Abiraterone-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Abiraterone-Teva (Abiraterone-Teva)

Composition:

Active substance: abiraterone acetate;

One film-coated tablet contains 250 mg of abiraterone acetate;

Excipients: core: microcrystalline cellulose, sodium croscarmellose, lactose monohydrate, povidone, sodium lauryl sulfate, colloidal anhydrous silicon dioxide, magnesium stearate;
film coating: polyvinyl alcohol (partially hydrolyzed), titanium dioxide (E 171), polyethylene glycol (macrogol), talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, modified oval-shaped film-coated tablets, with "TEVA" embossed on one side and "1125" on the other side.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Agents used in hormonal therapy. Hormone antagonists and related agents. Other hormone antagonists and related agents. Abiraterone. ATC code L02B X03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Abiraterone acetate is metabolized in vivo to abiraterone, which is an inhibitor of androgen biosynthesis and selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostate tumor tissues and is essential for androgen biosynthesis. The CYP17 enzyme catalyzes the conversion of pregnenolone and progesterone to precursors of testosterone—dehydroepiandrosterone (DHEA) and androstenedione, respectively—via 17α-hydroxylation and cleavage of the C17,20 bond. Inhibition of the CYP17 enzyme also leads to increased production of mineralocorticoids by the adrenal glands (see section "Special precautions for use").

Androgen-sensitive prostate cancer responds to treatment that reduces androgen levels. Androgen deprivation therapy, such as treatment with luteinizing hormone-releasing hormone (LHRH) agonists or orchiectomy, reduces androgen production in the testes but does not affect androgen production by the adrenal glands or tumor tissues. The use of abiraterone acetate reduces serum testosterone levels to undetectable levels when administered concurrently with LHRH agonists (or following orchiectomy).

Abiraterone acetate reduces serum testosterone and other androgen levels more effectively than LHRH agonists or orchiectomy. This effect results from selective inhibition of CYP17, which is required for androgen biosynthesis. Prostate-specific antigen (PSA) is a biological marker in patients with prostate cancer. In a phase III clinical trial involving patients who had previously failed taxane-based chemotherapy, a ≥50% reduction in PSA levels from baseline was observed in 38% of patients receiving abiraterone acetate compared to 10% of patients receiving placebo.

Pharmacokinetics.

The pharmacokinetics of abiraterone and abiraterone acetate were studied in healthy volunteers, patients with metastatic prostate cancer, and patients without cancer but with hepatic or renal impairment. In vivo, abiraterone acetate is converted to abiraterone, which is an inhibitor of androgen biosynthesis.

Absorption.

After oral administration of abiraterone acetate on an empty stomach, maximum plasma concentration is reached within 2 hours.

Systemic exposure to abiraterone is increased when abiraterone acetate is taken with food. Administration of abiraterone acetate with food, compared to fasting, results in a 10-fold increase in AUC and nearly a 17-fold increase in Cmax of abiraterone, relative to the average systemic exposure of abiraterone depending on the fat content of the meal. Therefore, taking abiraterone acetate with food may potentially lead to variable systemic exposure. For this reason, the medicinal product must not be taken with food. Abiraterone-Teva should be administered at least 1 hour before or 2 hours after eating. The tablets should be swallowed whole with sufficient water (see section "Dosage and administration").

Distribution.

The binding of 14C-abiraterone to plasma proteins is 99.8%. The volume of distribution is 5630 L, indicating extensive distribution of abiraterone into peripheral tissues.

Biological transformation.

After oral administration of 14C-abiraterone acetate in capsule form, abiraterone acetate is hydrolyzed to abiraterone, which then undergoes sulfation, hydroxylation, and oxidation reactions primarily in the liver. The majority of circulating radioactivity (approximately 92%) is present as abiraterone metabolites. Of the 15 detectable metabolites, two major metabolites—abiraterone sulfate and N-oxide abiraterone sulfate—account for approximately 43% of total radioactivity each.

Elimination.

The mean elimination half-life of abiraterone in plasma is approximately 15 hours, based on data obtained in healthy volunteers. After oral administration of 1000 mg of 14C-abiraterone acetate, approximately 88% of the radioactive dose is excreted in feces and about 5% in urine. The main compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).

Patients with hepatic impairment.

The pharmacokinetics of abiraterone acetate were evaluated in patients with pre-existing mild or moderate hepatic impairment (Child-Pugh classes A and B, respectively) and in a control group of healthy volunteers. Systemic exposure to abiraterone after a single oral dose of 1000 mg of the medicinal product increased by approximately 11% and 260% in patients with mild or moderate hepatic impairment, respectively. The mean elimination half-life of abiraterone was prolonged to approximately 18 hours in patients with mild hepatic impairment and to approximately 19 hours in patients with moderate hepatic impairment.

In another study, the pharmacokinetics of abiraterone were evaluated in patients (N=8) with pre-existing severe hepatic impairment (Child-Pugh class C) and in 8 healthy volunteers with normal liver function. Compared to healthy volunteers, systemic exposure (AUC) to abiraterone increased by approximately 600% in patients with severe hepatic impairment, and the fraction of unbound active substance increased by approximately 80%.

Dose adjustment is not required in patients with mild hepatic impairment.

Abiraterone acetate should be used with caution in patients with moderate hepatic impairment and only if the benefit of treatment clearly outweighs the potential risks (see sections "Dosage and administration" and "Special precautions for use").

Abiraterone acetate must not be used in patients with severe hepatic impairment (see sections "Dosage and administration", "Contraindications", and "Special precautions for use").

Patients who develop hepatotoxicity during treatment with abiraterone acetate may require treatment interruption and dose adjustment (see sections "Dosage and administration" and "Special precautions for use").

Patients with renal impairment.

The pharmacokinetics of abiraterone acetate were compared in patients with end-stage renal disease on hemodialysis and in a control group of patients with normal renal function. Systemic exposure to abiraterone after a single oral dose of 1000 mg of the medicinal product was not increased in patients with end-stage renal disease undergoing hemodialysis. Dose adjustment of the medicinal product is not required in patients with renal impairment, including severe renal impairment. However, the medicinal product should be used with caution in patients with metastatic prostate cancer who have severe renal impairment, as clinical data on the use of abiraterone acetate in such patients are lacking.

Clinical characteristics.

Indications.

Abiraterone acetate – a CYP17 inhibitor – is indicated in combination with prednisone or prednisolone for the treatment of:

• metastatic castration-resistant prostate cancer with asymptomatic or mildly symptomatic disease in adult men following inadequate response to androgen deprivation therapy and for whom chemotherapy is not clinically indicated;
• metastatic castration-resistant prostate cancer in adult men whose disease has progressed during or after prior chemotherapy containing docetaxel;
• newly diagnosed high-risk metastatic hormone-sensitive prostate cancer in adult men in combination with androgen deprivation therapy.

Contraindications.

• Hypersensitivity to abiraterone or to any of the excipients.
• Severe hepatic impairment (Child-Pugh class C).
• Contraindicated in women who are pregnant or potentially pregnant.
• Abiraterone with prednisone or prednisolone is contraindicated in combination with Ra-223.

Safety precautions.

Based on its mechanism of action, the medicinal product Abiraterone-Teva may affect fetal development. Therefore, pregnant women or women who may potentially be pregnant should wear protective gloves when handling the product.

Interaction with other medicinal products and other forms of interaction.

Effect of food on abiraterone acetate.

Administration of the medicinal product with food significantly increases the absorption of abiraterone acetate. The efficacy and safety of Abiraterone-Teva administered with food have not been established; therefore, the medicinal product must not be taken with food (see sections "Pharmacokinetics" and "Method of administration and dosage").

Effect of other medicinal products on abiraterone.

Some medicinal products may enhance or reduce the effect of abiraterone, potentially increasing the frequency of adverse reactions or reducing abiraterone's efficacy.

In a pharmacokinetic interaction study in healthy volunteers who initially received rifampicin, a strong CYP3A4 enzyme inducer, at a dose of 600 mg daily for 6 days, followed by a single 1000 mg dose of abiraterone acetate, the mean AUC∞ of abiraterone in plasma was reduced by 55%.

Concomitant use of strong CYP3A4 inducers (such as phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John's wort [Hypericum perforatum]) should be avoided, except when no therapeutic alternative exists.

In a separate clinical study in healthy volunteers, concomitant administration of ketoconazole, a strong CYP3A4 inhibitor, had no clinically significant effect on the pharmacokinetics of abiraterone.

Effect of abiraterone on other medicinal products.

Abiraterone is an inhibitor of hepatic enzymes CYP2D6 and CYP2C8, which are involved in drug metabolism. In a study assessing the effect of abiraterone acetate (with prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, systemic exposure (AUC) of dextromethorphan increased approximately 2.9-fold. The AUC24 of dextrorphan, the active metabolite of dextromethorphan, increased by 33%.

Caution is recommended when co-administering abiraterone acetate with medicinal products that are activated or metabolized by CYP2D6, particularly those with a narrow therapeutic index. Therefore, dose reduction of the CYP2D6 substrate with a narrow therapeutic index should be considered. Such medicinal products include, in particular, metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone, tramadol (the last three require CYP2D6 for the formation of active analgesic metabolites).

In a CYP2C8 drug interaction study in healthy volunteers, administration of pioglitazone with a single 1000 mg dose of abiraterone acetate resulted in a 46% increase in pioglitazone AUC, while AUC of each of the active metabolites of pioglitazone, M-III and M-IV, decreased by 10%. Patients should be closely monitored for signs of toxicity when co-administering substrates of CYP2C8 with a narrow therapeutic index (e.g., pioglitazone, repaglinide).

The major metabolites of abiraterone – abiraterone sulfate and N-oxide abiraterone sulfate – demonstrated in vitro inhibition of the OATP1B1 transporter. This may lead to increased concentrations of medicinal products eliminated via OATP1B1. There are no clinical data to confirm transporter-dependent interactions.

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL.

Since androgen deprivation therapy may lead to QT interval prolongation, Abiraterone-Teva should be used with caution in combination with medicinal products that may prolong the QT interval or that may induce torsades de pointes, such as class IA antiarrhythmics (e.g., quinidine, disopyramide) or class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, antipsychotics, etc. (see section "Special precautions for use").

Use with spironolactone.

Spironolactone binds to androgen receptors, which may lead to an increase in PSA levels. Concomitant use with Abiraterone-Teva is not recommended.

Special precautions for use.

Arterial hypertension, hypokalaemia, fluid retention and heart failure due to excess mineralocorticoids.

Abiraterone acetate may cause arterial hypertension, hypokalaemia and fluid retention (see section "Adverse reactions") as a result of increased mineralocorticoid levels due to CYP17 inhibition. Concomitant corticosteroid administration suppresses adrenocorticotropic hormone (ACTH) activity, thereby reducing the frequency and severity of these adverse effects. The medicinal product should be used with caution in patients in whom exacerbation of the underlying disease may manifest as elevated blood pressure, hypokalaemia (in patients receiving cardiac glycosides) or fluid retention, such as in heart failure, severe or unstable angina, recent myocardial infarction or ventricular arrhythmia, and in patients with severe renal impairment.

Abiraterone-Teva should be used with caution in patients with a history of cardiovascular disease. Patients with uncontrolled hypertension, clinically significant cardiac disease (e.g., myocardial infarction or arterial thrombotic events within the previous 6 months), severe or unstable angina, NYHA Class III or IV heart failure (study in patients previously treated with chemotherapy) or heart failure from Class II to IV (study in patients with newly diagnosed prostate cancer or for whom chemotherapy was clinically not indicated), or left ventricular ejection fraction < 50% were excluded from Phase III studies with abiraterone acetate. In studies involving patients with newly diagnosed prostate cancer or for whom chemotherapy was clinically not indicated, patients with atrial fibrillation and other cardiac arrhythmias requiring medical intervention were excluded. The safety of abiraterone acetate in patients with left ventricular ejection fraction < 50% or NYHA Class III or IV heart failure (study in patients previously treated with chemotherapy) or heart failure from Class II to IV (study in patients with newly diagnosed prostate cancer or for whom chemotherapy was clinically not indicated) has not been established (see section "Adverse reactions").

Prior to initiating treatment in patients at significant risk of developing congestive heart failure (e.g., heart failure, uncontrolled hypertension or a history of ischaemic heart disease), cardiac function should be assessed (e.g., by echocardiography). Patients with heart failure should be treated and cardiac function optimised prior to initiating therapy. Arterial hypertension, hypokalaemia and fluid retention should be corrected and monitored. Blood pressure, potassium levels, fluid retention (weight gain, peripheral oedema) and other signs of congestive heart failure should be monitored every 2 weeks during the first 3 months of treatment and monthly thereafter; any abnormalities should be corrected. QT interval prolongation has been observed when abiraterone acetate was administered to patients with hypokalaemia.

In case of clinically significant cardiac function abnormalities, appropriate therapy should be initiated and discontinuation of treatment should be considered if necessary.

Androgen deprivation therapy may prolong the QT interval.

Physicians should evaluate the benefit-risk ratio, including the potential for development of torsade de pointes, in patients with a history of or risk factors for QT interval prolongation and in patients receiving concomitant medicinal products that may prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction") before initiating abiraterone.

Hepatotoxicity and hepatic failure.

In clinical trials, cases of marked increases in liver enzymes were reported, requiring discontinuation or dose adjustment of the medicinal product (see section "Adverse reactions"). Serum transaminase levels should be monitored prior to administration of Abiraterone-Teva and every 2 weeks during the first 3 months of treatment, then monthly. If clinical symptoms or signs suggestive of hepatotoxicity occur, serum liver transaminases should be measured immediately.

If ALT or AST levels exceed the upper limit of normal (ULN) by more than 5 times, treatment with Abiraterone-Teva should be discontinued immediately and liver function should be carefully evaluated. Treatment may be resumed at a lower dose only after liver function has returned to baseline levels.

In case of severe hepatotoxicity (ALT or AST levels exceeding ULN by 20 times), the medicinal product should be discontinued and further use of abiraterone should be avoided. Patients with active viral hepatitis were not included in clinical trials; therefore, there are no data on the use of abiraterone acetate in this population.

There are no data on the safety and efficacy of multiple doses of abiraterone acetate in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The medicinal product should be used with caution in patients with moderate hepatic impairment and only if the benefit of treatment clearly outweighs the potential risks (see sections "Dosage and administration" and "Pharmacokinetics"). Abiraterone-Teva should not be used in patients with severe hepatic impairment.

In the post-marketing period, rare cases of acute liver failure and fulminant hepatitis, some of which were fatal, have been reported (see section "Adverse reactions").

Withdrawal of corticosteroids and stress situations.

Patients should be carefully monitored for signs of adrenal insufficiency when prednisone or prednisolone is discontinued. If Abiraterone-Teva is continued after corticosteroid withdrawal, patients should be monitored for excess mineralocorticoid effects. If a patient experiences a severe stress situation, increased doses of prednisone or prednisolone may be indicated during and after the stress event.

Bone density.

In men with metastatic prostate cancer (castration-resistant prostate cancer), decreased bone mineral density may occur. The use of abiraterone acetate in combination with glucocorticoids may exacerbate this effect.

Prior use of ketoconazole.

Reduced sensitivity to Abiraterone-Teva may be expected in patients previously treated with ketoconazole.

Hyperglycaemia.

The use of glucocorticoids may increase hyperglycaemia; therefore, blood glucose levels should be monitored frequently in patients with diabetes mellitus.

Hypoglycaemia.

Cases of hypoglycaemia have been reported when abiraterone acetate was administered to patients with pre-existing diabetes mellitus who were receiving pioglitazone or repaglinide (see section "Interaction with other medicinal products and other forms of interaction"); therefore, blood glucose levels should be monitored frequently in diabetic patients.

Use with chemotherapy.

The safety and efficacy of concomitant use of Abiraterone-Teva with cytotoxic chemotherapy have not been established.

Potential risks.

In men with metastatic castration-resistant prostate cancer, including those receiving Abiraterone-Teva, anaemia and sexual dysfunction may occur.

Effects on the musculoskeletal system.

Cases of myopathy and rhabdomyolysis have been reported in patients receiving abiraterone acetate. These events usually occurred within the first 6 months of treatment and resolved after discontinuation of the medicinal product. Caution should be exercised when Abiraterone-Teva is used concomitantly with medicinal products associated with the development of myopathy/rhabdomyolysis. In some patients, rhabdomyolysis with renal failure has been observed.

Interactions with other medicinal products.

Concomitant use of abiraterone acetate with strong CYP3A4 inducers should be avoided, unless no therapeutic alternative is available, due to the risk of reduced systemic exposure to abiraterone (see section "Interaction with other medicinal products and other forms of interaction").

Combination of abiraterone and prednisone/prednisolone with Ra-223.

Treatment with abiraterone and prednisone/prednisolone in combination with Ra-223 is contraindicated (see section "Contraindications") due to an increased risk of fractures and a trend towards increased mortality observed in clinical trials in patients with asymptomatic or mildly symptomatic prostate cancer.

Initiation of subsequent Ra-223 treatment less than 5 days after the last dose of Abiraterone-Teva in combination with prednisone/prednisolone is not recommended.

This medicinal product contains 26 mg of sodium in 4 tablets (daily dose), equivalent to 1.3% of the World Health Organization (WHO) recommended maximum daily intake of 2 g sodium for an adult. Caution should be exercised when prescribing to patients on a sodium-restricted diet.

Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Women of childbearing potential.

There is no information on the use of Abiraterone-Teva in pregnant women. This medicinal product is contraindicated in women who are or may become pregnant.

Contraception in men and women.

Data on the presence of abiraterone or its metabolites in semen are lacking. A condom should be used during sexual contact with a pregnant woman. If the patient has sexual intercourse with a woman who may become pregnant, a condom should be used in combination with other effective contraceptive methods. Animal studies have demonstrated reproductive toxicity.

Pregnancy.

Abiraterone-Teva is not indicated for use in women. Abiraterone acetate is contraindicated in pregnant women and in women who may become pregnant.

Lactation.

Abiraterone-Teva is not administered to women.

Fertility.

Animal studies indicated that abiraterone affects fertility, but this effect was reversible.

Ability to drive and use machines.

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

Method of Administration and Dosage

The medicinal product should be taken on an empty stomach (at least 2 hours after food, and food intake should be avoided for 1 hour after administration of the medicinal product). The tablet should be swallowed whole, without chewing or crushing. It is recommended to take with water.

The recommended dose of abiraterone is 1000 mg (4 tablets of 250 mg) as a single daily dose. The medicinal product must not be taken with food. Administration of the medicinal product with food increases systemic exposure to abiraterone.

Dosing of prednisone or prednisolone.

For treatment of newly diagnosed prostate cancer, the recommended dose of prednisone or prednisolone is 5 mg daily.

The recommended dose of prednisone or prednisolone for treatment of metastatic castration-resistant prostate cancer is 10 mg daily.

Patients who have not undergone surgical castration should continue medical castration with a GnRH analogue throughout the treatment period with Abiraterone-Teva.

Prior to initiating treatment with abiraterone, serum transaminase levels should be assessed, and then monitored every 2 weeks during the first 3 months of treatment, followed by monthly monitoring.

Blood pressure, serum potassium, and fluid retention should be monitored monthly. Patients at high risk of congestive heart failure should be monitored every 2 weeks during the first 3 months of treatment, and then monthly (see section "Special Warnings and Precautions for Use").

Patients with a history of hypokalaemia or those who develop hypokalaemia during abiraterone treatment should maintain potassium levels ≥ 4.0 mmol/L.

Treatment should be discontinued in patients who develop toxicity ≥ grade 3, including hypertension, hypokalaemia, oedema, and non-mineralocorticoid toxicity, and appropriate therapeutic measures should be taken. Treatment with Abiraterone-Teva may be resumed only after toxicity symptoms have resolved to grade 1 or have disappeared.

If a patient misses a daily dose of Abiraterone-Teva or prednisone/prednisolone, treatment should be resumed the next day with the usual daily dose.

Hepatotoxicity. If hepatotoxicity develops during treatment (ALT or AST > 5×ULN), administration of Abiraterone-Teva should be interrupted (see section "Special Warnings and Precautions for Use"). Treatment may be resumed after normalization of liver function tests at a reduced dose of 500 mg (2 tablets) daily. In such patients, serum transaminase levels should be monitored for 3 months and then monthly. If hepatotoxicity recurs while on the reduced dose of 500 mg/day, treatment should be discontinued.

If severe hepatotoxicity develops during treatment (ALT or AST > 20×ULN), abiraterone treatment should be discontinued and not restarted.

Hepatic impairment. Dose adjustment is not required in patients with Child–Pugh class A hepatic impairment.

Moderate hepatic impairment (Child–Pugh class B) has been shown to increase systemic exposure to orally administered abiraterone 1000 mg once daily by fourfold. There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate in patients with moderate or severe hepatic impairment (Child–Pugh class B or C). Dose adjustment cannot be predicted. The use of Abiraterone-Teva in patients with moderate hepatic impairment should be carefully considered: the benefit of treatment should clearly outweigh the potential risk. The medicinal product must not be used in patients with severe hepatic impairment.

Renal impairment. Patients with renal impairment do not require dose adjustment of abiraterone. There is no clinical experience with the use of the medicinal product in patients with prostate cancer and severe renal impairment. Caution should be exercised when administering abiraterone to this patient population.

Paediatric population.

The medicinal product is not intended for use in children.

Overdose.

Experience with abiraterone acetate overdose is limited.

There is no specific antidote. In case of overdose, administration of the medicinal product should be discontinued and symptomatic treatment and monitoring for arrhythmia, hypokalaemia, and signs of fluid retention should be instituted. Liver function should also be assessed.

Adverse Reactions

In a pooled analysis of adverse reactions observed during phase III clinical trials with abiraterone, the most commonly reported adverse reactions (≥10%) were peripheral oedema, hypokalaemia, hypertension, urinary tract infections, and increased levels of ALT and/or AST. Other important adverse reactions include cardiac disorders, hepatotoxicity, bone fractures, and allergic alveolitis.

Abiraterone acetate may cause hypertension, hypokalaemia, and fluid retention as a pharmacodynamic consequence of its mechanism of action. During clinical trials, mineralocorticoid-related adverse reactions were more frequently observed in patients receiving abiraterone acetate compared to those receiving placebo: hypokalaemia (18% vs. 8%), hypertension (22% vs. 16%), and fluid retention (peripheral oedema) (23% vs. 17%), respectively. In patients treated with abiraterone acetate, grade 3 and 4 hypokalaemia according to the CTCAE toxicity scale was observed in 6% and 2% of patients, respectively; hypertension in 8% and 5%, respectively; and fluid retention (peripheral oedema) in 1% and 1%, respectively. Mineralocorticoid-related effects are generally manageable with medical intervention. Concomitant corticosteroid administration reduces the frequency and severity of these adverse reactions (see section "Special Warnings and Precautions for Use").

In clinical trials involving patients with metastatic prostate cancer who were receiving a GnRH analogue or had undergone orchidectomy, abiraterone acetate was administered at a dose of 1000 mg/day in combination with prednisone or prednisolone (5 mg or 10 mg daily, depending on indication).

Adverse reactions observed during clinical trials and in the post-marketing period are listed by frequency categories: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); and not known (frequency cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Infections and infestations: very common – urinary tract infections; common – sepsis.

Immune system disorders: not known – anaphylactic reactions.

Endocrine disorders: uncommon – adrenal insufficiency.

Metabolism and nutrition disorders: very common – hypokalaemia; common – hypertriglyceridaemia.

Cardiac disorders: common – heart failure*, angina pectoris, atrial fibrillation, tachycardia; uncommon – other arrhythmias; not known – myocardial infarction, QT interval prolongation (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Vascular disorders: very common – hypertension.

Respiratory, thoracic and mediastinal disorders: rare – allergic alveolitis.

Gastrointestinal disorders: very common – diarrhoea; common – dyspepsia.

Hepatobiliary disorders: common – increased levels of ALT and/or ASTb; rare – acute liver failure, fulminant hepatitis.

Skin and subcutaneous tissue disorders: common – rash.

Musculoskeletal and connective tissue disorders: uncommon – myopathy, myalgia, rhabdomyolysis.

Renal and urinary disorders: common – haematuria.

General disorders and administration site conditions: very common – peripheral oedema.

Injury, poisoning and procedural complications: common – fractures (fractures include osteoporosis and all types of fractures, excluding pathological fractures).

* Heart failure also includes congestive heart failure, left ventricular dysfunction, and reduced ejection fraction.

a Spontaneous post-marketing reports.

b Increased levels of alanine aminotransferase and/or aspartate aminotransferase, including elevated AST, ALT, and hepatic function abnormalities.

Grade 3 adverse reactions according to the CTCAE scale observed in patients receiving abiraterone acetate were: hypokalaemia (5%), urinary tract infections (2%), increased ALT and/or AST (4%), hypertension (6%), fractures (2%), peripheral oedema, heart failure, atrial fibrillation (1%). Grade 3 adverse reactions such as hypertriglyceridaemia and angina pectoris occurred in <1% of patients.

Grade 4 adverse reactions according to the CTCAE scale, including urinary tract infections, increased ALT and/or AST, hypokalaemia, heart failure, atrial fibrillation, and fractures, were reported in <1% of patients.

Most cases of hypertension and hypokalaemia were observed in the hormone-sensitive population (study 3011). Hypertension was reported in 36.7% of patients in the hormone-sensitive population (study 3011), compared to 11.8% and 20.2% in studies 301 and 302, respectively. Hypokalaemia occurred in 20.4% of patients in the hormone-sensitive population (study 3011), compared to 19.2% and 14.9% in studies 301 and 302, respectively.

Description of selected adverse reactions.

Cardiovascular adverse reactions.

Patients with uncontrolled hypertension or clinically significant cardiovascular disease, including myocardial infarction, arterial thrombotic events within the previous 6 months, severe or unstable angina, NYHA Class III or IV heart failure (in the chemotherapy-pretreated study), or NYHA Class II to IV heart failure (in the chemotherapy-naïve study), and left ventricular ejection fraction <50%, were excluded from phase III trials. All patients enrolled in the trials (those receiving abiraterone and those receiving placebo) received concomitant androgen-lowering therapy with GnRH agonists, which has been associated with the development of diabetes mellitus, myocardial infarction, stroke, and sudden cardiac death.

The incidence of cardiovascular adverse reactions during phase III trials in patients receiving abiraterone versus placebo was as follows: atrial fibrillation – 2.6% vs. 2.0%, tachycardia – 1.9% vs. 1.0%, angina pectoris – 1.7% vs. 0.8%, heart failure – 0.7% vs. 0.2%, arrhythmia – 0.7% vs. 0.5%.

Hepatotoxicity.

Cases of hepatotoxicity with elevated ALT, AST, and total bilirubin have been reported in patients receiving abiraterone acetate. Phase III clinical trials showed that grade 3 and 4 hepatotoxicity (defined as AST and ALT >5× ULN and bilirubin >1.5× ULN) occurred in approximately 6% of patients receiving abiraterone, usually within the first 3 months of treatment.

In study 3011, grade 3 or 4 hepatotoxicity was observed in 8.4% of patients receiving abiraterone acetate. Treatment was discontinued in 10 patients due to hepatotoxicity: 2 patients had grade 2 hepatotoxicity, 6 had grade 3, and 2 had grade 4, with no fatal outcomes. In phase III clinical trials, hepatic function abnormalities occurred more frequently in patients with elevated baseline ALT or AST levels than in those with normal baseline values. Treatment with abiraterone was suspended or discontinued in cases of ALT or AST elevations >5× ULN or total bilirubin >3× ULN. Two cases of marked increases in liver function tests were reported. In these patients, who had normal liver function prior to treatment, ALT or AST increased 15–40 times above ULN and bilirubin increased 2–6 times above ULN during treatment. Liver function tests normalized after treatment discontinuation in both patients; one patient was rechallenged with abiraterone without recurrence of elevated liver enzymes.

In study 302, grade 3–4 toxicity with elevated ALT or AST occurred in 35 (6.5%) patients receiving abiraterone acetate. Elevated aminotransferase levels resolved in all but 3 patients (2 with new multiple liver metastases and 1 with elevated AST approximately 3 weeks after the last dose of abiraterone acetate). In phase III clinical trials, treatment discontinuation due to elevated ALT and AST or hepatic dysfunction was reported in 1.1% of patients receiving abiraterone acetate and in 0.6% of those receiving placebo. No fatal outcomes were reported.

In clinical trials, the risk of hepatotoxicity was minimized by excluding patients with hepatitis or significant abnormalities in liver function tests prior to treatment. In study 3011, patients were excluded if they had baseline ALT or AST >2.5× ULN, bilirubin >1.5× ULN, active or symptomatic viral hepatitis, chronic liver disease, ascites, or gastrointestinal bleeding due to hepatic dysfunction. In study 301, patients with baseline ALT or AST >2.5× ULN (without liver metastases) or >5× ULN (with liver metastases) were excluded. In study 302, patients with liver metastases and those with baseline ALT or AST >2.5× ULN were excluded. Liver function tests in patients enrolled in clinical trials were monitored and managed through treatment interruption and reinitiation only after return to baseline values. Re-treatment was not permitted in patients with ALT or AST elevations >20× ULN. The safety of re-treatment in such patients is unknown. The mechanism of hepatotoxicity has not been established.

Shelf life. 2 years.

After first opening of the bottle – 60 days.

Storage conditions. The medicinal product does not require special storage conditions. Keep out of the reach of children.

Packaging.

120 tablets in a bottle; 1 bottle in a carton.

Each bottle contains 6 oxygen-absorbing containers. Do not swallow the oxygen-absorbing containers; leave them in the bottle.

Prescription category. Prescription only.

Manufacturer. Teva Pharmaceutical Industries Ltd.

Manufacturer's address and place of business.

18 Hameyasdim Street, Industrial Zone, Kfar Saba, Israel.