Zytiga - instructions for use, dose, side effects, contraindications

Intragranular phase: lactose monohydrate 253.2 mg, croscarmellose sodium 22.4 mg, hypromellose 2910 15 mPa * with 16.8 mg, sodium lauryl sulfate 5.6 mg; extragranular phase: microcrystalline siliconized cellulose 184.8 mg, croscarmellose sodium 56.0 mg, sodium lauryl sulfate 56.0 mg, silicon dioxide colloid 8.4 mg, magnesium stearate 16.8 mg.

Tablet casing: fall off II85F90093 magenta 33.6 mg.

* Composition of Opadrai II 85F90093 purple: polyvinyl alcohol 40.00%, titanium dioxide 23.10%, macrogol 3350 20.20%, talc 14.80%, iron oxide red 1.40%, iron oxide black 0.50%.

Description:

Oval, biconvex tablets covered with a film coat of brownish pink color, engraved with the inscription "AA" on one side and "500" on the other side.

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. Anti-androgen therapy, for example, the use of lu-liberin agonists or conduction of orchidectomy, weaken the synthesis of androgens in the testicles, but does not affect the synthesis of androgens in the adrenals and in the tumor.The use of Zyttig together with agonists of lyu-liberin (or orchidectomy) reduces the concentration of serum testosterone to a level below the detection threshold.

Pharmacodynamics

Zitig's drug reduces the concentration of testosterone and other androgens in the serum 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 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 Zitig compared with the placebo group. In addition, compared to patients receiving placebo, a smaller proportion of patients receiving Zitig's preparation experienced progression of pain syndrome.

Risk of development of bone complications

Compared to the placebo group, a smaller proportion of patients treated with Zytig had bone lesions, including pathological fracture, spinal compression, palliative bone irradiation, and surgical bone treatment.

Use of spironolactone

Patients who participated in the main clinical trials of Zytig were not allowed to use spironolactone, t. 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

When oral Zitiga is administered on an empty stomach, the time to reach the maximum concentration of abiraterone in the blood plasma is approximately 2 hours. Taking Zitig with food, in comparison with taking the drug on an empty stomach, leads to a 10-fold increase in the area under the concentration-time curve (AUC) and a 17-fold increase in the maximum concentration of abiraterone (C_mOh), depending on the fat content of the food. Taking into account the normal diversity in the content and composition of food, taking Zitig's food with food has the ability to exert a variety of systemic effects.Therefore, the drug Zitiga can not be taken with food.

Distribution

Binding to plasma-labeled proteins ¹⁴C-abiraterone 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 capsules, abiraterone acetate hydrolyses 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 A-oxide abiraterone sulfate - accounted for 43% of the total radioactivity.

Excretion

According to studies conducted with healthy volunteers, the average half-life of abiraterone 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 was studied in patients with mild to moderate hepatic insufficiency (class A and B according to the Child-Pugh classification, respectively) and in healthy volunteers. Systemic exposure to abirterone after 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. 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. Zitiga 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, Zyttig should be used with caution in patients with moderate liver function disorders, only if the benefits of treatment clearly outweigh the possible risks. Zitig should not be given 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 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. Caution should be used to prescribe Zitig's drug to patients with prostate cancer with impaired renal function of severe severity, as there are no clinical data on the use of Zytig in these patients.

Influence on the interval Q-T

It was found that the Zitig preparation does not have a significant effect on the interval Q-T / QTc.

Indications:The preparation Zitiga 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 used to prescribe Zitig's drug to patients with prostate cancer with impaired renal function of severe severity, as there are no clinical data on the use of Zytig in these patients.

- Care should be taken in the treatment of patients whose condition may worsen with increased blood pressure or 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.

Pregnancy and lactation:

Zitiga does not apply the women. There are no data on the use of Zytiga in pregnant women. The drug Zitiga 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 Zyttig is 1 g (2 tablets of 500 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. Zitiga is used together with low doses of prednisolone. The recommended dose of prednisolone is 10 mg / day.

Zitig should not be taken with food.

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

Before starting treatment with Zitig, every 2 weeks for 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 miss a regular daily dose of Zitig, 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. Zitig should be used with caution in patients with moderate liver function disorders, and only if the benefits of treatment clearly outweigh the risks. Zitig preparation can not be administered to patients with 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 the concentration of bilirubin 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 (one tablet) once a day.In this case, the control of the activity of serum transaminases and bilirubin concentration should be carried out at least every two weeks for three months, and then monthly. If signs of hepatotoxicity occur when taking a dose of 500 mg, Zitig should be discontinued.

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

Special patient groups

Use in patients with hepatic impairment

For patients who have a mild liver function disorder (class A Child-Pugh classification) prior to treatment, dose adjustment is not required. Zitig should be used with caution in patients with moderate liver function disorders, and only if the benefits of treatment clearly outweigh the risks. Zitig can not be administered to patients with severe hepatic 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.

Nevertheless, caution should be given to Zitig in patients with prostate cancer with impaired renal function of severe severity, as there are no clinical data on the use of Zyttig in these patients.

Children

For children, the use of Zitiga is irrelevant, since prostate cancer does not occur in this age group.

Side effects:

The most common adverse events in Zitig's treatment 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 classification:

Very often (≥1 / 10)

Often (≥1 / 100, <1/10)

Infrequently (≥1 / 1000, <1/100)

Rarely (≥1 / 10000, <1/1000)

Very rarely (<1/10000), including isolated cases.

Infectious diseases

Very often: urinary tract infections.

Often: sepsis.

Disorders from the endocrine system

Infrequent: insufficiency of adrenal function.

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, including acute heart failure, left ventricular failure, a decrease in the fraction of the ejection of the left ventricle; stenocardia, arrhythmia, atrial fibrillation, tachycardia.

The frequency is 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.

Disturbances from the skin and subcutaneous tissues:

Often: skin rash.

Overdose:

Data on the overdose of Zytig are limited.

There is no specific antidote. In case of an overdose, Zitig should be discontinued and general supportive measures should be taken, 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 was reduced by 55%.

It is necessary to avoid joint use of Zitig and strong isoenzyme inducers CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital). The purpose of this group of drugs is possible only after a thorough evaluation of clinical efficacy.

Potential impact of Zitig 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 prednisone) per dose of the substrate dextromethorphan CYP2D6 systemic effect of dextromethorphan increased by about 200%. AUC₂₄ for dextrorphan, the active metabolite of dextromethorphan, increased by approximately 33%.

It is recommended to prescribe with caution the preparation Zitiga 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, 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 substrates of theophylline there was no systemic effect of theophylline substrate.

In the study CYP2C8 drug-drug interactions on healthy subjects, 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 Zitig preparation 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 concomitantly with Zitig's preparation.

Special instructions:

Taking Zitig while taking food significantly increases absorption of abiraterone. The effectiveness and safety of Zitig's drug, taken with food, is not established. Zitig should not be taken with food.

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

Zitig's drug 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).

Zitiga should be given 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 according to the NYHA classification is not established.

Before starting the use of Zitig, you 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 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 starting Zitig, every two weeks for the first three 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.

If the activity of alanine aminotransferase or aspartate 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, Zitig should be stopped immediately and liver function should be carefully monitored. Zitig's drug can be used again only after the return of liver function to the initial values, and only if lower doses are prescribed.

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.

Zitiga should be used with caution in patients with moderate liver function disorders, only if the benefits of treatment clearly exceed the risk. Zitig preparation can not be administered to patients with severe liver dysfunction.

Women of childbearing age

Zitiga is not suitable for use in women. It is assumed that taking CYP17 inhibitors 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 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 toxic effects of abiraterone acetate on 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 Zytiga continues after the removal of glucocorticosteroids, then the symptoms of excess 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.

Simultaneous administration of Zitig and chemotherapy

The safety and efficacy of simultaneous prescription of Zitig and cytotoxic chemotherapy have not been established.

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

Zitiga The drug has no effect or has a negligible effect on the ability to drive and moving machinery.

Form release / dosage:Tablets, film-coated, 500 mg.

Packaging:

6 or 12 tablets in blister PVDC \ polyethylene \ PVC substrate with aluminum foil.

For 5 blisters in a cardboard box together with instructions for use.

Storage conditions:

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-003965

Date of registration:15.11.2016

Expiration Date:15.11.2021

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

JANSSEN-CILAG, S.p.A. Italy

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp14.10.2017

Illustrated instructions

Instructions

Zytiga (Zytiga)