Abiraterone NV - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 198.65 mg, cellulose microcrystalline 141.22 mg, croscarmellose sodium 42,90 mg, povidone-K30 35.75 mg, sodium lauryl sulfate 28.60 mg, magnesium stearate 10.73 mg, silicon dioxide colloid 7.15 mg .

Description:Oval, biconvex tablets are white or almost white in color.

Pharmacotherapeutic group:Other hormone antagonists and their analogues

ATX: & nbsp

L.02.B Hormone antagonists and their analogues

L.02.B.X.03 Abiraterone

Pharmacodynamics:

Mechanism of action

Abiraterone acetate in vivo turns into abiraterone, which is an inhibitor of androgen biosynthesis. AT particular, abiraterone selectively inhibits the activity of the enzyme 17α-hydroxylase / C17,20-lyase (CYP17). This enzyme is expressed and is necessary for the biosynthesis of androgens in the testes, adrenals and prostate cancer cells. CYP17 catalyzes the conversion of pregnenolone and progesterone by 17α-hydroxylation and breaking of the C 17,20 bond into testosterone precursors: dehydroepiandrosterone and androstenedione, respectively. Deceleration of activity CYP17 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. Anti-androgen therapy, for example, the use of luliberin agonists or orchidectomy, weakens the synthesis of androgens in the testes, but does not affect the synthesis of androgens in the adrenals and in the tumor. The use of abiraterone acetate together with lylyberyrin agonists (or orchidectomy) reduces serum testosterone concentration to below the detection threshold.

Pharmacodynamics

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

Analgesic effect

The proportion of patients who had a palliative analgesic effect was significantly higher with abiraterone acetate, compared with the placebo group. In addition, compared with patients receiving placebo, a smaller proportion of patients receiving abiraterone acetate, progression of pain was noted.

Risk of development of bone complications

Compared to the placebo group, a smaller proportion of patients receiving abiraterone acetate had cases of bone tissue damage, including pathological fracture, spinal compression, palliative bone irradiation, and surgical bone treatment.

Pharmacokinetics:

Abiraterone acetate in vivo quickly turns into a abiraterone, which is an inhibitor of androgen biosynthesis.

Absorption

With oral administration of abirterone acetate on an empty stomach, the time to reach the maximum concentration (T_mOh) in blood plasma is approximately 2 hours. The intake of abiraterone acetate with food, compared with the administration of 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 maximum concentration (C_mOh) of abiraterone, depending on the fat content of the food taken. Taking into account the normal diversity in the content and composition of food, the intake of abiraterone acetate with food has the ability to exert a diverse systemic effect. Therefore, the drug Abiraterone HB can not be taken with food.

Distribution

Binding to plasma-labeled proteins ¹⁴C-abiraterone is 99.8%. Apparent volume of distribution (V_d) is approximately 5 630 liters, which indicates that abiraterone is actively distributed in peripheral tissues.

Metabolism

When administered orally ¹⁴C-abiraterone acetate, 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 acetate (approximately 92%) was in the form of metabolites of abiraterone. Of the 15 detectable metabolites, for each of the two major metabolites - abiraterone sulfate and N- oxide abiraterone sulfate - accounted for 43% of the total radioactivity.

Excretion

According to studies conducted with the participation of healthy volunteers, the average T_1/2abiraterone in plasma is approximately 15 hours. When administered orally to a labeled ¹⁴C-abiraterone acetate at a dose of 1 g of approximately 88% of the radioactive dose was excreted through the intestine and approximately 5% was excreted by the kidneys. The main substances found in the feces were unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).

Special patient groups

Patients with hepatic insufficiency

The pharmacokinetics of abiraterone acetate have been studied in patients with mild to moderate hepatic insufficiency (class A and B according to the Child-Pugh classification, respectively) and in healthy volunteers. The systemic effect of abirterone acetate after a single oral administration at a dose of 1 g increased by approximately 11% in patients with mild liver failure and by 260% in patients with moderate hepatic impairment. Average T_1/2Abiraterone increases to approximately 18 hours in patients with mild liver failure and up to about 19 hours in patients with moderate hepatic impairment.For patients with mild hepatic insufficiency, dose adjustment is not required. Abiraterone HB is not recommended for patients with moderate or severe hepatic insufficiency (Child-Pugh class B or C), since it is not possible to predict the necessary dose adjustment in this case. Therefore, the drug Abiraterone HB should be used with caution in patients with moderate liver function impairment only if the benefit of treatment clearly exceeds the potential risk. The drug Abiraterone HB can not be administered to patients with severe liver failure. Patients who developed hepatotoxicity during the treatment with the drug may need to temporarily stop the drug and adjust the dose.

Patients with renal insufficiency

The pharmacokinetics of abiraterone acetate were compared in patients with terminal renal failure receiving a standard hemodialysis regimen and in patients with normal renal function. Systemic exposure of abirterone acetate after oral administration at a dose of 1 g in patients with terminal stage of renal failure receiving hemodialysis did not increase.Care should be taken to prescribe the drug Abiraterone HB to patients with prostate cancer with impaired renal function of severe severity, as clinical data on the use of the drug Abiraterone HB in these patients are absent.

Influence on the interval Q-T

It has been established that the drug Abirateron HB does not have a significant effect on the interval QT/QTc.

Indications:The drug Abiraterone HB in combination with prednisolone is intended for the treatment of metastatic castration-resistant prostate cancer.

Contraindications:

- Hypersensitivity to the active component or any auxiliary substance of the drug;

- children's age till 18 years;

- severe liver dysfunction.

Carefully:

- Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption;

- caution should be given to the drug Abiraterone HB in patients with prostate cancer with impaired renal function of a serious degree (clinical data on the use of the drug Abiraterone HB in these patients are absent);

- caution should be exercised in the treatment of patients,which can worsen with increased blood pressure or hypokalemia (eg, patients with heart failure, recent myocardial infarction or ventricular arrhythmia, LVEF less than 50%, heart failure III-IV functional class by classification NYHA).

Pregnancy and lactation:

Abiraterone HB does not apply to women.

There are no data on the use of the drug Abiraterone HB in pregnant women. The drug Abiraterone HB is contraindicated in pregnant women and able to become pregnant with women. It is assumed that the intake of inhibitors of CYP 17 by pregnant women will change the concentration of hormones, which can affect the development of the fetus. To prevent accidental exposure, pregnant or pregnant women should not work with the drug without gloves.

It is not known whether abiraterone acetate or its metabolites with milk is excreted.

Dosing and Administration:

Inside, once a day for 1 hour before or 2 hours after a meal. Tablets should be swallowed whole, not liquid, squeezed with a small amount of water.

The recommended daily dose of the drug Abiraterone HB is 1 g (4 tablets of 250 mg). The drug Abiraterone HB is used together with low doses of prednisolone.The recommended dose of prednisolone is 10 mg / day.

A drug Abiraterone can not be taken with food.

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

Before the treatment with Abirateron HB, every 2 weeks for the first 3 months of treatment, and then monthly, the activity of serum transaminases and the concentration of bilirubin should be measured. Arterial pressure, potassium concentration in the blood and the degree of fluid retention in the body should be assessed on a monthly basis. If you skip the next daily dose of the drug Abiraterone HB, prednisolone the next day you should take the usual dose of the missed drug.

Correction of dose in patients with impaired liver function

Correction of the dose in patients with impaired liver function of mild degree is not required. There is no data on the efficacy and safety of abiraterone acetate in repeated use in patients with moderate or severe liver dysfunction (Child-Pugh class B or C), so it is impossible to predict the necessary dose adjustment. The drug Abiraterone HB should be used with caution in patients with moderate liver function disorders, and only if the benefit of treatment clearly exceeds the possible risk.The drug Abiraterone HB can not be administered to patients with severe hepatic dysfunction.

If during treatment with the drug in patients developed signs of hepatotoxicity (increased activity of alanine aminotransferase is 5 times higher than the upper limit of the norm or the concentration of bilirubin is 3 times higher than the upper limit of the norm), therapy should be immediately stopped until the liver functions are fully normalized.

Repeated therapy in patients with normalized liver function can begin with a reduced dose of 500 mg (2 tablets) once a day. In this case, control of the activity of serum transaminases and bilirubin concentration should be carried out at least every 2 weeks for 3 months, and then monthly. If signs of hepatotoxicity occur with a dose of 500 mg, therapy with Abiraterone HB should be discontinued.

If a severe form of hepatotoxicity develops in patients at any period of therapy (the activity of alanine aminotransferase exceeds the upper limit of the norm by a factor of 20), the drug Abiraterone HB should be discontinued, re-administration of the drug in such patients is impossible.

Special patient groups

Use in patients with hepatic impairment

For patients who have liver function disorder of a mild degree (class A according to Child-Pugh classification) prior to treatment, dose adjustment is not required. The drug Abiraterone HB can not be used in patients with moderate or severe hepatic impairment (Child-Pugh class B and C).

Use in patients with renal insufficiency

For patients with impaired renal function, dose adjustment is not required. Nevertheless, caution should be given to the drug Abiraterone HB in patients with prostate cancer with impaired renal function of a serious degree, because there are no clinical data on the use of the drug Abiraterone HB in such patients.

Children

For children, the use of the drug Abirateron HB is irrelevant, since this age group does not have prostate cancer.

Side effects:

The most frequent adverse events in the treatment with Abirateron HB are peripheral edema, hypokalemia, increased blood pressure, urinary tract infections, hematuria, increased activity of aspartate aminotransferase, increased activity of alanine aminotransferase, dyspepsia, fractures.

Undesirable reactions are systematized relative to each of the organ systems using the following frequency classifications: very often ≥ 1/10; often ≥ 1/100, <1/10; infrequently ≥ 1/1000, <1/100; rarely ≥1 / 10,000, <1/1000; very rarely <1/10 000, including isolated cases.

Infectious diseases:

Very often - urinary tract infections;

often - sepsis.

Disorders from the endocrine system:

Infrequent adrenal insufficiency is infrequent.

Effect on the results of laboratory studies:

Very often hypokalemia;

often - hypertriglyceridemia, increased activity of alanine aminotransferase, increased activity of aspartate aminotransferase.

Disturbances from the bone-muscular system and connective tissue:

Often - fractures (with the exception of pathological fractures);

infrequently - rhabdomyolysis, myopathy.

Disorders from the kidneys and urinary tract:

Often - hematuria.

Disorders from the cardiovascular system:

Very often - increased blood pressure;

often - heart failure, incl. acute heart failure, left ventricular failure, reduced left ventricular ejection fraction, angina pectoris, arrhythmia, atrial fibrillation, tachycardia;

frequency unknown - myocardial infarction.

Disturbances from the respiratory system:

Rarely - allergic alveolitis.

Disorders from the gastrointestinal tract:

Very often - diarrhea;

often - indigestion.

Disturbances from the liver and bile ducts:

Rarely - fulminant hepatitis, acute liver failure.

Common violations:

Very often peripheral edema.

Disturbance of the skin and subcutaneous tissues:

Often - skin rash.

Overdose:

Data on drug overdose Abirateron HB are limited.

There is no specific antidote. In case of an overdose, the drug Abiraterone HB should be discontinued and general supportive measures, including arrhythmia control, should be performed. Liver function should also be monitored.

Interaction:

Potential effects of other drugs on the effects of abirterone

When studying the pharmacokinetic interaction of a strong isoenzyme inducer CYP3A4 on healthy volunteers-rifampicin 600 mg per day for 6 days and then a single dose of abiraterone acetate 1000 mg, medium plasma AUC_∞abiraterone decreased by 55%. Avoid joint use of the drug Abirateron HB and strong isoenzyme inducers CYP3A4 (for example: phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital).The purpose of this group of drugs is possible only after a thorough evaluation of clinical efficacy.

The potential effect of Abirateron HB on the action of other drugs

Abiraterone inhibits "hepatic" isoenzymes involved in the metabolism of drugs - CYP2D6 and CYP2C8. In a clinical study in determining the efficacy of abiraterone acetate (plus prednisone) per dose of the substrate dextromethorphan CYP2D6 systemic effect of dextromethorphan, the active metabolite of dextromethorphan, increased by approximately 33%.

It is recommended to prescribe cautiously the drug Abiraterone HB to patients receiving drugs that are metabolized by isoenzyme CYP2D6, especially for drugs with a narrow therapeutic index. In such cases, one should consider the possibility of reducing the dose of drugs with a narrow therapeutic index metabolized by isoenzyme CYP2D6, including such drugs as metoprolol, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol.

In the same study, in determining the efficacy of abiraterone acetate (plus prednisone) for one dose of CYP1A2 of theophylline substrate, no systemic effect of theophylline substrate was observed.

In the study CYP2C8 drug-drug interactions on healthy subjects, AUC pioglitazone was increased by 46% and AUCs M-III and M-IV, of 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 clinically significant increases in exposure are not expected if the drug Abirateron HB is used in combination with other drugs that are eliminated predominantly CYP2C8, patients should be observed for signs of toxicity associated with the substrate CYP2C8 with a narrow therapeutic index, if used concurrently with the drug Abirateron HB.

Co-administration with spironolactone

Spironolactone binds to androgen receptors and can contribute to an increase in the concentration of PSA. The use of spironolactone is not recommended in patients using Abirateron HB.

Special instructions:

Reception of the drug Abiraterone HB concomitantly with food significantly increases the absorption of abiraterone acetate. The effectiveness and safety of the drug Abiraterone HB, taken with food, is not established.The drug Abiraterone NV can not be taken with food.

Increased blood pressure, hypokalemia and fluid retention due to excess mineralocorticoids

The drug Abiraterone HB can cause an increase in blood pressure, hypokalemia and fluid retention due to an increase in the concentration of mineralocorticoids due to inhibition of the enzyme CYP17. The intake of corticosteroids weakens the stimulating effect of adrenocorticotropic hormone (ACTH), which leads to a decrease in the frequency and severity of these adverse reactions. Caution should be exercised in the treatment of patients whose clinical condition may worsen with increased blood pressure, development of hypokalemia, or fluid retention in the body (eg, in patients with heart failure, recent myocardial infarction or ventricular arrhythmia).

The drug Abiraterone NV should be used with caution in patients with a history of cardiovascular disease. Safety of the drug in patients with a left ventricular ejection fraction <50% or heart failure III-IV functional class by classification NYHA not installed.Before starting the drug Abiraterone HB, hypokalemia and increased blood pressure should be adjusted.

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

Hepatotoxicity

In clinical studies, a marked increase in the activity of liver enzymes, requiring the elimination or correction of the dose of the drug. The activity of serum transaminases and bilirubin should be measured before the drug is started Abiraterone, every 2 weeks in the first 3 months of treatment, and then monthly. With the development of clinical symptoms and signs suggesting a violation of liver function, the activity of serum transaminases, in particular alanine aminotransferase, should be immediately measured. If the activity of alanine aminotransferase is increased 5 times higher than the upper limit of the norm or bilirubin concentration 3 times higher than the upper limit of the norm, the drug Abiraterone HB should be stopped immediately and the liver function is carefully monitored.

The drug Abiraterone HB can be used again only after the return of liver function indicators to the baseline values and only when treated with lower doses.

Correction of the dose in patients with impaired liver function of mild degree is not required. There is no data on the efficacy and safety of repeated use of abiraterone acetate in patients with moderate or severe liver dysfunction (Child-Pugh class B or C), so the need for dose adjustment can not be predicted. The drug Abiraterone HB should be used with caution in patients with impaired liver function of moderate degree, only if the benefit of treatment clearly exceeds the possible risk. The drug Abiraterone HB can not be administered to patients with impaired hepatic function.

Women of childbearing age

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

Contraception in men and women

It is not known whether abiraterone acetate or its metabolites are present in the sperm. It is necessary to use a condom if a sexual intercourse with a pregnant woman is planned. If the sexual act 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 toxicity of abiraterone acetate for the reproductive system have not been conducted, there is no evidence of the effect of the drug on fertility.

Abolition of glucocorticosteroids and relief of stressful situations

With the withdrawal of prednisolone, caution should be exercised and signs of adrenal cortex deficiency should be monitored. If the use of the drug Abirateron HB continues after the abolition of glucocorticosteroids, then the symptoms of excess mineralocorticoids should be monitored. In patients receiving prednisolone, with the development of stressful situations, you may need an increased dose of glucocorticosteroids before,during and after a stressful situation.

Simultaneous administration of the drug Abirateron HB and chemotherapy

The safety and efficacy of concurrent administration of the drug Abiraterone HB and cytotoxic chemotherapy have not been established.

Information on some of the excipients that make up the drug Abiraterone HB

This drug contains 1 mmol (27.2 mg) of sodium in each dose (4 tablets), which should be taken into account when treating patients receiving a diet with a controlled sodium content.

Effect on the ability to drive transp. cf. and fur:

The drug Abirateron HB does not affect or has a negligible effect on the ability to drive and move vehicles.

Form release / dosage:

Tablets, 250 mg.

Packaging:

For 120 tablets in a polymer jar for medicines, ukuporennuyu cover.

Each bank along with the instruction for use is placed in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003831

Date of registration:14.09.2016

Expiration Date:14.09.2021

The owner of the registration certificate:NewVac, Inc.NewVac, Inc. Russia

Manufacturer: & nbsp

Research Institute of Chemical Diversity, JSC Russia

Representation: & nbspResearch Institute of Chemical Diversity, JSCResearch Institute of Chemical Diversity, JSCRussia

Information update date: & nbsp08.02.2017

Illustrated instructions

Instructions

Abiraterone NV (Abiraterone NV)