Abiraterone acetate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABIRATERONE ACETATE (ABIRATERONE ACETATE)

Composition:

Active substance: abiraterone acetate;

1 tablet contains 250 mg of abiraterone acetate;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; povidone 30; sodium lauryl sulfate; colloidal silicon dioxide anhydrous; magnesium stearate.

Pharmaceutical form. Tablets.

Basic physicochemical properties: oval-shaped tablets of white to almost white color, with embossing “ABR” on one side and “250” on the other.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Agents used in hormonal therapy. Hormone antagonists and related substances. Other hormone antagonists and similar 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. Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is required for androgen biosynthesis in the testicular, adrenal, and prostate tumor tissues. CYP17 catalyzes the conversion of pregnenolone and progesterone to their respective precursors of testosterone, DHEA and androstenedione, via 17α-hydroxylation and C17,20 bond cleavage. Inhibition of CYP17 also leads to an increase in mineralocorticoid production by the adrenal glands (see section "Special warnings and precautions for use").

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

Pharmacodynamics

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

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 androgen biosynthesis inhibitor.

Absorption

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

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

Distribution

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

Metabolism

Following oral administration of 14C-abiraterone acetate in capsule form, abiraterone acetate is hydrolyzed to abiraterone, which is further metabolized by sulfonation, hydroxylation, and oxidation, primarily in the liver. The majority of circulating radioactivity (approximately 92%) is present as abiraterone metabolites. Of the 15 metabolites detected, 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 were 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 class 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 pre-existing 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) of abiraterone and an 80% increase in the unbound fraction of the active drug.

No dose adjustment is required in patients with mild hepatic impairment.

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

The drug is contraindicated 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 may require treatment interruption and dose adjustment (see sections "Dosage 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 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 on hemodialysis. Dose reduction is not required when abiraterone is administered to patients with renal impairment, including severe renal impairment. However, abiraterone should be used with caution in patients with metastatic prostate cancer and severe renal impairment, as clinical data on the use of abiraterone in such patients are limited.

Clinical characteristics

Indications

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

• newly diagnosed metastatic hormone-sensitive prostate cancer at high risk in adult men, in combination with androgen deprivation therapy;
• 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 with docetaxel.

Contraindications

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

Special safety precautions

Due to its mechanism of action, abiraterone may affect fetal development; therefore, pregnant women and women of reproductive potential should wear protective gloves when handling the medication.

Interaction with other medicinal products and other forms of interaction

Effect of food on abiraterone acetate

Administration of abiraterone with food significantly increases the absorption of abiraterone acetate. The efficacy and safety of administering the drug with food have not been established; therefore, abiraterone must not be taken with food (see sections "Dosage and administration" 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 AUC∞ of abiraterone in plasma was reduced by 55%.

Concomitant use of strong CYP3A4 inducers (e.g., 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, 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 effects 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 using abiraterone with medicinal products that are activated or metabolized by CYP2D6, particularly those with a narrow therapeutic index. Therefore, dose reduction of the CYP2D6-metabolized drug 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 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%. Although these results suggest no clinically significant increase in systemic exposure of drugs primarily metabolized by CYP2C8 when co-administered with abiraterone acetate, patients should be closely monitored for signs of toxicity when co-administered with CYP2C8 substrates with a narrow therapeutic index. The main metabolites of abiraterone—abiraterone sulfate and N-oxide abiraterone sulfate—in vitro—demonstrated inhibition of the OATP1B1 transporter. As a result, 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 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 (e.g., amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, and antipsychotic agents (see section "Special precautions").

Use with spironolactone

Spironolactone binds to androgen receptors, which may lead to an increase in prostate-specific antigen (PSA) levels. Concomitant use with abiraterone is not recommended.

Special precautions for use

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

Abiraterone acetate may cause arterial hypertension, hypokalaemia and fluid retention (see section "Side effects") as a result of increased mineralocorticoid levels due to CYP17 inhibition. Concomitant use of corticosteroids suppresses adrenocorticotropic hormone (ACTH) activity, thereby reducing the frequency and severity of these adverse effects. Caution should be exercised when using the medicinal product in patients in whom exacerbation of the underlying disease may manifest as increased 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 should be used with caution in patients with a history of cardiovascular disease. Phase III trials with abiraterone excluded patients with uncontrolled hypertension, clinically significant heart disease, as evidenced by myocardial infarction or arterial thrombotic events within the previous 6 months, severe or unstable angina, NYHA Class III or IV heart failure (trial in patients previously treated with chemotherapy) or heart failure from Class II to IV (trial in patients with newly diagnosed prostate cancer or for whom chemotherapy was not clinically indicated), and left ventricular ejection fraction < 50%. In trials involving patients with newly diagnosed prostate cancer or for whom chemotherapy was not clinically indicated, patients with atrial fibrillation and other types of cardiac arrhythmias requiring medical intervention were excluded. The safety of abiraterone use in patients with left ventricular ejection fraction < 50% or NYHA Class III or IV heart failure (trial in patients previously treated with chemotherapy) or heart failure from Class II to IV (trial in patients with newly diagnosed prostate cancer or for whom chemotherapy was not clinically indicated) has not been established (see section "Side effects").

Prior to initiating treatment in patients at significant risk of developing congestive heart failure (e.g., with heart failure, uncontrolled hypertension or a history of ischaemic heart disease), cardiac function should be assessed (e.g., by echocardiography). Heart failure should be treated and cardiac function optimised prior to starting abiraterone therapy. Arterial hypertension, hypokalaemia and fluid retention should be 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 for the first 3 months and then monthly thereafter, and any abnormalities should be corrected. In patients who developed hypokalaemia during abiraterone treatment, QT interval prolongation was observed. Appropriate therapy should be initiated in case of clinically significant cardiac dysfunction, and discontinuation of the medicinal product should be considered if necessary (see section "Method of administration and dosage").

Hepatotoxicity and hepatic failure

During clinical trials, cases of marked increases in liver enzymes were reported, requiring discontinuation or dose adjustment of the medicinal product (see section "Side effects"). Serum transaminase levels should be monitored prior to starting abiraterone and every 2 weeks during the first 3 months of treatment, then monthly. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminase levels should be measured immediately. If ALT or AST levels exceed the upper limit of normal by more than 5 times, abiraterone treatment should be discontinued immediately and liver function should be carefully evaluated. Treatment may be resumed with a reduced dose only if liver function normalises to baseline levels (see section "Method of administration and dosage").

If severe hepatotoxicity occurs (ALT or AST levels 20 times above the upper limit of normal), the medicinal product should be discontinued and abiraterone should not be used thereafter. Patients with active viral hepatitis were not included in clinical trials; therefore, there are no data on the use of abiraterone in this population. There are no data on the safety and efficacy of multiple doses of abiraterone 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 "Method of administration and dosage" and "Pharmacokinetics"). Abiraterone should not be used in patients with severe hepatic impairment (see sections "Method of administration and dosage", "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 "Side effects").

Discontinuation of corticosteroids and stress situations

When prednisone or prednisolone is discontinued, patients should be closely monitored for signs of adrenal insufficiency. If abiraterone treatment continues after corticosteroid discontinuation, 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 in combination with glucocorticosteroids may exacerbate this effect.

Prior use of ketoconazole

Lower sensitivity to abiraterone may be expected in patients previously treated with ketoconazole.

Hyperglycaemia

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

Hypoglycaemia

Cases of hypoglycaemia have been reported when abiraterone and prednisone/prednisolone were administered to patients with pre-existing diabetes mellitus who were receiving pioglitazone or repaglinide; therefore, blood glucose levels should be monitored in patients with diabetes mellitus.

Use with chemotherapy

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

Intolerance to excipients

The medicinal product contains lactose. Patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not take abiraterone acetate.

Potential risks

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

Effect on the musculoskeletal system

Cases of myopathy and rhabdomyolysis have been reported in patients receiving abiraterone. In some patients, rhabdomyolysis led to renal failure. 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 is used concomitantly with medicinal products associated with myopathy/rhabdomyolysis.

Interactions with other medicinal products

Concomitant use of abiraterone with strong CYP3A4 inducers 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 in patients with asymptomatic or mildly symptomatic prostate cancer.

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

Use during pregnancy or breastfeeding

Women of childbearing potential

There are no data on the use of abiraterone in pregnant women. This medicinal product is contraindicated in women who are or may 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 intercourse with a pregnant woman. If the patient has sexual intercourse with a woman of childbearing potential, a condom should be used in combination with other effective contraceptive methods. Animal studies have demonstrated reproductive toxicity.

Pregnancy

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

Lactation

Abiraterone acetate should not be administered to women.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

Abiraterone has no effect or has a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

This medicinal product should be prescribed by a qualified physician.

Dosage

The recommended dose of abiraterone is 1000 mg (4 tablets of 250 mg) as a single daily dose, which should not be taken with food. Administration of the drug with food increases systemic exposure to abiraterone (see section "Interaction with medicinal products and other forms of interaction" and "Pharmacokinetics").

Method of Administration

The medicinal product is intended for oral administration. Tablets should be taken on an empty stomach as a single dose once daily. The drug should be taken at least 2 hours after eating, and food intake should be avoided for 1 hour after administration of the drug. The tablet should be swallowed whole, without chewing or crushing, with water.

Dosing of prednisone or prednisolone

For the treatment of metastatic hormone-sensitive prostate cancer, the recommended dose of prednisone or prednisolone is 5 mg daily.

For the treatment of metastatic castration-resistant prostate cancer, the recommended dose of prednisone or prednisolone is 10 mg daily.

Patients who have not undergone surgical castration should continue medical castration with a GnRH analogue throughout abiraterone treatment.

Recommended Monitoring

Before initiating abiraterone therapy, serum transaminase levels should be assessed and monitored every 2 weeks during the first 3 months of treatment, 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, then monthly (see section "Special Warnings and Precautions for Use").

In patients with a history of hypokalaemia or who develop hypokalaemia during abiraterone treatment, serum potassium levels should be maintained ≥ 4.0 mM.

Treatment should be discontinued in patients who develop toxicity ≥ grade 3, including hypertension, hypokalaemia, oedema, and mineralocorticoid excess toxicity, and appropriate therapeutic measures should be taken. Treatment with the drug may be resumed only after toxicity symptoms have resolved to grade 1 or less.

If a daily dose of both abiraterone 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 (ALT or AST levels exceeding 5 times the upper limit of normal) during treatment (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) once daily. In such patients, serum transaminase levels should be monitored every 2 weeks during the first 3 months of treatment and monthly thereafter. If hepatotoxicity recurs while on the reduced dose of 500 mg daily, treatment should be discontinued.

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

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 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 the drug in patients with moderate hepatic impairment should be carefully considered: the benefit of treatment must clearly outweigh the potential risk. Abiraterone 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 drug in patients with prostate cancer and severe renal impairment. Caution should be exercised when administering abiraterone to this patient population.

Children

The drug is not intended for use in children.

Overdose

Experience with abiraterone overdose is limited.

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

Adverse Reactions

In the pooled analysis of adverse reactions observed during Phase III clinical trials with abiraterone at a frequency ≥ 10%, the most common were peripheral edema, hypokalemia, arterial hypertension, urinary tract infections, and increased levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST). Other important adverse reactions included cardiac disorders, hepatotoxicity, bone fractures, and allergic alveolitis.

Abiraterone may cause arterial hypertension, hypokalemia, and fluid retention as pharmacodynamic consequences of its mechanism of action. During clinical trials, expected mineralocorticoid-related adverse reactions were more frequently observed in patients receiving abiraterone 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 treated with abiraterone, 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 effects can generally be managed successfully with medical treatment. Concomitant use of corticosteroids 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 orchiectomy, abiraterone was administered at a dose of 1000 mg once daily in combination with prednisone or prednisolone (5 mg or 10 mg daily, depending on the indication).

Adverse reactions observed during clinical trials and in the post-marketing period with abiraterone are listed in Table 1, categorized by frequency of occurrence: 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 (cannot be estimated from available data).

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

Table 1

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

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

a Spontaneous post-marketing reports.

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

Grade III adverse reactions according to CTCAE scale observed in patients receiving abiraterone: hypokalaemia (5%); urinary tract infections (2%), elevated ALT and/or AST levels (4%), arterial hypertension (6%), fractures (2%); peripheral oedema, heart failure, atrial fibrillation (1%). Grade III adverse reactions according to CTCAE scale such as hypertriglyceridaemia and angina pectoris were observed in <1% of patients. Grade IV adverse reactions according to CTCAE scale such as urinary tract infections, elevated ALT and/or AST levels, 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 was observed 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 arterial hypertension and clinically significant heart diseases such as myocardial infarction, arterial thrombotic events within the last 6 months, severe or unstable angina, NYHA class III or IV heart failure (in studies involving patients previously treated with chemotherapy) or NYHA class II to IV heart failure (in studies involving patients not treated with chemotherapy), and left ventricular ejection fraction <50%. All patients enrolled in the studies (those receiving abiraterone and those receiving placebo) received concomitant androgen-deprivation therapy with LHRH agonists, which has been associated with the development of diabetes, myocardial infarction, stroke, and sudden cardiac death. The incidence of cardiovascular adverse reactions during phase III studies among patients receiving abiraterone versus those receiving 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 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 (elevated AST and ALT more than 5 times the upper limit of normal and bilirubin more than 1.5 times the upper limit of normal) 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 treatment was discontinued in 10 patients due to hepatotoxicity; of these, 2 patients 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 compared to patients with normal baseline ALT and AST values. Treatment with abiraterone was interrupted or discontinued in case of ALT or AST elevation more than 5 times the upper limit of normal or total bilirubin elevation more than 3 times the upper limit of normal. Two cases of marked elevation of liver function tests were observed. In these patients, with normal liver function prior to treatment, ALT or AST increased 15–40 times above the upper limit of normal, and bilirubin increased 2–6 times above the upper limit of normal. After discontinuation of treatment, normalization of liver tests occurred in both patients; one patient was re-challenged with abiraterone without recurrence of elevated liver enzymes. In study 302, grade III–IV toxicity with elevated 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 recorded.

In clinical trials, the risk of hepatotoxicity was minimized by excluding patients with hepatitis or significant abnormalities in liver function tests prior to treatment initiation. Study 3011 excluded patients with baseline ALT and AST levels exceeding 2.5 times the upper limit of normal, bilirubin >1.5 times the upper limit of normal, as well as patients with active or symptomatic viral hepatitis or chronic liver disease; ascites or gastrointestinal bleeding due to impaired liver function. Study 301 excluded patients with baseline ALT and AST levels exceeding 2.5 times the upper limit of normal in the absence of liver metastases and more than 5 times the upper limit of normal in the presence of liver metastases. Study 302 excluded patients with liver metastases, as well as patients with baseline ALT and AST levels exceeding 2.5 times the upper limit of normal. Liver function test elevations in patients enrolled in clinical trials were monitored and managed by treatment interruption and re-initiation only after liver tests returned to baseline levels. Re-treatment was not recommended for patients with ALT or AST elevations more than 20 times the upper limit of normal. The safety of re-treatment in such patients is unknown. The mechanism of hepatotoxicity has not been studied.

Reporting suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

Store at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging

120 tablets in a container.

Prescription status. Prescription only.

Manufacturer

MSN Laboratories Private Limited.

Manufacturer's address and location of operations

Formulations Division, Unit-II, Survey No. 1277 and 1319 to 1324, Nandigama (Village), Nandigama (Mandal), Rangareddy District, Telangana, 509228, India