Abiraterone-vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABIRATERONE-VISTA (ABIRATERONE-VISTA)

Composition:

Active substance: abiraterone acetate;

1 tablet contains 500 mg of abiraterone acetate;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, hypromellose (E 464), sodium lauryl sulfate, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: polyvinyl alcohol (E 1203), titanium dioxide (E 171), macrogol (E 1521), talc (E 553b), iron oxide red (E 172), iron oxide black (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated tablets, purple in colour, oval-shaped, approximately 19 mm in length and 11 mm in width, with "A7TN" engraved on one side and "500" on the other.

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 L02BX03.

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 testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes the conversion of pregnenolone and progesterone to precursors of testosterone, DHEA and androstenedione, respectively, through 17α-hydroxylation and cleavage of the C17,20 bond. 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 treatments that reduce androgen levels. However, therapies aimed at reducing androgen levels, including 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 tissue. Treatment with abiraterone reduces serum testosterone levels to undetectable levels when used concomitantly with LHRH agonists (or following orchiectomy).

Abiraterone-Vista 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 in patients who had previously failed taxane-based chemotherapy, 38% of patients receiving abiraterone acetate, compared to 10% receiving placebo, experienced a reduction in PSA levels by at least 50% 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 inhibitor of androgen biosynthesis.

Absorption

Following oral administration of abiraterone acetate in the fasting state, 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 systemic exposure to abiraterone, depending on the fat content of the meal. Therefore, taking Abiraterone-Vista with food may potentially lead to variable systemic exposure to the drug. Hence, Abiraterone-Vista must not be taken with food. Abiraterone-Vista should be administered at least 1 hour before or 2 hours after eating. The tablets should be swallowed whole and taken with sufficient fluid.

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.

Metabolism.

Following oral administration of 14C-abiraterone acetate in capsule form, abiraterone acetate is hydrolyzed to abiraterone, which is further 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 detectable metabolites, two major metabolites—abiraterone sulfate and N-oxide abiraterone sulfate—account for approximately 43% of total radioactivity each.

Elimination.

The mean elimination half-life of abiraterone in plasma is approximately 15 hours, based on data 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 (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 1 g 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, systemic exposure (AUC) to abiraterone increased by 600% and the fraction of unbound active substance increased by 80% in patients with severe hepatic impairment. Dose adjustment is not required in patients with mild hepatic impairment. Abiraterone-Vista 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-Vista is contraindicated 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 undergoing hemodialysis. Therefore, no dose adjustment is necessary when administering the drug to patients with renal impairment, including severe renal impairment. However, Abiraterone-Vista should be prescribed with caution to patients with prostate cancer and severe renal impairment, as clinical data on the use of abiraterone acetate in such patients are limited.

Clinical characteristics.

Indications.

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

• newly diagnosed metastatic hormone-sensitive prostate cancer of high risk in adult men in combination with androgen deprivation therapy;
• metastatic castration-resistant prostate cancer with asymptomatic or mild disease in adult men after inadequate response to androgen blockade 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.
• Abiraterone-Vista 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 "Pharmacological properties").
• Abiraterone-Vista in combination with prednisone or prednisolone is contraindicated in combination with Ra-223.

Special 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 medicinal product.

Interaction with other medicinal products and other types of interactions.

Effect of food on abiraterone acetate.

Administration of Abiraterone-Vista with food significantly increases the absorption of abiraterone acetate. The efficacy and safety of administering the medicinal product with food have not been established; therefore, Abiraterone-Vista must not be administered with food.

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, 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 conducted to determine 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 for 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, consideration should be given to reducing the dose of any medicinal product metabolized by CYP2D6 that has a narrow therapeutic index. 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 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, patients should be closely monitored for signs of toxicity when co-administering substrates of CYP2C8 with a narrow therapeutic index. Examples of medicinal products metabolized by CYP2C8 include pioglitazone and repaglinide (see section "Special precautions").

The main metabolites of abiraterone – abiraterone sulfate and N-oxide abiraterone sulfate – demonstrated inhibition of the OATP1B1 transporter in vitro. 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 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 medicinal products.

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.

Treatment with abiraterone and prednisone or prednisolone in combination with Ra-223 is contraindicated due to an increased risk of fractures and a trend towards increased mortality in patients with prostate cancer who are asymptomatic or have mild disease. It is recommended that subsequent treatment with Ra-223 should not be initiated within at least 5 days after the last dose of abiraterone acetate in combination with prednisone or prednisolone.

Special precautions for use.

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

Abiraterone acetate may cause hypertension, hypokalaemia and fluid retention as a result of increased mineralocorticoid levels due to inhibition of CYP17. Concomitant use of corticosteroids suppresses adrenocorticotropic hormone (ACTH) activity, thereby reducing the frequency and severity of these adverse effects. Abiraterone should be used with caution when treating patients in whom exacerbation of the underlying condition may manifest as increased blood pressure, hypokalaemia (in patients receiving cardiac glycosides) or fluid retention, for example, in patients with heart failure, severe or unstable angina, recent myocardial infarction or ventricular arrhythmia, and in patients with severe renal impairment.

Abiraterone-Vista 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, as evidenced by myocardial infarction or arterial thrombotic events within the previous 6 months, severe or unstable angina, heart failure NYHA class III or IV (trial in patients previously treated with chemotherapy) or heart failure NYHA class II to IV (trial in patients with newly diagnosed prostate cancer or for whom chemotherapy was clinically not indicated), and left ventricular ejection fraction < 50%. In trials involving patients with newly diagnosed prostate cancer or for whom chemotherapy was clinically not indicated, patients with atrial fibrillation and other cardiac arrhythmias requiring medical intervention were excluded. The safety of abiraterone acetate use in patients with left ventricular ejection fraction < 50% or heart failure NYHA class III or IV (trial in patients previously treated with chemotherapy) or heart failure NYHA class II to IV (trial in patients with newly diagnosed prostate cancer or for whom chemotherapy was clinically not indicated) has not been established (see section "Adverse reactions"). Prior to initiating treatment in patients at significant risk of congestive heart failure (e.g., heart failure, uncontrolled hypertension or 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 initiating abiraterone. Hypertension, hypokalaemia and fluid retention must be monitored. Blood pressure, potassium levels, fluid retention (weight gain, peripheral oedema) and other signs of congestive heart failure should be monitored every 2 weeks during the first 3 months of treatment and monthly thereafter, with any abnormalities corrected. In patients who developed hypokalaemia during treatment with abiraterone acetate, QT interval prolongation has been observed. Appropriate therapy should be initiated in case of clinically significant cardiac function abnormalities, and discontinuation of abiraterone should be considered if necessary.

Hepatotoxicity and hepatic failure.

During clinical trials, cases of elevated liver enzymes were reported, leading to discontinuation or dose adjustment of abiraterone. Serum transaminase levels should be monitored prior to initiating treatment, every 2 weeks during the first 3 months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminase levels should be determined immediately. If ALT or AST levels exceed 5 times the upper limit of normal, treatment with this medicinal product should be discontinued immediately and liver function should be carefully evaluated. Treatment may be resumed with a reduced dose of abiraterone only if liver function normalises to baseline levels. The medicinal product should be discontinued in cases of severe hepatotoxicity (ALT or AST levels 20 times the upper limit of normal), and abiraterone should be avoided thereafter. Patients with active viral hepatitis were not included in clinical trials with abiraterone acetate; therefore, there are no data on the use of the medicinal product 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 should be used with caution in patients with moderate hepatic impairment and only if the benefit of treatment clearly outweighs the potential risks. Abiraterone-Vista should not be used in patients with severe hepatic impairment. In the post-marketing period, rare cases of acute liver failure and fulminant hepatitis, some of which were fatal, have been reported (see section "Adverse reactions").

Withdrawal of corticosteroids and stress situations.

When discontinuing prednisone or prednisolone, patients should be closely monitored for signs of adrenal insufficiency. If abiraterone is continued after corticosteroid withdrawal, patients should be monitored for signs of 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), a decrease in bone mineral density may occur. The use of Abiraterone-Vista in combination with glucocorticosteroids may exacerbate this effect.

Prior use of ketoconazole.

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

Hyperglycaemia.

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

Hypoglycaemia.

Cases of hypoglycaemia have been reported when abiraterone was used concomitantly with prednisone/prednisolone in patients at risk of developing diabetes mellitus who were receiving pioglitazone or repaglinide (see section "Interaction with other medicinal products and other forms of interaction"); therefore, blood glucose levels should be monitored in diabetic patients.

Use with chemotherapy.

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

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 acetate. Most cases occurred within the first 6 months of treatment and resolved after discontinuation of abiraterone acetate. Caution should be exercised when administering abiraterone to patients receiving concomitant medicinal products associated with the development of myopathy/rhabdomyolysis.

Interactions with other medicinal products.

Concomitant use of Abiraterone-Vista with strong inducers of CYP3A4 should be avoided, except when 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. Initiation of subsequent Ra-223 treatment less than 5 days after the last dose of abiraterone in combination with prednisone/prednisolone is not recommended.

Important information on excipients.

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

The medicinal product contains more than 1 mmol of sodium in one dose (2 tablets), which should be taken into account 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-Vista in pregnant women. This medicinal product is contraindicated in women who are potentially capable of becoming pregnant.

Pregnancy.

The medicinal product Abiraterone-Vista is not indicated for use in women. Abiraterone acetate is contraindicated in pregnant women and in women who are potentially capable of becoming 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 other effective contraceptive methods. Animal studies have demonstrated reproductive toxicity.

Lactation.

The medicinal product Abiraterone-Vista should not be administered to women.

Fertility.

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

Ability to influence the speed of reactions when driving or operating machinery.

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

Method of Administration and Dosage.

Method of Administration.

The medicinal product should be taken on an empty stomach (at least 2 hours after food, and food should be avoided for 1 hour after administration of abiraterone). The tablet should be swallowed whole, without chewing or crushing. It is recommended to take with water. The recommended dose of abiraterone is 1000 mg (2 tablets of 500 mg) as a single daily dose. Administration of the medicinal product with food increases systemic exposure to abiraterone.

Dosage of prednisone or prednisolone.

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

The recommended dose of prednisone or prednisolone 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 abiraterone.

Prior to initiating abiraterone therapy, serum transaminase levels should be assessed and monitored every 2 weeks for the first 3 months of treatment, and thereafter 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.

Patients with a history of hypokalemia or who develop hypokalemia during treatment with Abiraterone-Vista should have potassium levels maintained ≥ 4 mM. Treatment should be discontinued in patients who develop grade 3 toxicity, including hypertension, hypokalemia, edema, and non-mineralocorticoid toxicity, and appropriate therapeutic measures should be taken. Abiraterone treatment may be resumed only after toxicity symptoms have resolved to grade 1 or less.

If a daily dose of both Abiraterone-Vista 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 normalization of liver function in patients who develop hepatotoxicity during treatment (ALT or AST levels exceeding the upper limit of normal by more than 5 times). Treatment may be resumed after normalization of liver function at a reduced dose of abiraterone – 500 mg (1 tablet) 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 signs of hepatotoxicity reappear while taking the reduced dose of 500 mg daily, treatment should be discontinued.

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

Hepatic Impairment.

No dose adjustment is 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 times. 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 classes B or C). Dose adjustment cannot be predicted. The use of the medicinal product in patients with moderate hepatic impairment should be carefully considered, and the benefits of treatment should clearly outweigh the potential risks. Abiraterone-Vista 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 medicinal product in patients with prostate cancer and severe renal impairment. Caution should be exercised when administering abiraterone to this patient population.

Children.

The medicinal product is not intended for use in children.

Overdose.

Symptoms. Experience with abiraterone overdose is limited.

Treatment. There is no specific antidote. In case of overdose, abiraterone administration 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

In a pooled analysis of adverse reactions observed during phase III clinical trials with abiraterone at a frequency ≥ 10%, the following were reported: peripheral edema, hypokalemia, arterial hypertension, urinary tract infections, and increased levels of alanine aminotransferase and/or aspartate aminotransferase. Other important adverse reactions include cardiac disorders, hepatotoxicity, bone fractures, and allergic alveolitis. Abiraterone may cause arterial hypertension, hypokalemia, and fluid retention as a pharmacodynamic consequence of its mechanism of action. During clinical trials, mineralocorticoid-related adverse reactions were more frequently observed in patients receiving abiraterone 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 treatment, grade III and IV hypokalemia according to the CTCAE (Common Terminology Criteria for Adverse Events) toxicity scale were observed in 6% and 2% of patients, respectively; arterial hypertension in 8% vs. 5% of patients, respectively; and fluid retention (peripheral edema) in 1% vs. 1% of patients, respectively. Mineralocorticoid-related effects can generally be managed successfully with concomitant medical therapy. Concomitant use of corticosteroids reduces the frequency and severity of these adverse reactions (see section "Special 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 indication).

Adverse reactions observed during clinical trials and in the post-marketing period with abiraterone are listed in Table 1 by frequency categories: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); and not known (frequency cannot be estimated from the 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, except pathological fractures.

a Spontaneously reported post-marketing data.

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

Grade III adverse reactions according to CTCAE scale observed in patients receiving abiraterone: hypokalaemia (5%); urinary tract infections (2%), increased alanine aminotransferase and/or aspartate aminotransferase levels (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 alanine aminotransferase and/or aspartate aminotransferase 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 occurred in 20.4% of patients in the hormone-sensitive population (study 3011) compared to 19.2% and 14.9% in studies 301 and 302, respectively.

Description of selected adverse reactions.

Cardiovascular adverse reactions.

Patients with uncontrolled arterial hypertension, clinically significant cardiac 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 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% were excluded from the Phase III studies. 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 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 (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; among them, two patients had Grade II hepatotoxicity, six had Grade III hepatotoxicity, and two 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 values. Treatment with abiraterone was interrupted or discontinued in case of ALT or AST elevations >5 times ULN or total bilirubin elevation >3 times ULN. Two cases of marked increases in liver function test parameters 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, normalization of liver tests was observed 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. Elevations in aminotransferases resolved in all but three patients (two with new multiple liver metastases and one 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 initiation. Patients with baseline ALT and AST levels exceeding 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 were excluded from study 3011. Patients with baseline ALT and AST levels exceeding 2.5 times ULN in the absence of liver metastases or 5 times ULN in the presence of liver metastases were excluded from study 301. Patients with liver metastases and baseline ALT and AST levels exceeding 2.5 times ULN were excluded from study 302. Elevations in liver function tests among 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 >20 times ULN. The safety of re-treatment in such patients is unknown. The mechanism of hepatotoxicity has not been established.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as 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.

No special storage conditions are required for this medicinal product. Keep out of reach of children.

Packaging. 60 tablets in a plastic container, 1 container in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Sandoz España, S.L.

Manufacturer's address and location of its business operations.

Calle C/ Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.