The instruction for medical use
of Trikvilarâ medicine
the Trade name
the International unlicensed name
Is not present
the Dosage form
of the Dragee
One white dragee contains
active agents: 0.04 mg of ethinylestradiol and 0.075 mg of levonorgestrel
One light brown dragee contain
active agents: 0.03 mg of ethinylestradiol and 0.05 mg of levonorgestrel
One yellow dragee contain
active agents: 0.03 mg of ethinylestradiol and 0.125 mg of levonorgestrel
excipients: lactoses monohydrate, starch corn, povidone 25,000, talc, magnesium stearate
structure of a cover:
sucrose, PVP 700,000, Makrogol 6000, calcium carbonate, talc, glitserol 85%, montanglikolevy wax, titan dioxide (E171), ferrous oxide yellow (E172), ferrous oxide red (E172).
Round dragees of white color, light brown color and yellow color (color of ochre).
Hormonal contraceptives for system use.
Progestogens and estrogen (for calendar reception). Levonorgestrel and estrogen.
The ATX G03AB03 code
Pharmacokinetics Levonorgestrel Later properties of oral administration levonorgestrel is quickly and completely soaked up, its maximum concentration in blood serum, equal 2.3 ng/ml, is reached approximately in 1 hour. After single dose in 0.125 mg of levonorgestrel together with 0.33 mg of ethinylestradiol (that corresponds to the largest content of levonorgestrel in three-phase drug), the highest concentration in serum making 4.3 ng/ml was defined approximately in an hour. At oral administration levonorgestrel almost completely biodostupen.
Levonorgestrel contacts albumine of blood serum and the globulin, connecting sex hormones (G,CSH). In a free look there are only 1.4% of the general concentration in blood serum whereas 55% are specifically connected with GSPG and about 44% – not specifically with albumine. As a result of induction by ethinylestradiol of synthesis of the connecting protein, the fraction connected with GSPG raises while the fraction connected with albumine decreases. The seeming volume of distribution of levonorgestrel is equal to about 128 l after single dose in a dragee of Trikvilara® containing the highest dose of levonorgestrel.
Levonorgestrel is completely metabolized, passing ways of a metabolization, characteristic of steroids. After single oral administration of the highest dose of levonorgestrel the clearance speed is about 1.0 ml/min. of serum.
Levonorgestrel content in blood serum is exposed to two-phase decrease. Elimination half-life in a terminal phase makes about 22 hours. Levonorgestrel in not changed form is not removed but only in the form of metabolites which are removed with elimination half-life about 24 hours with urine and bile in the ratio about 1: 1.
The pharmacokinetics of levonorgestrel is influenced by the GSPG level in blood serum which for a 21-day course of reception Trikvilara® increases approximately twice. As a result of daily administration of drug the level of content of substances in serum increases approximately four times, an equilibrium concentration is reached in the second half of a course. At equilibrium concentration the distribution volume, and speed of clearance are reduced respectively to 52 l and 0.5 ml/min.
After intake ethinylestradiol is soaked up quickly and completely. The maximum concentration in blood serum, equal about 116 pg/ml, is reached in 1.3 hours. During absorption and the first passage through a liver ethinylestradiol is metabolized therefore its bioavailability at intake averages about 45%, and significant individual differences within 20 — 65% are noted.
Ethinylestradiol almost completely (98%), though it is not specific, 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 presistemny conjugation, both in mucous a small intestine, and in a liver. The main way of metabolism – aromatic hydroxylation. Speed of metabolic clearance is 2.3 – 7 ml/min. of blood plasma.
Concentration of ethinylestradiol in blood serum decreases, and reduction has two-phase character, 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 is reached approximately in one week taking into account elimination half-life of a final phase and a daily dose.
At the end of treatment the maximum concentration in blood serum, equal about 132 pg/ml, are reached in 1.3 hours.
of Trikvilarâ – the combined estrogen-gestagenny low-dosed three-phase peroral contraceptive drug.
The contraceptive effect of Trikvilaraâ is based on interaction of various factors, the most important of which are the inhibition of an ovulation and change of secretion 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.
At the women accepting the combined oral contraceptives, the menstrual cycle becomes more regular, painful periods are less often observed, the intensity of bleeding decreases therefore the risk of an iron deficiency anemia decreases.
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
the Route of administration and doses
the Combined oral contraceptives at the correct and regular reception have contraceptive reliability, with an indicator of failure of a method no more than 1% a year. Contraceptive reliability can decrease at the admission of tablets or their wrong reception.
Strip planimetric packaging contains 21 dragees. As dragees have various structure, the drug should be taken inside strictly on the order specified on packing. It is necessary to begin administration of drug with dragee No. 1.
The foil of dragee No. 1 is painted in red color and noted by a word ‘Beginning’.
As soon as the first dragee is accepted, it is necessary to celebrate this day of the week under heading ‘A dragee began to accept. To make it, it is necessary to pierce a small unlabelled disk of a foil under the corresponding day of the week. For example, if the dragee is accepted on Wednesday, it is necessary to pierce a foil disk under day of the week of Sr. It will remind the woman in what day the reception of a dragee is begun. Accept one dragee a day inside on the order specified on packing, every day it is continuous within 21 days approximately at the same time, with a small amount of water. Reception of the following packing begins after a 7-day break in reception of a dragee during which cancellation bleeding usually takes place. Bleeding, as a rule, begins for 2-3 day after reception of the last dragee and can not end prior to reception of new packing.
How to begin reception of Trikvilaraâ.
– In the absence of reception of any hormonal contraceptives
the Reception of Trikvilaraâ begins in the first day of a menstrual cycle (i.e. in the first day of menstrual bleeding. The beginning of reception on 2-5 menstrual cycles 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 a dragee 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 Trikvilaraâ next day after reception of the last gormonsoderzhashchy dragee from the previous packing, but by no means no later than the next day after a usual 7-day break (for the drugs containing 21 dragees) or after intake of the last not containing dragee hormone (for the drugs containing 28 dragees in packing). Upon transition from a vaginal ring or a transdermalny plaster it is preferable to begin reception of Trikvilaraâ 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), or the intrauterine means (Naval Forces) releasing gestagen
the Woman can pass with mini-saw on Trikvilarâ in any day (without interruption), from an implant or Naval Forces with gestageny – 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 a dragee.
– After abortion in the first trimester of pregnancy
the Woman can begin administration of drug immediately. At observance of this condition the woman does not need 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 a dragee. However, if the woman already led sex life, prior to reception of Trikvilaraâ the pregnancy has to be excluded or it is necessary to wait for the first periods.
Reception of the passed dragees
If delay in reception of a dragee made less than 12 hours, contraceptive protection does not decrease. The woman has to accept a dragee as soon as possible, following is accepted in usual time.
If delay in reception of a dragee 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 a dragee 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 a dragee made more than 12 hours (an interval from the moment of reception of the last dragee more than 36 hours):
– The first week of administration of drug
the Woman has to accept the last passed dragee as soon as possible as soon as remembers (even if it means reception of two dragees at the same time). The following dragee is accepted 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 a dragee, it is necessary to consider pregnancy approach probability.
What more dragee is passed by, and than closer they to a break in intake of active agents, that high probability of pregnancy.
– The second week of administration of drug
the Woman has to accept the last passed dragee as soon as possible as soon as remembers (even if it means reception of two dragees at the same time). The following dragee is accepted in usual time.
Provided that the woman accepted a dragee correctly within 7 days preceding the first passed dragee there is no need for use of additional contraceptive measures. Otherwise and also at the admission of two and more dragees 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 a dragee.
The woman has to adhere strictly to one of two following options. At the same time if in 7 days preceding the first passed dragee all dragees were accepted correctly, there is no need to use additional contraceptive methods.
1. The woman has to accept the last passed dragee as soon as possible (even if it means, reception of two dragees at the same time). The following dragee is accepted in usual time, dragees from the current packing will not end yet. The following packing should be begun at once.
2. The woman can also interrupt reception of a dragee from the current packing. Then it has to take a break for 7 days, including day of the admission of a dragee and then begin reception of new packing.
If the woman missed reception of a dragee, and then during a break in reception of a dragee she has no cancellation bleeding, it is necessary to exclude pregnancy.
Recommendations in case of vomiting and diarrhea
In heavy gastrointestinal disorders the absorption of drug can be not full. In this case it is necessary to take additional measures of contraception.
If at the woman within 3-4 hours after reception of a dragee of Trikvilaraâ the vomiting was observed, it is necessary to be guided by the councils concerning the admission of a dragee. If the woman does not want to change the normal mode of administration of drug, she has to accept if necessary an additional dragee (or several dragee) from other packing.
Change of day of the beginning of a menstrual cycle
to delay the beginning of periods, the woman has to continue administration of drug, using the last 10 dragees from other packing of Trikvilaraâ, not taking at the same time a break in reception. Thus, the cycle can be extended for a period of up to 10 days up to the end of the second packing. Against the background of administration of drug from the second packing at the woman the smearing bloody discharges or breakthrough uterine bleedings can be noted. Regular reception of Trikvilaraâ then is resumed after a usual 7-day break in reception of a dragee.
To transfer day began periods the next day of week, the woman should reduce the following break in reception of a dragee by the desirable number of days. The interval is shorter, the risk is higher that it will have no bleeding of cancellation and, further, there will be smearing discharges and breakthrough bleedings during reception of the second packing (just as in case she like to delay the beginning of periods).
Additional information for special categories of patients
Children and teenagers
the Drug Trikvilarâ is shown only after approach of menarche.
Patients of advanced age
it is not applicable. The drug Trikvilarâ is not shown to women after approach of a menopause.
Patients with disturbances from a liver
the Drug Trikvilarâ is contraindicated to women with a serious illness of a liver until indicators of function of a liver do not return to normal.
Patients with disturbances from kidneys
the Drug Trikvilarâ specially was not studied at patients with disturbances from kidneys. The available data do not assume change of treatment at such patients.
in the course of treatment of Trikvilarom® it was most often reported about such side reactions as: nausea, abdominal pain, body weight increase, headaches, decrease in mood, morbidity and tension of mammary glands. They were observed with a frequency ≥ in 1%.
Treat serious side reactions of drug: arterial and venous thromboembolic disturbances.
– nausea, an abdominal pain
– a body weight increase
– a headache, decrease in mood, change of mood
– morbidity and tension of mammary glands
– vomiting, diarrhea
– a liquid delay
– decrease in a libido
– increase in mammary glands
– rash, urticaria
– reactions of hypersensitivity
– bad shipping of contact lenses
– decrease in body weight
– increase in a libido
– vaginal discharges, discharges from mammary glands
– a knotty erythema, a multiformny erythema
– arterial and venous thromboembolic disturbances **
** the Expected frequency based on data of epidemiological researches of a part of group of the combined oral contraceptives. Frequency was a pogranichna to category ‘very seldom.
– Arterial and venous thromboembolic disturbances summarizes the following diseases and states:
occlusion of deep peripheral veins, fibrinferments and embolism/occlusion of pulmonary vessels, fibrinferments, an embolism and a heart attack/heart attack a myocardium/heart attack of a brain and a stroke of not hemorrhagic character
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)
– women with a gipertriglitseridemiya (risk of developing pancreatitis when using of the combined oral contraceptives is increased)
– 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
of Interaction with other medicines (inductors of enzymes of a liver, some antibiotics) can lead to breakthrough uterine bleedings or decrease in contraceptive reliability.
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
– migraine with focal neurologic symptoms in the anamnesis
– diabetes with vascular complications
– high risk of developing venous or arterial thrombosis
– a serious illness of a liver (until indicators of function
of a liver do not return to normal)
– 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.
Effects of other drugs on Trikvilarâ
the 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 is possible.
During intake of such drugs, the woman should use in addition a barrier method of contraception in addition to Trikvilarâ 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 from unwanted pregnancy comes to an end later, than a dragee in packing, it is necessary to pass to the following packing of Trikvilaraâ without usual break in intake
of dragee / Substance, 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 in 1.4 up to 1.6 times, respectively 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.
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 (for example, midazolam) in blood plasma while concentration of CYP1A2 in blood plasma can increase in weak degree (for example, theophylline) or in moderated (for example, melatonin and tizanidin).
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 Trikvilaromâ 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 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 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 have life-threatening character 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),
– in the presence of the family anamnesis are more senior (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 (survey and a fence of a smear on an onkotsitologiya or cytology) and features of sexual behavior, including use of barrier methods of contraception.
The conducted researches showed that there is a little increased relative risk (RR=1.24) of development of the breast cancer diagnosed for women who at the time of the research used the combined oral contraceptives. The increased risk gradually disappears within 10 years after the termination of intake of these drugs. Because the breast cancer is noted seldom at women 40 years are younger, increase in number of diagnoses of a breast cancer at the women accepting the combined oral contraceptives now or accepting recently is insignificant in relation to the general risk of developing this disease. Its communication with reception of the combined oral contraceptives is not proved. Observed increase in risk can be a consequence of earlier diagnosis of a breast cancer at the women applying the combined oral contraceptives, biological effects of the combined oral contraceptives or a combination of both factors. At the women using combined