Climen® [Cyproterone, Estradiol]

Brand Bayer Pharma AG

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Clinical Pharmacology

Climen contains estrogen - estradiol valerate, which in the human body turns into natural 17β-estradiol. Also in the preparation Climen is a derivative of progesterone - cyproterone acetate, which has a gestagenic, antigonadotropic and antiandrogenic effect.

Due to the composition and cyclic regimen of Climen®e, (taking estrogen only for 11 days, then a combination of estrogen and progestogen for 10 days, and finally, a 7-day break), women with an unreduced uterus with a regular intake of the drug set the menstrual cycle .

On the background of Climen®e's reception, there is no suppression of ovulation, and hormone production in the body remains almost unchanged. Climen can be used by women of reproductive age for the regulation of the menstrual cycle, as well as women in perimenopause for the treatment of irregular uterine bleeding.

Estradiol compensates for the lack of estrogen in the female body after menopause and provides effective treatment of psycho-emotional and autonomic menopausal symptoms (such as hot flashes, increased sweating, sleep disturbances, increased nervous irritability, irritability, palpitations, cardialgia, dizziness, headache, depression, cardiac irritation, irritability, palpitations, cardialgia, dizziness, headache. 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) reduces the risk of peripheral bone fractures in women after menopause. With the abolition of HRT, the rate of decrease in bone mass is comparable to the indicators characteristic of the period immediately after menopause. It is not proved that, using HRT, it is possible to achieve recovery of bone mass to the 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 Climen®e leads to a decrease in total cholesterol, low-density lipoprotein (LDL) and an increase in high-density lipoprotein (HDL), which significantly increases the ratio of HDL / LDL, as well as increased triglycerides. 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 Climen®e 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 postmenopausal women, the incidence of colon cancer is reduced when using HRT. The mechanism of action is still unclear.

Pharmacokinetics

Estradiol Valerate

Absorption

After 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 serum estradiol concentration of approximately 30 pg / ml is usually reached 4–9 hours after taking the pills. 24 hours after administration, serum estradiol concentration decreases to a concentration of approximately 15 pg / ml.

Estradiol binds to albumin and sex hormone-binding globulin (SHBG). The free fraction of estradiol in serum is about 1-1.5%, and the fraction of the SHBH-bound substance is in the range of 30-40%.

The apparent volume of distribution of estradiol after a single intravenous injection is about 1 l / kg.

Metabolism

After hydrolysis of exogenous estradiol valerate, the substance passes through the same pathways of biotransformation as endogenous estradiol. Estradiol is metabolized mainly 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 no estrogenic activity at all.

Elimination

Serum estradiol clearance after a single intravenous administration is characterized by a high degree of variability in the range from 10 to 30 ml / min / kg. A certain part of estradiol is excreted in the bile and undergoes enterohepatic recycling. Estradiol metabolites are excreted mainly in the urine in the form of sulfates and glucuronides.

Equilibrium concentration

The concentration of estradiol in the serum after repeated administration is approximately two times higher than after the 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 discontinuation of Climen, estradiol and estrone levels return to their original values within two to three days.

Cyproteronea acetate

Absorption

After ingestion, a wide range of doses of cyproteran acetate is quickly and completely absorbed. Absolute bioavailability after oral administration is 88%.

Distribution

The maximum concentration of cyproterone acetate in serum, which is about 30 ng / ml, is achieved 1–2 hours after a single dose of 1 mg of cyproterone acetate. After that, there is a two-phase decrease in serum concentration of cyproterone acetate with a half-life of 0.8 hours and 2.3 days, respectively.

Cyproterone acetate binds almost exclusively to 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 HSPG levels do not affect the pharmacokinetics of cyproterone acetate.

Biotransformation

Cyproterone acetate is metabolized in various ways, including hydroxylation and conjugation. The main metabolite in human serum is the 15β-hydroxyl derivative.

Elimination

Serum cyproterone acetate clearance 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 excreted from serum with a similar half-life of 1.7 days.

Equilibrium concentration

Due to the long serum half-life of cyproterone acetate from serum, it can be expected that the serum concentration of cyproterone acetate in the course of one drug administration cycle will increase 2-2.5 times.

Indications

hormone replacement therapy (HRT) for menopausal disorders, involutional changes of the skin and urinary tract, menopausal depressions, as well as estrogen deficiency symptoms due to natural menopause or hypogonadismsterilization or primary ovarian dysfunction in women with an unreduced uterus;
prevention of postmenopausal osteoporosis;
normalization of irregular menstrual cycles;
treatment of primary or secondary amenorrhea.

Composition

1 white bean contains:

Active substance: estradiol valerate 2 mg;

Excipients: lactose monohydrate; corn starch; Povidone 25,000; talc; magnesium stearate; sucrose; Povidone 700,000 (K700); macrogol 6000; calcium carbonate; wax.

1 pink bean contains:

Active substances: estradiol valerat2 mg; cyproterone acetate 1 mg;

Excipients: lactose monohydrate, corn starch, povidone 25000 (K25), talc, magnesium stearate, sucrose, povidone 700000 (K700), macrogol 6000, calcium carbonate, glycerol 85%, titanium dioxide, iron oxide red, iron oxide yellow, wax.

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Method of administration and dosage

Insidewithout chewing, drinking a small amount of liquid at approximately the same time, 1 tablet per day, starting from the 5th day of the cycle. After taking the drug from 1 calendar pack, a 7-day break is taken, during which 2–4 days after taking the last bean, menstrual-like bleeding begins. If the doctor does not prescribe another therapy, after a 7-day break, begin to take the drug from the next calendar package. In the absence of a 7-day break of bleeding, treatment is continued only after exclusion of pregnancy.

Adverse reactions

From the reproductive system and mammary glands:changes in the frequency and intensity of uterine bleeding, breakthrough bleeding, intermenstrual bleeding (usually weakened during therapy), dysmenorrhea, changes in vaginal discharge, a condition similar to premenstrual syndrome; soreness, tension and / or enlargement of the mammary glands.

From the gastrointestinal tract:dyspepsia, bloating, nausea, vomiting, abdominal pain, relapse of cholestatic jaundice

From the skin and subcutaneous tissue: skin rash, pruritus, chloasma, erythema nodosum

From the side of the central nervous system: headache, migraine, dizziness, anxiety or depressive symptoms, fatigue

Other: heart palpitations, edema, increased blood pressure, venous thrombosis and thromboembolism, muscle cramps, changes in body weight, changes in libido, visual disturbances, intolerance to contact lenses, allergic reactions

Carefully: Arterial hypertension, congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic itch during pregnancy, endometriosis, uterine myoma, diabetes mellitus.

Drug interactions

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 anticonvulsant and antimicrobial drugs) can increase the clearance of sex hormones and reduce their clinical efficacy. A similar property to induce liver enzymes was 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 instances, a decrease in estradiol levels was observed against the background of the concomitant administration of certain antibiotics (for example, the penicillin and tetracycline groups).

Substances that are highly conjugated (for example, paracetamol) can increase the bioavailability of estradiol due to competitive inhibition of the conjugation system during the 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 Interaction

Excessive alcohol intake during HRT may lead to an increase in circulating estradiol levels.

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 early pregnancy.

A small amount of sex hormones can be excreted in breast milk.

Special instructions

Klymene 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, pills should be stopped until pregnancy is excluded.

If any of the following conditions or risk factors are present or worsening, before starting or continuing HRT, the ratio of the individual risk to the benefit of treatment should be evaluated.

Venous thromboembolism

In a number of controlled, randomized, and epidemiological studies, an increased relative risk of developing venous thromboembolism (VTE) was revealed against the background of HRT, i.e. Deep vein thrombosis or pulmonary embolism. Therefore, when prescribing HRT to women with VTE risk factors, the ratio of the risk and benefit of treatment should be carefully weighed and discussed with the patient.

Risk factors for VTE include an individual and family history (the presence of VTE in immediate 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 traumatic operations or massive injury. Depending on the cause or duration of immobilization, the question of whether to temporarily stop HRT should be decided.

Treatment should be discontinued immediately if symptoms of thrombotic disorders appear or if they are suspected.

Arterial thromboembolism

In the course of randomized controlled studies with long-term use of combined conjugated estrogens and medroxyprogesstron acetate, no evidence of a positive effect on the cardiovascular system was obtained. 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 other long-term randomized controlled trials have been conducted with other drugs for HRT in order to detect a positive effect on morbidity and mortality related to the cardiovascular system. Therefore, it is not known whether this increased risk is distributed to drugs for HRT containing other types of estrogens and progestogens.

Endometrial cancer

Long-term estrogen monotherapy increases the risk of endometrial hyperplasia or carcinoma. Studies have confirmed that adding progestogens reduces the risk of endometrial hyperplasia and cancer.

Mammary 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 has been 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 further increases when estrogen is 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 gradually decreases to the usual level during the first few years after the termination of HRT.

According to most studies, breast cancer found in women who take HRT is usually more differentiated than women who do not.

HRT increases the mammographic density of the mammary glands, which in some cases may have a negative effect on the x-ray detection of breast cancer.

Liver tumor

Against the background of the use of sex steroids, which include drugs for hormone replacement therapy, benign and, even more rarely, malignant tumors of the liver have been observed in rare cases. In some cases, these tumors led to life threatening intra-abdominal bleeding. For pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding, a differential diagnosis should take into account the likelihood of a liver tumor.

Cholelithiasis

It is known that estrogen increases the lithogenicity of bile. Some women are predisposed to the development of cholelithiasis with estrogen therapy.

Other states

Treatment should be stopped immediately, with the first appearance of migraine-like or frequent and unusually severe headaches, as well as with the appearance of other symptoms - possible harbingers of a cerebral thrombotic stroke.

The relationship between HRT and the development of 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 resistant clinically significant arterial hypertension, the withdrawal of HRT may be considered.

In cases of mild abnormalities in liver function, including various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, physician observation is required, as well as periodic liver function tests. With a deterioration in liver function, HRT should be abolished.

When recurrent cholestatic jaundice or cholestatic pruritus, observed for the first time during pregnancy or prior treatment with sex steroid hormones, it is necessary to immediately stop HRT.

Special attention should be paid to women with moderately elevated triglyceride levels. 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, it is usually not necessary to change the treatment regimen for diabetics when performing HRT. However, women with diabetes mellitus should be monitored during HRT.

In some patients, unwanted manifestations of estrogen stimulation, such as abnormal uterine bleeding, may develop under the influence of HRT. Frequent or persistent pathological uterine bleeding during treatment is an indication for endometrial research.

If the treatment of irregular menstrual cycles does not give results, an examination should be conducted to exclude diseases of an organic nature.

Under the influence of estrogen, uterine fibroids may increase in size. In this case, treatment should be discontinued.

It is recommended to stop treatment in case of endometriosis recurrence with HRT. If you suspect the presence of prolactinomas before the start of treatment, this disease should be excluded.

In some cases, chloasma may be observed, especially in women with a history of chloasma in pregnant women. During HRT, women with a tendency to chloasma should avoid prolonged exposure to the sun or ultraviolet radiation.

The following conditions may occur or worsen during 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 starting or resuming HRT, a woman is recommended to undergo a thorough general medical and gynecological examination (including breast examination 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.

Impact on laboratory results

The use of sex steroids can affect the biochemical indicators of liver, thyroid, adrenal and kidney function, the plasma levels of transport proteins such as corticosteroid binding globulin and lipid / lipoprotsin fractions, carbohydrate metabolism, coagulation and fibrinolysis.

Influence on ability to drive motor transport and control mechanisms

Does not affect.