Instructions for Climen (Estradiol, Cyproterone)
Climen (Estradiol, Cyproterone)
Pharmacological properties Climen:
Klymen refers to the combined biphasic estrogen-progestational hormonal drugs Climen intended for the prevention and treatment of complications of the climacteric period and estrogen deficiency. The drug Climen contains estrogen - estradiol valerate, which is a prodrug of natural human 17 β-estradiol and cyproterone acetate, a synthetic derivative of hydroxyprogesterone with progestogenic, antigonadotropic and antiandrogenic properties.
The composition and cyclic regimen of the drug Climen, which includes taking only estrogen for 11 days and an estrogen-progestogen combination for 10 days with a further 7-day break in therapy, causes a woman with an unremoved uterus to restore the menstrual cycle (provided that the drug is taken regularly).
During the intake of Klymene, ovulation is not inhibited, but there is a significant effect on the endogenous production of hormones. Due to the fact that Climen is a drug Climen for cyclic therapy, it can be used by young patients to establish and regulate the cycle, as well as to women in the perimenopausal period for the treatment of irregular bleeding.
With the onset of menopause, a decrease and then a cessation of the synthesis of estrogens 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 climacteric syndrome, such symptoms: complaints of angina pectoris, a feeling of 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 associated with estradiol deficiency in menopausal women. Climen
HRT with Climen reduces bone resorption, delays or stops the process of bone loss, which is noted in the postmenopausal period. It has been proven that long-term HRT reduces the risk of distal bone fractures in postmenopausal women. In the case of discontinuation of HRT, bone mass decreases at a rate inherent in the onset of the postmenopausal period. HRT also has a positive effect on the collagen content in the skin and on its density, which delays the process of wrinkle formation.
Estradiol valerate:
Estradiol valerate is rapidly and completely absorbed. The steroid ester is broken down into estradiol and valerian acid during adsorption and first pass through the liver. At the same time, estradiol goes through a further metabolic pathway - to estrone , estriol and estrone sulfate. Only about 3% of estradiol is bioavailable after oral administration of the drug Climen. Food intake does not affect the bioavailability of estradiol. Climen
The maximum concentration of estradiol in the blood serum, which is 30 pkg / ml, is reached within 4-9 hours after taking the pills. Estradiol binds to albumin and sex hormone binding globulins (SHBG). The unbound part of estradiol in the 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 muscle and target organs).
Estradiol metabolites are excreted from the body mainly in the form of sulfates and glucuronides in the urine.
Serum estradiol levels are 2 times higher after multiple doses than after a single dose. After the end of taking Klymene, the levels of estradiol and estrone , noted at the beginning of treatment, are restored within the next 2-3 days. Climen
Cyproterone acetate:
After oral administration of cyproterone acetate, it 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 after approximately 1-2 hours. Subsequently, the concentration of the drug Climen in the plasma decreases in two phases with half-lives of 0.8 hours and 2.3 days.
Cyproterone acetate almost completely binds to blood plasma albumin. Approximately 3.5–4% of the total hormone concentration remains unbound.
Metabolic pathways of cyproterone acetate are different, including hydroxylation and conjugation. The main metabolite in blood plasma is 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.
Considering the long half-life of cyproterone acetate from blood serum, its accumulation in blood serum can be observed during one cycle of therapy with a coefficient of 2–2.5.
Climen
Preclinical data
Estradiol valerate
The toxicity profile of estradiol valerate is well understood. There is no preclinical data supplementing the information regarding the safety of estradiol valerate indicated in the sections of the instructions for medical use of the drug Climen.
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
The recognized genotoxicity tests for 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 provide grounds for an increase in the incidence of liver tumors in humans. The results of studies of the carcinogenicity 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. Climen
Embryotoxicity / teratogenicity
Taking high doses of cyproterone acetate in the hormone-sensitive phase of genital differentiation leads to the appearance of female sexual characteristics in male fetuses. Observation of newborn boys who experienced the action of cyproterone acetate in utero 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 Climen in humans, with strict adherence to the instructions for its use and the recommended doses. Climen
Indications Climen:
HRT for menopausal symptoms, signs of involution of the skin and urogenital tract, depressive conditions during menopause, symptoms of hormone deficiency caused by natural menopause or hypogonadism, castration or primary ovarian failure in women with an unremoved uterus.
Prevention of postmenopausal osteoporosis . Climen
Regulation of the menstrual cycle.
Treatment of primary and secondary amenorrhea.
Application Climen:
If the patient continues to have 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, taking Klymen pills can be started at any time, provided that pregnancy is excluded.
Doses. One white dragee is taken daily for the first 11 days, then - one pink dragee daily for the next 10 days. After the 21st day of taking the drug Climen, a 7-day break in treatment is provided. Climen
Taking pills. Each pack is designed for 21 days of treatment. 7 days after taking the last pills from the previous package (on the same day of the week as for the previous package), they start taking pills from the new package.
Dragee should be taken without chewing with a small amount of liquid. It is advisable to adhere to the selected time of day.
Missed pills. The missed pills should be taken as soon as possible. If the delay in taking pills is more than 24 hours, additional pills should not be taken. If you miss a few pills, bleeding may begin. Climen
Menstrual bleeding usually occurs during a 7-day break in treatment, within a few days after taking the last tablet.
Contraindications Climen:
HRT should not be started in any of the following conditions. If any of these conditions occurs during HRT, the drug Climen should be discontinued immediately:
the period of pregnancy and lactation
vaginal bleeding of unknown etiology
diagnosed or suspected breast cancer
identified precancerous conditions or malignant tumors that are dependent on sex steroids, or if their presence is suspected
diagnosed liver tumors (benign or malignant) or their history
severe liver disease
arterial thromboembolism in the acute stage (eg myocardial infarction, stroke).
exacerbation of deep vein thrombosis, current thromboembolic disorders, or a history of such diseases.
severe form of hypertriglyceridemia;
information about hypersensitivity to active substances or to any of the components of the drug Climen.
Side effects Climen:
The most serious side effects associated with HRT are listed in the SPECIAL INSTRUCTIONS section.
The table shows data on other undesirable effects registered in women receiving HRT (post-marketing data), but for which the connection with the use of the drug Climen has not been reliably confirmed.
special instructions Climen:
Often (≥1 / 100) Uncommon (≥1 / 1000, ≤1 / 100) Single (≥1 / 10,000, ≤1 / 1000)
Immune system disorders Hypersensitivity reactions Metabolic and alimentary disorders Increase or decrease in body weight Mental disorders Depressed state Feeling anxious, decreased or increased libido
Nervous system disorders Headache Dizziness Migraine
Violations of the organs of vision Visual impairment Contact lens intolerance
Cardiovascular disorders Increased heart rate Gastrointestinal disorders Abdominal pain, nausea Dyspepsia Bloating, vomiting
Skin and subcutaneous tissue Rash, itching Erythema nodosum, urticaria Hirsutism, acne
Musculoskeletal system and connective tissues Muscle cramps
Reproductive system and breast disorders Uterine / vaginal bleeding, including spotting (these disorders tend to normalize with continued treatment) Breast pain, breast tension Dysmenorrhea, changes in vaginal secretion, PMS-like syndrome, breast enlargement
General violations Edema Increased fatigue
Klymen is not used as a contraceptive. Climen
If necessary, use non-hormonal methods of contraception, with the exception of calendar and temperature. If pregnancy is suspected, the drug Climen should be discontinued until the final exclusion of pregnancy.
Before starting HRT, when 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 is detected, as well as in the presence of the following conditions and diseases:
migraine-like or frequent and unusually severe headache that appears for the first time, or other symptoms that are likely prodromal signs of cerebral vascular occlusion;
recurrence of cholestatic jaundice or cholestatic pruritus, 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 balance of benefits and risks of therapy, taking into account the possible need to discontinue treatment. Climen
Venous thromboembolism (VTE)
The results of epidemiological and randomized-controlled studies suggest an increase in the relative risk of developing VTE, that is, deep vein thrombosis, or pulmonary embolism. As a result, when consulting for the appointment of HRT to women with a risk factor for the development of VTE, you should carefully weigh the balance of risk and benefit from the treatment.
The generally recognized risk factors for the development of VTE include: personal and family history (a case of VTE in a close relative at a relatively early age may indicate a genetic predisposition), 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 a serious injury. The question of temporarily stopping HRT should be decided depending on the nature of the surgery and the duration of immobilization.
Arterial thromboembolism
The results of two clinical studies using a combination of conjugated equine 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, subsequently, with continued treatment, the risk remains constant. The results of a clinical study showed a potential reduction in the incidence of coronary artery disease in women aged 50–59 years who received estrogen monotherapy. Another negative factor was a 30–40% increase in the risk of stroke with estrogen alone or in combination with MPA. Climen
Cholelithiasis
Estrogens increase the lithogenicity of bile. Some women have been shown to be prone to gallbladder disease during estrogen treatment.
Dementia
Based on clinical studies using HRT drugs Climen, it has not been proven that taking hormones increases the risk of developing dementia when treating women aged 65 and older. The risk can be reduced if HRT is started in the early menopausal period.
Tumors
Mammary cancer
The results of clinical studies and observations have shown an increased risk of developing breast cancer in women using HRT for several years.
The relative risk increases with the duration of treatment and may be lower or unchanged with estrogen monotherapy.
It is noted that tumors detected in women using or previously used HRT are characterized by a higher degree of differentiation.
HRT increases the density of images in mammography examinations, which can in some cases adversely affect the results of breast cancer diagnostics.
Endometrial cancer
Long-term estrogen monotherapy increases the risk of developing endometrial hyperplasia or carcinoma. It can be assumed that the inclusion of progestogens in the treatment regimen significantly reduces the risk.
Liver tumors
After the use of hormonal drugs Climen used for HRT, in isolated cases, the development of benign, and even less often malignant liver tumors was noted. In some cases, these tumors have caused life-threatening intra-abdominal bleeding. In case of pain in the upper abdomen, an increase in the size of the liver, or signs of intra-abdominal bleeding, differential diagnosis should take into account the likelihood of a liver tumor.
Other states Climen
The general relationship between the use of HRT and the development of clinical hypertension has not been established. A slight increase in blood pressure was reported in women receiving HRT, clinically significant cases of an increase in blood pressure were rarely observed. However, if in some cases persistent hypertension develops during HRT, the possibility of refusing HRT should be considered. Climen
With minor violations of liver function, including with various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, patients need careful monitoring, as well as periodic monitoring of liver function. If the indicators of liver function deteriorate, the use of HRT should be discontinued.
Women with moderately elevated TG levels need special monitoring. In such cases, the use of HRT can cause a further increase in the level of TG, which threatens the risk of developing acute pancreatitis.
Although HRT can affect peripheral insulin resistance and glucose tolerance, there is usually no need to change the therapeutic regimen for diabetic patients using HRT. However, patients with diabetes mellitus during HRT should be under constant medical supervision. Climen
Some patients during HRT may develop side effects of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent pathological uterine bleeding during treatment is an indication for examining the state of the endometrium. Climen
If the treatment of menstrual irregularities is unsuccessful, using appropriate diagnostic methods, it is necessary to exclude the presence of organic diseases.
Under the influence of estrogens, the size of uterine fibroids can increase. Under such circumstances, HRT treatment should be discontinued. Climen
It is recommended to discontinue treatment if endometriosis recurrence is noted during therapy.
If you suspect the presence of prolactinoma, before starting treatment, you need to exclude the likelihood of such a disease.
In some cases, chloasma may be noted, especially in women with a history of chloasma during pregnancy. When taking a course of HRT, women who are prone to chloasma should avoid exposure to the sun or ultraviolet radiation.
It was found that with the use of HRT, the following conditions and diseases can occur or worsen. Although it cannot be confidently asserted that these changes are associated with HRT, you need to closely monitor patients taking HRT and who have the following diseases: epilepsy; benign breast tumors; BA; migraine; porphyria; otosclerosis; systemic lupus erythematosus; chorea. Climen
Overdose Climen:
The results of studies of acute toxicity of the drug Climen do not indicate the existence of a risk of acute side effects even with accidental use of a dose several times higher than the therapeutic one.