Климонорм®

General characteristics. Structure:

Active components:
- 1 yellow dragee contains 2,0 mg of oestradiol of valerate
- 1 brown dragee contains 2,0 mg of oestradiol of valerate and 0,15 mg of levonorgestrel.
Excipients:
lactoses monohydrate, potato starch, поливидон K 25, talc, magnesium stearate, sucrose, glucose (dextrose), gelatin, a macrogoal 35000, calcium a carbonate, titanium E171 dioxide, ferrous oxide hydrate, ferrous oxide red, ferrous oxide brown, wax of karnaubskiya, magnesium a carbonate the main, the water purified.
Description. Round dragees of yellow color (9 dragees) and brown color (12 dragees).

Pharmacological properties:

Pharmacodynamics. Klimonorm contains estrogen - oestradiol valerate which in a human body turns into natural 170 oestradiol. Also Klimonorm is a part of drug derivative a 19-nortestosterona - levonorgestrel. Addition of levonorgestrel within 12 days of each cycle reduces risk of development of a hyperplasia and endometrial cancer.
Thanks to structure and the cyclic scheme of reception Klimonorm, (reception only of estrogen within 9 days, then - combinations of estrogen and a gestagen within 12 days, and, at last, a 7-day break), at women with an unextracted uterus at regular administration of drug is established a menstrual cycle.
Oestradiol fills shortage of estrogen in a female body after approach of a menopause and provides effective treatment of psychoemotional and vegetative climacteric symptoms (such as "inflows", the increased sweating, a sleep disorder, the increased nervous irritability, irritability, heartbeat, cardialgias, dizziness, a headache, decrease in a libido, muscular and joint pains); involution of skin and mucous membranes, especially mucous urinogenital system (an urine incontience, dryness and irritation mucous vaginas, morbidity at the sexual intercourse).
Oestradiol prevents the loss of bone weight caused by deficit of estrogen. Mainly it is connected with suppression of function of osteoclasts and shift of process of bone remodeling towards formation of a bone. It was proved that prolonged use of the replacement hormonal therapy (RHT) allows to reduce risk of fractures of peripheral bones at women after approach of a menopause. At cancellation of ZGT rates of decrease in bone weight are comparable with the indicators characteristic of the period directly after a menopause. It is not proved that, applying ZGT, it is possible to achieve recovery of bone weight to premenopausal level.
ZGT also has salutary effect on the content of collagen in skin, as well as on its density, and also can slow down process of formation of wrinkles.
Klimonorm's reception leads to decrease in level of the general cholesterol, lipoproteids of the low density (LPNP) and to increase in lipoproteids of the high density (LPVP) therefore LPVP/LPNP ratio, and also to increase in level of triglycerides considerably raises.
The observation researches give the grounds to believe that among women in a postmenopause when using ZGT the indicator of cancer cases of a large intestine decreases. The action mechanism is not clear so far.

Pharmacokinetics. After oestradiol intake valerate is quickly and completely absorbed from the digestive tract (DT). After receipt in an organism it is quickly metabolized with formation of 17v-oestradiol and estrone which are exposed further to standard metabolic transformations. After oral administration becomes biodustupny about 3% of oestradiol. The maximum concentration of oestradiol is reached in 2-3 hours, a ratio estrone-oestradiol equally 4:1. Oestradiol is removed in the form of metabolites, mainly with urine (90%) and, to a lesser extent - with bile.
After intake levonorgestrel is quickly and almost completely absorbed from a GIT. The maximum concentration in blood serum is reached in 1-2 hours. 93-95% of levonorgestrel contact albumine and the globulin, connecting sex hormones (G,CSH). Metabolites of levonorgestrel are removed with urine and bile, mainly, in the form of sulfates and glucuronides.

Indications to use:

• The Replacement Hormonal Therapy (RHT) at climacteric disorders, involutional changes of skin and an urinogenital path, depressions in a climacteric, and also symptoms of deficit of estrogen owing to a natural menopause or a hypogonadism, sterilization or primary dysfunction of ovaries at women with an unextracted uterus.
• Prevention of post-menopausal osteoporosis.
• Normalization of irregular menstrual cycles.
• Treatment of primary or secondary amenorrhea.

Route of administration and doses:

If at the patient periods still proceed, treatment should be begun for the 5th day of a menstrual cycle (the 1st day of menstrual bleeding corresponds to the 1st day of a menstrual cycle).
Patients with an amenorrhea or very rare periods, and also women in a postmenopause, can begin administration of drug at any time provided that pregnancy is excluded (see the section "Pregnancy and Lactation").
Each packaging is counted on 21-day reception.
Daily during the first 9 days accept on one yellow dragee, and then within 12 days - daily on one brown dragee. After 21-day administration of drug the 7-day break in administration of drug during which there comes the menstrualnopodobny bleeding caused by drug withdrawal follows (usually for 2-3 day after reception of the last dragee).
After a 7-day break in administration of drug begin new packaging of Klimonorm, accepting the first dragee of week on the same day, as the first dragee from the previous packaging.
The dragee is swallowed entirely, washing down with a small amount of liquid. Time of day when the woman accepts drug, does not matter, however, if she began to accept a dragee in any specific time, she has to adhere to this time further. If the woman forgot to accept a dragee, she can accept it within the next few 12 — 24 hours. If treatment is interrupted for longer time, developing of vaginal bleeding is possible.

Features of use:

Klimonorm is not applied for the purpose of contraception.
In need of contraception, it is necessary to apply non-hormonal methods (except for calendar and temperature methods). At suspicion on pregnancy, it is necessary to suspend reception of a dragee until pregnancy is not excluded (see the section "Pregnancy and Lactation").
At existence or deterioration any of the states or risk factors provided below before beginning or continuing ZGT it is necessary to estimate a ratio of individual risk and advantage of treatment.
• Venous thromboembolism
In a number of controlled randomized, and a tkazha of epidemiological researches the increased relative risk of development of a venous thromboembolism (VTE) against the background of ZGT, i.e. a deep vein thrombosis or an embolism of a pulmonary artery is revealed. Therefore, at purpose of ZGT to women with risk factors of VTE the ratio of risk and advantage of treatment has to be carefully weighed and discussed with the patient.
Risk factors of development of VTE include the individual and family anamnesis (existence of VTE at the immediate family at rather young age can indicate genetic predisposition) and heavy obesity. The risk of VTE also increases with age. The question of a possible role of a varicosity in development of VTE remains disputable.
The risk of VTE can temporarily increase at a long immobilization, "big" planned and traumatologic operations or a massive injury. Depending on the reason or duration of an immobilization it is necessary to resolve an issue of expediency of the temporary termination of ZGT
It is necessary to stop immediately treatment at emergence of symptoms of trombotichesky disturbances or at suspicion on their emergence.
• Arterial thromboembolism
During the randomized controlled researches at prolonged use of the combined conjugated estrogen and медроксипрогестерон acetate the evidence of positive influence on cardiovascular system was not obtained. In large-scale clinical tests of this connection possible increase of risk of a coronary disease in the first year of use was revealed. Also the increased risk of developing of a stroke was found. So far with other drugs for ZGT it was not carried out long-term randomized controlled tests for the purpose of identification of positive effect concerning the indicators of incidence and mortality concerning cardiovascular system. Therefore it is unknown whether this increased risk extends to the drugs for ZGT containing other types of estrogen and progestogens.
• Endometrial cancer
At long monotherapy by estrogen the risk of development of a hyperplasia or a carcinoma of an endometria increases. Researches confirmed that addition of gestagen reduces risk of a hyperplasia and endometrial cancer.
• Breast cancer
According to clinical tests 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, biological effect of ZGT or a combination of both factors. The relative risk increases with increase in duration of treatment (for 2.3% for a year of use) and increases at a combination of estrogen to progestogens perhaps even more. This increase is comparable to increase in risk of developing of cancer of mammary glands at women every year of a delay of approach of a natural menopause (for 2.8% for a year of a delay), and also at obesity and an alcohol abuse. The increased risk gradually decreases to usual level within the first 5 several years after the termination of ZGT.
According to researches the breast cancer revealed at the women accepting ZGT which was usually more differentiated than women have its not accepting.
ZGT increases the mammography density of mammary glands that in certain cases can exert a negative impact on radiological detection of a breast cancer.
• Liver tumor
Against the background of use of sexual steroids to which also means for ZGT belong 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 with use of estrogen.
• 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 a trombotichesky stroke of a brain.
The interrelation between ZGT and development is not established to clinically expressed arterial hypertension. At the women accepting ZGT small increase in arterial pressure is described, clinically significant increase is noted seldom. However, in some cases, at development against the background of reception of ZGT of persistent clinically significant arterial hypertension cancellation of ZGT can be considered.
At not heavy abnormal liver functions, including various forms of a hyperbilirubinemia, such as syndrome the Cudgel Johnson or a syndrome of the Rotor, are necessary observation of the doctor, and also periodic researches of function of a liver. At deterioration in indicators of function of a liver of ZGT it is necessary to cancel.
At a recurrence of cholestatic jaundice or cholestatic itch, observed for the first time during pregnancy or the previous treatment by sex steroid hormones, it is necessary to stop ZGT immediately.
Special observation of women with the moderate increased level of triglycerides is necessary. In similar cases use of ZGT can cause further increase of level of triglycerides in blood that increases risk of acute pancreatitis.
Though ZGT can influence peripheral insulin resistance and tolerance to glucose, need to change the scheme of treatment of patients with a diabetes mellitus when carrying out ZGT, usually does not arise. Nevertheless, the women suffering from a diabetes mellitus when carrying out ZGT have to be under observation.
At some patients under the influence of ZGT 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.
If treatment of irregular menstrual cycles does not yield results, it is necessary to conduct examination for an exception of a disease of organic character.
Under the influence of estrogen of a 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 ZGT.
At suspicion on existence of a prolaktinoma before an initiation of treatment it is necessary to exclude this disease.
In certain cases the hloazma, especially at women with hloazmy pregnant women in the anamnesis can be observed. During ZGT the woman with tendency to emergence of a hloazma have to avoid long stay in the sun or ultraviolet radiation.
The following states can arise or be aggravated against the background of ZGT. Though their interrelation with ZGT is not proved, women with these states when carrying out ZGT have to be under observation of the doctor: epilepsy; benign tumor of a mammary gland; bronchial asthma; migraine; porphyria; otosclerosis; system lupus erythematosus, hysterical chorea.

Medical examination and consultation
Before the beginning or resuming of ZGT the woman is recommended to undergo careful all-medical and gynecologic examination (including a research of mammary glands and a cytologic research of cervical slime), to exclude pregnancy. Besides, it is necessary to exclude disturbances of system of a blood coagulation. Periodically it is necessary to conduct control examinations.

Influence on results of laboratory researches
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 kortikosteroidsvyazyvayushchy globulin and lipid/lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and a fibrinolysis.

Influence on ability to drive the car and to use mechanisms
Does not influence.

Side effects:

• From reproductive system and mammary glands:
changes of frequency and intensity of uterine bleedings, the breakthrough bleedings, intermenstrual bloody allocations (which are usually weakened during therapy), a dysmenorrhea, changes of vaginal allocations, a state, similar to a premenstrual syndrome; morbidity, tension and/or increase in mammary glands.
• From digestive tract
dyspepsia, abdominal distention, nausea, vomiting, abdominal pain, recurrence of cholestatic jaundice
• From skin and hypodermic cellulose
skin rash, skin itch, hloazma, knotty erythema
• From TsNS
headache, migraine, dizziness, uneasiness or depressive symptoms, increased fatigue
• Other
tachycardia, hypostases, increase in arterial pressure, venous thrombosis and thromboembolism, muscular spasms, changes of body weight, change of a libido, vision disorder, intolerance of contact lenses, allergic reactions.

Interaction with other medicines:

At the beginning of ZGT it is necessary to stop use of hormonal contraceptives. If necessary the patient should recommend non-hormonal contraceptives.
Prolonged treatment by the drugs inducing liver enzymes (for example, some anticonvulsant and germicides) can increase clearance of sex hormones and reduce their clinical performance. Similar property was revealed to induce enzymes of a liver at hydantoins, barbiturates, Primidonum, carbamazepine and rifampicin, existence of this feature is also supposed at an okskarbazepin, a topiramat, a felbamat and griseofulvin. The maximum induction of enzymes is usually observed not earlier, than in 2-3 weeks, but then it can remain still, at least, within 4 weeks after the termination of administration of drug.
In rare instances against the background of the accompanying reception of some antibiotics
(for example, penicillinic and tetracycline groups) decrease in level of oestradiol was observed.
The substances which substantially are exposed to conjugation (for example, paracetamol), can increase bioavailability of oestradiol owing to competitive inhibition of system of conjugation in the course of absorption.
Owing to influence of ZGT on tolerance to glucose the need for peroral antidiabetic means or insulin in some cases can change.
• Interaction with alcohol
Overconsumption of alcohol during ZGT can lead to increase in level of the circulating oestradiol.

Contraindications:

It is not recommended to begin the replacement hormonal therapy (RHT), in the presence of any of the listed below states. If any of these states arises during ZGT, then it is necessary to stop drug use immediately.
• Pregnancy and lactation
• Vulval bleeding of not clear origin
• The confirmed or estimated diagnosis of a breast cancer
• The confirmed or estimated diagnosis of a hormonedependent precancerous disease or hormonedependent malignant tumor
• Liver tumors now or in the anamnesis (high-quality or malignant)
• Serious illness of a liver
• The acute or recently postponed arterial thrombosis or a thromboembolism (such as myocardial infarction, stroke)
• A deep vein thrombosis in a stage of an aggravation, a thromboembolism now or in the anamnesis
• The expressed gipertriglitseridemiya
• Hypersensitivity to drug components Klimonorm. Use with care
Klimonorm it is necessary to appoint with care at the following diseases: arterial hypertension, inborn hyperbilirubinemias (Gilbert's syndromes, the Cudgel Johnson and the Rotor), cholestatic jaundice or a cholestatic itch during pregnancy, endometriosis, a hysteromyoma, a diabetes mellitus (see. "Special instructions").
Pregnancy and lactation
ZGT is not appointed during pregnancy or feeding a breast.
Large-scale epidemiological researches of the steroid hormones used for contraception or ZGT did not reveal increase in risk of development of inborn defects in the children who were born at women who accepted such hormones before pregnancy, and also teratogenic influence of hormones at their accidental inclusion in early durations of gestation.
A small amount of sex hormones can be allocated with maternal milk.

Overdose:

Researches of acute toxicity did not reveal risk of acute side effects at accidental administration of drug Klimonorm in the quantity which is repeatedly exceeding a daily therapeutic dose. Symptoms which can be noted at overdose: nausea, vomiting, vaginal bleeding. There is no specific antidote, a symptomatic treatment.

Storage conditions:

At a temperature not above 25 °C in the place, unavailable to children. Period of validity of 5 years. It is impossible to apply on expiry date, specified on packaging! List B.

Issue conditions:

According to the recipe

Packaging:

The calendar packaging (blister) containing 9 dragees of yellow color and 12 dragees of brown color. On 21 dragees or 3 blisters on 21 dragees together with the application instruction place in a cardboard box.