The instruction for medical use
of Klimonormâ medicine
the Trade name
of Klimonormâ
the International unlicensed name
Is not present
the Dosage form
of the Dragee
Structure
1 yellow dragee contains active agent - oestradiol the valerate micronized 2.0 mg,
1 brown dragee contains active agents: oestradiol the valerate micronized 2.0 mg, levonorgestrel of 0.15 mg,
excipients: lactoses monohydrate, potato starch, gelatin, talc, magnesium stearate, water purified
structure of a cover (yellow dragee): sucrose, glucose syrup, gelatin, magnesium carbonate of the main easy, K 25 povidone, macrogoal 35000, calcium carbonate, talc, titan dioxide (E171), ferrous oxide yellow (E172), wax of karnaubskiya,
structure of a cover (brown dragee): sucrose, glucose syrup, gelatin, magnesium carbonate of the main easy, K 25 povidone, macrogoal 35000, calcium carbonate, talc, titan dioxide (E171), ferrous oxide yellow (E172), ferrous oxide red (E 172), ferrous oxide brown (E 172), wax of karnaubskiya.
Description
Brilliant dragees of yellow color, round, with a diameter of 5.8 - 6.2 mm, 3.2 - 3.7 mm thick. Brilliant dragees of brown color, round, with a diameter of 5.8 - 6.2 mm, 3.2 - 3.7 mm thick.
Pharmacotherapeutic group
Sex hormones and modulators of a reproductive system. Progestogens and estrogen in a combination. Progestogens and estrogen (for consecutive calendar reception). Levonorgestrel and estrogen.
The ATX G03FB09 code
the Pharmacological
Pharmacokinetics Oestradiol properties valerate
After oestradiol intake valerate is completely absorbed from digestive tract. After intake of 4 mg of oestradiol of the valerate corresponding to 2 dragees of yellow color of 1 phase, the maximum concentration of oestradiol in blood plasma is reached in 12 hours. The maximum concentration of oestradiol after intake of 4 mg of oestradiol makes about 40-52 pg/ml Average plasma elimination half-life of blood makes 1 hour.
Oestradiol partially contacts proteins of blood plasma.
Orally entered oestradiol during the first passing through a liver is metabolized for 90%, mainly in estrone, estrone sulfate and estriol and also to free or metilirovanny katekholestrogen. Oestradiol, mainly, is metabolized in a liver, as well as other ways.
Oestradiol and its metabolites (estrone and estriol) are generally removed with urine within 48 hours in the form of conjugates with sulphuric and glucuronic acid and also in a small amount in not changed look. A part of metabolites is removed with excrements.
Levonorgestrel
After intake levonorgestrel is quickly and almost completely absorbed from a GIT.
After intake of 0.3 mg of the levonorgestrel corresponding to 2 dragees of brown color 2 phases, the maximum concentration of levonorgestrel in blood plasma, the component about 6 ng/ml is reached in 1-2 hours. Elimination half-life makes 2 h in a phase of distribution and 10–24 h in an elimination phase.
Levonorgestrel for 93-95% contacts albumine of blood serum and specifically contacts the globulin, connecting sex hormones (G,CSH).
The effect of the first passage through a liver did not come to light.
The clearance of removal from plasma is 106 ml/h/kg.
Metabolites of levonorgestrel are removed with urine and bile approximately in an identical ratio, mainly, in the form of sulfates and glucuronides.
The insignificant amount of levonorgestrel is excreted in breast milk.
The pharmacodynamics
Active ingredient of the drug Klimonormâ is synthetic valerate of 17b-oestradiol which in a human body turns into 17b-oestradiol on chemical and biological properties identical to endogenous natural oestradiol. Oestradiol fills shortage of estrogen at women during the post-menopausal period and promotes simplification of climacteric symptoms.
As a result of a cyclic combination of estrogen with levonorgestrel, the mitogenetic activity of estrogen is suppressed. Thus, the increased risk of developing a hyperplasia and endometrial cancer connected with intake only of estrogen decreases.
Data of clinical trials
Relief of symptoms of the caused deficiency of estrogen and influence on bleedings.
Simplification of climacteric symptoms, was observed from first weeks of treatment.
Bleedings of cancellation were noted in 84.4% of cycles within the first year of therapy. Average duration was 5 days.
Breakthrough bleedings and (or) the smearing discharges were noted at 12.9% of women within the first three months of therapy and at 7.9% of women within 10–12 months of therapy.
The amenorrhea (absence of bleedings or the smearing discharges) was noted in 6.4% of cycles within the first year of therapy.
Indications
- the replacement hormonal therapy (RHT) at symptoms of deficiency of estrogen at women during the post-menopausal period.
Experience of use of drug for women is more senior than 65 years is limited.
The route of administration and doses
of Klimonormâ is intended for hormonal replacement therapy on a cyclic basis.
The dosing mode
Each packing 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 3 weeks of reception of a dragee it is necessary to take a 7-day break in administration of drug during which it is possible to expect approach of menstrualnopodobny bleeding.
After a 7-day break in administration of drug begin new packing of Klimonormaâ irrespective of whether menstrualnopodobny bleeding began or it proceeds.
How to begin reception of Klimonormaâ
- in the absence of reception of replacement hormonal therapy earlier Treatment of Klimonormomâ can be begun at any time.
- Upon transition from various drugs for replacement hormonal therapy
Upon transition from the continuous combined replaceable hormonal therapy, treatment of Klimonormomâ should be begun next day after the end of the previous therapy.
Upon transition from cyclic hormonal therapy, treatment of Klimonormomâ should be begun next day after a break in reception of a dragee.
At the beginning or continuation of treatment of post-menopausal symptoms it is necessary to apply the smallest effective dose during the shortest period.
The route of administration
of the Dragee is swallowed entirely, washing down with a small amount of liquid. It is preferable to accept a dragee every day in one and too time, it is desirable for avoidance of gastrointestinal disorders in the evening.
Duration of treatment is defined by the doctor.
Reception of the passed dragees
If the woman forgot to take a pill at the scheduled time in time, then it should be accepted within the next 12 hours. Otherwise treatment should be continued by administration of drug next day, disregarding the forgotten dragee. The admission in reception of a dragee raises a likelihood of developing breakthrough bleeding.
Side effects
Side effects, the connected or perhaps connected with use Klimonormaâ are based on results of the clinical trials including 588 women and post-marketing observations including 10.115 women.
The serious side effects connected with reception of ZGT are also listed in the section Special Instructions.
Often (≥1/100, & lt, 1/10)
- headaches, migraine
- arterial hypertension
- tension and mammary gland pain, a neoplasia of mammary glands
(benign mastopathy)
Infrequently (≥1/1000, & lt, 1/100)
- reactions of hypersensitivity
- infections of a respiratory system, bronchitis
- change of mood, including uneasiness or depressive mood
- memory disturbance *, confusion of consciousness, dizziness
- a disorder of vision
- tachycardia/heartbeat, a varicosity, hemorrhoids, cardiovascular disturbances
- dyspepsia, nausea, vomiting, an abdominal distension, pains in a stomach, the profound constipations *
- cholangites, cholecystitises, abnormal liver functions
- acne rash, seborrhea, a skin itching and burning
- intermenstrual bleedings, vaginal discharges / changes of vaginal discharges, mastitis *, vulvovaginity* / vulvovaginal symptoms, a neck hyperplasia matki* / a dysplasia of a neck of the uterus, an endometrium hypertrophy, an endometrium hyperplasia *, a breast cancer
- inflows of heat, an asthenia, peripheral hypostases, feeling of weight in the lower extremities, pains in pelvic area
- anemia, changes in body weight, the increased sugar level in blood, a hyperbilirubinemia
Seldom (≥1/10000, & lt, 1/1000)
- disturbance of a libido
- insomnia
- venous thrombosis **, thrombophlebitises of superficial veins, arterial hypotension
- a hair loss
* the Only message about this by-effect which is perhaps connected with drug use belongs to the category 'infrequently' in connection with the small volume of sample of clinical trial (n=588).
** the venous thrombembolia, for example deep veins of the lower extremities or fibrinferments of pelvic veins, an embolism of a pulmonary artery is more often observed at the women using ZGT than at the women who are not using ZGT. For further information see the section Special Instructions.
Other side reactions connected with use it is oestrogenic / progestagenov:
- cholelithiasis
- disturbances of skin and hypodermic cellulose: the hloazma, a knotty erythema and a multformny erythema, a vascular purpura
- perhaps development of dementia in women is more senior than 65 years
- at women with a hereditary Quincke's disease exogenous estrogen can provoke or aggravate symptoms of this disease.
The risk of a breast cancer
Is reported that at the women who are on the therapy combined estrogen-progestagennoy more than 5 years, risk of developing a breast cancer increases twice. Any increase in risk at the women receiving estrogen in monotherapy is much lower, than at the women accepting estrogen in a combination with progestogens. The risk level depends on duration of use of drugs.
The risk level depends on treatment duration.
Results of large randomized placebo - a controlled research (WHI – study) and an epidemiological research (MWS) are given below.
A research of one million women (MWS) - the expected additional risk of developing a breast cancer after 5 years of treatment.
The age
(years)
Quantity of additional cases on 1000 women who earlier were not accepting ZGT within 5 years *
the Relation of risks and 95% КИ#
Quantity of additional cases on 1000 women, users of ZGT within 5 years (95% of KI)
estrogen 50-65 9-12 1.2 1-2 (0-3)
Combination therapy is oestrogenic ZGT in the form of monotherapy +
progestogen 50-65 9-12 1.7 6 (5-7)
* Are taken from initial indicators of incidence in the developed countries
# the Cumulative relation of risks. This size is non-constant, but will increase in process of increase in duration of treatment.
Note: as the cancer cases of a mammary gland differ in EU countries, the quantity of additional cases of a breast cancer will also change in proportion.
The research US WHI (Research Initiative of Health of the Woman) - additional risk of developing a breast cancer after 5 years of treatment.
Age
(years)
Incidence on 1000 women accepting placebo for 5 years
the Relation of risks and 95% of KI
Quantity of additional cases on 1000 women, users of ZGT within 5 years (95% of KI)
of Monoterapiya
the conjugated horse estrogen (CHE) 50-79 21 0.8 (0.7-1.0)-4 (-6 – 0) *
KLE+ of a medroksiprogesteron acetate (estrogen + прогестаген#)
50-79 17 1.2 (1.0-1.5) +4 (0 - 9)
* in the research WHI of the woman with a remote uterus at which increase in risk of a breast cancer
# was not observed in the analysis limited to women who before inclusion in a research did not use earlier ZGT was not noted increase in risk in the first 5 years of treatment: after 5 years the risk was higher, than at the women who are not accepting ZGT.
2 – group of women in the research WHI with a remote uterus at whom increase in risk of RMZh is not revealed.
Risk of endometrial cancer
of the Woman with an unextracted uterus in a postmenopause
everyone 5 of 1000 women with an unextracted uterus who are not accepting ZGT is subject to Risk of developing endometrial cancer approximately. For women with an unextracted uterus the monotherapy by estrogen is not recommended as it increases risk of developing endometrial cancer. Depending on duration of estrogenic therapy and a dose of estrogen, increase in risk of endometrial cancer in epidemiological researches varied from 5 to 55 additional cases on 1000 women aged from 50 up to 65 years. Addition of progestogen to estrogenic therapy during, at least, 12 days of a cycle, allows to avoid the increased risk. In the research MWS use combined (cyclic or continuous) ZGT within 5 years did not cause increase in risk of endometrial cancer (the SHOUTING 1.0 (0.8-1.2)).
Ovary cancer
Long-term use of estrogenic therapy and combined ZGT estrogen-progestagennoy can be connected with a little increased risk of ovarian cancer. In the Research Million Women Study ZGT lasting 5 years caused 1 additional case of ovarian cancer on 2500 patients.
The risk of a venous thrombembolia
of ZGT can be connected with 1.3 - 3-multiply increased relative risk of developing a venous thrombembolia (VTE), i.e. a deep vein thrombosis or pulmonary embolism. Emergence of such phenomena is most probable within the first year of ZGT.
Results of the research WHI are given below:
The research WHI (Research Initiative of Health of the Woman) - additional risk of VTE after 5 years of use of ZGT
the Age
(years)
Incidence on 1000 women accepting placebo for 5 years
the Relation of risks and 95% of KI
Quantity of additional cases on 1000 women accepting ZGT within 5 years (95% of KI)
of Monoterapiya estrogen for oral administration *
50-59 7 1.2 (0.6-2.4) 1 (-3–10)
Combined peroral is oestrogenic + progestogen the containing
drugs 50-59 4 2.3 (1.2-4.3) 5 (1-13)
* a research at women with a remote uterus
Risk of coronary heart disease
Risk of developing coronary heart disease is a little increased at women aged 60 years accepting combined ZGT estrogen-progestagennuyu are more senior.
The risk of an ischemic stroke
Use of estrogenic monotherapy and estrogen-progestagennoy of therapy is followed by 1.5-fold increase in relative risk of an ischemic stroke. ZGT does not increase risk of a hemorrhagic stroke.
Such relative risk does not depend on age of the patient or duration of therapy. However, as the initial risk is closely connected with age, the general risk of a stroke at women against the background of ZGT increases with age, see the section Special Instructions.
The research WHI (Research Initiative of Health of the Woman) - additional risk of an ischemic stroke * after 5 years of use of ZGT
Age
(years)
Incidence on 1000 women accepting placebo for 5 years
the Relation of risks and 95% of KI
Additional quantity of cases on 1000 women accepting ZGT within 5 years (95% of KI)
50-59 8 1.3 (1.1-1.6)
3 (1–5)
* there Are no differences between an ischemic and hemorrhagic stroke
of the Contraindication
- the known hypersensitivity to one of drug components
- a breast cancer in the anamnesis, now either assumed
- the confirmed or expected estrogenzavisimy malignant tumors (for example, endometrial cancer)
- vaginal bleeding of not clear origin
- an endometrium hyperplasia (earlier not treated)
- venous a thrombembolia now or in the anamnesis (deep vein thrombosis, a pulmonary embolism)
- trombofilichesky disturbances, for example deficit of a protein With, a protein of S or antithrombin (see the section Special Instructions)
- the acute or recently postponed arterial thrombosis or a thrombembolia (such as, a myocardial infarction and a stroke)
- acute diseases of a liver (or in the anamnesis) before normalization of hepatic tests
- a porphyria
Medicinal interactions
Metabolism of estrogen and levonorgestrel can increase at the accompanying administration of drugs inducing liver enzymes, for example, of the system of P450 cytochrome such as anticonvulsant (phenobarbital, Phenytoinum, carbamazepine, okskarbazepin, topiramat, felbamat and Primidonum) and germicides, such as rifampicin, rifabutin, not Virapinum, efavirenz and also griseofulvin, meprobamate and phenylbutazone and its salts.
Ritonavir and nelfinavir, known as strong inhibitors, on the contrary, show the stimulating properties at use in combination with steroid hormones.
The vegetable drugs containing a St. John's wort can induce metabolism of estrogen and progestogen also.
Acceleration of metabolism of estrogen and progestogen can clinically cause decrease in effect and lead to any changes in the nature of uterine bleedings. Substances which inhibit metabolic enzymes for example ketokonazol, can increase the plasma level of active agents of drug.
Estrogen is capable to increase the frequency of manifestation of side effects of Imipraminum.
Simultaneous treatment with cyclosporines can increase the level of cyclosporine, creatine and transaminases owing to decrease in elimination in a liver.
Estrogen is capable to increase clinical performance and undesirable effects of the drugs containing corticosteroids. At replacement therapy by thyroid hormones increase in a dose of left thyroxine can be required.
The changes in indestinal flora connected with use of activated carbon and/or antibiotics, such as ampicillin, tetracycline) can lead to decrease in level of hormones that promotes decrease in their effect. In such cases the increased frequency of development of intermenstrual bloody discharges is observed.
Requirement in a treatment / dose of oral antihyperglycemic means or insulin can change as a result of influence of estrogen on tolerance to glucose (decrease) and the answer to insulin.
Intake of estrogen can affect results of laboratory tests, for example, indicators of function of a thyroid gland (see the section Special Instructions or the tolerance test to glucose.
Special instructions
For treatment of post-menopausal symptoms ZGT should be begun only in the presence of symptoms which adversely affect quality of life.
In all cases it is necessary to carry out carefully the ratio assessment risk/advantage, at least, annually, and ZGT should be continued only if advantages exceed risk.
Data on the risks connected with ZGT at treatment of a premature menopause are limited. Considering low absolute risk at young women, these women can have more favorable ratio of advantages and risks, than at women of more advanced age.
Medical examination and consultation
Before the beginning or resuming of ZGT to the woman is recommended to undergo careful all-medical examination (including a research of the family anamnesis) and gynecologic inspection (including a research of mammary glands and a cytologic research of cervical slime), to consider contraindications and precautionary measures. In the course of treatment it is necessary to perform periodically control examinations which frequency is defined individually.
The woman should be informed that it is necessary to report about any changes in mammary glands to the doctor or the nurse. Inspection of mammary glands, including mammography, should be carried out according to the established schedule of screening and depending on individual clinical need.
States at which observation is required
If any of the following states were observed earlier, are available now and/or were aggravated during pregnancy or earlier carried out hormonal therapy, the patient should be observed carefully.
It is necessary to take into account that the specified states can renew and/or be aggravated during performing therapy of Klimonormomâ:
- the leiomyoma (fibromyoma) or endometriosis
- risk factors, including in the anamnesis of thromboembolic disturbances
- risk factors of developing estrogenzavisimy tumors (for example, presence of a breast cancer at relatives of 1 degree of relationship)
- arterial hypertension
- liver diseases (for example, liver adenoma)
- diabetes with vascular disorders or without them
- cholelithiasis
- migraine or the profound headaches
- a system lupus erythematosus
- an endometrium hyperplasia in the anamnesis
- epilepsy
- bronchial asthma
- an otosclerosis
of the Reason for the immediate termination of administration of drug
- jaundice or deterioration in function of a liver
- substantial increase of arterial blood pressure
- again appeared attacks of a migrenepodobny headache
- pregnancy
the Hyperplasia of endometrium and endometrial cancer
At women with an unextracted uterus at long monotherapy by estrogen raises risk of developing a hyperplasia or carcinoma of endometrium.
At the women accepting only are oestrogenic, the increased risk of developing endometrial cancer is higher than from 2 to 12 times in comparison with the women who are not using estrogen depending on duration of treatment and a dose of estrogen. After the treatment termination the risk remains raised approximately within 10 years.
Addition of progestogen in the cyclic mode throughout a 28-day cycle or continuous therapy by the drug combined estrogen-progestagennym at women with an unextracted uterus is prevented at least 12 days by the increased risk connected with ZGT containing only estrogen.
Breakthrough uterine bleedings and the smearing discharges can sometimes be noted within the first several months of treatment. If breakthrough uterine bleedings and the smearing discharges develop after several cycles of treatment, or proceed after the treatment termination, it is necessary to investigate the reason that can include an endometrium biopsy for an exception of malignant process in endometrium.
The breast cancer
On the available data exists the increased risk of developing a breast cancer at the women using ZGT the drugs combined estrogen-progestagennymi and possible also estrogenic drugs which depends on duration of carrying out ZGT.
Combination therapy it is oestrogenic + progestogens
according to randomized placebo - a controlled research (WHI) and epidemiological researches increase in risk of a breast cancer at the women accepting combination therapy estrogen-progestagenami for ZGT that is shown approximately in 3 years after an initiation of treatment is revealed.
Monotherapy estrogen
In the research WHI did not reveal increase in risk of a breast cancer at the women with a remote uterus using ZGT only estrogen. According to observation researches it is generally reported about slight increase of risk of a breast cancer that in considerable the degrees are lower, than it is revealed at the women taking the drugs combined estrogen-progestagennye. The increased risk can come to light within several years of use and is restored to initial during several (as a rule, five) years after the therapy termination.
ZGT, especially combination therapy estrogen-progestagenami increases the mammography density of mammary glands that in certain cases can have negative impact on radiological detection of a breast cancer.
Ovary cancer
Cancer of an ovary is observed much more less than a breast cancer.
Long use (at least 5-10 years) of ZGT the drugs containing only are oestrogenic, it is associated with slight increase of risk of cancer of ovary.
Proceeding from some researches, including WHI, it is supposed that long use of the combined ZGT can cause similar or a little smaller risk.
The venous thrombembolia
of ZGT can be connected with 1.3 - 3-multiply increased relative risk of developing a venous thrombembolia (VTE), i.e. a deep vein thrombosis or pulmonary embolism. Emergence of such phenomena is most probable within the first year of ZGT.
The patients having thromboembolic states have the increased risk of development of VTE. ZGT can increase this risk. Therefore, ZGT is contraindicated at such patients.
Well-known risk factors of development of VTE are use of estrogen, advanced age, extensive surgical interventions, a long immobilization, obesity (body mass index exceeds 30 kg/sq.m), pregnancy and the postnatal period, the system lupus erythematosus (SLE) and cancer.
The issue of a possible role of a varicosity in development of VTE remains controversial.
At all women during the postoperative period it is necessary to consider preventive measures for prevention of VTE during the postoperative period. In cases of the long immobilization, as a rule, following later extensive surgery it is necessary to resolve an issue of need of the temporary termination of ZGT whenever possible not earlier than in 4-6 weeks prior to its carrying out. It is not necessary to resume reception before the termination of an immobilization.
At women with lack of VTE in the personal anamnesis, but presence of close relatives with fibrinferments at young age, can offer screening after detailed consultation in connection with its limited opportunities (not all patients with a thrombophilia can be revealed when screening). In case of identification of the trombofilichesky defect connected with fibrinferments at family members or if it is heavy defect (for example, deficiency of antithrombin, a protein of S or protein of C, or a combination of defects), in such cases of ZGT it is contraindicated.
The ratio of risk and advantage of treatment has to be carefully weighed and discussed at the women who are on anti-coalugating therapy.
At emergence of VTE against the background of Klimonormaâ it is necessary to stop treatment immediately. The woman needs to stop administration of drug and to see a doctor at development of symptoms of venous thrombosis, for example at appearance of pain and/or hypostasis in legs, sudden severe pain in breasts and asthmas.
The Coronary Heart Disease (CHD)
In randomized clinical trials of women with the existence or lack of an ischemic heart disease receiving ZGT estrogen or a combination of estrogen and progestogen the data indicating protection against a myocardial infarction were not obtained.
Combination therapy it is oestrogenic + progestogens
the Relative risk of an ischemic heart disease when using combined ZGT estrogen-progestagennoy is increased slightly. As the initial absolute risk of an ischemic heart disease is directly connected with age, the number of additional cases of an ischemic heart disease when using estrogen-progestagennykh of drugs is small at women closer to a menopause, but can raise at more advanced age.
Monotherapy by estrogen
In randomized controlled study the increase in risk of development of an ischemic heart disease at the women with a remote uterus using ZGT only estrogen is not revealed.
The ischemic stroke
Risk of an ischemic stroke at ZGT the drugs combined estrogen-progestagenovymi or monotherapies by estrogen raises by 1.5 times. The relative risk does not change depending on age or duration of a menopause. However, considering that the initial risk of an ischemic stroke directly depends on age, the risk of a stroke in general at women against the background of receiving ZGT, will increase with age.
Other states
Estrogen can promote a liquid delay in an organism in this connection patients with cardiovascular or renal disturbances have to be examined carefully. In a terminal renal failure the careful monitoring as increase in level of the circulating Klimonormaâ active agents in blood plasma is possible is necessary.
During ZGT the special observation of women with earlier increased level of triglycerides as in rare instances use of ZGT can cause considerable increase of level of triglycerides in blood that increases risk of developing acute pancreatitis is necessary.
Estrogen can increase the level of tireoidsvyazyvayushchy globulin that leads to increase in level of the circulating general thyroid hormone which is defined by the level (SBI), T4 iodine connected with proteins (at measurement columns or in a radio immunological way) or T3 level measured in the radio immunological way. Level of free T3 and T4 does not change. Also increase in level of other connecting globulins, for example a corticosteroid - the connecting globulin, globulins connecting sex hormones that respectively leads to increase in level of the circulating corticosteroids and sex hormones can be noted. Concentration of free or biologically active hormones remains not changed. Increase in other proteins of plasma, such as substrates of renin/angiotensin, alpha 1 - antitrypsin, ceruloplasmin is noted.
Against the background of ZGT the improvement of cognitive function was not noted.
There are data on the increased risk of possible development of dementia in women who began to use continuous ZGT after 65 years.
At women with a hereditary Quincke's disease exogenous estrogen can provoke or aggravate symptoms of this disease.
Drug should not be used in the presence of the rare hereditary diseases connected with the broken tolerance to a galactose, Lapp a lactose intolerance or glyukozo-galaktozny malabsorption
Pregnancy and the period of a lactation
of Klimonormâ not nazn
to Develop
of Klimonormâ medicine
the Trade name
of Klimonormâ
the International unlicensed name
Is not present
the Dosage form
of the Dragee
Structure
1 yellow dragee contains active agent - oestradiol the valerate micronized 2.0 mg,
1 brown dragee contains active agents: oestradiol the valerate micronized 2.0 mg, levonorgestrel of 0.15 mg,
excipients: lactoses monohydrate, potato starch, gelatin, talc, magnesium stearate, water purified
structure of a cover (yellow dragee): sucrose, glucose syrup, gelatin, magnesium carbonate of the main easy, K 25 povidone, macrogoal 35000, calcium carbonate, talc, titan dioxide (E171), ferrous oxide yellow (E172), wax of karnaubskiya,
structure of a cover (brown dragee): sucrose, glucose syrup, gelatin, magnesium carbonate of the main easy, K 25 povidone, macrogoal 35000, calcium carbonate, talc, titan dioxide (E171), ferrous oxide yellow (E172), ferrous oxide red (E 172), ferrous oxide brown (E 172), wax of karnaubskiya.
Description
Brilliant dragees of yellow color, round, with a diameter of 5.8 - 6.2 mm, 3.2 - 3.7 mm thick. Brilliant dragees of brown color, round, with a diameter of 5.8 - 6.2 mm, 3.2 - 3.7 mm thick.
Pharmacotherapeutic group
Sex hormones and modulators of a reproductive system. Progestogens and estrogen in a combination. Progestogens and estrogen (for consecutive calendar reception). Levonorgestrel and estrogen.
The ATX G03FB09 code
the Pharmacological
Pharmacokinetics Oestradiol properties valerate
After oestradiol intake valerate is completely absorbed from digestive tract. After intake of 4 mg of oestradiol of the valerate corresponding to 2 dragees of yellow color of 1 phase, the maximum concentration of oestradiol in blood plasma is reached in 12 hours. The maximum concentration of oestradiol after intake of 4 mg of oestradiol makes about 40-52 pg/ml Average plasma elimination half-life of blood makes 1 hour.
Oestradiol partially contacts proteins of blood plasma.
Orally entered oestradiol during the first passing through a liver is metabolized for 90%, mainly in estrone, estrone sulfate and estriol and also to free or metilirovanny katekholestrogen. Oestradiol, mainly, is metabolized in a liver, as well as other ways.
Oestradiol and its metabolites (estrone and estriol) are generally removed with urine within 48 hours in the form of conjugates with sulphuric and glucuronic acid and also in a small amount in not changed look. A part of metabolites is removed with excrements.
Levonorgestrel
After intake levonorgestrel is quickly and almost completely absorbed from a GIT.
After intake of 0.3 mg of the levonorgestrel corresponding to 2 dragees of brown color 2 phases, the maximum concentration of levonorgestrel in blood plasma, the component about 6 ng/ml is reached in 1-2 hours. Elimination half-life makes 2 h in a phase of distribution and 10–24 h in an elimination phase.
Levonorgestrel for 93-95% contacts albumine of blood serum and specifically contacts the globulin, connecting sex hormones (G,CSH).
The effect of the first passage through a liver did not come to light.
The clearance of removal from plasma is 106 ml/h/kg.
Metabolites of levonorgestrel are removed with urine and bile approximately in an identical ratio, mainly, in the form of sulfates and glucuronides.
The insignificant amount of levonorgestrel is excreted in breast milk.
The pharmacodynamics
Active ingredient of the drug Klimonormâ is synthetic valerate of 17b-oestradiol which in a human body turns into 17b-oestradiol on chemical and biological properties identical to endogenous natural oestradiol. Oestradiol fills shortage of estrogen at women during the post-menopausal period and promotes simplification of climacteric symptoms.
As a result of a cyclic combination of estrogen with levonorgestrel, the mitogenetic activity of estrogen is suppressed. Thus, the increased risk of developing a hyperplasia and endometrial cancer connected with intake only of estrogen decreases.
Data of clinical trials
Relief of symptoms of the caused deficiency of estrogen and influence on bleedings.
Simplification of climacteric symptoms, was observed from first weeks of treatment.
Bleedings of cancellation were noted in 84.4% of cycles within the first year of therapy. Average duration was 5 days.
Breakthrough bleedings and (or) the smearing discharges were noted at 12.9% of women within the first three months of therapy and at 7.9% of women within 10–12 months of therapy.
The amenorrhea (absence of bleedings or the smearing discharges) was noted in 6.4% of cycles within the first year of therapy.
Indications
- the replacement hormonal therapy (RHT) at symptoms of deficiency of estrogen at women during the post-menopausal period.
Experience of use of drug for women is more senior than 65 years is limited.
The route of administration and doses
of Klimonormâ is intended for hormonal replacement therapy on a cyclic basis.
The dosing mode
Each packing 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 3 weeks of reception of a dragee it is necessary to take a 7-day break in administration of drug during which it is possible to expect approach of menstrualnopodobny bleeding.
After a 7-day break in administration of drug begin new packing of Klimonormaâ irrespective of whether menstrualnopodobny bleeding began or it proceeds.
How to begin reception of Klimonormaâ
- in the absence of reception of replacement hormonal therapy earlier Treatment of Klimonormomâ can be begun at any time.
- Upon transition from various drugs for replacement hormonal therapy
Upon transition from the continuous combined replaceable hormonal therapy, treatment of Klimonormomâ should be begun next day after the end of the previous therapy.
Upon transition from cyclic hormonal therapy, treatment of Klimonormomâ should be begun next day after a break in reception of a dragee.
At the beginning or continuation of treatment of post-menopausal symptoms it is necessary to apply the smallest effective dose during the shortest period.
The route of administration
of the Dragee is swallowed entirely, washing down with a small amount of liquid. It is preferable to accept a dragee every day in one and too time, it is desirable for avoidance of gastrointestinal disorders in the evening.
Duration of treatment is defined by the doctor.
Reception of the passed dragees
If the woman forgot to take a pill at the scheduled time in time, then it should be accepted within the next 12 hours. Otherwise treatment should be continued by administration of drug next day, disregarding the forgotten dragee. The admission in reception of a dragee raises a likelihood of developing breakthrough bleeding.
Side effects
Side effects, the connected or perhaps connected with use Klimonormaâ are based on results of the clinical trials including 588 women and post-marketing observations including 10.115 women.
The serious side effects connected with reception of ZGT are also listed in the section Special Instructions.
Often (≥1/100, & lt, 1/10)
- headaches, migraine
- arterial hypertension
- tension and mammary gland pain, a neoplasia of mammary glands
(benign mastopathy)
Infrequently (≥1/1000, & lt, 1/100)
- reactions of hypersensitivity
- infections of a respiratory system, bronchitis
- change of mood, including uneasiness or depressive mood
- memory disturbance *, confusion of consciousness, dizziness
- a disorder of vision
- tachycardia/heartbeat, a varicosity, hemorrhoids, cardiovascular disturbances
- dyspepsia, nausea, vomiting, an abdominal distension, pains in a stomach, the profound constipations *
- cholangites, cholecystitises, abnormal liver functions
- acne rash, seborrhea, a skin itching and burning
- intermenstrual bleedings, vaginal discharges / changes of vaginal discharges, mastitis *, vulvovaginity* / vulvovaginal symptoms, a neck hyperplasia matki* / a dysplasia of a neck of the uterus, an endometrium hypertrophy, an endometrium hyperplasia *, a breast cancer
- inflows of heat, an asthenia, peripheral hypostases, feeling of weight in the lower extremities, pains in pelvic area
- anemia, changes in body weight, the increased sugar level in blood, a hyperbilirubinemia
Seldom (≥1/10000, & lt, 1/1000)
- disturbance of a libido
- insomnia
- venous thrombosis **, thrombophlebitises of superficial veins, arterial hypotension
- a hair loss
* the Only message about this by-effect which is perhaps connected with drug use belongs to the category 'infrequently' in connection with the small volume of sample of clinical trial (n=588).
** the venous thrombembolia, for example deep veins of the lower extremities or fibrinferments of pelvic veins, an embolism of a pulmonary artery is more often observed at the women using ZGT than at the women who are not using ZGT. For further information see the section Special Instructions.
Other side reactions connected with use it is oestrogenic / progestagenov:
- cholelithiasis
- disturbances of skin and hypodermic cellulose: the hloazma, a knotty erythema and a multformny erythema, a vascular purpura
- perhaps development of dementia in women is more senior than 65 years
- at women with a hereditary Quincke's disease exogenous estrogen can provoke or aggravate symptoms of this disease.
The risk of a breast cancer
Is reported that at the women who are on the therapy combined estrogen-progestagennoy more than 5 years, risk of developing a breast cancer increases twice. Any increase in risk at the women receiving estrogen in monotherapy is much lower, than at the women accepting estrogen in a combination with progestogens. The risk level depends on duration of use of drugs.
The risk level depends on treatment duration.
Results of large randomized placebo - a controlled research (WHI – study) and an epidemiological research (MWS) are given below.
A research of one million women (MWS) - the expected additional risk of developing a breast cancer after 5 years of treatment.
The age
(years)
Quantity of additional cases on 1000 women who earlier were not accepting ZGT within 5 years *
the Relation of risks and 95% КИ#
Quantity of additional cases on 1000 women, users of ZGT within 5 years (95% of KI)
estrogen 50-65 9-12 1.2 1-2 (0-3)
Combination therapy is oestrogenic ZGT in the form of monotherapy +
progestogen 50-65 9-12 1.7 6 (5-7)
* Are taken from initial indicators of incidence in the developed countries
# the Cumulative relation of risks. This size is non-constant, but will increase in process of increase in duration of treatment.
Note: as the cancer cases of a mammary gland differ in EU countries, the quantity of additional cases of a breast cancer will also change in proportion.
The research US WHI (Research Initiative of Health of the Woman) - additional risk of developing a breast cancer after 5 years of treatment.
Age
(years)
Incidence on 1000 women accepting placebo for 5 years
the Relation of risks and 95% of KI
Quantity of additional cases on 1000 women, users of ZGT within 5 years (95% of KI)
of Monoterapiya
the conjugated horse estrogen (CHE) 50-79 21 0.8 (0.7-1.0)-4 (-6 – 0) *
KLE+ of a medroksiprogesteron acetate (estrogen + прогестаген#)
50-79 17 1.2 (1.0-1.5) +4 (0 - 9)
* in the research WHI of the woman with a remote uterus at which increase in risk of a breast cancer
# was not observed in the analysis limited to women who before inclusion in a research did not use earlier ZGT was not noted increase in risk in the first 5 years of treatment: after 5 years the risk was higher, than at the women who are not accepting ZGT.
2 – group of women in the research WHI with a remote uterus at whom increase in risk of RMZh is not revealed.
Risk of endometrial cancer
of the Woman with an unextracted uterus in a postmenopause
everyone 5 of 1000 women with an unextracted uterus who are not accepting ZGT is subject to Risk of developing endometrial cancer approximately. For women with an unextracted uterus the monotherapy by estrogen is not recommended as it increases risk of developing endometrial cancer. Depending on duration of estrogenic therapy and a dose of estrogen, increase in risk of endometrial cancer in epidemiological researches varied from 5 to 55 additional cases on 1000 women aged from 50 up to 65 years. Addition of progestogen to estrogenic therapy during, at least, 12 days of a cycle, allows to avoid the increased risk. In the research MWS use combined (cyclic or continuous) ZGT within 5 years did not cause increase in risk of endometrial cancer (the SHOUTING 1.0 (0.8-1.2)).
Ovary cancer
Long-term use of estrogenic therapy and combined ZGT estrogen-progestagennoy can be connected with a little increased risk of ovarian cancer. In the Research Million Women Study ZGT lasting 5 years caused 1 additional case of ovarian cancer on 2500 patients.
The risk of a venous thrombembolia
of ZGT can be connected with 1.3 - 3-multiply increased relative risk of developing a venous thrombembolia (VTE), i.e. a deep vein thrombosis or pulmonary embolism. Emergence of such phenomena is most probable within the first year of ZGT.
Results of the research WHI are given below:
The research WHI (Research Initiative of Health of the Woman) - additional risk of VTE after 5 years of use of ZGT
the Age
(years)
Incidence on 1000 women accepting placebo for 5 years
the Relation of risks and 95% of KI
Quantity of additional cases on 1000 women accepting ZGT within 5 years (95% of KI)
of Monoterapiya estrogen for oral administration *
50-59 7 1.2 (0.6-2.4) 1 (-3–10)
Combined peroral is oestrogenic + progestogen the containing
drugs 50-59 4 2.3 (1.2-4.3) 5 (1-13)
* a research at women with a remote uterus
Risk of coronary heart disease
Risk of developing coronary heart disease is a little increased at women aged 60 years accepting combined ZGT estrogen-progestagennuyu are more senior.
The risk of an ischemic stroke
Use of estrogenic monotherapy and estrogen-progestagennoy of therapy is followed by 1.5-fold increase in relative risk of an ischemic stroke. ZGT does not increase risk of a hemorrhagic stroke.
Such relative risk does not depend on age of the patient or duration of therapy. However, as the initial risk is closely connected with age, the general risk of a stroke at women against the background of ZGT increases with age, see the section Special Instructions.
The research WHI (Research Initiative of Health of the Woman) - additional risk of an ischemic stroke * after 5 years of use of ZGT
Age
(years)
Incidence on 1000 women accepting placebo for 5 years
the Relation of risks and 95% of KI
Additional quantity of cases on 1000 women accepting ZGT within 5 years (95% of KI)
50-59 8 1.3 (1.1-1.6)
3 (1–5)
* there Are no differences between an ischemic and hemorrhagic stroke
of the Contraindication
- the known hypersensitivity to one of drug components
- a breast cancer in the anamnesis, now either assumed
- the confirmed or expected estrogenzavisimy malignant tumors (for example, endometrial cancer)
- vaginal bleeding of not clear origin
- an endometrium hyperplasia (earlier not treated)
- venous a thrombembolia now or in the anamnesis (deep vein thrombosis, a pulmonary embolism)
- trombofilichesky disturbances, for example deficit of a protein With, a protein of S or antithrombin (see the section Special Instructions)
- the acute or recently postponed arterial thrombosis or a thrombembolia (such as, a myocardial infarction and a stroke)
- acute diseases of a liver (or in the anamnesis) before normalization of hepatic tests
- a porphyria
Medicinal interactions
Metabolism of estrogen and levonorgestrel can increase at the accompanying administration of drugs inducing liver enzymes, for example, of the system of P450 cytochrome such as anticonvulsant (phenobarbital, Phenytoinum, carbamazepine, okskarbazepin, topiramat, felbamat and Primidonum) and germicides, such as rifampicin, rifabutin, not Virapinum, efavirenz and also griseofulvin, meprobamate and phenylbutazone and its salts.
Ritonavir and nelfinavir, known as strong inhibitors, on the contrary, show the stimulating properties at use in combination with steroid hormones.
The vegetable drugs containing a St. John's wort can induce metabolism of estrogen and progestogen also.
Acceleration of metabolism of estrogen and progestogen can clinically cause decrease in effect and lead to any changes in the nature of uterine bleedings. Substances which inhibit metabolic enzymes for example ketokonazol, can increase the plasma level of active agents of drug.
Estrogen is capable to increase the frequency of manifestation of side effects of Imipraminum.
Simultaneous treatment with cyclosporines can increase the level of cyclosporine, creatine and transaminases owing to decrease in elimination in a liver.
Estrogen is capable to increase clinical performance and undesirable effects of the drugs containing corticosteroids. At replacement therapy by thyroid hormones increase in a dose of left thyroxine can be required.
The changes in indestinal flora connected with use of activated carbon and/or antibiotics, such as ampicillin, tetracycline) can lead to decrease in level of hormones that promotes decrease in their effect. In such cases the increased frequency of development of intermenstrual bloody discharges is observed.
Requirement in a treatment / dose of oral antihyperglycemic means or insulin can change as a result of influence of estrogen on tolerance to glucose (decrease) and the answer to insulin.
Intake of estrogen can affect results of laboratory tests, for example, indicators of function of a thyroid gland (see the section Special Instructions or the tolerance test to glucose.
Special instructions
For treatment of post-menopausal symptoms ZGT should be begun only in the presence of symptoms which adversely affect quality of life.
In all cases it is necessary to carry out carefully the ratio assessment risk/advantage, at least, annually, and ZGT should be continued only if advantages exceed risk.
Data on the risks connected with ZGT at treatment of a premature menopause are limited. Considering low absolute risk at young women, these women can have more favorable ratio of advantages and risks, than at women of more advanced age.
Medical examination and consultation
Before the beginning or resuming of ZGT to the woman is recommended to undergo careful all-medical examination (including a research of the family anamnesis) and gynecologic inspection (including a research of mammary glands and a cytologic research of cervical slime), to consider contraindications and precautionary measures. In the course of treatment it is necessary to perform periodically control examinations which frequency is defined individually.
The woman should be informed that it is necessary to report about any changes in mammary glands to the doctor or the nurse. Inspection of mammary glands, including mammography, should be carried out according to the established schedule of screening and depending on individual clinical need.
States at which observation is required
If any of the following states were observed earlier, are available now and/or were aggravated during pregnancy or earlier carried out hormonal therapy, the patient should be observed carefully.
It is necessary to take into account that the specified states can renew and/or be aggravated during performing therapy of Klimonormomâ:
- the leiomyoma (fibromyoma) or endometriosis
- risk factors, including in the anamnesis of thromboembolic disturbances
- risk factors of developing estrogenzavisimy tumors (for example, presence of a breast cancer at relatives of 1 degree of relationship)
- arterial hypertension
- liver diseases (for example, liver adenoma)
- diabetes with vascular disorders or without them
- cholelithiasis
- migraine or the profound headaches
- a system lupus erythematosus
- an endometrium hyperplasia in the anamnesis
- epilepsy
- bronchial asthma
- an otosclerosis
of the Reason for the immediate termination of administration of drug
- jaundice or deterioration in function of a liver
- substantial increase of arterial blood pressure
- again appeared attacks of a migrenepodobny headache
- pregnancy
the Hyperplasia of endometrium and endometrial cancer
At women with an unextracted uterus at long monotherapy by estrogen raises risk of developing a hyperplasia or carcinoma of endometrium.
At the women accepting only are oestrogenic, the increased risk of developing endometrial cancer is higher than from 2 to 12 times in comparison with the women who are not using estrogen depending on duration of treatment and a dose of estrogen. After the treatment termination the risk remains raised approximately within 10 years.
Addition of progestogen in the cyclic mode throughout a 28-day cycle or continuous therapy by the drug combined estrogen-progestagennym at women with an unextracted uterus is prevented at least 12 days by the increased risk connected with ZGT containing only estrogen.
Breakthrough uterine bleedings and the smearing discharges can sometimes be noted within the first several months of treatment. If breakthrough uterine bleedings and the smearing discharges develop after several cycles of treatment, or proceed after the treatment termination, it is necessary to investigate the reason that can include an endometrium biopsy for an exception of malignant process in endometrium.
The breast cancer
On the available data exists the increased risk of developing a breast cancer at the women using ZGT the drugs combined estrogen-progestagennymi and possible also estrogenic drugs which depends on duration of carrying out ZGT.
Combination therapy it is oestrogenic + progestogens
according to randomized placebo - a controlled research (WHI) and epidemiological researches increase in risk of a breast cancer at the women accepting combination therapy estrogen-progestagenami for ZGT that is shown approximately in 3 years after an initiation of treatment is revealed.
Monotherapy estrogen
In the research WHI did not reveal increase in risk of a breast cancer at the women with a remote uterus using ZGT only estrogen. According to observation researches it is generally reported about slight increase of risk of a breast cancer that in considerable the degrees are lower, than it is revealed at the women taking the drugs combined estrogen-progestagennye. The increased risk can come to light within several years of use and is restored to initial during several (as a rule, five) years after the therapy termination.
ZGT, especially combination therapy estrogen-progestagenami increases the mammography density of mammary glands that in certain cases can have negative impact on radiological detection of a breast cancer.
Ovary cancer
Cancer of an ovary is observed much more less than a breast cancer.
Long use (at least 5-10 years) of ZGT the drugs containing only are oestrogenic, it is associated with slight increase of risk of cancer of ovary.
Proceeding from some researches, including WHI, it is supposed that long use of the combined ZGT can cause similar or a little smaller risk.
The venous thrombembolia
of ZGT can be connected with 1.3 - 3-multiply increased relative risk of developing a venous thrombembolia (VTE), i.e. a deep vein thrombosis or pulmonary embolism. Emergence of such phenomena is most probable within the first year of ZGT.
The patients having thromboembolic states have the increased risk of development of VTE. ZGT can increase this risk. Therefore, ZGT is contraindicated at such patients.
Well-known risk factors of development of VTE are use of estrogen, advanced age, extensive surgical interventions, a long immobilization, obesity (body mass index exceeds 30 kg/sq.m), pregnancy and the postnatal period, the system lupus erythematosus (SLE) and cancer.
The issue of a possible role of a varicosity in development of VTE remains controversial.
At all women during the postoperative period it is necessary to consider preventive measures for prevention of VTE during the postoperative period. In cases of the long immobilization, as a rule, following later extensive surgery it is necessary to resolve an issue of need of the temporary termination of ZGT whenever possible not earlier than in 4-6 weeks prior to its carrying out. It is not necessary to resume reception before the termination of an immobilization.
At women with lack of VTE in the personal anamnesis, but presence of close relatives with fibrinferments at young age, can offer screening after detailed consultation in connection with its limited opportunities (not all patients with a thrombophilia can be revealed when screening). In case of identification of the trombofilichesky defect connected with fibrinferments at family members or if it is heavy defect (for example, deficiency of antithrombin, a protein of S or protein of C, or a combination of defects), in such cases of ZGT it is contraindicated.
The ratio of risk and advantage of treatment has to be carefully weighed and discussed at the women who are on anti-coalugating therapy.
At emergence of VTE against the background of Klimonormaâ it is necessary to stop treatment immediately. The woman needs to stop administration of drug and to see a doctor at development of symptoms of venous thrombosis, for example at appearance of pain and/or hypostasis in legs, sudden severe pain in breasts and asthmas.
The Coronary Heart Disease (CHD)
In randomized clinical trials of women with the existence or lack of an ischemic heart disease receiving ZGT estrogen or a combination of estrogen and progestogen the data indicating protection against a myocardial infarction were not obtained.
Combination therapy it is oestrogenic + progestogens
the Relative risk of an ischemic heart disease when using combined ZGT estrogen-progestagennoy is increased slightly. As the initial absolute risk of an ischemic heart disease is directly connected with age, the number of additional cases of an ischemic heart disease when using estrogen-progestagennykh of drugs is small at women closer to a menopause, but can raise at more advanced age.
Monotherapy by estrogen
In randomized controlled study the increase in risk of development of an ischemic heart disease at the women with a remote uterus using ZGT only estrogen is not revealed.
The ischemic stroke
Risk of an ischemic stroke at ZGT the drugs combined estrogen-progestagenovymi or monotherapies by estrogen raises by 1.5 times. The relative risk does not change depending on age or duration of a menopause. However, considering that the initial risk of an ischemic stroke directly depends on age, the risk of a stroke in general at women against the background of receiving ZGT, will increase with age.
Other states
Estrogen can promote a liquid delay in an organism in this connection patients with cardiovascular or renal disturbances have to be examined carefully. In a terminal renal failure the careful monitoring as increase in level of the circulating Klimonormaâ active agents in blood plasma is possible is necessary.
During ZGT the special observation of women with earlier increased level of triglycerides as in rare instances use of ZGT can cause considerable increase of level of triglycerides in blood that increases risk of developing acute pancreatitis is necessary.
Estrogen can increase the level of tireoidsvyazyvayushchy globulin that leads to increase in level of the circulating general thyroid hormone which is defined by the level (SBI), T4 iodine connected with proteins (at measurement columns or in a radio immunological way) or T3 level measured in the radio immunological way. Level of free T3 and T4 does not change. Also increase in level of other connecting globulins, for example a corticosteroid - the connecting globulin, globulins connecting sex hormones that respectively leads to increase in level of the circulating corticosteroids and sex hormones can be noted. Concentration of free or biologically active hormones remains not changed. Increase in other proteins of plasma, such as substrates of renin/angiotensin, alpha 1 - antitrypsin, ceruloplasmin is noted.
Against the background of ZGT the improvement of cognitive function was not noted.
There are data on the increased risk of possible development of dementia in women who began to use continuous ZGT after 65 years.
At women with a hereditary Quincke's disease exogenous estrogen can provoke or aggravate symptoms of this disease.
Drug should not be used in the presence of the rare hereditary diseases connected with the broken tolerance to a galactose, Lapp a lactose intolerance or glyukozo-galaktozny malabsorption
Pregnancy and the period of a lactation
of Klimonormâ not nazn
to Develop
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