Oestradiol

General characteristics. Structure:

Klimar transdermal system releasing 50 mkg of substance a day within 7 days represents the plaster of 12,5 cm2 containing 3,8 mg of oestradiol (equivalent 3,9 mg of oestradiol of a gemigidrat) in an acrylic adhesive matrix. Klimar transdermal system releasing 100 mkg of substance a day within 7 days represents the plaster of 25,0 cm2 containing 7,6 mg of oestradiol (equivalent 7,8 mg of oestradiol of a gemigidrat) in an acrylic adhesive matrix. Excipients: For a dosage of 3,9 mg / 12,5 cm 2
Pauly (акриламид-к-изооктилакрилат-к-винилацетат) (5:75:20) - 99,90 mg, ethyl oleate of-19,25  mg,  isopropyl myristate  -  9,65  mg,  глицеролмонододеканоат  -  4,80  mg, a polyethylene film (LDPE) - 12,5 cm2 For a dosage of 7,8 mg / 25,0 cm 2
Pauly (акриламид-к-изооктилакрилат-к-винилацетат) (5:75:20) - 99,90 mg, ethyl oleate of-19,25 mg, isopropyl myristate - 9,65 mg, глицеролмонододеканоат - 4,80 mg, a polyethylene film (LDPE) - 25,0 cm2
DESCRIPTION
The plaster of an oval form (about 4,5 cm by 3,3 cm that corresponds to 12,5 cm2) consisting of a transparent film carrier with the transparent homogeneous matrix containing active ingredient.
The plaster of an oval form (about 6,30 cm by 4,7 cm that corresponds to 25 cm2) consisting of a transparent film carrier with the transparent homogeneous matrix containing active ingredient.

Pharmacological properties:

Pharmacodynamics. The depression of function of ovaries which is followed by decrease in products of estrogen conducts to the menopausal syndrome which is characterized by vasculomotor and vegetative and organic symptoms.
Performing the replacement hormonal therapy (RHT) is directed to reduction of these symptoms. From all physiological estrogen, oestradiol is the most active, possessing greatest affinity to oestrogenic receptors.
17 - beta oestradiol is identical to the endogenous oestradiol produced by ovaries.
Exerts feminizing impact on an organism. Stimulates development of a uterus, uterine tubes, vaginas, a stroma and channels of mammary glands, pigmentation in nipples and generative organs, formation of secondary sexual characteristics on female type. Oppresses a resorption of a bone tissue, stimulates synthesis of a number of transport proteins (tiroksinsvyazyvayushchy globulin, transcortinum, transferrin, the globulin connecting sex hormones), fibrinogen. Increases concentration in blood of thyroxine, iron, copper, etc. Modulates receptors to progesterone and sympathetic regulation of a tone of smooth muscles, stimulates transition of intravascular liquid to fabrics and causes a compensatory delay of sodium and water. In high doses interferes with degradation of endogenous catecholamines, competing for active receptors catechol-au-methyltransferase.
Oestradiol in the form of the transdermal therapeutic system (TTS) represents the plaster attached to the site of skin. The control membrane provides gradual and continuous release of oestradiol from a tank with active agent through adherent layer on skin. Due to lack of effect of "the first passing" through a liver, TTS provides high performance when using smaller doses of drug. TTS delivers oestradiol in not changed look in a blood stream and maintains its concentration in plasma during therapy at the constant level, to adequate level on an early or average follicular phase.
Irrespective of a way of introduction, an estrogen dose, necessary for reduction of menopausal complaints, render the dozozavisimy stimulating effect on a mitosis and proliferation of an endometria. Monotherapy by estrogen increases endometria hyperplasia frequency and by that, risk of a carcinoma of an endometria. For prevention of a hyperplasia of an endometria at women with the kept uterus consecutive purpose of a gestagen within 10-14 days is recommended.

Pharmacokinetics. After skin application of Klimara, oestradiol is well absorbed through skin. Average speed of absorption makes 50 mkg/day and 100 mkg/day, respectively.
Weekly application of Klimara is comparable with the continuous low-dosed intravenous infusion directed to creation of equal, stable, platopodobny level of oestradiol in serum is similar to the level which is created during an early/average follicular phase in the reproductive period of life. Transdermalny appointment allows to avoid high fluctuations of oestradiol and its metabolites in serum as it is observed after peroral replacement therapy by oestradiol and, respectively, to avoid liver loading a large amount of oestradiol and its metabolites owing to high presistemny metabolism ("effect of primary passing") after oral administration. Thus, after transdermalny administration of oestradiol, influence on synthesis of protein in a liver is not noted.
Absolute value of serumal level of oestradiol in direct ratio areas of a plaster. Average equilibrium concentration of oestradiol in serum makes about 35 pg/ml (a plaster of 12,5 cm2) and 70 pg/ml (a plaster of 25 cm2).
After application of the TTS systems of 50 mkg (a plaster, of 12,5 cm2) and 100 mkg (a plaster, of 25 cm2) physiological concentration of oestradiol in blood serum is reached in 2-4 h. In 24 h after removal of system concentration of oestradiol in plasma decreases to initial value. The maintenance of metabolites of oestradiol in urine for the 2nd day after removal of system reaches the same values which were measured before application.
About 61% of oestradiol contact nonspecific a seralbumin and about 37% specifically the globulin connecting sexual steroids.
After transdermalny introduction transformation of oestradiol into estrone and conjugates remains in the physiological limits noted in an early follicular phase during the reproductive period of life with a ratio of levels oestradiol/estrone in serum about 1:1. High level of estrone as the result of intensive metabolism at "primary passing" through a liver during peroral ZGT oestradiol reflected by the relation oestradiol/estrone is lower than 0,1 at the same time is not observed.
Biotransformation transdermalno of the appointed oestradiol is similar to biotransformation of endogenous hormones: oestradiol, mainly, is metabolized in a liver, but also extrahepatically, for example, in intestines, kidneys, skeletal muscles and target organs. These processes include formation of estrone, estriol, katekholestrogen and their conjugates - sulfates and glucuronides which have clearly smaller oestrogenic properties or have even no them.
Some part of metabolites of oestradiol is excreted with bile and is exposed to so-called enterogepatichesky circulation. Eventually, oestradiol metabolites, mainly, are excreted in the form of sulfates and glucuronides with urine.
Metabolism and removal at use of TTS corresponds to metabolism and removal of natural estrogen.
At repeated weekly application of a plaster accumulation of either oestradiol, or estrone is not observed. Respectively, the equilibrium serumal level of both hormones corresponds to the level observed after single application.

Indications to use:

• Hormonal replacement therapy (ZGT) for treatment of symptoms of deficit of estrogen owing to a natural menopause or surgical removal of ovaries.
• Prevention of post-menopausal osteoporosis.

Route of administration and doses:

- Treatment of symptoms of a menopausal syndrome

Treatment begins with the smallest dose of a plaster of Klimara®. If necessary it is possible to use more high-dosage plaster. After selection of a dose for relief of symptoms the lowest effective dosage of a plaster has to be used.

- Prevention of osteoporosis

Treatment for the prevention of post-menopausal loss of bone weight has to be begun at once after approach of a menopause. The prolonged treatment based on individual approach is recommended.
Treatment has to be carried out either in continuous, or in the cyclic mode. Upon transition from long continuous or cyclic therapy: treatment should be begun next day after the termination of the previous scheme of treatment.
Therapy is only used by estrogen if the woman had a hysterectomy. At women with an intact uterus progestogen should be added to treatment by Klimara for 10-14 days every month. When using plasters, release more than 50 mkg hormones/days, protective influence on an endometria at addition of progestogens were not revealed.
The plaster has to be attached weekly in the constant mode, each used plaster has to be removed in 7 days then the fresh plaster is attached on other place.
Plasters can be also recommended for treatment in the cyclic mode. In this case, the plaster is attached weekly within 3 consecutive weeks, with the subsequent 7-day interval without plaster attachment to the following course of treatment.
Menstrualnopodobny bleeding normal develops in 2-3 days after the termination of reception of gestagen.

• Plaster attachment technique
After removal of a protective film the plaster of Klimara® is attached by the glued party on the pure, dry site of skin along a backbone or on buttocks. Климара® it should not be attached in mammary glands or near them. The site chosen for fixation of a plaster should not be fat, damaged or angry, it is also necessary to avoid area of a waist as at friction by close clothes the plaster can come unstuck. It is necessary to avoid gluing of a plaster on those sites of skin where the plaster can be displaced in a sitting position.
The plaster has to be attached at once after opening of packaging and removal of a protective film. The plaster has to be firmly pressed by a palm to the place of fixing during, about, 10 sec. It is necessary to make sure that there is a good contact with skin, especially at the edges. If the plaster adjoins leaky, for the best gluing it is necessary to pressure him.
The place of application has to change with an interval, on extremely measure, in one week, between applications.
If the plaster is attached correctly, the patient can wash in a bathroom or soul, as usual. However the plaster can come unstuck from skin under the influence of very hot water or in a sauna.
Untimely replacement or loss of a plaster
- In case of unsticking of a plaster before the termination of a 7-day course of treatment, it can try to be pasted again. If necessary it is possible to paste a new plaster for the remained days from a 7-day interval of use.
- If the patient forgot to replace a plaster in time, replacement should be made as soon as possible after establishment of the fact of the admission. The new plaster should be used after the end of the normal 7-day period of treatment.

Features of use:

If any of the states/risk factors provided below are available now or worsen, in each individual case the potential risk and the expected advantage of treatment by the drug Klimara® before or continuations of ZGT have to be considered. •  Venous thromboembolism
A number of epidemiological researches revealed some increase in frequency of development of venous thromboembolisms (VTE), for example, of a deep vein thrombosis or a thromboembolism of pulmonary arteries at the women receiving the drug Klimara®. The ratio risk/advantage has to be carefully weighed if the drug Klimara® is recommended by women with risk factors of VTE.
Risk factors of VTE include existence of VTE in the individual and family anamnesis (development of VTE in direct relatives at rather young age can indicate genetic predisposition), and also a gross obesity. The risk of VTE also increases with age. There is no uniform point of view of rather possible role of a varicosity in development of VTE.
The risk of VTE temporarily increases at a long immobilization, serious surgical intervention or an extensive injury. Depending on an etiology of a disease and duration of an immobilization, temporary phase-out of the drug Klimara® has to be considered.
Treatment has to be immediately stopped if there are symptoms of a thromboembolism and suspicion on them.
• Arterial thromboembolism
During the randomized controlled researches at prolonged use of the combined conjugated horse estrogen (CHE) and медроксипрогестерон acetate (MPA) the evidence of positive influence on cardiovascular system was not obtained. In large-scale clinical tests of this connection possible increase of risk of the coronary heart disease (CHD) in the first year of use with the subsequent lack of positive effect was revealed. In one large clinical trial when using only KLE was found potential reduction of cases of an ischemic heart disease among women at the age of 50-59 years in the absence of the cumulative positive effect among cumulative population of a research. As secondary result in two large-scale clinical trials with use of KLE as monotherapies or in combination with MPA 30-40% increase of risk of development of a stroke were revealed. It is unknown whether this increased risk extends to the drugs for ZGT containing other types of estrogen and progestogens or on not peroral routes of administration.
• Endometrial cancer
At long therapy by estrogen the risk of development of a hyperplasia or endometrial cancer increases. Researches confirmed that additional purpose of gestagen reduces risk of a hyperplasia and/or endometrial cancer.
• Breast cancer
According to clinical trials and to results of the observation researches increase in relative risk of development of a breast cancer in the women using ZGT within several years was revealed. It can be connected with earlier diagnosis, acceleration of growth of already available tumor against the background of ZGT or a combination of both factors.
Assumptions concerning increase in risk of development of a breast cancer are made on the basis of results of more than 50 epidemiological researches (the risk varies from 1 to 2).
In two large-scale randomized researches with KLE separately or at a constant combination to MPA the settlement indicators of risk equal 0,77 were received (95% a confidence interval: 0,59 - 1,01) or 1,24 (95% confidence interval: 1,01 - 1,54) after about 6 years of use of ZGT. It is unknown whether this increased risk as well extends to other products for ZGT.
The relative risk increases with increase in duration of use, but can be absent or be reduced at treatment only estrogen. This increase is comparable to increase in risk of developing of cancer of mammary glands at women of a delay of approach of a natural menopause every year, and also at obesity and an alcohol abuse. The increased risk gradually decreases to usual level within the first several years after drug Klimara® phase-out.
ZGT increases the mammography density of mammary glands that in certain cases can complicate radiological detection of cancer.
• Ovarian cancer
During the epidemiological research insignificant increase in risk of development of ovarian cancer in the women applying replacement therapy by estrogen a long time (more than 10 years) was noted. At the same time meta-analysis of 15 researches did not reveal increase in risk at drug Klimara® use. Thus, data on influence of the drug Klimara® on risk of ovarian cancer are currently disputable.
• Liver tumor
Against the background of use of sex hormones to which also the drug Klimara® belongs were in rare instances observed high-quality, and is even more rare - malignant tumors of a liver. In some cases these tumors led to the intra belly bleeding posing a threat for life. At pains in an upper part of a stomach, the increased liver or symptoms of intra belly bleeding at differential diagnosis it is necessary to consider probability of existence of a tumor of a liver.
• Cholelithiasis
It is known that estrogen increases a bile litogennost. Some women are predisposed to development of cholelithiasis at treatment using estrogen.
•  Dementia
There are limited data of clinical trials on possible increase in risk of development of dementia in the women beginning administration of drugs, containing KLE at the age of 65 years and are more senior. As it was observed in researches, the risk can be reduced if administration of drugs for ZGT containing KLE is begun in an early menopause. It is unknown whether it extends to other drugs for ZGT.
• Other states
It is necessary to stop immediately treatment at emergence for the first time migrenepodobny or frequent and extraordinary severe headaches, and also at emergence of other symptoms - possible harbingers of an ischemic stroke.
If, despite change of the place of application, according to recommendations, the repeating persistent irritation of skin is noted (for example, a persistent erythema or an itch in the place of application), the termination of transdermalny treatment has to be considered.
The interrelation between ZGT and development is not established to clinically expressed arterial hypertension. At the women receiving ZGT small increase in arterial pressure is described, at the same time clinically significant increase is noted seldom. In individual cases, at development of persistent clinically significant arterial hypertension during treatment of ZGT drug withdrawal can be considered.

Sexual steroids can badly be metabolized at patients with reduced function of a liver. Though at transdermalny ZGT there is no hepatic metabolism at primary passing through a liver, to these patients of ZGT has to be appointed with care.
At a recurrence of cholestatic jaundice or cholestatic itch, observed for the first time during pregnancy or the previous treatment by sex hormones, it is necessary to stop drug Klimara® use immediately.
At some patients under the influence of the drug Klimara® undesirable manifestations of stimulation by estrogen, for example pathological uterine bleeding can develop. Frequent or persistent pathological uterine bleedings against the background of treatment are the indication for an endometria research for an exception of a disease of organic character.
Under the influence of estrogen the hysteromyoma can increase in sizes. In this case treatment has to be stopped.
It is recommended to stop treatment at development of a recurrence of endometriosis against the background of treatment by the drug Klimara®.
At suspicion on existence of a prolaktinoma before an initiation of treatment it is necessary to exclude this disease. In case of identification of a prolaktinoma, the patient has to be under fixed medical observation (including periodic assessment of concentration of prolactin).
In certain cases the hloazma, especially at women with hloazmy pregnant women in the anamnesis can be observed. During use of the drug Klimara® of the woman with tendency to emergence of a hloazma have to avoid long stay to the sun or influences of ultraviolet radiation.
The following states can arise or be aggravated against the background of drug Klimara® use. Though their interrelation about use of the drug Klimara® is not proved, women with the listed below states when carrying out ZGT have to be under observation of the doctor: epilepsy, benign diseases of a mammary gland, bronchial asthma, migraine, porphyria, otosclerosis, system lupus erythematosus, hysterical chorea.
At women with hereditary forms of a Quincke's disease exogenous estrogen can cause or worsen symptoms of a Quincke's disease.
Pregnancy and lactation
ZGT is not appointed during pregnancy or a lactation.
Extensive epidemiological researches did not reveal any increased risk of defects of development in the children born by the women receiving sex hormones for contraception or ZGT before pregnancy or teratogenic action when sex hormones were accepted on imprudence in early durations of gestation.
A small amount of sexual steroids can be excreted with milk.
Medical examinations
Before the beginning or resuming of administration of drug of Klimara® it is necessary to get acquainted in detail with a case history of the patient and to conduct physical and gynecologic examination. Frequency and the nature of such inspections have to be based on the existing norms of medical practice at the necessary accounting of specific features of each patient (but at least 1 time in 6 months) and have to include measurement of arterial pressure, assessment of a condition of mammary glands, abdominal organs and pelvic bodies, including a cytologic research of an epithelium of a neck of uterus.
In the presence of a prolaktinoma periodic definition of concentration of prolactin is required.
Influence on results of laboratory indicators.
Reception of sexual steroids can influence biochemical indicators of function of a liver, thyroid gland, adrenal glands and kidneys, the content in plasma of transport proteins, such as the globulin connecting sex hormones and lipid/lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and a fibrinolysis. Климара® does not exert a negative impact on tolerance to glucose.

Influence on ability to drive the car and to use mechanisms.

Side effects:

Information on the frequency of the undesirable phenomena at drug Klimara® use is reflected in the table given below (MedDRA - the Medical dictionary of regulatory activity). Information is based on data of clinical trials.
The most frequent side reactions about which it was reported during clinical tests were irritation of skin in the place of application and a mammary gland pain (> 10%). Local symptoms in the place of application are generally expressed in easy degree and include reddening, an itch, burning and formation of vesicles.

Systemically - an organ class                      Often (> 1/100 and 1 <10)               Infrequently (> 1/1000 and <1/100)
Digestive tract               Abdominal pain, swelling, nausea 
The general and local reactions                        Swelled 
Musculoskeletal system,
connecting fabric                                                                                 Muscular spasms
Nervous system                               Headache, dizziness           Migraine

Reproductive system,                        Nagrubaniye milk                      Increase in mammary glands
mammary glands                              of glands, character change
                                                         breakthrough uterine
                                                          bleedings and smearing
                                                         allocations from a vagina
Other                                              Changes of body weight
Gastrointestinal                          Vomiting
path                                        
Liver                                              Cholestatic jaundice
Mental disorders                 of Change of a libido
Reproductive system,                  Changes of the size of a leiomyoma
mammary glands                             of a uterus, change in volume
                                                        cervical secret
Skin and hypodermic tissues                   of Hloazm or melazm,
                                                         which can persistirovat
                                                         after drug withdrawal,
                                                         allergic contact
                                                        dermatitis, post-inflammatory
                                                        itch, generalized dieback

At women with hereditary forms of a Quincke's disease exogenous estrogen can cause or worsen symptoms of a Quincke's disease.
See also "SPECIAL INSTRUCTIONS".

Interaction with other medicines:

Prolonged treatment by the drugs inducing work of liver enzymes (for example, some anticonvulsant and antimicrobic drugs) can increase clearance of sex hormones and reduce clinical performance. It was established concerning hydantoins, barbiturates, Primidonum, carbamazepine and rifampicin; also there is a suspicion against an okskarbazepin, topiramat, felbamat and griseofulvin. The maximum induction of enzymes in general is not shown within 2-3 weeks, but can then remain, at least, within 4 weeks after the termination of medicinal therapy.

Contraindications:

Hormonal replacement therapy (ZGT) drug Klimara should not begin in the presence of any of the states or diseases which are listed below. If any of them are shown in usage time of ZGT, stop administration of drug and consult with the doctor.
• Pregnancy or period of feeding by a breast.
• Bleeding from a genital tract which reason is not clear.
• A breast cancer or suspicion on it.
• Hormonedependent malignant new growths or precancerous states, or suspicion on them.
• A benign or malignant tumor of a liver now or in the anamnesis.
• An aggravation of a deep vein thrombosis, thromboembolic diseases now or in the anamnesis.
• Hypersensitivity to Klimara's components.
• Acute arterial thrombosis or thromboembolism (such as myocardial infarction, stroke).
Use with care - arterial hypertension, abnormal liver functions, endometriosis, a hysteromyoma, a diabetes mellitus (see. "Special instructions").

Overdose:

At application the overdose is improbable. Symptoms which can be noted at overdose: nausea, vomiting, at some women can develop cancellation bleeding. There is no specific antidote; it is necessary to carry out a symptomatic treatment and to remove a plaster.

Storage conditions:

Period of validity 3 years. Not to use after the term specified on packaging. To store at a temperature above 30 °C in the place, unavailable to children. Not to store unpacked. To paste immediately after removal of protective packaging.

Issue conditions:

According to the recipe

Packaging:

One plaster is placed in a tight package from aluminum foil of a covering from a polyvinyl chloride film in which on one party the drying sack from a foil is pasted. Packaging contains 4 plasters in hermetic packages.