Abirateron TL pills 250mg, 120pcs

Composition

For 1 tablet: Active ingredient:  Abiraterone acetate-250.00 mgm Auxiliary substances: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone K 25, sodium lauryl sulfate, magnesium stearate, silicon dioxide colloidal

Pharmacological action

Pharmacotherapy group: other hormone antagonists and their other analogs ATX code: L02BX03 Pharmacological properties

Mechanism of action

Abiraterone acetate is converted in vivo to abiraterone, which is an inhibitor of androgen biosynthesis. In particular, abiraterone selectively suppresses the activity of the 17α-hydroxylase enzyme/With 17,20-lyase (CYP17). This enzyme is expressed and is essential for androgen biosynthesis in the testicles, adrenal glands, and prostate tumor cells. CYP17 catalyzes the conversion of pregnenolone and progesterone by 17α-hydroxylation and breaking the bond with 17,20 to 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 the concentration of androgens. Antiandrogenic therapy, such as the use of lyuliberin agonists or orchidectomy, weakens the synthesis of androgens in the testicles, but does not affect the synthesis of androgens in the adrenal glands and in the tumor. Abiraterone combined with lyuliberin agonists (or orchidectomy) reduces the concentration of testosterone in the blood serum to a level below the threshold of determination.

Pharmacodynamics

Abiraterone reduces the concentration of testosterone and other androgens in the serum below those indicators that can be obtained against the background of the use of lyuliberin agonists or after orchidectomy. This is due to selective inhibition of the enzyme CYP17, which is required for androgen biosynthesis. Prostate-specific antigen (PSA) concentration serves as a biomarker in patients with prostate cancer.

Analgesic effect

The proportion of patients who had a palliative analgesic effect was significantly higher when using abiraterone compared to the placebo group. In addition, compared to placebo-treated patients, a smaller proportion of abiraterone-treated patients experienced pain progression.

Risk of bone complications

Compared to the placebo group, a smaller proportion of patients treated with abiraterone had cases of bone damage, which included pathological fracture, spinal compression, palliative bone irradiation, and bone surgery.

Application of spironolactone

Patients who participated in major clinical trials of abiraterone were not allowed to use spironolactone, as its molecules bind to androgen receptors and can increase PSA levels.

Pharmacokinetics

The pharmacokinetics of abiraterone acetate and abiraterone were studied in healthy volunteers, in patients with advanced metastatic prostate cancer, and in non-oncological patients with renal or hepatic insufficiency.

Abiraterone acetate is rapidly converted in vivo to abiraterone, which is an inhibitor of androgen biosynthesis.

Absorption rate

When the drug is administered orally on an empty stomach, the time to reach the maximum concentration (Cmax) of abiraterone in blood plasma is approximately 2 hours. Taking abiraterone with food compared to taking the drug on an empty stomach leads to a 10-fold increase in the area under the concentration-time curve (AUC) and a 17-fold increase in the Cmax of abiraterone, depending on the fat content of the food taken. Taking into account the normal variety of food content and composition, taking abiraterone with food has the ability to have a variety of systemic effects. Therefore, abiraterone should not be taken with food.

Distribution

The plasma protein binding of 14C-labeled abiraterone is 99.8%. The apparent volume of distribution is approximately 5630 L, which indicates that abiraterone is actively distributed in peripheral tissues.

Metabolism

When 14C-abiraterone acetate is administered orally, abiraterone acetate is hydrolyzed to abiraterone, which in turn undergoes metabolism, including sulfation, hydroxylation, and oxidation, mainly in the liver. Most of the circulating 14C-abiraterone (approximately 92%) was in the form of abiraterone metabolites. Of the 15 detectable metabolites, each of the 2 major metabolites – abiraterone sulfate and N-oxide abiraterone sulfate-accounted for 43% of total radioactivity.

Deduction

According to studies conducted in healthy volunteers, the average plasma half-life of abiraterone is approximately 15 hours. When 14C-labeled abiraterone acetate was administered orally at a dose of 1000 mg, approximately 88% of the radioactive dose was excreted through the intestine and approximately 5% through the kidneys. The main substances found in faeces were unchanged abiraterone acetate and abiraterone (approximately 55 and 22% of the administered dose, respectively).

Pharmacokinetics in special patient groups

Patients with hepatic insufficiency

The pharmacokinetics of abiraterone were studied in patients with mild and moderate hepatic insufficiency (Child-Pugh class A and B, respectively) and in healthy volunteers. Systemic exposure to abiraterone after a single oral dose of 1000 mg increased by approximately 11% in patients with mild hepatic insufficiency and by 260% in patients with moderate hepatic insufficiency. The mean elimination half-life of abiraterone increases to approximately 18 hours in patients with mild hepatic insufficiency and to approximately 19 hours in patients with moderate hepatic insufficiency. For patients with mild hepatic insufficiency, no dose adjustment is required. Abiraterone should not be used in patients with moderate or severe hepatic insufficiency (Child-Pugh Class B or C). Patients who develop hepatotoxicity during therapy with the drug may need to temporarily discontinue the drug and adjust the dose.

Patients with renal insufficiency

The pharmacokinetics of abiraterone were compared in patients with end-stage renal insufficiency receiving a standard hemodialysis regimen and in patients with normal renal function. Systemic exposure to abiraterone acetate after oral use at a dose of 1000 mg in patients with end-stage renal failure receiving hemodialysis did not increase. Abiraterone should not be prescribed to patients with prostate cancer with severe renal impairment, since there are no clinical data on the use of abiraterone in such patients.

Effect on the QT interval

Abiraterone was found to have no significant effect on the QT/QTc interval.

Indications

The drug Abiraterone-TL in combination with prednisone is intended for the treatment of metastatic castration-resistant prostate cancer.

Contraindications

• Hypersensitivity to the Active ingredient or any auxiliary substance of the drug.
• Children under 18 years of age.
• Moderate to severe hepatic insufficiency.
• Severe renal failure.

Use caution

• for lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
• Caution should be exercised when treating patients whose condition may worsen with increased blood pressure or hypokalemia, for example, patients with heart failure, recent myocardial infarction or ventricular arrhythmia, left ventricular ejection fraction less than 50%, NYHA functional Class III— IV heart failure, severe and unstable angina.

Side effects

The most common adverse events during abiraterone treatment are peripheral edema, hypokalemia, increased blood pressure, urinary tract infections, hematuria, increased activity of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT), dyspepsia, fractures. Adverse reactions are classified according to each of the organ systems using the following frequency classification: very common (>1/10); common (>>1/100, >><1/10); infrequently (>1/1000, <1/10); infrequently (><1/100); rarely (>1/10 000, <1/100); rarely (><1/1000); very rarely (Infectious diseases: very often-urinary tract infections; often-sepsis. Endocrine system disorders: infrequently-adrenal insufficiency. Effects on laboratory results: very often – hypokalemia; often-hypertriglyceridemia, increased ALT and ACT activity. Musculoskeletal disorders: often – fractures (except for pathological fractures); infrequently-rhabdomyolysis, myopathy. Disorders of the kidneys and urinary tract: often-hematuria. Disorders of the cardiovascular system: very often – increased blood pressure; often-heart failure, including acute heart failure, left ventricular failure, a decrease in the left ventricular ejection fraction; angina, arrhythmia, atrial fibrillation, tachycardia; frequency unknown – myocardial infarction. Respiratory system disorders: rarely-allergic alveolitis. Disorders of the gastrointestinal tract: very often-diarrhea; often-dyspepsia. Liver and biliary tract disorders: rarely-lightning-fast hepatitis, acute liver failure.General disorders: very often – peripheral edema. Skin and subcutaneous tissue disorders: often-skin rash.

Interaction

Potential effects of other drugs on abiraterone exposure

In the study of the pharmacokinetic interaction of a strong inducer of the CYP3A4 isoenzyme rifampicin at a dose of 600 mg / day. during 6 days and then abiraterone acetate in a single dose of 1000 mg in healthy volunteers, the average plasma AUC∞ of abiraterone decreased by 55%. The combined use of Abiraterone-TL and strong inducers of the CYP3A4 isoenzyme (for example, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital, St. John’s wort) should be avoided. Prescribing this group of drugs is possible only after a thorough assessment of clinical efficacy.

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

Potential effect of abiraterone on the action of other drugs

Abiraterone inhibits the hepatic isoenzymes CYP2D6 and CYP2C8 involved in drug metabolism. In a clinical study, when determining the effectiveness of abiraterone acetate (plus prednisone) per dose of dextromethorphan CYP2D6 substrate, the systemic exposure to dextromethorphan increased approximately 2.9 times. AUC24 for dextrorphan, the active metabolite of dextromethorphan, increased by approximately 33%.

Caution is recommended when prescribing abiraterone to patients receiving drugs that are metabolized by the CYP2D6 isoenzyme, especially for drugs with a narrow therapeutic index. In such cases, consideration should be given to reducing the dose of drugs with a narrow therapeutic index that are metabolized by the CYP2D6 isoenzyme, including metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol.

In the same study, when determining the effectiveness of abiraterone acetate (plus prednisone) per dose of CYP1A2 theophylline substrate, no systemic effects of theophylline substrate were observed.

In the CYP2C8 drug-drug interaction study in healthy volunteers, the AUC of pioglitazone was increased by 46% and the AUCS of M-III and M-IV, each of the active metabolites of pioglitazone, decreased by 10% when pioglitazone was administered together with a single dose of abiraterone acetate 1000 mg. Although these results indicate that no clinically significant increases in exposure are expected if abiraterone is used in combination with other drugs that are eliminated predominantly by CYP2C8, patients should be monitored for signs of toxicity associated with a CYP2C8 substrate with a narrow therapeutic index if it is used simultaneously with abiraterone. Medications that can prolong the QT interval

Since androgen deprivation therapy may lead to prolongation of QT interval, are advised to exercise caution in the use of abiraterone with other drugs that can prolong the QT interval or medicinal products able to induce ventricular tachycardia type “pirouette”, such as antiarrhythmic drugs of class IA (e. g. quinidine, disopyramide) or class III (e. g., amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, antipsychotics, etc.

Combined use with spironolactone

Spironolactone binds to androgen receptors and may contribute to an increase in PSA concentrations. The use of spironolactone is not recommended in patients taking abiraterone.

How to take, course of use and dosage

The recommended daily dose of Abiraterone-TL is 1000 mg (4 tablets of 250 mg) once a day for 1 hour before meals or 2 hours after meals. Tablets should be swallowed whole, without chewing, with a small amount of water.

The drug Abiraterone-TL is used together with low doses of prednisone. The recommended dose of prednisone is 10 mg / day.

Abiraterone-TL should not be taken with food.

Within 1 hour after taking the drug, food intake is not recommended.

Before starting treatment with Abiraterone-TL, serum transaminase activity and bilirubin concentration should be measured every 2 weeks for the first 3 months of treatment, and then monthly. Blood pressure, blood potassium concentrations, and the degree of fluid retention in the body should be assessed monthly. If you miss the next daily dose of Abiraterone-TL, prednisone on the next day, you should take the usual dose of the missed drug.

Dose adjustment in patients with hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment. There are no data on the efficacy and safety of abiraterone acetate when used repeatedly in patients with moderate or severe hepatic impairment (Child-Pugh class B or C), so it is impossible to predict the necessary dose adjustment. Abiraterone-TL should not be used in patients with moderate to severe hepatic impairment. If during treatment with the drug, patients develop signs of hepatotoxicity (increased activity of alanine aminotransferase (ALT) or aspartate aminotransferase (ACT) is 5 times higher than the upper limit of normal or bilirubin concentration is 3 times higher than the upper limit of normal), therapy should be stopped immediately until complete normalization of liver function indicators.

Repeated therapy in patients with normalized liver function indicators can be started with a reduced dose of 500 mg (2 tablets) once a day. 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 at a dose of 500 mg, Abiraterone-TL therapy should be discontinued.

If patients develop severe hepatotoxicity during any period of therapy (ALT or ACT activity exceeds the upper limit of normal by 20 times), Abiraterone-TL should be discontinued. Repeated use of the drug in such patients is impossible.

Special patient groups

Use in patients with hepatic insufficiency

For patients with mild hepatic impairment (Child-Pugh class A) prior to treatment, no dose adjustment is required. Abiraterone-TL should not be used in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C).

Use in patients with renal insufficiency

No dose adjustment is required for patients with impaired renal function. However, Abiraterone-TL should not be prescribed to patients with prostate cancer with severe renal impairment, since there are no clinical data on the use of abiraterone in such patients.

Children

For children, the use of Abiraterone-TL is irrelevant, since this age group does not have prostate cancer.

Overdose

Data on overdose with Abiraterone-TL are limited. There is no specific antidote. In case of overdose, Abiraterone-TL should be discontinued and general supportive measures should be taken, including arrhythmia control. Liver function should also be monitored.

Description

Oval biconvex tablets are white or almost white in color, marbling is allowed on the surface of tablets.

Special instructions

Taking abiraterone simultaneously with food significantly increases the absorption of abiraterone. The efficacy and safety of abiraterone taken with food has not been established. Abiraterone should not be taken with food. Increased blood pressure, hypokalemia, and fluid retention due to excess mineralocorticoids, Viraterone can cause increased blood pressure, hypokalemia, and fluid retention due to increased mineralocorticoid concentrations due to inhibition of the CYP17 enzyme. Taking mineralocorticoids weakens the stimulating effect of adrenocorticotropic hormone, which leads to a decrease 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, hypokalemia, or fluid retention (for example, in patients with heart failure, recent myocardial infarction or ventricular arrhythmia, severe or unstable angina, and those with severe renal impairment). Abiraterone should be used with caution in patients with a history of cardiovascular disease. Safety of the drug in patients with left ventricular ejection fraction Hypokalemia and elevated blood pressure should be corrected before starting abiraterone use.

Blood pressure, plasma potassium concentrations, and fluid retention should be monitored at least once a month.

Hepatotoxicity and impaired liver function

In clinical studies, a pronounced increase in the activity of liver enzymes was recorded, which required discontinuation or dose adjustment of the drug. Serum transaminase and bilirubin activity should be measured before starting abiraterone, every 2 weeks during the first months of treatment, and then monthly.

If clinical symptoms and signs suggest impaired liver function develop, serum transaminase activity should be measured immediately. If the ALT or ACT activity is 5 times higher than the upper limit of normal or the bilirubin concentration is 3 times higher than the upper limit of normal, abiraterone should be discontinued immediately and liver function should be carefully monitored. Abiraterone can be used again only after the liver function indicators return to their original values, and only if lower doses are prescribed.

If patients develop severe hepatotoxicity during any period of therapy (ALT or ACT activity exceeds the upper limit of normal by 20 times), abiraterone should be discontinued. Repeated use of the drug in such patients is impossible.

No dose adjustment is required in patients with mild hepatic impairment. 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. Abiraterone-TL should not be used in patients with moderate to severe hepatic impairment.

Women of childbearing age

Abiraterone is not intended for use in women. It is assumed that taking CYP17 inhibitors in pregnant women will change the concentration of hormones, which may affect the development of the fetus. To prevent accidental exposure, pregnant or potentially pregnant women should not work with the drug without gloves.

Contraception in men and women

It is not known whether abiraterone or its metabolites are present in semen. It is necessary to use a condom if sexual intercourse with a pregnant woman is planned. If sexual intercourse is planned with a woman of childbearing age, it is necessary to use a condom along with other effective methods of contraception.

Ability to conceive

Studies of the toxic effect of abiraterone acetate on the reproductive system have not been conducted, and there is no data on the effect of the drug on the ability to conceive.

Pregnancy and lactation

Abiraterone is not used in women. There are no data on the use of the drug in pregnant women. Abiraterone-TL is contraindicated in pregnant women and women who may become pregnant. It is not known whether abiraterone acetate or its metabolites are excreted in milk.

Withdrawal of glucocorticosteroids and relief of stressful situations

Caution should be exercised when discontinuing prednisone and signs of adrenal insufficiency should be monitored. If the use of abiraterone continues after the withdrawal of glucocorticosteroids, then the appearance of symptoms of excess mineralocorticoids should be monitored. Patients receiving prednisone for the development of stressful situations may require an increased dose of glucocorticosteroids before, during and after a stressful situation.

Bone density

Men with metastatic castration-resistant prostate cancer may experience a decrease in bone density. With the simultaneous use of abiraterone and glucocorticosteroids, this effect may be enhanced.

Previous use of ketoconazole

Patients who have previously received ketoconazole for the treatment of prostate cancer can expect a lower response rate to abiraterone therapy.

Hyperglycemia

The use of glucocorticosteroids can lead to hyperglycemia, so in patients with diabetes, it is necessary to frequently measure the concentration of glucose in the blood.

Simultaneous use of abiraterone and chemotherapy

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

Effect on the musculoskeletal system

Cases of myopathy have been reported with the use of abiraterone. Some patients experienced rhabdomyolysis with renal insufficiency. In most cases, these conditions developed during the first month of treatment, and after abiraterone was discontinued, recovery occurred. Caution should be exercised when using abiraterone concomitantly with other drugs that may cause myopathy/rhabdomyolysis.

Information on some excipients that make up the preparation Abiraterone-TL

This medicine contains lactose. Abiraterone-TL should be used with caution in patients with lactose intolerance, lactase deficiency, or glucose-galactose malabsorption. This medicinal product contains more than 1 mmol (27.2 mg) of sodium in each dose (4 tablets), which should be taken into account when treating patients receiving a controlled sodium diet.

Influence on the ability to drive vehicles and mechanisms

The drug Abiraterone-TL does not affect or has a slight effect on the ability to drive a car and moving mechanisms.

Storage conditions

In a place protected from light, at a temperature not exceeding 25°C. Keep out of reach of children.

Shelf

life is 2 years. Do not use after the expiration date.

Active ingredient

Abiraterone

Conditions of release from pharmacies

By prescription

Dosage form

Tablets