Klimara - instructions for use, doses, side effects, contraindications

Active substanceEstradiolEstradiol

Similar drugsTo uncover

Divigel

gel externally

Orion Corporation Finland

Klimara®

patch through.

Bayer Pharma AG Germany

Estrogele®

gel through.

Bezen Helskea SA Belgium

Estrofem®

pills inwards

Novo Nordisk A / S Denmark

Dosage form: & nbsptransdermal therapeutic system

Composition:

The transdermal system of Climart®, releasing 50 μg substance per day for 7 days, is a patch area of 12.5 cm², containing 3.8 mg of estradiol (equivalent to 3.9 mg of estradiol hemihydrate) in an acrylic adhesive matrix.

The transdermal system of Climart®, releasing 100 μg substance per day for 7 days, is a plaster area of 25.0 cm², containing 7.6 mg of estradiol (equivalent to 7.8 mg of estradiol hemihydrate) in an acrylic adhesive matrix.

Excipients:

For a dosage of 3.9 mg / 12.5 cm²

Poly (acrylamide-to-isooctyl acrylate-to-vinyl acetate) (5:75:20) -99.90 mg, ethyl oleate - 19.25 mg, isopropyl myristate 9.65 mg, glycerol monododecanoate 4.80 mg, polyethylene film (LDPE) - 12.5 cm².

For dosage 7.8 mg / 25,0 cm²

Poly (acrylamide-to-isooctyl acrylate-to-vinyl acetate) (5:75:20) -99.90 mg, ethyl oleate - 19.25 mg, isopropyl myristate 9.65 mg, glycerol monododecanoate - 4.80 mg, polyethylene film (LDPE) - 25.0 cm².

Description:

The patch is oval (about 4.5 cm by 3.3 cm, which corresponds to 12.5 cm²), consisting of a transparent carrier film with a transparent homogeneous matrix containing the active substance.

The patch is oval (about 6.30 cm by 4.7 cm, which corresponds to 25 cm²), consisting of a transparent carrier film with a transparent homogeneous matrix containing the active substance.

Pharmacotherapeutic group:estrogen

ATX: & nbsp

G.03.C.A.03 Estradiol

Pharmacodynamics:

Decreased ovarian function, accompanied by a decrease in the production of estrogens, leads to a menopausal syndrome characterized by vasomotor-vegetative and organic symptoms.

Carrying out hormone replacement therapy (HRT) is aimed at reducing these symptoms. Of all physiological estrogens, estradiol is the most active, having the greatest affinity for estrogen receptors.

17-beta-estradiol is identical to endogenous estradiol produced by the ovaries.

Has a feminizing effect on the body. Stimulates the development of the uterus, fallopian tubes, vagina, stroma and ducts of the mammary glands, pigmentation in the nipple and genital area, the formation of secondary sex characteristics by the female type.Oppresses the resorption of bone tissue, stimulates the synthesis of a number of transport proteins (thyroxine-binding globulin, transcortin, transferrin, globulin, binding sex hormones), fibrinogen. Increases blood levels of thyroxin, iron, copper, etc. Modulates receptors for progesterone and sympathetic regulation of smooth muscle tone, stimulates the transfer of intravascular fluid into tissues and causes compensatory retention of sodium and water. In large doses, it prevents the degradation of endogenous catecholamines, competing for the active receptors of catechol-O-methyltransferase.

Estradiol in the form of a transdermal therapeutic system (TTS) is a patch attached to a skin site. The control membrane provides a gradual and continuous release of estradiol from the reservoir with the active substance through the adhesive layer onto the skin. Due to the lack of the "first pass" effect through the liver, the TTC provides high efficacy when using smaller doses of the drug. TTC delivers estradiol unchanged in the bloodstream and maintains its concentration in the plasma during therapy at a constant level, adequate level in the early or middle follicular phase.

Regardless of the route of administration, estrogen doses necessary to reduce menopausal complaints have a dose-dependent stimulating effect on mitosis and endometrial proliferation. Monotherapy with estrogens increases the frequency of endometrial hyperplasia and thus the risk of endometrial carcinoma.

In order to prevent endometrial hyperplasia in women with a preserved uterus, sequential prescription of progestogen for 10-14 days is recommended.

Pharmacokinetics:

After dermal application Climaria® estradiol well absorbed through the skin. The average absorption rate is 50 μg / day and 100 μg / day, respectively.

The weekly Climara® application is comparable to a continuous low-dose intravenous infusion aimed at creating an even, stable, plate-like serum estradiol level similar to the level that is created during the early / middle follicular phase in the reproductive period of life. The transdermal administration allows to avoid high oscillations of estradiol and its metabolites in the serum as it is observed after oral substitution therapy with estradiol and, accordingly,avoid loading the liver with a large amount of estradiol and its metabolites due to high pre-systemic metabolism (the "primary passage effect") after oral administration. Thus, after transdermal administration of estradiol, no effect on protein synthesis in the liver has been observed.

The absolute value of the serum level of estradiol is directly proportional to the area of the plaster. The average equilibrium concentration of estradiol in the serum is approximately 35 pg / ml (12.5 cm plaster²) and 70 pg / ml (25 cm adhesive patch²).

After the application of TTS systems, 50 μg (patch, an area of 12.5 cm²) and 100 μg (25 cm plaster²), the physiological concentration of estradiol in the blood serum is reached after 2-4 hours. After 24 hours after removal of the system, the concentration of estradiol in the plasma is reduced to the initial value. The content of metabolites of estradiol in urine on day 2 after removal of the system reaches the same values that were measured before application.

About 61% of estradiol binds nonspecifically to serum albumin and about 37% specifically to globulin binding sex steroids.

After transdermal administration, the conversion of estradiol to estrone and conjugates remains within the physiological limits noted in the early follicular phase during the reproductive period of life, with a serum estradiol / estrone ratio of about 1: 1. A high level of estrone as a result of intensive metabolism during "primary passage" through the liver during oral HRT with estradiol, reflected by an estradiol / estrone ratio lower than 0.1, is not observed.

Biotransformation of transdermally administered estradiol is similar to the biotransformation of endogenous hormones: estradiol, mainly metabolized in the liver, but also extrahepatic, for example, in the intestines, kidneys, skeletal muscles and target organs. These processes include the formation of estrone, estriol, catechol estrogens and their conjugates - sulfates and glucuronides, which have distinctly less estrogenic properties or even do not have them.

Some of the metabolites of estradiol excreted with bile and is subjected to the so-called enterohepatic circulation. Ultimately, estradiol metabolites are mainly excreted in the form of sulfates and glucuronides in the urine.

Metabolism and excretion in the application of TTS corresponds to the metabolism and excretion of natural estrogens.

With repeated weekly patch application, no accumulation of either estradiol or estrone is observed. Accordingly, the equilibrium serum level of both hormones corresponds to the level observed after a single application.

Indications:

- Hormone replacement therapy (HRT) for the treatment of symptoms of estrogen deficiency due to natural menopause or surgical removal of the ovaries;

- prevention of postmenopausal osteoporosis.

Contraindications:

Hormone replacement therapy (HRT) with Climara® should not begin with any of the conditions or diseases listed below. If any of these occur during use of HRT, stop taking the drug and consult a doctor.

- Pregnancy or lactation period;

- bleeding from the genital tract, the cause of which is unclear;

- breast cancer or suspected of it;

- hormone-dependent malignant neoplasms or precancerous conditions, or suspicion of them;

- benign or malignant liver tumor at present or in the anamnesis;

- exacerbation of deep vein thrombosis, thromboembolic disease at present or in the anamnesis;

- Hypersensitivity to Climaria® components;

- Acute arterial thrombosis or thromboembolism (such as myocardial infarction, stroke).

Carefully:

Arterial hypertension, violations of the liver function, endometriosis, uterine fibroids, diabetes mellitus (see "Special instructions").

Pregnancy and lactation:

HRT is not prescribed during pregnancy or lactation.

Extensive epidemiological studies did not reveal an increased risk of developmental defects in children born to women who received sex hormones for contraception or HRT prior to pregnancy or teratogenicity when sex hormones were mistaken for early pregnancy.

A small amount of sex steroids can be excreted with milk.

Dosing and Administration:

- Treatment of symptoms of climacteric syndrome

Treatment begins with the lowest dose of Klimara® patch. If necessary, you can use a higher-dose patch.After choosing the dose, the lowest effective dosage of the patch should be used to alleviate the symptoms.

- Prevention of osteoporosis

Treatment for the prevention of postmenopausal bone loss should be started immediately after the onset of menopause. Long-term treatment based on an individual approach is recommended.

Treatment should be carried out either in a continuous or cyclic mode.

In the transition from long-term continuous or cyclic therapy: treatment should begin the day after the end of the previous treatment regimen. Therapy with estrogen alone is used if the woman has a hysterectomy. In women with an intact uterus, the progestogen should be added to the Klimaroy® treatment for 10-14 days each month. When using a patch that releases more than 50 μg of hormone / day, no protective effect on the endometrium was observed when adding progestogens.

The patch should be attached weekly in a constant mode, each used patch should be removed after 7 days, after which the fresh patch is attached to another place.Plasters can also be recommended for treatment in a cyclic mode. In this case, the patch is attached weekly for 3 consecutive weeks, followed by a 7-day interval without attaching the patch until the next course of treatment.

Menstrualnopodobnoe bleeding normally develops 2-3 days after stopping the use of gestagens.

Method of attaching a plaster

After removing the protective film, the Climara® patch is attached by the adhesive side to a clean, dry area of the skin along the spine or on the buttocks. Climara® should not be attached to or close to the mammary glands. The site chosen for fixing the patch should not be fat, damaged or irritated, it is also necessary to avoid the waist region, since when rubbing with tight clothing, the patch can become unstuck. Avoid sticking the patch on those areas of the skin where the patch can move in the "sitting" position. The patch should be attached immediately after opening the package and removing the protective film. The patch should be firmly pressed against the place of fixation by the palm for about 10 seconds.It is necessary to make sure that there is good contact with the skin, especially around the edges. If the adhesive tape does not fit tightly, for better adhesion, you should press on it. The application site should be changed at intervals of at least one week between applications.

If the patch is attached correctly, the patient can wash herself in the bath or shower, as usual. However, the patch can peel off from the skin under the influence of very hot water or in the sauna.

Untimely replacement or loss of plaster

- In the case of peeling off the patch before the end of the 7-day course of treatment, you can try to paste it again. If necessary, you can paste a new patch for the remaining days from the 7-day interval of use.

- If the patient has forgotten to replace the patch in time, the replacement should be made as soon as possible after the fact of the pass is established. The new patch should be used after the end normal 7-day treatment period.

Side effects:

The table below provides information on the incidence of adverse events with the use of the drug Klimara® (MedDRA - Medical Dictionary of Regulatory Activity).

The information is based on clinical research data.

The most frequent adverse reactions reported during clinical trials were skin irritation at the site of application and pain in the mammary gland (> 10%). Local symptoms at the site of application are mostly mild and include redness, itching, burning and vesicle formation.

System-Organic grade	Often (≥1/100 and <1/10)	Infrequently (≥1/1000 and <1/100)
Gastrointestinal tract	Abdominal pain, bloating, nausea
General and local	Edema at the site of application
Musculoskeletal system, connecting the cloth		Muscle cramps
Nervous system	Headache, giddiness	Migraine
Reproductive system, mammary glands	Breaking milk glands, change in character breakthrough uterine bleeding and smearing vaginal discharge	Increase in dairy glands
Other	Changes in body weight	-

With estrogen replacement therapy, other adverse events have been reported, but their association with the use of the drug Klimara® can not be either disproved or proven:

System-Organ Class	Adverse events
Congenital, hereditary and genetic diseases	Deterioration of symptoms of concomitant porphyria
Gastrointestinal tract	Vomiting
Liver	Cholestatic jaundice
Mental disorders	Changes in libido
Reproductive system, mammary glands	Changes in the size of the uterus leiomyoma, changes in the volume of the cervical secret
Skin and subcutaneous tissue	Chloasma or melasma that can persist after drug withdrawal, allergic contact dermatitis, post-inflammatory itching, generalized exanthema

In women with hereditary forms of angioedema, exogenous estrogens can cause or worsen withimpotentomy angioedema. See also "Special instructions".

Overdose:

In case of overdose, an overdose is unlikely. Symptoms that may be noted in an overdose: nausea, vomiting, some women may develop withdrawal bleeding. There is no specific antidote; should be symptomatically treated and remove the patch.

Interaction:

Long-term treatment with drugs that induce hepatic enzymes work (for example, some anticonvulsants and antimicrobials) can increase the clearance of sex hormones and reduce clinical efficacy. This has been established with respect to hydantoins, barbiturates, primidon,carbamazepine and rifampicin; there is also suspicion of oxcarbazepine, topiramate, felbamate and griseofulvin. The maximum induction of enzymes as a whole does not appear within 2-3 weeks, but can then persist for at least 4 weeks after discontinuation of drug therapy.

Special instructions:

If any of the conditions / risk factors indicated below are present or worsen, in each individual case, the potential risk and the expected benefit of drug treatment should be considered Klimara® before the beginning or continuation of HRT.

- Venous thromboembolism

A number of epidemiological studies have revealed a slight increase in the incidence of venous thromboembolism (VTE), for example, deep vein thrombosis or pulmonary embolism in women receiving Climara®. The risk / benefit ratio should be carefully weighed, if the Climara® preparation is recommended by women with VTE risk factors. Risk factors VTE include the presence of VTE in the individual and family history (the development of VTE in direct relatives at a relatively young age may indicate a genetic predisposition), as well as a pronounced obesity. The risk of VTE also increases with age.There is no single point of view regarding the possible role of varicose veins in the development of VTE.

The risk of VTE increases temporarily with prolonged immobilization, serious surgery or extensive trauma. Depending on the etiology of the disease and the duration of immobilization, a temporary discontinuation of the use of the Climara® preparation should be considered.

Treatment should be stopped immediately if there are signs of thromboembolism and suspicion of them.

- Arterial thromboembolism

During the course of randomized controlled trials with long-term use of combined conjugated equine estrogens (EML) and medroxyprogesterone acetate (MPA), no evidence of a positive effect on cardiovascular-The vascular system. In large-scale clinical trials of this compound, a possible increase in the risk of coronary heart disease (CHD) in the first year of use was found with a subsequent lack of positive effect. In one large clinical study, using only EFE, a potential reduction in CHD among women aged 50-59 years was found, with no overall positive effect among the cumulative study population.As a secondary result in two large-scale clinical studies using EFS as monotherapy or in combination with IPA revealed a 30-40% increase in the risk of stroke. It is not known, whether this increased risk extends to HRT preparations containing other types of estrogens and progestogens or to non-oral uses.

- Endometrial cancer

With long-term estrogen therapy, the risk of developing hyperplasia or endometrial cancer increases. Studies have confirmed that the additional administration of gestagens reduces the risk of hyperplasia and / or endometrial cancer.

- Mammary cancer

According to clinical studies and the results of observational studies, An increase of the relative risk of developing breast cancer in women who have used HRT for several years. This may be due to earlier diagnosis, the acceleration of growth of an already existing tumor in the background of HRT, or a combination of both.

Assumptions for an increased risk of developing breast cancer are based on the results of more than 50 epidemiological studies (the risk varies from 1 to 2).

AT two large-scale randomized studies with EML alone or in a constant combination with MPA, calculated risk indices of 0.77 (95% confidence interval: 0.59-1.01) or 1.24 (95% confidence interval: 1.01-1 , 54) after approximately 6 years of HRT use. It is not known whether this increased risk also extends to other products for HRT.

Relative risk increases with increasing duration application, but may be absent or be reduced when treated with estrogen alone. This increase is comparable to the increase in the risk of breast cancer in women every year, the delay in the onset of natural menopause, as well as with obesity and alcohol abuse. The increased risk gradually decreases to the usual level during the first few years after the termination of the use of the Klimara® preparation.

HRT increases the mammographic density of the mammary glands, which in some cases may make it difficult to detect radiological evidence of cancer.

- Ovarian Cancer

During the epidemiological study, there was a slight increase in the risk of ovarian cancer in women who use estrogen replacement therapy for a long time (more than 10 years).At the same time, a meta-analysis of 15 studies did not reveal an increased risk with the use of the drug Klimara®. Thus, data on the effect of the Climara® preparation on the risk of ovarian cancer are currently controversial.

- Tumor of the liver

Against the background of the use of sex hormones, which includes the drug Klimara®, in rare cases were observed benign, and even less often - malignant liver tumors. In some cases, these tumors led to a life-threatening intra-abdominal bleeding. With pain in the upper abdomen, enlarged liver, or signs of intra-abdominal bleeding in differential diagnosis, the probability of a liver tumor should be taken into account.

- Cholelithiasis

It is known that estrogens increase the lithogenicity of bile. Some women are predisposed to development cholelithiasis in treatment with the use of estrogens.

- Dementia

There are limited data from clinical studies on the possible increase in the risk of dementia in women starting to take drugs containing EML at the age of 65 years and over. As observed in studies, the risk can be reduced,if the use of drugs for HRT, containing EML, started in early menopause. It is not known whether this applies to other drugs for HRT.

- Other states

Immediately stop treatment, with the appearance of migraine-like or frequent and unusually severe headaches for the first time, and also with the appearance of other symptoms-possible precursors of ischemic stroke. If, despite the change in the place of application, according to the recommendations, there is a repeated persistent skin irritation (eg, persistent erythema or itching at the site of application), termination of transdermal treatment should be considered. The relationship between HRT and the development of clinically significant arterial hypertension has not been established. In women receiving HRT, a small increase in blood pressure is described, with a clinically significant increase seen rarely. In individual cases, with the development of persistent clinically significant arterial hypertension during the treatment of HRT, cancellation of the drug can be considered.

Sexual steroids can be poorly metabolized in patients with reduced liver function.Although there is no hepatic metabolism in transdermal HRT during primary passage through the liver, HRT should be given with caution to these patients.

In case of recurrence of cholestatic jaundice or cholestatic pruritus observed for the first time during pregnancy or previous treatment with sex hormones, it is necessary to immediately stop using Climara®.

In some patients under the influence of the drug Klimara ® may develop unwanted manifestations of estrogen stimulation, for example, pathological uterine bleeding. Frequent or persistent abnormal uterine bleeding against the background of treatment is an indication for endometrial research to eliminate organic disease.

Under the influence of estrogen, uterine fibroids may increase in size. In this case, treatment should be discontinued. It is recommended to stop treatment with the development of recurrence of endometriosis on the background of treatment with the drug Klimara®.

If you suspect a prolactinoma before starting treatment, you should exclude this disease. In case of detection of prolactinoma, the patient should be under close medical supervision (including periodic evaluation of prolactin concentration).

In some cases, there may be a chloasma, especially in women with a history of pregnant women with chloasma. During the use of the Climara® drug, women with a tendency to develop chloasma should avoid prolonged exposure to sunlight or exposure to ultraviolet radiation.

The following conditions may occur or worsen when using the Klimara® drug. Although their relationship with the use of the drug Klimara® is not proven, women with the following conditions during HRT should be under the supervision of a doctor: epilepsy, benign diseases of the breast, bronchial asthma, migraine, porphyria, otosclerosis, systemic lupus erythematosus, small chorea.

In women with hereditary forms of angioedema, exogenous estrogens can cause or worsen symptoms of angioedema.

Medical examinations

Before starting or resuming the use of the Klimara® drug, you should familiarize yourself with the history of the patient's illness and conduct a physicawgynecological examination. The frequency and nature of such surveys should be based on existing standards of medical practice with the necessary consideration of individualcharacteristics of each patient (but not less than once in 6 months) and should include measurement of blood pressure, assessment of the mammary glands, abdominal organs and pelvic organs, including cytological examination of the cervical epithelium.

In the presence of prolactinoma, a periodic determination of the concentration of prolactin is required.

Impact on laboratory results

Reception of sex steroids can affect the biochemical parameters of liver function, thyroid gland, adrenals and kidneys, plasma transport proteins such as globulin, sex hormone binding and lipid / lipoprotein fractions, carbohydrate metabolism, coagulation and fibrinolysis. Climara® does not adversely affect glucose tolerance.

Effect on the ability to drive transp. cf. and fur:Not found.

Form release / dosage:The transdermal therapeutic system, 12.5 cm2, 25 sq.cm.

Packaging:

One patch is placed in a sealed bag of aluminum foil with a coating of polyvinyl chloride film, inside of which a foil drying bag is glued on one side.

The package contains 4 patches in sealed bags.

Storage conditions:

At temperatures not higher than 30 ° C, out of reach of children.

Do not store printed. Immediately glue after removing the protective packaging.

Shelf life:

3 years.

Do not use after the time specified on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015577 / 01

Date of registration:26.05.2009

The owner of the registration certificate:Bayer Pharma AGBayer Pharma AG Germany

Manufacturer: & nbsp

BAYER WEIMAR, GmbH & Co. KG. KG Germany

Representation: & nbspBAYER, AOBAYER, AO

Information update date: & nbsp01.10.2015

Illustrated instructions

Instructions

Klimara® (Climara®)