Abiron

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABIRONE (ABIRONE)

Composition:

Active substance: abiraterone acetate;

1 tablet contains 250 mg of abiraterone acetate;

Excipients: microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; povidone; sodium lauryl sulfate; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets of almost white to cream color, oval-shaped, biconvex, with the imprint «A1» on one side and «H» on the other side.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Agents used for hormonal therapy. Hormone antagonists and similar agents. Other hormone antagonists and similar agents. Abiraterone.

ATC code L02BX03.

Pharmacological Properties

Mechanism of Action

Abiraterone acetate is metabolized in vivo to abiraterone, which is an inhibitor of androgen biosynthesis. Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is required for androgen biosynthesis in the testes, adrenal cortex, and prostate tumor tissues. CYP17 catalyzes the conversion of pregnenolone and progesterone to precursors of testosterone, DHEA, and androstenedione, respectively, via 17α-hydroxylation and cleavage of the C17,20 bond. Inhibition of CYP17 also leads to increased production of mineralocorticoids by the adrenal glands (see section "Special Warnings and Precautions for Use").

Androgen-sensitive prostate cancer responds to treatments that reduce androgen levels. However, therapies aimed at reducing androgen levels, such as the use of luteinizing hormone-releasing hormone (LHRH) agonists or orchiectomy, reduce androgen production in the testes but do not affect androgen production by the adrenal glands or tumor tissue. Treatment with abiraterone acetate reduces serum testosterone levels to undetectable levels when used concomitantly with LHRH agonists (or following orchiectomy).

Pharmacodynamics

Abiraterone acetate reduces serum testosterone and other androgen levels more profoundly than LHRH agonists or orchiectomy. This effect results from selective inhibition of CYP17, which is essential 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 have been studied in healthy volunteers, patients with metastatic prostate cancer, and patients without cancer but with hepatic or renal impairment. Abiraterone acetate is rapidly metabolized in vivo to abiraterone, the active inhibitor of androgen biosynthesis.

Absorption

Following oral administration of abiraterone acetate under fasting conditions, peak plasma concentrations are reached within 2 hours.

Administration of abiraterone acetate with food, compared to administration under fasting conditions, results in a 10-fold increase in AUC and nearly a 17-fold increase in Cmax of abiraterone, depending on the fat content of the meal. Therefore, taking abiraterone acetate with food may lead to variable systemic exposure. Hence, Abiron must not be taken with food. Abiron should be administered at least 1 hour before or 2 hours after a meal. The tablets should be swallowed whole and taken with sufficient fluid (see section "Dosage and Administration").

Distribution

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

Biological Transformation

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

Elimination

The mean elimination half-life of abiraterone in plasma is approximately 15 hours, based on data from healthy volunteers. After oral administration of 1000 mg of 14C-abiraterone acetate, approximately 88% of the radioactive dose was recovered in feces and about 5% in urine. The main components excreted in feces are unchanged abiraterone acetate and abiraterone, accounting for 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 1000 mg oral dose 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 those with moderate hepatic impairment.

In another study, the pharmacokinetics of abiraterone were evaluated in 8 patients with severe hepatic impairment (Child-Pugh class C) and 8 healthy volunteers with normal liver function. Compared to healthy volunteers, patients with severe hepatic impairment showed a 600% increase in systemic exposure (AUC) to abiraterone and an 80% increase in the unbound fraction of the active substance.

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 potential benefits outweigh the risks (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

Abiraterone acetate must not be used in patients with severe hepatic impairment (see sections "Dosage and Administration", "Contraindications", and "Special Warnings and Precautions for Use").

Patients who develop hepatotoxicity during treatment with abiraterone acetate may require treatment interruption and dose adjustment (see sections "Dos游戏副本 and Administration" and "Special Warnings and 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 1000 mg oral dose was not increased in patients with end-stage renal disease undergoing hemodialysis. No dose reduction is required when administering abiraterone acetate to patients with renal impairment, including severe renal impairment. However, abiraterone acetate should be prescribed with caution to patients with prostate cancer and severe renal impairment due to the lack of clinical data on the use of abiraterone acetate in this population.

Clinical characteristics.

Indications.

Abiron is indicated for use in combination with prednisone or prednisolone for the treatment of:

• high-risk metastatic hormone-sensitive prostate cancer in adult men, newly diagnosed, in combination with androgen deprivation therapy;
• metastatic castration-resistant prostate cancer with asymptomatic or mildly symptomatic disease in adult men after failure of androgen deprivation therapy and for whom chemotherapy is not clinically indicated;
• metastatic castration-resistant prostate cancer in adult men whose disease progresses during or after prior chemotherapy with docetaxel.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Severe hepatic impairment (Child-Pugh class C) (see sections "Method of administration and dosage", "Special precautions for use", and "Pharmacokinetics").
• Abiron in combination with prednisone or prednisolone is contraindicated in combination with Ra-223.
• Abiron is contraindicated in pregnant women and women of reproductive potential.

Special safety precautions.

Due to the mechanism of action of abiraterone, abiraterone acetate may affect fetal development. Therefore, pregnant women and women of reproductive potential should wear protective gloves when handling the drug.

Interaction with other medicinal products and other types of interactions.

Effect of food on abiraterone acetate.

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

Effect of other medicinal products on abiraterone.

In a pharmacokinetic interaction study in healthy volunteers who initially received rifampicin, a strong CYP3A4 inducer, at a dose of 600 mg daily for 6 days, followed by a single 1000 mg dose of abiraterone acetate, the mean plasma AUC∞ of abiraterone decreased 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 unless there is no therapeutic alternative.

In a separate clinical study in healthy volunteers, co-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 the metabolism of medicinal products. 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%.

Abiraterone acetate should be used with caution in combination with medicinal products that are activated or metabolized by CYP2D6, particularly those with a narrow therapeutic index. Therefore, consideration should be given to reducing the dose of any medicinal product metabolized by CYP2D6 and having a narrow therapeutic index. Such medicinal products include, in particular, metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone, and 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 increased the AUC of pioglitazone by 46%, while the AUC of each of the active metabolites of pioglitazone, M-III and M-IV, decreased by 10%. Patients should be monitored for signs of toxicity associated with CYP2C8 substrates with a narrow therapeutic index when used concomitantly. Examples of medicinal products metabolized by CYP2C8 include pioglitazone and repaglinide (see section "Special precautions for use").

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 acetate should be used with caution in combination with medicinal products that may prolong the QT interval or drugs that may cause torsades de pointes ventricular tachycardia, such as class IA antiarrhythmics (e.g., quinidine, disopyramide) or class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, and antipsychotic agents (see section "Special precautions for use").

Use with spironolactone.

Spironolactone binds to androgen receptors, which may lead to an increase in prostate-specific antigen (PSA) levels. Concomitant use with abiraterone acetate 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 drug should be used with caution in patients in whom exacerbation of the underlying condition 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 acetate should be used with caution in patients with a history of cardiovascular disease. Patients with uncontrolled hypertension or clinically significant cardiac disease — including myocardial infarction or arterial thrombotic events within the previous 6 months, severe or unstable angina, NYHA Class III or IV heart failure (in the study involving chemotherapy-pretreated patients) or NYHA Class II to IV heart failure (in the study involving 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 clinical trials. Patients with atrial fibrillation and other cardiac arrhythmias requiring medical intervention were excluded from trials involving patients with newly diagnosed prostate cancer or for whom chemotherapy was clinically not indicated. The safety of abiraterone acetate in patients with left ventricular ejection fraction < 50% or NYHA Class III or IV heart failure (in the study involving chemotherapy-pretreated patients) or NYHA Class II to IV heart failure (in the study involving 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 congestive heart failure (e.g., those with a history of heart failure, uncontrolled hypertension, or 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 abiraterone acetate therapy. Arterial hypertension, hypokalaemia and fluid retention should be monitored and managed. During treatment, 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 and monthly thereafter, and any abnormalities should be corrected. Hypokalaemia associated with abiraterone acetate treatment has been linked to QT interval prolongation. In cases of clinically significant cardiac dysfunction, appropriate therapy should be initiated and discontinuation of abiraterone acetate treatment should be considered if necessary (see section "Dosage and administration").

Hepatotoxicity and hepatic failure.

In clinical trials, cases of marked increases in liver enzymes have been reported, requiring treatment discontinuation or dose adjustment (see section "Adverse reactions"). Serum transaminase levels should be monitored prior to initiating abiraterone acetate and every 2 weeks during the first 3 months of treatment, then monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should be measured immediately. If ALT or AST levels exceed 5 times the upper limit of normal, abiraterone acetate treatment should be discontinued immediately and liver function carefully evaluated. Treatment may be resumed with a reduced dose of abiraterone acetate only if liver function normalises to baseline levels (see section "Dosage and administration").

If severe hepatotoxicity occurs (ALT or AST levels exceeding 20 times the upper limit of normal), the drug should be discontinued and abiraterone should be avoided thereafter.

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). 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 "Pharmacokinetics"). Abiraterone acetate should not be used in patients with severe hepatic impairment (see sections "Dosage and administration", "Contraindications" and "Pharmacokinetics").

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.

When prednisone or prednisolone is discontinued, patients should be closely monitored for signs of adrenal insufficiency. If abiraterone acetate treatment continues after corticosteroid withdrawal, patients should be monitored for mineralocorticoid excess.

If a patient experiences a significant stress event, 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 acetate may be expected in patients previously treated with ketoconazole.

Hyperglycaemia.

The use of glucocorticoids may increase hyperglycaemia; therefore, patients with diabetes should frequently monitor their blood glucose levels.

Hypoglycaemia.

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

Use with chemotherapy.

The safety and efficacy of concomitant use of abiraterone acetate with cytotoxic chemotherapy have not been established.

Intolerance to excipients.

Abirone contains lactose. Patients with hereditary galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption syndrome should not take Abirone.

The product contains more than 1 mmol (27.2 mg) of sodium per dose (4 tablets), which should be taken into account for patients on a controlled sodium diet.

Potential risks.

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

Effect 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 abiraterone acetate. Caution should be exercised when abiraterone acetate is used concomitantly with medicinal products associated with myopathy/rhabdomyolysis.

Interactions with other medicinal products.

Concomitant use of abiraterone acetate with strong inducers of CYP3A4 should be avoided, unless no therapeutic alternative exists, 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 among patients with asymptomatic or mildly symptomatic prostate cancer.

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

Use during pregnancy or breastfeeding.

Women of reproductive potential.

There are no data on the use of abiraterone acetate in pregnant women. This medicinal product is contraindicated in women who are or may potentially become pregnant.

Contraception in men and women.

There are no data on the presence of abiraterone or its metabolites in semen. A condom should be used during sexual intercourse with a pregnant woman. If the patient has sexual relations with a woman of reproductive potential, a condom should be used in combination with another effective method of contraception. Animal studies have demonstrated reproductive toxicity.

Pregnancy.

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

Breastfeeding.

Abiraterone acetate should not be administered to women.

Fertility.

Abiraterone affected fertility in animal studies, but this effect was reversible.

Ability to influence reaction speed when driving or operating machinery.

Abiraterone acetate has no effect or a negligible effect on the ability to drive and use machinery.

Method of Administration and Dosage

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

The recommended dose of abiraterone is 1000 mg (4 tablets of 250 mg) as a single daily dose. Administration of the medication with food increases systemic exposure to abiraterone.

Dosage of Prednisone or Prednisolone

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

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

Patients who have not undergone surgical castration should continue medical castration with a gonadotropin-releasing hormone (GnRH) analogue throughout treatment with Abiron.

Recommended Monitoring

Before initiating treatment with abiraterone, serum transaminase levels should be assessed and monitored every 2 weeks during the first 3 months of treatment, and then monthly. 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 Precautions").

Patients with a history of hypokalemia or who develop hypokalemia during treatment with Abiron should maintain potassium levels ≥ 4 mM.

Treatment should be discontinued in patients who develop toxicity ≥ grade 3, including hypertension, hypokalemia, edema, and non-mineralocorticoid toxicity, and appropriate therapeutic measures should be taken. Treatment with Abiron may be resumed only after toxicity symptoms have resolved to grade 1 or less.

If a daily dose of both Abiron and prednisone or prednisolone is missed, treatment should be resumed the next day with the usual daily dose.

Hepatotoxicity

Treatment should be immediately suspended until liver function normalizes in patients who develop hepatotoxicity during treatment (ALT or AST levels exceeding 5 times the upper limit of normal) (see section "Special Precautions"). Treatment may be resumed after normalization of liver function tests at a reduced dose of 500 mg (2 tablets) once daily. In such patients, serum transaminase levels should be monitored every 2 weeks for the first 3 months of treatment and monthly thereafter. If hepatotoxicity recurs while taking the reduced dose of 500 mg daily, treatment should be discontinued.

If severe hepatotoxicity develops during treatment (ALT or AST levels exceeding 20 times the upper limit of normal), abiraterone treatment should be discontinued and not resumed.

Hepatic Impairment

Dose adjustment is not required in patients with a history of Child-Pugh class A hepatic impairment.

Moderate hepatic impairment (Child-Pugh class B) has been shown to increase systemic exposure to orally administered abiraterone at a dose of 1000 mg once daily by 4-fold. 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 acetate in patients with moderate hepatic impairment should be carefully considered, with the benefit of treatment clearly outweighing the potential risk. Abiraterone acetate is contraindicated 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 medication in patients with prostate cancer and severe renal impairment. Caution should be exercised when administering abiraterone to this patient population.

Children

The medication 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 Abiron should be discontinued and symptomatic treatment and monitoring for arrhythmia, hypokalemia, and signs of fluid retention should be initiated. Liver function should also be assessed.

Adverse reactions.

The most commonly observed adverse reactions during abiraterone administration were peripheral edema, hypokalemia, arterial hypertension, urinary tract infections, and elevated levels of alanine aminotransferase and/or aspartate aminotransferase. Other important adverse reactions include cardiac disorders, hepatotoxicity, bone fractures, and allergic alveolitis.

Abiraterone acetate may cause arterial hypertension, hypokalemia, and fluid retention as a pharmacodynamic consequence of its mechanism of action. During clinical trials, expected mineralocorticoid-related adverse reactions were more frequently observed in patients receiving abiraterone acetate compared to those receiving placebo: hypokalemia 18% vs. 8%, arterial hypertension 22% vs. 16%, and fluid retention (peripheral edema) 23% vs. 17%, respectively. In patients receiving abiraterone acetate treatment, grade III and IV hypokalemia according to the CTCAE (Common Terminology Criteria for Adverse Events) toxicity scale occurred in 6% vs. 1% of patients, arterial hypertension in 7% vs. 5%, and fluid retention (peripheral edema) in 1% vs. 1%, respectively. Mineralocorticoid-related reactions are generally manageable with medical treatment. Concomitant administration of corticosteroids reduces the frequency and severity of these adverse reactions (see section "Special precautions").

In clinical trials involving patients with metastatic prostate cancer who were receiving a GnRH analogue or had undergone orchiectomy, 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 the post-marketing period with the use of abiraterone acetate are listed in the table below by frequency categories: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); and not known (frequency cannot be estimated from available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 1

Organ systems	Adverse reactions and frequency
Immune system disorders	Unknown: anaphylactic reactions
Infections and infestations	Very common: urinary tract infections
	Common: sepsis
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
	Unknown: myocardial infarction, QT interval prolongation (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction")
Vascular disorders	Very common: arterial hypertension
Respiratory system disorders	Rare: allergic alveolitis
Gastrointestinal disorders	Very common: diarrhoea
	Common: dyspepsia
Hepatobiliary disorders	Very common: increased alanine aminotransferase (ALT) and/or increased aspartate aminotransferase (AST)b Rare: fulminant hepatitis, acute liver failure
Skin and subcutaneous tissue disorders	Common: rash
Musculoskeletal and connective tissue disorders	Uncommon: myopathy, rhabdomyolysis
Renal and urinary disorders	Common: haematuria
General disorders and administration site conditions	Very common: peripheral oedema
Injury, poisoning and procedural complications	Common: fractures**

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

** Fractures include osteoporosis and all types of fractures, excluding pathological fractures.

a Spontaneous post-marketing reports.

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

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

Most cases of arterial 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.

Phase III studies excluded patients with uncontrolled hypertension and clinically significant heart diseases, such as myocardial infarction, arterial thrombotic events within the previous 6 months, severe or unstable angina, NYHA Class III or IV heart failure (in the study involving chemotherapy-pretreated patients) or NYHA Class II to IV heart failure (in the study involving chemotherapy-naïve patients), and left ventricular ejection fraction <50%. All patients enrolled in the studies (those receiving abiraterone and those receiving placebo) concurrently received 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 studies was as follows in patients receiving abiraterone versus placebo: 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 increased levels of ALT, AST, and total bilirubin have been reported in patients receiving abiraterone acetate. Phase III clinical trials showed that Grade III and IV hepatotoxicity (elevations in AST and ALT >5 times the upper limit of normal [ULN] and bilirubin >1.5 times ULN) occurred in approximately 6% of patients receiving abiraterone, usually within the first three months of treatment.

In Study 3011, Grade III or IV hepatotoxicity was observed in 8.4% of patients receiving abiraterone. Abiraterone was discontinued in 10 patients due to hepatotoxicity; of these, 2 had Grade II hepatotoxicity, 6 had Grade III hepatotoxicity, and 2 had Grade IV hepatotoxicity, with no fatal outcomes. In Phase III clinical trials, hepatic dysfunction occurred more frequently in patients with elevated baseline ALT or AST levels than in those with normal baseline ALT and AST levels. Treatment with abiraterone was interrupted or discontinued in cases of ALT or AST elevations >5 times ULN or total bilirubin >3 times ULN. Two cases of marked increases in liver function tests were reported. In these patients, who had normal liver function before treatment, ALT or AST increased 15–40 times above ULN, and bilirubin increased 2–6 times above ULN during treatment.

After discontinuation of treatment, liver tests normalized in both patients. One patient was rechallenged with abiraterone without recurrence of elevated liver enzymes. In Study 302, Grade III–IV toxicity with increased ALT or AST was observed 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 patients 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. Study 3011 excluded patients with baseline ALT and AST levels >2.5 times ULN, bilirubin >1.5 times ULN, active or symptomatic viral hepatitis, chronic liver disease, ascites, or gastrointestinal bleeding due to hepatic dysfunction. Study 301 excluded patients with baseline ALT and AST levels >2.5 times ULN in the absence of liver metastases and >5 times ULN in the presence of liver metastases. Study 302 excluded patients with liver metastases and those with baseline ALT and AST levels >2.5 times ULN. Elevations in liver function tests among patients enrolled in clinical trials were monitored and managed by treatment interruption and reinitiation only after liver tests returned to baseline levels. Re-treatment was not recommended for patients with ALT or AST elevations >20 times ULN. The safety of re-treatment in such patients is unknown. The mechanism of hepatotoxicity has not been established.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C, in a place inaccessible to children.

Packaging. 120 tablets in a container; 1 container in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer’s address and location of operations.

Unit-V, Block-VB, TSIIC Formulation SEZ, Sy. No. 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India