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

Excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone K 25, sodium lauryl sulfate, magnesium stearate, silicon dioxide colloid.

Description:

Oval biconvex tablets are white or almost white, marble is allowed on the surface of the tablets.

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. In particular, abiraterone selectively inhibits the activity of the enzyme 17α-hydroxylase / C17,20-lyase (CYP 17).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. Antiandrogenic therapy, such as the use of lyuliberin agonists or orchidectomy, weakens the synthesis of androgens in the testes, but does not affect the synthesis of androgens in the adrenal glands and in the tumor. The use of abiraterone together with lylyberyrin agonists (or orchidectomy) lowers serum testosterone concentrations to below the detection threshold.

Pharmacodynamics

Abiraterone reduces the concentration of testosterone and other androgens in the serum 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 abirterone compared with the placebo group. In addition, compared to patients receiving placebo, a smaller proportion of patients who received abiraterone, there was a progression of pain syndrome.

Risk of development of bone complications

Compared to the placebo group, a smaller proportion of patients who received abiraterone, there were cases of damage to the bone tissue, which included a pathological fracture, spinal compression, palliative bone irradiation, and surgical bone treatment.

Use of spironolactone

Patients who participated in the main clinical trials of abiraterone were not allowed to use spironolactone, since its molecules bind to androgen receptors and can increase the level of PSA.

Pharmacokinetics:

The pharmacokinetics of abiraterone acetate and abiraterone have been studied in healthy volunteers, in patients with advanced metastatic prostate cancer and in non-oncological patients with renal or hepatic insufficiency. Abiraterone acetate in vivo quickly turns into a abiraterone, which is an inhibitor of androgen biosynthesis.

Absorption

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

Distribution

Binding to plasma-labeled proteins ¹⁴Abiraterone is 99.8%. The apparent volume of distribution is approximately 5,630 liters, indicating 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 (approximately 92%) was in the form of metabolites of abiraterone. Of the 15 detectable metabolites for each of the two main 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 half-life of abiraterone in plasma is approximately 15 hours. With oral administration of the labeled ¹⁴With abiraterone acetate 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 the feces 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 was studied in patients with mild to moderate hepatic insufficiency (Child-Pugh classes A and B, respectively) and in healthy volunteers.Systemic exposure to abirterone after a single oral dose of 1000 mg increased by approximately 11% in patients with mild liver failure and 260% in patients with moderate degree of hepatic insufficiency. The average half-life of abiraterone 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 Do not administer to patients with moderate or severe hepatic impairment (Child-Pugh class B or C). 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 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 1000 mg in patients with terminal stage of renal failure receiving hemodialysis did not increase. Abiraterone can not be administered to patients with prostate cancer, with impaired renal function of severe severity, as there is no clinical data on the use of abiraterone in such patients.

Influence on the interval QT

Determined that abiraterone does not have a significant effect on the interval QT/QTc.

Indications:

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

Contraindications:

- Hypersensitivity to the active or any auxiliary substance of the drug.

- Children under 18 years.

- Moderate and severe hepatic impairment.

- Severe degree of renal failure.

Carefully:

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

- Caution should be exercised in the treatment of patients whose condition may worsen with increased blood pressure or the development of hypokalemia,for example, patients with heart failure, with recent myocardial infarction or ventricular arrhythmia, left ventricular ejection fraction less than 50%, heart failure III-IV functional class by classification NYHA, severe and unstable angina.

Pregnancy and lactation:

Abiraterone not applicable the women. There are no data on the use of the drug in pregnant women. The drug Abiraterone-TL is contraindicated in pregnant women and able to become pregnant women. It is not known whether abiraterone acetate or its metabolites with milk is excreted.

Dosing and Administration:

Doses

The recommended daily dose of the drug Abiraterone-TL is 1000 mg (4 tablets of 250 mg) 1 time per day for 1 hour before meals or 2 hours after meals. Tablets should be swallowed whole, not liquid, squeezed with a small amount of water. The drug Abiraterone-TL is used together with low doses of prednisolone. The recommended dose of prednisolone is 10 mg / day.

The drug Abiraterone-TL can not be taken with food.

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

Before the beginning of treatment with Abariton-TL, every 2 weeks during 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 miss a regular daily dose of the drug Abiraterone-TL, prednisolone the next day should take the usual dose of the missed drug.

Correction of dose in patients with impaired liver function

Dose adjustments in patients with mild liver function are 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 (class B or C according to Child-Pugh classification), so it is impossible to predict the necessary dose adjustment. The drug Abiraterone-TL can not be administered to patients with impaired liver function of moderate and severe severity.

If during the treatment with the drug the patients developed signs of hepatotoxicity (increased activity of alanine aminotransferase (ALT) or aspartate aminotransferase (ACT) 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 stopped immediately before the liver function is 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 when taking a dose of 500 mg, therapy with Abiraterone-TL should be discontinued.

If patients in any period of therapy develop a severe form of hepatotoxicity (ALT activity or ACT exceeds the upper limit of the norm by 20 times), the drug Abiraterone-TL should be discontinued. Repeated prescription 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 mild severity (class A according to Child-Pugh classification) prior to treatment, dose adjustment is not required. The drug Abiraterone-TL can not be administered to patients with moderate and severe severity of liver function (Child-Pugh classes B and C).

Use in patients with renal insufficiency

For patients with impaired renal function, dose adjustment is not required. Nevertheless, the drug Abiraterone-TL can not be administered to patients with prostate cancer, with renal dysfunction of severe severity, since there are no clinical data on the use of abiraterone in such patients.

Children

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

Side effects:

The most frequent adverse events in the treatment of abirterone are peripheral edema, hypokalemia, increased blood pressure, urinary tract infections, hematuria, increased activity of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT), dyspepsia, fractures.

Undesirable reactions are systematized relative to each of the organ systems using the following classification of frequency: 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.

Influence on the results of laboratory studies: very often - hypokalemia; often hypertriglyceridemia, increased ALT activity and ACT.

Disturbances from the musculoskeletal system: 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, including acute heart failure, left ventricular failure, a decrease in the fraction of the ejection of the left ventricle; 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.

Disorders from the liver and bile ducts: rarely - fulminant hepatitis, acute liver failure.

Common violations: very often peripheral edema.

Disturbances from the skin and subcutaneous tissues: often - skin rash.

Overdose:

Data on drug overdose Abirateron-TL are limited. There is no specific antidote. In case of an overdose, the drug Abiraterone-TL 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 rifampicin in a dose of 600 mg / day. for 6 days and then abiraterone acetate in a single dose of 1000 mg in healthy volunteers the average plasma AUC ∞ abiraterone decreased by 55%. Avoid joint use of the drug Abiraterone-TL and strong isoenzyme inducers CYP3A4 (eg, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital, St. John's wort perfumed). The purpose of this group of drugs is possible only after a thorough evaluation of clinical efficacy.

In clinical studies of pharmacokinetic interactions of drugs in healthy volunteers, the use of ketoconazole, strong inhibitor of isoenzyme CYP3A4, had no clinically significant effect on the pharmacokinetics of abiraterone.

The potential effect of abiraterone on the action of other drugs

Abiraterone inhibits hepatic isozymes CYP2D6 and CYP2C8, participating in the metabolism of drugs. In a clinical study, in determining the efficacy of abiraterone acetate (plus prednisone) per single dose of substrate dextromethorphan CYP2D6 The systemic effect of dextromethorphan increased approximately 2.9 times. AUC24 for dextrorphan, an active metabolite of dextromethorphan, increased by approximately 33%.

It is recommended that caution be given abiraterone 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 as metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol.

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

In the study CYP2C8 drug-drug interactions on healthy volunteers AUC pioglitazone was increased by 46% and AUC_S 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 abiraterone apply in combination with other drugs that are eliminated primarily CYP2C8, patients should be observed for signs of toxicity associated with the substrate CYP2C8 with a narrow therapeutic index, if it is used concomitantly with abiraterone.

Medications that can lengthen the interval QT

Because androgen deprivation therapy can lead to lengthening of the interval QT, caution should be exercised when using abirterone with other medications that can lengthen the interval QT, or drugs capable of inducing ventricular tachycardia such as pirouettes, such as antiarrhythmic drugs of class IA (eg, quinidine, disopyramide) or class III (for example, amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, antipsychotics etc.

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 taking abiraterone.

Special instructions:

Reception of abiraterone simultaneously with food significantly increases the absorption of abiraterone. The effectiveness and safety of abiraterone taken with food is not established. Abiraterone can not be taken with food.

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

Abiraterone 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 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 in the treatment of patients whose clinical condition may worsen with increased blood pressure, hypokalemia or fluid retention in the body (eg, in patients with heart failure, recent myocardial infarction or ventricular arrhythmia, severe or unstable angina, and those with severe impairment kidney function).

Abiraterone 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 with heart failure III-IV functional class by classification NYHA not installed.

Before starting the use of abiraterone, hypokalemia and increased blood pressure should be corrected.

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

Hepatotoxicity and impaired liver function

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 start of abirterone, every 2 weeks during the first months of treatment, and then monthly. With the development of clinical symptoms and signs suggesting a violation of liver function, it should immediately measure the activity of serum transaminases.

When the activity of ALT is increased or ACT 5 times higher than the upper limit of the norm or bilirubin concentration 3 times higher than the upper limit of the norm, the use of abiraterone should be stopped immediately and the liver function is carefully monitored. Abiraterone can be used again only after the return of liver function to the initial values, and only if lower doses are prescribed.

If patients in any period of therapy develop a severe form of hepatotoxicity (ALT activity or ACT exceeds the upper limit of the norm by 20 times), abiraterone should be canceled. Repeated prescription of the drug in such patients is impossible. Dose adjustments in patients with mild liver function are not required. There is no data on the efficacy and safety of repeated use of abirateroneacetate in patients with impaired liver function of moderate or severe severity (class B or C according to the Child-Pugh classification), so the need for dose adjustment can not be predicted. The drug Abiraterone-TL can not be administered to patients with impaired liver function of moderate and severe severity.

Women of childbearing age

Abiraterone is not suitable for use in women. It is assumed that taking inhibitors of SRM 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.

Contraception in men and women

It is not known whether there is abiraterone or its metabolites in semen. It is necessary to use a condom if a 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 were not conducted,data on the effect of the drug on the ability to conceive there.

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 abirterone continues after the abolition of glucocorticosteroids, then the symptoms of an excess of mineralocorticoids should be monitored. In patients receiving prednisolone when developing stressful situations, you may need an increased dose of glucocorticosteroids before, during, and after a stressful situation.

Density of bone tissue

In men with metastatic castration-resistant prostate cancer, a decrease in bone density may be observed. With the simultaneous use of abiraterone and glucocorticosteroids, this effect can be intensified.

Previous use of ketoconazole

In patients who had previously received ketoconazole for the treatment of prostate cancer, a lower response rate to abiraterone therapy can be expected.

Hyperglycaemia

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

Simultaneous administration of abiraterone and chemotherapy

The safety and efficacy of concurrent administration of abiraterone and cytotoxic chemotherapy have not been established.

Effect on the musculoskeletal system

When using abirterone, cases of myopathy were recorded. In some patients, rhabdomyolysis with renal insufficiency was observed. In most cases, these conditions developed during the first month of treatment, and after

Abortion was reversed. Caution should be exercised when using abirterone and other drugs that can cause myopathy / rhabdomyolysis.

Information on some excipients, included in the drug Abirateron-TL

This medication contains lactose. The drug Abiraterone-TL should be taken with caution in patients with lactose intolerance, lactase deficiency or glucose-galactose malabsorption. This drug contains more than 1 mmol (27.2 mg) of sodium in each dose (4 tablets), which must 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 Abiraterone-TL does not affect or has little effect on the ability to drive and move vehicles.

Form release / dosage:

Tablets 250 mg.

Packaging:

For 10 tablets in a contour mesh package made of a combination film (polyvinyl chloride / polyvinylidene chloride) and foil aluminum printed lacquered.

For 120 tablets in a can of polymer (made of polyethylene or polypropylene) for drugs, sealed with a polymer cover (made of polyethylene or polypropylene) with a desiccant and control of the first opening.

Each jar or 12 contour squares, together with instructions for use, is placed in a pack of cardboard boxes.

Storage conditions:

In 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 the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004543

Date of registration:15.11.2017

Expiration Date:15.11.2022

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

Information update date: & nbsp12.12.2017

Illustrated instructions

Instructions

Abiraterone-TL (Abiraterone-TL)