Зоэли®

General characteristics. Structure:

Active ingredients: 1,55 mg of oestradiol of a gemigidrat that sootveststvut 1,5 mg of oestradiol, 2,5 mg of a nomegestrol of acetate.

Excipients: cellulose microcrystallic, кросповидон, talc, magnesium stearate, silicon dioxide colloid, lactoses monohydrate.

Structure of a cover: опадрай the II white (polyvinyl alcohol, titanium dioxide, macrogoal 3350, talc.

Placebo excipients: cellulose microcrystallic, кросповидон, talc, magnesium stearate, silicon dioxide colloid, lactoses monohydrate.

Structure of a cover of placebo: опадрай the II yellow (polyvinyl alcohol, titanium dioxide, macrogoal 3350, talc, dye ferrous oxide yellow, dye ferrous oxide black.

Pharmacological properties:

Pharmacodynamics. The combined hormonal contraceptive drug containing estrogen 17β-estradiol and progestogen of a nomegestrol acetate.

Oestradiol (17β-эстрадиол) - the natural estrogen identical endogenous human 17β-эстрадиолу (E2). Unlike ethinylestradiol which is a part of other combined oral contraceptives E2 has no etinilny group in 17α-положении. At drug Zoeli® use average concentration of E2 are comparable to those in an initial follicular phase and a late phase of a yellow body of a menstrual cycle.

Nomegestrola acetate is the high-selection progestogen which is to derivatives of natural steroid hormone of progesterone and structurally similar to it. Nomegestrola acetate has the expressed affinity to a human receptor of progesterone, has the high anti-gonadotropic activity moderated by anti-androgenic activity and has no oestrogenic, androgenic, glucocorticoid and mineralokortikoidny activity.

The contraceptive effect of the drug Zoeli® is caused by a combination of various factors, the most important of which consist in suppression of an ovulation and change of secretion of cervical slime. At reception of Zoeli® of a nomegestrol acetate generally suppresses an ovulation, and E2 strengthens effects of progestogen. After cancellation of Zoeli® at most of women the ovulation is quickly recovered.

During reception concentration of folic acid in serum does not change and remains at basic level within 6 consecutive months of administration of drug of Zoeli®.

In clinical trials it was established that Perl's index for women aged from 18 up to 50 years made 0.66 (the upper bound of 95% of a confidence interval 1.07), and for women aged from 18 up to 35 years Perl's index made 0.75 (the upper bound of 95% of a confidence interval 1.23).

In clinical trials it was established that at reception of Zoeli® portability of glucose and sensitivity to insulin did not change, clinically significant effects on metabolism of lipids and a hemostasis are not revealed. Reception of Zoeli® increased the content of proteins of carriers thyroxine - the connecting globulin and the corticosteroid-the connecting globulin (CCG), but to a lesser extent, than a levonorgestrel combination with ethinylestradiol. At administration of drug of Zoeli® the content of the globulin, connecting sex hormones (G,CSH) slightly increased, the content of androstendion, a degidroepiandrosteron, the general and free testosterone considerably decreased. After 13 cycles of administration of drug pathological changes at a histologic research of an endometria were not observed.

Pharmacokinetics. Oestradiol (E2). Absorption. 17β-эстрадиол (E2) is exposed to the expressed metabolism at "the first passing" after intake. Absolute bioavailability makes about 5%. Meal does not exert clinically significant impact on bioavailability of E2.

Distribution. Distribution of exogenous and endogenous E2 similar. Estrogen is actively distributed on all organism. Their concentration are usually higher in target organs of sex hormones. In blood oestradiol contacts GSPG (37%) and albumine (61%) and only 1-2% of oestradiol circulate in an untied look.

Cmax E2 in serum makes about 90 pg/ml and is reached in 6 h after reception. Average serumal concentration - 50 pg/ml. These concentration of E2 correspond to that in initial and late phases of a menstrual cycle.

Metabolism and removal. Exogenous E2 biotransformirutsya actively after intake. Metabolism of exogenous and endogenous E2 similar. E2 quickly turns into several metabolites in intestines and a liver, generally in estrone (E1) which in the subsequent are conjugated and exposed to enterohepatic circulation. There is a dynamic equilibrium between E2, E1 and E1 sulfate (E1S) due to activity of various enzymes, including E2 dehydrogenase, sulfotransferases and arylsulphatases. Oxidation of E1 and E2 happens under the influence of P450 cytochrome isoenzymes, in the main CYP1A2, CYP1A2 (out of a liver), CYP3A4, CYP3A5, CYP1B1 and CYP2C9.

E2 is quickly brought out of blood. Due to metabolism and enterohepatic circulation there is a big pool of the circulating sulfates and glucuronides of estrogen. As a result, T1/2 E2 varies over a wide range and makes 8.4±6.4 h later in/in introductions.

Nomegestrola acetate. Absorption. Nomegestrola acetate is quickly soaked up after intake. After a single dose of Cmax in plasma makes about 7 ng/ml and it is reached in 2 h. Absolute bioavailability after a single dose makes 63%. Food does not exert clinically significant impact on bioavailability of a nomegestrol of acetate.

Linearity of pharmacokinetics depending on a dose was noted in the range of 0.625-5 mg (estimated at women of reproductive and postmenopauzny age).

Distribution. Nomegestrola acetate actively contacts albumine (97-98%), but does not contact GSPG or KSG.

GSPG does not exert impact on pharmacokinetics of a nomegestrol of acetate. The equilibrium state is reached in 5 days. Average Css makes 4 ng/ml. Cmax of a nomegestrol of acetate in plasma makes about 12 ng/ml and is reached in 1.5 h after administration of drug in an equilibrium state.

Metabolism. Nomegestrola acetate is metabolized to several inactive hydroxylated metabolites under the influence of liver P450 cytochrome isoenzymes, in the main CYP2C8, CYP2C19, CYP3A4 and CYP3A5. Nomegestrola acetate and its hydroxylated derivatives are exposed to the expressed metabolism 2 phases with formation of glyukuronidny and sulphatic conjugates. The clearance in an equilibrium state makes 26 l/h.

In vitro of a nomegestrol acetate has no the essential inducing or inhibiting effect on isoenzymes of P450 cytochrome and does not interact with a P-glycoprotein.

Removal. T1/2 in an equilibrium state makes 46 h (from 28 to 83 h). T1/2 of metabolites is not established.

Nomegestrola acetate is brought by kidneys and through intestines. About 80% of a dose are removed by kidneys and through intestines within 4 days. Nomegestrola acetate is almost completely brought within 10 days. Removal through intestines exceeds excretion kidneys.

Pharmacokinetics in special clinical cases. Pharmacokinetic modeling did not reveal distinctions of pharmacokinetics of a nomegestrol of acetate at girls at the age of 12-17 years after approach of menarche and at adult women.

Influence of diseases of kidneys on pharmacokinetics of the drug Zoeli® was not studied.

Influence of diseases of a liver on pharmacokinetics of Zoeli® was not studied. However at patients with an abnormal liver function deterioration in metabolism of sex hormones is possible.

The drug pharmacokinetics at representatives of ethnic groups specially was not studied.

Indications to use:

Contraception.

Route of administration and doses:

Drug is intended for intake. Recommendations about reception of tablets are identical to all women.

Pill is taken daily at the same time day irrespective of meal in the order specified on packaging if necessary washing down with a small amount of water. It is necessary to accept on 1 таб. / days during 28 days in a row. Reception should be begun with the white tablets containing active ingredients during the first 24 days, and during the next 4 days - the yellow tablets which are not containing active ingredients (placebo). Reception of tablets from each subsequent packaging should be begun next day after reception of the last tablet from the previous packaging, irrespective of existence or absence of bleeding of cancellation. Cancellation bleeding usually begins in 2-3 days after reception of the last white tablet and can not stop by the beginning of reception of tablets from the following packaging.

Beginning of administration of drug of Zoeli®. In the absence of the previous use of hormonal contraceptives. Reception of tablets should be begun in the 1st day of a menstrual cycle (in the first day of menstrual bleeding). In this case use of additional contraceptive resources is not required. It is possible to begin reception of tablets and from the 2-5th day of a cycle, but then during the first 7 days of reception of tablets it is recommended to use a barrier method of contraception in addition.

Transition from the combined hormonal contraceptive (the combined oral contraceptive, a vaginal ring or a transdermalny plaster)

Administration of drug of Zoeli® is recommended to be begun next day after reception of the last tablet containing active ingredients, but no later than next day after end of a usual interval between cycles or reception of tablets of placebo. If the woman used a vaginal ring or a transdermalny plaster, then it is desirable to begin administration of drug of Zoeli® in day of their removal, but no later than in day when it would be necessary to enter a new ring or to paste the next plaster.

If the woman constantly and correctly used the previous method of contraception, and there are no doubts that she is not pregnant, then it is possible to pass to administration of drug of Zoeli® also into any in day. It is not necessary to exceed the recommended bezgormonalny interval of the previous method at all.

Transition from the drugs containing only progestogen (tablets, implants, injection forms or gormonosoderzhashchy intrauterine systems - Naval Forces)

The woman can stop reception of the tablets containing only progestogen in any day and next day to begin administration of drug of Zoeli®. The implant or Naval Forces can be removed in any day, administration of drug of Zoeli® should be begun in day of their removal.

If the woman received injections, then reception of Zoeli® is begun in day when it was necessary to make the next injection. In all these cases to the woman recommend to use in addition a barrier method of contraception during the first 7 days of reception of the tablets containing active ingredients.

After the abortion made in the I trimester of pregnancy. The woman can begin administration of drug at once; in this case there is no need for an additional method of contraception.

After the delivery or abortion in the II trimester of pregnancy. The woman should begin administration of drug between the 21st and 28th day after the delivery or abortion in the II trimester. At later beginning of administration of drug it is recommended to apply an additional barrier method of contraception during the first 7 days of reception of tablets. However if after the delivery or abortion there were already sexual contacts, before administration of drug of Zoeli® it is necessary to exclude pregnancy or to wait for the first periods.

In case of the admission of tablets. The recommendations given below concern only the admission of reception of the white tablets containing active ingredients.

If the woman takes the next pill with delay less than 12 h, then the contraceptive effect does not decrease. The woman should take a pill as soon as possible as soon as she remembers it. The subsequent pill needs to be taken in usual time.

If the woman takes an active pill with delay more than 12 h, then the contraceptive effect can decrease. At the admission of reception of tablets it is reasonable to carry out two rules:

— to achieve adequate suppression гипоталамо - pituitary and ovarian system, the white tablets containing active ingredients need to be accepted during, at least, 7 days in a row;

— the more it is passed the white tablets containing active ingredients and time of reception of 4 yellow tablets of placebo is closer, the risk of approach of pregnancy is higher.

If reception of one white tablet containing active ingredients is missed. The contraceptive effect is not reduced. The woman has to take the last passed white pill as soon as she remembers it even if she should take at the same time two pill. Then a pill should be taken as usual. Additional contraceptive measures are not required.

If reception of two white tablets or more is missed. If after the admission of reception of two or more white tablets containing active ingredients there was no cancellation bleeding during reception of yellow tablets of placebo, then it is necessary to exclude pregnancy.

Days 1-7. The woman has to take the last passed white pill as soon as she remembers it even if she should take at the same time two pill. Then a pill should be taken as usual. At the same time within the first week of continuous reception of white tablets it is necessary to use a barrier method of contraception. If during the previous 7 days sexual intercourse took place, then it is necessary to consider a possibility of approach of pregnancy.

Days 8-17. The woman has to take the last passed white pill as soon as she remembers it even if she should take at the same time two pill. Then a pill should be taken as usual. At the same time during the next 7 days of reception of white tablets it is necessary to use a barrier method of contraception.

Days 18-24. The risk of decrease in contraceptive effect increases with approach of the beginning of reception of yellow tablets of placebo. However change of the scheme of reception of tablets allows to avoid decrease in contraceptive action. The woman has to take the last passed white pill as soon as she remembers it even if she should take at the same time two pill. It is impossible to take at the same time more than two white pill containing active ingredients. During the next 7 days of reception of white tablets it is necessary to use a barrier method of contraception, and to begin the following packaging at once after the termination of white tablets from the previous packaging, i.e. the woman should not take a yellow pill of placebo. In this case cancellation bleeding usually comes during reception of yellow tablets from the following packaging, however during reception of white tablets breakthrough bleedings or the smearing allocations can be observed.

If the woman is not sure of number of the passed tablets or their color and, respectively, does not know what recommendations she should implement, then it is necessary to use a barrier method of contraception till the moment as the woman will take a white pill within 7 consecutive days.

If reception of yellow tablets of placebo is missed. The contraceptive effect is not reduced. The woman can not take a yellow pill from the last (fourth) number of the blister. However the passed tablets should be thrown out to avoid inadvertent increase in duration of a phase of placebo.

Recommendations in case of gastrointestinal frustration. In case of gastrointestinal frustration (for example, vomitings or diarrheas) absorption of drug can be incomplete therefore it is necessary to resort to additional measures of contraception.

If vomiting arises during 3-4 h after reception of a tablet, then its reception should be considered passed. If reception of one white tablet is missed, then the contraceptive effect is not reduced. If next day or days vomiting develops again, then it is necessary to implement recommendations about the admission of two and more tablets. If the woman does not want to change the usual scheme of reception of tablets, then she has to take an additional white pill or tablets from other packaging.

How to shift or delay approach of menstrualnopodobny bleeding. To delay approach of menstrualnopodobny bleeding, the woman should continue reception of white tablets from other packaging without reception of yellow tablets. White tablets from the second packaging can continue to be accepted until they do not end. After completion of reception of yellow tablets from the second packaging it is necessary to resume administration of drug of Zoeli® according to the usual scheme. At the extended scheme of reception breakthrough bleedings or the smearing allocations can be observed.

To displace day of the beginning of menstrualnopodobny bleeding the next day, it is possible to reduce a phase of reception of tablets of placebo (at most 4 days). The break is shorter, the risk of absence of menstrualnopodobny bleeding of cancellation and developing of breakthrough bleedings or the smearing bloody allocations is higher during reception of tablets from the second packaging.

Features of use:

Use at pregnancy and feeding by a breast. Use of the drug Zoeli® at pregnancy is contraindicated. In case of pregnancy at use of Zoeli® it is necessary to stop administration of drug.

In the majority of epidemiological researches increase in risk of inborn defects at children of the women accepting ethinylestradiol - the containing combined oral contraceptives before pregnancy was not revealed. At accidental reception at the beginning of pregnancy of the combined oral contraceptives containing ethinylestradiol teratogenic effects were not noted.

Limited experience of use of Zoeli® for pregnant women testifies to lack of undesirable influence of drug on a condition of a fruit or the newborn.

The combined oral contraceptives can exert impact on a lactation since they cause change of quantity and structure of breast milk. Therefore, use of the combined oral contraceptives is not recommended before complete cessation of breastfeeding. Small amounts of contraceptive steroids and/or their metabolites can be removed with breast milk, however there are no data on their undesirable influence on health of the newborn.

Use at abnormal liver functions. Contraindications: a serious illness of a liver, including in the anamnesis, before normalization of indicators of function of a liver; liver tumors (malignant or high-quality), including in the anamnesis.

Use for children. Data on efficiency and safety of use of drug for children aged up to 18 years are absent.

Special instructions. The data given below were obtained in epidemiological researches at use of the combined oral contraceptives containing ethinylestradiol. Зоэли® contains 17β-эстрадиол, nevertheless, the special instructions concerning reception of the combined contraceptives containing oestradiol are considered applicable and for Zoeli®.

Vascular disorders. In epidemiological researches connection between use of the combined oral contraceptives containing ethinylestradiol and the increased risk of arterial and venous thromboses and thromboembolisms, such as myocardial infarction, stroke, deep vein thrombosis and thromboembolism of a pulmonary artery is established. These complications develop seldom.

Use of any combined oral contraceptives containing ethinylestradiol is followed by increase in risk of the development of venous thromboses and embolisms which is the highest within the first year after the beginning of reception of the combined oral contraceptive. This increased risk is lower than risk of development of the venous thromboses and an embolism associated with pregnancy (60 for 100 000 cheloveko-years). At the women who are not accepting oral contraceptives, the risk of venous thromboses and an embolism makes 5-10 for 100 000 cheloveko-years. Venous fibrinferments and embolisms reach a limit with death in 1-2% of cases.

Data on influence of the drug Zoeli® on risk of development of venous thromboses and embolism in comparison with other combined oral contraceptives are absent.

At the patients accepting the combined oral contraceptives thrombosis of other vessels, including hepatic, mezenterialny, renal, cerebral arteries and veins or vessels of a retina exclusively seldom developed. There is no sufficient information about communication between emergence of these complications and use of the combined oral contraceptives.

Symptoms of venous and arterial thromboses can include the following states: the pain and/or hypostasis of a leg, the sudden megalgia in a breast which is irradiating or not irradiating in the left hand, a sudden asthma, sudden cough, an unusual heavy and long headache, sudden partial or total loss of sight, a diplopia, disturbance of the speech or aphasia, dizziness, the collapse which is followed or not followed by focal spasms, weakness or the expressed numbness which suddenly appear on one side of a body, motive frustration, a syndrome "acute abdomen".

Risk factors of venous thromboses and embolisms:

— age;

— existence of diseases in the family anamnesis (venous fibrinferments and embolisms at brothers, sisters or parents at rather early age). If genetic predisposition is supposed, then before reception of any hormonal contraceptives it is necessary to consult with the specialist;

— long immobilization, extensive operative measure, any lower extremity operation or serious injury. In these cases it is recommended to stop reception of hormonal contraceptives (at least in 4 weeks prior to planned surgical intervention) and to resume it only in 2 weeks after a complete recovery of a physical activity;

— obesity (IMT more than 30 kg/sq.m);

— perhaps, thrombophlebitis of superficial veins and varicosity.

There is no sufficient information about a role of these states in an etiology of venous thromboses.

Risk factors of arterial thromboses:

— age;

— smoking (the risk still more increases at intensive smoking, especially at women 35 years are more senior);

— dislipoproteinemiya;

— obesity (IMT more than 30 kg/sq.m);

— arterial hypertension;

— migraine;

— defect of valves of heart;

— fibrillation of auricles;

— existence of diseases in the family anamnesis (arterial fibrinferments at brothers, sisters or parents at rather early age). If genetic predisposition is supposed, then before reception of any hormonal contraceptives it is necessary to consult with the specialist.

Other states which were followed by undesirable vascular disorders: diabetes mellitus, system lupus erythematosus, hemolitic uraemic syndrome, inflammatory diseases of intestines (disease Krone and ulcer colitis) and sickemia.

It is necessary to consider the increased risk of tromboembolic episodes in a puerperal period.

Increase in frequency or weight of migraine (which can precede development of a cerebrovascular complication) is the basis for immediate cancellation of administration of drug of Zoeli®.

The women accepting the combined oral contraceptives need to see a doctor at emergence of possible symptoms of thrombosis. In cases of the assumed or confirmed thrombosis, reception of the combined oral contraceptive should be stopped. At the same time it is necessary to begin adequate contraception, considering teratogenecity of therapy by anticoagulants (coumarins).

Tumors. The most significant risk factor of development of cancer of neck of uterus - the persistent infection caused by a virus of papilloma of the person (HPV). In epidemiological researches it was shown that prolonged use of the combined contraceptives containing ethinylestradiol promotes increase in this risk, however remains not clear in what degree this effect is connected with other factors, such as more frequent research of a neck of uterus or feature of sexual behavior, including use of barrier contraceptives, or is a combination of these factors.

At use of the combined oral contraceptives in higher doses (50 mkg of ethinylestradiol) the risk of development of endometrial cancer and ovaries decreases. Remains not clear whether it extends to the combined oral contraceptives containing 17β-эстрадиол.

At meta-analysis of 54 epidemiological researches at the women receiving ethinylestradiol - the containing combined oral contraceptives, small increase in relative risk of development of a breast cancer was revealed (relative risk = 1.24). The increased risk gradually disappears within 10 years after the termination of reception of the combined oral contraceptives. The breast cancer seldom develops at women aged up to 40 years therefore the additional number of cases of a breast cancer at women who accept or was accepted by the combined oral contraceptives, small in comparison with the general risk of a breast cancer. The breast cancer diagnosed for the women applying the combined oral contraceptives is clinically less expressed, than the revealed cancer at the women never using these drugs. During use of the combined oral contraceptives the risk of a breast cancer slightly increases that is perhaps caused by earlier diagnosis, effect of drug or a combination of these two factors.

In rare instances at the women accepting the combined oral contraceptives observed development of benign tumors of a liver and is even more rare - malignant. In some cases these tumors led to life-threatening intra belly bleedings. At emergence of a megalgia in an upper part of a stomach, increase in a liver or symptoms of intra belly bleeding at the women accepting the combined oral contraceptives it is necessary to exclude a liver tumor.

Other states. At women with a gipertriglitseridemiya or the corresponding family anamnesis the risk of development of pancreatitis at reception of the combined oral contraceptives is increased.

At many women receiving the combined oral contraceptives noted small increase in the ABP though clinically significant increase in the ABP was observed seldom. Communication between reception of the combined oral contraceptives and development of arterial hypertension is not established. However if against the background of reception of the combined oral contraceptive persistent arterial hypertension develops, then it is reasonable to cancel the combined oral contraceptives and to appoint anti-hypertensive therapy. At adequate control of the ABP by means of anti-hypertensive drugs resuming of reception of the combined oral contraceptive is possible. In clinical trials duration till 1 year did not reveal clinically significant changes of the ABP at use of Zoeli®.

Against the background of pregnancy and during use of the combined oral contraceptives development or deterioration in the following states was noted though their communication with reception of contraceptives is not finalized: the jaundice and/or an itch connected with a cholestasia, formation of stones in a gall bladder, a porphyria, a system lupus erythematosus, a hemolitic uraemic syndrome, a chorea of Sidenkhem, gestational herpes, the hearing loss connected with an otosclerosis, (hereditary) Quincke's disease.

At acute and chronic abnormal liver functions cancellation of the combined oral contraceptives until indicators of function of a liver are normalized can be required. At a recurrence of the cholestatic jaundice for the first time observed at pregnancy or at the previous use of sexual steroids it is necessary to stop reception of the combined oral contraceptives.

Need for change of the scheme of reception of the low-dosed combined oral contraceptives (containing less than 0.05 mg of ethinylestradiol) at women with diabetes is absent. However it is necessary to perform carefully periodic inspections of the women with a diabetes mellitus accepting the combined oral contraceptives, especially within the first months. Зоэли® also tolerance to glucose at healthy women does not exert impact on insulin resistance of peripheral fabrics.

Deterioration in a course of a depression, disease Krone and ulcer colitis were associated with reception of the combined oral contraceptives.

Sometimes the hloazma, especially at women with this disease in the anamnesis developed. The women predisposed to development of a hloazma should avoid solar radiation or influence of ultra-violet light during reception of the combined oral contraceptives.

Medical inspections / consultations. Before purpose of drug it is necessary to study carefully the medical anamnesis (including family) women and to exclude pregnancy.

It is necessary to measure the ABP and in the presence of indications to conduct physical examination taking into account contraindications and cautions. The interval between control medical examinations is defined in each case separately, but at least 1 time in 6 months.

Women have to be informed that the combined oral contraceptives do not protect from HIV infection (AIDS) and from other diseases, sexually transmitted.

Decrease in efficiency. Efficiency of the combined oral contraceptives can decrease in case of the admission of tablets, gastrointestinal frustration during reception of active tablets or the accompanying therapy.

Changes of character of periods. As well as at reception of any combined oral contraceptives, breakthrough bleedings or the smearing allocations, especially in the first several months can be observed. Therefore, carrying out inspection at irregular bleedings is proved only after the adaptation period (about 3 cycles). If irregular bleedings remain or arise after the previous regular cycles, it is necessary to assume the non-hormonal reasons and to conduct diagnostic testings for an exception of a malignant tumor or pregnancy. The diagnostic scraping can be required.

In clinical trials the women accepting the drug Zoeli®, had a low frequency of the side effects connected with bleedings. Bleedings of cancellation were easy, short-term (on average 3-4 days) and frequent less painful.

Some women accepting the drug Zoeli® noted absence of bleeding of cancellation during reception of yellow tablets of placebo though they were not pregnant. In such cases absence of bleeding of cancellation was not associated with higher frequency of irregular bleedings in the following cycles. The nature of menstrualnopodobny bleedings at the beginning of administration of drug of Zoeli® (cycles 2-4) allow to predict the nature of menstrualnopodobny bleedings in the subsequent cycles.

If at reception of Zoeli® according to the recommended mode of dosing there is no cancellation bleeding, then probability of pregnancy low. However if the woman did not accept drug according to these recommendations or two bleedings of cancellation are absent in a row, then it is necessary to exclude pregnancy.

Laboratory analyses. The data obtained concerning the combined oral contraceptives showed that use of these drugs can exert impact on results of some laboratory analyses, including biochemical indicators of function of a liver, thyroid gland, adrenal glands and kidneys, on concentration of transport proteins in plasma, for example, on corticosteroid hormones, on fractions of lipids/lipoproteids, indicators of carbohydrate metabolism, coagulability of blood and a fibrinolysis. Usually these changes remain within normal values.

Use in pediatrics. Data on efficiency and safety of use of drug for children and teenagers aged up to 18 years are absent.

Influence on ability to driving of motor transport and to control of mechanisms. The drug Zoeli® does not exert impact on ability to manage vehicles and to work with mechanisms.

Side effects:

Portability of the drug Zoeli® good, and the profile of safety is similar to that of other combined oral contraceptives. Possible undesirable effects which were registered at drug use are listed in the table.

Determination of frequency of side reactions: often (≥1/100), infrequently (<1/100, ≥1/1000), it is rare (<1/1000).

Side effects which arose at reception of the combined oral contraceptives containing ethinylestradiol: venous and arterial thromboembolisms, increase in the ABP, hormonedependent tumors (for example, liver tumors, breast cancer), hloazma.

Frequency of detection of a breast cancer above at the women accepting the combined oral contraceptives is insignificant. The breast cancer is observed seldom at women up to 40 years and the quantity of additional cases at reception of the combined oral contraceptives are not enough in comparison with the general risk of a breast cancer. Connection with reception of the combined oral contraceptives is not established.

At patients with a renal failure or a liver researches of drug were not conducted. At women with an abnormal liver function deterioration in metabolism of steroid hormones is possible.

Interaction with other medicines:

For an exception of possible interaction it is necessary to study the application instruction of the accompanying drugs.

Influence of other medicines on Zoeli®. Interaction of oral contraceptives with other medicines can lead to breakthrough bleedings and/or decrease in efficiency of contraception. In literature medicinal interaction with the combined oral contraceptives in general is described.

Hepatic metabolism: interaction with inductors of microsomal enzymes of a liver is possible that can lead to increase in clearance of sex hormones. Interaction, for example, with Phenytoinum, barbiturates, Primidonum, carbamazepine, rifampicin, and also, perhaps, with okskarbazepiny, topiramaty, felbamaty, the griseofulvin and drugs containing a St. John's Wort made a hole (Hypericum perforatum) is established. HIV protease inhibitors (for example, ритонавир) and nenukleozidny inhibitors of the return transcriptase (for example, not Virapinum) and their combinations also exerted impact on hepatic metabolism.

During the accompanying administration of drugs, inducing microsomal enzymes, and within 28 days after their cancellation it is necessary to use barrier methods of contraception. In need of prolonged treatment by the drugs inducing microsomal enzymes it is necessary to consider use of other method of contraception.

The drugs inhibiting microsomal enzymes (for example, кетоконазол), can cause increase in concentration of sex hormones in plasma.

Antibiotics: decrease in efficiency of the oral contraceptives containing ethinylestradiol was noted at the accompanying reception of antibiotics, such as ampicillin and tetracyclines. The mechanism of this effect is not studied. Data on interaction of antibiotics with the contraceptives containing 17β-эстрадиол no. The women accepting antibiotics (except for rifampicin and griseofulvin), have to use in addition a barrier method of contraception during the entire period of therapy by antibiotics and within 7 days after their cancellation. If the period during which the barrier method of contraception is applied proceeds also after the end of reception of white tablets from packaging of Zoeli®, then it is necessary to miss reception of yellow tablets from the current packaging and at once to begin reception of white tablets from the following packaging.

Influence of the drug Zoeli® on other medicines. Oral contraceptives can influence metabolism of other medicines. Respectively, their concentration in plasma and fabrics can increase (for example, cyclosporine) or to decrease (for example, ламотриджин).

Contraindications:

There are no epidemiological data on use of the combined oral contraceptives containing 17β-эстрадиол however contraindications to use of the drug Zoeli® correspond to contraindications to use of the contraceptives containing ethinylestradiol. In case of any of these states during use of Zoeli® it is necessary to stop administration of drug immediately:

— a deep vein thrombosis or a thromboembolism of a pulmonary artery, including in the anamnesis;

— arterial fibrinferments (a myocardial infarction, disturbance of cerebral circulation) or prodromal states (the tranzitorny ischemic attack, stenocardia), including in the anamnesis;

— migraine with focal neurologic symptoms, including in the anamnesis;

— the expressed or multiple factors of risk of venous or arterial thromboses, such, as: a diabetes mellitus with vascular symptoms, heavy arterial hypertension, a heavy dislipoproteinemiya;

— the hereditary or acquired predisposition to development of venous or arterial thrombosis, for example, resistance of the activated protein With, deficit of antithrombin III, deficit of proteins of C and S, a gipergomotsisteinemiya and anti-phospholipidic antibodies (antibodies to cardiolipin, lupoid anticoagulant);

— pancreatitis with a heavy gipertriglitseridemiya, including in the anamnesis;

— a serious illness of a liver, including in the anamnesis, before normalization of indicators of function of a liver;

— liver tumors (malignant or high-quality), including in the anamnesis;

— known or estimated hormonedependent malignant tumors (for example, generative organs or mammary gland);

— vaginal bleedings of not clear etiology;

— postmenopause;

— the established or alleged pregnancy;

— period of a lactation (breastfeeding);

— deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption;

— hypersensitivity to drug components.

With care. In the presence of any of the listed below states/diseases it is necessary to estimate advantage of use Zoeli® and possible risk for each woman. It should be discussed with the woman still before she begins administration of drug of Zoeli®. In cases of deterioration, an exacerbation of a disease or emergence of any of these states for the first time the woman should see a doctor for the solution of a question of a possibility of further use of Zoeli®:

— a diabetes mellitus without defeat of vessels;

— heavy depression or existence of this disease in the anamnesis;

— system lupus erythematosus;

— disease Krone;

— ulcer colitis;

— abnormal liver functions;

— a gipertriglitseridemiya, including in the family anamnesis;

— risk factors of an ischemic heart disease (obesity, smoking in 35 years is also more senior, arterial hypertension);

— long immobilization or extensive surgery;

— existence in the family anamnesis of venous thromboses, an arterial embolism at brothers, sisters or parents at rather young age.

Overdose:

It was not reported about serious side effects as a result of overdose. Repeated use of Zoeli® in doses which by 5 times exceeded recommended and a single dose of a nomegestrol of acetate in doses which by 40 times exceeded recommended, were not followed by undesirable reactions.

Symptoms which can arise at overdose: nausea, vomiting, bloody allocations from a vagina.

Treatment: in case of symptoms of overdose performing symptomatic therapy is shown. Specific antidotes do not exist.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature from 2 °C to 30 °C. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

28 pieces - blisters from PVC / aluminum foil (1) in a set with a sticker with days of the week - packs cardboard.
28 pieces - blisters from PVC / aluminum foil (3) in a set with a sticker with days of the week - packs cardboard.