Teronred

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT THERONRED (TERONRED)

Composition:

Active substance: abiraterone acetate;

1 tablet contains 250 mg of abiraterone acetate;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; povidone; sodium lauryl sulfate; colloidal anhydrous silicon dioxide; magnesium stearate; film coating Opadry White OY-58900 (composition of the film coating: hypromellose, titanium dioxide (E 171), polyethylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex, oval-shaped, film-coated tablets, white or almost white in color, with an engraving "358" on one side and the company's logo on the other side.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Agents used for hormonal therapy. Hormone antagonists and related substances. 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, dehydroepiandrosterone (DHEA), and androstenedione, respectively, via 17α-hydroxylation and cleavage of the C17,20 bond. Inhibition of CYP17 also leads to increased production of mineralocorticoids by the adrenal glands (see section "Special precautions").

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 in the adrenal glands or tumor tissue. Treatment with abiraterone acetate reduces serum testosterone levels to undetectable levels when used concomitantly with LHRH agonists (or following orchiectomy).

Pharmacodynamics.

The medicinal product reduces serum testosterone and other androgen levels more effectively than LHRH agonists or orchiectomy. This effect results from selective inhibition of CYP17, an enzyme essential for androgen biosynthesis. Prostate-specific antigen (PSA) is a biological marker in patients with prostate cancer. In a phase III clinical study involving patients who had previously failed taxane-based chemotherapy, a reduction in PSA levels by at least 50% 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 on an empty stomach, 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, relative to the average systemic exposure of abiraterone, depending on the fat content of the meal. Therefore, taking the medicinal product with food may potentially lead to variable systemic exposure. Hence, the medicinal product should not be taken with food and should be administered at least 1 hour before or 2 hours after a meal. Tablets should be swallowed whole with sufficient liquid (see section "Dosage and administration").

Distribution.

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

Biotransformation.

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

Elimination.

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

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

Dose adjustment is not required in patients with mild hepatic impairment.

The medicinal product should be used with caution in patients with moderate hepatic impairment and only if the benefits of treatment outweigh the potential risks (see sections "Dosage and administration" and "Special precautions"). Abiraterone acetate should not be used in patients with severe hepatic impairment (see sections "Dosage and administration", "Contraindications", and "Special precautions").

Patients who develop hepatotoxicity during treatment may require treatment interruption and dose adjustment (see sections "Dosage and administration" and "Special precautions").

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. Dose reduction is not required when administering the medicinal product to patients with renal impairment, including severe renal impairment. However, the medicinal product 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.

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

• metastatic castration-resistant prostate cancer (mCRPC) with asymptomatic or mildly symptomatic disease in adult men following inadequate response to androgen deprivation therapy, and for whom chemotherapy is not clinically indicated;
• metastatic castration-resistant prostate cancer (mCRPC) 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;
• Pregnancy and reproductive potential in women;
• Severe hepatic impairment (Child-Pugh class C) (see sections "Method of administration and dosage", "Special precautions", and "Pharmacokinetics").
• Theronred with prednisone or prednisolone is contraindicated in combination with Ra-223.

Interaction with other medicinal products and other forms of interaction.

Effect of food on abiraterone acetate.

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

Interaction with other medicinal products.

In a pharmacokinetic interaction study involving 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 during treatment with Theronred, except when no therapeutic alternative exists.

In a separate clinical study involving healthy volunteers, co-administration of ketoconazole, a strong CYP3A4 inhibitor, had no clinically significant effect on the pharmacokinetics of abiraterone.

Effect on other medicinal products.

Abiraterone is an inhibitor of hepatic enzymes CYP2D6 and CYP2C8, which are involved in drug metabolism. In a study evaluating the effect 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 approximately 33%.

Theronred should be used with caution in combination with medicinal products that are activated or metabolized by CYP2D6, particularly those with a narrow therapeutic index. Therefore, 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 formation of active analgesic metabolites).

In a CYP2C8 drug interaction study involving healthy volunteers, administration of pioglitazone with a single 1000 mg dose of abiraterone acetate resulted in a 46% increase in pioglitazone AUC, while AUC of each of the active metabolites of pioglitazone, M-III and M-IV, decreased by 10%. Patients should be closely monitored for signs of toxicity when concomitantly receiving substrates of CYP2C8 with a narrow therapeutic index. 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. 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, Theronred should be used with caution in combination with medicinal products that may prolong the QT interval or with medicinal products that may cause torsades de pointes ventricular tachycardia, such as Class IA antiarrhythmics (e.g., quinidine, disopyramide) or Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, antipsychotic agents, etc. (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 Theronred is not recommended.

Special precautions for use.

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

Theronred may cause arterial hypertension, hypokalemia, and fluid retention (see section "Adverse reactions") as a result of increased mineralocorticoid levels due to CYP17 inhibition. Concomitant use of corticosteroids suppresses adrenocorticotropic hormone (ACTH) activity, thereby reducing the frequency and severity of these adverse effects. The drug should be used with caution in patients in whom exacerbation of the underlying disease may manifest as elevated blood pressure, hypokalemia (in patients receiving cardiac glycosides), or fluid retention, such as in heart failure, severe or unstable angina, recent myocardial infarction, or ventricular arrhythmia, as well as in patients with severe renal impairment.

Theronred should be used with caution in patients with a history of cardiovascular disease. Phase 3 clinical trials excluded patients with uncontrolled hypertension, clinically significant heart disease including myocardial infarction or arterial thrombosis within the previous 6 months, severe or unstable angina, or heart failure classified as NYHA (New York Heart Association) functional class III or IV (in trials involving patients previously treated with chemotherapy) or heart failure classified from class II to IV (in trials involving patients with newly diagnosed prostate cancer or for whom chemotherapy was not clinically indicated), and left ventricular ejection fraction < 50%. In trials involving patients with newly diagnosed prostate cancer or for whom chemotherapy was not clinically indicated, patients with atrial fibrillation and other cardiac arrhythmias requiring medical intervention were excluded. The safety of Theronred in patients with left ventricular ejection fraction < 50% or NYHA functional class III or IV heart failure (in trials involving patients previously treated with chemotherapy) or heart failure from class II to IV (in trials involving 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 ischemic heart disease), cardiac function should be assessed (e.g., by echocardiography). Heart failure should be treated and cardiac function optimized prior to starting Theronred therapy. Arterial hypertension, hypokalemia, and fluid retention must be monitored and managed. During treatment, blood pressure, serum potassium levels, signs of fluid retention (weight gain, peripheral edema), and other manifestations of congestive heart failure should be monitored every 2 weeks for the first 3 months and monthly thereafter. Any abnormalities should be corrected. Hypokalemia observed during treatment with Theronred has been associated with QT interval prolongation. In cases of clinically significant cardiac dysfunction, appropriate therapy should be initiated and discontinuation of Theronred should be considered if necessary (see section "Dosage and administration").

Hepatotoxicity and hepatic impairment.

Clinically significant elevations in liver enzymes have been reported during clinical trials, requiring discontinuation or dose adjustment of the drug (see section "Adverse reactions"). Serum transaminase levels should be monitored before initiating Theronred 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 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels exceed 5 times the upper limit of normal (ULN), Theronred treatment should be discontinued immediately and liver function should be carefully evaluated. Treatment may be resumed with a reduced dose of Theronred only if liver function returns to baseline levels (see section "Dosage and administration").

In cases of severe hepatotoxicity (ALT or AST levels 20 times above 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). The drug 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 "Pharmacokinetics"). Theronred is contraindicated in patients with severe hepatic impairment (see sections "Dosage and administration", "Contraindications", and "Pharmacokinetics").

In the post-marketing period, rare cases of acute liver failure and fulminant hepatitis, some of which were fatal, have been reported (see section "Adverse reactions").

Withdrawal of corticosteroids and stress situations.

When corticosteroids (prednisone or prednisolone) are discontinued, patients should be closely monitored for signs of adrenal insufficiency. If Theronred is continued after corticosteroid withdrawal, patients should be monitored for signs of mineralocorticoid excess.

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

Bone density.

In men with metastatic prostate cancer (castration-resistant prostate cancer), a decrease in bone mineral density may occur. The use of Theronred in combination with glucocorticosteroids may exacerbate this effect.

Prior use of ketoconazole.

Reduced sensitivity to Theronred may be expected in patients previously treated with ketoconazole.

Hyperglycemia.

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

Hypoglycemia.

Cases of hypoglycemia have been reported when the drug was used concomitantly with prednisone/prednisolone in patients at risk of developing diabetes who were also 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 Theronred with cytotoxic chemotherapy have not been established.

Intolerance to excipients.

The medicinal product contains lactose. Patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not take Theronred. The product contains more than 1.18 mmol (or 27 mg) of sodium per 4-tablet dose, which should be taken into account by patients on a sodium-controlled diet.

Potential risks.

In men with metastatic castration-resistant prostate cancer, including those receiving Theronred, anemia and sexual dysfunction may occur.

Effect on the musculoskeletal system.

Cases of myopathy and rhabdomyolysis have been reported in patients receiving Theronred. These events usually occur within the first 6 months of treatment and resolve after discontinuation of the drug. Caution should be exercised when Theronred is used concomitantly with medicinal products associated with myopathy or rhabdomyolysis.

Interaction with other medicinal products.

Concomitant use of Theronred with strong CYP3A4 inducers should be avoided due to the risk of reduced systemic exposure to abiraterone, unless no therapeutic alternative is available (see section "Interaction with other medicinal products and other forms of interaction").

Combination of abiraterone and prednisone/prednisolone with Ra-223.

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

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

Use during pregnancy or breastfeeding.

Women of reproductive potential.

There are no data on the use of this medicinal product during pregnancy. This drug is contraindicated in women who are or may become pregnant.

Contraception in men and women.

There are no data on the presence of abiraterone or its metabolites in semen. A condom should be used during 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.

Pregnancy.

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

Lactation.

Theronred is not administered to women.

Fertility.

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

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

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

Dosage.

The recommended dose is 1000 mg (4 tablets of 250 mg) as a single daily dose. The medication must not be taken with food. Administration of the medication with food increases systemic exposure to abiraterone.

Dosing of prednisone and prednisolone.

The recommended dose of prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer in combination with the medication Teronred is 10 mg daily.

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

Prior to initiating treatment with abiraterone, serum transaminase levels should be monitored, and then every two weeks during the first three months of treatment, followed by monthly monitoring. Blood pressure, serum potassium levels, and fluid retention should be monitored monthly. Patients at high risk of congestive heart failure should be monitored every two weeks during the first three months of treatment, and then monthly (see section "Special Warnings and Precautions for Use").

Patients with a history of hypokalemia or who develop hypokalemia during treatment with Teronred should maintain potassium levels ≥ 4.0 mM.

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

If a daily dose of both Teronred 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 five times the upper limit of normal) (see section "Special Warnings and Precautions for Use"). Resumption of treatment may be considered after normalization of liver function and liver tests, at a reduced dose of 500 mg (2 tablets) once daily. In such patients, serum transaminase levels should be monitored every two weeks during the first three months of treatment and monthly thereafter. If hepatotoxicity recurs while on the reduced dose of 500 mg daily, treatment should be discontinued.

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

Hepatic impairment.

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

Moderate hepatic impairment (Child-Pugh class B) has been shown to increase systemic exposure to orally administered abiraterone at a dose of 1000 mg once daily by fourfold. 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 Teronred in patients with moderate hepatic impairment should be carefully considered, with the benefit of treatment clearly outweighing the potential risk. Teronred is contraindicated in patients with severe hepatic impairment.

Renal impairment.

Patients with renal impairment do not require dose adjustment of abiraterone. There is no clinical experience with the use of the medication in patients with prostate cancer and severe renal impairment. Caution should be exercised when administering abiraterone to this patient population.

Pediatric population.

Teronred is not intended for use in children.

Overdose.

Experience with Teronred overdose is limited. There is no specific antidote. In case of overdose, administration of the medication should be discontinued and symptomatic treatment initiated, with monitoring for arrhythmias, hypokalemia, and signs of fluid retention. Liver function should also be assessed.

Adverse reactions

In a pooled analysis of adverse reactions observed during Phase 3 studies with abiraterone, those occurring at a frequency ≥ 10% were 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 due to its mechanism of action. During clinical trials, expected mineralocorticoid-related adverse reactions were more frequently observed in patients receiving the drug 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 treatment with the medicinal product, Grade 3 and Grade 4 hypokalemia according to the CTCAE (Common Terminology Criteria for Adverse Events, version 4.0) toxicity scale was observed in 6% and 2% of patients, respectively; arterial hypertension in 8% and 5%, respectively; and fluid retention (peripheral edema) in 1% and 1% of patients, respectively. Mineralocorticoid-related reactions 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 trials, patients with metastatic prostate cancer who were receiving a GnRH analogue or had undergone orchiectomy were treated with Tharonred at a dose of 1000 mg daily in combination with low-dose prednisone or prednisolone (10 mg daily).

Adverse reactions observed during clinical trials and in the post-marketing period 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 (cannot be estimated from available data).

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

Table

Body systems	Adverse reactions
Infections and infestations	very common: urinary tract infection common: sepsis
Immune system disorders	unknown: anaphylactic reactions
Endocrine system disorders	uncommon: adrenal gland dysfunction
Metabolism and nutrition disorders	very common: hypokalemia common: hypertriglyceridemia
Cardiac disorders	common: heart failure*, angina pectoris, atrial fibrillation, tachycardia uncommon: other arrhythmias unknown: myocardial infarction, QT interval prolongation (see sections "Interaction with other medicinal products and other forms of interactions" and "Special warnings and precautions for use").
Vascular disorders	very common: arterial hypertension
Respiratory system disorders	rare: allergic alveolitis
Gastrointestinal disorders	very common: diarrhea common: dyspepsia
Hepatobiliary disorders	very common: increased levels of alanine aminotransferase and/or aspartate aminotransferaseb 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: hematuria
General disorders and administration site conditions	very common: peripheral edema
Injury, poisoning and procedural complications	common: fractures**

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

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

a Spontaneous post-marketing reports.

b Elevations in alanine aminotransferase and/or aspartate aminotransferase levels and hepatic dysfunction.

Grade 3 adverse reactions according to the CTCAE scale (version 4.0) observed in patients receiving the medicinal product: hypokalemia (5%); urinary tract infections (2%); elevations in ALT and/or AST levels (4%); arterial hypertension (6%); fractures (2%); peripheral edema (1%), heart failure (1%), atrial fibrillation (1%). Grade 3 adverse reactions according to the CTCAE scale (version 4.0), such as hypertriglyceridemia and angina pectoris, were observed in less than 1% of patients. Grade 4 adverse reactions according to the CTCAE scale (version 4.0), such as urinary tract infections, elevations in alanine aminotransferase and/or aspartate aminotransferase levels, hypokalemia, heart failure, atrial fibrillation, and fractures, were observed in less than 1% of patients.

Description of selected adverse reactions.

Cardiovascular adverse reactions.

Patients with uncontrolled arterial hypertension and clinically significant cardiac diseases, such as myocardial infarction, arterial thrombosis within the last 6 months, severe or unstable angina pectoris, heart failure of NYHA functional class II to IV (in the study involving patients previously treated with chemotherapy) or heart failure of functional class II to IV (in the study involving chemotherapy-naïve patients), and left ventricular ejection fraction < 50%, were excluded from phase III studies. All patients participating in the studies (those receiving abiraterone and those receiving placebo) concurrently received androgen deprivation therapy, primarily using GnRH analogs, which has been associated with the development of diabetes mellitus, myocardial infarction, stroke, and sudden cardiac death. The frequency of cardiovascular adverse reactions during phase III studies in patients receiving abiraterone versus those receiving placebo was as follows: atrial fibrillation – 2.6% vs. 2.0%, tachycardia – 1.9% vs. 1.0%, angina pectoris – 1.7% vs. 0.8%, heart failure – 0.7% vs. 0.2%, arrhythmia – 0.7% vs. 0.5%.

Hepatotoxicity.

Cases of hepatotoxicity with elevated levels of ALT, AST, and total bilirubin have been reported in patients receiving abiraterone acetate. Phase III clinical studies showed that grade 3 and 4 hepatotoxicity (elevations in 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 treated with abiraterone, usually within the first 3 months of treatment. In clinical trials, grade 3 or 4 hepatotoxicity was observed in 8.4% of patients receiving the medicinal product. Treatment was discontinued due to hepatotoxicity in 10 patients receiving the medicinal product; among them, 2 patients had grade 2 hepatotoxicity, 6 patients had grade 3 hepatotoxicity, and 2 patients had grade 4 hepatotoxicity, with no fatal outcomes. Hepatic function abnormalities occurred more frequently in patients with elevated baseline ALT and AST levels compared to patients with normal baseline ALT and AST values. Treatment with abiraterone was interrupted or discontinued in case of ALT or AST elevations > 5 times the upper limit of normal or total bilirubin elevation > 3 times the upper limit of normal.

Two cases of significant increases in liver function test parameters were reported. In these patients, who had normal liver function before treatment, ALT or AST levels increased 15–40 times the upper limit of normal, and bilirubin levels increased 2–6 times the upper limit of normal during treatment. After discontinuation of treatment, liver function parameters normalized in both patients; one patient was rechallenged with abiraterone without recurrence of elevated liver enzymes. During the study, grade 3–4 toxicity with elevated ALT or AST levels 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). 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 hepatic dysfunction 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 the study. Patients with baseline ALT and AST levels exceeding 2.5 times the upper limit of normal in the absence of liver metastases or exceeding 5 times the upper limit of normal in the presence of liver metastases were excluded from clinical studies. If abnormalities in liver function tests occurred during the study, treatment was interrupted and resumed only after liver enzymes returned to baseline levels. Treatment was not resumed in patients whose ALT or AST levels increased more than 20 times the upper limit of normal. The safety of reinitiating treatment in such patients has not been established. The mechanism of hepatotoxicity has not been studied.

Shelf life.

2 years.

Storage conditions.

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

Packaging.

120 tablets in a high-density polyethylene (HDPE) container with a child-resistant cap. An oxygen-absorbing packet with a warning label is placed inside the container. One container per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Dr. Reddy’s Laboratories Ltd, FTO-7.

Manufacturer’s location and address of the site of operation.

Plot No. R1-R9, Phase-III, VSE3, Duvvada, Visakhapatnam District, Andhra Pradesh, 530046, India.

To report an adverse reaction or lack of efficacy with this medicinal product, please call (24/7):
+380 44 207 51 97 or +380 50 414 39 39; or send an email to: [email protected]