Abiraterone-vista

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

Composition:

Active substance: abiraterone acetate;

1 tablet contains 250 mg of abiraterone acetate;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, oval tablets. One side of the tablet is marked with "ATN", the other side with "250".

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Agents used for 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 prostate tumor tissues. CYP17 catalyzes the conversion of pregnenolone and progesterone to precursors of testosterone, DHEA and androstenedione, respectively, through 17α-hydroxylation and C17,20 bond cleavage. Inhibition of CYP17 also leads to increased production of mineralocorticoids by the adrenal glands (see section "Special warnings and precautions for use"). Androgen-sensitive prostate cancer responds to treatments that lower androgen levels. However, therapies aimed at reducing androgen levels, such as the use of luteinizing hormone-releasing hormone (LHRH) agonists or orchiectomy, reduce androgen production in the testes but do not affect androgen production by the adrenal glands or tumor tissue. Treatment with abiraterone 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 effectively 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, 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.
After oral administration of abiraterone acetate in the fasted state, maximum plasma concentration is reached within 2 hours. Administration of abiraterone acetate with food, compared to administration in the fasted 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 acetate with food may potentially lead to variable systemic exposure to the drug. Hence, Abiraterone-Vista must not be taken with food. The medicinal product 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 of abiraterone into peripheral tissues.

Biological transformation.
Following oral administration of 14C-abiraterone acetate in capsule form, abiraterone acetate is hydrolyzed to abiraterone, which is 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 detectable metabolites, 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 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 1000 mg oral dose increased by approximately 11% and 260% in patients with mild or moderate hepatic impairment, respectively. The mean elimination half-life of abiraterone was prolonged to approximately 18 hours in patients with mild hepatic impairment and to approximately 19 hours in those with moderate hepatic impairment. In another study, the pharmacokinetics of abiraterone were evaluated in 8 patients with severe hepatic impairment (Child-Pugh class C) and 8 healthy volunteers with normal liver function. Compared to healthy volunteers, systemic exposure (AUC) to abiraterone increased by 600% in patients with severe hepatic impairment, and the fraction of unbound active substance increased by 80%. No dose adjustment is required in patients with mild hepatic impairment. Abiraterone-Vista should be used with caution in patients with moderate hepatic impairment and only if the benefit of treatment clearly outweighs the potential risks (see sections "Dosage and administration" and "Special warnings and precautions for use"). The medicinal product must not be used in patients with severe hepatic impairment (see sections "Dos游戏副本 and administration", "Contraindications", and "Special warnings and precautions for use"). Patients who develop hepatotoxicity during treatment with Abiraterone-Vista 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 of patients with normal renal function. Systemic exposure to abiraterone after a single 1000 mg oral dose was not increased in patients with end-stage renal disease undergoing hemodialysis. No dose reduction is required when administering Abiraterone-Vista 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-Vista in this patient population are limited.

Clinical characteristics.

Indications.

Abiraterone-Vista medicinal product 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 blockade 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-Vista is contraindicated in pregnant women and women of childbearing potential.
• Severe hepatic impairment (Child-Pugh class C) (see sections "Method of administration and dosage", "Special precautions", and "Pharmacological properties").
• Abiraterone-Vista 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 childbearing potential must 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 taken with food (see sections "Method of administration and dosage" 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 decreased 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 dextromethorphan, a CYP2D6 substrate, 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, consideration should be given to reducing the dose of any medicinal product metabolized by CYP2D6 and having a narrow therapeutic index. Such medicinal products include, in particular: metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone, tramadol (the last three require CYP2D6 for the formation of active analgesic metabolites).

In a CYP2C8 drug interaction study in healthy volunteers, coadministration of pioglitazone with a single 1000 mg dose of abiraterone acetate increased the AUC of pioglitazone by 46%, while the AUC of each of the active metabolites of pioglitazone, M-III and M-IV, decreased by 10%. Although these results suggest no clinically significant increase in systemic exposure of drugs primarily metabolized by CYP2C8 when coadministered with abiraterone acetate, patients should be closely monitored for signs of toxicity when coadministering substrates of CYP2C8 with a narrow therapeutic index. The main metabolites of abiraterone—abiraterone sulfate and N-oxide abiraterone sulfate—have demonstrated in vitro 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 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 (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 "Adverse reactions") as a result of increased mineralocorticoid levels due to CYP17 inhibition. Concomitant corticosteroid use 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 disease progression may manifest as elevated blood pressure, hypokalaemia (while taking 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-Vista should be used with caution in patients with a history of cardiovascular disease. Phase III clinical trials with Abiraterone-Vista 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 (trial in patients previously treated with chemotherapy), or heart failure from Class II to IV (trials in patients with newly diagnosed prostate cancer or for whom chemotherapy was not clinically indicated), and left ventricular ejection fraction < 50%. Patients with atrial fibrillation and other cardiac arrhythmias requiring medical intervention were excluded from trials in patients with newly diagnosed prostate cancer or for whom chemotherapy was not clinically indicated. The safety of Abiraterone-Vista 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 (trials in patients with newly diagnosed prostate cancer or for whom chemotherapy was not clinically indicated) has not been established (see section "Adverse reactions"). Prior to initiating treatment in patients at significant risk of developing congestive heart failure (e.g., those with heart failure, uncontrolled hypertension, or a history of ischaemic heart disease), cardiac function should be evaluated (e.g., by echocardiography). Heart failure should be treated and cardiac function optimised prior to initiating abiraterone therapy. Arterial hypertension, hypokalaemia and fluid retention must be monitored. During treatment, blood pressure, potassium levels, fluid retention (weight gain, peripheral oedema), and other signs of congestive heart failure should be assessed every 2 weeks for the first 3 months and monthly thereafter, and any abnormalities should be corrected. Hypokalaemia observed during treatment with Abiraterone-Vista has been associated with QT interval prolongation. In cases of clinically significant cardiac dysfunction, appropriate therapy should be initiated and discontinuation of abiraterone should be considered if necessary (see section "Dosage and administration").

Hepatotoxicity and hepatic failure.

Clinically significant elevations in liver enzymes requiring dose modification or discontinuation of treatment have been reported during clinical trials (see section "Adverse reactions"). Serum transaminase levels should be monitored prior to initiating treatment, every 2 weeks for the first 3 months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should be measured immediately. If ALT or AST levels exceed 5 times the upper limit of normal (ULN), treatment with this medicinal product should be discontinued immediately and liver function should be closely monitored. Treatment with a reduced dose of abiraterone may be resumed only if liver function returns to baseline levels (see section "Dosage and administration").

In cases of severe hepatotoxicity (ALT or AST levels exceeding 20 times ULN), the drug should be discontinued permanently, and abiraterone should be avoided thereafter. Patients with active viral hepatitis were not included in clinical trials; therefore, there are no data on the use of this 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 (see sections "Dosage and administration" and "Pharmacological properties"). Abiraterone-Vista should not be used 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 of adrenal insufficiency following discontinuation of prednisone or prednisolone. If abiraterone treatment continues after corticosteroid withdrawal, patients should be monitored for signs of mineralocorticoid excess.

If a patient experiences a major 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-Vista in combination with glucocorticoids may exacerbate this effect.

Prior use of ketoconazole.

Reduced sensitivity to Abiraterone-Vista may be expected in patients previously treated with 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 with abiraterone in combination with prednisone/prednisolone in diabetic patients 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 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. In some patients, rhabdomyolysis led to renal failure. These events mostly occurred within the first 6 months of treatment and resolved after discontinuation of abiraterone acetate. Caution should be exercised when co-administering Abiraterone-Vista with medicinal products associated with myopathy/rhabdomyolysis.

Interactions with other medicinal products.

Concomitant use of Abiraterone-Vista with strong CYP3A4 inducers 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.

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 clinical trials in asymptomatic or mildly symptomatic patients with prostate cancer.

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

Important information on excipients.

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

The medicinal 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 childbearing potential. There are no data on the use of Abiraterone-Vista in pregnant women. This medicinal product is contraindicated in women who are or may become pregnant.

Pregnancy. Abiraterone-Vista is not indicated for use in women. Abiraterone acetate is contraindicated in pregnant women and women who 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 sexual intercourse with a pregnant woman. If the patient is sexually active with a woman of childbearing potential, a condom should be used in combination with other effective contraceptive methods. Animal studies have demonstrated reproductive toxicity.

Lactation. Abiraterone-Vista should not be administered to women.

Fertility. Abiraterone has been shown to affect fertility in animals, but this effect was reversible.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

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

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

The recommended dose of abiraterone is 1000 mg (4 tablets of 250 mg) as a single daily dose.

Administration of the medicinal product with food increases systemic exposure to abiraterone. The medicinal product should be administered in combination with prednisone or prednisolone. 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 then monitored every 2 weeks for the first 3 months of treatment, and monthly thereafter. 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 monthly thereafter (see section "Special Warnings and Precautions for Use"). In patients with a history of hypokalemia or who develop hypokalemia during treatment with Abiraterone-Vista, potassium levels should be maintained ≥ 4 mM. Treatment should be discontinued in patients who develop toxicity ≥ grade 3, including hypertension, hypokalemia, edema, and mineralocorticoid excess toxicity, and appropriate therapeutic measures should be taken. Abiraterone treatment may be resumed only after toxicity symptoms have resolved to grade 1 or baseline.

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 liver function normalizes in patients who develop hepatotoxicity during treatment (ALT or AST levels exceeding 5 times the upper limit of normal) (see section "Special Warnings and Precautions for Use"). Treatment may be resumed after normalization of liver function tests at a reduced dose of the medicinal product – 500 mg (2 tablets) once daily. In such patients, serum transaminase levels should be monitored for 3 months after resuming treatment and monthly thereafter. If hepatotoxicity recurs while receiving 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 discontinued and not resumed.

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-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-Vista in patients with moderate hepatic impairment should be carefully considered: the benefit of treatment should clearly outweigh the potential risk. 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 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, those occurring at a frequency ≥ 10% included peripheral edema, hypokalemia, 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 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%, hypertension 22% vs 16%, and fluid retention (peripheral edema) 23% vs 17%, respectively. In patients receiving abiraterone treatment, grade III–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 effectively managed with medical therapy. Concomitant administration of corticosteroids reduces the frequency and severity of these adverse reactions (see section "Special precautions"). In clinical trials involving patients with metastatic prostate cancer who were receiving a GnRH analogue or had undergone orchiectomy, abiraterone 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 the use of 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 unknown (frequency cannot be determined from available data).

Within each frequency category, adverse reactions are listed in order of decreasing clinical 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, and hepatic function disorders.

Grade III adverse reactions according to the CTCAE scale observed in patients receiving abiraterone: hypokalaemia (5%); urinary tract infections (2%); increased ALT and/or AST levels (4%); arterial hypertension (6%); fractures (2%); peripheral oedema, heart failure, atrial fibrillation (1%). Grade III adverse reactions according to the CTCAE scale such as hypertriglyceridaemia and angina pectoris were observed in <1% of patients. Grade IV adverse reactions according to the CTCAE scale such as urinary tract infections, increased 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 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%. All patients enrolled in the studies (those receiving abiraterone and those receiving placebo) received concomitant androgen-deprivation 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 the Phase III studies among 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 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 treated with 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-Vista. Abiraterone was discontinued in 10 patients due to hepatotoxicity; 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 ALT or AST levels prior to treatment compared to patients with normal ALT and AST levels before treatment initiation. Treatment with abiraterone was suspended or discontinued when ALT or AST levels increased more than 5 times the upper limit of normal or total bilirubin increased more than 3 times the upper limit of normal. In two cases, significant elevations in liver function tests occurred. In these patients, who had normal liver function before treatment, ALT or AST levels increased 15–40 times above the upper limit of normal, and bilirubin levels increased 2–6 times above the upper limit of normal during treatment. After treatment discontinuation, liver function tests normalized in both patients; one patient resumed 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 reduced 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 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 were excluded from study 3011. Patients with baseline ALT and AST levels exceeding 2.5 times the upper limit of normal (in the absence of liver metastases) or more than 5 times the upper limit of normal (in the presence of liver metastases) were excluded from study 301. Patients with liver metastases and those with baseline ALT and AST levels exceeding 2.5 times the upper limit of normal were excluded from study 302. Liver function tests in patients enrolled in clinical trials were monitored and managed by treatment interruption and reinitiation only after liver test values returned to baseline levels. Re-treatment was not permitted in patients with ALT or AST levels elevated 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 established.

Reporting suspected adverse reactions.

Reporting of adverse reactions after marketing authorization of the medicinal product is important. It allows 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: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

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

Prescription status. Prescription only.

Manufacturer.

Cinfa España, S.L.

Manufacturer's address and location of its business operations.

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