Estradiol valerate tablets/estradiol cyproterone acetate tablets combined packaging

Pharmacodynamic properties The combination package of estradiol valerate tablets/estradiol cyproterone acetate contains the estrogen estradiol valerate, which is a precursor of natural human 17beta;-estradiol. Its other component, cyproterone acetate, is a synthetic hydroxyprogesterone derivative with progestogenic, antigonadotropic and antiandrogenic properties. The composition and sequential regimen of the combination package of estradiol valerate tablets/estradiol cyproterone acetate tablets include an 11-day estrogen-only phase, a 10-day estrogen-progestogen combined phase and a 7-day drug-free interval. If the medication is taken regularly, the menstrual cycle can be established in women with an intact uterus. During the use of the combination package of estradiol valerate tablets/estradiol cyproterone acetate tablets, ovulation is not inhibited and the production of endogenous hormones is almost unaffected. Due to its sequential composition, the preparation can be used for cycle induction and regulation in younger women and for the treatment of irregular uterine bleeding in perimenopausal women. During menopause, the decrease and eventual disappearance of ovarian estradiol secretion leads to unstable thermoregulation, causing hot flashes with sleep disturbances and excessive sweating. Signs of degeneration of the skin and mucous membranes (particularly in the urogenital tract) are more susceptible. Frequently mentioned but less specific symptoms of some menopausal syndromes are such as complaints of angina, palpitations, irritability, nervousness, fatigue, inability to concentrate, forgetfulness, loss of libido and joint and muscle pain. Hormone replacement therapy (HRT) can alleviate many of the symptoms of estrogen deficiency in menopausal women. HRT with a combination of estradiol valerate tablets/estradiol cyproterone acetate tablets reduces bone resorption and delays or prevents postmenopausal bone loss. Long-term treatment with HRT has been shown to reduce the risk of peripheral fractures in postmenopausal women. When HRT is discontinued, the rate of bone mass loss is similar to that of the immediate postmenopausal period. There is no evidence that HRT restores bone mass to premenopausal levels. HRT also has a positive effect on skin collagen content and thickness and can delay the development of skin wrinkles. In addition, the antiandrogenic properties of cyproterone acetate may support the beneficial effects of estradiol valerate/estradiol cyproterone acetate combination on androgen-related diseases such as acne, seborrheic dermatitis, androgenic alopecia. HRT with estradiol valerate/estradiol cyproterone acetate combination alters the lipid profile. It lowers total cholesterol and low-density lipoprotein cholesterol and may increase levels of high-density lipoprotein cholesterol and triglycerides. Since cyproterone acetate has no androgenic properties, it has little or no antagonism to the metabolic effects of estradiol valerate/estradiol cyproterone acetate combination estrogens. This effect of estradiol valerate/estradiol cyproterone acetate combination has been found to be particularly pronounced in women with atherogenic lipoprotein types. In an estrogen supplementation regimen, such as estradiol valerate/estradiol cyproterone acetate combination, the addition of a progestogen for at least 10 days per cycle can reduce the risk of endometrial hyperplasia and the concomitant risk of adenocarcinoma in women with an intact uterus. The addition of a progestin to an estrogen replacement regimen has not been shown to interfere with the efficacy of estrogen for the approved indication. Observational studies and the Women's Health Initiative (WHI) study indicate a reduced incidence of colon cancer in postmenopausal women treated with HRT in combination with conjugated estrogens and medroxyprogesterone acetate (MPA). A similar risk reduction was not observed in the WHI study of conjugated estrogens alone. It is not known whether similar findings exist for other HRT products. Preclinical Safety Information Estradiol valerate The toxicity profile of estradiol valerate is well known. In addition to the safety information contained in other sections of this product labeling, no additional relevant preclinical data are available to prescribers. Cyproterone acetate systemic toxicity Preclinical data for cyproterone acetate indicate that routine repeated-dose toxicity studies have not revealed any particular hazard to humans. Genotoxicity and carcinogenicity Cyproterone acetate showed negative results in recognized first-line genotoxicity tests. However, further experiments showed that cyproterone acetate was able to form adducts with DNA (and an increase in DNA repair activity) in rat and monkey liver cells, and also in freshly isolated human hepatocytes. Very low levels of DNA adducts were detected in dog hepatocytes. The expected formation of DNA adducts occurred when systemic exposure was achieved at the recommended dose regimen for cyproterone acetate. In vivo, an increased incidence of localized, possibly pre-neoplastic liver lesions occurred after cyproterone acetate administration, alterations in cellular enzyme systems in the liver lesions of female rats, and an increased frequency of mutations was found in transgenic rats carrying a bacterial gene as a target for mutation. Clinical experience to date and well-conducted epidemiological studies do not support an increased incidence of liver tumors in humans. Studies of the tumorigenicity of cyproterone acetate in rodents have also failed to show any indication of its specific tumorigenic potential. However, it must be borne in mind that sex hormones can promote the growth of certain hormone-dependent tissues and tumors. Embryotoxicity and teratogenesis Administration of high doses of cyproterone acetate during the differentiation period of reproductive organs that are sensitive to sex hormones results in feminization of male fetuses. Observations of male newborns who had been exposed to cyproterone acetate in utero did not show any signs of feminization. However, in any case, the combination package of estradiol valerate tablets/estradiol cyproterone acetate tablets is contraindicated during pregnancy. In general, if used according to the given doses and indications, the existing data do not oppose the use of the combination package of estradiol valerate tablets/estradiol cyproterone acetate tablets in humans.

This product is a compound preparation, its components are: 11 white sugar-coated tablets, each containing 2 mg of estradiol valerate; 10 pink sugar-coated tablets, each containing 2 mg of estradiol valerate and 1 mg of cyproterone acetate.

Estradiol valerate tablets are white sugar-coated tablets, which appear white after removing the sugar coating; estradiol cyproterone acetate tablets are pink sugar-coated tablets, which appear white after removing the sugar coating.

This product is used in combination with estrogen and progesterone to establish an artificial menstrual cycle for the treatment of estrogen deficiency mainly associated with natural or artificial menopause: vasomotor diseases (hot flashes), reproductive urinary tract nutritional diseases (vulvovaginal atrophy, dyspareunia, urinary incontinence) and mental disorders (sleep disorders, weakness). It can also prevent bone loss caused by primary or secondary estrogen deficiency.

The combined package of estradiol valerate tablets/estradiol cyproterone acetate for oral administration is to be administered according to the following treatment regimen: one tablet per day, without interruption, for 21 days, in the following order: 11 white tablets, 10 pink tablets. After this package is completed, this treatment period is followed by a 7-day treatment break. During the treatment break, withdrawal bleeding may occur. Treatment can be started on any day. However, when switching from other sequential hormone replacement therapy to the combined package of estradiol valerate tablets/estradiol cyproterone acetate tablets, it is recommended to start taking the tablets after bleeding, i.e. a new sequential hormone replacement therapy starts on this day. For the prevention of osteoporosis after menopause, the course of treatment is several years. If the patient forgets to take a tablet, the missed tablet should be taken within 24 hours to avoid withdrawal bleeding. If intermittent bleeding occurs, continue to take the tablets to avoid more severe bleeding. If bleeding persists, or recurs over several consecutive cycles, or if it is the first time bleeding occurs after long-term treatment with estradiol valerate/estradiol cyproterone acetate combination pack, a comprehensive gynecological examination is necessary to exclude any organic cause. The benefits and risks should be reassessed regularly (every 6 months) so that treatment can be adjusted or discontinued if necessary: during the entire estradiol valerate/estradiol cyproterone acetate combination pack treatment period, or when switching from other hormone therapy to estradiol valerate/estradiol cyproterone acetate combination pack, or as directed by your doctor

The following adverse reactions have been reported in users of hormone replacement therapy; a relationship to climen has not been confirmed or excluded (postmarketing data). The frequency of adverse reactions is indicated using the following categories: Very common (ge; 1/10) Common (ge; 1/100-1) Uncommon (ge; 1/1000-1) Rare (ge; 1/10000-1) Very rare (1) Unknown (cannot be estimated based on available data) The most appropriate MedDRA term (version 8.0) to describe the adverse reaction is listed. Synonyms and related conditions are not listed but should also be considered. Breast Cancer The risk of developing breast cancer is increased by 2-fold in women treated with combined estrogen-progestin therapy for more than 5 years. The increased risk is significantly lower in patients treated with estrogen alone than in those treated with combined estrogen-progestin therapy. The magnitude of the risk depends on the duration of treatment (see PRECAUTIONS). Results of the largest randomized, placebo-controlled study (the WHI study) and the largest epidemiological study (MWS)

Hormone replacement therapy (HRT) should not be started if any of the following conditions exist. If any of the following conditions occur during HRT, the drug should be discontinued immediately. Pregnancy and breastfeeding Undiagnosed vaginal bleeding Known or suspected breast cancer Known or suspected precancerous lesions or malignant tumors affected by sex hormones Current or previous history of liver tumors (benign or malignant) Severe liver disease High risk factors for venous or arterial thrombosis Acute arterial thromboembolic disease (such as myocardial infarction, stroke) Active deep vein thrombosis, thromboembolic disease, or a documented history of these diseases Severe hypertriglyceridemia Known hypersensitivity to any of the ingredients in the combination package of estradiol valerate tablets/estradiol cyproterone acetate tablets Although coagulation factors will not change in the short term during treatment, this product should generally not be used in the following situations (as a precaution, because there is currently insufficient epidemiological data); Heart disease that may cause embolism

Precautions for children: This product is not for children and adolescents. Precautions for pregnancy and lactation: HRT is not suitable for pregnant or lactating women. If you become pregnant during treatment with this product, you must stop the treatment immediately. Large-scale epidemiological studies of steroid hormones have shown that women who use such hormones before pregnancy have no increased risk of birth defects in their newborns, and accidental use of these drugs in early pregnancy has no teratogenic effect. Small amounts of sex hormones can be secreted in human breast milk. Precautions for the elderly: There is no data showing that the dose needs to be adjusted for elderly patients. For use in women aged 65 and over, please refer to

Note: The prescribing information of concomitant medications should be consulted to identify possible interactions. Effects of other drugs on Clemen can increase substances that clear sex hormones (reducing efficacy through enzyme induction) such as: Concomitant administration of substances that can induce drug-metabolizing enzymes, especially cytochrome P450 enzymes, can increase the metabolism of estrogen and progesterone; these substances include anticonvulsants (such as barbiturates, phenytoin, primidone, carbamazepine) and anti-infectives (such as rifampicin, rifabutin, nevirapine, efavirenz), felbamate, griseofulvin, oxcarbazepine, topiramate, and Chinese herbal medicines containing St. Johns Wort (Hypericum perforatum). Clinically, increased metabolism of estrogen and progesterone can weaken the effects of these hormones, leading to changes in the endometrial bleeding pattern. Enzyme induction can be observed after a few days of treatment. Maximum enzyme induction is usually observed within a few weeks. Enzyme induction may last for about 4 weeks after the end of drug treatment. Substances that affect the clearance of sex hormones: When taken with sex hormones, multiple HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including HCV inhibitors, may increase or decrease plasma concentrations of estrogen or progestin, or both. In some cases, the net effect of these changes may be clinically relevant. Therefore, the prescribing information of the co-administered HIV/HCV therapeutic should be consulted to determine possible interactions and to provide all relevant advice. Substances that reduce the clearance of sex hormones (enzyme inhibitors): Strong and moderate CYP3A4 inhibitors, such as azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolide antibiotics (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice, may increase plasma concentrations of estrogen or progestin, or both. In rare cases, decreased estradiol levels have been observed with the concomitant use of certain antibiotics (e.g., penicillins and tetracyclines). Other substances that bind strongly during passage through the intestine, such as paracetamol, can act as competitors in the binding of estrogens and thus lead to an increase in the bioavailability of estradiol. Effects on glucose tolerance may alter the need for oral hypoglycemic agents or insulin. Other forms of interaction Laboratory tests The use of sex hormones can affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, as well as plasma levels of (carrier) proteins (e.g. corticosteroid binding globulin) and lipid/lipoprotein fractions, carbohydrate metabolism parameters and coagulation and fibrinolysis parameters. The values of the changes usually remain within the normal reference range (for more detailed information, see Precautions Other pathological conditions).

Store below 30°C. Store all medicines properly and keep out of the reach of children.

21 pieces (calendar packing)

60 months