Abiter - instructions for use, doses, side effects, contraindications

giprolose 50.0 mg, silicon dioxide colloid 7.2 mg, croscarmellose sodium 43.0 mg, lactose monohydrate 189.7 mg, sodium lauryl sulfate 28.6 mg, sodium stearyl fumarate 10.7 mg, povidone K30 35.8 mg, cellulose microcrystalline 100.0 mg.

Description:

Tablets of oval form biconcave from white to white with a yellowish tint of 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. In 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. Antiandrogenic therapy, such as the use of lu-liberin agonists or orchidectomy, weakens the synthesis of androgens in the testes, but does not affect the synthesis of androgens in the adrenal gland and tumor. The use of abirterone together with agonists, lu-liberin (or orchidectomy), reduces testosterone concentration in serum to a level 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 lu-liberin agonists 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 PSA serves as a biomarker in patients with prostate cancer. Use of spironolactone

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

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 receiving abiraterone, there were cases of damage to the bone tissue, which included a 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

For oral administration of abirterone acetate on an empty stomach. Achievement of maximum concentration (Tmoh) 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 curve "concentration-time" (AUC) and a 17-fold increase in the maximum concentration (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 acetate with food has the ability to exert a diverse systemic effect. Therefore, the drug abiraterone can not be taken with food.

Distribution

Binding to plasma-labeled proteins¹⁴C-abiraterone is 99.8%. Apparent volume of distribution (Vd) 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 underwent 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 main metabolites - abiraterone sulfate and N- oxide abiraterone sulfate - accounted for 43% of the total radioactivity.

Excretion

According to studies conducted with healthy volunteers, the mean T1 / 2 of abiraterone in plasma is approximately 15 hours. With oral administration of 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 abiraterone after a single oral administration at a dose of 1 g increasedapproximately 11% in patients with mild liver failure and 260% in patients with moderate hepatic impairment. 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. A drug abiraterone It can not be administered to patients with moderate or severe liver dysfunction. 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 1 g in patients with terminal stage of renal failure receiving hemodialysis did not increase. A drug abiraterone can not be prescribed to patients with prostate cancer, with impaired renal function of a serious degree, because clinical data on the use of the drug abiraterone these patients are absent.

Influence on the interval Q-T.

It was found that the drug abiraterone does not have a significant effect on the interval QT/QTc.

Indications:

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 under 18 years;

- The average and severe degree of hepatic insufficiency;

- 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 (eg, patients with heart failure, 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).

Dosing and Administration:

Inside once a 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 recommended daily dose of the drug abiraterone is 1 g (4 tablets of 250 mg each). A drug abiraterone is used together with low doses of prednisolone. The recommended dose of prednisolone is 10 mg / day.

Abiraterone can not be taken with food.

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

Before starting treatment with the drug abiraterone, every 2 weeks during the first three 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, prednisolone the next day 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. A drug abiraterone It can not be administered to patients with moderate or severe liver dysfunction.

If during treatment with the drug in patients developed signs of hepatotoxicity (increased activity of alanine aminotransferase or aspartate aminotransferase, 5 times higher than the upper limit of the norm, or bilirubin concentration 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 (two 250 mg 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, drug therapy abiraterone should be discontinued.

If patients in any period of therapy develop a severe form of hepatotoxicity (the activity of alanine aminotransferase exceeds the upper limit of the norm by a factor of 20), the drug abiraterone should be abolished, 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, dosage adjustment is not required.

A drug abiraterone can not be administered to patients with a moderate and severe liver dysfunction, Class B and C according to Child-Pugh classification.

Use in patients with renal insufficiency

For patients with impaired renal function, dose adjustment is not required.

However, the drug abiraterone can not be prescribed to patients with prostate cancer, with impaired renal function of a serious degree, because clinical data on the use of the drug abiraterone these patients are absent.

Children

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

Side effects:

The most frequent adverse events in the treatment of the drug abiraterone 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 classification: very frequent (≥1 / 10); frequent (≥1 / 100, <1/10); infrequent (≥1 / 1000, <1/100); Rare (≥1 / 10000, <1/1000); very rare (<1/10000), 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 activity of alanine aminotransferase, increased activity of aspartate aminotransferase.

Disturbances from the musculoskeletal 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, reduction of the 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 the excretory pathways:

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 abiraterone are limited. There is no specific antidote. In case of an overdose, taking the drug abiraterone should be discontinued and general supportive interventions, including arrhythmia control. 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 abiraterone and strong isoenzyme inducers CYP3A4 (eg, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital, St. John's wort pitted). The purpose of this group of drugs is possible only after a thorough evaluation of clinical efficacy.

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

Potential impact of the drug abiraterone on the effect 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 prednisolone) per dose of the substrate dextromethorphan CYP2D6 the systemic effect of dextromethorphan, the active metabolite of dextromethorphan, increased by approximately 33%.

It is recommended to prescribe with caution the drug 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 drugs 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 prednisolone) per dose CYP1A2 substrates of theophylline did not observe the systemic effect of theophylline.

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 the drug abiraterone apply in combination with other drugs that are predominantly elliminated 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 the drug abiraterone.

Medicines that can lengthen the interval QT

Because androgen deprivation therapy can lead to lengthening of the interval QT, It is recommended to exercise caution when using the drug abiraterone with other drugs capable of lengthening the interval QT, or drugs capable of inducing a ventricular pirouette tachycardia, 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 using the drug abiraterone.

Special instructions:

Reception of the drug abiraterone simultaneously with food significantly increases the absorption of abiraterone. Efficacy and safety of the drug abiraterone, taken with food, is not established. A drug abiraterone can not be taken with food.

Increased blood pressure, Hypokalaemia and fluid retention and heart failure due to excess mineralocorticoids

A drug 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 corticosteroids weakens the stimulating effect of adrenocorticotropic hormone (ACTH), which leads to a decrease in the frequency and severity of these adverse reactions. Care should be taken when treating patients,the clinical state of which may worsen with increased blood pressure, development of hypokalemia, or fluid retention in the body (for example, in patients with heart failure, recent myocardial infarction, ventricular arrhythmia, severe or unstable angina, and those with severe renal impairment).

A drug 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 preparation abiraterone should correct hypokalemia and increase blood pressure.

Arterial pressure, the concentration of potassium in the blood plasma and the degree of fluid retention should be monitored at least 1 time per 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 drug is started abiraterone, every 2 weeks for the first 3 months of treatment, and then monthly. With the development of clinical symptoms and signs that allow suggest a violation of liver function, should immediately measure the activity of serum transaminases.

If the activity of alanine aminotransferase or aspartate aminotransferase is increased 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, abiraterone should be stopped immediately, and liver function should be carefully monitored. A drug abiraterone can be used again only after the return of liver function to the baseline values and only if lower doses are prescribed.

If patients in any period of therapy develop a severe form of hepatotoxicity (the activity of alanine aminotransferase or aspartate aminotransferase exceeds the upper limit of the norm by a factor of 20), the drug abiraterone should be abolished, re-administration of the drug in such patients is impossible.

Dose adjustments in patients with mild liver function disorder are 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. A drug abiraterone It can not be administered to patients with moderate or severe liver dysfunction.

Women of childbearing age

A drug abiraterone not suitable 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 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 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.

Pregnancy and lactemia

A drug abiraterone does not apply to women. Data on the use of the drug abiraterone Pregnant women do not. A drug abiraterone contraindicated in pregnancy and able to become pregnant with women. It is not known whether abiraterone acetate or its metabolites with milk is excreted.

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 abiraterone continues after the abolition of glucocorticosteroids, then the symptoms of an excess of mineralocorticoids should be monitored. In patients receiving prednisolone, with the development of stressful situations, an increased dose of glucocorticosteroids may be required 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 the drug abiraterone and glucocorticosteroids, this effect can be enhanced.

Previous use of ketoconazole

In patients who had previously received ketoconazole for prostate cancer therapy, a lower response rate to drug therapy abiraterone.

Hyperglycaemia

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

Simultaneous administration of the drug abiraterone and chemotherapy

Safety and efficacy of concomitant administration of the drug abiraterone and cytotoxic chemotherapy have not been established.

Effect on the musculoskeletal system

When using the drug abiraterone cases of myopathy have been reported. To some patients rhabdomyolysis with renal insufficiency was observed. In most cases, these conditions developed during the first month of treatment, and after the drug was discontinued abiraterone there was a recovery. Care should be taken when using the drug simultaneously abiraterone and other drugs that can cause myopathy / rhabdomyolysis.

Information on some of the excipients included with the preparation of abiraterone

This medication contains lactose. A drug abiraterone should be taken with caution to patients with lactose intolerance, lactase deficiency or glucose-galactose malabsorption. This medication contains more than 1 mmol (27.2 mg) of sodium in each dose (4 tablets), which must be taken into account in the treatment of patients receiving a diet with a controlled sodium content.

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

A drug abiraterone has little or no effect on the ability to drive and move vehicles.

Form release / dosage:

Tablets 250 mg.

Packaging:

Primary packaging of medicinal product.

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 30, 60, 120 tablets in a can of polymeric polyethylene with a cover pulled with the control of the first opening. Free space is filled with cotton wool. On cans are labeled with paper label or from polymer materials, self-adhesive.

Secondary packaging of medicinal product.

For 3 or 6 contour squares, together with the instructions for use, they are placed in a pack of cardboard for consumer containers.

On 1 bank together with instructions on application place in a pack from a cardboard for consumer tare.

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 the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004531

Date of registration:13.11.2017

Expiration Date:13.11.2022

The owner of the registration certificate:Pharmaceuticals Nord, JSCPharmaceuticals Nord, JSC Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp05.12.2017

Illustrated instructions

Instructions

Abiter (Abitera)