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

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Dosage form: & nbsp

Film-coated tablets.

Composition:

For one dark-yellow tablet, covered with a film sheath:

Core:

- Active component

Estradiol valerate, micro 20 - 3,000 mg.

- Auxiliary components

Lactose monohydrate - 48.3600 mg, corn starch - 14.4000 mg, corn pregelatinised corn starch - 9.6000 mg, povidone-25 - 4.0000 mg, magnesium stearate - 0.6400 mg

Sheath:

Gipromellose - 1.5168 mg, macrogol-6000 - 0.3036 mg, talc 0.3036 mg, titanium dioxide 0.5840 mg, iron oxide yellow oxide 0.22920 mg.

On one pink tablet, covered with a film sheath:

Core:

- Active components

Estradiol valerate, micro 20 - 2.00000 mg.

Dienogest, micro - 2.00000 mg.

- Auxiliary components

Lactose monohydrate - 47.36000 mg, corn starch - 14.40000 mg, corn pregelatinised corn starch - 9.60000 mg, povidone-25 - 4.00000 mg, magnesium stearate - 0.64000 mg.

Sheath:

Gipromellose - 1.51680 mg, macrogol-6000 - 0.30360 mg, talc 0.30360 mg, titanium dioxide 0.83694 mg, iron oxide red oxide 0.03906 mg.

On one pale yellow tablet, covered with a film sheath:

Core:

- Active components

Estradiol valerate, micro 20 - 2.00000 mg.

Dienogest, micro - 3.00000 mg.

- Auxiliary components

Lactose monohydrate - 46.36000 mg, corn starch - 14.40000 mg, corn pregelatinised corn starch - 9.60000 mg, povidone-25 - 4.00000 mg, magnesium stearate - 0.64000 mg.

Sheath:

Gipromellose - 1.51680 mg, macrogol-6000 - 0.30360 mg, talc 0.30360 mg, titanium dioxide 0.83694 mg, iron oxide yellow oxide 0.03906 mg.

For one red tablet covered with a film sheath:

Core:

- Active component

Estradiol valerate, micro 20 - 1.0000 mg.

- Auxiliary components

Lactose monohydrate - 50.3600 mg, corn starch - 14.4000 mg, corn pregelatinised corn starch - 9.6000 mg, povidone-25 - 4.0000 mg, magnesium stearate - 0.6400 mg.

Sheath:

Gipromellose - 1.5168 mg, macrogol-6000 - 0.3036 mg, talc 0.3036 mg, titanium dioxide 0.5109 mg, iron oxide red oxide 0.361 kg.

For one white film-coated tablet (placebo):

Core:

- Auxiliary components

Lactose monohydrate - 52.1455 mg, corn starch - 24.0000 mg, povidone-25 - 3.0545 mg, magnesium stearate - 0.8000 mg.

Sheath:

Gipromellose - 1.0112 mg, talc 0.2024 mg, titanium dioxide 0.7784 mg.

Description:

Dark yellow tablets: round biconvex tablets coated with film shell of dark yellow color, with engraving “DD” in the right hexagon on one side. Type of tablets on a cross-section: the kernel is from white to almost white, the shell is dark yellow.

Pink tablets: round biconvex tablets, covered with a film shell of pink color, with engraving “DJ” in the right hexagon on one side. Kind of tablets on a cross-section: the kernel from white up to almost white color, a cover - pink.

Pale yellow tablets: round biconvex tablets covered with a film membrane of pale yellow color, with engraving “DH” in the right hexagon on one side. Kind of tablets on a cross-section: the kernel from white up to almost white color, a cover - pale yellow.

Red tablets: round biconvex tablets, covered with a film shell of red color, engraved “DN” in the right hexagon on one side. Type of tablets on a cross-section: the kernel is from white to almost white, the shell is red.

White tablets (placebo): round biconvex tablets, coated with a white film shell, engraved “DT” in the right hexagon on one side. Type of tablets on a cross-section: the kernel is from white to almost white, the shell is white.

Pharmacotherapeutic group:Contraceptive agent combined (estrogen + progestogen)

ATX: & nbsp

Estradiol

Progestogens and estrogens (fixed combinations)

Pharmacodynamics:

The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of various factors, the most important of which are suppression of ovulation and changes in the properties of the secretion of the cervix.Along with the prevention of unwanted pregnancy, COCs have a number of positive properties, which, while taking into account also the negative properties (cf. "Special instructions", "Side effect") can help in choosing the most appropriate method of contraception. In women taking COC, tenderness and intensity of menstrual bleeding decrease, which reduces the risk of iron deficiency anemia. In addition, there is evidence of a reduced risk of developing endometrial cancer and ovarian cancer.

Clyra® has a beneficial effect on the endometrium, which can be used to treat profuse and / or prolonged menstrual bleeding without organic pathology. The efficacy and safety of estradiol valerate / dienogest tablets in the treatment of dysfunctional uterine bleeding symptoms have been studied in two double-blind, placebo-controlled clinical trials. Both studies demonstrated a clinically and statistically significant reduction in menstrual blood loss. This was accompanied by a statistically significant improvement in the parameters of iron metabolism (hemoglobin, hematocrit and ferritin).

The estrogen in the Claira® preparation is estradiol valerate, the predecessor of the natural 17b-estradiol (1 mg of estradiol valerate corresponds to 0.76 mg of 17b-estradiol). The estrogen component used in this COC is thus different from the commonly used in COC estrogens, which are synthetic estrogens - ethinyl estradiol or its precursor, mestranol, both containing an ethynyl group at position 17a. This group causes a higher metabolic stability, however, also a more pronounced effect on the liver.

The administration of Claira® leads to a less pronounced effect on the liver compared to three-phase COCs containing ethinyl estradiol and levonorgestrel. It has been shown that the effect on the concentration of sex hormone binding globulin (SHBG) and the parameters of hemostasis is less pronounced. In combination with dienogestom estradiol valerate demonstrates an increase in the concentration of high-density lipoprotein (HDL), while the concentration of low-density lipoprotein (LDL) cholesterol is somewhat reduced.

Dienogest is a progestogen that is characterized by additional partial antiandrogenic effects.Its estrogenic, anti-estrogenic and androgenic properties are insignificant. Thanks to a special chemical structure, a spectrum of pharmacological action is provided that combines the most important advantages of 19-nor-progestogens and progesterone derivatives.

Preclinical data obtained from routine toxicity studies with repeated doses, genotoxicity, carcinogenic potential, and toxicity to the reproductive system do not indicate a specific risk to humans. However, it should be borne in mind that sex hormones can stimulate the growth of a number of hormone-dependent tissues and tumors.

When used correctly, Perl's index (an indicator that reflects the frequency of pregnancy in 100 women during the year of contraceptive use) is less than 1. When missing tablets or improperly used, the Pearl index may increase.

Pharmacokinetics:

- Dienogest

Absorption

After oral administration dienogast quickly and almost completely absorbed. The maximum plasma concentration of 90.5 ng / ml is achieved approximately 1 hour after oral administration of the Clayra® tablet containing 2 mg of estradiol valerate + 3 mg of dienogest. Bioavailability is about 91%.The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is characterized by dose dependence.

Simultaneous food intake does not have a clinically significant effect on the speed and degree of absorption of dienogest.

Distribution

A relatively large (10%) part of the circulating dienogest is unbound, while about 90% is nonspecifically associated with albumin. Dienogest does not bind to SHBG and corticosteroid-binding globulin (CSG). For this reason, there is no possibility of displacing testosterone from its association with SHBG or cortisol from its association with CRS. Any influence on the physiological processes of transport of endogenous steroids, therefore, is unlikely. The volume of distribution of dienogest at an equilibrium concentration is 46 L after intravenous administration of 85 μg of tritiated dienogest.

Metabolism

Dienogest is almost completely metabolized, passing through the known ways of metabolizing sex hormones (hydroxylation, conjugation), with the formation of predominantly endocrinologically inactive metabolites. Metabolites are excreted very quickly,so that the predominant fraction in the blood plasma is unchanged dienogast.

The total clearance after intravenous administration of tritiated dienogest is 5.1 l / h.

Elimination

The half-life of dienogest from plasma is approximately 11 o'clock. After oral administration at a dose of 0.1 mg / kg dienogast is excreted as metabolites by the kidneys and through the intestine in a ratio of approximately 3: 1. After oral administration, 42% of the dose is excreted within the first 24 hours, and 63% within 6 days by renal excretion. In 6 days, 86% of the dose is excreted by the kidneys and through the intestine.

The equilibrium concentration

The pharmacokinetics of dienogest does not depend on the concentration of SHBG. The equilibrium concentration is achieved after 3 days of the same dose, which is 3 mg of dienogest in combination with 2 mg of estradiol valerate. The minimum, maximum and average concentrations of dienogest in blood plasma at an equilibrium state are, respectively, 11.8 ng / ml, 82.9 ng / ml and 33.7 ng / m. The average cumulation coefficient over the area under the concentration-time curve (AUC0-24 h) - 1,24.

- Estradiol valerate

Absorption

After oral administration estradiol valerate quickly and completely absorbed. Splitting into estradiol and valerian acid occurs during absorption in the mucosa of the gastrointestinal tract or during the first passage through the liver, resulting in the formation of estradiol and its metabolites are estrone and estriol. The maximum concentration of estradiol in the blood plasma, equal to 70.6 pg / ml, is achieved between 1.5 and 12 hours after a single oral intake of a tablet containing 3 mg of estradiol valerate on the 1 st day of the course.

Simultaneous food intake does not have a clinically significant effect on the rate and extent of absorption of estradiol valerate.

Metabolism

Valeric acid is very rapidly metabolized. After oral administration, approximately 3% of the dose becomes directly bioavailable in the form of estradiol. Estradiol is subjected to an intensive effect of "primary transmission" through the liver, and a significant part of the administered dose is already metabolized in the gastrointestinal mucosa. Together with the presystemic metabolism in the liver, about 95% of the ingested dose is metabolized before entering the systemic circulation. The main metabolites are estrone, estrone sulfate and estrone glucuronide.

Distribution

In plasma, 38% of estradiol is associated with SHBG, 60% - with albumin and 2-3% circulate unbound. Estradiol may slightly increase the concentration of SHBG in blood plasma; this effect is dose dependent. On the 21st day of the intake cycle, the concentration of SHBG was approximately 148% of the initial, and by the 28th day (completion of the phase of inactive tablet intake) decreased to approximately 141% of the baseline. The apparent volume of distribution after intravenous administration is 1.2 l / kg.

Elimination

Due to the large circulating pool of sulfates and estrogen glucuronides, as well as intestinal-hepatic recirculation, the elimination half-life of estradiol in the terminal phase after oral administration is a complex parameter that depends on all these processes and is in the range of about 13-20 hours.

Estradiol and its metabolites are excreted mainly by the kidneys, while about 10% is excreted through the intestine.

The equilibrium concentration

The pharmacokinetics of estradiol are affected by the concentration of SHBG. In women, the measured concentration of estradiol in blood plasma is a combination of endogenous estradiol and estradiol, which was received with the drug Claira®.During the phase of taking tablets containing 2 mg of estradiol valerate + 3 mg of dienogest, the maximum and average concentrations of estradiol in blood plasma at an equilibrium state are 66.0 pg / ml and 51.6 pg / ml, respectively. During the entire 28-day cycle, stable minimal estradiol concentrations were maintained in the range from 28.7 pg / ml to 64.7 pg / ml.

Indications:

- Oral contraception.

- Oral contraception and treatment of profuse and / or prolonged menstrual bleeding without organic pathology.

Contraindications:

The use of Claira® is contraindicated in the presence of any of the conditions listed below. If any of these conditions develop for the first time against the background of the drug, the drug should be immediately withdrawn.

- Thrombosis (venous and arterial) and thromboembolism now or in history (including deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI)), a stroke now or in the anamnesis.

- Conditions preceding thrombosis (including, transient ischemic attacks, angina pectoris) are currently or in history.

- Revealed acquired or hereditary predisposition to venous or arterial thrombosis, including resistance to activated protein C, deficiency of antithrombin III, deficiency of protein C, protein deficiency S, hyperhomocysteinemia, antibodies to phospholipids (antibodies to cardiolipin, lupus anticoagulant).

- The presence of a high risk of venous or arterial thrombosis (see section "Special instructions").

- Migraine with focal neurological symptoms, including in the anamnesis.

- Diabetes mellitus with vascular complications.

- Pancreatitis with severe hypertriglyceridemia at present or in the anamnesis.

- Hepatic failure and severe liver disease (before the normalization of liver function);

- Liver tumors (benign and malignant) are currently or in the anamnesis.

- Revealed hormone-dependent malignant tumors (including genitals or mammary glands) or suspected of them.

- Bleeding from the vagina of unknown origin.

- Pregnancy or suspicion of it.

- Breastfeeding period.

- Hypersensitivity to active substances or to any of the excipients.

- Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Carefully:

If any of the diseases / conditions / risk factors listed below are currently available, the potential risk and the expected benefit of using Clayra® in each individual case should be carefully correlated.

- Risk factors for thrombosis and thromboembolism: smoking; obesity; dyslipoproteinemia; arterial hypertension; migraine; heart valve diseases; heart rhythm disorder; extensive surgical interventions without prolonged immobilization.

- Other diseases in which there may be violations of peripheral circulation: diabetes mellitus; systemic lupus erythematosus; hemolytic-uremic syndrome; Crohn's disease and ulcerative colitis; sickle-cell anemia.

- Hereditary angioedema.

- Hypertriglyceridemia.

- Diseases that first appeared or worsened during pregnancy or on the background of previous reception of sex hormones (for example, cholestatic jaundice, cholestatic itching, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes pregnant, Sydenham's chorea).

- Postpartum period.

Pregnancy and lactation:

The use of the drug Claira® is contraindicated during pregnancy. If the pregnancy has occurred while using the drug Claira®, further reception should be discontinued. However, large-scale epidemiological studies did not reveal an increase in the risk of birth defects in children born to women who used COC prior to pregnancy, as well as teratogenic effects of COCs when they were randomly taken at the beginning of pregnancy.

COCs can affect the period of breastfeeding, as they are able to reduce the amount of produced breast milk, as well as change its composition. The use of the drug is contraindicated until the termination of breastfeeding. A small number of contraceptive hormones and / or their metabolites can be excreted in breast milk.

Dosing and Administration:

How and when to take Clyra®

Tablets should be taken daily in the order indicated on the packaging, regardless of food intake, approximately at the same time, and washed down with water. The tablets are taken continuously.One tablet per day should be taken consecutively for 28 days. Receipt of tablets from each new package begins after receiving the last tablet from the previous calendar package. Menstruation-like bleeding usually begins during the reception of the last tablets of the calendar pack and may not yet be completed before taking the tablets from the next calendar package. In some women, bleeding begins after taking the first tablets from a new calendar package.

Preparation of a cot-book

In order to monitor the reception of tablets, 7 labels are attached to the package with the names of 7 days of the week affixed to them.

It is necessary to choose a sticker that starts from the day of the week in which the woman starts to take the tablets. For example, if the reception starts on Wednesday, you should use a sticker that starts with the word "CP".

The sticker is applied to the top of the unfolding pack of the Claira® preparation, where the inscription "Put a calendar here" is located, so that the name of the first day is above the tablet with the number "1".

Now over each tablet is the name of the corresponding day of the week, and it is clear whether the tablet has already been taken on this or that day or not.It is necessary to follow the direction of the arrow on the clamshell book until all 28 tablets are taken.

Usually, the so-called menstrual bleeding begins when the second dark red tablet or white tablets is taken and may not end before the next package is started. In some women, bleeding continues after taking the first tablets from a new package.

The next packing begins without a break, i.e. the day after the current packaging is finished, even if the bleeding has not stopped. It means that The next packing should start on the same day of the week as the current one, and that menstrual bleeding should fall every month on the same days of the week.

If Clira® is used as directed, the woman is protected from unwanted pregnancy even during those 2 days when she takes inactive tablets.

How to start taking tablets from the first package?

- If hormonal contraceptives were not applied last month

Begin the administration of the drug Claira® on the first day of the cycle, i.e. the first day of menstrual bleeding.

- If a woman switches to taking Clyra® from other COCs, a combined contraceptive vaginal ring or plaster

Begin taking Clayra® the day after the last active tablet (the last tablet with active ingredients) from the current package of hormonal contraceptives was taken. If inactive capsules are contained in the package of old contraceptives, they should be discarded and continue to be taken from the first package of the Clayra® preparation without taking a break. If a woman previously used a combined contraceptive vaginal ring or plaster, take the Clira® preparation should begin on the day of removal of the ring / patch.

- When switching from contraceptive preparations containing only progestogen (from "minipill", injection, implant or intrauterine system with the release of progestogen (IUD))

You can switch to taking Clyra® from contraceptive preparations containing only gestagen, any day (from the implant or the IUD on the day they are removed, from the injection method on the day the next injection is given), but in all cases during the first 9 days Clayra® should be taken with additional contraceptive measures (for example, condoms).

- After abortion in the first trimester of pregnancy

A woman can start taking pills immediately. In this case, there is no need for additional contraceptive measures.

- After childbirth, with no breastfeeding or abortion in the second trimester of pregnancy

It should be recommended to the woman to start taking pills on the 21-28th day after giving birth, without breastfeeding, or abortion in the second trimester of pregnancy. If a woman starts taking pills later, she is recommended to use the barrier method of contraception during the first 9 days of taking the pills. However, if sexual intercourse has already taken place, the pregnancy should be excluded before the actual start of the Clira® preparation, or the woman should wait for the onset of the first menstruation.

Recommendations in case of missing tablets

Missed (white) inactive tablets can be neglected. However, they should be discarded to avoid inadvertently prolonging the interval between taking active tablets.

The following recommendations apply exclusively to the omission of active tablets:

If delay in taking any active tablet is less than 12 hours, Contraceptive protection is not reduced. A woman should drink a missed pill right away, as soon as she remembers it, and take the rest of the pills at the usual time.

If the delay in taking any active tablet is more than 12 hours, contraceptive protection may decrease. A woman must accept the last missed pill right away, as soon as he remembers it, even if it means that she will have to drink 2 tablets at the same time. Then she will continue to take the pill at the usual time.

Depending on the day of the menstrual cycle in which the pill was missed (see Table 1 for details), additional contraceptive measures (for example, barrier method of protection, in particular condoms) are required in accordance with the following recommendations.

Table 1. Recommendations in case of missing tablets

DAY		Colour / The content of estradiol valerate (EV) and dienogast (DNG)		Recommendations to be followed if one tablet was missed and more than 12 hours passed:
1-2		Dark yellow tablets (3.0 mg EV)		- Take the missed tablet immediately, and the next pill - at the usual time (even
3-7		Pink tablets (2.0 mg EV + 2.0 mg DNG)		if this means that you have to take 2 tablets in one day)
8-17		Pale yellow pills (2.0 mg EV + 3.0 mg DNG)		- Continue to take the pill in the usual way - Additional contraceptive measures for the next 9 days
18-24	Pale yellow pills (2.0 mg EV + 3.0 mg DNG)		Discard the current calendar package and immediately start receiving the first tablet from the new calendar package. Continue to take the pill in the usual way Additional contraceptive measures for the next 9 days
25-26	Red tablets (1.0 mg EV)		Immediately take the missed pill, and the next pill - at the usual time (even if it means that you have to take 2 tablets in one day) In additional contraceptive measures, there is no need
27-28	White tablets (placebo)		Discard the missed pill and continue taking the tablets in the usual manner In additional contraceptive measures, there is no need

It is allowed to take no more than 2 tablets in one day.

If a woman forgot to start a new calendar package or missed one or more tablets from the 3rd to the 9th day of the calendar package,she can already be pregnant (in the event that she had sexual intercourse for 7 days before missing the pill). The more pills (especially with the combination of the two active ingredients on days 3 to 24) are missed, and the closer they are to the phase of taking inactive tablets, the higher the probability of pregnancy.

If the woman missed taking the tablets, and then at the end of the calendar packing / at the beginning of the new calendar package menstrual bleeding was absent, the probability of pregnancy should be considered.

For convenience, this information is presented on the packaging in the form of the following scheme:

See Attachment

Recommendations for gastrointestinal disorders

If, after taking any of the 26 active tablets of the Clayra® preparation, a woman begins vomiting or severe diarrhea, the absorption of the active substances may be incomplete. If vomiting occurred 3-4 hours after taking the pill, it is equivalent to skipping the tablet. Therefore, in this case, you should take into account the information indicated in the section "Receiving Missed Tablets".

Recommendations in case of missing tablets. Vomiting or diarrhea on the days of taking the last 2 inactive tablets does not have any effect on the effectiveness of contraception.

How to stop taking Clayra®

You can stop taking the drug Claira® at any time. If a woman does not plan pregnancy, care should be taken for other methods of contraception. If pregnancy is planned, you should just stop taking Clayra®.

Additional information for specific categories of patients

Children and teens

Data on the efficacy and safety of the drug in girls under the age of 18 years are absent.

Older patients

Not applicable. Clayra® is not indicated after menopause.

Patients with impaired hepatic function

The drug Clyra® is contraindicated in women with severe liver disease until the liver function test results are normal. See also "Contraindications".

Patients with impaired renal function

Clayra® was not specifically studied in patients with impaired renal function. The available data do not suggest correction of the dosing regimen in such patients.

Side effects:

Undesirable effects divided into groups depending on frequency of occurrence: frequent (> 1/100 and <1/10), infrequent (> 1/1000 and <1/100) and rare (> 1/10000 and <1/1000) , are given in the table:

System-Organ Class	Often (from> 1/100 to < 1/10)	Infrequently (from> 1/1000 to <1/100)	Rarely (from> 1/10 000 to <1/1000) **
Infectious and parasitic diseases		Infection of the vagina, unspecified Candidiasis vulvovaginitis	Candidiasis Labial herpes Syndrome presumed histoplasmosis of the eye Shingles Infection urinary tract Bacterial vaginitis Inflammatory diseases of the pelvic organs
Disorders from the metabolism and nutrition		Increased appetite	Fluid retention Hypertriglyceridemia
Disturbances from the nervous system	Headache (including headache "voltage") Pain in the sinus of the nose	Dizziness Migraine with aura Migraine without aura	Violation of attention Paresthesia Vertigo
Disorders from the psyche		Depression / mood reduction Decreased libido Mental disorder Mood swings Affective lability Insomnia	Aggressiveness Anxiety Dysphoria Increased libido Nervousness Anxiety Sleep disturbance Stress
Disturbances on the part of the organ of sight			Intolerance to contact lenses Dry eye mucosa Edema of eyelids
Vascular disorders		Increased blood pressure "Tides"	Bleeding from varicose veins Reduction of arterial pressures Pain along the veins Venous thromboembolism Arterial thromboembolism Phlebitis of superficial veins Thrombophlebitis
Heart Disease			Myocardial infarction Heart palpitations
Disorders from the gastrointestinal tract	Stomach ache Bloating Nausea	Diarrhea Vomiting	Constipation Dyspepsia Gastroesophageal reflux Dry mouth
Disturbances from the liver and bile ducts		An increase in the activity of "hepatic" enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase)	Focal Nodular Hyperplasia of the Liver Chronic cholecystitis
Disturbances from the skin and subcutaneous tissues	Acne	Alopecia Itching, including generalized itching and itching rash Rash, including spotted rash Hyperhidrosis	Allergic skin reaction, including allergic dermatitis and urticaria Chloasma Dermatitis Hirsutism Hypertrichosis Neurodermatitis Pigmentation disorder Seborrhea Lesion of the skin, including a violation of the skin turgor
Disturbances from musculoskeletal and connective tissue		Muscle spasms	Back pain A feeling of heaviness Pain in the jaw
Disorders from the kidneys and urinary tract			Pain in the urinary tract
Violations of the genitals and mammary gland	Absence of menstrual bleeding Discomfort in the mammary glands, pain in the mammary glands, soreness of the nipples, pain in the nipples Painful menstrual bleeding Irregular menstrual-like bleeding (metrorrhagia)	Mammary gland enlargement Diffuse mammary gland thickening Dysplasia of the cervix epithelium Dysfunctional uterine bleeding Dyspareunia Fibrous-cystic mastopathy Abundant menstrual bleeding Cyst in the ovaries Pain in the pelvic region Premenstrual-like syndrome Leiomyoma of the uterus Spasm of uterine muscles Discharge from the vagina Dryness of the vulvar and vaginal mucosa Bloody discharge / bleeding from the vagina, incl. "Spotlight" selection	Benign neoplasm in the mammary gland, including the breast cyst Breast cancer in situ Cervical polyp Bleeding during intercourse Galactorrhea Scanty bloody menstrual-like discharge Delay of menstrual bleeding Ovarian cyst rupture Burning sensation in the vagina Smell from the vagina Vulvovaginal discomfort
Violations from			Lymphadenopathy
the sides of the blood and
lymphatic
systems
Violations from side of the respiratory system, chest and mediastinal organs			Bronchial asthma Dyspnea Nose bleed
Are common	Increase	Irritability	Chest pain
disorders	body weight	Peripheral edema
		Weight loss Fatigability	Malaise Fever
Laboratory and instrumental data		Increase or decrease in blood pressure	Pathological results of the Pap smear

The following undesirable phenomena with very low frequency or delayed development of symptoms that are considered to be associated with the COC group (see also the sections "Contraindications", "Special instructions"):

Tumors

Women who use COC have a slightly increased incidence of breast cancer detection.Since breast cancer is rare in women younger than 40 years, excess of frequency is insignificant in relation to the general risk of occurrence of a cancer of a mammary gland. The causal relationship of the occurrence of breast cancer with the use of COCs is not established.
Liver tumors (benign and malignant)

Other states

Arterial and venous thromboses and thromboembolic complications
Nodular erythema, erythema multiforme
Discharge from the mammary glands
Women with hypertriglyceridemia (increased risk of developing pancreatitis when using COCs)
Increased blood pressure
The onset or deterioration of conditions, in which communication with the use of COCs is not undeniable: jaundice and / or itching associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; chorea; herpes during pregnancy; hearing loss associated with otosclerosis
In women with hereditary angioedema, exogenous estrogens can cause or exacerbate symptoms of angioedema
Dysfunction of the liver
Impairment of glucose tolerance or influence on peripheral insulin resistance
Crohn's disease, ulcerative colitis
Chloasma
Hypersensitivity (including symptoms such as rash, hives)

Interaction

Interactions of other drugs (inducers of enzymes) with oral contraceptives can lead to "breakthrough" bleeding and / or a reduction in the contraceptive effect (see "Interactions with Other Drugs").

Overdose:

No serious violations were reported with an overdose of Clayra®. Based on the combined experience of the use of COC, symptoms that can be noted in an overdose of active tablets: nausea, vomiting, "spotting" spotting or metrorrhagia.

Treatment: symptomatic.

Interaction:

The effect of other drugs on the active components of the Clirare® preparation

The interaction of COC with other drugs can lead to "breakthrough" uterine bleeding and / or lack of contraceptive effect. The following types of interaction have been described in the literature on COCs as a whole or have been studied in the clinical trials of the Clayra® preparation.

Inductors or inhibitors of individual enzymes (isoenzyme CYP3A4)

- Inductors of isoenzymes

There may be interaction with drugs that induce microsomal enzymes (eg, cytochrome P450 systems), resulting in increased clearance of sex hormones (such drugs include phenytoin, barbiturates, primidon, carbamazepine, rifampicin and, possibly, also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as preparations containing St. John's wort pitted). It was reported that the influence on hepatic metabolism can also be caused by HIV protease inhibitors (for example, ritonavir), non-nucleoside reverse transcriptase inhibitors (eg, nevirapine) and their combinations.

When combined with induction products with microsomal liver enzymes in addition to the Claira® preparation, it is recommended that the barrier method of contraception be used temporarily or another method of contraception should be chosen. The barrier method of protection should be used during the entire period of taking concomitant medications and for another 28 days after their withdrawal.

- Effect on intestinal hepatic recirculation

Against the background of taking certain groups of antibiotics (for example, penicillin and tetracycline groups), entero-hepatic recirculation of estrogens may decrease, which can lead to a decrease in the concentration of estradiol. Barrier methods of contraception should be used additionally during the whole cycle of therapy and another 7 days after its termination.

- Inhibitor inhibitors

Simultaneous reception of rifampicin together with tablets containing estradiol valerate and dienogast, led to a significant decrease in the equilibrium concentration and systemic exposure of dienogest and estradiol. Systemic exposure of dienogest and estradiol at equilibrium concentration, measured on the basis of AUC0-24 h, decreased by 83% and 44%, respectively.

Known inhibitors of CYP3A4, such as azole antifungal agents, cimetidine, verapamil, macrolides, diltiazem, antidepressants and grapefruit juice, can increase the concentration of dienogest in the blood plasma. When administered simultaneously with a potent inhibitor of ketoconazole, the AUC0-24 hour value in the equilibrium state in dienogest increased by 186%, and in estradiol - by 57%.In an application with a moderate inhibitor erythromycin value AUC0-24 h at dienogest and estradiol in an equilibrium state, respectively, increased by 62% and 33%.

Effect of Claira® on the metabolism of other drugs

COC may affect the metabolism of other medicines (e.g., lamotrigine), which may lead either to increase or to decrease the concentration of these substances in the blood plasma and tissues. However, based on research data in vitro, inhibition of enzymes CYP When using the drug Claira® in a therapeutic dose is unlikely.

To identify possible interactions, you should read the instructions for concomitant medications.

Incompatibility

Absent.

Special instructions:

If any of the diseases, conditions or risk factors mentioned below are currently available, it is necessary to carefully correlate the potential risks and expected benefits of the drug application Klayra® in each individual case and discuss it with the woman before she decides to start receiving preparation. In case of weighting, strengthening or the first manifestation of any of these conditions or risk factors, a woman should consult her doctor,who can decide whether to cancel the drug.

Diseases of the cardiovascular system

The results of epidemiological studies indicate the existence of a relationship between the use of COCs and an increase in the incidence of venous and arterial thrombosis and thromboembolism (such as DVT, PE, MI, and cerebrovascular disorders).

The risk of developing venous thromboembolism (VTE) is maximal in the first year of taking such drugs, mainly during the first 3 months. The increased risk is present after the initial use of COC or the resumption of the use of the same or different COCs (after a break between doses of 4 weeks or more).

The overall risk of VTE in patients taking low-dose COCs (<50 mcg ethinylestradiol) is 2-3 times higher than in patients who do not take COC, however, this risk remains lower compared with the risk of VTE during pregnancy and childbirth.

VTE can lead to death (in 1-2% of cases).

VTE, manifested as DVT or PE, can occur with any COCs. Very rarely, when using COC, thrombosis occurs in other blood vessels, for example, liver, mesenteric, renal, cerebral arteries and veins or retinal vessels.A common opinion regarding the relationship between the occurrence of these events and the use of COC is absent.

Arterial thromboembolism can be fatal.

In women with a combination of several risk factors or high severity of one of them (for example, complicated heart valve disease, uncontrolled arterial hypertension, extensive surgical interventions with prolonged immobilization, etc.), the possibility of their mutual amplification should be considered. In such cases, the total value of the available risk factors is increased. In this case, the use of Clira® is contraindicated (see the section "Contraindications"),

The risk of developing thrombosis (venous and / or arterial) and thromboembolism increases:

- with age;

- for smokers (with an increase in the number of cigarettes smoked or an increase in the age, the risk increases, especially in women over 35);

in the presence of:

- family history (for example, venous or arterial thromboembolism ever at close relatives or parents at a relatively young age). In case of a hereditary or acquired predisposition, a woman should be examined by an appropriate specialist to decide on the possibility of taking Clyra®;

- obesity (body mass index more than 30 kg / m²);

- dyslipoproteinemia;

- arterial hypertension;

- migraine;

- heart valve diseases;

- atrial fibrillation;

- prolonged immobilization, extensive surgical intervention, any operation on the lower limbs or extensive trauma. In such situations, it is advisable to stop taking Clayra® (at the planned operation, at least 4 weeks before it) and not to resume taking it within 2 weeks after the end of immobilization.

The question of the possible role of varicose veins and superficial thrombophlebitis in the development of VTE remains controversial.

You should consider the increased risk of thromboembolism in the postpartum period. Violations of peripheral circulation can also occur in diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle-cell anemia.

An increase in the frequency and severity of migraine during the use of the Clira® preparation (which may precede cerebrovascular disorders) may be the reason for the immediate discontinuation of this drug.

Biochemical factors that indicate hereditary or acquired predispositions to arterial or venous thrombosis include: resistance to activated protein C, hyperhomocysteinemia, deficiency of antithrombin III, deficiency of protein C, protein deficiency S, antiphospholipid antibodies (anticardiolipid antibodies, lupus anticoagulant).

In assessing the relationship between risk and benefit, it should be borne in mind that treatment of an appropriate condition can reduce the risk of thrombosis associated with it. It should also be taken into account that the risk of thrombosis and thromboembolism in pregnancy is higher than when taking low-dose oral contraceptives (<0.05 ethinyl estradiol).

Tumors

The most significant risk factor associated with the development of cervical cancer is persistent papillomavirus infection (PID). There are reports of a slight increase in the risk of developing cervical cancer with prolonged use of COCs. The connection with the reception of the COC has not been proved. The possibility of interrelation of these data with screening of diseases of the cervix uteri and with the peculiarities of sexual behavior is discussed (more rare application of barrier methodscontraception).

A meta-analysis of 54 epidemiological studies revealed a slight increase in relative risk (OP = 1.24) of the development of breast cancer in women taking COC at the present time. The increased risk gradually disappears within 10 years after discontinuation of these medications. Because breast cancer is rare in women younger than 40 years, a slight increase in the number of diagnosed breast cancers in women who are currently taking COCs or who have recently taken COC is insignificant in relation to the overall risk of this disease. His connection with the use of COC has not been proven. The observed increase in risk may also be a consequence of an earlier diagnosis of breast cancer in women using COCs. Women who have ever used COC have earlier stages of breast cancer than women who have never used it.

In rare cases, with the use of COC, benign, and in very rare cases, malignant liver tumors, which in some cases led to life-threatening intraabdominal hemorrhage, was observed.If there are severe pain in the upper abdomen, increased liver size, or signs of intra-abdominal bleeding in women taking COC, differential diagnosis should exclude liver tumors.

Other states

In women with hypertriglyceridemia (or in the presence of this condition in a family history), an increased risk of developing pancreatitis during COC administration is possible.

Although a small increase in blood pressure has been reported in many women taking COC, clinically significant increases have been rare. However, if a persistent, clinically significant increase in blood pressure develops with the Clayra® drug, it is necessary to cancel the drug and begin treatment of hypertension. The administration of CliraR® can be resumed if necessary, if normal blood pressure can be achieved through antihypertensive therapy.

The following conditions develop or worsen both during pregnancy and when taking COC, but their relationship with the administration of COC is not proven: jaundice and / or cholestatic itching, cholelithiasis, porphyria, systemic lupus erythematosus, haemolytic uremic syndrome, Sydenham's chorea, , due to otosclerosis, hearing loss.

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

Acute or chronic liver dysfunction may require the withdrawal of Clyra® until liver function returns to normal. Recurrent cholestatic jaundice, which develops for the first time during pregnancy or previous reception of sex hormones, requires the discontinuation of the Clira® drug. Although COCs may have an effect on insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in diabetic patients who use Claira®. Nevertheless, women with diabetes mellitus should be closely monitored during the administration of the Clira® drug.

Also, cases of worsening of the course of endogenous depression, epilepsy, Crohn's disease and ulcerative colitis are described along with the use of COCs.

Since estrogens can cause fluid retention, women with cardiac or renal insufficiency need careful monitoring.

Sometimes chloasma can develop, especially in women with a history of chloasma. Women who are prone to develop chloasma, during the period of taking Clyra® should avoid exposure to sun or ultraviolet radiation.

Impact on laboratory tests

The administration of Clira® can influence the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney functions, the concentration of transport proteins in plasma, for example, KCG and lipid / lipoprotein fractions, parameters of carbohydrate metabolism and parameters of clotting and fibrinolysis. These changes usually remain within the limits of laboratory norms.

Medical examinations

Before starting the use of the Clayra® preparation, it is necessary to carefully evaluate the contraindications to the prescription of the drug based on anamnesis of life, family history of the woman, as well as general medical and gynecological examination. The frequency and nature of these surveys should be based on existing standards of medical practice, with the necessary consideration of the individual characteristics of each patient, but not less than once every six months.As a rule, BP is measured, the condition of mammary glands, abdominal cavity and pelvic organs is checked, including cervical cytology. It is necessary to explain to women that the Claira® preparation does not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Decreased efficiency

The effectiveness of the Clayra® preparation can be reduced by skipping tablets with active ingredients (see recommendations in the case of missing tablets in the "Dosage and Administration" section), gastrointestinal disorders during taking tablets with active ingredients (see recommendations for gastrointestinal disorders in the section "Method of administration and dose") or on the background of concomitant drug treatment (see "Interactions with other drugs").

Insufficient control of the menstrual cycle

Against the backdrop of the use of Clyra®, especially in the first months of admission, irregular menstrual bleeding ("spotting" or "breakthrough" uterine bleeding) may occur. Therefore, any irregular menstrual bleeding should be evaluated only after a period of adaptation, which is approximately 3 menstrual cycle-like.

If irregular menstrual bleeding repeats or first occurs after previous regular cycles, you should consider the probability of non-hormonal causes and conduct a thorough examination to exclude malignant neoplasms or pregnancy. Such activities may include diagnostic scraping.

In some women, while receiving inactive white tablets, menstrual bleeding may not develop. If the Clira® drug was administered in accordance with the rules listed in the "Application and dose" section, pregnancy is unlikely. However, if the tablets were taken irregularly before the first menstrual-like bleeding, or there are no contractions of menstrual bleeding, do not continue using Claira® until pregnancy is excluded.

Effect on the ability to drive transp. cf. and fur:

There was no adverse effect on the ability to drive and work with the vehicle, but the patients,which during the period of adaptation (the first 3 months of taking the drug) are marked by episodes of dizziness and impaired concentration, must be careful.

Form release / dosage:Film-coated tablets.

Packaging:

Film-coated tablets.

2 dark yellow tablets, 5 pink tablets, 17 pale yellow tablets, 2 red tablets and 2 white tablets (total of 28 tablets) in one blister of PVC / aluminum foil.

1 blister is pasted into a cardboard cot. 1 or 3 clamshells together with a self-adhesive appointment calendar and instructions for use are sealed in a transparent film.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

4 years. Do not use after the expiration date!

Terms of leave from pharmacies:On prescription

Registration number:LP-000010

Date of registration:21.10.2010

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

Manufacturer: & nbsp

BAYER PHARMA, AG Germany

Representation: & nbspBAYER, AOBAYER, AO

Information update date: & nbsp15.02.16

Illustrated instructions

Instructions

Clayra® (Qlaira®)