Cyproterone, Estradiol

Pharmacological properties

Klimen refers to combined biphasic estrogen-progestogen hormonal preparations intended for the prevention and treatment of complications of the menopause and estrogen deficiency. the preparation contains estrogen - estradiol valerate, which is a prodrug of natural human 17 β-estradiol and cyproterone acetate - a synthetic derivative of hydroxyprogesterone with progestogen, antigonadotropic and antiandrogenic properties.

The composition and cyclic regimen of the use of the drug, which includes taking estrogen only for 11 days and an estrogen-progestogen combination for 10 days with a further 7-day break in therapy, causes a woman to recover the menstrual cycle in a woman with an unexplained uterus (subject to regular use of the drug).

While taking Klymene, ovulation is not inhibited, but there is a significant effect on the endogenous production of hormones. Due to the fact that Klimen is a drug for cyclic therapy, it can be used by young patients to establish and regulate the cycle, as well as by women in the perimenopausal period for the treatment of irregular bleeding.

With the onset of the menopause, the decrease, and then the cessation of estrogen synthesis in the ovaries, can lead to a violation of thermoregulation. This contributes to the appearance of hot flashes, combined with sleep disturbances and increased sweating. There are signs of involution of the skin and mucous membranes (especially in the genital area). Less specific, but often noted as components of the climacteric syndrome, are such symptoms: complaints of angina pectoris, a feeling of a strong heartbeat, irritability, nervousness, loss of strength and decreased ability to concentrate, forgetfulness, loss of libido, pain in joints and muscles. Hormone replacement therapy (HRT) minimizes most of these symptoms due to estradiol deficiency in women during menopause.

HRT with Klimen reduces bone resorption, delays or stops the process of its loss, which is noted in the postmenopausal period. Proved that long-term HRT reduces the risk of distal bone fractures in women in the postmenopausal period. If HRT is discontinued, bone mass decreases at a rate inherent in the onset of the postmenopausal period. HRT also positively affects the collagen content in the skin and its density, which delays the formation of wrinkles.

In addition, the anti-androgenic properties of cyproterone acetate determine the positive effect of Klymene on androgen-dependent complications (for example, acne, seborrhea, androgenetic alopecia).

HRT with the use of Klymene changes the lipid profile. The drug reduces the level of total cholesterol and LDL cholesterol and can increase the levels of HDL cholesterol and triglycerides. Due to the lack of androgenic properties in cyproterone acetate, it does not counteract the metabolic effects of estrogen. It was revealed that these positive effects are especially pronounced in women with significant changes in the direction of atherogenic lipoproteins.

The additional inclusion of progestogen in estrogen replacement therapy for at least 10 days in each cycle reduces the risk of endometrial hyperplasia and, accordingly, the risk of adenocarcinoma. The inclusion of progestogens in estrogen replacement therapy does not affect the effectiveness of estrogens.

Based on research data using a combination of conjugated equin estrogens from medroxyprogesterone acetate, it is estimated that the incidence of colon cancer in women receiving HRT is reduced. In studies with monotherapy with conjugated equin estrogens, this risk was not reduced.

Estradiol valerate

Estradiol Valerate is rapidly and completely absorbed.The steroidal ester is cleaved into estradiol and valerianic acid during adsorption and first passage through the liver. At the same time, estradiol passes the further path of metabolism - to estrone, estriol and estrone sulfate. Only about 3% of estradiol is bioavailable after oral administration of the drug. Eating does not affect the bioavailability of estradiol.

The maximum concentration of estradiol in blood serum, amounting to 30 PCG / ml, is achieved within 4–9 hours after taking the dragee. Estradiol binds to albumin and sex hormone binding globulins (SHBG). The unbound portion of estradiol in blood serum is about 1–1.5%, and 30–40% is associated with SHBG.

The metabolism of exogenously administered estradiol valerate occurs in the same way as endogenous estradiol. Estradiol is mainly metabolized in the liver, as well as outside it (for example, in the intestines, kidneys, skeletal muscles and target organs).

Estradiol metabolites are excreted mainly in the form of sulfates and glucuronides in the urine.

Serum estradiol levels are 2 times higher after repeated use than after a single dose. After taking Klymene, the levels of estradiol and estrone noted at the beginning of treatment are restored for the next 2-3 days.

Cyproterone acetate

After oral administration of cyproterone, acetate is rapidly and completely absorbed. Its absolute bioavailability is about 88% of the dose taken.

After a single dose of 1 mg, the maximum concentration of cyproterone acetate in the blood plasma (about 8 ng / ml) is reached in about 1-2 hours. Subsequently, the concentration of the drug in the plasma decreases two-phase with a half-life of 0.8 hours and 2.3 days.

Cyproterone acetate is almost completely bound to plasma albumin. About 3.5–4% of the total concentration of the hormone remains unbound.

There are various ways of metabolizing cyproterone acetate, including hydroxylation and conjugation. The main plasma metabolite is the 15β-hydroxy derivative.

The total clearance rate of cyproterone acetate from blood plasma is 3.6 ml / min / kg. The half-life of metabolites from blood plasma is 1.7 days.

Given the long half-life of cyproterone acetate from blood serum, its cumulation in blood serum can be noted during one cycle of therapy with a coefficient of 2–2.5.

Preclinical Studies

Estradiol valerate

The toxicity profile of estradiol valerate is well understood. There are no preclinical data supplementing the information regarding the safety of estradiol valerate specified in the sections of the instructions for medical use of the drug.

Cyproterone acetate

Systemic toxicity

Data from standard preclinical toxicity studies with repeated use of cyproterone acetate do not indicate the existence of a specific risk to humans.

Genotoxicity and carcinogenicity

Recognized tests for the genotoxicity of cyproterone acetate were initially negative. However, the results of further tests indicate that cyproterone acetate has the ability to form adducts with DNA, which leads to an increase in DNA repair in liver cells.

At this time, clinical experience and the results of epidemiological studies do not give reason to allow an increase in the incidence of liver tumors in humans. The carcinogenicity studies of cyproterone acetate carried out in rodents do not indicate the existence of any specific carcinogenic effect. However, sex steroids can promote the growth of certain hormone-dependent tissues and tumors.

Embryotoxicity / Teratogenicity

The intake of high doses of cyproterone acetate in the hormone-sensitive phase of the differentiation of the genitals leads to the appearance of female sexual characteristics in male fetuses. Observation of newborn boys who in utero experienced the effects of cyproterone acetate did not reveal the development of any female sexual characteristics. Nevertheless, taking Klymene is contraindicated during pregnancy.

According to existing data, there are no contraindications regarding the use of the drug Klimen in people with strict adherence to the instructions for its use and recommended doses.

Indications

HRT for menopausal symptoms, signs of involution of the skin and urogenital tract, depressive states in the menopause, hormone deficiency symptoms due to natural menopause or hypogonadism, castration or primary ovarian failure in women with an unexplained uterus.

Prevention of postmenopausal osteoporosis.

Regulation of the menstrual cycle.

Treatment of primary and secondary amenorrhea.

Application

If the patient retains menstruation, treatment should be started on the 5th day of the menstrual cycle (the 1st day of menstruation corresponds to the 1st day of the cycle).

In the event that menstruation occurs very rarely, with amenorrhea or in the postmenopausal period, Klymene dragee can be started at any time, provided that pregnancy is excluded.

Doses One white tablet is taken daily for the first 11 days, then one pink tablet daily for the next 10 days. After the 21st day of taking Klimen, a 7-day break in treatment is provided.

Reception pills. Each package is designed for 21 days of treatment. 7 days after taking the last dragee from the previous package (on the same day of the week as for the previous package), they start taking dragees from the new package.

Take dragees without chewing with a small amount of liquid. It is advisable to adhere to the selected time of day.

Missed jelly beans. Missed tablets should be taken as soon as possible. If the delay in taking the dragee is more than 24 hours, an additional dragee should not be taken. If you skip a few drops, bleeding may begin.

Menstrual bleeding usually occurs during a 7-day break in treatment, within a few days after taking the last dragee.

Contraindications

HRT should not begin in any of the following conditions. if any of these conditions occurs during HRT, the drug should be stopped immediately:

During pregnancy and breastfeeding;

vaginal bleeding of unknown etiology;

diagnosed or suspected breast cancer;

identified pre-tumor conditions or malignant tumors that are dependent on sex steroids, or if they are suspected;

diagnosed liver tumors (benign or malignant) or their history;

severe liver disease;

acute arterial thromboembolism (e.g. myocardial infarction, stroke).

exacerbation of deep vein thrombosis, current thromboembolic disorders or history of such diseases.

severe hypertriglyceridemia;

information about hypersensitivity to active substances or to any of the components of the drug.

Side effects

The most serious side effects associated with the use of HRT are indicated in the special instructions section.

The table shows data on other undesirable effects recorded in women receiving HRT (post-marketing data), but for which the relationship with the use of the drug Klimen was not reliably confirmed.

special instructions

often (≥1 / 100) infrequently (≥1 / 1000, 1/100) single (≥1 / 10,000, 1/1000) immune system disorders hypersensitivity reactions metabolic and nutritional disorders increase or decrease in body weight mental disorders depressed state sensation of concern, decreased or increased libido disorders of the nervous system headache dizziness migraine visual impairment visual impairment contact lens intolerance disorders of the cardiovascular system palpitations gastrointestinal disorders abdominal pain, nausea dyspepsia bloating, vomiting skin and subcutaneous tissue rash, itching erythema nodosum, urticaria hirsutism, acne musculoskeletal system and connective tissue muscle cramps disorders of the reproductive system and mammary glands uterine / vaginal bleeding, including spotting (these disorders usually normalize with continued treatment) pain in the mammary glands, tension of the mammary glands dysmenorrhea, changes in vaginal secretion, PMS-like syndrome, breast enlargement general violations edema fatigue

Klimen is not used as a contraceptive.

If necessary, non-hormonal methods of contraception are used, with the exception of calendar and temperature. If pregnancy is suspected, the drug should be discontinued before the final exclusion of pregnancy.

Before starting HRT, in assessing the risk / benefit of treatment, taking into account the individual characteristics of each patient, the following conditions / risk factors should be taken into account.

The use of HRT should be stopped immediately if any of the contraindications are detected, as well as in the presence of the following conditions and diseases:

migraine-like or frequent and unusually severe headache, appearing for the first time, or other symptoms that are likely prodromal signs of cerebral vascular occlusion;

relapse of cholestatic jaundice or cholestatic itching, first noted during pregnancy or previous use of sex steroids;

symptoms of thrombotic disorders or suspicion of their occurrence.

In the event of a relapse or exacerbation of any of the following diseases or risk factors, it is recommended to re-conduct an individual analysis of the ratio of benefit and risk of therapy, taking into account the possible need for discontinuation of treatment.

Venous Thromboembolism (VTE)

The results of epidemiological and randomized controlled trials suggest that there is an increase in the relative risk of developing VTE, i.e. deep vein thrombosis, or pulmonary embolism. As a result, when consulting women with HRT for women with a risk factor for developing VTE, the ratio of risk and benefit of the treatment should be carefully weighed.

Commonly recognized risk factors for the development of VTE include: personal and family history (the case of VTE in a close relative at a relatively young age may indicate a genetic tendency), severe obesity. The risk of VTE also increases with age. The question of the possible role of varicose veins in the development of VTE remains controversial.

The risk of VTE may temporarily increase with prolonged immobilization, after a serious planned or emergency surgery or severe injury. The question of the temporary cessation of HRT should be decided depending on the nature of the surgical intervention and the duration of the immobilization.

Arterial thromboembolism

The results of two clinical trials using a combination of conjugated equin estrogens and medroxyprogesterone acetate (MPA) in a continuous mode indicate a possible increase in the risk of developing coronary heart disease during the first year of their use, and subsequently, with continued treatment, the risk remains constant. The results of a clinical study showed a potential reduction in the incidence of coronary heart disease in women aged 50–59 years who underwent estrogen monotherapy. Another negative factor was an increase in risk of 30–40% of the development of stroke during monotherapy with estrogens or their use in combination with MPA.

Cholelithiasis

Estrogens increase the lithogenicity of bile. Some women have a tendency to gallbladder disease during estrogen treatment.

Dementia

Based on clinical studies using HRT drugs, it has not been proven that taking hormones increases the risk of dementia in treating women 65 years of age or older. The risk can be reduced by starting treatment for HRT in early menopausal women.