Abiraterone* (Abiraterone*)

ATX

L02BX03 Abiraterone

Фармакологическая группа

• Other antagonists other hormones and their analogues [anti-hormonal agents and antagonists of hormones]

Nosological classification (ICD-10)

• C61 Malignant neoplasm of prostate
• C79.8 secondary malignant neoplasm of other specified sites

Composition

Description pharmaceutical form

Oval biconvex tablets from white to almost white, engraved with "АА250".

Pharmacological action

The drugs — protivoopujolevoe, antiandrogenic.

Pharmacodynamics

Mechanism of action

Abiraterone acetate in vivo is transformed into abiraterone, which is an inhibitor of the biosynthesis of androgens. In particular, abiraterone selectively inhibits the activity of the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed and is essential for the biosynthesis of androgens in the testes, adrenal glands and tumor cells of the prostate gland. CYP17 catalyzes the conversion of pregnenolone and progesterone by the 17α-hydroxylation and disconnect the C17,20 in precursors of testosterone: dehydroepiandrosterone and Androstenedione, respectively. Inhibition of CYP17 is also accompanied by increased synthesis of mineralocorticoids in the adrenal glands.

Androgenously prostate cancer responds to the treatment, decreasing the concentration of androgens. Antiandrogen therapy, for example the use of agonists luliberin or for orchidectomy, reduces the synthesis of androgens in the testes but does not affect the synthesis of androgens in the adrenal glands and the tumor. The use of the drug Xbira ^® in conjunction with agonists luliberin (or orchidectomy) reduces the concentration of testosterone in the serum to below the threshold.

The drug Xbira ^® reduces the concentration of testosterone and other androgens in the serum lower than those of indicators that are able to application of agonists luliberin or after orchidectomy. This is due to selective inhibition of the enzyme CYP17, which is required for the biosynthesis of androgens. The concentration of PSA serves as a biomarker in patients with prostate cancer.

The analgesic effect. The proportion of patients who have had palliative analgesic effect was significantly higher when using the drug Xbira ^®compared to the placebo group. In addition, compared with patients receiving placebo, a smaller proportion of patients receiving the drug Xbira ^®progressed pain syndrome.

The risk of developing bone complications. Compared with the placebo group, a smaller proportion of patients receiving the drug Xbira ^®, there were cases of destruction of bone tissue, which were classified as pathological fracture, spinal cord compression, palliative radiation of bone, surgical treatment of bones.

Pharmacokinetics

Фармакокинетика абиратерона ацетата и абиратерона была изучена у здоровых добровольцев, больных с поздними стадиями метастатического рака предстательной железы и неонкологических пациентов с почечной или печеночной недостаточностью. Абиратерона ацетат in vivo быстро превращается в абиратерон, который является ингибитором биосинтеза андрогенов.

Абсорбция. При пероральном применении препарата Xbira ^® натощак T_max в плазме крови составляет приблизительно 2 ч. Прием препарата Xbira ^® с пищей, по сравнению с приемом препарата натощак, приводит к 10-кратному увеличению AUC и 17-кратному увеличению C_max абиратерона, в зависимости от жирности принятой пищи. Принимая во внимание нормальное разнообразие содержания и состава пищи, прием препарата Xbira ^® с пищей обладает способностью оказывать разнообразное системное воздействие. Поэтому препарат Xbira ^® нельзя принимать с пищей.

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

Metabolism. Oral application ^{of 14}C-abiraterone acetate capsules, abiraterone acetate gidrolizuacy to abiraterone, which in turn was subjected to metabolism including sulphation, hydroxylation and oxidation primarily in the liver. Majority of circulating ¹⁴C-abiraterone acetate (approximately 92%) were in the form of a metabolite of abiraterone. Of 15 detectable metabolites in each of the two main metabolites of abiraterone sulfate and N-oxide of abiraterone sulfate accounted for 43% of the total radioactivity.

Excretion. According to the research conducted with the participation of healthy volunteers, the average T_1/2of abiraterone in plasma was approximately 15 h after oral administration of labeled ¹⁴C-abiraterone acetate at a dose of 1 g, approximately 88% of the radioactive dose were derived through the intestine and approximately 5% were withdrawn by the kidneys. The main substances found in the feces was unchanged abiraterone of acetate and abiraterone (approximately 55 and 22% of the administered dose, respectively).

Special groups of patients

Patients with hepatic insufficiency. The pharmacokinetics of abiraterone acetate was studied in patients with mild to moderate hepatic insufficiency (class A and b according to the classification of child-Pugh, respectively), and healthy volunteers. Systemic effects of abiraterone acetate after a single oral administration at a dose of 1 g was estimated to be 11% in patients with mild hepatic insufficiency and 260% in patients with moderate hepatic insufficiency. The Average T_1/2 abiraterone increased until about 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, dosage adjustment is not required. The drug Xbira ^® not recommended to appoint patients with moderate or severe hepatic insufficiency (class B or C child-Pugh), because in this case it is impossible to predict the necessary dose adjustment. Therefore, the drug Xbira ^® should be used with caution in patients with impaired hepatic function moderate degree only if the benefit of treatment clearly outweighs the potential risk. The drug Xbira ^® should not be prescribed to patients with severe impairment of liver function. The patients in whom the therapy with the drug developed hepatotoxicity, may require temporary drug discontinuation and dose adjustment.

Patients with renal insufficiency. The pharmacokinetics of abiraterone compared in patients with end-stage renal disease receiving standard pattern of hemodialysis, and in patients with normal renal function. Systemic effects of abiraterone acetate after ingestion in a dose of 1 g in patients with end-stage renal disease receiving hemodialysis, have not increased. Caution is advised when prescribing the drug Xbira ^®to patients with prostate cancer with impaired renal function, severe as clinical data on the use of drugs Xbira ^®such patients do not exist.

The influence of the interval QT. Established that the drug Xbira ^® has no significant influence on the interval QT/QTc.

The testimony of the drug Xbira ^®

The treatment of metastatic castrate-resistant prostate cancer (in combination with prednisone).

Contraindications

hypersensitivity to the active substance or to any subsidiary of the drug substance;

severe impairment of liver function;

children up to age 18 years.

C caution: lactase deficiency, lactose intolerance, glucose-galactose malabsorption; patients with prostate cancer with impaired renal function severe (clinical data on the use of drugs Xbira ^® in such patients do not exist); treatment of patients whose condition may deteriorate due to the increase in blood pressure or the development of hypokalemia (including patients with heart failure, recent myocardial infarction or ventricular arrhythmia, ejection fraction of left ventricle less than 50%, heart failure III–IV functional class classification NYHA).

Side effects

The most frequent adverse events in the treatment of drug Xbira ^® are peripheral edema, hypokalemia, increased blood pressure, urinary tract infection, hematuria, increased activity of AST, increased ALT activity, dyspepsia, fractures.

Adverse reactions are systematized with respect to each of the organ systems using the following classification of frequency: very common (≥1/10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), including isolated cases.

Infections and infestations: very often — infection of the urinary tract; often sepsis.

From the endocrine system: rare — lack of adrenal function.

Laboratory findings: very often — hypokalemia; often hypertriglyceridemia, increased ALT activity, AST.

From the side of musculoskeletal system and connective tissue: often — fractures (excluding pathological fractures); rarely, rhabdomyolysis, myopathy.

The kidneys and urinary tract: often — hematuria.

From the CCC: often — the AD; often — heart failure, including congestive heart failure, left ventricular failure, the decrease of the ejection fraction of the left ventricle; angina, arrhythmia, atrial fibrillation, tachycardia; frequency is unknown, myocardial infarction.

The respiratory system: rarely, allergic alveolitis.

From the blood: very often — diarrhea; often — neuralgia.

General disorders: very often — peripheral edema.

The skin and subcutaneous tissue: often — skin rash.

Interaction

The potential impact of other drugs on the impact of abiraterone. In the study in healthy volunteers pharmacokinetic interaction strong inducer of the isoenzyme CYP3A4 rifampicin, 600 mg daily for 6 days and then single dose of abiraterone acetate 1000 mg, the mean plasma AUC_∞of abiraterone decreased by 55%.

Avoid joint use of the drug Xbira ^® and strong inducers of isoenzyme CYP3A4(e.g. phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). The purpose of this group of drugs is possible only after a careful evaluation of clinical efficacy.

The potential impact of the drug Xbira ^® 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 effectiveness of abiraterone acetate (plus prednisone) on a single dose of substrate CYP2D6 of dextromethorphan, the systemic impact of dextromethorphan was increased approximately 200%. AUC₂₄ for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%.

Recommended with caution the drug Xbira ^® patients receiving drugs that are metabolized by the isoenzyme CYP2D6, especially for drugs with a narrow therapeutic index. In such cases, consider dose reduction of drugs with a narrow therapeutic index metabolized by the isoenzyme CYP2D6, including such as metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecanide, codeine, oxycodone and tramadol.

In the same study when determining the effectiveness of abiraterone acetate (plus prednisone) on a single dose of the substrate CYP1A2 theophylline was observed a change in systemic exposure to theophylline.

The study CYP2C8 interactions drug-drug in healthy subjects, the AUC of pioglitazone was increased by 46% and AUC of M-III and M-IV, each of the active metabolites of pioglitazone, decreased by 10% with the introduction of pioglitazone together with a single dose of abiraterone acetate 1000 mg. Although these results show that not expected to be clinically significant increase of exposure if the drug Xbira ^® used in combination with other drugs that are eliminated mainly CYP2C8, patients should be observed for signs of toxicity of substrates of CYP2C8 with a narrow therapeutic index if used simultaneously with the drug Xbira ^®.

Method of application and doses

Inside, 1 hour before or 2 hours after a meal, swallow whole, not liquid, squeezed small amounts of water.

The recommended daily dose of Xbira ^® is 1 g (4 table. 250 mg) 1 times a day. The drug Xbira ^® is applied together with low dose prednisolone. The recommended dose of prednisolone is 10 mg/day.

The drug Xbira ^® can not be taken with food.

Within 1 h after administration of the drug is not recommended meal. Before the start of drug treatment Xbira ^®, every 2 weeks during the first 3 months of treatment and then monthly to measure the activity of serum transaminases and bilirubin concentration. HELL, the concentration of potassium in the blood and the degree of fluid retention in the body should be assessed on a monthly basis. When skipping the next daily dose Xbira ^® next day should take a missed dose of the drug.

Dose adjustment in patients with hepatic impairment

Dose adjustment in patients with liver dysfunction of mild degree is not required. There is no data on the efficacy and safety of abiraterone acetate after repeated use in patients with impaired liver moderate or severe degree (grade B or C child-Pugh), so it is impossible to predict the necessary dose adjustment. The drug Xbira ^® should be used with caution in patients with impaired hepatic function moderate extent and only in case if the benefit of treatment clearly outweighs the potential risk. The Drug Xbira ^® should not be prescribed to patients with impaired liver function severe.

If in the course of drug treatment patients developed signs of hepatotoxicity (increased ALT or AST 5 times ULN, or concentration of bilirubin 3 times ULN), therapy should be discontinued immediately until complete normalization of liver function.

Re-therapy in patients with normalizenewlines the liver can begin with a reduced dose of 500 mg (2 table.) 1 time a day. In this case, the control of activity of serum transaminases and bilirubin concentrations should be carried out at least every 2 weeks for 3 months, and then monthly. If hepatotoxicity occurs at doses of 500 mg, therapy drug Xbira ^® should be discontinued.

If patients in any treatment period develop severe form of hepatotoxicity (the activity of ALT or AST exceeds 20 times the ULN), the drug Xbira ^® should be abolished, the re-appointment of the drug in such patients is impossible.

Special groups of patients

Use in patients with hepatic insufficiency. For patients with before treatment of the liver mild (class a according to the classification of child-Pugh), dosage adjustment is not required. The drug Xbira ^® should be used with caution in patients with impaired liver moderate extent and only in case if the benefit of treatment clearly outweighs the potential risk. The drug Xbira ^® should not be prescribed to patients with liver dysfunction severe (grade b and C according to the classification of child-Pugh).

Use in patients with renal insufficiency. For patients with impaired renal function dose adjustment is not required. However, care should be taken to prescribe the drug Xbira ^® to patients with prostate cancer with impaired renal function, severe as clinical data on the use of drugs Xbira ^® in these patients are lacking.

Children. For children the drug Xbira ^® are out of date, since this age group is not prostate cancer.

Overdose

Treatment: no specific antidote. In case of overdose, the drug Xbira ^® should be discontinued and undertake General supportive measures, including monitoring of arrhythmia. You should also monitor liver function.

Special instructions

The drug Xbira ^® in conjunction with food significantly increases the absorption of abiraterone. The efficacy and safety of the drug Xbira ^®, taken with food, is not established. The drug Xbira ^®can not be taken with food.

Increase in blood pressure, hypokalemia and fluid retention due to mineralocorticoid excess

The drug Xbira ^® may cause increased blood pressure, hypokalemia and fluid retention due to the increase in the concentration of mineralocorticoids by inhibiting the enzyme CYP17. Use of corticosteroids weakens the stimulating effect of ACTH that leads to a decrease in the frequency and severity of these adverse reactions. Caution should be exercised when treating patients, the clinical condition which may worsen with increased blood pressure, the development of hypokalemia, or fluid retention in the body (e.g. patients with heart failure, recent myocardial infarction or ventricular arrhythmia).

The drug Xbira ^® should be used with caution in patients with cardiovascular diseases in anamnesis. The safety of the drug in patients with ejection fraction of left ventricle <50% or with heart failure III–IV functional class classification NYHA not installed.

Before beginning use of the drug Xbira ^® should be adjusted hypokalemia and increased blood pressure.

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

Hepatotoxicity and abnormal liver function

In clinical studies was a marked increase in the activity of liver enzymes that required cancellation or correction of the dose. The activity of serum transaminases and bilirubin should be measured prior to use of the drug Xbira ^®, every 2 weeks during the first 3 months of treatment, and then monthly. With the development of clinical symptoms and signs that suggest liver dysfunction, should immediately to measure the activity of serum transaminases.

Increased activity of ALT or AST 5 times ULN or bilirubin concentrations 3 times the ULN the drug Xbira ^® should be discontinued immediately and closely monitor liver function. The drug Xbira ^® , you can apply again only after return of liver function tests to the original values, but only if the appointment of lower doses.

If patients in any treatment period develop severe form of hepatotoxicity (the activity of ALT or AST exceeds 20 times the ULN), the drug Xbira ^® should be abolished, the re-appointment of the drug in such patients is impossible.

Dose adjustment in patients with liver dysfunction of mild degree is not required. There is no data on the efficacy and safety of repeated use of abiraterone acetate in patients with impaired liver moderate or severe degree (grade B or C child-Pugh), therefore the need for dose adjustment cannot be predicted. The drug Xbira ^® should be used with caution in patients with impaired hepatic function moderate degree only if the benefits of treatment clearly outweigh the potential risks. The Drug Xbira ^® should not be prescribed to patients with impaired liver function severe.

Женщины детородного возраста

Препарат Xbira ^® не предназначен для применения у женщин. Предполагается, что прием ингибиторов CYP17беременными женщинами изменит концентрацию гормонов, что может повлиять на развитие плода. Для предотвращения случайного воздействия беременные или способные забеременеть женщины не должны работать с препаратом без перчаток.

Contraception men and women

It is unknown whether abiraterone or its metabolites in the semen. You must use a condom if you plan to have sexual intercourse with a pregnant woman. If intercourse is planned with a woman of childbearing age, you must use a condom along with other effective methods of contraception.

Fertility

Studies of the toxic effects of abiraterone acetate on the reproductive system have not been conducted, data on the impact of the drug on fertility is not.

Pregnancy and lactation

The drug Xbira ^® is not used in women. Data on the use of drugs Xbira ^® in pregnant women no. The drug Xbira ^® is contraindicated in pregnant and fertile women.

Unknown is displayed if abiraterone acetate or its metabolites in milk.

The abolition of corticosteroids, and relief of stressful situations

If you cancel the prednisolone should be cautious and control the signs of failure of function of the adrenal cortex. If the drug Xbira ^® continues after the abolition of GCS, you should control the symptoms of mineralocorticoid excess. In patients receiving prednisone during the development of stressful situations may require increased dosage of corticosteroids before, during, and after the stressful situation.

Co-administration of the drug Xbira ^® and chemotherapy

The safety and efficacy of co-administration of the drug Xbira ^® and cytotoxic chemotherapy not established.

Some of the auxiliary substances with the drug Xbira ^®

This medicinal product contains 1 mmol (to 27.2 mg) sodium per dose (4 tab.), what you need to take into account when treating patients receiving a diet with controlled sodium content.

Effect on driving and operating machinery. The drug Xbira ^® no effect or has a negligible influence on the ability to control the car and moving mechanisms.

Release form

Tablets, 250 mg , 120 tabl. in a bottle of HDPE, sealed polypropylene lid with protection against opening by children. 1 FL. in the cardboard pack.