Cyproterone

Pharmacological properties

Cyproterone acetate has an antiandrogenic, progestogen and antigonadotropic effect, confirmed during animal studies and with the participation of volunteers.

Preclinical studies. Antiandrogenic effect. Cyproterone acetate competitively suppresses the influence of androgens, which are formed endogenously and end up exogenously, on target organs. This leads to blockade of translocation of the DHT receptor complex in the cell nucleus. The results of experiments on cell cultures in vitro, conducted to test the effect of cyproterone acetate on the functions of androgen receptors, indicate a high antiandrogenic efficacy of cyproterone acetate. In addition, some in vitro test systems have shown a slight partial agonistic effect of cyproterone acetate on androgen receptors. Cyproterone acetate weakens or stops the stimulating effect of male sex hormones on androgen-dependent structures and functions: depending on the dose of cyproterone acetate in animals causes atrophy of the secondary sex glands. The testicular function is affected: spermatogenesis is inhibited depending on the dose. As in humans, in dogs, rabbits, pigs and monkeys, libido is suppressed as a result of the use of cyproterone acetate.

In rats, obstruction or a delay in the onset of puberty can occur. Cyproterone acetate inhibits the physiological closure of the bone growth zone and bone maturation.

The function of the sebaceous glands is disturbed, the thickness of the epidermis decreases.

Treatment of pregnant animals with cyproterone acetate leads to impaired development of the male fetus. The effect on the testosterone-dependent processes of differentiation is carried out, which leads to the emergence of more or less pronounced phenomena of feminization.

Gestagen action. The results of the Klauberg test (in rabbits) showed that the effectiveness of cyproterone acetate after sc administration was 100 times higher than the effectiveness of progesterone. In tests for the progestogenic effect in rats of cyproterone, acetate after sc administration was approximately as effective as progesterone.

Antigonadotropic effect. Like all potent gestagens, cyproterone acetate has antigonadotropic properties, which are manifested in males by inhibition of testicular growth, and in females - by inhibition of ovulation.

Clinical researches. Antiandrogenic effect. Cyproterone acetate competitively inhibits the effect of androgens on target organs. In humans, the following interrelated states have been described: inhibition of sexual desire, decreased activity of the sebaceous glands, effect on hair growth, delayed androgenic growth impulses in the tissue of the prostate gland, inhibition of premature pubertal development processes, as well as in bone tissue.

Gestagen action. Cyproterone acetate is a potent progestogen. According to the results of the Kaufman test, a total dose of 20-30 mg of the drug already leads to the transformation of the endometrium.

Antigonadotropic effect. As a strong progestogen, cyproterone acetate depresses the central nervous system. Due to this anti-gonadotropic effect, there is no increase in the secretion of LH reverse regulation, although as a result of the anti-androgenic effect of cyproterone acetate, androgens are replaced by hypothalamic receptors, with which they have a negative feedback. Even more secretion of LH and FSH is suppressed by the gestagen action of cyproterone acetate. As a result, the level of testosterone and estrogen in the blood serum decreases. This antigonadotropic effect in men is weakened, since the inhibitory effect of androgens decreases through the antiandrogenic components of the active substance that affects the hypothalamus.

Other effects on the function of the endocrine system. In the case of cyproterone acetate, the concentration of testosterone and estrogen is reduced.There was no significant effect on 17-ketosteroids and 17-ketogenic steroids. Cortisol secretion remains unchanged or decreased. The function of the hypothalamic-pituitary-adrenal axis in adults mainly remains unchanged. Evaluation of all the results allows us to conclude that the reactivity of the system, as a rule, is not damaged.

Pharmacokinetics After the intramuscular administration of cyproterone, the acetate is gradually released from the intramuscular depot. Its c_max in blood plasma is 180 ± 54 ng / ml and is achieved after 2-3 days. After this, the level of the hormone in the blood serum decreases with the final T_½ equal to 4 ± 1.1 days. The total clearance of cyproterone acetate from blood serum is 2.8 ± 1.4 ml / min / kg. Cyproterone acetate is metabolized in various ways, including hydroxylation and conjugation. The main plasma metabolite is the 15β-hydroxy derivative. Phase I metabolism is mainly catalyzed by the CYP 3A4 cytochrome P450 enzyme. An insignificant part of the dose taken is excreted unchanged with bile. Most of the substance is excreted in the form of metabolites with urine and bile in a ratio of 3: 7. Cyproterone acetate is almost completely bound to plasma albumin. About 3.5–4% of the total steroid level remains in a free state. Since protein binding is non-specific, a change in the level of sex steroid binding globulin does not affect the pharmacokinetics of cyproterone acetate. Due to long T_½ from the blood plasma in the final phase and the 7-day dosing interval with repeated administration, cumulation of cyproterone acetate in the blood plasma can be expected. After about 5 weeks, an equilibrium is reached between the release of cyproterone acetate from the depot and its elimination. The absolute bioavailability of cyproterone acetate after i / m injection is considered complete. Smoking does not affect the pharmacokinetics of cyproterone acetate.

Indications

Androfarm is intended for use exclusively in men.

Applicable:

• to reduce sexual desire during sexual deviations;
• for palliative therapy of metastatic or locally progressive inoperable prostate cancer, if treatment with LH-RH analogues or surgical intervention were insufficient or contraindicated;
• initially to reduce hot flashes, which may be caused by increased serum testosterone levels at the beginning of treatment with LH-RH agonists.

Application

Injections should be performed very slowly. the drug is intended for intramuscular injection only. Care must be taken to ensure that the substance that is administered does not enter the vessel.

To reduce sexual desire with pathological abnormalities in the genital area in men. Deviations in sexual behavior require treatment only if the symptoms of the disease are significant. The condition for the treatment is the patients desire to be treated.

The contents of one ampoule of the drug (3 ml) is administered every 10-14 days as a deep i / m injection. In exceptional cases, if the effect of the treatment is insufficient, 2 ampoules can be administered every 10-14 days, preferably 3 ml (content of one ampoule) in the right and left gluteus muscle (M. glutaeus maximus).

To stabilize the therapeutic effect, Androfarm must be used for a long time and, if possible, simultaneously with the implementation of psychotherapeutic measures. After achieving a satisfactory therapeutic result, it is advisable to reduce the dose by gradually increasing the interval between injections. Dose reduction or discontinuation of the drug should occur gradually.

For the treatment of inoperable prostate cancer. The content of one ampoule of the drug (3 ml) is administered 1 time per week in the form of a deep IM injection.With an improvement in the condition or remission of the disease, the prescribed dose of the drug should not be changed or treatment should be discontinued.

Initially to reduce hot flashes. The contents of one ampoule of the drug Androfarm (300 mg) should be administered once in the form of a deep IM injection.

Contraindications

• Liver disease Dabin-Johnson syndrome, rotor syndrome; liver tumors, including a history of; meningioma, including a history of; established malignant diseases or suspicion of their presence; severe chronic depression; thromboembolic conditions, including a history of; severe forms of diabetes with vascular complications; sickle cell anemia; hypersensitivity to the active substance or any of the components of the drug; children and adolescents until the end of the puberty (see application).

Side effects

The most common side effects observed in patients include decreased libido, erectile dysfunction, and reversible suppression of spermatogenesis.

The most serious adverse reactions observed in patients include hepatic toxicity, benign and malignant tumors of the liver, which can lead to the development of intra-abdominal bleeding, and thromboembolic events.

Neoplasms are benign, malignant and indefinite (including cysts and polyps): benign and malignant tumors of the liver, meningiomas.

From the circulatory and lymphatic systems: anemia.

From the immune system: hypersensitivity reactions.

Metabolic and nutritional disorders: an increase or decrease in body weight, an increase in blood glucose in patients with diabetes.

From the psyche: decreased libido, erectile dysfunction, depressed mood, anxiety (temporary).

Vascular disorders: pulmonary microembolism caused by the introduction of oil solutions, vasovagal reactions, thromboembolic events.

Diseases of the respiratory tract, organs of the chest cavity and mediastinum: shortness of breath.

From the gastrointestinal tract: nausea, vomiting, intra-abdominal hemorrhage.

From the hepatobiliary system: hepatotoxicity, including jaundice, hepatitis, liver failure.

From the side of the heart: coronary heart disease.

On the part of the skin and subcutaneous tissue: rash.

From the musculoskeletal system and connective tissue: osteoporosis.

From the reproductive system and mammary glands: reversible suppression of spermatogenesis, gynecomastia, sometimes combined with increased sensitivity of the breast nipples when touched and, as a rule, after the drug is discontinued.

General disorders and local reactions: increased fatigue, instantaneous general indifference, hot flashes, increased sweating, reactions at the injection site.

From the nervous system: headache.

Research: elevated prolactin levels, decreased cortisol levels.

During treatment with Androfarm, sexual desire and potency are reduced and the function of the sex glands is suppressed. These phenomena disappear after discontinuation of therapy.

Cyproterone acetate, due to its antiandrogenic and antigonadotropic effects, inhibits spermatogenesis within a few weeks of use. After cessation of treatment, spermatogenesis is gradually restored over several months.

As with other antiandrogen drugs, a prolonged decrease in androgen levels with the help of cyproterone acetate can cause osteoporosis. The development of meningiomas has been reported in connection with the prolonged use (for several years) of the drug at a dose of 25 mg or higher.

special instructions

Damage to the liver. in patients using cyproterone acetate, cases of hepatotoxicity, including jaundice, hepatitis and liver failure, have been reported.with the use of the drug in a dose of 100 mg and above, fatal cases have also been reported. most deaths occurred in the treatment of men with advanced prostate cancer. the toxicity of the drug is dose-dependent and usually develops after several months of treatment. Before starting treatment, regularly throughout the entire period of treatment and if any symptoms of hepatotoxicity are noted, liver function tests should be performed. if hepatotoxicity is confirmed in the absence of another reason for its occurrence (for example, in the presence of metastases), the use of cyproterone acetate is recommended to be canceled. treatment can only be continued if the benefits of the therapy outweigh the risk.

After the use of cyproterone acetate in isolated cases, the development of benign, and even less often, malignant liver tumors was observed. In some cases, intra-abdominal bleeding caused by these tumors was life threatening. With pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding during treatment with Androfarm, differential diagnosis should take into account the likelihood of a liver tumor. If necessary, treatment with the drug should be discontinued.

Meningioma The development of meningiomas (single or multiple) associated with prolonged use (for several years) of cyproterone acetate at a dose of 25 mg / day or higher has been reported. If a patient who is treated with Androfarm is diagnosed with meningioma, treatment with the drug must be discontinued.

Thromboembolic events. Thromboembolic events have been reported in patients using cyproterone acetate.

Patients with arterial or venous thrombotic / thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, myocardial infarction) or a history of cerebrovascular disease and patients with advanced tumors are at increased risk of developing further thromboembolic events.

It is necessary to be especially careful in prescribing the drug to patients with inoperable prostate cancer with a history of thromboembolic events, severe forms of diabetes with vascular lesions, or sickle cell anemia. In each case, it is necessary to assess the expected benefits of treatment and potential risk.

Anemia. During the use of cyproterone acetate, anemia has been reported. Given this, during the entire period of treatment, it is necessary to regularly do a blood test to determine the number of red blood cells.

Metabolism. In patients with diabetes mellitus during the use of cyproterone acetate, an increase in blood glucose levels was noted. Given this, it is recommended to carefully monitor the carbohydrate metabolism in patients with diabetes mellitus, since during the treatment with Androfarm the necessary dose of oral antidiabetic drugs or insulin can be changed.

At the beginning of treatment with Androfarm, a negative nitrogen balance may appear, which levels out during the period of use. In connection with this starting catabolic action, the Androfarm drug should not be prescribed for established malignant diseases or suspected their presence (with the exception of prostate cancer).

Dyspnea. In some cases, during the use of the drug Androfarm in high doses, a feeling of shortness of breath may be noted.

If you experience shortness of breath during the use of the Androfarm drug in differential diagnosis, it is necessary to take into account the known stimulating effect of progesterone and synthetic progestogens on the respiratory system, accompanied by hypocapnia and compensatory respiratory alkalosis. It is believed that such conditions do not require treatment.

Function of the adrenal cortex. During the entire period of treatment, it is necessary to regularly check the function of the adrenal cortex, since preclinical data indicate a possible suppression due to the corticoid-like effect of cyproterone acetate.

Spermatogenesis. Inhibition of spermatogenesis, which slowly develops during treatment and may be accompanied by infertility, is gradually restored after cessation of treatment. Within a few months, sometimes up to 20 months, after the end of therapy, spermatogenesis gradually normalizes, returning to the state that was before the start of taking Androfarm. Men of reproductive age for whom reproductive ability matters after the end of treatment is recommended to have at least one control spermatogram before treatment. Thus, it will be possible to refute possible unfounded allegations regarding the onset of infertility in the future as a result of antiandrogen therapy.

Depression. The action of cyproterone acetate is sometimes associated with an increased incidence of depressive mood, especially during the first 6-8 weeks of treatment. Patients with a history of depression should be closely monitored.

Cardiovascular diseases. Swelling and weight gain may occur. In this regard, cyproterone acetate should be used with caution in patients with thromboembolic cardiovascular disease.

Other data. Like all oil solutions, Androfarm should be administered only in oil and very slowly. Pulmonary microembolism caused by the introduction of oil solutions can lead to the development of symptoms such as coughing, shortness of breath and chest pain. Other symptoms are also possible, including vasovagal reactions, such as malaise, hyperhidrosis, dizziness, paresthesia, and a syncope. These reactions can occur during or immediately after injection and are reversible. Supportive therapy, such as oxygen administration, should also be used.

When prescribing the drug Androfarm for the treatment of pathological abnormalities in the genital area, it should be remembered that alcohol can neutralize the effect of the drug in relation to decreased sexual desire.

Elderly patients. There is no evidence of a dose adjustment for elderly patients.

Patients with liver failure. The use of the drug Androfarm is contraindicated in patients with liver diseases (until the parameters of the liver function return to normal).

Patients with renal failure. There is no evidence of dose adjustment for patients with renal failure.

Use during pregnancy and lactation. Do not use the drug in women.

Children. Androfarm is not recommended for use in children and adolescents (under 18 years of age) due to the lack of data on safety and effectiveness. Androfarm is not prescribed until puberty is completed, since the negative effect of the drug on the growth and endocrine system of the patient cannot be ruled out.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Patients whose activities require increased attention (for example, machine operators, drivers, etc.) should take into account that the use of the Androfarm drug can cause fatigue and a decrease in activity and ability to concentrate. The ability to respond can change in such a way that it decreases, actively participating in traffic and working with mechanisms.

Interactions

When treating with andropharm, it may be necessary to adjust the dose of oral antidiabetic drugs or insulin.

Clinical studies of the drug’s drug interaction have not been performed, but since it is metabolized with the participation of the CYP 3A4 enzyme, it is expected that ketoconazole, itraconazole, clotrimazole, ritonavir and other strong CYP 3A4 inhibitors inhibit the metabolism of cyproterone acetate.

Rifampicin, phenytoin, and medicines containing St. Johns wort, on the other hand, can lower cyproterone acetate.

Based on the results of an in vitro study, it can be assumed that the use of high therapeutic doses of cyproterone acetate (100 mg 3 times a day) may inhibit such isoenzymes of the P450 cytochrome system: CYP 2C8, 2C9, 2C19, 3A4 and 2D6. With the simultaneous use of statins and high therapeutic doses of cyproterone acetate, the risk of myopathy or rhabdomyolysis associated with statins may increase due to the same pathway of metabolism of these substances.

Overdose

The results of studies of acute toxicity of the drug after a single injection show that cyproterone acetate is a practically non-toxic substance. after a single random use of a dose several times higher than the therapeutic, acute intoxication was not observed.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° c.