the International unlicensed name
Is not present
the Dosage form
of the Tablet, film coated, 3mg/0.02 mg
One tablet contains
active agents: drospirenona of crystal 100% 3 mg and ethinylestradiol mikronizirovannogo100% of 0.02 mg,
excipients: lactoses monohydrate, starch corn, starch prezhelatinizirovanny, macrogoal and polyvinyl alcohol copolymer, magnesium stearate,
structure of a film covering: opadray II white 85G18490: polyvinyl alcohol, titan dioxide (E171), macrogoal 3350, talc, lecithin (soy),
composition of placebo: microcrystalline cellulose, type 12, lactose anhydrous, starch prezhelatinizirovanny, magnesium stearate, silicon dioxide colloidal anhydrous,
structure of a film covering (placebo): opadray II green 85F21389: polyvinyl alcohol, titan dioxide (E 171), macrogoal 3350, talc, indigo carmine (E 132), quinolinic yellow (E 104), ferrous oxide black (E 172), yellow sunset (E 110).
of the Tablet, round shape, with a biconvex surface, film coated white or almost white color, with an engraving on one party of G73
of the Tablet, film coated green color, round shape, with a biconvex surface (placebo).
Hormonal oral contraceptives. Progestogens and estrogen (the fixed combinations).
The ATX G03AA12 code
Pharmacokinetics Drospirenon properties Absorption At oral administration drospirenon quickly and almost is completely absorbed. The maximum concentration of a drospirenon in serum, equal 37 ng/ml, is reached in 1-2 hours after single dose inside. The bioavailability fluctuates from 76 to 85%. Meal does not affect bioavailability of a drospirenon.
After oral administration the levels of a drospirenon in serum decrease with final elimination half-life of 31 h. Communication of a drospirenon with seralbumin is observed, but drug does not contact the globulin, connecting sex hormones (G,CSH), or kortikosteroidsvyazyvayushchy globulin (KSG). Only 3 – 5% of the general concentration of active agent in serum are presented in the form of free steroid. The increase in GSPG induced by ethinylestradiol does not influence binding of a drospirenon serum proteins. The average seeming volume of distribution of a drospirenon is 3.7±, 1.2 l/kg.
Drospirenon is actively metabolized after intake. The main metabolites in blood plasma is the acid form of a drospirenon formed at disclosure of a lactone ring and 4.5-dihydro-drospirenon-3-sulfate, both are formed without participation of P450 system. Drospirenon in small degree is metabolized by P450 3A4 cytochrome, and is capable to inhibit this enzyme and also P450 1A1 cytochrome, P450 2C9 cytochrome and P450 2C19 in vitro cytochrome.
is the Speed of metabolic clearance of a drospirenon in serum 1.5±, 0.2 ml/min. Drospirenon is excreted only in trace quantities in not changed look. Metabolites of a drospirenon are excreted with excrements and urine in the ratio about 1,2:1,4. Elimination half-life for excretion of metabolites with urine and excrements makes about 40 hours.
during one cycle of treatment the maximum equilibrium concentration of a drospirenon in serum (about 70 ng/ml) is reached after 8 days of treatment. Serumal concentration of a drospirenon increase approximately by 3 orders, owing to a ratio of final time of semi-removal and an interval of dosing.
Ethinylestradiol, after oral administration, is quickly and completely soaked up. The maximum concentration in blood serum after single dose of 33 pg/ml is reached in 1-2 hours. After presistemny conjugation and presistemny metabolism in a small intestine and a liver the absolute bioavailability is 60%. The accompanying meal reduces bioavailability of ethinylestradiol approximately at 25% of the examined people whereas at other people similar changes were not revealed.
ethinylestradiol Levels in serum decrease in two phases, the final pharmacokinetic phase is characterized elimination half-life about 24 hours. Ethinylestradiol contacts albumine about 98.5% and induces increase concentration of GSPG and KSG in serum. The seeming volume of distribution is about 5 l/kg.
Ethinylestradiol is exposed to a presistemny konjyugirovaniye in mucous a small intestine and in a liver. Ethinylestradiol is initially metabolized by aromatic hydroxylation, at the same time the 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.
Ethinylestradiol is completely metabolized. Speed of metabolic clearance of ethinylestradiol is 5 ml/min.
Ethinylestradiol is practically not excreted in not changed look. Metabolites of ethinylestradiol are excreted with urine and bile in the ratio 4:6. Elimination half-life of metabolites makes about 1 day. Eliminative elimination half-life makes 20 hours.
the Condition of equilibrium concentration is reached during the second half of a cycle of treatment, and the serumal level of ethinylestradiol increases with frequency rate about 2.0-2.3.
Separate categories of the population
Influence on function of kidneys
the Equilibrium level of a drospirenon in serum at women with weak degree of a renal failure (clearance of CLcr creatinine = 50-80 ml/minute) was comparable with that at women with normal function of kidneys (CLcr & gt, 80 ml/minute). Level of a drospirenon in serum was on average 37% higher at women with average degree of a renal failure of t (CLcr = than 30-50 ml/minute) in comparison with that at women with normal function of kidneys. Therapy drospirenony was well transferred by women both with weak, and with average degree of a renal failure.
Treatment drospirenony had no clinically significant impact on potassium concentration in serum.
Influence on function of a liver
In a one-dose research, the general clearance (CL/f) at volunteers with a moderate liver failure approximately was reduced by 50% in comparison with people with normal function of a liver.
Noted decrease in clearance of a drospirenon at volunteers with a moderate liver failure does not result in any significant differences concerning potassium concentration in serum.
Even in diabetes and simultaneous treatment Spironolactonum (two factors which can provoke a hyperpotassemia at the patient) did not note increase in potassium concentration in serum above the upper bound of norm.
It is possible to conclude that the combination drospirenon / ethinylestradiol is well transferred by patients with a moderate liver failure (class B on the Chayld-Pyyu system).
clinically relevant distinctions of pharmacokinetics of a drospirenon or ethinylestradiol at the Japanese women and women of Caucasian race are not revealed.
Pearl’s Index: 0.31 (upper 95% confidence interval: 0.85).
The contraceptive effect of drug is based on interaction of various factors, the most important of which are braking of an ovulation and change of endometrium.
Drug DIMIA 24+4 is the combined oral contraceptive (COC) with a combination of ethinylestradiol and progestin – a drospirenona. In a therapeutic dose, drospirenon also possesses anti-androgenic and weak antimineralokortikoidny action. Has no estrogenic, glucocorticoid and anti-glucocorticoid activity. Thus, drospirenon possesses the pharmacological profile close to natural hormone to progesterone.
In clinical trials it is revealed that antimineralokortikoidny properties of drug DIMIA result in weak antimineralokortikoidny effect.
Has anti-androgenic activity that leads to reduction of formation of an acne and decrease in products of sebaceous glands, does not influence the increase in formation of the globulin connecting sex hormones (inactivation of endogenous androgens) caused by ethinylestradiol.
– oral contraception
Drug has positive influence on the symptoms connected with a liquid delay in an organism and also on an acne and seborrhea, owing to the antimineralokortikoidny and anti-androgenic action.
The route of administration and doses
of the Tablet need to be accepted every day approximately at the same time, if necessary washing down with a small amount of liquid, in the sequence specified on packing. It is necessary to accept on one tablet a day within 28 days in a row. Each following packing has to begin after reception of the last tablet from the previous packing. Cancellation bleeding usually begins for 2-3 day after intake of placebo tablets (last row) and can not end by the time of the beginning of the following packing.
If earlier hormonal contraceptives were not used (in the last month)
Administration of drug of DIMIA begins in the first day of a natural menstrual cycle of the woman (that is in the first day of menstrual bleeding).
In case of replacement of another the COOK, a vaginal ring or a transdermalny plaster
For the woman it is preferable to begin administration of drug of DIMIA next day after a usual bezgormonalny interval in the scheme of the previous combined contraceptive. When replacing a vaginal ring or transdermalny plaster it is desirable to begin administration of drug of DIMIA in day of their removal of the previous means, in such cases the administration of drug of DIMIA has to begin no later than day of the planned procedure of replacement.
In case of replacement of a method using only progestins (mini-drank, injection forms, implants) or an intrauterine system (intrauterine system, IUS) with release of progestins
the Woman can pass with mini-saw in any day (from an implant or IUS – in day of its removal, from an injection form – from day when the following injection had to be made). However in all these cases it is desirable to use in addition barrier method of contraception during the first 7 days of reception of tablets.
After termination of pregnancy in the first trimester
the Woman can begin reception immediately. At observance of this condition there is no need for additional measures of contraception.
After the delivery or termination of pregnancy in the second trimester
it is desirable for Woman to begin administration of drug of DIMIA for 21-28 day after the delivery or termination of pregnancy in the second trimester. 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. In case of existence of sexual contact prior to administration of drug the pregnancy has to be excluded or it is necessary to wait for the first periods.
Reception of the passed
tablets Admission of Placebo Tablet from the last (4th) number of the blister can be ignored. However they should be thrown out in order to avoid inadvertent extension of placebo phase. Instructions belong only to the passed active tablets below:
If delay in reception of a tablet made less than 12 hours, contraceptive protection does not decrease. The woman needs to take the passed pill as soon as possible, the following pill is taken in usual time.
If delay in reception of tablets made more than 12 hours, contraceptive protection can be reduced. Correction of the passed tablets has to be guided by the following two simple rules:
1. It is impossible to stop reception of tablets more than for 7 days,
2. To reach adequate suppression gipotalamo – a hypophysial and ovarian system, 7 days of continuous reception of tablets are necessary.
Respectively in daily practice it is possible to give the following advice:
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. The barrier method of contraception during the next 7 days has to be in addition used. If the sexual intercourse took place within 7 days before the admission of a tablet, it is necessary to consider pregnancy approach probability. Than more tablets are passed and the this admission is closer to a 7-day break in administration of drug, the risk of approach of pregnancy is higher.
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. If the woman during the previous 7 days took a pill correctly, there is no need to use additional resources of contraception. However, if it passed more than 1 tablet, it is necessary to use additional precautionary measures in the next 7 days.
Probability of decrease in contraceptive effect is considerable because of approach of a phase of placebo tablets. However, correcting the schedule of reception of tablets, it is possible to prevent decrease in contraceptive protection.
If to follow any of two following councils, additional ways of contraception it is not required if during the previous 7 days before the admission of a tablet the woman took all pill correctly. If it not so, it has to follow the first of two ways and also use additional precautionary measures during the next 7 days.
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 takes a pill in usual time until active tablets do not end. 4 placebos it is not necessary to take a pill from the last row, it is necessary to begin reception of tablets from the following packing at once. Most likely, bleeding of cancellation will not be until the end of the second packing, but the smearing bloody discharges or breakthrough uterine bleeding in days of reception of tablets can be observed.
2. The woman can recommend to stop reception of active tablets from the begun packing. Instead it has to accept placebo tablet from the last row within 4 days, including days of the admission of tablets, and then begin reception of tablets from the following packing.
In case of the admission in reception of tablets and absence of bleeding of cancellation in a placebo tablets phase, it is necessary to exclude pregnancy.
Councils in case of digestive tract disorders
in case of heavy reactions from digestive tract (such as vomiting or diarrhea), absorption can be incomplete, and it is necessary to take additional measures of contraception.
In case of vomiting within 3-4 hours after reception of an active tablet, it is necessary to take the new, replacing pill as soon as possible. The following pill at an opportunity needs to be taken within 12 hours after usual time of reception. If more than 12 hours are missed, it is whenever possible necessary to follow the Regulations of Admission of drug specified in the section Reception of the Passed Tablets. If the patient does not want to change the normal mode of administration of drug, she has to take an additional pill (or several tablets) from other packing.
How to delay cancellation bleeding
For a delay of day of the beginning of periods it is necessary to miss intake of placebo tablets from the begun packing and to begin reception of active tablets DIMIA 24+4 from new packing without interruption in reception. The delay is possible before the termination of tablets in the second packing.
During lengthening of a cycle the smearing bloody discharges from a vagina or uterine breakthrough bleedings can be noted. Regular reception of DIMIA 24+4 comes to an end after a placebo phase.
For postponement of day of the beginning of periods the next day weeks of the usual schedule it is necessary to truncate the forthcoming phase of placebo tablets for so many days on how many it is necessary. The interval is shorter, the risk that bleeding of cancellation will not be is higher, and during reception of the second packing the smearing bloody discharges and breakthrough bleedings will be noted (just as in case of a delay of the beginning of periods).
Often (& gt, 1/100 to & lt, 1/10)
– a headache
– emotional lability, a depression
– disturbances of a menstrual cycle (metrorrhagia, an amenorrhea), intermenstrual bleedings
– a stethalgia
Infrequently (& gt, 1/1,000 to & lt, 1/100)
– dizziness, migraine
– nervousness, drowsiness decrease in mood, paresthesia
– a hypertension
– a varicosity
– morbidity and tension of mammary glands, fibrocystic changes of a mammary gland
– nausea, vomiting, gastritis, an abdominal pain, dyspepsia, a meteorism, diarrhea
– an acne, a skin itching, xeroderma
– dorsodynias, extremity pains, muscular spasms
– decrease in a libido
– vaginal discharges, vagina candidiasis, dryness in a vagina, a vaginitis
– disturbances of a menstrual cycle (dysmenorrhea, a hypomenorrhea, a menorrhagia)
– an asthenia, the strengthened sweating, a liquid delay in an organism
– increase in body weight
Is rare (& gt, 1/10,000 to & lt, 1/1,000)
– weight reduction
– increase in appetite, anorexia
– anemia, thrombocytopenia
– a hyperpotassemia, a hyponatremia
– an anorgazmiya, insomnia
– vertigo, a tremor
– nasal bleeding, a faint
– a thrombembolia, venous thromboses / a thrombembolia, arterial fibrinferments / a thrombembolia
– conjunctivitis, dryness in eyes, bad shipping of contact lenses
– tachycardia, arterial hypertension
– liver tumors
– Crohn’s disease, nonspecific ulcer colitis
– endometriosis, a hysteromyoma
– a porphyria
– a system lupus erythematosus
– herpes of pregnant women
– Sydenham’s trochee
– a hemolytic uraemic syndrome
– cholestatic jaundice
– a hloazma, xeroderma, acne or contact dermatitis
– a Quincke’s disease
– eczema, a hypertrichosis, a photodermatitis, a knotty erythema, a multiformny erythema
– a lactocele, a hyperplasia of a mammary gland
– painful sexual intercourse, post-coital bleeding, cancellation bleeding, polyps of a neck of the uterus, an endometrium atrophy, an oothecoma, increase in a uterus
– increase in a libido
of the Contraindication
– pregnancy and the period of a lactation
– presence of vein thromboses now or in the anamnesis (for example, a deep vein thrombosis, a pulmonary embolism)
– presence of thromboses of arteries now or in the anamnesis (for example, a myocardial infarction) or the previous states (for example, stenocardia and the tranzitorny ischemic attack)
– cerebrovascular diseases now or in the anamnesis
– existence of heavy or multiple factors of risk of arterial thrombosis
– diabetes with vascular complications
– the profound arterial hypertension
– the expressed dislipoproteinemiya
– the hereditary or acquired predisposition to venous or arterial fibrinferments, such as resistance to ARS (to activated protein C, the activated protein C), insufficiency of antithrombin-III, insufficiency of a protein With, insufficiency of a protein of S, a gipergomotsisteinemiya and anti-phospholipidic antibodies (antibodies to cardiolipin, lupoid anticoagulant)
– pancreatitis with the expressed gipertriglitseridemiya, including in the anamnesis
– a serious illness of a liver (to normalization of hepatic tests) now or in the anamnesis
– the profound chronic kidney disease or an acute renal failure
– liver tumors (benign or malignant), now or in the anamnesis
– hormonedependent malignant diseases of a reproductive system (genitals, mammary glands) or suspicion on them
– vaginal bleeding of not clear genesis
– migraine with local neurologic symptomatology in the anamnesis
– hypersensitivity to active agent or any of excipients
– intolerance of a galactose, a lactose intolerance or a sprue of glucose and a galactose
Metabolism in a liver
Some drugs owing to induction of microsomal enzymes sposobna to increase clearance of sex hormones (hydantoin, Phenytoinum, barbiturates, Primidonum, carbamazepine and rifampicin, the same influence of oxycarboazepine, the topiramat, felbamat, a ritonavir, griseofulvin and vegetable means on the basis of a St. John’s wort (Hypericum perforatum) is also possible. The maximum induction of microsomal enzymes of a liver usually is not shown during 2-3 weeks, but can then remain at least during 4 weeks after the termination of medicinal therapy.
It was reported about possible effect of inhibitors of HIV proteases (for example, a ritonavira) and nenukleozidny inhibitors of reverse transcriptase (for example, not Virapinum) and their combinations on metabolism in a liver.
Co-administration with some antibiotics, such as penicillin and tetracyclines, reduces enterohepatic recirculation of estrogen that can lead to decrease in concentration of ethinylestradiol.
The women receiving any of above-mentioned classes of medicines or separate active agents have to use a barrier method of contraception in addition to drug DIMIA, or pass to any other method of contraception. The women receiving continuous treatment by the drugs containing the active agents influencing liver enzymes within 28 days after their cancellation in addition have to use a non-hormonal method of contraception.
The women receiving therapy by rifampicin except reception the COOK have to use a barrier method of contraception and continue its use within 28 days after the treatment termination by rifampicin. If intake of the accompanying drugs lasts longer than completion date of active tablets in packing, placebo of a tablet should be thrown out and at once to begin reception of active tablets from the following packing.
The main metabolism of a drospirenon in plasma of the person is generated without involvement of a system of P450 cytochrome. Inhibitors of this fermental system, thus, do not influence metabolism of a drospirenon.
Influence of drug DIMIA on other medicines
Oral contraceptives can influence metabolism of separate other active connections. Besides, their concentration in plasma and fabrics how to raise (for example, cyclosporine), and to decrease can change (for example, lamotrigin).
At the female volunteers accepting omeprazolum, simvastatin and midazolam as indicators substrates, influence of a drospirenon in a dose of 3 mg on metabolism of other active agents is improbable.
At patients with a renal failure, co-administration of a drospirenon and APF or NPVP inhibitors (non-steroidal anti-inflammatory drugs) has no significant effect on potassium level in blood serum. However, simultaneous use of drug DIMIA and antagonists of Aldosteronum or kaliysberegayushchy diuretics was not studied. In this case the potassium level research in serum during the first cycle of administration of drug is necessary.
Note: It is necessary to discuss co-administration of drugs to reveal possible medicinal interactions.
researches Intake of Hormones for contraception can affect results of separate laboratory tests, including biochemical indicators of function of a liver, thyroid gland, adrenal glands and kidneys and also levels of transport proteins of plasma, such as kortikosteroidsvyazyvayushchy globulin and lipidno / lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and a fibrinolysis. Changes usually happen within laboratory norms.
Owing to the small antimineralokortikoidny activity drospirenon increases activity of renin and Aldosteronum of blood plasma.
of the Precautionary measure
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 use the COOK in each individual case and to discuss it with the woman before she decides to begin administration of drug. In case of deterioration, strengthening or the first manifestation of any of these states or risk factors, the woman has to consult with the doctor who can make the decision on need of cancellation the COOK.
Disturbances of the blood circulatory system
Epidemiological researches showed that VTE frequency (venous thrombembolia) at women without risk factors of VTE accepting the combined oral contraceptives with a low dose of estrogen (& lt, 50 mkg of ethinylestradiol) is approximately from 20 cases on 100,000 women a year (for levonorgestrel – containing the COOK of the second generation or up to 40 cases on 100,000 women a year (for dezogestrel/gestoden-containing the COOK of the third generation). It is comparable with figures from 5 to 10 cases on 100,000 women who are not using contraceptives, and 60 cases on 100,000 pregnancies.
Use of any combined oral contraceptives is connected with the increased risk of a thrombembolia of veins, comparable with that without use. The additional risk is maximum within the first year of use of the combined oral contraceptive. The thrombembolia of veins leads to a lethal outcome in 1-2% of cases.
Epidemiological researches also connect reception the COOK with the increased risk of an arterial thrombembolia (myocardial infarction, the tranzitorny ischemic attacks).
At the women accepting the combined oral contraceptives extremely exceptional cases of thrombosis of other blood vessels, for example, of hepatic, mezenterialny, renal arteries and veins, the central vein of a retina and its branches are described.
Symptoms of venous or arterial thrombosis / thrombembolia or cerebrovascular disease can include:
& middot, unusual unilateral pain and/or swelled extremities
& middot, sudden severe pain in a breast, with or without irradiation in the left hand
& middot, a sudden asthma
& middot, a sudden fit of coughing
& middot, any unusual, severe, long headache
& middot, sudden partial or total loss of sight
& middot, a diplopia
& middot, the inarticulate speech or aphasia
& middot, dizziness
& middot, a loss of consciousness with or without convulsive attack
& middot, weakness or extremely profound anesthesia which suddenly developed from one party or in one part of a body
& middot, motive disturbances
& middot, a symptom of an acute abdomen.
The risk of the complications connected with a thrombembolia of veins at reception the COOK increases:
& middot, with age
& middot, in the presence of the family anamnesis (a venous or arterial thrombembolia ever at close relatives or parents at rather young age) if genetic predisposition is supposed, is necessary for the woman consultation of the expert before appointment the COOK
& middot, after a long immobilization, serious surgical intervention, any operation standing or an extensive injury. In these situations it is recommended to stop administration of drug (in case of planned operation, at least, in four weeks prior to it) and not to resume reception within two weeks after the termination of an immobilization. Purpose of antitrombotichesky therapy is in addition possible if reception of tablets was not stopped in the recommended terms
& middot, obesity (body mass index more than 30 mg/m)
& middot, there is no consensus about a possible role of a varicosity and thrombophlebitis of superficial veins at the beginning or progressing of venous thrombosis.
The risk of arterial tromboembolic episodes of thrombosis or cerebrovascular disturbance at the women accepting the COOK increases:
& middot, with age
& middot, at smokers (to women 35 years strictly are more senior it is not recommended to smoke if they want to apply the COOK)
& middot, at a dislipoproteinemiya
& middot, in hypertensia
& middot, in migraine
& middot, in diseases of valves of heart
& middot, at fibrillation of auricles.
Existence of one of serious risk factors or multiple factors of risk of a disease of arteries or veins, respectively, can be a contraindication. The women applying the COOK have to see immediately a doctor at emergence of symptoms of possible thrombosis. In cases of suspicion of thrombosis or the confirmed thrombosis reception the COOK needs to be stopped. It is necessary to pick up an adequate method of contraception owing to teratogenecity of anticoagulating therapy (coumarins).
It is necessary to consider the increased risk of tromboemboliya in a puerperal period.
Other diseases which are connected with heavy vascular pathology include diabetes, a system lupus erythematosus, a hemolytic uraemic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or nonspecific ulcer colitis) and a sickemia.
Increase in frequency and weight of migraine during a usage time the COOK (that can precede cerebrovascular disturbances) can be the basis for the immediate termination of intake of these drugs.
About the increased risk of developing cervical cancer at prolonged use of the combined oral contraceptives it was reported in some epidemiological researches. Its communication with reception of the combined oral contraceptives is not proved. Contradictions concerning in what degree these results belong to features of sexual behavior and other factors, like human papillomavirus (HPV) remain.
Meta-analysis of 54 epidemiological 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. 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. Cancer tumors of mammary glands at the women ever using the combined oral contraceptives were clinically less profound, than at the women never using similar drugs.
In rare instances against the background of use of the combined oral contraceptives the development of benign tumors of a liver, and in extremely exceptional cases development of malignant tumors of a liver was observed. In some cases these tumors lead to zhizneugrozhayushchy intra belly bleeding. In case of appearance of severe pains in a stomach, increases in a liver or symptoms of intra belly bleeding when carrying out the differential diagnosis at the woman accepting the COOK it is necessary to consider a likelihood of developing a tumor of a liver.
Progestinovy of a computer
to Develop other states