Zoely film-coated pills 2.5 mg + 1.5 mg N28
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Active ingredients
Nomegastrol + Estradiol
Release form
Pills
Composition
1 tablet contains: Active substance: estradiol hemihydrate 1.55 mg, estradiol 1.5 mg, nomegestrol acetate 2.5 mg Auxiliary substances: microcrystalline cellulose - 14 mg, crospovidone - 2.4 mg, talc - 0.7 mg, magnesium stearate - 0.7 mg, colloidal silicon dioxide - 0.44 mg , lactose monohydrate - 57.71 mg. The composition of the shell: opadry II white - 1.6 mg (polyvinyl alcohol - 0.64 mg, titanium dioxide - 0.4 mg, macrogol 3350 - 0.32 mg, talc - 0.24 mg).
Pharmacological effect
Combined hormonal contraceptive drug containing estrogen 17β-estradiol and progestogen nomegestrol acetate. Estradiol (17β-estradiol) is a natural estrogen, identical to the endogenous human 17β-estradiol (E2). Unlike ethinyl estradiol, which is part of other combined oral contraceptives, E2 does not have an ethynyl group in the 17α position. When using the drug Zoely; The average concentrations of E2 are comparable to those in the initial follicular phase and the late phase of the corpus luteum of the menstrual cycle. Nomestrol acetate is a highly selective progestogen that is derived from natural steroid hormone progesterone and is structurally similar to it. Nomegastrol acetate has a pronounced affinity for the human progesterone receptor, has a high antigonadotropic activity, moderate anti-androgenic activity and does not possess estrogenic, androgenic, glucocorticoid and mineralocorticoid activity. The contraceptive effect of the Zoely drug; due to a combination of various factors, the most important of which are in suppressing ovulation and changing the secretion of cervical mucus. When taking Zoely; Nomegestrol acetate mainly suppresses ovulation, and E2 enhances the effects of progestogen. After the abolition of Zoely; in most women, ovulation is quickly restored. During administration, serum folate concentration does not change and remains at a basic level for 6 consecutive months of taking Zoely;. In clinical studies, it was found that Pearl's index is for women aged 18 to 50 years amounted to 0.66 (the upper limit of the 95% confidence interval 1.07), and for women aged 18 to 35, the Pearl index was 0.75 (the upper limit of the 95% confidence interval 1.23). In clinical studies, it was found that the name of Zoely; glucose tolerance and insulin sensitivity did not change, there were no clinically significant effects on lipid metabolism and hemostasis.Reception Zoely; increased the content of protein carriers of thyroxin-binding globulin and corticosteroid-binding globulin (CSG), but to a lesser extent than the combination of levonorgestrel with ethinyl estradiol. When taking the drug Zoely; the content of sex hormone-binding globulin (SHBG) slightly increased, androstenedione, dehydroepiandrosterone, total and free testosterone significantly decreased. After 13 cycles of the drug was not observed pathological changes in the histological study of the endometrium.
Pharmacokinetics
Estradiol (E2) Absorption 17β-estradiol (E2) undergoes a pronounced metabolism during the first passage after oral administration. Absolute bioavailability is approximately 5%. Eating does not have a clinically significant effect on the bioavailability of E2. The distribution of exogenous and endogenous E2 is similar. Estrogens are actively distributed throughout the body. Their concentrations are usually higher in the target organs of sex hormones. In the blood, estradiol binds to SHBG (37%) and albumin (61%) and only 1-2% of estradiol circulates in unbound form. Cmax E2 in serum is about 90 pg / ml and is reached 6 hours after ingestion. Average serum concentrations are 50 pg / ml. These concentrations of E2 correspond to those in the initial and late phases of the menstrual cycle. Metabolism and excretion Exogenous E2 is actively biotransformed after ingestion. The metabolism of exogenous and endogenous E2 is similar. E2 quickly turns into several metabolites in the intestine and liver, mainly in estrone (E1), which are subsequently conjugated and undergo enterohepatic circulation. There is a dynamic equilibrium between E2, E1 and E1-sulfate (E1S) due to the activity of various enzymes, including E2-dehydrogenase, sulfotransferase and aryl sulfatase. Oxidation of E1 and E2 occurs under the action of cytochrome P450 isoenzymes, mainly CYP1A2, CYP1A2 (outside the liver), CYP3A4, CYP3A5, CYP1B1 and CYP2C9.E2 is rapidly eliminated from the blood. Due to metabolism and enterohepatic circulation there is a large pool of circulating sulphates and estrogen glucuronides. As a result, T1 / 2 E2 varies widely and amounts to 8.4 ± 6.4 h after iv administration. Nomestrol acetate Absorption Nomegrol acetate is rapidly absorbed after ingestion. After a single dose of Cmax in plasma is about 7 ng / ml and is achieved after 2 hours. The absolute bioavailability after a single dose is 63%.Food does not have a clinically significant effect on the bioavailability of nomegastrol acetate. Dose-dependent pharmacokinetics were dose-dependent in the range of 0.625–5 mg (estimated in women of reproductive and post-menopausal age). The distribution of Homestrol acetate is actively associated with albumin (97-98%), but not associated GSPG or KSG.GSPG does not affect the pharmacokinetics of nomegestrol acetate. The equilibrium state is reached in 5 days. The average Css is 4 ng / ml. Cmax of nomegastrol acetate in plasma is about 12 ng / ml and is reached 1.5 hours after taking the drug in an equilibrium state. Metabolism Nomestrol acetate is metabolized to several inactive hydroxylated metabolites under the action of liver cytochrome P450 isoenzymes, mainly CYP2C8, CYP2C19, CYP3444a4a4a4a44a44a4. Nomegastrol acetate and its hydroxylated derivatives undergo a pronounced 2 phase metabolism to form glucuronide and sulfate conjugates. The equilibrium clearance is 26 l / h. In vitro nomegestrol acetate does not have a significant inducing or inhibitory effect on the cytochrome P450 isoenzymes and does not interact with P-glycoprotein. Excretion of T1 / 2 in the equilibrium state is 46 hours (from 28 to 83 hours). T1 / 2 metabolites not established. Nomegastrol acetate is excreted by the kidneys and through the intestines. Approximately 80% of the dose is excreted by the kidneys and through the intestines for 4 days. Nomegestrol acetate is almost completely excreted within 10 days. Excretion through the intestine exceeds kidney excretion. Pharmacokinetics in special clinical situations. Pharmacokinetic modeling revealed no differences in the pharmacokinetics of nomegrol acetate in girls aged 12–17 years after menarche and in adult women. The effect of kidney disease on the pharmacokinetics of Zoely; not studied. The effects of liver disease on the pharmacokinetics of Zoely; not studied However, in patients with impaired liver function, the metabolism of sex hormones may worsen. The pharmacokinetics of the drug in representatives of ethnic groups have not been specifically studied.
Indications
- contraception.
Contraindications
There are no epidemiological data on the use of combined oral contraceptives containing 17β-estradiol, however, contraindications to the use of the drug Zoely correspond to contraindications to the use of contraceptives containing ethinyl estradiol.If any of these conditions occur during the period of Zoeli's application, the drug should be immediately discontinued: - deep vein thrombosis or pulmonary embolism, incl. in history - arterial thrombosis (myocardial infarction, cerebrovascular accident) or prodromal conditions (transient ischemic attack, angina), incl. in history - migraine with focal neurological symptoms, incl. history of severe or multiple risk factors for venous or arterial thrombosis, such as: diabetes mellitus with vascular symptoms, severe arterial hypertension, severe dyslipoproteinemia, hereditary or acquired susceptibility to the development of venous or arterial thrombosis, for example, resistance of a protein-activated protein antithrombin III, deficiency of proteins C and S, hyperhomocysteinemia and antiphospholipid antibodies (antibodies to cardiolipin, lupus anticoagulant); - pancreatitis with strains loi hypertriglyceridemia, including in history; - severe liver disease, incl. in history, to normalization of liver function indicators; - liver tumors (malignant or benign), incl. in history - known or suspected hormone-dependent malignant tumors (for example, genital organs or mammary gland); - vaginal bleeding of unknown etiology; - postmenopause; - established or suspected pregnancy; - lactation period (breastfeeding); - lactase deficiency, lactose intolerance, glucose-galactose malabsorption; - hypersensitivity to the components of the drug. With caution If you have any of the following conditions / diseases, you should evaluate the benefits of using C Oeli and the possible risk for each woman. This should be discussed with the woman before she starts taking the drug. Zoely. In cases of worsening, exacerbation of the disease or the occurrence of any of these conditions, for the first time a woman should consult a doctor to decide on the possibility of further use of Zoely ;: - diabetes mellitus without vascular lesion; - severe depression or the presence of this disease in history; - Crohn's disease; - ulcerative colitis; - abnormal liver function; - hypertriglyceridemia, includingfamily history: risk factors for CHD (obesity, smoking 35 years and older, arterial hypertension); prolonged immobilization or extensive surgery; family history of venous thrombosis, arterial embolism in brothers, sisters or parents at a relatively young age .
Use during pregnancy and lactation
The use of the drug Zoely during pregnancy is contraindicated. In the case of pregnancy with the use of Zoely, the drug should be discontinued. In most epidemiological studies, there was no increase in the risk of congenital malformations in children of women who took ethinyl estradiol-containing combined oral contraceptives before pregnancy. In case of accidental use of combined oral contraceptives containing ethinyl estradiol at the beginning of pregnancy, no teratogenic effects were noted. The limited experience of using Zoely in pregnant women indicates the absence of undesirable effects of the drug on the condition of the fetus or newborn. Combined oral contraceptives can affect lactation, because . they cause a change in the amount and composition of breast milk. Therefore, the use of combined oral contraceptives is not recommended until complete cessation of breastfeeding. Small amounts of contraceptive steroids and / or their metabolites can be eliminated with breast milk, but there is no evidence of their undesirable effect on the health of the newborn.
Dosage and administration
The drug is intended for ingestion. Recommendations for taking the pills are the same for all women. Tablets are taken daily at the same time of the day, regardless of the meal, in the order indicated on the package, if necessary, with a small amount of water. It should be taken on 1 tab. / Day for 28 consecutive days. Reception should begin with white pills containing the active ingredients, within the first 24 days, and over the next 4 days - yellow pills that do not contain the active ingredients (placebo). Taking pills from each subsequent package should be started the next day after taking the last tablet from the previous package, regardless of the presence or absence of withdrawal bleeding.Withdrawal bleeding usually begins 2-3 days after taking the last white pill and may not stop by the start of taking the pills from the next package. Start taking Zoely; In the absence of previous use of hormonal contraceptives, you should start taking the pills on the 1st day of the menstrual cycle day of menstrual bleeding). In this case, the use of additional contraceptives is not required. You can start taking the pills from the 2nd to 5th day of the cycle, but then during the first 7 days of taking the pills, it is recommended to additionally use a barrier method of contraception. Transfer from a combined hormonal contraceptive (combined oral contraceptive, vaginal ring or transdermal patch) Taking the Soely drug; It is recommended to start the day after taking the last pill containing the active ingredients, but no later than the next day after completing the usual interval between cycles or taking placebo pills. If a woman used a vaginal ring or transdermal patch, then start taking the drug Zoely; preferably on the day of their removal, but not later than the day when you should introduce a new ring or stick another patch. If a woman constantly and correctly used the previous method of contraception, and there is no doubt that she is not pregnant, then go to the reception Zoeli's drug; can also be any day. In no case should you exceed the recommended hormone-free interval of the previous method. Transfer from drugs containing only progestogen (pills, implants, injection forms or hormone-containing intrauterine systems - IUD) A woman can stop taking pills containing only progestogen on any given day and day start taking the drug Zoely ;. The implant or IUD can be removed on any day, taking the Zoely drug; should begin on the day they are removed. If the woman received the injection, then take Zoely; begin on the day when you had to make another injection. In all these cases, the woman is recommended to additionally use a barrier method of contraception during the first 7 days of taking pills containing active substances. After abortion,produced in the first trimester of pregnancy. A woman can start taking the drug immediately; in this case, there is no need for an additional method of contraception. After delivery or abortion in the second trimester of pregnancy. Women should start taking the drug between the 21st and 28th day after delivery or abortion in the second trimester. At a later start of the drug is recommended to use an additional barrier method of contraception during the first 7 days of taking the pills. However, if after childbirth or abortion there was already sexual intercourse, before taking the drug Zoely; It is necessary to exclude pregnancy or wait for the first menstruation. If you miss a pill The following recommendations only concern not to take white pills containing active ingredients. If a woman takes another pill with less than 12 hours late, then the contraceptive effect is not reduced. A woman should take a pill as soon as possible as soon as she remembers. Subsequent pills must be taken at the usual time. If a woman takes an active pill more than 12 hours late, then the contraceptive effect may be reduced. When you skip taking pills, it is advisable to follow two rules: - to achieve adequate suppression of the hypothalamic-pituitary-ovarian system, white pills containing active ingredients must be taken for at least 7 consecutive days; - the more missed white pills containing active substances, and the closer the time taken to take 4 yellow placebo pills, the higher the risk of pregnancy. If you miss one white pill containing the active ingredients, the contraceptive effect is not reduced. A woman should take the last white pill she missed as soon as she remembers, even if she has to take two pills at the same time. Then the pills should be taken as usual. Additional contraceptive measures are not required. If two white pills or more are missed. If two or more white pills containing the active ingredients were missed, there was no withdrawal bleeding while taking yellow placebo pills, then pregnancy should be excluded. Days 1-7 The woman should take the last missed a white pill, as soon as she remembers, even if she had to take two pills at the same time. Then the pills should be taken as usual. At the same time during the first week of continuous use of white pills, you must use the barrier method of contraception.If during the previous 7 days there was sexual intercourse, then the possibility of pregnancy should be considered. Days 8-17 A woman should take the last missed white pill as soon as she remembers, even if she has to take two pills at the same time. Then the pills should be taken as usual. At the same time, over the next 7 days of taking white pills, you must use a barrier method of contraception. Days 18-24 The risk of a decrease in the contraceptive effect increases with the onset of the start of taking yellow placebo pills. However, a change in the pill regimen avoids a reduction in contraceptive action. A woman should take the last white pill she missed as soon as she remembers, even if she has to take two pills at the same time. You can not simultaneously take more than two white pills containing active ingredients. Over the next 7 days of taking the white pills, you must use a barrier method of contraception, and the next pack should be started immediately after the end of the white pills from the previous pack, i.e. women should not take yellow placebo pills. In this case, withdrawal bleeding usually occurs while taking the yellow pills from the next pack, but while taking the white pills, breakthrough bleeding or spotting may be observed. If the woman is not sure about the number of missed pills or their color and, accordingly, does not know what recommendations she should be taken, it is necessary to use a barrier method of contraception until the woman takes white pills for 7 consecutive days. If you miss the yellow placebo pills Contraceptive the effect is not reduced. A woman may not take yellow pills from the last (fourth) row of blisters. However, missed pills should be discarded to avoid an unintended increase in the duration of the placebo phase. Recommendations for gastrointestinal disorders In case of gastrointestinal disorders (such as vomiting or diarrhea), absorption of the drug may be incomplete, therefore additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after taking the pill, then its reception should be considered missed.If you miss one white pill, the contraceptive effect is not reduced. If vomiting develops again the next day or days, it is necessary to follow the recommendations for skipping two or more pills. If a woman does not want to change the usual pill regimen, she should take an additional white pill or pills from another package. To shift or delay the onset of menstrual bleeding To delay the onset of menstrual bleeding, a woman should continue taking white pills from another package without taking yellow pills. White pills from the second package can be continued until they run out. After you finish taking the yellow pills from the second pack, you must resume taking the drug Zoely; in the usual way. With an extended regimen, breakthrough bleeding or spotting may be observed. In order to shift the day of the onset of menstrual bleeding to another day, the phase of taking placebo pills can be reduced (maximum 4 days). The shorter the break, the higher the risk of the absence of menstrual-like withdrawal bleeding and the occurrence of breakthrough bleeding or spotting bleeding while taking the pills from the second package.
Side effects
The tolerability of the drug Zoely is good, and the safety profile is similar to that of other combined oral contraceptives. Side effects that occurred when taking combined oral contraceptives containing ethinyl estradiol: venous and arterial thromboembolism, increased blood pressure, hormone-dependent tumors (eg, liver tumors, breast cancer), chloasma. The frequency of breast cancer detection is slightly higher in women taking combined oral contraceptives. Breast cancer is rarely observed in women under 40 years of age and the number of additional cases when taking combined oral contraceptives is small compared with the overall risk of breast cancer. The relationship with the reception of combined oral contraceptives has not been established. In patients with impaired renal or liver function, no studies have been conducted. In women with impaired liver function, the metabolism of steroid hormones may worsen.
Overdose
No serious adverse effects have been reported as a result of overdose. Repeated use of Zoely in doses that are 5 times higher than recommended, and a single dose of nomegastrol acetate in doses that are 40 times higher than the recommended, were not accompanied by undesirable reactions. Symptoms that may occur during overdose: nausea, vomiting, bloody discharge from the vagina. Treatment: in case of overdose symptoms, symptomatic therapy is indicated. There are no specific antidotes.
Interaction with other drugs
To exclude possible interactions, it is necessary to familiarize yourself with the instructions for use of concomitant medications. Effect of other drugs on Zoelis Interaction of oral contraceptives with other drugs may lead to breakthrough bleeding and / or decrease in the effectiveness of contraception. The literature describes drug interactions with combined oral contraceptives in general. Hepatic metabolism: interaction with inducers of liver microsomal enzymes is possible, which can lead to an increase in the clearance of sex hormones. The interaction has been established, for example, with phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and, possibly, with oxcarbazepine, topiramate, felbamate, griseofulvin and preparations containing St. John's wort (Hypericum perforatum). HIV protease inhibitors (for example, ritonavir) and non-nucleoside reverse transcriptase inhibitors (for example, nevirapine) and their combinations also had an effect on hepatic metabolism. During concomitant use of drugs that induce microsomal enzymes, barrier methods should be used within 28 days after their withdrawal contraception. If necessary, long-term treatment with drugs that induce microsomal enzymes, it is necessary to consider using another method of contraception. Preparations that inhibit microsomal enzymes (for example, ketoconazole) can cause an increase in the concentration of sex hormones in plasma. concomitant use of antibiotics such as ampicillin and tetracyclines.The mechanism of this effect has not been studied. Information about the interaction of antibiotics with contraceptives containing 17β-estradiol, no. Women taking antibiotics (with the exception of rifampicin and griseofulvin) should additionally use a barrier method of contraception during the entire period of antibiotic therapy and within 7 days after their withdrawal. If the period during which the barrier method of contraception is applied continues even after you finish taking the white pills from the Zoely package, you should skip the yellow pills from the current package and start taking the white pills from the next package right away. The effect of the Zoely drug on other medicines Oral contraceptives can affect the metabolism of other drugs. Accordingly, their concentrations in plasma and tissues may increase (for example, cyclosporine) or decrease (for example, lamotrigine).
special instructions
The following data was obtained in epidemiological studies with the use of combined oral contraceptives containing ethinyl estradiol. Zoely contains 17β-estradiol, however, specific instructions regarding the administration of combined estradiol-containing contraceptives are also applicable to Zoely. and thromboembolism, such as myocardial infarction, stroke, deep vein thrombosis and pulmonary thromboembolism. These complications rarely develop. The use of any combined oral contraceptives containing ethinyl estradiol is accompanied by an increased risk of venous thrombosis and embolism, which is highest during the first year after the start of the combined oral contraceptive. This increased risk is lower than the risk of developing venous thrombosis and embolism associated with pregnancy (60 per 100,000 person-years). For women who do not take oral contraceptives, the risk of venous thrombosis and embolism is 5-10 per 100,000 person-years. Venous thrombosis and embolism end in death in 1-2% of cases. Data on the effect of the drug Zoely; on the risk of venous thrombosis and embolism compared with other combined oral contraceptives are absent. Patients taking combined oral contraceptives rarely developed thrombosis of other vessels, includinghepatic, mesenteric, renal, cerebral arteries and veins or retinal vessels. There is insufficient information about the relationship between the occurrence of these complications and the use of combined oral contraceptives. Symptoms of venous and arterial thrombosis may include the following conditions: pain and / or leg edema, sudden intense chest pain, radiating or not radiating to the left hand, sudden dyspnea , sudden cough, unusual severe and prolonged headache, sudden partial or complete loss of vision, diplopia, speech or aphasia, dizziness, collapse, accompanied by and not accompanied by focal convulsions, weakness or pronounced numbness that suddenly appear on one side of the body, movement disorders, acute abdomen syndrome. Risk factors for venous thrombosis and embolism: - age; - presence of diseases in the family history (venous thrombosis and embolism in brothers, sisters or parents at a relatively early age). If a genetic predisposition is expected, then before starting any hormonal contraceptives you should consult with a specialist; - long-term immobilization, extensive surgery, any operation on the lower limbs or a serious injury. In these cases, it is recommended to stop taking hormonal contraceptives (at least 4 weeks before a planned surgical intervention) and resume it only 2 weeks after full restoration of motor activity; - obesity (BMI over 30 kg / m2); - possibly, thrombophlebitis of superficial veins and varicose veins. There is no sufficient information about the role of these conditions in the etiology of venous thrombosis. Risk factors for arterial thrombosis: - age; - smoking (the risk is even more increased with intensity wicked smoking, especially in women over 35); - dyslipoproteinemia; - obesity (BMI over 30 kg / m2); - arterial hypertension; - migraine; - valvular heart disease; - atrial fibrillation; - presence of diseases in the family history (arterial thrombosis with brothers, sisters or parents at a relatively early age). If hereditary predisposition is expected,then you should consult a specialist before starting any hormonal contraceptives. Other conditions that were accompanied by unwanted vascular disorders: diabetes, systemic lupus erythematosus, hemolytic uremic syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis) and sickle cell anemia. It is necessary to consider increased risk of thromboembolic complications in the postpartum period. An increase in the frequency or severity of migraine (which may precede the development of cerebrovascular complications) is the basis for immediate lifting of the drug Zoely.Zhenschinam receiving combined oral contraceptives, it is necessary to consult a doctor when a possible symptom of thrombosis. In cases of suspected or confirmed thrombosis, the combined oral contraceptive should be discontinued. At the same time, adequate contraception should be initiated, given the teratogenicity of anticoagulant therapy (coumarins). Tumors The most significant risk factor for cervical cancer is persistent infection caused by the human papillomavirus (HPV). Epidemiological studies have shown that long-term use of combined contraceptives containing ethinyl estradiol increases this risk, but it is unclear to what extent this effect is related to other factors, such as more frequent cervical studies or sexual behavior, including the use of barrier contraceptives. , or is a combination of these factors. When using combined oral contraceptives at higher doses (50 μg of ethinyl estradiol) c development of endometrial cancer and ovarian cancer is reduced. It remains unclear whether this applies to combination oral contraceptives containing 17β-estradiol. A meta-analysis of 54 epidemiological studies in women who received ethinyl estradiol-containing combined oral contraceptives revealed a slight increase in the relative risk of developing breast cancer (relative risk = 1.24) . Increased risk gradually disappears within 10 years after discontinuation of combined oral contraceptives.Breast cancer rarely develops in women under the age of 40, so the additional number of breast cancers in women who take or have taken combined oral contraceptives is small compared with the overall risk of breast cancer. Breast cancer diagnosed in women using combined oral contraceptives is clinically less pronounced than the revealed cancer in women who have never used these drugs. The risk of breast cancer slightly increases during the use of combined oral contraceptives, which may be due to an earlier diagnosis, the effect of the drug or a combination of these two factors. In some cases, these tumors led to life-threatening intra-abdominal bleeding.