Silhouette of the tab. of p/o No. 21

Pharmacological properties

Siluyet's

— the combined contraceptive contraceptive with anti-androgenic effect containing ethinylestradiol as estrogen and diyenogest as progesterone.

Pharmacodynamics. The contraceptive effect of the tablets Siluyet is based on interaction of various factors, the most important of which are braking of an ovulation and change of endometrium. The anti-androgenic effect of a combination of ethinylestradiol and the diyenogest is based generally on decrease in level of androgens in blood plasma.

Diyenogest is derivative Norethisteronum of which lower affinity to in vitro progesterone receptors in comparison with other synthetic progesterona is characteristic at 10-30 times.

Diyenogest does not reveal essential androgenic, mineralokortikoidny or glyukortikoidny effects of in Vivo.

At application separately diyenogest the Pharmacokinetics inhibits an ovulation in a dose of 1 mg/days

. Ethinylestradiol (30 mkg)

Absorption. Ethinylestradiol after oral administration is quickly and completely absorbed. The C _max in blood serum after single dose of 30 mkg is reached in 1–2 h and makes about 100 pg/ml. Ethinylestradiol is exposed to extensive effect of the first passing through a liver with high individual variability. The absolute bioavailability varies and is about 45%.

Distribution. The expressed volume of distribution is about 5 l/kg of body weight, communication with proteins of blood plasma — about 98%. Ethinylestradiol induces synthesis of the globulin, connecting sex hormones (G,CSH), and kortikosteroidsvyazyvayushchy globulin (KSG) in a liver. At daily reception of 30 mkg of ethinylestradiol the plasma concentration of GSPG increases from 70 to ≈350 nmol/l. Ethinylestradiol in small amounts gets into breast milk (≈0.02% of a dose).

Metabolism. Ethinylestradiol is completely metabolized (the clearance is 5 ml/min.).

Removal. Ethinylestradiol is practically not removed in not changed look. Metabolites of ethinylestradiol are removed with urine and bile in the ratio 4:6. The t _½ for metabolites makes about 1 days. Eliminative the T _½ makes 20 h

Equilibrium concentration. The condition of equilibrium concentration is reached during the second half of a cycle of treatment, and the serumal level of ethinylestradiol accumulates with frequency rate about 1.4-2.1.

Diyenogest

Absorption. At oral administration diyenogest it is soaked up quickly and completely. The C _max in blood plasma (51 ng/ml) is reached in 2.5 h after reception.

Absolute bioavailability at the combined application with ethinylestradiol is 96%.

Distribution. Diyenogest contacts seralbumin and does not contact GSPG or KSG. The fraction of the free diyenogest makes 10% while 90% are nonspecific connected with albumine. The expected volume of distribution is 37–45 l.

Metabolism. Diyenogest it is generally metabolized by hydroxylation, an alternative way is the glyukuronization. Its metabolites are inactive and eliminirutsya quickly from blood plasma therefore in considerable concentration it is not possible to reveal metabolites in blood plasma that concerns the changed diyenogest. The general clearance after single dose (Cl/F) is 3.6 l/h

Removal. The t _½ diyenogest makes ≈9 h. The fraction of not changed diyenogest allocated by kidneys is insignificant. After intake of 0.1 mg/kg the removal with a stake and urine is characterized by a ratio about 3:2. At intake of 86% it is allocated within 6 days, 42% are brought out of them in the first 24 h mainly with urine.

Equilibrium concentration. The GSPG level in blood plasma does not influence diyenogest pharmacokinetics. Diyenogest level in blood serum increases by 1.5 times, and steady state is reached within 4 days.

Indication

Oral contraception.

Use

needs to take the Pill daily approximately at the same time, if necessary washing down with a small amount of liquid, in the sequence specified on the blister packing. it is necessary to accept on 1 tablet a day within 21 days in a row. reception of the first tablet from each following packing has to begin after a 7-day interval during which usually there comes menstrualnopodobny bleeding which begins in 2–3 days after reception of the last tablet and can not end prior to reception of tablets from the following packing.

If hormonal contraceptives during the previous period (last month) were not used by

. Reception of tablets should be begun in the first day of menstrual bleeding.

Transition from other combined hormonal contraceptive. It is desirable that the woman began reception of the tablets Siluyet next day after reception of the last active tablet of the previous the combined oral contraceptive (COC) or next day after the last active day of the previous PDA.

Transition from the method based on use only of progestogen (mini-drank, injections, implants). The woman can begin administration of medicament of Siluyet in any day after the termination of reception mini-saw (in case of an implant or an intrauterine system — in day of their removal, in case of an injection — instead of the following injection).

After abortion in І a pregnancy trimester. Administration of medicament should be begun immediately on the same day after operation. In that case there is no need to apply additional resources of contraception.

After the delivery or after abortion in ІІ a pregnancy trimester. Women need to recommend to begin administration of medicament of Siluyet from the 21-28th day after the delivery or abortion in ІІ a pregnancy trimester. If the woman begins reception of tablets later, it is necessary to recommend to use in addition a barrier method of contraception during the first 7 days of application of tablets. However, if sexual intercourse already took place, then before use of the CPC it is necessary to exclude pregnancy or the woman should wait for the first periods.

in case of feeding by a breast see Use during pregnancy and feeding by a breast.

Admission of reception of a tablet. If delay in reception of a tablet does not exceed 12 h, contraceptive effect of medicine does not decrease. The passed pill should be taken at once as soon as it became clear. The following pill from this packing should be taken in usual time. If delay in reception of a tablet exceeds 12 h, contraceptive protection can decrease. In that case it is possible to be guided by two basic rules:

1. Having rummaged in reception of tablets can never make more than 7 days.

2. Adequate oppression of a system a hypothalamus — a hypophysis — ovaries is reached by continuous reception of tablets within 7 days.

According to it in everyday life needs to be guided by the following recommendations:

1st week. The woman has to take the last passed pill as soon as possible even if it is necessary to take 2 pill at the same time. After that she continues to take a pill in usual time. Besides, during the next 7 days it is necessary to use a barrier method of contraception, for example condom. If in the last 7 days the sexual intercourse took place, it is necessary to consider a possibility of approach of pregnancy. Than more receptions of tablets are missed and the admission to a 7-day break in administration of medicament is closer, the risk of approach of pregnancy is higher.

2nd week. The woman has to take the last passed pill as soon as possible even if it is necessary to take 2 pill at the same time. After that she continues to take a pill in usual time. Provided that the woman correctly took a pill within 7 days before the admission, there is no need to use additional contraceptives. Otherwise or at the admission of 1 tablet it is recommended to use in addition a barrier method of contraception within 7 days.

3rd week. Probability of decrease in contraceptive effect considerable because of the forthcoming break in reception of tablets lasting 7 days. However at observance of the scheme of reception of tablets it is possible to avoid decrease in contraceptive protection. If to adhere to one of the following options, then there will be no need to use additional contraceptive resources on condition of the correct reception of tablets within 7 days to the admission. If it not so, is recommended to adhere to the first of the following options and to use additional methods of contraception during the next 7 days.

1. The woman has to take the last passed pill as soon as possible even if it is necessary to take 2 pill at the same time. After that she continues to take a pill in usual time. Reception of tablets from new packing should begin to be accepted at once after the termination previous, that is there should not be a break in reception of tablets. It is improbable that at the woman the menstrualnopodobny bleeding before the end of reception of tablets from the second packing will begin though the smearing bloody discharges or breakthrough bleeding can be observed.

2. The woman can also advise to stop reception of tablets from the current packing. In the second case having rummaged in administration of medicament has to make 7 days, including days of the admission of tablets; reception of tablets should be begun with the following packing.

If the woman missed reception of tablets and it has no menstrualnopodobny bleeding during the first usual break in administration of drug, it is necessary to consider pregnancy probability.

Recommendation in case of violations from a GIT. At heavy violations from a GIT (vomiting, diarrhea) perhaps incomplete absorption of medicine; in that case it is necessary to apply additional resources of contraception.

If during 3–4 h after reception of a tablet the vomiting occurred, it is necessary to take a new pill as soon as possible. The new pill should be taken during 12 h after usual time of reception. If there passed 12 h, it is necessary to follow Regulations of Admission of medicine (see the Admission of reception of a tablet). If the woman does not want to change the usual scheme of administration of drug, she needs to take an additional pill (- and) from other packing.

How to change time of developing of bleeding of "cancellation". To detain day of the beginning of periods, the woman should continue to take the pill Siluyet from new packing and not to take a break in administration of drug. If desired the term of reception can be prolonged up to the end of the second packing. At the same time breakthrough bleeding or the smearing bloody discharges are possible. The standard practice of the medicine Siluyet is resumed after a 7-day break in reception of tablets.

to displace time of approach of periods the next day of week, the woman recommends to reduce a break in reception of tablets by so many days on how many she wants. It should be noted that the break will be shorter, the absence of menstrualnopodobny bleeding and breakthrough bleeding or the smearing bloody discharges during reception of tablets from the second packing is observed more often (as in case of a delay of approach of periods).

CPC should not be applied by

Contraindication

in the presence of one of the below-mentioned states or diseases. if any of these states or diseases arises for the first time during use of the PDA, administration of medicament should be stopped immediately:

• existence or the instruction in the anamnesis on venous thromboembolic diseases (for example a deep vein thrombosis, a pulmonary embolism);
• existence or the instruction in the anamnesis on arterial thromboembolic diseases (myocardial infarction), prodromal symptoms of thrombosis (for example the tranzitorny ischemic attack, stenocardia) or cerebrovascular frustration;
• existence of heavy or multiple factors of risk of rather venous or arterial thrombosis: diabetes with defeat of vessels, heavy AG, a heavy dislipoproteinemiya;
• hereditary or acquired predisposition to venous or arterial fibrinferments, for example resistance to argonoplazmenny coagulation (agrarian and industrial complex), 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);
• smoking;
• pancreatitis at present or in the anamnesis if it is connected with a heavy gipertriglitseridemiya;
existence or the instruction in the anamnesis on a serious illness of a liver, so far indicators of function of a liver are not normalized by
• ;
• existence or the instruction in the anamnesis on a liver tumor (benign or malignant);
• known or suspected malignant tumors (for example genitals or mammary glands) which are dependent on sex hormones;
• vaginal bleeding of the obscure etiology;
• existence of pregnancy or suspicion on pregnancy;
• migraine with focal neurologic symptoms in the anamnesis;
• hypersensitivity to active ingredients or any of medicine components.

Side effects

Most serious side effects connected with use of the CPC are described by

in the section special instructions.

to

At simultaneous application of the diyenogest and ethinylestradiol it was reported about the following side reactions: often (≥1/100–1/10); infrequently (≥1/1000–1/100); seldom (≥1/10 000–1/1000).

Laboratory indicators: seldom — anemia.

from a cardiovascular system: seldom — tachycardia, thrombophlebitis, thrombosis / a pulmonary embolism, a hematoma, violation of cerebral circulation; infrequently — AG, arterial hypotension, a varicosity.

from nervous system: often — a headache; infrequently — migraine, hyperexcitability.

from an organ of sight: seldom — disorders of vision, conjunctivitis.

from an organ of hearing: seldom — a gipoakuziya.

from a respiratory system: seldom — sinusitis, OH, bronchitis.

from digestive system: often — an abdominal pain; infrequently — nausea, vomiting; seldom — diarrhea.

from an urinary system: infrequently — infections of an urinary system.

from skin: infrequently — an acne, akneformny dermatitis, a dieback, skin allergic reactions, hloazma, an alopecia; seldom — a multiformny erythema, a skin itch, a hypertrichosis, a virilism.

from a metabolism: infrequently — increase in appetite; seldom — a loss of appetite.

Infection: infrequently — a vaginitis, vaginal candidiasis.

General violations: infrequently — a fatigue/indisposition, change of body weight; seldom — the symptoms arising at flu.

from the immune system: seldom — allergic reactions.

from a reproductive system and mammary glands: often — morbidity of mammary glands, tension in mammary glands; infrequently — irregular bleedings, a dysmenorrhea, increase in mammary glands, a cyst of ovaries, a dispaureniye, change of a vaginal secret; seldom — a hypomenorrhea, mastitis, a fibrous and cystous dysplasia of mammary glands, emergence of a secret from mammary glands, a leiomyoma, an endometritis, a salpingitis.

from mentality: infrequently — violations of mood (including a depression); seldom — anorexia, change of a libido, aggression, apathy.

Following serious side reactions described in the section SPECIAL INSTRUCTIONS are registered by

at the women accepting contraceptives: venous and arterial thromboembolic violations; arterial thromboembolic violations; AG; liver tumors; emergence or deterioration in states which connection with reception of oral contraceptives is not proved: Crohn's disease, nonspecific ulcer colitis, porphyria, system lupus erythematosus, herpes of pregnant women, Sydenham's trochee, hemolytic uraemic syndrome, cholestatic jaundice; hloazma.

Frequency of diagnosing of a breast cancer among the women accepting oral contraceptives is increased by

slightly. As the breast cancer at women is aged younger than 40 years it is noted seldom, increase is small in comparison with the general risk of developing a breast cancer. Relationship of cause and effect with reception of oral contraceptives is not proved. Detailed information in the sections CONTRAINDICATIONS and SPECIAL INSTRUCTIONS.

Special instructions

in the presence of any of states / risk factors stated below should weigh carefully potential risk and the expected advantage of use of the PDA in each individual case and to discuss it with the woman before she decides to begin administration of drug. at aggravation, strengthening or the first emergence of any of states stated below or risk factors the woman is recommended to see a doctor who can make the decision on need of medicament withdrawal.

Disturbance from the blood circulatory system. Use of any PDA is connected with the increased risk of a venous thrombembolia. The additional risk of developing of a venous thrombembolia is maximum within the first year of use of the combined contraceptive.

by

described exceptional cases of thrombosis of other blood vessels, for example arteries and veins of a liver, kidneys, mezenterialny vessels, vessels of a brain or a retina at the women applying the combined contraceptives. Communication with use of the PDA is not proved.

Symptoms venous or arterial tromboticheskikh / the thromboembolic or cerebrovascular phenomena can be

:

• unilateral lower extremity pain or their hypostasis;
• sudden expressed stethalgia with/without irradiation in the left hand;
• sudden short wind;
• suddenly begun cough;
• any the unusual, expressed, long headache;
• sudden partial or total loss of sight;
• diplopia;
• violation of the speech or aphasia;
• dizziness;
• a loss of consciousness with a partial epileptic attack or without it;
• weakness or severe sudden numbness of one party or one part of a body;
• violation of motility;
• acute abdomen.

Factors increasing risk of emergence venous or arterial tromboticheskikh / the thromboembolic phenomena or risk of a stroke at women:

• age;
• family anamnesis (a venous or arterial thrombembolia at close relatives at rather early age). If genetic predisposition is supposed, consultation of the expert before appointment of the CPC is necessary for the woman;
• a long immobilization, radical surgical interventions, any surgeries on the lower extremities, extensive injuries. In these cases it is recommended to stop use of medicine (at planned operations not less than for 4 weeks before carrying out) and not to resume its reception earlier than in 2 weeks after the termination of a remobilization. Purpose of antitrombotichesky therapy is in addition possible if reception of tablets was not stopped in the recommended terms;
• obesity (body mass index of 30 kg/m ² );
does not have
• a consensus of rather possible role of varicose veins and superficial thrombophlebitis in development of a venous thrombembolia;
• smoking (in combination with intensive smoking and increase in age the risk increases, especially at women 35 years are aged more senior);
• dislipoproteinemiya;
• AG;
• a disease of valves of heart;
• fibrillation of auricles.

to Women 35 years are aged more senior than

it is recommended to leave off smoking if they decided to accept the CPC. If the woman cannot refuse smoking, it is necessary to use other method of contraception, especially with other risk factors.

Existence of one of serious risk factors or multiple factors of risk of a disease of arteries or veins can be a contraindication. The women using the PDA have to see immediately a doctor at emergence of symptoms of possible thrombosis. In cases of suspicion of thrombosis or the confirmed thrombosis reception of the CPC needs to be stopped. It is required to pick up an adequate method of contraception owing to teratogenecity of anticoagulating therapy (coumarins).

needs to consider the increased risk of developing a thrombembolia during a puerperal period.

treat other diseases which can be connected with serious circulator violations: diabetes, system lupus erythematosus, hemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcer colitis).

Increase in frequency and weight of migraine or its aggravation during use of the PDA (that can be a prodromal symptom of violation of cerebral circulation) can demand urgent phase-out of the CPC.

Tumour. Results of some epidemiological researches indicate additional increase in risk of developing cervical cancer at prolonged use of the CPC (5 years), however this statement is still controversial as it is finally not found out as far as results of researches consider sexual behavior and contributing factors of risk, for example human papillomavirus.

Research is pointed to slight increase of risk of developing a breast cancer at the women using the PDA. This increased risk gradually disappears within 10 years after the end of reception of the CPC.

In rare instances at the women using the PDA were observed by

benign, and is even more rare — malignant tumors of a liver. In some cases these tumors caused life-threatening intra belly bleeding. In case of complaints to the expressed pain in epigastric area, increase in a liver or symptoms of intra belly bleeding at differential diagnostics it is necessary to consider a possibility of presence of a tumor of a liver at the women accepting the CPC.

Other states. Women with a gipertriglitseridemiya or with this violation in the family anamnesis make risk group of development of pancreatitis at use of the PDA.

Though small increase in the ABP is described by

at many women accepting the CPC, clinically significant increase in the ABP is the single phenomenon. Only in rare instances immediate phase-out of the CPC is necessary. If during use of the PDA in cases of AG of the ABP existing earlier it is constantly raised or hypotensive therapy does not give adequate effect, reception of the CPC needs to be stopped. If necessary reception of the CPC can be continued if thanks to hypotensive therapy the AD normal values are reached.

to

It was reported about emergence or exacerbation of the diseases provided below during pregnancy and at use of the PDA, but their connection with use of the PDA is not finally found out: jaundice and/or an itch connected with a cholestasia; formation of stones in a gall bladder; porphyria; system lupus erythematosus; gemolitiko-uraemic syndrome; Sydenham's chorea; herpes of pregnant women; the hearing loss connected with an otosclerosis.

In sharp or chronic abnormal liver functions the need for phase-out of the CPC until indicators of function of a liver are not normalized can arise. At a recurrence of cholestatic jaundice which for the first time arose during pregnancy or the previous use of sex hormones the reception of the CPC should be stopped.

Though PDA can affect peripheral insulin resistance and tolerance to glucose, there are no data on need to change the therapeutic mode at the women with diabetes accepting the low-dosed PDA (containing ≤0.05 mg of ethinylestradiol). However women with diabetes have to be under careful observation during reception of the CPC.

Crohn's disease and ulcer colitis can be connected by

with use of the PDA.

hloazma, especially at women with hloazmy pregnant women in the anamnesis can Sometimes arise. The women inclined to emergence of a hloazma have to avoid influence of direct sunshine and ultra-violet radiation during reception of the CPC.

Medical examination. Before use of the PDA it is necessary to study carefully the anamnesis of the patient, including family and to perform medical examination, to exclude pregnancy. It is necessary to measure the ABP and to perform the general inspection, in view of contraindications (see CONTRAINDICATIONS) and side reactions (see. Side EFFECTS). It is necessary that the patient attentively read the instruction for medical use and followed the recommendations specified in it. Frequency and the nature of surveys have to be based on the existing norms of medical practice taking into account specific features of each woman.

Should warn the patient that oral contraceptives do not protect from HIV infection (AIDS) and other diseases, sexually transmitted.

Decrease in efficiency. The efficiency of the CPC can decrease in case of the admission of tablets, violations from a GIT or at a concomitant use of other medicines.

Control of a cycle. At reception of the CPC there can be intermenstrual bleedings (smearing bloody discharges or breakthrough bleedings), especially within the first months of use of medicine. Considering it, examinations at appearance of any irregular bleedings should be performed only after the period of adaptation of the organism to medicament making about 3 cycles.

If irregular bleedings proceed or arise after several normal regular cycles, it is necessary to consider a question of the non-hormonal reasons and to hold the relevant diagnostic activities for an exception of malignant new growths or pregnancy. They can include a curettage. At some women there can not come menstrual bleeding during a break in reception of the CPC. If PDA accepted as directed, described in the section USE, then pregnancy is improbable. Nevertheless, if application of a contraceptive was carried out irregularly or if menstrual bleeding is absent during 2 cycles, before continuation of use of the PDA it is necessary to exclude pregnancy.

Medications on the basis of herbs containing a St. John's wort (Hypericum perforatum) should not be applied along with Siluyet as they can reduce medicine level in blood plasma and reduce efficiency of a combination of the diyenogest with ethinylestradiol.

Medicine contains 47.66 mg of lactose in 1 tablet. The patients with rare hereditary intolerance of a galactose, a lactose intolerance of Lapp or violations of absorption of glucose galactose who are on a diet with a lactose exception have to consider it.

Use during pregnancy and feeding by a breast. Drug is contraindicated during pregnancy. In case of approach of pregnancy during Siluyet's application the administration of medicament needs to be stopped. However results of epidemiological researches do not indicate increase in risk of emergence of congenital defects in the children who were born at the women accepting oral contraceptives before pregnancy as well as on existence of teratogenic action at inadvertent reception of oral contraceptives in early pregnancy. Such researches with the medicine Siluyet were not conducted.

Hormonal contraceptives can reduce development of milk and change its structure and also in a small amount get into breast milk therefore intake of these medicines during feeding by a breast is contraindicated.

Children. Drug is not intended for application for children.

Ability to influence speed of response at control of vehicles or work with other mechanisms. The tablets Siluyet do not affect ability to control of vehicles or work with mechanisms with the increased risk of traumatism.

Interaction

Interaction, connected with activation of microsomal enzymes (for example hydantoin, phenobarbital, Primidonum, carbamazepine, rifampicin and, perhaps, also a rifabutina, efavirenets, not Virapinum, an okskarbazepin, the topiramat, the felbamat, a ritonavir, griseofulvin and the medicines containing a St. John's wort), between oral contraceptives and other medicines can be led to breakthrough bleedings and/or to decrease in contraceptive effect. the mechanism of these interactions is based on ability of the above-stated medicines to activate microsomal enzymes of a liver.

Results of some researches give to

chance to assume that enterogepatichesky circulation of estrogen can decrease at reception of certain antibiotics which can reduce concentration of ethinylestradiol (for example antibiotics of a penicillinic and tetracycline row).

At treatment by any of the medicines given above the woman has to use temporarily a barrier method of contraception in addition to reception of the CPC or choose other method of contraception.

At treatment by rifampicin a barrier method of contraception should be applied during the entire period of treatment by the corresponding medicine and on an extent of 28 days after the termination of its reception. If tablets of the CPC in packing already ended and it is necessary to take the accompanying drug, application of tablets from the following packing should be begun without usual break.

At prolonged use of the accompanying medicine having ability to activate liver enzymes, the doctor can consider need of increase in doses of contraceptive steroids. If this method leads to the undesirable phenomena (for example to irregular bleedings) or to decrease in efficiency, it is necessary to use other method of contraception.

Diyenogest at application in usual concentration is not inhibited by P450 cytochrome therefore interactions of this character are noted.

Laboratory researches. Reception of contraceptives can affect results of separate laboratory tests, including biochemical indicators of function of a liver, thyroid gland, adrenal glands and kidneys and also on levels of transport proteins of blood plasma, such as kortikosteroidsvyazyvayushchy globulin and lipidic and lipoprotein fractions, indicators of carbohydrate metabolism, coagulation and fibrinolysis. Changes usually happen within laboratory norms.

Overdose

Acute toxicity at the combined overdose of the diyenogest and ethinylestradiol very low. probability of emergence of symptoms of intoxication low even at children who accidentally took several pill.

At overdose the nausea, vomiting, insignificant bleeding from a vagina can arise. There is no antidote, treatment has to be symptomatic.

Storage conditions

does not demand special temperature storage conditions. to store in original packing for protection against light influence.