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 lauryl sulfate, sodium croscarmellose, povidone K-30, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: oval tablets, white to almost white, with an engraved "AN65" on one side and smooth on the other side.

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

ATC code L02B X03.

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 essential for androgen biosynthesis in testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes the conversion of pregnenolone and progesterone to precursors of testosterone, DHEA, and androstenedione via 17α-hydroxylation and C17,20 bond cleavage. Inhibition of CYP17 also leads to increased mineralocorticoid production by the adrenal glands (see section "Special precautions for use").

Androgen-sensitive prostate cancer responds to therapy that reduces androgen levels. However, therapies aimed at lowering 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 in the adrenal glands or tumor tissues. Treatment with abiraterone acetate reduces serum testosterone levels to undetectable levels when used concurrently 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, an enzyme 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 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, maximum plasma concentration is reached within 2 hours.

Administration of abiraterone acetate with food, compared to administration in the fasting state, results in a 10-fold increase in AUC and nearly a 17-fold increase in Cmax of abiraterone, with the magnitude of increase dependent on the fat content of the meal. Therefore, taking abiraterone acetate with food may potentially lead to variable systemic exposure. Hence, abiraterone acetate must not be taken with food. The drug should be administered at least 1 hour before or 2 hours after a meal. 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 into peripheral tissues.

Biological transformation.

Following oral administration of 14C-abiraterone acetate in capsule form, abiraterone acetate is hydrolyzed to abiraterone, which is then subject to sulfonation, hydroxylation, and oxidation reactions 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 obtained in 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 primary components excreted 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 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 pre-existing 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) of 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 benefit 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 1000 mg oral dose was not increased in patients with end-stage renal disease on hemodialysis. No dose reduction is required when abiraterone acetate is administered 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 patient population.

Clinical characteristics.

Indications.

The medicinal product is indicated for use in combination with prednisone or prednisolone for the treatment of:

• newly diagnosed high-risk metastatic hormone-sensitive prostate cancer in adult men in combination with androgen deprivation therapy;
• metastatic castration-resistant prostate cancer with asymptomatic or mild 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 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 "Dosage and administration", "Special precautions" and "Pharmacological properties").
• Abiraterone acetate with prednisone or prednisolone is contraindicated in combination with Ra-223.
• Abiraterone acetate is contraindicated in pregnant women and women of reproductive potential.

Safety precautions.

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

Interaction with other medicinal products and other forms of interaction.

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 "Dosage and administration" and "Pharmacological properties").

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 (such as phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John’s wort [Hypericum perforatum]) should be avoided, except when no therapeutic alternative is available.

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 evaluating the effect of abiraterone acetate (with prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, systemic exposure (AUC) to dextromethorphan increased approximately 2.9-fold. The AUC24 of dextrorphan, the active metabolite of dextromethorphan, increased by 33%.

Caution is recommended when using 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-metabolized medicinal product 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, and a 10% decrease in AUC of each of the active metabolites of pioglitazone, M-III and M-IV. Patients should be monitored for signs of toxicity associated with CYP2C8 substrates with a narrow therapeutic index if such drugs are to be used concomitantly. Examples of medicinal products metabolized by CYP2C8 include pioglitazone and repaglinide (see section "Special precautions").

The major metabolites of abiraterone – abiraterone sulfate and N-oxide abiraterone sulfate – demonstrated inhibition of the OATP1B1 transporter in vitro. 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 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 acetate is not recommended (see section "Pharmacological properties").

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 (see section "Pharmacological properties"). Concomitant corticosteroid administration suppresses adrenocorticotropic hormone (ACTH) activity, thereby reducing the frequency and severity of these adverse effects. Caution should be exercised when treating patients in whom exacerbation of the underlying condition may manifest as elevated blood pressure, hypokalaemia (particularly in patients receiving cardiac glycosides) or fluid retention, such as those with heart failure, severe or unstable angina, recent myocardial infarction, or ventricular arrhythmias, as well as patients with severe renal impairment.

Abiraterone acetate should be used with caution in patients with a history of cardiovascular disease. Phase III clinical trials with abiraterone acetate excluded patients with uncontrolled hypertension, 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 trials involving patients previously treated with chemotherapy) or NYHA Class II to IV heart failure (in trials involving patients with newly diagnosed prostate cancer or those for whom chemotherapy was not clinically indicated), or left ventricular ejection fraction < 50%. In trials involving patients with newly diagnosed prostate cancer or those for whom chemotherapy was not clinically indicated, patients with atrial fibrillation and other cardiac arrhythmias requiring medical intervention were excluded. The safety of abiraterone acetate has not been established in patients with left ventricular ejection fraction < 50% or NYHA Class III or IV heart failure (in trials involving patients previously treated with chemotherapy) or NYHA Class II to IV heart failure (in trials involving patients with newly diagnosed prostate cancer or those for whom chemotherapy was not clinically indicated) (see sections "Adverse reactions" and "Pharmacological properties").

Prior to initiating treatment in patients at significant risk of congestive heart failure (e.g., those with 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 starting abiraterone acetate therapy. Arterial hypertension, hypokalaemia and fluid retention must be monitored and managed. Blood pressure, serum 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. In patients who developed hypokalaemia during treatment with abiraterone acetate, QT interval prolongation has been observed. Appropriate therapy should be initiated in cases of clinically significant cardiac dysfunction, and discontinuation of abiraterone acetate should be considered if necessary (see section "Dosage and administration").

Hepatotoxicity and hepatic failure.

During clinical trials, cases of marked elevations in liver enzymes were reported, necessitating discontinuation or dose adjustment of the drug (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 transaminase levels should be measured immediately. If ALT or AST levels exceed 5 times the upper limit of normal (ULN), abiraterone acetate treatment should be discontinued immediately and liver function should be carefully evaluated. Reinitiation of treatment with a reduced dose of abiraterone acetate may only be considered if liver function returns to baseline levels (see section "Dosage and administration").

If severe hepatotoxicity occurs (ALT or AST levels ≥ 20 times ULN), the drug should be discontinued permanently, 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). Abiraterone acetate should be used with caution in patients with moderate hepatic impairment and only if the therapeutic benefit outweighs the potential risks (see sections "Dosage and administration" and "Pharmacological properties"). Abiraterone acetate is contraindicated in patients with severe hepatic impairment (see sections "Dosage and administration", "Contraindications" and "Pharmacological properties").

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 closely monitored for signs and symptoms of adrenal insufficiency following withdrawal of prednisone or prednisolone. If abiraterone acetate treatment is continued after corticosteroid withdrawal, patients should be monitored for mineralocorticoid excess.

If a patient experiences a severe stress event, increased doses of prednisone or prednisolone may be indicated during and after the stress event.

Bone mineral density.

In men with metastatic prostate cancer (castration-resistant prostate cancer), bone mineral density may decrease. 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 who have previously received ketoconazole.

Hyperglycaemia.

Glucocorticoid use 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 a history of diabetes 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 acetate with cytotoxic chemotherapy have not been established (see section "Pharmacological properties").

Potential risks.

In men with metastatic castration-resistant prostate cancer, including those receiving abiraterone acetate therapy, 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 typically 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 the risk of myopathy/rhabdomyolysis.

Interactions with other medicinal products.

Concomitant use of abiraterone acetate with strong CYP3A4 inducers should be avoided, unless no alternative therapy 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.

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

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

Intolerance to excipients.

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

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

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 potentially fertile.

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 intercourse with a woman of reproductive potential, a condom should be used in combination with other effective contraceptive methods. 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 are potentially fertile (see section "Contraindications").

Breastfeeding.

Abiraterone acetate should not be administered to women.

Fertility.

Abiraterone has shown effects on fertility in animal studies, but this effect was reversible.

Effects on ability to drive and use machines.

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

Method of Administration and Dosage

This medicinal product must be prescribed by a qualified medical specialist.

The tablet should be taken on an empty stomach (at least 2 hours after food, and food should be avoided for at least 1 hour after administration of the drug). 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, which must not be taken with food. Administration of the drug with food increases systemic exposure to abiraterone.

Prednisone or Prednisolone Dosing

For the 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 the treatment of metastatic castration-resistant prostate cancer is 10 mg daily.

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

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 Warnings and Precautions").

Patients with a history of hypokalemia or those who develop hypokalemia during treatment should maintain potassium levels ≥ 4 mmol/L.

Treatment should be discontinued in patients who develop toxicity of ≥ grade 3, including hypertension, hypokalemia, edema, and mineralocorticoid excess, and appropriate therapeutic measures should be initiated. Treatment with the drug may be resumed only after toxicity symptoms have resolved to grade 1 or baseline.

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

Hepatotoxicity

Treatment should be immediately interrupted until liver function normalizes in patients who develop hepatotoxicity (ALT or AST > 5 times the upper limit of normal) during treatment (see section "Special Warnings and Precautions"). Resumption of treatment may be considered after normalization of liver function tests, starting with 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 permanently discontinued.

If severe hepatotoxicity (ALT or AST > 20 times the upper limit of normal) occurs during treatment, abiraterone therapy should be 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 abiraterone acetate in patients with moderate hepatic impairment should be carefully considered, with the benefit of treatment clearly outweighing the potential risk (see sections "Method of Administration and Dosage" and "Pharmacological Properties"). Abiraterone acetate must not be used in patients with severe hepatic impairment (see sections "Method of Administration and Dosage", "Contraindications", and "Pharmacological Properties").

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 (see section "Special Warnings and Precautions").

Children

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

Adverse reactions

The most commonly observed adverse reactions during abiraterone treatment were peripheral edema, hypokalemia, 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 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 acetate compared to those receiving placebo: hypokalemia (18% vs. 8%), 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, 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 administration of corticosteroids reduces the frequency and severity of these adverse reactions (see section "Special precautions").

In clinical studies 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 in the post-marketing period with abiraterone acetate are listed in the table below, categorized by frequency: 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 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 warnings and 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 levels of alanine aminotransferase (ALT) and/or increased levels of 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 elevated ALT, elevated AST, and hepatic function abnormalities.

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

Most cases of arterial hypertension and hypokalemia 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. Hypokalemia 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 trials excluded patients with uncontrolled hypertension, clinically significant cardiac disease such as myocardial infarction, arterial thrombotic events within the previous 6 months, severe or unstable angina, NYHA Class III or IV heart failure (in trials involving chemotherapy-pretreated patients) or NYHA Class II to IV heart failure (in trials involving chemotherapy-naïve patients), and left ventricular ejection fraction <50%. All patients enrolled in the trials (those receiving abiraterone and those receiving placebo) concurrently received androgen-lowering therapy with LHRH 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 levels have been reported in patients receiving abiraterone acetate. Phase III clinical trials showed that Grade III and IV hepatotoxicity (elevated AST and ALT >5 times the upper limit of normal and bilirubin >1.5 times the upper limit of normal) occurred in approximately 6% of patients receiving abiraterone, typically 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 compared to those with normal baseline ALT and AST. Treatment with abiraterone was interrupted or discontinued in cases of ALT or AST elevations >5 times the upper limit of normal or total bilirubin elevations >3 times the upper limit of normal. 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 the upper limit of normal, and bilirubin increased 2–6 times the upper limit of normal during treatment.

After discontinuation of treatment, liver tests normalized 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 reported.

In clinical trials, the risk of hepatotoxicity was minimized by excluding patients with hepatitis or significant abnormalities in liver tests prior to treatment initiation. Study 3011 excluded patients with baseline ALT and AST levels >2.5 times the upper limit of normal, bilirubin >1.5 times the upper limit of normal, 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 the upper limit of normal in the absence of liver metastases and >5 times the upper limit of normal in the presence of liver metastases. Study 302 excluded patients with liver metastases and those with baseline ALT and AST levels >2.5 times the upper limit of normal. Liver 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. Re-treatment was not permitted in patients with ALT or AST elevations >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 suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25°C in the original packaging.

Keep out of reach of children.

Packaging.

120 tablets in a bottle.

Prescription status.

Prescription only.

Manufacturer.

Amneal Pharmaceuticals Private Limited.

Manufacturer's address and location of its business operations.

Survey No. 634, 637 to 641, Near Kanakavati Hotel, Sarkhej-Bavla Highway, Village Rajoda, Taluka Bavla, Ahmedabad, Gujarat 382220, India (IN).