Klayra

General characteristics. Structure:

On one dark yellow tablet film coated: Kernel:
• Active component

Oestradiol valerate, micro 20 - 3,0000 mg
• Auxiliary components

Lactoses monohydrate - 48,3600 mg, starch corn - 14,4000 mg, starch corn prezhelatinizirovanny - 9,6000 mg, povidone-25 - 4,0000 mg, magnesium stearate - 0,6400 mg the Cover: a gipromelloza - 1,5168 mg, a macrogoal-6000 - 0,3036 mg, talc - 0,3036 mg, titanium dioxide - 0,5840 mg, dye ferrous oxide yellow - 0,2920 mg.

On one pink tablet film coated:
Kernel:
• Active components
Oestradiol valerate, micro 20 - 2,00000 mg of Diyenogest, micro - 2,00000 mg
• Auxiliary components
Lactoses monohydrate - 47,36000 mg, starch corn - 14,40000 mg, starch corn prezhelatinizirovanny - 9,60000 mg, povidone-25 - 4,00000 mg, magnesium stearate - 0,64000 mg the Cover: a gipromelloza - 1,51680 mg, a macrogoal-6000 - 0,30360 mg, talc - 0,30360 mg, titanium dioxide - 0,83694 mg, dye ferrous oxide red - 0,03906 mg.
On one pale yellow tablet film coated:
Kernel:
• Active components
Oestradiol valerate, micro 20 - 2,00000 mg of Diyenogest, micro - 3,00000 mg
• Auxiliary components
Lactoses monohydrate - 46,36000 mg, starch corn - 14,40000 mg, starch corn prezhelatinizirovanny - 9,60000 mg, povidone-25 - 4,00000 mg, magnesium stearate - 0,64000 mg the Cover: a gipromelloza - 1,51680 mg, a macrogoal-6000 - 0,30360 mg, talc - 0,30360 mg, titanium dioxide - 0,83694 mg, dye ferrous oxide yellow - 0,03906 mg.

On one red tablet, film coated:
Kernel:
• Active component
Oestradiol valerate, micro 20 - 1,0000 mg
• Auxiliary components
Lactoses monohydrate - 50,3600 mg, starch corn - 14,4000 mg, starch corn prezhelatinizirovanny - 9,6000 mg, povidone-25 - 4,0000 mg, magnesium stearate - 0,6400 mg the Cover: a gipromelloza - 1,5168 mg, a macrogoal-6000 - 0,3036 mg, talc - 0,3036 mg, titanium dioxide - 0,5109 mg, dye ferrous oxide red - 0,3651 mg.

On one white tablet film coated (placebo):
Kernel:
• Auxiliary components
Lactoses monohydrate - 52,1455 mg, starch corn - 24,0000 mg, povidone-25 - 3,0545 mg, magnesium stearate - 0,8000 mg.
Cover: a gipromelloza - 1,0112 mg, talc - 0,2024 mg, titanium dioxide - 0,7864 mg.

Description
Dark yellow tablets: round biconvex tablets, film coated dark yellow color, with an engraving of "DD" in the correct hexagon on one party. A type of tablets on cross section: a kernel from white till almost white color, a cover dark yellow.

Pink tablets: round biconvex tablets, film coated pink color, with an engraving of "DJ" in the correct hexagon on one party. A type of tablets on cross section: a kernel from white till almost white color, a cover - pink.
Pale yellow tablets: round biconvex tablets, film coated pale yellow color, with an engraving of "DH" in the correct hexagon on one party. A type of tablets on cross section: a kernel from white till almost white color, a cover - pale yellow.

Red tablets: round biconvex tablets, film coated red color, with an engraving of "DN" in the correct hexagon on one party. A type of tablets on cross section: a kernel from white till almost white color, a cover - red.

White tablets (placebo): round biconvex tablets, film coated white color, with an engraving of "DT" in the correct hexagon on one party. A type of tablets on cross section: a kernel from white till almost white color, a cover - white.

Pharmacological properties:

Pharmacodynamics. The contraceptive effect of the combined oral contraceptives (COOK) is based on interaction of various factors, the most important of which are suppression of an ovulation and change of properties of cervical slime. Along with the prevention of undesirable pregnancy, the COOK have a number of positive properties which at the account as well negative properties (see. "Special instructions", "Side effect") can help with the choice of the most suitable method of contraception. At the women accepting the COOK morbidity and intensity of menstrualnopodobny bleedings therefore the risk of an iron deficiency anemia decreases decrease. Besides, there are data on decrease in risk of development of endometrial cancer and ovarian cancer.
Estrogen in Klayr's drug is oestradiol valerate, the predecessor of natural 17v-oestradiol of the person (1 mg of oestradiol of valerate corresponds to 0,76 mg of 17v-oestradiol). The oestrogenic component used in it the COOK, thus, differs from the estrogen which is usually used in the COOK which synthetic estrogen - ethinylestradiol or its predecessor местранол is, containing etinilny group in situation 17a both. This group causes higher metabolic stability, however, as well more expressed action on a liver.
Administration of drug of Klayr is led to less expressed action on a liver in comparison with three-phase by the COOK, containing ethinylestradiol and levonorgestrel. It was shown that influence on concentration of the globulin, connecting sex hormones (G,CSH) and parameters of a hemostasis is less expressed. In a combination with diyenogesty oestradiol valerate shows increase in lipoproteids of the high density (LPVP) whereas concentration of cholesterol of lipoproteids of the low density (LPNP) decreases a little.
Диеногест represents the progestogen operating at oral administration which is characterized by additional partial anti-androgenic effects. Its oestrogenic, anti-oestrogenic and androgenic properties are insignificant. Thanks to special chemical structure the range of pharmacological action combining the most important advantages of 19-holes-progestagenov and derivatives of progesterone is provided. The preclinical data obtained during the standard researches of toxicity at repeated introduction of doses, genotoxicity, the cancerogenic potential and toxicity for reproductive system do not indicate existence of specific risk for the person. However it is necessary to consider that sex hormones are capable to stimulate growth of a number of hormonedependent fabrics and tumors.
At the correct use Perl's index (the indicator reflecting the frequency of approach of pregnancy at 100 women within a year of use of a contraceptive) makes less than 1. At the admission of tablets or the wrong use Perl's index can increase.

Pharmacokinetics.

• Диеногест
Absorption
After oral administration диеногест it is quickly and almost completely soaked up. The maximum concentration in blood serum making 90,5 ng/ml is reached approximately in 1 hour after oral administration of a tablet of Klayra containing 2 mg of oestradiol of valerate + 3 mg of a diyenogest. Bioavailability makes about 91%. The pharmacokinetics of a diyenogest in the dose range from 1 to 8 mg is characterized by dependence on a dose.
The concomitant use of food does not exert clinically significant impact on speed and extent of absorption of a diyenogest.
Distribution
Rather big (10%) a part of the circulating diyenogest is in an untied look whereas about 90% are nonspecific connected with albumine. Диеногест does not contact GSPG and about the corticosteroid-the connecting globulin (CCG). For this reason there is no possibility of replacement of testosterone from its communication with GSPG or cortisol from its communication with KSG. Any influence on physiological processes of transport of endogenous steroids, therefore, is improbable. The volume of distribution of a diyenogest at equilibrium concentration makes 46 l after intravenous administration of 85 mkg marked hyzone of a diyenogest.

Metabolism
Диеногест it is almost completely metabolized, passing the known ways of metabolism of steroid hormones (a hydroxylation, a konjyugirovaniye), with formation preferential endocrinological of inactive metabolites. Metabolites are removed very quickly so the prevailing fraction in a blood plasma is not changed диеногест. The general clearance after intravenous administration marked hyzone of a diyenogest - 5,1 l/h.
Elimination
The elimination half-life of a diyenogest makes about 11 h of a blood plasma. After intake in a dose of 0,1 mg/kg диеногест it is removed in the form of metabolites which are removed by kidneys and through intestines in the ratio about 3:1. After oral administration of 42% of a dose 63% - within 6 days by renal excretion are removed within the first 24 hours, and. In 6 days kidneys and through intestines remove in total 86% of a dose. Equilibrium concentration
The pharmacokinetics of a diyenogest does not depend on concentration of GSPG. Equilibrium concentration is reached in 3 days of reception of the same dose making 3 mg of a diyenogest in combination with 2 mg of oestradiol of valerate. The minimum, maximum and average concentration of a diyenogest in blood serum at an equilibrium state make, respectively, 11,8 ng/ml, 82,9 ng/ml and 33,7 ¡ú/m. Average coefficient of cumulation on the area under a curve "concentration time" (AUC0-24 of the h) - 1,24.
• Oestradiol valerate
Absorption
After oestradiol intake valerate is quickly and completely absorbed. Splitting on oestradiol and valerianic acid happens during absorption in a mucous membrane of the digestive tract (DT) or during the first passage through a liver therefore oestradiol and its metabolites - estrone and estriol are formed. The maximum concentration of oestradiol in blood serum, equal 70,6 pg/ml, is reached between 1,5 and 12 hours after one-time intake of the tablet containing 3 mg of oestradiol of valerate in the 1st day of a course. The concomitant use of food does not exert clinically significant impact on speed and extent of absorption of oestradiol of valerate.

Metabolism
Valerianic acid is very quickly metabolized. After intake about 3% of a dose become directly bioavailable in the form of oestradiol. Oestradiol is exposed to intensive effect of "primary passing" through a liver, and a considerable part of the entered dose is metabolized already in mucous by a GIT. In total with presistemny metabolism in a liver about 95% of the dose accepted inside are metabolized before receipt in system circulation. The main metabolites are estrone, estrone sulfate and estrone a glucuronide.

Distribution
In blood serum of 38% of oestradiol 60% with albumine are connected with GSPG, and 2-3% circulate in an untied look. Oestradiol can slightly increase concentration of GSPG in blood serum; this effect depends on a dose. For the 21st day of a cycle of reception concentration of GSPG made about 148% from initial, and by 28th day (end of a phase of reception of inactive tablets) decreased approximately to 141% of initial. The seeming distribution volume after intravenous administration - 1,2 l/kg.

Elimination
Owing to the big circulating pool of sulfates and glucuronides of estrogen, and also enterohepatic recirculation, the oestradiol elimination half-life in a terminal phase after oral administration represents the complex parameter which depends on all these processes and is in range about 13-20 h.
Oestradiol and its metabolites are removed, mainly, by kidneys, at the same time about 10% are removed through intestines. Equilibrium concentration
The pharmacokinetics of oestradiol is influenced by concentration of GSPG. At women the measured concentration of oestradiol in a blood plasma represents set of the endogenous oestradiol and oestradiol which arrived at administration of drug of Klayr. During a phase of reception of the tablets containing 2 mg of oestradiol of valerate + 3 mg of a diyenogest the maximum and average concentration of oestradiol in blood serum at an equilibrium state make, respectively, 66,0 pg/ml and 51,6 pg/ml. During all 28-day cycle stable minimum concentration of oestradiol in the range from 28,7 pg/ml to 64,7 pg/ml were maintained.

Indications to use:

Peroral contraception

Route of administration and doses:

Inside, irrespective of meal.
Pill should be taken in the order specified on packaging every day approximately at the same time, if necessary washing down with water or other liquid. Reception of tablets is carried out continuously. It is necessary to accept on one tablet a day consistently within 28 days. Each new packaging is begun after reception of the last tablet from the previous calendar packaging. Menstrualnopodobny bleeding usually begins during reception of the last tablets of calendar packaging and can not come to the end prior to the following calendar packaging yet. At some women menstrualnopodobny bleeding begins after reception of the first tablets from new calendar packaging.
If hormonal contraception was not used earlier (last month)
Pill begins to be taken in the 1st day of a natural menstrual cycle of the woman (i.e. in the 1st day of menstrual bleeding).
Transition from other combined hormonal contraceptive (another the COOK, a vaginal ring or a transdermalny plaster)
The woman should begin administration of drug of Klayr next day after the last active medicine (the tablet containing active agents) from packaging previous the COOK was taken. When using a vaginal ring or transdermalny plaster the woman should begin administration of drug of Klayr in day of their removal.
If earlier only the progestagenny method of contraception (mini-drank, an injection, an implant) or intrauterine system with release of progestogen (Naval Forces) was used
The woman can pass to administration of drug of Klayr with mini-saw in any day (from an implant or Naval Forces – in day of their removal; from an injection method — in day to which the next injection is appointed), but in all cases during the first 9 days of reception of tablets it is recommended to use a barrier method of contraception in addition.
After abortion in the first trimester of pregnancy
The woman can begin reception of tablets immediately. In this case in additional measures of contraception there is no need.
After the delivery or abortion in the second trimester of pregnancy:
About the feeding women see the section Pregnancy and a lactation.
It is necessary to recommend to the woman to start reception of tablets for 21-28 day after the delivery or abortion in the second trimester of pregnancy. If the woman began to take a pill later, then she is recommended to use in addition a barrier method of contraception during the first 9 days of reception of tablets. However if the sexual contact already took place, before the actual beginning of administration of drug of Klayr it is necessary to exclude pregnancy, or the woman should wait for approach of the first periods.
Reception of the passed tablets
The passed (white) inactive tablets can be neglected. However they should be thrown out in order to avoid inadvertent extension of an interval between reception of active tablets.
The following councils treat only the admission of active tablets.
If the delay in reception of any of tablets makes less than 12 hours, contraceptive protection does not decrease. The woman has to take the passed medicine at once as soon as she remembers it, and to take other pill in usual time.
If the delay in reception of any of tablets makes more than 12 hours, contraceptive protection can decrease. The woman has to take the last passed pill at once as soon as she remembers it even if it will mean that she should take 2 medicines at the same time. Then she will continue to take a pill in usual time.
Depending on day of a menstrualnopodobny cycle in which the tablet was passed (for more details see Table 1), it is required to apply additional measures of contraception (for example, a barrier method of protection, in particular condoms) according to the following principles:

Table 1. The principles of the address with the passed tablets

Day	Color Content of the valerate oestradiol (VO) and diyegnogest (DNG)	The principles which are required to be followed if one tablet was passed and there passed more than 12 hours:
1-2	Dark yellow tablets (3,0 мгЭВ)	- To take the passed pill immediately, and the following tablet – in usual time (even if it means that it is necessary to take 2 pill in one day)
3-7	Pink tablets (2,0 mg of EV + 2,0 mg of DNG)	- To continue to take a pill regularly - Additional measures of contraception during the next 9 days
8-17	Pale yellow tablets (2,0 mg of EV + 3,0 mg of DNG)
18-24	Pale yellow tablets (2,0 mg of EV + 3,0 mg of DNG)	To throw out the current calendar packaging and to immediately begin reception with the first tablet from new calendar packaging To continue to take a pill regularly Additional measures of contraception during the next 9 days
25-26	Red tablets (1,0 мгЭВ)	To immediately take the passed pill, and the following tablet – in usual time (even if it means that it is necessary to take 2 pill in one day) In additional measures of contraception there is no need
27-28	White tablets (Placebo)	To throw out the passed tablet and to continue reception of tablets regularly In additional measures of contraception there is no need

It is allowed to take no more than 2 pill in one day.
If the woman forgot to begin new calendar packaging or passed one or more tablets from the 3rd to the 9th day of calendar packaging, she can be already pregnant (if it had a sexual contact within 7 days before the admission of a tablet). Than more tablets (especially with a combination of two active components in days from the 3rd on the 24th) are passed, and the closer they to a phase of reception of inactive tablets, the are higher probability of pregnancy.
If the woman missed reception of tablets, and then at the end of calendar packaging / at the beginning of new calendar packaging menstrualnopodobny bleeding at it was absent, it is necessary to consider probability of pregnancy.
Recommendations at gastrointestinal frustration
At heavy gastrointestinal frustration absorption can be incomplete therefore it is necessary to take additional contraceptive measures (for example, a barrier method of protection, in particular condoms).
If in 3-4 hours after reception of an active tablet there is vomiting, then in this case the recommendations concerning the passed tablets which are given in the section "Reception of the Passed Tablets" work. If the woman does not want to change the usual scheme of reception of tablets, she needs to take an additional medicine (or tablets) from new packaging.

Additional information for separate groups of patients
Patients of advanced age
It is not applicable. Klayr's drug is not shown after approach of a menopause.
Patients with abnormal liver functions
Klayr's drug is contraindicated at women with a serious illness of a liver until indicators of function of a liver do not return to normal. See also section "Contraindications".
Patients with renal failures
Klayr's drug specially was not studied at patients with renal failures.
The available data do not assume correction of the mode of dosing at such patients.

Features of use:

If any of the diseases/states/risk factors provided below are available now, then it is necessary to correlate carefully potential risk and the expected advantage of use Klayr's drug in each individual case and to discuss it with the woman before she decides to begin administration of drug. In case of weighting, strengthening or the first manifestation of any of these states or risk factors, the woman has to consult with the doctor who can make the decision on need of drug withdrawal.
Diseases of cardiovascular system
Results of epidemiological researches indicate existence of interrelation between use the COOK and increase in frequency of development of venous and arterial thromboses and thromboembolisms (such as TGV, TELA, IM and cerebrovascular disturbances).
The risk of development of a venous thromboembolism (VTE) is maximum in the first year of reception of such drugs, is preferential within the first 3 months. The increased risk is present after initial use the COOK or resuming of use same or different the COOK (after a break between administrations of drug in 4 weeks and more).
The general risk of VTE at the patients accepting low-dosed the COOK (<50 mkg of ethinylestradiol) is 2-3 times higher, than at patients who do not accept the COOK, nevertheless, this risk remains lower in comparison with risk of VTE at pregnancy and childbirth.
VTE can lead to a lethal outcome (in 1-2% of cases).
VTE which is shown as TGV or TELA can occur when using any the COOK.
Extremely seldom when using the COOK arises thrombosis of other blood vessels, for example, of hepatic, mesenteric, renal, brain arteries and veins or vessels of a retina.
A consensus concerning communication between emergence of these events and use the COOK is absent.
The arterial thromboembolism can lead to a lethal outcome.
The risk of development of thrombosis (venous and/or arterial) and thromboembolisms increases:
- with age;
- at smokers (with increase in quantity of the smoked cigarettes or increase in age the risk increases, especially at women 35 years are more senior);
in the presence:
- the family anamnesis (for example, a venous or arterial thromboembolism ever at close relatives or parents at rather young age). In case of the hereditary or acquired predisposition, the woman has to be examined by the corresponding specialist for the solution of a question of a possibility of administration of drug of Klayr;
- obesity (index of body weight of more than 30 kg/m ²);
- dislipoproteinemiya;
- arterial hypertension;
- migraines;
- diseases of valves of heart;
- fibrillations of auricles;
- long immobilization; extensive surgical intervention, any lower extremity operation or extensive injury. In similar situations it is reasonable to stop administration of drug of Klayr (at planned operation, at least, in 4 weeks prior to it) and not to resume reception within 2 weeks after the termination of an immobilization.
The question of a possible role of a varicosity and superficial thrombophlebitis in development of VTE remains disputable.
It is necessary to consider the increased risk of development of a thromboembolism in a puerperal period. Disturbances of peripheric circulation can be also noted at a diabetes mellitus, a system lupus erythematosus, a gemolitiko-uraemic syndrome, chronic inflammatory diseases of intestines (a disease Krone or ulcer colitis) and a sickemia. Increase in frequency and weight of migraine during use of drug of Klayr (that can precede tserebrovakulyarny disturbances) can be the basis for the immediate termination of reception of this drug.
The following belongs to the biochemical factors indicating the hereditary or acquired predispositions to arterial or venous thrombosis: resistance to the activated protein With, a gipergomotsisteinemiya, deficit of antithrombin III, deficit of a protein With, deficit of a protein of S, anti-phospholipidic antibodies (anti-cardiolipidic antibodies, lupoid anticoagulant).
At assessment of a ratio of risk and advantage, it is necessary to consider that treatment of the corresponding state can reduce the related risk of thrombosis. Also it is necessary to consider that the risk of thromboses and a thromboembolism at pregnancy is higher, than at reception of the low-dosed oral contraceptives (<0.05 ethinylestradiol).
Tumors
The most essential risk factor connected with development of cancer of neck of uterus is the persistent human papillomavirus infection (PVI). There are messages on some increase in risk of development of cancer of neck of uterus at prolonged use the COOK. Communication with reception the COOK is not proved. The possibility of interrelation of these data with screening of diseases of a neck of uterus and is discussed with features of a sexual behavior (more rare use of barrier methods of contraception).
Meta-analysis of 54 epidemiological researches revealed small increase in relative risk (the SHOUTING = 1,24) development of a breast cancer in the women accepting the COOK now. The increased risk gradually disappears within 10 years after the termination of reception of these drugs. Because the breast cancer is noted seldom at women more young than 40 years, some increase in number of the diagnosed breast cancer at the women accepting the COOK now or accepting recently is insignificant in relation to the general risk of this disease. Its communication with reception the COOK is not proved. Observed increase in risk can be also a consequence of earlier diagnosis of a breast cancer at the women applying the COOK. At the women ever using the COOK earlier stages of a breast cancer, than at women, never applying come to light.
In rare instances against the background of use the COOK development high-quality, and in extremely exceptional cases – malignant tumors of a liver which in some cases led to life-threatening intra belly bleeding was observed. At emergence of severe pains in upper parts of a stomach, increase in the sizes of a liver or symptoms of intra belly bleeding at the women accepting the COOK at differential diagnosis it is necessary to exclude liver tumors.
Other states
At women with a gipertriglitseridemiya (or existence of this state in the family anamnesis) increase in risk of development of pancreatitis is possible during reception the COOK.
Though small increase in arterial pressure was described at many women accepting the COOK, clinically significant increases were noted seldom. However if against the background of administration of drug of Klayr develops permanent, clinically significant increase in arterial pressure, it is necessary to cancel drug and to begin treatment of arterial hypertension. Administration of drug of Klayr if necessary can be resumed if by means of hypotensive therapy it is possible to reach normal indicators of the arterial pressure (AP).
The following states develop or worsen both during pregnancy, and at reception the COOK, but their communication with reception the COOK is not proved: jaundice and/or a cholestatic itch, a cholelithiasis, a porphyria, a system lupus erythematosus, a gemolitiko-uraemic syndrome, Sydenham's chorea, herpes of pregnant women caused by an otosclerosis a hearing loss.
At women with hereditary forms of a Quincke's disease exogenous estrogen can induce or worsen symptoms of a Quincke's disease.
Acute or chronic abnormal liver functions can demand drug withdrawal of Klayr until indicators of function of a liver do not return to normal. Recurrent cholestatic jaundice which develops for the first time in time of pregnancy or previous reception of sex hormones demands the termination of administration of drug of Klayr.
Though the COOK can exert impact on resistance to insulin and tolerance to glucose, patients with a diabetes mellitus who use Klayr's drug have no need of change of the therapeutic mode. Nevertheless, the women suffering from a diabetes mellitus during administration of drug of Klayr need careful observation.
Disease cases Krone and ulcer colitis against the background of use the COOK are also described.
The hloazma, especially at women with hloazmy pregnant women in the anamnesis can sometimes develop.
To the women inclined to development of a hloazma, during administration of drug of Klayr it is necessary to avoid influence of the sun or ultraviolet radiation.
Influence on laboratory tests
Administration of drug of Klayr can influence results of some laboratory researches, including biochemical parameters of function of a liver, thyroid gland, adrenal glands and kidneys, concentration of transport proteins in plasma, for example, of KSG and fractions of lipids/lipoproteids, parameters of carbohydrate metabolism and parameters of coagulation and a fibrinolysis. These changes usually remain within laboratory norms.

Medical examinations
Before use of drug of Klayr it is necessary to estimate carefully contraindications to purpose of drug on the basis of the anamnesis of life, the family anamnesis of the woman, and also all-medical and gynecologic examination, the Frequency and the nature of these inspections have to be based on the existing norms of medical practice at the necessary accounting of specific features of each patient. As a rule, the ABP is measured, the condition of mammary glands, an abdominal cavity and bodies of a small pelvis, including cytology of a neck of uterus is checked.
It is necessary to explain to women that Klayr's drug is not protected from HIV infections (AIDS) and other diseases, sexually transmitted.

Decrease in efficiency
Efficiency of drug of Klayr can be reduced at the admission of tablets with active components (see recommendations about reception of the passed tablets in the section "Route of Administration and Doses"), gastrointestinal frustration during reception of tablets with active components (see recommendations at gastrointestinal frustration in the section "Route of Administration and Doses") or against the background of the accompanying medicinal treatment (see. "Interactions with other medicines").

Insufficient control of a menstrualnopodobny cycle
Against the background of use of drug of Klayr, especially in the first months of reception, there can be irregular menstrualnopodobny bleedings (smearing allocations or breakthrough uterine bleedings). Therefore, assessment of any irregular menstrualnopodobny bleedings has to be carried out only after the adaptation period which makes about 3 menstrualnopodobny cycles.
If irregular menstrualnopodobny bleedings repeat or for the first time arise after the previous regular cycles, it is necessary to consider probability of the reasons of also non-hormonal character and to conduct careful examination for an exception of malignant new growths or pregnancy. Similar actions can include a diagnostic scraping.
At some women during reception of inactive tablets of white color menstrualnopodobny bleeding can not develop. If administration of drug of Klayr was carried out according to the rules specified in the section "Route of Administration and Doses", pregnancy is improbable. However if before the first being absent menstrualnopodobny bleeding a pill was taken irregularly, or there are no in a row 2 menstrualnopodobny bleedings, it is not necessary to continue use Klayr's drug until pregnancy is excluded.

Influence on ability to drive the car and the equipment.
Negative influence of drug of Klayr on ability to driving and work with mechanisms is noted, however the patient at whom during the adaptation period (the first 3 months of administration of drug) episodes of dizzinesses are noted and disturbance of concentration of attention have to be careful.

Side effects:

On frequency undesirable effects are divided on frequent (> 1/100 and <1/10), infrequent (> 1/1000 and <1/100) and rare (> 1/10000 and <1/1000).

System and organ class	Often (from> 1/100 to <1/10)	Infrequently (from> 1/1000 to <1/100)	Seldom (from> 1/10 000 to <1/1000) **
Infections and invasions		Fungal infection Vagina candidiasis Vagina infection not specified	Candidiasis Herpes Syndrome of estimated histoplasmosis of eyes Multi-colored deprive Infection of urinary tract Bacterial vaginosis Vulvovaginal fungal infection
Metabolism and alimentary disturbances		Increase in appetite	Liquid delay Gipertriglitseridemiya
Nervous system	Headache (including headache of "tension")	Depression/decrease in mood Decrease in a libido Mental disturbance Changes of mood Dizziness	Affective lability Aggression Uneasiness Dysphoria Increase in a libido Nervousness Concern Sleep disorder Stress Disturbance of attention Paresthesias Vertigo
Organ of sight			Intolerance of contact lenses
Cardiovascular system		Increase in arterial pressure Migraine (including migraine with aura and migraine without aura)	Bleeding from varicose expanded veins Heat "inflows" Lowering of arterial pressure Pains on the course of veins
Alimentary system	Abdominal pains (including abdominal distention	Diarrhea Nausea Vomiting	Lock Dyspepsia Gastroesophagal reflux
Gepatobiliarny system			Increase in activity of alaninaminotranspherase Focal nodular hyperplasia of a liver
Skin and hypodermic cellulose	Acne	Alopecia Itch, in a t.ch.generalizovanny itch and pruritic rash Rash, including menocelis	Allergic skin reaction, including allergic dermatitis and a small tortoiseshell Hloazma Dermatitis Hirsutism Hypertrichosis Neurodermatitis Pigmentation disturbance Seborrhea The damage of skin which is not specified including feeling of stiffness of skin
Musculoskeletal system			Dorsodynias Muscular spasms Heavy feeling
Reproductive system and mammary glands	Amenorrhea Discomfort in mammary glands, mammary gland pains, disturbance in nipples, nipple pains Dysmenorrhea Irregular menstrualnopodobny bleedings (metrorrhagia)	Increase in mammary glands Diffusion consolidation of mammary glands Dysplasia of an epithelium of a neck of uterus Dysfunctional uterine bleeding Dispareuniya Fibrous and cystous mastopathy Menorrhagia Cysts in ovaries Pains in pelvic area Premenstrual syndrome Uterus leiomyoma Uterus spasms Allocations from a vagina Dryness in vulvovaginal area	High-quality new growth in a mammary gland Lactocele Bleeding during the sexual intercourse Galactorrhoea Bleeding from a vagina Hypomenorrhea Delay of menstrualnopodobny bleeding Rupture of an oothecoma Burning sensation in a vagina Uterine/vulval bleeding, including the smearing allocations Smell from a vagina Vulvovaginal discomfort
Hemolymphatic system			Lymphadenopathy
General symptoms	Increase in body weight	Irritability Hypostasis Weight reduction	Pain behind a breast Fatigue Indisposition

Interaction with other medicines:

Influence of other medicines on active components of drug of Klayr
The COOK with other medicines can lead interaction to breakthrough uterine bleedings and/or lack of contraceptive effect. The following types of interaction were described in literature on the COOK in general or were studied in the course of clinical trials of drug of Klayr: Inductors or inhibitors of separate enzymes (CYP3A4 isoenzyme)
- Inductors of isoenzymes
Interaction with the medicines inducing microsomal enzymes (for example, systems of P450 cytochrome) can take place therefore the clearance of sex hormones can increase (to it medicinal to means Phenytoinum, barbiturates, Primidonum, carbamazepine, rifampicin and, perhaps, also окскарбазепин, топирамат, фелбамат, ритонавир, griseofulvin, and also the drugs containing the St. John's Wort which is made a hole belong). It was reported that HIV protease inhibitors (for example, ритонавир), nenukliozidny inhibitors of the return transcriptase (for example, not Virapinum can also exert impact on hepatic metabolism) and their combinations.
- Influence on enterogepatichesky circulation
Against the background of reception of certain groups of antibiotics (for example, penicillinic and tetracycline groups) enterogepatichesky circulation of estrogen can decrease that can lead to decrease in concentration of oestradiol.
Women who receive treatment by the drugs inducing microsomal enzymes or antibiotics in addition to Klayr's drug are recommended to use temporarily a barrier method of contraception or to choose other method of contraception. The barrier method of protection should be used during the entire period of reception of the accompanying drugs and within 28 days after their cancellation.
- Inhibitors of isoenzymes
The concomitant use of rifampicin together with the tablets containing oestradiol valerate and диеногест led to essential decrease in equilibrium concentration and system exposure of a diyenogest and oestradiol. The system exposure of a diyenogest and oestradiol at equilibrium concentration measured on the basis of AUC0-24 of the h decreased, respectively, by 83% and for 44%.
The known CYP3A4 inhibitors, such as azolny antifungal drugs, Cimetidinum, verapamil, macroleads, diltiazem, antidepressants and grapefruit juice, can increase concentration of a diyenogest in a blood plasma. At a concomitant use with powerful inhibitor ketokonazoly the size AUC0-24 of the h at a diyenogest increased in an equilibrium state for 186%, and at oestradiol – for 57%. At simultaneous use with moderate inhibitor erythromycin the size AUCo-24 of the h At a diyenogest and oestradiol in an equilibrium state increased, respectively, by 62% and for 33%.
Effects of drug of Klayr concerning other medicines
The COOK can influence metabolism of some other medicines (for example, a lamotridzhina) that can lead either to increase, or to decrease in concentration of these substances in a blood plasma and fabrics. However, proceeding from these researches in vitro, the inhibition of CYP enzymes at use of drug of Klayr in a therapeutic dose is improbable.
Note: for identification of possible interactions it is necessary to study instructions of the accompanying medicines.

Contraindications:

Klayr's drug should not be used in the presence of any of the states which are listed below. If any of these states develop for the first time against the background of reception, drug has to be immediately cancelled.

Fibrinferments (venous and arterial) and thromboembolisms now or in the anamnesis (including, the deep vein thrombosis (DVT), a thromboembolism of a pulmonary artery (TELA), the myocardial infarction (MI)), a stroke now or in the anamnesis.
The states preceding thrombosis (including, the tranzitorny ischemic attacks, stenocardia) now or in the anamnesis.
Existence of the expressed or multiple factors of risk of venous or arterial thrombosis (including extensive surgical intervention with a long immobilization, the complicated diseases of the valve device of heart, uncontrollable arterial hypertension – watch the section "Special Instructions").
Migraine with focal neurologic symptoms, including in the anamnesis.
Diabetes mellitus with vascular complications.
Pancreatitis with the expressed gipertriglitseridemiya now or in the anamnesis.
Liver failure and serious illness of a liver (before normalization of indicators of function of a liver);
Liver tumors (high-quality and malignant) now or in the anamnesis.
The revealed hormonedependent malignant tumors (including, generative organs or mammary glands) or suspicion of them.
Krovecheniye from a vagina of not clear genesis.
Pregnancy or suspicion on it.
Hypersensitivity to active agents or to any of excipients.
Use with care
If any of the diseases/states/risk factors provided below are available now, then it is necessary to correlate carefully potential risk and the expected advantage of use of drug of Klayr in each individual case:

Risk factors of development of thrombosis and thromboembolism: smoking; obesity; dislipoproteinemiya; arterial hypertension; migraine; diseases of valves of heart; disturbance of a cordial rhythm; long immobilization; extensive surgical interventions; extensive injury;
Other diseases at which disturbances of peripheric circulation can be noted: diabetes mellitus; system lupus erythematosus; gemolitiko-uraemic syndrome; disease Krone and ulcer colitis; drepanocytic anemia;
Hereditary Quincke's disease
Gipertriglitseridemiya
The diseases which for the first time arose or aggravated during pregnancy or against the background of the previous reception of sex hormones (for example, cholestatic jaundice, a cholestatic itch, a cholelithiasis, an otosclerosis with deterioration in hearing, a porphyria, herpes of pregnant women, Sydenham's trochee)
Puerperal period
Pregnancy and lactation
Administration of drug of Klayr is contraindicated during pregnancy. If pregnancy occurred against the background of use of drug of Klayr, further reception needs to be stopped. However large-scale epidemiological researches did not reveal increase in risk of development of inborn defects in the children who were born at women who used the COOK before pregnancy, as well as teratogenic influence the COOK at their accidental reception at the beginning of pregnancy.
The COOK can influence a lactation as they are capable to reduce the volume of the developed breast milk, and also to change its structure. Therefore, the COOK usually is not recommended to use before the end of the period of a lactation. A small amount of contraceptive hormones and/or their metabolites can be allocated with breast milk.

Use for children and teenagers
Klayr's drug is shown only after approach of menarche.

Overdose:

About serious violations at overdose by Klayr's drug it was not reported. On the basis of total experience of use the COOK symptoms which can be noted at overdose by active tablets: nausea, vomiting, the smearing bloody allocations or a metrorrhagia.
Treatment: symptomatic.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children. Period of validity 4 years. Not to apply after a period of validity!

Issue conditions:

According to the recipe

Packaging:

Tablets are film coated.
2 dark yellow tablets, 5 pink tablets, 17 pale yellow tablets, 2 red tablets and 2 white tablets (only 28 tablets) in one blister from a PVC film/-алюминиевой a foil.
1 blister is pasted in the book folding bed cardboard. 1 or 3 books folding beds together with a self-adhesive calendar of reception and the application instruction are sealed in a transparent film.