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Yaryna (Drospirenone/Ethinyl Estradiol) 21 coated tablets




The instruction for medical use

of Yarinaâ medicine

the Trade name

of Yarin â Mezhdunarodnoye the unlicensed name
Is not present

the Dosage form
of the Tablet, film coated

One tablet contains
active agents: drospirenon 3 mg, ethinylestradiol of 0.03 mg,
kernel: lactoses monohydrate, starch corn, the starch modified, K 25 povidone, magnesium stearate,
a cover:
hydroksipropilmetiltsellyuloza, macrogoal 6000, talc, titan E171 dioxide, gland (ІІІ) oxide yellow E172.

The description
of the Tablet, film coated light yellow color, round shape, with a biconvex surface, with an engraving of DO in the correct hexagon on one party.

Pharmacotherapeutic group
Sex hormones and modulators of a reproductive system. Hormonal contraceptives for system use. Progestogens and estrogen (the fixed combinations). Drospirenon and esrogena
the ATX G03AA12 Code

the Pharmacological

Pharmacokinetics Drospirenon properties Absorption At oral administration drospirenon quickly and almost is completely absorbed. After single dose inside the maximum concentration of a drospirenon in serum, equal 37 ng/ml, are reached in 1-2 hours. The bioavailability fluctuates from 76 to 85%. Meal does not affect bioavailability of a drospirenon.
Drospirenon contacts seralbumin and the corticosteroid-the connecting globulin (CCG) does not contact the globulin, connecting sex hormones (G,CSH), or. Only 3-5% of the general serumal level of hormone are in a free form, 95-97% are specifically connected with GSPS.
The increase in the GSPG level induced by ethinylestradiol does not influence binding of a drospirenon proteins of blood plasma. The average seeming volume of distribution is about 3.7-4.2 l/kg.
after oral administration drospirenon is completely metabolized.
The majority of metabolites in blood plasma are provided by acid forms of a drospirenon, derivatives with an open lactonic ring, and 4.5-dihydro-drosperinon-3-sulfate which are formed without involvement of P450 system.
According to the researches in vitro drospirenon in small quantity it is metabolized with participation of P450 3A4 cytochrome.
Clearance speed is about 1.2-1.5 ml/min. of serum.
the Maintenance of a drospirenon in blood serum is exposed to two-phase decrease. Elimination half-life in a terminal phase makes about 31 hours. Drospirenon in not changed form is not removed, brought in the form of metabolites with elimination half-life of metabolites about 1.7 days with bile and urine in the ratio about 1,2:1,4.
Equilibrium concentration
does not influence the GSPG level in blood serum pharmacokinetics of a drospirenon. As a result of daily administration of drug the level of content of substances in serum increases approximately by two-four times, an equilibrium concentration is reached in the second half of a course.
Absorption. After intake, ethinylestradiol is soaked up quickly and completely. The maximum concentration in blood plasma, equal about 54-100 pg/ml, is reached in 1-2 hours. During absorption and the first passage through a liver ethinylestradiol is extensively metabolized therefore its bioavailability at intake averages about 45%, and significant individual differences within 20-65% are noted.
Ethinylestradiol almost completely (98%) communicates albumine. Ethinylestradiol induces synthesis of GSPS. The seeming volume of distribution of ethinylestradiol is equal to 2.8 – 8.6 l/kg.
Ethinylestradiol is exposed to a presistemny konjgirovaniye in mucous a small intestine and in a liver, is initially metabolized by aromatic hydroxylation, at the same time various hydroxylated and metilirovanny metabolites provided both in the form of free metabolites, and in the form of conjugates with glucuronic and sulfuric acids are formed. Speed of metabolic clearance of ethinylestradiol is about 2.3 – 7.0 ml/min.
ethinylestradiol Content in blood serum is exposed to two-phase decrease, the first phase is characterized elimination half-life about 1 hour, the second – 10-20 hours. In not changed view from an organism it is not removed. Metabolites of ethinylestradiol are removed by kidneys and a liver in the ratio 4:6, with elimination half-life about 24 hours.
Equilibrium concentration
Equilibrium concentration is reached approximately in the second half of a cycle of treatment.
A pharmacodynamics
of Yarinaâ – the low-dosed monophase oral contraceptive with antimineralokortikoidny and anti-androgenic action.
The contraceptive effect of Yarinyâ is based on interaction of various factors, the most important of which are braking of an ovulation and change of viscosity of cervical slime. Besides contraceptive action, the combined oral contraceptives make positive impact which should be considered when choosing a control method of birth rate. The cycle becomes more regular, painful periods are less often observed, the intensity of bleeding decreases therefore the risk of an iron deficiency anemia decreases.
Drospirenon who is contained in Yarineâ has antimineralokortikoidny activity that can prevent the increase in body weight and other symptoms connected with a liquid delay prevents the sodium delay caused by estrogen provides very good tolerance and makes positive impact at a premenstrual syndrome. In a combination with ethinylestradiol, drospirenon improves a lipidic profile and increases the level of lipoproteids of the high density (LPVP). Drospirenon has anti-androgenic activity that leads to reduction of manifestations of an acne and decrease in products of sebaceous glands.
Drospirenon does not counteract the increase in level of the globulin, connecting sex hormones (G,CSH) induced by ethinylestradiol that is useful to binding and an inactivation of endogenous androgens.
Drospirenon is deprived of any androgenic, estrogenic, glucocorticoid and anti-glucocorticoid activity. It, in combination with antimineralokortikoidny and anti-androgenic action, provides to a drospirenon the biochemical and pharmacological effect similar to natural hormone to progesterone. There is development of endometrial cancer and ovaries which are also given about risk reduction. High-dosage oral contraceptives (0.05 mg of ethinylestradiol) reduce the frequency of development of cysts of ovaries, inflammatory diseases of a small pelvis, benign diseases of a mammary gland and an extrauterine pregnancy. As far as these data belong to the low-dosed contraceptives, demands further study.

– oral contraception
– purpose of the combined contraceptive with antimineralokortikoid-ny and anti-androgenic properties (Yarinyâ) also can be useful for women with a hormonedependent delay of liquid and at the symptoms caused by it at women and also to women with acne rash (acne) and seborrhea.

A route of administration and doses
the Combined oral contraceptives including Yarinaâ, differ in high contraceptive reliability. The rate of failure of a method is no more than 1% a year. Contraceptive reliability can decrease at the admission of tablets or their wrong reception.
A pill should be taken inside on the order specified on packing, every day approximately at the same time with a small amount of water. Accept on one tablet a day continuously within 21 days. Reception of each following packing begins after a 7-day break during which menstrualnopodobny bleeding is observed. It usually begins for 2-3 day from reception of the last tablet and can not end prior to reception of new packing.
How to begin reception of Yarinyâ
– in the absence of reception of any hormonal contraceptives last month
the Reception of Yarinyâ begins in the first day of a menstrual cycle (i.e. in the first day of menstrual bleeding). The beginning of reception for 2-5 day of a menstrual cycle is allowed, but in this case it is recommended to use in addition a barrier method of contraception during the first 7 days of reception of tablets from the first packing.
– upon transition from the combined hormonal contraceptives (the combined oral contraceptive, a vaginal ring, a transdermalny plaster)
it is preferable to begin reception of Yarinyâ next day after reception of the last gormonsoderzhashchy tablet from the previous packing, but by no means no later than the next day after a usual 7-day break in reception (for the drugs containing 21 tablets) or after reception of the last tablet which is not containing hormone (for the drugs containing 28 tablets in packing). Upon transition from a vaginal ring or a transdermalny plaster it is preferable to begin reception of Yarinyâ in day of removal of a ring or plaster, but by no means no later than that day when the following ring or a plaster had to be applied.
– upon transition from the contraceptives containing only gestagena (mini-drank, injection forms, an implant)
It is possible to pass with mini-saw on Yarinuâ in any day (without interruption), from an implant – in day of its removal, from an injection form – from day when the following injection would have to be made. In all cases it is necessary to use in addition barrier method of contraception during the first 7 days of reception of tablets.
– after abortion in the first trimester of pregnancy
It is possible to begin reception immediately, at observance of this condition there is no need for additional contraceptive protection.
– after the delivery or abortion in the second trimester of pregnancy
It is recommended to begin administration of drug for 21-28 day after the delivery or abortion in the second trimester of pregnancy. If reception is begun later, it is necessary to use in addition barrier method of contraception during the first 7 days of reception of tablets. However if the woman already led sex life, prior to reception of Yarinyâ the pregnancy has to be excluded or it is necessary to wait for the first periods.
Reception of the passed tablets
If delay in reception of a tablet made less than 12 hours, contraceptive protection does not decrease, it is necessary to take a pill as soon as possible, following is accepted in usual time.
If delay in reception of tablets made more than 12 hours, contraceptive protection can be reduced. At the same time it is possible to be guided by the following two basic rules:
· Administration of drug never has to be interrupted, more than for 7 days.
· 7 days of continuous reception of tablets are required for achievement of adequate suppression gipotalamo – a hypophysial and ovarian system.
Respectively the following advice can be given if delay in reception of tablets made more than 12 hours (an interval from the moment of reception of the last tablet more than 36 hours):
The first week of administration of drug
the Woman has to take the last passed pill as soon as possible as soon as she remembers (even if it means reception of two tablets at the same time). The following pill is taken in usual time. The barrier method of contraception (for example, condom) during the next 7 days has to be in addition used. If the sexual contact took place within a week before the admission of tablets, it is necessary to consider pregnancy approach probability.
In process of increase in quantity of the passed tablets and approach of the period of a regular break in reception, pregnancy approach probability increases.
· The second week of administration of drug
the Woman has to take the last passed pill as soon as possible as soon as she remembers (even if it means reception of two tablets at the same time). The following pill is taken in usual time.
If the woman took a pill correctly within 7 days preceding the first admission of tablets there is no need for use of additional contraceptive measures. Otherwise and also at the admission of two and more tablets it is necessary to use in addition barrier methods of contraception (for example, condom) within 7 days.
· The third week of administration of drug
the Risk of decrease in reliability is inevitable because of the forthcoming break in reception of tablets.
The woman has to adhere strictly to one of two following options.
1. It is necessary to take the last passed pill as soon as possible (even if it means, reception of two tablets at the same time). The following pill is taken in usual time, tablets from the current packing will not end yet. The following packing should be begun at once. Bleeding of cancellation is improbable, the second packing will not end yet, but the smearing discharges and breakthrough bleedings can be noted during reception of tablets.
2. It is also possible to interrupt reception of tablets from the current packing. Then it has to take a break for 7 days, including day of the admission of tablets and then begin reception of new packing.
There is no need for use of additional contraceptive measures if in the last 7 days to the admission of tablets the administration of drug was correct.
If the woman missed reception of tablets, and then during a 7-day break in reception of tablets the menstrualnopodobny bleeding was not observed, it is necessary to exclude pregnancy existence.
Councils in case of gastrointestinal disorders
In heavy gastrointestinal disorders the absorption of drug can be incomplete. In this case it is necessary to take additional measures of contraception. If at the woman within 3-4 hours after reception of the tablets Yarinyâ the vomiting was observed that can be equivalent to the admission of reception of tablets it is necessary to be guided by the councils concerning the admission of tablets. If the woman does not want to change the normal mode of administration of drug, she has to take if necessary an additional pill (or several tablets from other packing).
Change of day of the beginning of a menstrual cycle
For a delay of day of the beginning of periods, it is necessary to continue reception of a tablet from new packing of Yarinyâ right after all pill from previous, without interruption in reception is taken. A pill from this new packing can be taken as long as the woman wishes (it is possible until packing does not end). Against the background of administration of drug from the second packing at the woman the smearing discharges or breakthrough uterine bleedings can be noted. It is necessary to resume reception of Yarinyâ from new packing after a usual 7-day break.
For postponement of day of the beginning of periods the next day of week, it is necessary to truncate the next break in reception of tablets for so many days on how many it is necessary to move the beginning of periods. The interval is shorter, the risk of lack of developing of bleeding of cancellation is higher and, further, than emergence of the smearing bloody discharges and breakthrough bleedings during reception of the second packing (just as in case the woman wishes to delay the beginning of periods).

Side effects
often (³1/100, & lt, 1/10):
– emotional lability, a depression, decrease in mood
– nausea
– migraine
– decrease or loss of a libido
– mammary gland pain, irregular uterine bleedings, bleedings from a genital tract of not specified character
Seldom (³1/10,000, & lt, 1/1000):
– venous or arterial thromboembolic processes (with a frequency, as well as at other oral contraceptives, including occlusion of peripheral deep veins, fibrinferments and embolism/occlusion of vessels of lungs, a myocardial infarction, a cerebral stroke of not hemorrhagic character).
With an unknown frequency (are revealed in the course of post-marketing observations)
– the multiformny erythema
For designation of specific side reaction or its synonym or the accompanying state is given the most suitable term from MedDRA – the Medical dictionary for regulatory activity (version 12.1).
The description of separate side reactions
Side reactions with very low frequency or with the delayed beginning of emergence of symptoms which are considered as the groups of the combined oral contraceptives which are perhaps interconnected with drugs are listed below:
– the frequency of the diagnosis of a breast cancer is slightly increased among the women accepting oral contraceptives. As the breast cancer is noted seldom at women 40 years are younger, increase in number of diagnoses is insignificant in relation to the general risk of developing this disease, its communication with reception of the combined oral contraceptives is not proved.
– liver tumors (benign and malignant)
Other states
– a knotty erythema
– women with a gipertriglitseridemiya have the increased risk of developing of pancreatitis when using of the combined oral contraceptives
– arterial hypertension
– emergence or deterioration in states for which the interrelation with reception of the combined oral contraceptives is not proved: jaundice and/or an itching connected with a cholestasia, forming of stones in a gall bladder, a porphyria, a system lupus erythematosus, a hemolytic uraemic syndrome, Sydenham’s chorea, herpes of pregnant women, a hearing loss connected with an otosclerosis
– at women with a hereditary Quincke’s disease exogenous estrogen can provoke or aggravate symptoms of this disease
– an abnormal liver function
– change of tolerance to glucose or effects of peripheral insulin resistance
– Crohn’s disease and nonspecific ulcer colitis
– a hloazma
– reactions of hypersensitivity (including such symptoms as rash and urticaria)

the Combined oral contraceptives should not be applied 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.
– hypersensitivity to any of drug components
– a fibrinferment/thrombembolia (venous and arterial) now or in the anamnesis (for example, a deep vein thrombosis, a pulmonary embolism, a myocardial infarction) or cerebrovascular disturbances
– the states preceding thrombosis (for example, the tranzitorny ischemic attacks, stenocardia) now or in the anamnesis
– high risk of developing venous or arterial thrombosis
– migraine with focal neurologic symptoms in the anamnesis
– diabetes with vascular complications
– a serious illness of a liver (before normalization of hepatic tests)
– a heavy renal failure or an acute renal failure
– liver tumors (benign or malignant) now or in the anamnesis
– the revealed hormonedependent malignant diseases (for example, genitals or mammary glands) or suspicion on them
– vaginal bleeding of not clear genesis
– pregnancy or suspicion on it

Medicinal interactions
Effects of other drugs on Yarina â
Vozmozhno interaction with the medicines inducing liver enzymes that can promote to increase of clearance of sex hormones and a message to breakthrough bleedings and/or decrease in contraceptive efficiency of drug.
During intake of such drugs, the woman should use in addition a barrier method of contraception in addition to Yarineâ or to choose other method of contraception. At the same time the barrier method of contraception should be used during the period of the accompanying administration of drugs and within 28 days after their cancellation.
If the period of use of a barrier method of protection comes to an end later, than tablets in packing, it is necessary to pass to the following packing of Yarinyâ without usual break in reception of tablets.
The substances increasing clearance of sex hormones (reducing efficiency of the combined hormonal contraceptives owing to induction of enzymes of a liver), for example:
Phenytoinum, barbiturates, Primidonum, carbamazepine and rifampicin, are also the assumptions concerning an okskarbazepin, the topiramat, the felbamat, griseofulvin and the drugs containing a St. John’s wort.
Substances with various effects on clearance of the combined oral contraceptives
At the combined use with the combined oral contraceptives many VICh/HCV protease inhibitors and nenukleozidny inhibitors of reverse transcriptase can raise or reduce concentration of estrogen or progestins in blood plasma. The specified changes in certain cases can have relevant value.
The substances reducing clearance of the combined oral contraceptives (inhibitors of enzymes)
Strong and moderate CYP3A4 inhibitors, such as antifungal drugs (for example, itrakonazol, vorikonazol, flukonazol), verapamil, macroleads (for example, klaritromitsin, erythromycin), diltiazem and grapefruit juice can increase concentration of estrogen or progestin, or both substances, in blood plasma.
The Etorikoksib in a dose from 60 to 120 mg/day increases concentration of ethinylestradiol in plasma by 1.4-1.6 times at a concomitant use with the combined hormonal contraceptives containing 0.035 mg of ethinylestradiol.
Influence of the combined oral contraceptives on other drugs
the Combined oral contraceptives can influence metabolism of some other drugs that leads to increase (for example, cyclosporine) or to reduction (for example, a lamotridzhina) their concentration in blood plasma and fabrics.
Proceeding from results of researches of interactions of in Vivo among the voluntary participants using omeprazolum as marker substrates simvastatin or midazolam, clinically significant influence of the drospirenon in a dose of 3 mg on metabolism of other drugs mediated by the system of P450 cytochrome it is improbable.
In clinical trials the purpose of the hormonal contraceptives containing ethinylestradiol did not lead to any increase or at least to weak increase in concentration of CYP3A4 substrate (for example, midazolam) in blood plasma while concentration of CYP1A2 substrate in blood plasma can increase in weak degree (for example, theophylline) or in moderated (for example, melatonin and a tizanidin).
Other forms of interaction
the women receiving the tablets Yarinyâ along with other drugs which can increase the serumal level of potassium Have a theoretical possibility of increase in serumal level of potassium. Antagonists of receptors of angiotensin-II, kaliysberegayushchy diuretics and antagonists of Aldosteronum treat these drugs. However when studying interaction between drospirenony (in a combination) and APF inhibitor or indometacin of any significant changes of levels of potassium in blood serum did not decide on oestradiol.
Besides the aforesaid, when assigning of the accompanying therapy it is necessary to study the section of medicinal interactions of each of the appointed drugs.

Special indications
of the Precautionary measure and prevention
If any of the states/risk factors provided below are available now, then it is necessary to weigh carefully potential risk and the expected advantage of treatment of Yarinyâ in each individual case and to discuss it with the woman before she decides to begin administration of drug. In case of strengthening or the first manifestation of any of these states or risk factors it is necessary to make the decision on drug withdrawal.
Diseases of a cardiovascular system
indicate Results of epidemiological researches presence of interrelation between use of the combined oral contraceptives and the increased risk of developing venous and arterial thromboses and thromboembolic processes, such as myocardial infarction, deep vein thrombosis, pulmonary embolism and cerebrovascular disturbances. These diseases are noted seldom.
Risk of developing a venous thrombembolia (VTE) is maximum in the first year of reception of oral contraceptives. The increased risk is present after initial use of the combined oral contraceptives or resuming of use of the same or the different combined oral contraceptives (after a break between administrations of drug in 4 weeks and more). Data of a large prospective research with participation of 3 groups of patients show that this increased risk is present mainly within the first 3 months.
The general risk of a venous thrombembolia at the patients accepting oral contraceptives with a low dose of estrogen (it is less than 50 mkg of ethinylestradiol) is 2-3 times higher, than at the women who are not using them in the absence of pregnancy, nevertheless, this risk remains to lower in comparison with risk of a venous thrombembolia at pregnancy and childbirth.
The venous thrombembolia can be zhizneugrozhayushchy or lead to a lethal outcome in 1-2% of cases.
The venous thrombembolia which is shown as a deep vein thrombosis and/or an embolism of a pulmonary artery can occur when using of any combined oral contraceptives.
At the women accepting the combined oral contraceptives extremely exceptional cases of thrombosis of other blood vessels, for example hepatic, mezenterialny, renal, cerebral arteries and veins and also retina vessels are described.
Symptoms of a deep vein thrombosis include the following: unilateral hypostasis in a leg or along a vein on a leg, pain or discomfort in a leg only in vertical position or when walking, local temperature increase in the affected extremity, reddening or change of coloring of integuments on a leg.
Symptoms of a pulmonary embolism consist in the following: the sudden beginning of an inexplicable short wind or rapid breathing, the sudden attack of cough which can be followed by a pneumorrhagia, an acute pain in a thorax which can amplify at deep breath, feeling of alarm, the severe dizziness which is speeded up or irregular heartbeat. Some of these symptoms (for example, short wind and cough) are nonspecific and in this regard can be mistakenly interpreted as signs of more frequent and less heavy disturbances (for example, respiratory infections).
The arterial thrombembolia can include cerebrovascular disturbances, occlusion of vessels or a myocardial infarction.
The sudden weakness or numbness of the face, upper and lower extremities, especially on the one side of a body, sudden confusion of consciousness, disturbance of the speech or difficulty with perception, sudden deterioration in sight of one or both eyes, sudden disturbance of gait, dizziness, loss of balance or coordination of movements, a sudden heavy or long headache for no apparent reason, a loss of consciousness or a faint with an attack or without it can be symptoms of cerebrovascular disturbances. Also sudden pain, hypostasis or weak cyanosis of extremities, symptoms of ‘acute abdomen’ can be other signs of occlusion of vessels.
Symptoms of a myocardial infarction include: pain, discomfort, pressure, weight, feeling of compression or a raspiraniye in a breast, in a hand or behind a breast, feeling of discomfort with irradiation in a back, cheekbones, a throat, a hand, a stomach, feeling of completeness or a raspiraniye in a stomach, feeling of suffocation, cold sweat, nausea, vomiting or dizziness, strong weakness, the feeling of alarm, an asthma which is speeded up or irregular heartbeat.
Arterial thromboembolic processes can be zhizneugrozhayushchy or lead to a lethal outcome.
It is necessary to consider the probability of the increased synergy risk of thrombosis at women with a combination of several risk factors or higher expressiveness of one of risk factors. In such cases the increased risk can be higher, than just overall risk taking into account all factors.
The combined oral contraceptives it is not necessary to appoint in case of negative assessment of a ratio risk/advantage (see the section Contraindications).
Risk of developing thrombosis (venous and/or arterial), thromboembolic or cerebrovascular disturbances increases:
– with age
– at smokers (with increase in quantity of cigarettes or increase in age the risk increases further, especially at women 35 years are more senior)
– in the presence of the family anamnesis (i.e. a venous or arterial thrombembolia ever at close relatives or parents at rather young age). If genetic predisposition is known or is supposed, the woman needs to consult with the doctor for the solution of a question of a possibility of reception of the combined oral contraceptives
– in obesity (body mass index of more than 30 kg/sq.m)
– at a dislipoproteinemiya
– in arterial hypertension
– in migraine
– in diseases of valves of heart
– at fibrillation of auricles
– at a long immobilization, serious surgical intervention, any lower extremity surgery or an extensive injury. In these situations it is desirable to stop use of the combined oral contraceptives (in case of the planned operation, at least, in four weeks prior to it) and not to resume reception within two weeks after the termination of an immobilization.
The issue of a possible role of a varicosity and superficial thrombophlebitis in development of venous tromboemboliya remains controversial. It is necessary to consider the increased risk of developing a thrombembolia in a puerperal period.
Circulator disturbances can be also noted in diabetes, a system lupus erythematosus, a gemolitiko-uraemic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or nonspecific ulcer colitis) and a sickemia.
Increase in frequency and weight of migraine during use of the combined oral contraceptives (that can precede cerebrovascular disturbances) can be the basis for the immediate termination of intake of these drugs.
Biochemical parameters which can be indicators of the hereditary or acquired predisposition to venous or arterial thrombosis include resistance to the activated protein With, a gipergomotsisteinemiya, deficiency of antithrombin-III, deficit of a protein With, deficit of a protein of S, anti-phospholipidic antibodies (antibodies to cardiolipin, lupoid anticoagulant).
At ratio assessment risk/advantage, the doctor should take into account that adequate treatment of the corresponding state can reduce the related risk of developing thrombosis. Also it is necessary to consider that the risk of thromboses and tromboemboliya at pregnancy is higher, than at reception of the low-dosed combined oral contraceptives (it is less than 0.05 mg of ethinylestradiol).
the Most essential risk factor of developing cervical cancer is the viral infection – persistent papilloma of the person (HPV). There are messages about some increase in risk of developing cervical cancer at prolonged use of the combined oral contraceptives, however there are contradictory data on in what degree it can be connected with other factors, including with screening of a neck of the uterus and features of sexual behavior, including use of barrier methods of contraception.
Meta-analysis of 54 pharmako-epidemiological researches showed that there is a little increased relative risk (RR=1.24) of development of the breast cancer diagnosed for women a kotor
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