Abirat^® (Tablets) Instructions for Use

Marketing Authorization Holder

Hetero Labs, Limited (India)

Manufactured By

Hetero Labs, Limited (India)

Primary Packaging

HETERO LABS, Limited (India)

Secondary Packaging

HETERO LABS, Limited (India)

Or

MAKIZ-PHARMA, LLC (Russia)

Quality Control Release

HETERO LABS, Limited (India)

Or

MAKIZ-PHARMA, LLC (Russia)

ATC Code

L02BX03 (Abiraterone)

Active Substance

Abiraterone (Rec.INN registered by WHO)

Dosage Form

Abirat®

Tablets 250 mg: 120 pcs.

Dosage Form, Packaging, and Composition

Tablets from almost white to light brown or brownish in color, oval, biconvex, with an engraving “A1” on one side and “H” on the other; both sides of the tablet have a bevel.

Excipients: microcrystalline cellulose (PH101) – 216 mg, lactose monohydrate – 189 mg, croscarmellose sodium – 22.5 mg, povidone K-29/32 – 7 mg, sodium lauryl sulfate – 17 mg, colloidal silicon dioxide – 3.5 mg, magnesium stearate – 10 mg.

120 pcs. – high-density polyethylene jars (1) – cardboard packs.

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

A steroid-structured agent with antiandrogenic activity. Abiraterone is an inhibitor of androgen biosynthesis. In particular, Abiraterone selectively suppresses the activity of the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed 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 luteinizing hormone-releasing hormone 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 abiraterone in combination with luteinizing hormone-releasing hormone agonists (or orchiectomy) reduces serum testosterone concentrations to levels below the detection threshold.

Abiraterone causes a decrease in serum testosterone and other androgen concentrations below those achievable with luteinizing hormone-releasing hormone agonists or after orchiectomy. This occurs due to selective inhibition of the CYP17 enzyme, which is required for androgen biosynthesis. PSA concentration is a biomarker in patients with prostate cancer.

Pharmacokinetics

After oral administration on an empty stomach, the time to reach C_max of the active substance in blood plasma is approximately 2 hours. Administration with food, compared to administration on an empty stomach, leads to a 10-fold increase in AUC and a 17-fold increase in C_max, depending on the fat content of the food taken. The plasma protein binding of labeled ¹⁴C-abiraterone is 99.8%. The apparent V_d is approximately 5,630 L, indicating that Abiraterone is actively distributed in peripheral tissues.

Abiraterone undergoes metabolism, including sulfation, hydroxylation, and oxidation, mainly in the liver. Most of the circulating ¹⁴C-abiraterone acetate (approximately 92%) was in the form of the metabolite abiraterone. Of the 15 detectable metabolites, each of the two main metabolites – abiraterone sulfate and abiraterone sulfate dioxide – accounted for 43% of the total radioactivity.

The mean plasma T_1/2 of abiraterone is about 15 hours. After oral administration of labeled ¹⁴C-abiraterone acetate at a dose of 1 g, approximately 88% of the radioactive dose was excreted through the intestine and approximately 5% was excreted by the kidneys. The feces contained mainly unchanged abiraterone acetate and Abiraterone (approximately 55% and 22% of the administered dose, respectively).

Indications

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

ICD codes

Dosage Regimen

Intended for oral administration.

As part of combination therapy with low-dose prednisolone, the recommended daily dose of abiraterone is 1 g once daily, taken 1 hour before or 2 hours after meals.

If signs of hepatotoxicity develop during treatment (ALT activity increased to 5 times the upper limit of normal or bilirubin concentration increased to 3 times the upper limit of normal), therapy should be immediately discontinued until liver function parameters have completely normalized. Retreatment in patients with normalized liver function parameters can be started at a reduced dose of 500 mg once daily.

If symptoms of hepatotoxicity occur at a dose of 500 mg, therapy with abiraterone should be discontinued. If severe hepatotoxicity develops (ALT activity exceeding 20 times the upper limit of normal) at any period of therapy, Abiraterone should be discontinued; re-administration in such cases is not possible.

Adverse Reactions

Hepatobiliary disorders hepatotoxicity, accompanied by increased ALT, AST, and total bilirubin activity (the mechanism of hepatotoxicity is currently unknown).

Urinary system disorders: very common – urinary tract infections; common – hematuria.

Cardiovascular system disorders: very common – arterial hypertension; common – heart failure, including acute heart failure, left ventricular failure, decreased left ventricular ejection fraction, angina pectoris, arrhythmia, atrial fibrillation, tachycardia.

Digestive system disorders: common – dyspepsia.

Musculoskeletal system disorders: common – fractures (excluding pathological fractures).

Endocrine system disorders: uncommon – adrenal insufficiency.

Respiratory system disorders: rare – allergic alveolitis.

Laboratory parameters: very common – hypokalemia; common – hypertriglyceridemia, increased ALT activity.

General disorders: very common – peripheral edema.

Contraindications

Severe hepatic impairment; age under 18 years; hypersensitivity to abiraterone.

Use in Pregnancy and Lactation

Abiraterone is not intended for use in women.

To prevent accidental exposure, pregnant women or women of childbearing potential should not handle abiraterone without gloves.

It is not known whether Abiraterone or its metabolites are present in semen. During treatment, 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 contraceptive methods.

Special Precautions

Use with caution in patients with severe renal impairment, as clinical data on use in this category of patients are lacking.

Caution is required when using in patients whose condition may worsen with increased blood pressure or the development of hypokalemia, for example, in heart failure, recent myocardial infarction, or ventricular arrhythmia; with left ventricular ejection fraction less than 50%, heart failure of NYHA functional class III-IV. The safety of the drug in patients with left ventricular ejection fraction < 50% or with heart failure of NYHA functional class III-IV has not been established. Hypokalemia and arterial hypertension should be corrected before starting abiraterone.

In patients receiving Abiraterone, increased blood pressure, hypokalemia, and fluid retention may be observed due to increased concentrations of mineralocorticoids in the blood resulting from CYP17 inhibition. The administration of glucocorticoids simultaneously with abiraterone attenuates the stimulatory effect of ACTH, leading to a reduction in the frequency and severity of these adverse reactions.

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

Serum transaminase activity and blood bilirubin levels should be measured before starting treatment, every 2 weeks for the first 3 months of treatment, and then monthly. If clinical symptoms and signs suggesting liver dysfunction develop, serum transaminase activity, in particular ALT, should be determined immediately. If ALT activity increases to 5 times the upper limit of normal or bilirubin concentration increases to 3 times the upper limit of normal, abiraterone should be discontinued immediately; careful monitoring of liver function is necessary.

Caution and monitoring for symptoms of adrenal insufficiency are required when discontinuing prednisolone.

Drug Interactions

In a study evaluating the effect of abiraterone acetate, taken together with prednisone, on dextromethorphan (a CYP2D6 substrate) when taken as a single dose, the AUC of dextromethorphan increased by approximately 200%. The AUC₂₄ of dextrorphan, the active metabolite of dextromethorphan, increased by approximately 33%.

It is recommended to use Abiraterone with caution in patients receiving drugs that are metabolized by CYP2D6, especially drugs with a narrow therapeutic index. In such cases, consideration should be given to reducing the dose of drugs, including dextromethorphan, metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone, and tramadol.

Based on in vitro data, Abiraterone is a substrate of the CYP3A4 isoenzyme. Caution is required when co-administered with strong inhibitors of the CYP3A4 isoenzyme (ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) and inducers (phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.