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Active ingredients
Tsiproteron + Estradiol
Release form
Dragee
Composition
Active ingredient: Aestradiol valeratActivating substances: lactose monohydrate, corn starch, povidone 25000 (K25), talc, magnesium stearate, sucrose, povidone 700000 (K700), macrogol 6000, calcium carbonate, wax. Base volume: Dragee Active ingredient concentration (mg): 2 mg
Pharmacological effect
Climen contains estrogen - estradiol valerate, which in the human body turns into natural 17β-estradiol. Also included in the drug Climen is a progesterone derivative - cyproterone acetate, which has a gestagenic, antigonadotropic and antiandrogenic effect. Due to the composition and cyclic regimen of Klymene, (taking only estrogen for 11 days, then a combination of estrogen and gestagen for 10 days, and finally, a 7-day break), in women with an unremoved uterus, with a regular intake of the drug, the menstrual cycle is established. Against the background of Klymen's intake, there is no suppression of ovulation, and hormone production hardly changes in in the body. Climen can be used by women of reproductive age to regulate the menstrual cycle, as well as by perimenopausal women for the treatment of irregular uterine bleeding. Estradiol compensates for the estrogen deficiency in the female body after menopause and provides effective treatment of psycho-emotional and autonomic menopausal symptoms (such as menopausal symptoms (such as menopause) , sleep disturbance, increased nervous irritability, irritability, palpitations, cardialgia, dizziness, headache, with izhenie libido, muscle and joint pain); involutions of the skin and mucous membranes, especially the mucous membranes of the urogenital system (urinary incontinence, dryness and irritation of the vaginal mucosa, pain during sexual intercourse). Estradiol prevents bone loss caused by estrogen deficiency. This is mainly due to the suppression of osteoclast function and the shift of the bone remodeling process towards bone formation. It has been proven that prolonged use of hormone replacement therapy (HRT) can reduce the risk of peripheral bone fractures in women after menopause.With the abolition of HRT, the rate of decrease in bone mass is comparable with the indicators characteristic of the period immediately after menopause. It is not proven that using HRT can restore bone mass to a premenopausal level. HRT also has a beneficial effect on the collagen content in the skin, as well as on its density, and can also slow down the formation of wrinkles. In addition, due to the antiandrogenic properties of cyproterone acetate, Climen has a therapeutic effect on androgen-dependent diseases such as acne, seborrhea, androgenetic alopecia. Taking Klymene leads to a decrease in the level of total cholesterol, lipoproteins is low. Its high density (LDL) and an increase in high-density lipoprotein (HDL), resulting in a significantly increased ratio of HDL / LDL, as well as an increase in triglyceride levels. Due to the lack of androgenic properties of cyproterone acetate, it practically does not interfere with the effect of estradiol on lipid metabolism. The effect of Klymene is especially noticeable in women with pronounced atherogenic changes in the lipid profile. The addition of cyproterone acetate for 10 days each cycle prevents the development of hyperplasia and endometrial cancer. Observational studies suggest that among patients with post-menopausal cancer, the incidence of colon cancer is reduced. The mechanism of action is still unclear.
Pharmacokinetics
Estradiol valerateAbsorptionAfter oral ingestion of estradiol, valerate is rapidly and completely absorbed. During absorption and first passage through the liver, the hormone ester is broken down into estradiol and valeric acid. At the same time, estradiol is largely subjected to further metabolization, for example, to estrone, estriol, and estrone sulfate. After oral administration, the bioavailability of estradiol is about 3%. Eating does not affect the bioavailability of estradiol. Distribution The maximum concentration of estradiol in serum, approximately 30 pg / ml, is usually reached 4 to 9 hours after ingestion of dragees. 24 hours after administration, serum estradiol concentration drops to about 15 pg / ml. Estradiol binds to albumin and sex hormone-binding globulin (GSPH).The free fraction of estradiol in serum is about 1-1.5%, and the fraction of the SHBG-bound substance is in the range of 30-40%. The apparent distribution of estradiol after a single intravenous injection is about 1 l / kg. Metabolism After hydrolysis of exogenous estradiol valerate, the substance passes the same biotransformation paths as endogenous estradiol. Estradiol is metabolized primarily in the liver, and also partially in the intestine, kidneys, skeletal muscles and target organs. These processes are accompanied by the formation of estrone, estriol, catechol estrogen, as well as sulfate and glucuronide conjugates of these compounds, all of which have significantly less estrogenic activity or do not have estrogenic activity at all. EliminationClirence of serum estradiol after a single intravenous administration is characterized by a high degree of variability ranging from 10 up to 30 ml / min / kg. A certain part of estradiol is excreted in the bile and undergoes enterohepatic recirculation. Estradiol metabolites are excreted mainly with urine in the form of sulfates and glucuronides. Equilibrium concentration The concentration of estradiol in the blood serum after repeated administration is approximately two times higher than after administration of a single dose. On average, serum estradiol concentration ranges from 40 pg / l (minimum level) to 90 pg / l (maximum level). The concentration of estrone (weaker estrogen) is about 8 times, and the concentration of estrone sulfate is about 150 times higher than the concentration of estradiol. After cessation of Climen, estradiol and estrone levels return to their original values within two to three days. Ziproterone acetate Absorption After ingestion, a wide range of cyproterane acetate is rapidly and completely absorbed. Absolute bioavailability after oral administration is 88%. Distribution The maximum serum concentration of cyproterone acetate in serum is about 30 ng / ml, achieved 1–2 hours after a single dose of 1 mg cyproterone acetate. After that, a biphasic decrease in serum concentration of ziproterone acetate with a half-life of 0.8 hours and 2.3 days, respectively, is observed. Cyproterone acetate is almost exclusively associated with serum albumin. About 3.5-4% of the total serum concentration of cyproterone acetate is not associated with protein.Because plasma protein binding is not specific, changes in the HSPG level do not affect the pharmacokinetics of cyproterone acetate. Biotransformation Ciproterone acetate is metabolized in various ways, including hydroxylation and conjugation. The main metabolite in human serum is a 15β-hydroxyl derivative. The elimination of serum cyproterone acetate from serum is 3.6 ml / min / kg. Some of the dose received is excreted unchanged with the bile. Most of the dose is excreted in the form of metabolites with urine and bile in the ratio of 3: 7, with a half-life of 1.9 days. Metabolites are derived from serum with a similar half-life of 1.7 days. Equilibrium concentration Due to the long half-life of cyproterone acetate from the serum, it can be expected that the serum concentration of cyproterone acetate in the serum will increase 2-2.5 times.
Indications
- hormone replacement therapy for climacteric disorders, manifested by psycho-emotional, vegetative-vascular, urogenital disorders, atrophic processes on the skin, involution of the bladder and genital organs, androgenization phenomena; menstrual cycle disorders (including primary and secondary amenorrhea).
Contraindications
- pregnancy; - lactation (breastfeeding); - breast cancer and suspicion of it; - hormone-dependent neoplasms or suspicion of them; - benign or malignant tumors of the liver (including history) - severe liver disease; - deep thrombosis veins of the lower extremities (including in history); - severe hypertriglyceridemia; - hypersensitivity to the drug.
Precautionary measures
Do not exceed recommended doses. Use with caution: arterial hypertension, congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic itch during pregnancy, endometriosis, uterine fibroids, diabetes.
Use during pregnancy and lactation
HRT is not prescribed during pregnancy or lactation. Large-scale epidemiological studies of steroid hormones used for contraception or HRT did not reveal an increase in the risk of birth defects in children born to women who took these hormones before pregnancy.as well as the teratogenic effects of hormones when they are accidentally taken in the early stages of pregnancy. A small amount of sex hormones can be excreted with mother's milk.
Dosage and administration
Climen is prescribed from the 5th to the 25th day of the menstrual cycle daily. Drops are taken at the same time, without chewing, with a small amount of liquid. After completing the intake, Klymene from 1 calendar package takes a break for 7 days, during which approximately 2-4 days after taking the last dragee, menstrual-like bleeding begins. After 7 -day break start taking Climen from the next calendar package. In the absence of a 7-day break in bleeding, taking the drug should be continued only after pregnancy is excluded. Patients in menopause (in the absence of menstruation), as well as with amenorrhea or bleeding after oophorectomy, Climen is prescribed independently of the phases of 1 tablet / day for 21 cycles day with a 7-day break. In case of skipping the drug intake at the scheduled time, Klimen must be taken within the next 12 hours.
Side effects
On the part of the endocrine system: rarely - a feeling of tension, tenderness and enlargement of the mammary glands, changes in body weight. On the part of the digestive system: rarely - discomfort in the epigastric region, nausea, vomiting, flatulence, increased appetite. On the side of the CNS: in some cases - headache pain, migraine, dizziness, feeling of fatigue, decrease in mood, visual disturbances. On the part of the reproductive system: in the first months of admission, the appearance of spotting intermenstrual bleeding may occur, changes in libido, dysmenorrhea, condition, reminding yuschee premenstrual syndrome, vaginal changes sekretsii.Prochie: skin rash, impaired tolerability of contact lenses, allergic reactions, palpitations, edema, muscle cramps.
Overdose
There is no risk of serious side effects if you accidentally take the drug in an amount that exceeds many times the daily therapeutic dose. Symptoms that can occur during overdose: nausea, vomiting, vaginal bleeding. Treatment: no specific antidote, symptomatic treatment.
Interaction with other drugs
At the beginning of HRT it is necessary to stop the use of hormonal contraceptives. If necessary, the patient should be recommended non-hormonal contraceptives. Long-term treatment with drugs that induce liver enzymes (for example, some anticonvulsants and antimicrobial drugs) can increase the clearance of sex hormones and reduce their clinical efficacy. A similar property to induce liver enzymes has been found in hydantoins, barbiturates, primidone, carbamazepine and rifampicin, the presence of this feature is also expected in oxcarbazepine, topiramate, felbamate and griseofulvin. The maximum induction of enzymes is usually observed not earlier than in 2-3 weeks, but then it can be maintained for at least 4 weeks after stopping the drug. In rare cases, against the background of the concomitant use of certain antibiotics (for example, penicillin and tetracycline groups) there was a decrease in estradiol. Substances that are largely subject to conjugation (for example, paracetamol) may increase the bioavailability of estradiol due to competitive inhibition of the conjugation system in n absorption process. Due to the effect of HRT on glucose tolerance in some cases, the need for oral antidiabetic agents or insulin may change. Alcohol intake. Excessive alcohol consumption during HRT may lead to an increase in circulating estradiol.
special instructions
Climen is not used for contraception. If contraception is necessary, non-hormonal methods should be used (except for the calendar and temperature methods). If pregnancy is suspected, dragee should be stopped until pregnancy is excluded. If any of the conditions or risk factors mentioned below are present or worsen, the ratio of the individual risk and benefit of treatment should be assessed before starting or continuing HRT. thromboembolism. In a number of controlled, infected, and epidemiological studies, an increased relative risk of developing venous thromboembolism (VTE) with HRT, Deep vein thrombosis or pulmonary embolism.Therefore, when prescribing HRT to women with risk factors of VTE, the ratio of risk and benefits of treatment should be carefully weighed and discussed with the patient. Risk factors for developing VTE include an individual and family history (the presence of VTE in close relatives at a relatively young age may indicate a genetic predisposition) and 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, large planned and trauma operations, or massive trauma. Depending on the cause or duration of immobilization, the question of whether to temporarily stop ZGTS should be resolved should immediately be stopped if symptoms of thrombotic disorders appear or if they are suspected. Arterial thromboembolism. effects on the cardiovascular system. In large-scale clinical trials of this compound, a possible increase in the risk of coronary disease in the first year of use was identified. An increased risk of stroke was also detected. So far, no long-term randomized controlled trials have been conducted with other drugs for HRT in order to identify a positive effect on morbidity and mortality rates related to the cardiovascular system. Therefore, it is not known whether this increased risk is applied to drugs for HRT containing other types of estrogens and progestogens. Endometrial cancer. With prolonged estrogen monotherapy, the risk of endometrial hyperplasia or carcinoma increases. Studies have confirmed that adding progestogens reduces the risk of endometrial hyperplasia and cancer. Breast cancer According to clinical trials and observational studies, an increase in the relative risk of developing breast cancer in women using HRT for several years was found.This may be due to an earlier diagnosis, the biological effect of HRT, or a combination of both factors. The relative risk increases with increasing duration of treatment and possibly even more with estrogen combined with progestogens. This increase is comparable to the increase in the risk of breast cancer in women with every year delay in the onset of natural menopause, as well as in obesity and alcohol abuse. The increased risk is gradually reduced to the usual level during the first few years after the termination of HRT. According to most studies, breast cancer found in women taking HRT is usually more differentiated than in women who do not. HRT increases mammographic density of the mammary glands, which in some cases may have a negative effect on the x-ray detection of breast cancer. Liver tumors. Against the background of the use of sex steroids, which include drugs for hormone therapy, in rare Luciano observed benign, and even more rarely - malignant tumors of the liver. In some cases, these tumors led to life threatening intra-abdominal bleeding. When pain in the upper abdomen, enlarged liver or signs of intra-abdominal bleeding with a differential diagnosis should take into account the likelihood of a liver tumor. Gastrointestinal disease It is known that estrogens increase the lithogenicity of bile. Some women are susceptible to the development of cholelithiasis with estrogen treatment. Other conditions It is necessary to immediately stop treatment when migraine-like or frequent and unusually severe headaches appear for the first time, as well as other symptoms - possible harbingers of thrombotic stroke of the brain. clinically severe arterial hypertension has not been established. In women taking HRT, a slight increase in blood pressure has been described, a clinically significant increase is rare. However, in some cases, with the development of HRT with persistent clinically significant arterial hypertension, the withdrawal of HRT may be considered. For mild abnormalities of liver function, including various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, doctor's observation is necessary and periodic liver function tests.If your liver function deteriorates, HRT should be canceled. When cholestatic jaundice or cholestatic pruritus recurs, observed for the first time during pregnancy or prior to treatment with sex steroid hormones, it is necessary to stop HRT immediately. Special attention should be paid to women with moderately elevated triglycerides. In such cases, the use of HRT may cause a further increase in the level of triglycerides in the blood, which increases the risk of acute pancreatitis. Although HRT may affect peripheral insulin resistance and glucose tolerance, the need to change the treatment regimen for diabetics during HRT usually does not occur. However, women with diabetes mellitus should be monitored when performing HRT. In some patients, unwanted estrogen stimulation, such as abnormal uterine bleeding, may develop under the effect of HRT. Frequent or persistent abnormal uterine bleeding during treatment is an indication for endometrial research. If the treatment of irregular menstrual cycles does not produce results, an examination should be conducted to exclude an organic disorder. Under the influence of estrogens, uterine fibroids may increase in size. In this case, treatment should be discontinued. It is recommended to stop treatment if endometriosis recurs in the presence of HRT. If you suspect the presence of prolactinoma before the start of treatment, this disease should be excluded. In some cases, chloasma can be observed, especially in women with a chloasma of pregnant women in history. During HRT, women with a tendency to chloasma should avoid prolonged exposure to the sun or ultraviolet radiation. The following conditions may occur or be aggravated against the background of HRT. Although their relationship with HRT has not been proven, women with these conditions should be monitored by a physician during an HRT: epilepsy; benign breast tumor; bronchial asthma; migraine; porphyria; otosclerosis; systemic lupus erythematosus, small chorea. Medical examination and counseling Before beginning or resuming HRT, a woman is recommended to undergo a thorough general medical and gynecological examination (including examination of the mammary glands and cytological examination of cervical mucus), to exclude pregnancy. In addition, violations of the blood coagulation system should be excluded.Periodic control tests should be carried out. Effect on laboratory results Admission of sex steroids can affect the biochemical indicators of liver, thyroid, adrenal glands and kidney function, the content of transport proteins in plasma, such as corticosteroid binding globulin and lipid / lipoprotsin fractions, carbohydrate metabolism, coagulation and fibrinolysis. Influence on ability to drive motor transport and control mechanismsNo effect.