benefit for treatment with abiraterone acetate(see Figure 7).

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

AA = Abiraterone acetate; BPI = Brief Pain Inventory; C.I. = confidence interval; ECOG = Eastern

Cooperative Oncology Group performance score; HR = hazard ratio; NE = not evaluable

In addition to the observed improvement in overall survival, all secondary study endpoints favouredabiraterone acetate and were statistically significant after adjusting for multiple testing as follows:

Patients receiving abiraterone acetate 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 abiraterone acetate 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 withabiraterone acetate and 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 abirateronegroup 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 at twoconsecutive evaluations four weeks apart. Only patients with a baseline pain score of ≥ 4 and at leastone post-baseline pain score were analysed (N = 512) for pain palliation.

A lower proportion of patients treated with abiraterone acetate had pain progression compared topatients taking placebo at 6 (22% vs. 28%), 12 (30% vs. 38%) and 18 months (35% vs. 46%). Painprogression was defined as an increase from baseline of ≥ 30% in the BPI-SF worst pain intensityscore over the previous 24 hours without a decrease in analgesic usage score observed at twoconsecutive visits, or an increase of ≥ 30% in analgesic usage score observed at two consecutive visits.

The time to pain progression at the 25th percentile was 7.4 months in the abiraterone group, versus4.7 months in the placebo group.

A lower proportion of patients in the abiraterone 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 abiraterone group was twice that ofthe control group at 9.9 months versus 4.9 months. A skeletal-related event was defined as apathological fracture, 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 thereference medicinal product containing abiraterone acetate in all subsets of the paediatric population inadvanced prostate cancer. See section 4.2 for information 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 abiraterone acetate with meals has the potential to result in highly variable exposures.

Therefore, Abiraterone Mylan must not be taken with food. Abiraterone Mylan must be taken as asingle dose once daily on an empty stomach. Abiraterone Mylan must be taken at least two hours aftereating and food must not be eaten for at least one hour after taking the tablets. The tablets must beswallowed whole with water (see section 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 1000 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 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 1000 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.

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 1000 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 study, 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).

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.

Croscarmellose sodium(E468)

Sodium laurilsulfate

Povidone

Cellulose, microcrystalline (E460)

Lactose monohydrate

Silica, colloidal anhydrous (E551)

Magnesium stearate (E470b)

Poly(vinyl alcohol)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Iron oxide red (E172)

Iron oxide black (E172)

Not applicable

3 years

This medicinal product does not require any special storage conditions.

Alu-OPA/Alu/PVC blister pack containing 56, 60 tablets

Alu-OPA/Alu/PVC perforated unit dose blister pack containing 56 x 1, 60 x 1 tablets

Alu-PVC/PE/PVDC blister pack containing 56, 60 tablets

Alu-PVC/PE/PVDC perforated unit dose blister pack containing 56 x 1, 60 x 1 tablets

Abiraterone Mylan1000 mg film-coated tablets:

High density polyethylene (HDPE) bottles with oxygen absorbing canister and closed with apolypropylene (PP) child resistant closure containing 28, 30 tablets.High density polyethylene (HDPE)bottles closed with a polypropylene (PP) child resistant closure containing 28, 30 tablets

Alu-OPA/Alu/PVC blister pack containing 28, 30 tablets

Alu-OPA/Alu/PVC perforated unit dose blister pack containing 28 x 1, 30 x 1 tabletsNot all pack sizesmay be marketed.

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).

Mylan Pharmaceuticals Limited

Damastown Industrial Park,

Mulhuddart, Dublin 15,

DUBLIN

Ireland

EU/1/21/1571/001

EU/1/21/1571/002

EU/1/21/1571/003

EU/1/21/1571/004

EU/1/21/1571/005

EU/1/21/1571/006

EU/1/21/1571/007

EU/1/21/1571/008

EU/1/21/1571/009

EU/1/21/1571/010

EU/1/21/1571/011

EU/1/21/1571/012

EU/1/21/1571/013

EU/1/21/1571/014

EU/1/21/1571/015

EU/1/21/1571/016

Date of first Authorisation: 20 August 2021

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

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