Андрокур®

General characteristics. Structure:

Active agent:
tsiproterona acetate, micro 20 - 100,0 mg
Excipients:
lactoses monohydrate - 193,0 mg, starch corn - 100,0 mg, povidone of 25000 - 4,0 mg,
magnesium stearate - 3,0 mg.
Description. Kapsulovidnye, from white till light yellow color of a tablet, with risky on one party, on both sides risks squeezed out "LA". On other party of a tablet the hexagon is squeezed out.

Pharmacological properties:

Pharmacodynamics. Андрокур® is an anti-androgenic hormonal drug. Tsiproteron on the competitive mechanism oppresses action of androgens on their target organs, for example, protects a prostate from influence of androgens of gonads and/or bark of adrenal glands. Tsiproteron possesses the central anti-gonadotropic action leading to decrease in synthesis of testosterone in testicles and its contents in blood serum.  As a result  androgenic  stimulation of fabric is suppressed.
prostate. At men at use of the drug Androkur® oppression of sexual desire, potentiality and function of testicles is observed. These effects are completely reversible and pass after the treatment termination. The anti-gonadotropic effect of a tsiproteron is also shown in a combination with agonists a gonadotrophin-rileasing of hormone (GNRG). The temporary increase in concentration of testosterone in blood serum observed at an initial stage of therapy by GNRG agonists decreases at reception of a tsiproteron. Sometimes at reception of high doses of a tsiproteron increase in concentration of prolactin was noted.
System toxicity. According to standard preclinical trials of toxicity at repeated long introduction there is no specific risk for the person.

Pharmacokinetics.

Absorption. Tsiproteron is completely soaked up after intake. Absolute bioavailability of a tsiproteron about 88%.
Distribution. The maximum concentration of a tsiproteron (Cmax) in blood serum after reception of a dose in 100 mg reaches 239,2±114,2 ng/ml on average in 2,8±1,1 hours. Decrease in concentration of a tsiproteron in blood serum has two-phase character and happens during 24-120 h to a final elimination half-life (T1/2) of 42,8±9,7 h. The general clearance of a tsiproteron makes 3,8±2,2 ml/min. of serum. Tsiproteron almost completely contacts plasma albumine. About 3,5-4% of a tsiproteron remain untied. As communication with proteins is not specific, change of content of the globulin connecting sex hormones does not influence pharmacokinetics of a tsiproteron. Owing to the long period of removal in a final phase of elimination from plasma, and also daily reception, cumulation of a tsiproteron in serum by 3 times big is probable at use of repeated doses for one cycle of treatment.
Metabolism / biotransformation. Tsiproteron is metabolized by a hydroxylation and conjugation. The main metabolite in a blood plasma - 15P-hydroxy-derivative. The first phase of metabolism is catalyzed preferential by an isoenzyme of P450 CYP3A4 cytochrome.
Removal. Is exposed to biotransformation in a liver, it is removed generally in the form of metabolites with bile and kidneys (an elimination half-life of 1,9 days) in the ratio 3:7, a part is removed in not changed view with bile. Metabolism in a blood plasma happens to the same speed (an elimination half-life of 1,7 days).

Indications to use:

Widespread inoperable or metastatic prostate cancer in need of suppression of effect of testosterone:
• anti-androgenic therapy of an inoperable prostate cancer;
• reduction of expressiveness of the giperandrogeniya which is observed at the beginning of therapy by agonists a gonadotrophin-rileasing of hormone (GNRG);
• stopping of "inflows" at the patients with cancer of a prostate receiving therapy by GNRG agonists or at the patients who transferred an orkhiektomiya.

Route of administration and doses:

Pill should be taken daily inside after food, washing down with a small amount of liquid. At emergence of signs of progressing of a disease drug should be cancelled.
The maximum daily dose of the drug Androkur® makes 300 mg.
Anti-androgenic therapy of an inoperable prostate cancer
On 200-300 mg a day (on 1 tablet 2-3 times a day). At improvement of a state or
achievement of remission it is not necessary to interrupt treatment or to reduce a dose.
Reduction of expressiveness of the giperandrogeniya which is observed at the beginning of therapy by agonists a gonadotrophin-rileasing of hormone (GNRG);
On 200 mg a day (on 1 tablet 2 times a day) as monotherapy during 5-7
days, then within 3-4 weeks in the same dose in combination with GNRG analogs in the dose recommended by the manufacturer.
Stopping of "inflows" at the patients with cancer of a prostate receiving therapy by GNRG agonists or at the patients who transferred an orkhiektomiya.
On 50-150 mg a day (on V2-1V2 to a tablet in day) if necessary with the subsequent increase in a dose up to 300 mg a day (on 1 tablet 3 times a day). Use for certain categories of patients: Children's and teenage age.
Андрокур® it is not recommended to apply at children and teenagers up to 18 years because of insufficient information by efficiency and safety at this category of patients. Advanced age
There are no data on need to change a drug dose at elderly patients. Liver failure
Use of the drug Androkur® is contraindicated to patients with liver diseases (until indicators of a liver are not normalized). Renal failure
There are no data on need to change a dose at this category of patients.

Features of use:

There are messages on direct dozozavisimy toxic impact of the drug Androkur® on a liver (development of jaundice, hepatitis and liver failure). Besides, at use of drug in a dose of 100 mg and it was reported about cases from the death above. The majority of cases with deadly an outcome was noted at men at a late stage of a prostate cancer. Usually a hepatotoxic is shown in several months after an initiation of treatment.
During treatment regular control of function of a liver is necessary. Functional hepatic trials should be carried out before an initiation of treatment, it is regular during treatment, and also at emergence of the signs allowing to assume a hepatotoxic action of drug. In the presence of hepatotoxic signs administration of drug should be cancelled. At patients with metastasises of a prostate cancer in a liver and in the presence of signs of an abnormal liver function, in cases when the expected advantage of the carried-out therapy exceeds possible risk, the issue of continuation of administration of drug is resolved individually.
Seldom or never against the background of use of the drug Androkur® development of tumors of a liver which could lead to life-threatening intra belly bleeding was noted. In case of severe pains in a stomach, increases in a liver or symptoms of intra belly bleeding when carrying out the differential diagnosis it is necessary to consider a possibility of existence of tumors of a liver. Also more was reported about development of meningiomas (single and multiple) in connection with long (within several years) administration of drug of Androkur® in a dose of 25 mg. In case of identification of a meningioma at the patient receiving treatment by the drug Androkur®, reception of this drug has to be stopped.
It was reported about emergence of tromboembolic episodes at the patients accepting Androkur® though existence of relationship of cause and effect was not revealed. At patients with the previous тромботическими / thromboembolic diseases of arteries or veins (for example, a deep vein thrombosis, an embolism of a pulmonary artery, a myocardial infarction), with disturbances of cerebral circulation in the anamnesis or at late stages of malignant diseases the risk of emergence of tromboembolic episodes is increased.
During treatment by the drug Androkur® it was reported about development of anemia. Therefore during treatment by the drug Androkur® it is necessary to make a research of peripheral blood regularly.
Patients with a diabetes mellitus need careful medical observation as the need for peroral hypoglycemic means or insulin can change.
Use of the drug Androkur® in high doses can sometimes be followed by an asthma. In similar cases when carrying out the differential diagnosis it is necessary to take into account the known promoting effect of progesterone and synthetic gestagen on the breath accompanied with a hypocapny and a compensatory respiratory alkalosis. Special treatment at this symptom complex is not required.
During treatment by the drug Androkur® it is regularly necessary to check function of a bast layer of adrenal glands as, proceeding from preclinical data, possible suppression of function of adrenal glands in connection with kortikoidopodobny effect of the drug Androkur® in high doses is supposed.
The drug Androkur® contains 193,0 mg of lactose in 1 tablet. Patients with rare hereditary diseases of intolerance of milk sugar, a lactose intolerance, a sprue of glucose and a galactose have to use this drug with care.
Influence on driving of motor transport and control of mechanisms
During treatment by the drug Androkur® it is necessary to be careful during the driving of the car and occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

The most often observed side effects: decrease in a libido, impotence and reversible suppression of a spermatogenesis.
The most serious side effects: a hepatotoxic, benign and malignant tumors of a liver which can lead to intra belly bleeding and development of thromboembolic processes.
The undesirable phenomena about which it was reported at drug Androkur® use are listed below. Frequency is determined as: very often (> 1/10), it is frequent (from> 1/100 to <1/10), infrequently (from> 1/1000 to <1/100), is rare (from> 1/10000 to <1/1000), is very rare (<1/10000). For the undesirable   effects revealed only in the course of post-marketing observations and for which it is not possible to estimate frequency it is specified "frequency is unknown".
From the hemopoietic system:
frequency is unknown - anemia.
From immune system:
seldom - hypersensitivity reactions.
Disturbances of mentality:
often - a depression, the suppressed mood, feeling of concern (temporary). From vessels:
frequency is unknown - thrombosis and thromboembolisms. From system of breath: often - an asthma.
From digestive tract:
frequency is unknown - intra belly bleeding.
From a liver and biliary tract:
often - jaundice, hepatitis, a liver failure.
From skin and hypodermic fabrics:
infrequently - rash.
From a musculoskeletal system:
frequency is unknown - osteoporosis.
From generative organs and mammary glands:
very often - reversible suppression of a spermatogenesis, decrease in a libido, erectile
dysfunction;
often - a gynecomastia.
Others:
often - increase or decrease in body weight, increased fatigue, "inflows", the increased perspiration;
very seldom - development of benign or malignant tumors of a liver; frequency is unknown - development of a meningioma.
The undesirable phenomena for which it is possible to find more detailed information in the section "Special Instructions" are marked with an asterisk the Undesirable phenomena for which the causal interrelation with administration of drug of Androkur® is not proved, marked with asterisks. Address the section "Contraindications".
Against the background of treatment by the drug Androkur® sexual desire and a potentiality decrease, besides, function of gonads is suppressed. These changes have reversible character and take place after therapy cancellation.
Within several weeks as a result of anti-androgenic and anti-gonadotropic
effects of the drug Androkur® there is a suppression of a spermatogenesis which is gradually recovered in several months after therapy cancellation. At men administration of drug of Androkur® can lead to development of a gynecomastia (that sometimes is followed by the increased tactile sensitivity and morbidity of nipples), which usually passes after drug withdrawal or a dose decline. As well as when using other anti-androgenic drugs, caused by drug
Андрокур® long deficit of androgens can lead to development of osteoporosis. Also more was reported about development of meningiomas in connection with long (within several years) administration of drug of Androkur® in a dose of 25 mg.

Interaction with other medicines:

Patients with a diabetes mellitus need careful medical observation as the need for peroral hypoglycemic means or insulin can change.
As ципротерон it is metabolized by CYP3A4 isoenzyme, it is supposed that its combined use with ketokonazoly, itrakonazoly, Clotrimazolum, ritonaviry and other powerful inhibitors of an isoenzyme CYP3A4 will suppress metabolism of a tsiproteron. CYP3A4 isoenzyme inductors, such as rifampicin, Phenytoinum and drugs of a plant origin on the basis of the St. John's Wort which is made a hole can reduce concentration of a tsiproteron.
In the researches in vitro it is shown that at high therapeutic doses of a tsiproteron (100 mg 3 times a day) the inhibition of isoenzymes of system of P450 cytochrome, such as CYP2C8, 2S9, 2S19, 3A4 and 2D6 is possible. Nevertheless, in the researches in vivo interaction with CYP2C8 substrates (for example, пиоглитазон, росиглитазон) was not studied and not fixed.
At combined use of high doses of a tsiproteron with GMG-KOA-reduktazy inhibitors (statines) which are also metabolized preferential by SUR3A4 isoenzyme the risk of development of a myopathy and rabdomioliz which are connected with reception of statines can increase.

Contraindications:

• Hypersensitivity to a tsiproteron or to other components of drug.
• Liver diseases (including a syndrome the Cudgel Johnson, the Rotor syndrome), liver tumors in the anamnesis or now (except for metastasises of a prostate cancer in a liver).
• A cachexia (except for a cachexia at a prostate cancer).
• Heavy chronic depression.
• Thromboses and thrombembolia now.
• Existence of a meningioma now or in the anamnesis.
• Children and teenagers up to 18 years.
 With care
In the presence patients with an inoperable prostate cancer have fibrinferment and thromboembolisms in the anamnesis, a severe form of a diabetes mellitus with an angiopatiya, a sickemia of Androkur® is appointed only after assessment of an individual ratio of advantage and risk in each case.
Patients with rare hereditary diseases of intolerance of milk sugar, a lactose intolerance, a sprue of glucose and a galactose have to use this drug with care.

Overdose:

Researches of acute toxicity after single use of drug showed what ципротерон can be considered as almost non-toxic substance. The risk of acute intoxication after single accidental dose of the dose several times exceeding the recommended therapeutic dose is improbable. There is no specific antidote. If necessary it is recommended to carry out symptomatic therapy.
Interaction with other medicines
Patients with a diabetes mellitus need careful medical observation as the need for peroral hypoglycemic means or insulin can change.
As ципротерон it is metabolized by CYP3A4 isoenzyme, it is supposed that its combined use with ketokonazoly, itrakonazoly, Clotrimazolum, ritonaviry and other powerful inhibitors of an isoenzyme CYP3A4 will suppress metabolism of a tsiproteron. CYP3A4 isoenzyme inductors, such as rifampicin, Phenytoinum and drugs of a plant origin on the basis of the St. John's Wort which is made a hole can reduce concentration of a tsiproteron.
In the researches in vitro it is shown that at high therapeutic doses of a tsiproteron (100 mg 3 times a day) the inhibition of isoenzymes of system of P450 cytochrome, such as CYP2C8, 2S9, 2S19, 3A4 and 2D6 is possible. Nevertheless, in the researches in vivo interaction with CYP2C8 substrates (for example, пиоглитазон, росиглитазон) was not studied and not fixed.
At combined use of high doses of a tsiproteron with GMG-KOA-reduktazy inhibitors (statines) which are also metabolized preferential by SUR3A4 isoenzyme the risk of development of a myopathy and rabdomioliz which are connected with reception of statines can increase.

Storage conditions:

To store at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity of 5 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets on 100 mg.
On 10 tablets in the blister from PVC and aluminum foil. 6 blisters together with the application instruction place in a cardboard pack.