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

Composition:Each tablet contains:
Active substance: abiraterone acetate 250 mg.
Excipients: lactose monohydrate - 198.65 mg, microcrystalline cellulose - 141.22 mg, croscarmellose sodium - 42.90 mg, povidone (K29 / K32) - 35.75 mg, sodium lauryl sulfate - 28.60 mg, silicon dioxide colloid - 7.15 mg, magnesium stearate - 10.73 mg.

Description:

Oval biconvex tablets from white to almost white with engraving "AA250".

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 17a-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 17a-hydroxylation and breaking of the C 17.20 bond into the testosterone precursors: dehydroepiandrosterone and androstenedione, respectively. Deceleration of activity CYP17 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 Zitig® together with the agonists of lu-liberin (or orchidectomy) lowers serum testosterone concentrations to below the detection threshold.

Pharmacodynamics

Zitiga® 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® received progression of the pain syndrome.

Risk of development of bone complications

In comparison with the placebo group, a smaller proportion of patients receiving Zitig® received bone lesions, including pathological fracture, spinal compression, palliative bone irradiation, and surgical bone treatment.

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 Zitig® is administered orally, the time to reach the maximum concentration of abiraterone in the blood plasma is approximately 2 hours. Taking Zitiga® with food, in comparison with taking 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 of abiraterone (C_m_Oh), depending on the fat content of the food. Taking into account the normal diversity in the content and composition of food, taking Zitig® with food has the ability to exert a variety of systemic effects. Therefore, Zitiga® should 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 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 major metabolites - abiraterone sulfate and N- 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 abiraterone after single administration in a dose of 1 gincreased 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, the preparation Zitiga® Caution should be used with caution in patients with moderate liver function impairment only if the benefit of treatment clearly outweighs the possible risk. Zitig's drug® It 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 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 administer Zitig® to patients with prostate cancer who have severe renal dysfunction, as there are no clinical data on the use of Zytiga® in these patients.

Influence on the interval Q-T

It has been established that the Zitiga® preparation has no 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 under 18 years;

- Severe liver dysfunction.

Carefully:

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

- Caution should be used to administer Zitig® to patients with prostate cancer who have severe renal dysfunction, as there are no clinical data on the use of Zytiga® in these patients.

- Caution should be exercised 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 with women. It is not known whether abiraterone acetate or its metabolites with milk is excreted.

Dosing and Administration:

Doses

The recommended daily dose of Zytiga® is 1 g (4 tablets of 250 mg) once a day for 1 hour before meals or 2 hours after eating. 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. Blood pressure, concentration potassium in the blood and the degree of fluid retention in the body should be evaluated 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.Zitiga® should be used with caution in patients with moderate liver function disorders, and only if the benefits of treatment clearly outweigh the risks. Zitig® should not be given to patients with severe liver dysfunction.

If during the treatment with the drug the 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 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 (two tablets) 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® therapy should be discontinued.

If patients at 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), Zytiga® should be withdrawn, 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. Zitiga® should be used with caution in patients with impaired liver function of moderate degree, and only if the benefit of treatment clearly outweighs the possible risk. Zitig® should not be given to patients with severe hepatic dysfunction, Class B and C, 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 Zitiga® in patients with prostate cancer who have severe renal dysfunction, as there are no clinical data on the use of Zytiga® in these patients.

Children

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

Side effects:

The most frequent adverse events in Zitig® 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 with using the next classification of frequency occurrence:

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

Highly often: infection urinary tract.

Often: sepsis.

Disorders from the endocrine system

Infrequently: insufficiency of function adrenal glands.

Influence on the results of laboratory studies

Very often: hypokalemia.

Often: hypertriglyceridemia, increased activity alanine aminotransferase, increased activity aspartate aminotransferase.

Musculoskeletal disorders

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.

Common violations

Very often: peripheral edema.

Disturbances from the skin and subcutaneous tissues:

Often: skin rash.

Overdose:

Data on overdose of Zitig® 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 decreased by 55%.

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

Potential impact of Zitig's drug® 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 The systemic effect of dextromethorphan increased by approximately 200%. AUC₂₄ for dextrorphan, an active metabolite of dextromethorphan, increased by approximately 33%.

It is recommended that the Zitig® preparation be administered with caution to patients receiving drugs that are metabolized by an 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 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 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 Zitig® is used 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 used concomitantly with Zitiga®.

Special instructions:

Taking Zitiga® concomitantly with food significantly increases absorption of abiraterone. The effectiveness and safety of Zitig®, 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® can cause increased blood pressure, hypokalemia and fluid retention due to increased mineralocorticoid concentrations 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).

Zitig® should be given with caution to 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 Zitig®, hypokalemia and increased blood pressure should be corrected.

Blood pressure, concentration potassium in blood plasma and the degree of delay liquid should be monitored as 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® 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 (activity alanine aminotransferase or Aspartate aminotransferase exceeds the upper limit of the norm by a factor of 20), Zytiga® should be withdrawn, re-administration of the drug in such patients is impossible.

Correction of the dose in patients with impaired liver function of mild degree is not required. No performance or safety data 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 potential risk. Zitig® should not be given to patients with severe liver dysfunction.

Women of childbearing age

Zitiga® is 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 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 abolition of glucocorticosteroids, then symptoms of an excess of mineralocorticoids should be monitored. In patients receiving prednisolone when developing stressful situations, an increased dose of glucocorticosteroids may be required before, during and after a stressful situation.

Simultaneous administration of Zitig® and chemotherapy

The safety and efficacy of the simultaneous administration of Zitig® and cytotoxic chemotherapy have not been established.

Information on some of the excipients included in the preparation Zitiga®

This medication contains 1 mmol (27.2 mg) of sodium in each dose (four tablets) that must be taken into account when treating patients receiving a diet with a controlled sodium.

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

Zitiga® 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 bottle of high-density polyethylene, sealed with a polypropylene lid with a system to protect children from opening.

One bottle in a pack of cardboard along with instructions for medical use.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep in original packaging 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-001632

Date of registration:06.04.2012

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

Manufacturer: & nbsp

BIOSINTEZ, PAO Russia

JANSSEN-CILAG, S.p.A. Italy

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

Information update date: & nbsp09.06.2015

Illustrated instructions

Instructions

Zitiga® (Zytiga®)