Expiration date: 02/2025

Structure and Composition:

Tablets, film-coated in different colors 1 blister

Tablets, film-coated dark yellow. 1 tablet contains active ingredient:

estradiol valerate, micro 20 mg

Excipients: lactose monohydrate, corn starch, corn starch, pregelatinized povidone 25 Magnesium stearate

shell: hypromellose macrogol 6000 talc titanium dioxide, iron oxide yellow dye

Tablets, film-coated pink. 1 tablet contains active ingredients:

estradiol valerate, micro 20 mg

dienogest, micro 2mg

Excipients: lactose monohydrate, corn starch, corn starch, pregelatinized povidone 25 Magnesium stearate

shell: hypromellose macrogol 6000 talc titanium dioxide, iron oxide red dye

Tablets, film-coated pale yellow. 1 tablet contains active ingredients:

estradiol valerate, micro 20 mg

dienogest, micro 3mg

Excipients: lactose monohydrate, starch, corn starch, povidone, magnesium stearate 25

shell: hypromellose macrogol 6000 talc titanium dioxide, iron oxide yellow dye

Tablets, film-coated red. 1 tablet contains active ingredients:

estradiol valerate, micro 20 mg

Excipients: lactose monohydrate, corn starch, corn starch, pregelatinized povidone 25 Magnesium stearate

shell: hypromellose macrogol 6000 talc titanium dioxide, iron oxide red dye

Tablets, film-coated white (placebo), 1 tablet contains:

lactose monohydrate, corn starch, povidone 25, magnesium stearate

shell: hypromellose talc, titanium dioxide

Table 28 in the blister. (2 dark yellow, pink 5, 17, pale yellow, 2 red, 2 white) in the cover of the carton 1 blister glued into the book-cot in a cardboard transparencies 1 or 3-up storybook, complete with admission calendar.

Description pharmaceutical form:

Dark yellow tablets: Round, biconvex, film-coated dark yellow, engraved with «DD» in a regular hexagon on one side. View tablet in cross section: core from white to almost white, jacket - dark yellow.

Pink tablets: Round, biconvex, film-coated pink, engraved with «DJ» in a regular hexagon on one side. View tablet in cross section: core from white to almost white, shell - pink.

Pale yellow tablets: Round, biconvex, film-coated pale yellow, engraved with «DH» in a regular hexagon on one side. View tablet in cross section: core from white to almost white, shell - pale yellow.

Red tablets: Round, biconvex, film-coated red, engraved with «DN» in a regular hexagon on one side. View tablet in cross section: core from white to almost white, shell - red.

White tablet (placebo): round, biconvex, film-coated white, engraved with «DT» in a regular hexagon on one side. View tablet in cross section: core from white to almost white, shell - white.

Pharmacokinetics:

dienogest

Absorption. After oral administration of dienogest is rapidly and almost completely absorbed. Cmax serum component of 90.5 ng / ml, is reached in approximately 1 hour after oral Klayry tablets containing 2 mg estradiol valerate + 3 mg of dienogest. The bioavailability is about 91%. Pharmacokinetics of dienogest in a dosage range from 1 mg to 8 characterized by a dose-dependent.

Simultaneous food intake has no clinically significant effect on the rate and extent of absorption of dienogest.

Distribution. The relatively large (10%) portion of the circulating dienogest is in the unbound form, while about 90% of non-specifically associated with albumin. Dienogest does not bind to globulin, sex hormone binding (SHBG), and kortikosteroidsvyazyvayuschim globulin (CBG). For this reason, there is no possibility of testosterone replacement from its association with SHBG and cortisol from its connection with the DRG. Any influence on the physiological processes of transport of endogenous steroids is therefore unlikely. Vd dienogest at an equilibrium concentration of 46 L after intravenous administration of 85 mg dienogest tritiated.

Metabolism. Dienogest almost completely metabolized, according to known ways steroid metabolism (hydroxylation, conjugation), to form predominantly hormonally inactive metabolites. Metabolites are excreted very quickly so that the predominant fraction in plasma is unchanged dienogest.

Total clearance after intravenous administration of tritiated dienogest - 5.1 l / h.

Elimination. T1 / 2 dienogest from plasma is approximately 11 hours after oral dose of 0.1 mg / kg dienogest displayed as metabolites that are output via the kidneys and intestines in a ratio of about 3:. 1. After 42% of the oral dose was excreted within the first 24 hours, and 63% - within 6 days by renal excretion. After 6 days, the kidneys and through the intestines collectively displays 86% of the dose.

The equilibrium concentration. The pharmacokinetics of dienogest are not dependent on the concentration of SHBG. CSS is reached after 3 days receive the same dose of 3 mg dienogest in combination with 2 mg Estradiol valerate. Cmin, Cmax and average concentration of serum dienogest at steady state is 11.8 to 82.9 and 33.7 ng / ml. The average coefficient of cumulation on AUC0-24 hr - 1.24.

estradiol valerate

Absorption. After oral administration estradiol valerate is rapidly and completely absorbed. Cleavage to estradiol and valeric acid takes place during absorption from the gastrointestinal tract mucosa, or during the first passage through the liver, resulting in formation of estradiol and its metabolites - estrone and estriol. Cmax serum estradiol equal to 70.6 pg / ml, is reached between 1,5 and 12 h after a single oral tablet containing 3 mg of estradiol valerate in 1-day course. Simultaneous food intake has no clinically significant effect on the rate and extent of absorption of estradiol valerate.

Metabolism. Valerian acid is very rapidly metabolized. After oral administration of approximately 3% of the dose are directly in the form of bioavailable estradiol. Estradiol undergoes extensive first pass effect through the liver, and a significant portion of the administered dose is metabolized in the gastrointestinal mucosa. In conjunction with the first-pass metabolism in the liver, about 95% of an oral dose is metabolized before entering the systemic circulation. The major metabolites are estrone, estrone sulfate, estrone glucuronide.

Distribution. In 38% serum estradiol is associated with SHBG, 60% - albumin, and 3.2% is circulated in the unbound form. Estradiol can slightly increase the concentration in the serum SHBG This effect is dose-dependent. On the 21 th day of the cycle receiving the concentration of SHBG was approximately 148% of the original, and by day 28 (end phase of receiving the inactive tablets) decreased to about 141% of the original. Apparent Vd after intravenous - 1.2 l / kg.

Elimination. Because of the large pool of circulating estrogen sulfates and glucuronides and enterohepatic recycling, T1 / 2 of estradiol in the terminal phase after oral administration is a complex parameter, which depends on all these processes and is in the range of about 13-20 hours.

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

The equilibrium concentration. On impact the pharmacokinetics of estradiol concentration of SHBG. In women, the measured estradiol concentration in blood plasma is a collection of endogenous estradiol and estradiol, when receiving incoming Qlaira drug. During the reception phase tablets containing 2 mg estradiol valerate + 3 mg of dienogest, and the average Cmax serum concentration of estradiol in an equilibrium state are respectively 66.0 and 51.6 pg / ml. Throughout the 28-day cycle were maintained stable Cmin estradiol in the range of 28.7 to 64.7 pg / ml.

Description of the pharmacological actions:

The contraceptive effect of the combined oral contraceptives (COCs) based on the interaction of various factors, most important of which are inhibition of ovulation and changes in the properties of cervical mucus. Along with the prevention of unwanted pregnancy, COCs have several positive properties which, taking into account also the negative properties (see. "Special Instructions", "Side effects") can help in choosing the most suitable method of contraception. Women using COCs, decreases pain and bleeding intensity menstrualnopodobnoe, thereby reducing the risk of iron deficiency anemia. Furthermore, there is evidence of reducing the risk of endometrial cancer and ovarian cancer.

Estrogen preparation Qlaira is estradiol valerate, the predecessor of the natural 17 &, beta-estradiol person (1 mg estradiol valerate 0.76 mg corresponds to 17 &, beta-estradiol). Estrogenic component used in this CCO thus differs from conventionally used in COCs estrogens are synthetic estrogens that - ethinyl estradiol or mestranol precursor, both contain a methyl group at position 17 &, alpha. This group causes a high metabolic stability, but also a more pronounced effect on the liver.

Admission Qlaira preparation leads to a less pronounced effect on the liver compared to the three-phase COCs containing ethinyl estradiol and levonorgestrel. It was shown that the effect of the concentration of SHBG and hemostatic parameters is less pronounced. The combination of estradiol valerate with dienogest exhibits increase HDL while LDL cholesterol concentration decreases slightly.

Progestin dienogest is acting upon oral administration, which is characterized by the additional partial antiandrogenic effects. Its estrogenic, anti-estrogenic and androgenic properties are insignificant. Due to the special chemical structure of pharmacological action spectrum is provided, which combines the most important advantages of 19-nor-progesterone derivatives and progestogens.

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

When used properly, Pearl Index (an indicator of the rate of pregnancy in 100 women during the year contraceptive use) is less than 1. When skipping pills or incorrect use Pearl Index may increase.

Testimony:

Oral contraception.

Contraindications:

Qlaira The drug should not be applied if any of the conditions listed below. The drug should be immediately withdrawn if any of these conditions develop for the first time against the backdrop of his reception:

• Hypersensitivity to the active substances or any of the excipients
  
• thrombosis (venous and arterial) and thromboembolism present or in history (including deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), stroke now or in history)
  
• state prior thrombosis (including transient ischemic attack, angina) currently or history
  
• availability expressed or multiple risk factors for venous or arterial thrombosis (including major surgery with prolonged immobilization, complicated valvular heart disease, uncontrolled hypertension - see "Special Instructions".)
  
• Migraine with focal neurological symptoms, including history
  
• diabetes with vascular complications
  
• pancreatitis with severe hypertriglyceridemia now or in history
  
• hepatic failure and severe liver disease (up to normalization of liver function)
  
• liver tumors (benign or malignant) currently or history
  
• hormone-dependent cancers identified (including genital or mammary glands) or are suspected
  
• krovechenie of vagina of unknown origin
  
• pregnancy or suspected it.
  

The use with caution

If any of the diseases / conditions / risk factors mentioned below are currently available, you should carefully correlate the potential risks and expected benefits of the drug Qlaira application in each individual case:

• thrombosis and thromboembolism risk factors (smoking dislipoproteinemia obesity hypertension migraine valvular heart disease irregular heartbeat prolonged immobilization extensive surgical interventions extensive trauma)
  
• Other diseases in which may occur peripheral circulatory disorders (diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, Crohn's disease and ulcerative colitis, sickle cell anemia)
  
• hereditary angioedema
  
• hypertriglyceridemia
  
• the disease first appeared or worsen during pregnancy, or on the background of the previous use of sex hormones (eg cholestatic jaundice, cholestatic pruritus, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes gestationis, Sydenham's chorea)
  
• postpartum period.
  

Application of pregnancy and breastfeeding:

Admission Qlaira drug is contraindicated during pregnancy. If the pregnancy during treatment with the drug Qlaira, further intake must be stopped. However, large-scale epidemiological studies have found no increased risk of birth defects in children born to women who used COCs prior to pregnancy, as well as teratogenic effects of COCs during their casual reception at the beginning of pregnancy.

COCs may interfere with lactation, because they can reduce the amount of breast milk is produced, and also to change its composition. Consequently, the COC is not usually recommended for use before the end of the lactation period. Small amounts of contraceptive hormones and / or their metabolites may be excreted in breast milk.

Side effect:

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Drug Interactions:

The influence of other drugs on the active components of the drug Qlaira

COC Interactions with other drugs may lead to breakthrough uterine bleeding and / or lack of effectiveness. The following types of interactions have been described in the literature for COCs in general or were studied in the clinical trials of the drug Qlaira:

Inducers or inhibitors of specific enzymes (isoenzyme SYP3A4)

Inductors isoenzymes. May have an interaction with drugs that induce microsomal enzymes (such as cytochrome P450), whereby the clearance of hormones can be increased (to such drugs include phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate , ritonavir, griseofulvin, and preparations containing St. John's wort). It has been reported that the effect on hepatic metabolism may also provide HIV protease inhibitors (such as Ritonavir), non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine) and combinations thereof.

The effect on the enterohepatic circulation. While taking some groups of antibiotics (e.g. penicillin and tetracycline groups) may decrease estrogen enterohepatic circulation, which can lead to a decrease in estradiol concentration.

Women who receive treatment with drugs that induce microsomal enzymes, or antibiotics, in addition to the drug Qlaira recommended to temporarily use a barrier method of contraception or choose another method of contraception. Barrier protection method to be used during the reception period and concomitant medications for an additional 28 days after their withdrawal.

Inhibitors isoenzymes. Simultaneous administration of rifampicin with pills containing estradiol valerate and dienogest, led to a significant reduction in CSS and systemic exposure of dienogest and estradiol. Systemic exposure of dienogest and estradiol at the equilibrium concentration, as measured by AUC0-24 h, declined respectively by 83%

Known inhibitors of CYP3A4, such as azole antifungal agents, cimetidine, verapamil, macrolides, diltiazem, antidepressants and grapefruit juice may increase the concentration in plasma dienogest. At the same time taking a potent inhibitor ketoconazole value of AUC0-24 h at steady state dienogest have increased by 186%, and estradiol - by 57%. In an application with a moderate inhibitor erythromycin value of AUC0-24 h in dienogest and estradiol at steady state increased respectively by 62 and 33%.

Qlaira drug effects in relation to other medicines: COCs may affect the metabolism of other drugs (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 data from studies in vitro, inhibition of CYP enzymes Qlaira when using a therapeutic dose of the drug is unlikely.

Note: should refer to the instructions accompanying drugs for possible interactions.

Incompatibility. Absent.

Dosage and administration:

Inside, regardless of meals.

Tablets should be indicated on the packaging in order each day at approximately the same time, if necessary with water or other liquid. Reception of tablets is carried out continuously. It should take one tablet a day successively for 28 days. Each new package is started after reception of the last tablet preceding calendar packaging. Menstrualnopodobnoe bleeding usually starts during the reception of the last calendar packaging of tablets and may not yet be completed before the start of the next calendar packaging. Some women menstrualnopodobnoe bleeding begins after receiving the first of the new tablets calendar packaging.

If hormonal contraception has not been used previously (in the previous month)

Tablets are starting to take a 1-day woman's natural menstrual cycle (ie the 1st day of menstrual bleeding).

Switching from another combined hormonal contraceptive (COC another, vaginal ring or transdermal patch)

Women should start taking the drug Qlaira the next day after was drunk last active tablet (tablet containing the active substances) of the previous COC package. If you use a vaginal ring or transdermal patch, women should start taking the drug Qlaira the day of their removal.

If you previously used progestogen only contraceptive method (minipill, injection, implant) or intrauterine system with the release of progestogen (IUD)

A woman can go to the drug Qlaira mini-pill any day (from an implant or an IUD - the day of their removal from the injection method - the day on which scheduled the next injection), but in all cases within the first 9 days of tablet recommended additionally use a barrier method of contraception.

After the abortion I trimester of pregnancy

The woman may start taking the tablets immediately. In this case there is no need for additional measures of contraception.

After delivery or abortion in the II trimester of pregnancy

About breastfeeding women see. Section "Pregnancy and breast-feeding."

Woman should be advised to start reception of tablets on 21-28 days after delivery or abortion in the II trimester of pregnancy. If a woman has started taking pills later, then it is recommended to additionally use a barrier method of contraception during the first 9 days of tablet-taking. However, if intercourse has already taken place before the actual start of the drug Qlaira pregnancy should be excluded or the woman should wait for the onset of menarche.

Admission missed pills. Missed (white) inactive tablets can be disregarded. However, they should be discarded to avoid unintentionally prolonging the interval between taking active pills.

The following tips are specific to missing active tablets

If any delay in reception of the tablets is less than 12 hours, contraceptive protection is not reduced. A woman should drink a missed tablet as soon as you remember it and take the remaining tablets at the usual time.

If the delay in receiving any of the pills is more than 12 hours, contraceptive protection may be reduced. The woman should take the last missed tablet as soon as you remember about it, even if it would mean that she would have to drink 2 table. simultaneously. Then, you must continue to take the tablets at the usual time.

Depending on the day menstrualnopodobnoe cycle, in which the tablet has been missed (see chart 2). Is required to use additional contraceptive measures (eg barrier methods, particularly condoms) in accordance with the following principles:

Are allowed to take no more than 2 tablets. one day.

If the woman has forgotten to start a new calendar package or missed one or more tablets from the 3rd to the 9th day of the calendar packaging, she may already be pregnant (in the event that she had sexual contact for 7 days before skipping pills). The more tablets (particularly with the combination of two active ingredients on days 3 to 24 minutes) is omitted and the closer they are to the receiving inactive phase tablet, the higher the chance of pregnancy.

If a woman misses pills, and then at the end of the calendar packaging / at the beginning of a new calendar packaging menstrualnopodobnoe bleeding she was missing, you should consider the likelihood of pregnancy.

Recommendations in the gastro-intestinal disorders

In severe gastrointestinal disorders, absorption may not be complete, therefore it is necessary to take additional contraceptive measures (eg barrier methods, particularly condoms).

If within 3-4 hours after taking active pill vomiting occurs, in this case, there are recommendations concerning missed tablets, which are listed in the "Admission of missed tablets" section. If a woman does not want to change their usual scheme of taking the pills, she should drink an extra tablet (or tablets) from a new package.

Additional information for certain groups of patients

Elderly patients. Not applicable. The drug is not shown Qlaira after menopause.

Patients with impaired hepatic function. The drug Qlaira contraindicated in women with severe liver disease as long as liver function tests have not come back to normal (see. Also "Contraindications").

Patients with impaired renal function. The drug Qlaira not been specifically studied in patients with impaired renal function. Available data do not suggest the correction of dosing regimen in these patients.

Use in children and adolescents. The drug Qlaira shown only after menarche.

Overdose:

Symptoms of serious violations of an overdose of the drug Qlaira were reported. Based on the cumulative experience of the COC - symptoms that may elev