Zitiga

General characteristics. Structure:

Active agent: abiraterone acetate - 250 mg.

Excipients: lactoses monohydrate - 198,65 mg, cellulose microcrystallic - 141,22 mg, sodium of a kroskarmelloz - 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.

Pharmacological properties:

Action mechanism.

Abiraterone in vivo acetate turns into abiraterone which is inhibitor of biosynthesis of androgens. In particular, abiraterone selectively suppresses activity of enzyme 17α-gidroksilazy/C17,20-liazy (CYP17). This enzyme expresses and is necessary for biosynthesis of androgens in testicles, adrenal glands and cells of a tumor of a prostate. CYP17 catalyzes transformation of a pregnenolon and progesterone by 17α-гидроксилирования and a rupture of communication of C17,20 in predecessors of testosterone: дегидроэпиандростерон and androstendion, respectively. Braking of activity of CYP17 is also followed by strengthening of synthesis of mineralokortikoid in adrenal glands.

The androgen-sensitive prostate cancer reacts to the treatment reducing concentration of androgens. Anti-androgenic therapy, for example, use of agonists of a lyu-liberin or carrying out an orchidectomy, weaken synthesis of androgens in testicles, but do not influence synthesis of androgens in adrenal glands and in a tumor. Use of the drug Zitiga® together with agonists of a lyu-liberin (or an orchidectomy) reduces concentration of testosterone in blood serum of definition up to one level lower than a threshold.

Pharmacodynamics. The drug Zitiga® reduces concentration of testosterone and other androgens in serum is lower than those indicators which manage to be received against the background of use of agonists lyu-a liberina or after an orchidectomy. It happens because of the selection inhibition of CYP17 enzyme which is required for biosynthesis of androgens. Concentration of the prostates-specific antigen (PSA) serves as a biomarker at patients with a prostate cancer.

Analgetic effect. The share of patients at whom the palliative analgetic effect was noted was authentically higher when using drug Zitiga®, in comparison with group of placebo. Besides, in comparison with the patients receiving placebo at a smaller share of the patients receiving the drug Zitiga® progressing of a pain syndrome was noted.

Risk of development of bone complications. In comparison with group of placebo at a smaller share of the patients receiving the drug Zitiga® cases of damage of a bone tissue to which the pathological fracture, a spinal compression, palliative radiation of a bone, surgical treatment of a bone were carried were noted.

Pharmacokinetics. The pharmacokinetics of abiraterone of acetate and abiraterone was studied at healthy volunteers, at patients with late stages of a metastatic prostate cancer and at not oncological patients, with a renal or liver failure. Abiraterone in vivo acetate quickly turns into abiraterone which is inhibitor of biosynthesis of androgens.

Absorption. At oral administration of the drug Zitiga® on an empty stomach time of achievement of the maximum concentration of abiraterone in a blood plasma makes about 2 hours. Administration of drug of Zitiga® with food, in comparison with administration of drug on an empty stomach, is led to 10-fold increase in the area under a curve by "concentration time" (AUC) and to 17-fold increase in the maximum concentration of abiraterone (Cmax), depending on fat content of the eaten food. In view of a normal variety of contents and structure of food, administration of drug of Zitiga® with food possesses to sposobnostyyuokazyvat various system influence. Therefore, the drug Zitiga® cannot be accepted with food.

Distribution. Linkng with proteins of plasma of marked 14C-abiraterone makes 99,8%. The seeming volume of distribution makes about 5 630 l that demonstrates that abiraterone is actively distributed in peripheral fabrics.

Metabolism. At oral administration of 14C-abiraterone of acetate in capsules, abiraterone acetate is hydrolyzed to abiraterone which in turn is exposed to metabolism, including sulphation, a hydroxylation and oxidation, mainly, in a liver. The most part of the circulating 14C-abiraterone (about 92%) was in a form of metabolites of abiraterone. From 15 metabolites which are giving in to detection, - abiraterone sulfate and N-oxide of abiraterone sulfate - was the share of each of two main metabolites on 43% of the general radioactivity.

Removal. According to the researches conducted with participation of healthy volunteers, the average elimination half-life of abiraterone in plasma makes about 15 hours. At oral administration of marked 14C-abiraterone of acetate in a dose of 1 g about 88% of a radioactive dose it was removed through intestines and about 5% were removed by kidneys. The main substances found in excrements were the acetate which is not changed abiraterone and abiraterone (about 55% and 22% of the entered dose respectively).

Special groups of patients. Patients with a liver failure. The pharmacokinetics of abiraterone was studied at patients with easy and moderate degree of a liver failure (a class A and B on classification of Chayld-Pyyu respectively) and at healthy volunteers. System influence of abiraterone after single use inside in a dose of 1 g increased approximately by 11% at patients with easy degree of a liver failure and for 260% at patients with moderate degree of a liver failure. The average elimination half-life of abiraterone increases approximately till 18 o'clock at patients with easy degree of a liver failure and approximately till 19 o'clock at patients with moderate degree of a liver failure. For the patients having easy degree of a liver failure, dose adjustment of drug is not required. Patients are not recommended to appoint drug of Zitiga with moderate or heavy degree of a liver failure (a class B ilis on Chayld-Pyyu) as in this case it is impossible to predict necessary dose adjustment. Therefore drug of Zitiga should be used with care at patients with abnormal liver functions of moderate degree, only if the advantage of treatment obviously outweighs possible risk. Patients cannot appoint drug of Zitiga with heavy insufficiency of function of a liver. Temporary drug withdrawal and dose adjustment can be required by patients at whom in the course of therapy by drug a hepatotoxic developed.

Patients with a renal failure. The pharmacokinetics of abiraterone was compared at the patients with an end-stage of a renal failure receiving the standard scheme of a hemodialysis and at patients to normal function of kidneys. System influence of abiraterone of acetate after intake in a dose of 1 g at the patients with an end-stage of a renal failure receiving a hemodialysis did not increase. It is necessary to appoint with care the drug Zitiga® to patients, patients with cancer of a prostate with a renal failure of heavy degree as clinical data on use of the drug Zitiga® for such patients are absent.

Influence on Q-T interval. It is established that the drug Zitiga® does not exert significant impact on Q-T/QTc interval.

Indications to use:

The drug Zitiga® in a combination with Prednisolonum is intended for treatment of a metastatic kastratsionno-resistant prostate cancer.

Route of administration and doses:

Doses.

The recommended daily dose of the drug Zitiga® makes 1 g (4 tablets on 250 mg) in 1 hour prior to food or in 2 hours after food once a day. It is necessary to swallow of tablets entirely, without chewing, washing down with a small amount of water.

The drug Zitiga® is used together with low doses of Prednisolonum. The recommended dose of Prednisolonum makes 10 mg/days. The drug Zitiga® cannot be accepted with food.

Within 1 hour after administration of drug meal is not recommended.

Prior to treatment by the drug Zitiga®, each 2 weeks within the first three months of treatment, and then monthly it is necessary to measure activity of serumal transaminases and concentration of bilirubin. Arterial pressure, potassium concentration in an organism should be estimated at blood and degree of a delay of liquid monthly. At the admission of the next daily dose of the drug Zitiga®, Prednisolonum it is necessary to accept a usual dose of the passed drug next day.

Dose adjustment at patients with an abnormal liver function.

Dose adjustment with an abnormal liver function of easy degree is not required from patients. There are no data on efficiency and safety of abiraterone of acetate at numerous use for patients with an abnormal liver function of moderate or heavy degree (the class B or C on Chayld-Pyyu) therefore it is impossible to predict necessary dose adjustment. The drug Zitiga® should be used with care at patients with abnormal liver functions of moderate degree and only if the advantage of treatment obviously outweighs possible risk. Patients cannot appoint the drug Zitiga® with an abnormal liver function of heavy degree.

If during treatment by drug at patients hepatotoxic signs developed (increase in activity of alaninaminotranspherase or aspartate aminotransferase by 5 times of the norm exceeding the upper bound or concentration of bilirubin by 3 times exceeding the upper bound of norm), therapy should be stopped immediately before full normalization of indicators of function of a liver.

Repeated therapy at patients with the normalized indicators of function of a liver it is possible to begin with the reduced dose 500 mg (two tablets) once a day. In this case control of activity of serumal transaminases and concentration of bilirubin has to be carried out, at least, each two weeks within three months, and then – monthly. If signs of a hepatotoxic arise at reception of a dose of 500 mg, therapy by the drug Zitiga® should be stopped.

If at patients the severe form of a hepatotoxic (activity of alaninaminotranspherase or aspartate aminotransferase exceeds the upper bound of norm by 20 times) develops in any period of therapy, the drug Zitiga® should be cancelled, repeated purpose of drug at such patients is impossible.

Special groups of patients.

Use for patients with a liver failure. For the patients having disturbance of functions of a liver of easy degree prior to treatment (a class A on classification of Chayld-Pyyu) dose adjustment of drug is not required. The drug Zitiga® should be used with care at patients with abnormal liver functions of moderate degree and only if the advantage of treatment obviously outweighs possible risk. Patients cannot appoint the drug Zitiga® with an abnormal liver function of heavy degree, a class B and C on classification of Chayld-Pyyu.

Use for patients with a renal failure. For patients with a renal failure of dose adjustment it is not required. Nevertheless, should appoint with care the drug Zitiga® patients, patients with cancer of a prostate with a renal failure of heavy degree as clinical data on use of the drug Zitiga® for such patients are absent.

Children.

For children use of the drug Zitiga® is irrelevant as this age category has no prostate cancer.

Features of use:

Administration of drug of Zitiga® along with food considerably increases abiraterone absorption. Efficiency and safety of the drug Zitiga® accepted with food is not established. The drug Zitiga® cannot be accepted with food.

Increase in arterial pressure, hypopotassemia and delay of liquid owing to surplus of mineralokortikoid.

The drug Zitiga® can cause increase in arterial pressure, a hypopotassemia and a delay of liquid because of increase in concentration of mineralokortikoid owing to CYP17 enzyme inhibition. Reception of corticosteroids weakens a promoting effect of adrenocorticotropic hormone (AKTG) that leads to decrease in frequency and weight of these side reactions. It is necessary to show care at treatment of patients whose clinical condition can worsen at increase in arterial pressure, development of a hypopotassemia or a delay of liquid in an organism (for example, at patients with heart failure, recently postponed myocardial infarction or with ventricular arrhythmia).

Patients should appoint the drug Zitiga® with care with cordial vascular diseases in the anamnesis. Safety of drug at patients with fraction of emission of a left ventricle <50% or with heart failure of the III-IV functional class on classification of NYHA is not established.

Before use of the drug Zitiga® it is necessary to correct a hypopotassemia and increase in arterial pressure.

Arterial pressure, potassium concentration in a blood plasma and degree of a delay of liquid should be controlled, at least, once a month.

Hepatotoxic and abnormal liver function.

In clinical trials the expressed increase in activity of liver enzymes demanding cancellation or dose adjustment of drug is registered. Activity of serumal transaminases and bilirubin should be measured prior to drug Zitiga® use, each two weeks within the first three months of treatment, and then monthly. At development of the clinical symptoms and signs allowing to assume an abnormal liver function it is necessary to measure activity of serumal transaminases immediately.

At increase in activity of alaninaminotranspherase or aspartate aminotransferase of norm 5 times higher than the upper bound or concentration of bilirubin is 3 times higher than the upper bound of norm, use of the drug Zitiga® should be stopped immediately, and it is necessary to control function of a liver carefully. The drug Zitiga® can be used again only after return of indicators of function of a liver to reference values, and only on condition of purpose of lower doses.

If at patients the severe form of a hepatotoxic (activity of alaninaminotranspherase or aspartate aminotransferase exceeds the upper bound of norm by 20 times) develops in any period of therapy, the drug Zitiga® should be cancelled, repeated purpose of drug at such patients is impossible.

Dose adjustment with an abnormal liver function of easy degree is not required from patients. There are no data on efficiency and safety of numerous use of abiraterone of acetate for patients with an abnormal liver function of moderate or heavy degree (the class B or C on Chayld-Pyyu) therefore need of dose adjustment cannot be predicted. The drug Zitiga® should be used with care at patients with abnormal liver functions of moderate degree, only in that case, the eslipolza from treatment obviously exceeds possible risk. Patients cannot appoint the drug Zitiga® with an abnormal liver function of heavy degree.

Women of childbearing age.

The drug Zitiga® is not intended for use for women. It is supposed that reception of CYP17 inhibitors by pregnant women will change concentration of hormones that can affect fetation. For prevention of accidental influence, pregnant or capable to become pregnant women should not work with drug without gloves.

Contraception at men and women.

It is unknown whether there is an abiraterone or its metabolites at sperm. It is necessary to use condom if sexual intercourse with the pregnant woman is planned. If sexual intercourse is planned with the woman of childbearing age, it is necessary to use condom along with other effective methods of contraception.

Ability to conceive.

Researches of toxic impact of abiraterone of acetate on reproductive system were not conducted, there are no data on influence of drug on ability to conceive.

Pregnancy and lactation.

The drug Zitiga® is not used at women. There are no data on use of the drug Zitiga® for pregnant women. The drug Zitiga® is contraindicated pregnant and capable to become pregnant to women. It is unknown whether acetate or its metabolites with milk is removed abiraterone.

Cancellation of glucocorticosteroids and stopping of stressful situations. At cancellation of Prednisolonum it is necessary to show care and to control signs of insufficiency of function of bark of adrenal glands. If use of the drug Zitiga® continues after cancellation of glucocorticosteroids, then it is necessary to control emergence of symptoms of surplus of mineralokortikoid. At the patients receiving Prednisolonum at development of stressful situations the raised dose of glucocorticosteroids before, in time and after a stressful situation can be required.

Co-administration of the drug Zitiga® and chemotherapy. Safety and efficiency of co-administration of the drug Zitiga® and cytotoxic chemotherapy are not established.

Information on some excipients entering about composition of the drug Zitiga®.

This medicine contains 1 mmol (27,2 mg) of sodium in each dose (four tablets) that it is necessary to take into account at treatment of the patients receiving a diet with the controlled content of sodium.

Influence on driving of the car and work with mechanisms.

The drug Zitiga® does not influence or renders small influence on ability to drive the car and moving mechanisms is insignificant.

Side effects:

The most frequent undesirable phenomena at treatment by the drug Zitiga® are peripheral hypostases, a hypopotassemia, increase in arterial pressure, an infection of urinary tract, a hamaturia, increase in activity of aspartate aminotransferase, increase in activity of alaninaminotranspherase, dyspepsia, fractures.

Undesirable reactions are systematized concerning each of systems of bodies with use of the following classification of frequency of occurrence:

- 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 frequent: infections of urinary tract.

Disturbances from endocrine system:

- Infrequent: insufficiency of function of adrenal glands.

Influence on results of laboratory researches:

- Very frequent: hypopotassemia.

- Frequent: gipertriglitseridemiya, increase in activity of alaninaminotranspherase, increase in activity of aspartate aminotransferase.

From a musculoskeletal system and connecting fabric:

- Frequent: changes (except for pathological changes).

Disturbances from kidneys and urinary tract:

- Frequent: hamaturia.

Disturbances from cardiovascular system:

- Very frequent: increase in arterial pressure.

- Frequent: heart failure, including acute heart failure, left ventricular failure, reduction of fraction of emission of a left ventricle; stenocardia, arrhythmia, fibrillation of auricles, tachycardia.

Disturbances from respiratory system:

- Rare: allergic alveolitis.

Disturbances from digestive tract:

- Frequent: dyspepsia.

General disturbances:

- Very frequent: peripheral hypostases.

Interaction with other medicines:

In the researches in vitro it was shown that abiraterone inhibits the hepatic isoenzymes participating in metabolism of medicines – CYP1A2, CYP2D6 and CYP2C8.

It is recommended to appoint with care the drug Zitiga® to the patients receiving drugs which are metabolized by CYP2D6 isoenzyme especially it concerns drugs with a narrow therapeutic index. In such cases it is necessary to consider the possibility of a dose decline of drugs with a narrow therapeutic index, metabolized CYP2D6 isoenzyme, including such drugs as метопролол, propranolol, desipramine, венлафаксин, a haloperidol, рисперидон, пропафенон, флекаинид, codeine, oxycodone and трамадол.

There are no clinical data on use of the drug Zitiga® with the drugs which are CYP2C8 isoenzyme substrates (for example, with paklitaksely and repaglidiny).

On the basis of these in vitro abiraterone is CYP3A4 isoenzyme substrate. It is necessary to show care at a concomitant use with strong inhibitors of an isoenzyme CYP3A4 (кетоконазол, итраконазол, кларитромицин, атазанавир, нефазодон, саквинавир, телитромицин, ритонавир, индинавир, нелфинавир, вориконазол) and inductors (Phenytoinum, carbamazepine, rifampicin, рифабутин, rifapentine, phenobarbital).

At a research of pharmacokinetic interaction of the strong inductor of an isoenzyme CYP3A4 on healthy volunteers - rifampicin, 600 mg a day within 6 days and then a single dose of abiraterone of acetate of 1000 mg, average plasma AUC ∞ abiraterone decreased by 55%.

It is necessary to avoid combined use of the drug Zitiga® and strong inductors of an isoenzyme CYP3A4 (for example, Phenytoinum, carbamazepine, rifampicin, рифабутин, rifapentine, phenobarbital). Appointment of this group of drugs is possible only after careful assessment of clinical performance.

In clinical pharmacokinetic trials on healthy volunteers the concomitant use of a ketokonazol, strong CYP3A4 inhibitor, did not render clinically significant effect on abiraterone pharmacokinetics.

Contraindications:

- Hypersensitivity to active component or any excipient of drug;

- Children's age up to 18 years;

- Heavy abnormal liver function.

With care:

- Deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption.

- It is necessary to appoint with care the drug Zitiga® to patients, patients with cancer of a prostate with a renal failure of heavy degree as clinical data on use of the drug Zitiga® for such patients are absent.

- It is necessary to show care at treatment of patients whose condition can worsen at increase in arterial pressure or development of a hypopotassemia, for example, of patients with heart failure, with recently postponed myocardial infarction or ventricular arrhythmia; fraction of emission of a left ventricle less than 50%, heart failure of the III-IV functional class on NYHA classification.

Overdose:

Data on overdose are limited to the drug Zitiga®. There is no specific antidote. In case of overdose administration of drug of Zitiga® should be stopped, and it is necessary to hold the general supporting events, including control of arrhythmia. Also it is necessary to control function of a liver.

Storage conditions:

At a temperature not above 30 °C. To store in original packaging in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, 250 mg. On 120 tablets in the bottle from polyethylene of high density corked by a polypropylene cover with system of protection against opening by children. On one bottle in a pack from a cardboard together with the instruction on a medical use.