Zytiga^® (Tablets) Instructions for Use

ATC Code

L02BX03 (Abiraterone)

Active Substance

Abiraterone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiandrogenic drug with antitumor activity

Pharmacotherapeutic Group

Antineoplastic hormonal preparations and hormone antagonists, hormone antagonists and related compounds, other hormone antagonists and related compounds

Pharmacological Action

Zytiga^® reduces serum testosterone and other androgen concentrations below the levels achievable with luteinizing hormone-releasing hormone (LHRH) agonist therapy or after orchiectomy. This occurs due to selective inhibition of the CYP17 enzyme, which is required for androgen biosynthesis. PSA concentration serves as a biomarker in patients with prostate cancer.

Mechanism of action

Abiraterone acetate is converted in vivo to Abiraterone, which is an inhibitor of androgen biosynthesis. In particular, Abiraterone selectively inhibits the activity of 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in and is necessary for androgen biosynthesis in the testes, adrenal glands, and prostate tumor cells. CYP17 catalyzes the conversion of pregnenolone and progesterone via 17α-hydroxylation and cleavage of the C17,20 bond into testosterone precursors: dehydroepiandrosterone and androstenedione, respectively. Inhibition of CYP17 activity is also accompanied by increased synthesis of mineralocorticoids in the adrenal glands.

Androgen-sensitive prostate cancer responds to treatment that reduces androgen concentrations. Antiandrogen therapy, such as the use of LHRH agonists or orchiectomy, reduces androgen synthesis in the testes but does not affect androgen synthesis in the adrenal glands and in the tumor. The use of Zytiga^® in combination with LHRH agonists (or orchiectomy) reduces serum testosterone levels to below the detection threshold.

Use of spironolactone

Patients who participated in the main clinical studies of Zytiga^® were not prescribed spironolactone, as its molecules bind to androgen receptors and may increase PSA levels.

Analgesic effect

The proportion of patients who experienced a palliative analgesic effect was significantly higher with the use of Zytiga^® compared to the placebo group. Furthermore, compared to patients receiving placebo, a smaller proportion of patients receiving Zytiga^® experienced progression of pain syndrome.

Risk of bone complications

Compared to the placebo group, a smaller proportion of patients receiving Zytiga^® experienced bone tissue events, which included pathological fracture, spinal cord compression, the need for palliative radiation therapy, and the need for surgical intervention.

Pharmacokinetics

The pharmacokinetics of abiraterone acetate and abiraterone have been studied in healthy volunteers, in patients with late-stage metastatic prostate cancer, and in non-oncological patients with renal or hepatic impairment. Abiraterone acetate is rapidly converted in vivo to Abiraterone, which is an inhibitor of androgen biosynthesis.

Absorption

When Zytiga^® is taken orally on an empty stomach, the time to reach C_max of abiraterone in plasma is approximately 2 hours. Taking Zytiga^® with food, compared to taking the drug on an empty stomach, leads to a 10-fold increase in AUC and a 17-fold increase in C_max of abiraterone, depending on the fat content of the food consumed. Given the normal variation in food content and composition, taking Zytiga^® simultaneously with food has the potential to cause variable systemic exposure. Therefore, Zytiga^® should not be taken with food.

Distribution

The plasma protein binding of radiolabeled ¹⁴C-abiraterone is 99.8%. The apparent V_d is approximately 5630 L, indicating that Abiraterone is extensively distributed in peripheral tissues.

Metabolism

Following oral administration of ¹⁴C-abiraterone acetate in capsules, abiraterone acetate is hydrolyzed to abiraterone, which in turn undergoes metabolism, including sulfation, hydroxylation, and oxidation, primarily in the liver. The majority of circulating ¹⁴C-abiraterone (approximately 92%) is in the form of abiraterone metabolites. Of the 15 detectable metabolites, the two main metabolites – abiraterone sulfate and N-oxide abiraterone sulfate – accounted for 43% of the total radioactivity each.

Excretion

According to studies involving healthy volunteers, the mean plasma T_1/2 of abiraterone is approximately 15 hours. Following oral administration of radiolabeled ¹⁴C-abiraterone acetate at a dose of 1 g, approximately 88% of the radioactive dose was excreted via the intestine and approximately 5% was excreted by the kidneys. The main substances detected in feces were unchanged abiraterone acetate and Abiraterone (approximately 55% and 22% of the administered dose, respectively).

Pharmacokinetics in special patient groups

Patients with hepatic impairment

The pharmacokinetics of abiraterone were studied in patients with mild and moderate hepatic impairment (Child-Pugh class A and B, respectively) and in healthy volunteers. The systemic exposure of abiraterone after a single oral dose of 1 g increased by approximately 11% in patients with mild hepatic impairment and by 260% in patients with moderate hepatic impairment. The mean T_1/2 of abiraterone increases to approximately 18 hours in patients with mild hepatic impairment and to approximately 19 hours in patients with moderate hepatic impairment. For patients with mild hepatic impairment, no dose adjustment of the drug is required. Zytiga^® should not be administered to patients with moderate or severe hepatic impairment. Patients who develop hepatotoxicity during therapy may require temporary discontinuation of the drug and dose adjustment.

Patients with renal impairment

The pharmacokinetics of abiraterone were compared in patients with end-stage renal disease receiving standard hemodialysis and in patients with normal renal function. The systemic exposure of abiraterone acetate after oral administration of a 1 g dose in patients with end-stage renal disease receiving hemodialysis was not increased. Zytiga^® should not be administered to patients with prostate cancer and severe renal impairment, as there are no clinical data on the use of Zytiga^® in such patients.

Effect on QT interval

Zytiga^® has been found to have no significant effect on the QT/QT_c interval.

Indications

• For the treatment of metastatic castration-resistant prostate cancer (in combination with prednisolone).

ICD codes

Dosage Regimen

Tablets

The recommended daily dose of Zytiga^® is 1 g (4 tablets of 250 mg) once daily, taken 1 hour before a meal or 2 hours after a meal. The tablets should be swallowed whole, without chewing, with a small amount of water.

Zytiga^® should not be taken with food. Food intake is not recommended for 1 hour after taking the drug.

Zytiga^® is prescribed in combination with low-dose prednisolone. The recommended dose of prednisolone is 10 mg/day.

Before starting treatment with Zytiga^®, serum transaminase activity and bilirubin concentration should be measured every 2 weeks for the first 3 months of treatment, and then monthly. Blood pressure, serum potassium concentration, and the degree of fluid retention should be assessed monthly.

If a daily dose of Zytiga^® and prednisolone is missed, the usual dose of the missed drug should be taken the next day.

Dose adjustment in patients with hepatic impairment

Dose adjustment in patients with mild hepatic impairment is not required. There are no data on the efficacy and safety of repeated use of abiraterone acetate in patients with moderate or severe hepatic impairment (Child-Pugh class B or C), so the necessary dose adjustment cannot be predicted. Zytiga^® should not be administered to patients with moderate or severe hepatic impairment.

If signs of hepatotoxicity develop in patients during treatment with the drug (increase in ALT or AST activity to more than 5 times the upper limit of normal (ULN) or bilirubin concentration to more than 3 times ULN), therapy should be discontinued immediately until liver function parameters return to normal.

Retreatment in patients after normalization of liver function parameters can be started at a reduced dose – 500 mg (2 tablets) once daily. In this case, monitoring of serum transaminase activity and bilirubin concentration should be performed at least every 2 weeks for 3 months, and then monthly. If signs of hepatotoxicity occur while taking the drug at a dose of 500 mg, therapy with Zytiga^® should be discontinued.

If patients develop severe hepatotoxicity (ALT or AST activity exceeding 20 times ULN) at any time during therapy, Zytiga^® should be discontinued, and re-administration of the drug in such patients is not possible.

Special patient groups

For patients with mild hepatic impairment (Child-Pugh class A) before starting treatment, no dose adjustment is required. Zytiga^® should not be administered to patients with moderate or severe hepatic impairment (Child-Pugh class B and C).

For patients with renal impairment, no dose adjustment is required. However, Zytiga^® should not be administered to patients with prostate cancer and severe renal impairment, as there are no clinical data on the use of Zytiga^® in such patients.

The use of Zytiga^® is not relevant for children, as this age category does not develop prostate cancer.

Adverse Reactions

The most frequent adverse events during treatment with Zytiga^® are peripheral edema, hypokalemia, increased blood pressure, urinary tract infections, hematuria, increased AST activity, increased ALT activity, dyspepsia, fractures.

Adverse reactions are systematized by organ system using the following frequency classification: 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), including isolated cases.

Infections and infestations: very common – urinary tract infections; common – sepsis.

Endocrine disorders: uncommon – adrenal insufficiency.

Investigations: very common – hypokalemia; common – hypertriglyceridemia, increased ALT, increased AST.

Musculoskeletal and connective tissue disorders: common – fractures (excluding pathological fractures); uncommon – rhabdomyolysis, myopathy.

Renal and urinary disorders: common – hematuria.

Cardiac disorders: very common – increased blood pressure; common – cardiac failure, including acute cardiac failure, left ventricular failure, decreased left ventricular ejection fraction; angina pectoris, arrhythmia, atrial fibrillation, tachycardia; frequency unknown – myocardial infarction.

Respiratory, thoracic and mediastinal disorders: rare – allergic alveolitis.

Gastrointestinal disorders: very common – diarrhea; common – dyspepsia.

Hepatobiliary disorders: rare – fulminant hepatitis, acute hepatic failure.

Skin and subcutaneous tissue disorders: common – skin rash.

General disorders and administration site conditions: very common – peripheral edema.

Contraindications

• Moderate and severe hepatic impairment;
• Severe renal impairment;
• Childhood and adolescence under 18 years of age;
• Hypersensitivity to abiraterone acetate or any excipient of the drug.

With caution

• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• When treating patients whose condition may worsen with increased blood pressure or the development of hypokalemia, for example, patients with heart failure, recent myocardial infarction, or ventricular arrhythmia; left ventricular ejection fraction less than 50%, NYHA class III-IV heart failure, severe or unstable angina.

Use in Pregnancy and Lactation

Zytiga^® is not used in women. There are no data on the use of Zytiga^® in pregnant women. Zytiga^® is contraindicated in pregnant women and women capable of becoming pregnant. It is not known whether abiraterone acetate or its metabolites are excreted in breast milk.

Women of childbearing potential

Zytiga^® is not intended for use in women. It is assumed that the use of CYP17 inhibitors by pregnant women will alter hormone concentrations, which may affect fetal development. To prevent accidental exposure, pregnant women or women capable of becoming pregnant should not handle the drug without gloves.

Contraception in men and women

It is not known whether Abiraterone or its metabolites are present in semen. A condom must be used if sexual intercourse with a pregnant woman is planned. If sexual intercourse is planned with a woman of childbearing potential, a condom must be used along with other effective methods of contraception.

Fertility

No studies on the toxic effects of abiraterone acetate on the reproductive system have been conducted, and there are no data on the effect of the drug on fertility.

Use in Hepatic Impairment

Zytiga^® should not be administered to patients with moderate or severe hepatic impairment (Child-Pugh class B and C).

Use in Renal Impairment

Zytiga^® should not be administered to patients with prostate cancer and severe renal impairment, as there are no clinical data on the use of Zytiga^® in such patients.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

The use of Zytiga^® is not relevant for children and adolescents, as this age category does not develop prostate cancer.

Special Precautions

Taking Zytiga^® simultaneously with food significantly increases the absorption of abiraterone. The efficacy and safety of Zytiga^® taken with food have not been established. Zytiga^® should not be taken simultaneously with food.

Increased blood pressure, hypokalemia, fluid retention, and heart failure due to mineralocorticoid excess

Zytiga^® may cause increased blood pressure, hypokalemia, and fluid retention due to increased mineralocorticoid concentrations resulting from CYP17 enzyme inhibition. The administration of corticosteroids attenuates the stimulatory effect of ACTH, leading to a reduction in the frequency and severity of these adverse reactions. Caution should be exercised when treating patients whose clinical condition may worsen with increased blood pressure, the development of hypokalemia, or fluid retention (for example, patients with heart failure, recent myocardial infarction, ventricular arrhythmia, severe or unstable angina, and individuals with serious renal impairment).

Zytiga^® should be used with caution in patients with a history of cardiovascular disease. The safety of the drug in patients with left ventricular ejection fraction <50% or with NYHA class III-IV heart failure has not been established.

Hypokalemia and increased blood pressure should be corrected before starting Zytiga^®.

Blood pressure, plasma potassium concentration, and the degree of fluid retention should be monitored at least once a month.

Hepatotoxicity and hepatic impairment

Clinical studies have reported marked increases in liver enzymes requiring discontinuation or dose adjustment of the drug. Serum transaminase activity and bilirubin should be measured before starting Zytiga^®, every 2 weeks for the first 3 months of treatment, and then monthly. If clinical symptoms and signs suggestive of hepatic impairment develop, serum transaminase activity should be measured immediately.

If ALT or AST activity increases to more than 5 times ULN or bilirubin concentration increases to more than 3 times ULN, the use of Zytiga^® should be discontinued immediately, and liver function should be carefully monitored. Zytiga^® can be used again only after liver function parameters return to baseline, and only if the drug is prescribed at lower doses.

If patients develop severe hepatotoxicity (ALT or AST activity exceeding 20 times ULN) at any time during therapy, Zytiga^® should be discontinued, and re-administration of the drug in such patients is not possible.

Dose adjustment in patients with mild hepatic impairment is not required. There are no data on the efficacy and safety of repeated use of abiraterone acetate in patients with moderate or severe hepatic impairment (Child-Pugh class B or C), so the need for dose adjustment cannot be predicted. Zytiga^® should not be administered to patients with moderate or severe hepatic impairment.

Discontinuation of Glucocorticosteroids and Management of Stressful Situations

Caution should be exercised when discontinuing prednisone, and signs of adrenal cortical insufficiency should be monitored. If Zytiga^® treatment continues after glucocorticosteroid discontinuation, monitoring for symptoms of mineralocorticoid excess is recommended. In patients receiving prednisone, the development of stressful situations may require an increased dose of glucocorticosteroids before, during, and after the stressful situation.

Bone Mineral Density

Men with metastatic castration-resistant prostate cancer may experience decreased bone mineral density. This effect may be enhanced with the concomitant use of Zytiga^® and glucocorticosteroids.

Prior Use of Ketoconazole

A lower response rate to Zytiga^® therapy can be expected in patients who have previously received ketoconazole for prostate cancer treatment.

Hyperglycemia

The use of glucocorticosteroids can lead to hyperglycemia; therefore, blood glucose concentrations should be measured frequently in patients with diabetes.

Concomitant Use of Zytiga^® and Chemotherapy

The safety and efficacy of the concomitant use of Zytiga^® and cytotoxic chemotherapy have not been established.

Effect on the Musculoskeletal System

Cases of myopathy have been reported with the use of Zytiga^®. Some patients experienced rhabdomyolysis with renal failure. In most cases, these conditions developed within the first month of treatment and resolved after discontinuation of Zytiga^®. Caution is advised when Zytiga^® is used concomitantly with other drugs that can cause myopathy/rhabdomyolysis.

Information about Certain Excipients in Zytiga^®

The product contains lactose and should be used with caution in patients with lactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

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

Effect on Ability to Drive and Use Machines

Zytiga^® has no or negligible influence on the ability to drive and use machines.

Overdose

Data on overdose with Zytiga^® are limited.

Treatment: There is no specific antidote. In case of overdose, Zytiga^® should be discontinued; general supportive measures, including monitoring for cardiac arrhythmia, should be instituted. Liver function should also be monitored.

Drug Interactions

Potential Effects of Other Drugs on Abiraterone Exposure

In a study in healthy volunteers investigating the pharmacokinetic interaction of the strong CYP3A4 isoenzyme inducer rifampicin at a dose of 600 mg/day for 6 days followed by a single 1000 mg dose of abiraterone acetate, the mean plasma AUC_∞ of abiraterone decreased by 55%.

Concomitant use of Zytiga^® and strong inducers of the CYP3A4 isoenzyme (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John’s wort) should be avoided. Prescription of this group of drugs is possible only after careful assessment of clinical efficacy.

In clinical drug interaction pharmacokinetic studies in healthy volunteers, the use of ketoconazole, a strong CYP3A4 inhibitor, did not have a clinically significant effect on the pharmacokinetics of abiraterone.

Potential Effects of Zytiga^® on the Action of Other Drugs

Abiraterone inhibits hepatic isoenzymes involved in drug metabolism – CYP2D6 and CYP2C8.

In a clinical study evaluating the effect of abiraterone acetate (plus prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure of dextromethorphan increased approximately 2.9-fold. The AUC₂₄ for dextrorphan, an active metabolite of dextromethorphan, increased by approximately 33%.

It is recommended to use caution when prescribing Zytiga^® to patients receiving drugs that are metabolized by the CYP2D6 isoenzyme, particularly those with a narrow therapeutic index. In such cases, consideration should be given to reducing the dose of drugs with a narrow therapeutic index metabolized by the CYP2D6 isoenzyme, including drugs such as metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone, and tramadol.

In the same study evaluating the effect of abiraterone acetate (plus prednisone) on a single dose of the CYP1A2 substrate theophylline, no systemic effect on the theophylline substrate was observed.

In a CYP2C8 drug-drug interaction study involving healthy volunteers, the AUC of pioglitazone was increased by 46%, and the AUC_s of M-III and M-IV, each active metabolites of pioglitazone, decreased by 10% when pioglitazone was administered with a single 1000 mg dose of abiraterone acetate. Although these results indicate that a clinically significant increase in exposure is not expected when Zytiga^® is used in combination with other drugs that are eliminated primarily by CYP2C8, patients should be monitored for signs of toxicity associated with the CYP2C8 substrate with a narrow therapeutic index when used concomitantly with Zytiga^®.

Drugs That Can Prolong the QT Interval

Since androgen deprivation therapy can lead to QT interval prolongation, caution is advised when using Zytiga^® with other drugs that can prolong the QT interval, or drugs that can cause torsades de pointes ventricular tachycardia, such as class IA antiarrhythmic drugs (e.g., quinidine, disopyramide) or class III antiarrhythmic drugs (e.g., amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, antipsychotic drugs, etc.

Concomitant Use with Spironolactone

Spironolactone binds to androgen receptors and may contribute to an increase in PSA concentration. The use of spironolactone is not recommended in patients taking Zytiga^®.

Storage Conditions

The product should be stored in the original packaging in a place inaccessible to children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The product is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.