Modern contraception: trends and development. Zoely - a safe oral contraceptive

Compound

1 tablet - 2.5 mg of nomegestrol acetate and 1.55 mg of estradiol hemihydrate (respectively 1.5 mg of estradiol ) - active substances.
Auxiliary ingredients:

• 0.7 mg - talc;
• 14 mg - microcrystalline cellulose;
• 0.7 mg - magnesium stearate;
• 2.4 mg - crospovidone;
• 57.71 mg - lactose monohydrate;
• 0.44 mg - colloidal silicon dioxide.

Shell:

• 1.6 mg - opadry II white.

Placebo tablets :

• 0.7 mg - talc;
• 14 mg - microcrystalline cellulose;
• 0.7 mg - magnesium stearate;
• 2.4 mg - crospovidone;
• 61.76 mg - lactose monohydrate;
• 0.44 mg - colloidal silicon dioxide.

Shell:

• 2.4 mg - opadry II yellow.

Pharmacodynamics and pharmacokinetics

Zoely is a hormonal combined contraceptive drug consisting, in addition to additional substances, of the active components: estradiol (17β) and nomegestrol.

Estradiol is a naturally occurring estrogen identical to human endogenous 17β-estradiol (E2) . The main difference from ethinyl estradiol , which is part of the structure of other COCs (combined oral contraceptives), is the absence of an ethynyl group in the 17α-position. Taking Zoely's medication causes average concentrations of E2 , which correspond to those in the initial follicular phase and the final luteal phase of the menstrual cycle.

A derivative of natural progesterone, nomegestrol , is similar to it in structure and is a highly selective progestogen . Having a pronounced affinity for the progesterone (human), it exhibits high antigonadotropic and moderate antiandrogenic activity, without having androgenic, glucocorticoid, estrogenic and mineralocorticoid effects.

The contraceptive effect of Zoely is a combination of several effects, the most significant of which are changes in the secretion of the cervical and suppression of ovulation . E2 increases the effects of progestogen , and nomegestrol is involved in the process of suppressing ovulation. After stopping taking Zoely, normal ovulation , in most women, is restored quite quickly.

The serum folic acid content does not change while taking Zoely and remains at the baseline level for six months of sequential use.

Clinical studies have established a Pearl index of 0.66 for the age category of women 18-50 years old and 0.75 for women 18-35 years old, with a corresponding upper limit of the 95% confidence interval of 1.07/1.23.

Studies have shown that taking Zoely does not lead to significant changes in lipid metabolism and does not affect insulin glucose tolerance and hemostasis . The drug increased the amount of proteins that transport CSG (corticosteroid-binding) and TSH (thyroxine-binding) globulins , but to a much lesser extent than the combination of ethinyl estradiol and levonorgestrel . Also, the content of free and total testosterone, dehydroepiandrosterone, and androstenedione globulin increased slightly . When conducting a histological examination of the endometrium , after using Zoely for 13 cycles, no pathological changes were observed.

Nomegestrol, when taken internally, is rapidly absorbed and detects Cmax (7 ng/ml) in plasma after 2 hours. When taken once, the absolute bioavailability, regardless of food intake, is 63%.

97-98% binds to albumin , without binding to CSG or SHBG. Vss - 1.645±576 l.

Metabolized by cytochrome P450 to several hydroxylated inactive metabolites, which in turn, together with nomegestrol , form sulfate and glucuronide conjugates. At steady state, the clearance is 26 l/h.

At steady state, T1/2 is on average 46 hours (from 28 to 83 hours). Nomegestrol is excreted through the kidneys to a lesser extent and through the intestines to a greater extent. Approximately 80% is eliminated within 4 days and almost completely within 10 days.

The linearity of the pharmacokinetics of nomegestrol depends on the dose taken (in the range of 0.625–5 mg).

the pharmacokinetics of nomegestrol . The equilibrium state is observed after 5 days. Average Css is 4 ng/ml. Cmax in plasma is approximately 12 ng/ml and appears 90 minutes after administration.

Nomegestrol does not interact with glycoprotein P and does not have a significant inhibitory or inducing effect on cytochrome P450.

Estradiol , when taken orally, is subject to significant first-pass metabolism. Absolute bioavailability, regardless of food intake, is about 5%.

Actively spreads throughout the body. The highest content is shown in target organs of PG ( sex hormones ). In the blood it binds 37% to SHBG, 61% to albumin . Only 1–2% of estradiol is found in unbound form.

When taken orally, exogenous estradiol is actively biotransformed and, due to its similarity with endogenous estradiol , is quickly converted in the liver and intestines into several metabolites (mainly estrone ). The latter are conjugated, undergoing hepatic-intestinal circulation. Oxidation occurs due to cytochrome P450 isoenzymes.

Cmax in serum is observed after 6 hours and is equal to 90 pg/ml. The average serum concentration is 50 pg/ml.

It is cleared from the blood quickly, T1/2 fluctuates over a wide range and after intravenous administration is 8.4 ± 6.4 hours.

Pharmacodynamics

Nomegestrol acetate is a highly selective progestogen that is a derivative of the natural steroid hormone progesterone. Nomegestrol acetate has a strong affinity for the human progesterone receptor, has antigonadotropic activity, progesterone receptor-mediated antiestrogenic activity, moderate antiandrogenic activity, and no estrogenic, androgenic, glucocorticoid or mineralocorticoid activity. Zoely® contains 17β-estradiol, a natural estrogen identical to endogenous human 17β-estradiol. Unlike ethinyl estradiol, which is included in other COCs, E2 does not have an ethynyl group at 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 (see “Pharmacokinetics”). The contraceptive effect of Zoely® is due to a combination of various factors, the most important of which are suppression of ovulation and changes in the viscosity of cervical secretions.

In two randomized, open-label comparative studies of efficacy and safety, more than 3,200 women aged 18–50 years took Zoely® for 13 consecutive cycles and more than 1,000 women took the combination of drospirenone (3 mg)/ethinyl estradiol (30 mcg) in a dosing regimen of 21 /7. In the group taking Zoely®, weight gain was reported in 8.6% of women (in the comparison group - 5.7%), irregular withdrawal bleeding (mainly the absence of such) was reported in 10.5% of women (in the group comparison - 0.5%), acne was reported in 15.4% of women (in the comparison group - 7.9%) (see "Side effects"). An assessment of the development of acne while taking Zoely® showed that the majority of women (73.1%) did not experience a change in condition compared to the condition before treatment, 16.8% of women experienced an improvement in condition and 10.1% of women experienced appearance or worsening of acne. In a clinical study of the drug Zoely®, conducted in the EU, Asia and Australia, the following Pearl index indicators were calculated for the age group 18–35 years: ineffectiveness of the method - 0.4 (upper limit of the 95% confidence interval 1.03); ineffectiveness of the method and patient error - 0.38 (upper limit of 95% confidence interval 0.97).

In a clinical study of Zoely® conducted in the USA, Canada and Latin America, the following Pearl index values ​​were calculated for the age group 18–35 years: method ineffectiveness - 1.22 (upper limit of 95% confidence interval 2.18); method ineffectiveness and patient error - 1.16 (upper limit of 95% confidence interval 2.08).

In a randomized, open-label study, 32 women received Zoely® for 6 cycles. After stopping Zoely®, ovulation was restored on average 20.8 days after the last pill, with the earliest date of ovulation recorded on the 16th day.

Folic acid is an important vitamin in early pregnancy. While taking Zoely®, the concentration of folic acid in the blood plasma does not change and remains at the baseline level for 6 consecutive months of taking the drug. In a randomized, open-label comparative study of 2 years duration, Zoely® was administered to women aged 21–35 years and there was no clinically significant effect of Zoely® on bone mineral density.

A randomized, open-label, comparative multicenter study was conducted to evaluate the effect of Zoely® on blood coagulation parameters, lipid profile, carbohydrate metabolism, the functional state of the adrenal glands and thyroid gland, as well as androgen concentrations. 60 women aged 18–50 years took Zoely® for 6 consecutive cycles. In clinical studies, it was found that when taking Zoely®, insulin resistance and glucose tolerance did not change, and clinically significant effects on lipid metabolism and hemostasis were not detected. Taking Zoely® increased the concentrations of the transport proteins thyroxine-binding globulin and corticosteroid-binding globulin (CBG). When taking Zoely®, the concentration of sex hormone binding globulin (SHBG) slightly increased and the concentrations of androstenedione, dehydroepiandrosterone, total and free testosterone significantly decreased. In a clinical study in a group of women (n=32), after 13 cycles of taking Zoely®, no pathological changes were observed in histological examination of the endometrium.

Contraindications

exact data on contraindications for oral contraceptives containing 17β-estradiol . However, it can be assumed that they correspond to those when taking ethinyl estradiol-containing drugs. While taking Zoely, if any of the following conditions occur, you should stop taking it immediately.

• hypersensitivity to any of the components of the tablet;
• pulmonary embolism thrombosis , both current and past;
• arterial thrombosis (pathologies of cerebral circulation, myocardial infarction );
• migraine with focal neurological symptoms, including a history;
• prodromal conditions ( angina pectoris, transient ischemic attack ), including a history of;
• multiple and/or pronounced factors for the occurrence of arterial or venous thrombosis ( severe hypertension, diabetes mellitus with vascular symptoms, severe dyslipoproteinemia );
• pancreatitis with severe hypertriglyceridemia, both currently and in the past;
• acquired or hereditary predisposition of the patient to arterial or venous thrombosis , for example: deficiency of antithrombin III and proteins C and S, protein C resistance, hyperhomocysteinemia and the presence of antiphospholipid antibodies (lupus anticoagulant, antibodies to cardiolipin);
• tumors and severe pathologies of the liver, including a history of it;
• suspected or diagnosed malignant hormone-dependent neoplasms ( tumors of the breast or genital organs );
• breastfeeding period;
• suspected or diagnosed pregnancy ;
• vaginal bleeding of unknown etiology;
• lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• postmenopause.

With extreme caution:

• severe depression , also in history;
• diabetes mellitus , passing without vascular pathologies;
• systemic lupus erythematosus;
• ulcerative colitis;
• Crohn's disease;
• pathologies of liver function;
• hypertriglyceridemia , currently present or traced in a family history;
• risk factors for ischemic heart disease ( smoking, obesity, arterial hypertension );
• presence in the family history of arterial embolism and venous thrombosis ;
• major surgery and prolonged immobilization.

Zoely

Use during pregnancy and breastfeeding

The use of Zoely® during pregnancy is contraindicated.
If pregnancy occurs while using Zoely®, you should stop taking the drug. Most epidemiological studies have not found an increased risk of birth defects in children of women who took ethinyl estradiol-containing combined oral contraceptives before pregnancy. No teratogenic effects were observed with random administration of combined oral contraceptives containing ethinyl estradiol at the beginning of pregnancy.

Limited experience with the use of Zoely® in pregnant women indicates the absence of undesirable effects of the drug on the condition of the fetus or newborn.

Combined oral contraceptives may affect lactation because... they cause changes in the quantity and composition of breast milk. Therefore, the use of combined oral contraceptives is not recommended until breastfeeding is completely stopped. Small amounts of contraceptive steroids and/or their metabolites can be excreted in breast milk, but there is no evidence of their adverse effects on the health of the newborn.

Use for liver dysfunction

Contraindications: severe liver diseases, incl. in the anamnesis, until normalization of liver function indicators; liver tumors (malignant or benign), incl. in the anamnesis.

Use in children

There are no data on the effectiveness and safety of the drug in children under 18 years of age.

special instructions

The following data were obtained from epidemiological studies using combined oral contraceptives containing ethinyl estradiol. Zoely® contains 17β-estradiol, however, special instructions regarding the use of combined contraceptives containing estradiol are considered to apply to Zoely®.

Vascular disorders

Epidemiological studies have established an association between the use of combined oral contraceptives containing ethinyl estradiol and an increased risk of arterial and venous thrombosis and thromboembolism, such as myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism. These complications develop rarely.

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 starting the combined oral contraceptive. This increased risk is lower than the risk of venous thrombosis and embolism associated with pregnancy (60 per 100,000 person-years). In women not taking oral contraceptives, the risk of venous thrombosis and embolism is 5-10 per 100,000 person-years. Venous thrombosis and embolism result in death in 1-2% of cases.

There are no data on the effect of Zoely® on the risk of developing venous thrombosis and embolism compared to other combined oral contraceptives.

In patients taking combined oral contraceptives, thrombosis of other vessels, incl. hepatic, 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: pain and/or swelling of the leg, sudden intense chest pain, whether or not radiating to the left arm, sudden shortness of breath, sudden cough, unusual severe and prolonged headache, sudden partial or complete loss of vision, diplopia, speech impairment or aphasia, dizziness, collapse with or without focal seizures, weakness or severe numbness that suddenly appears 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 hereditary predisposition is suspected, then before starting any hormonal contraceptives, you should consult a specialist;
• prolonged immobilization, extensive surgery, any surgery on the lower extremities or serious injury. In these cases, it is recommended to stop taking hormonal contraceptives (at least 4 weeks before planned surgery) and resume it only 2 weeks after complete restoration of motor activity;
• obesity (BMI more than 30 kg/m2);
• possibly thrombophlebitis of the superficial veins and varicose veins.

There is not enough information about the role of these conditions in the etiology of venous thrombosis.

Risk factors for arterial thrombosis:

• age;
• smoking (the risk increases even more with heavy smoking, especially in women over 35 years of age);
• dyslipoproteinemia;
• obesity (BMI more than 30 kg/m2);
• arterial hypertension;
• migraine;
• heart valve disease;
• atrial fibrillation;
• presence of diseases in the family history (arterial thrombosis in brothers, sisters or parents at a relatively early age). If a hereditary predisposition is suspected, then before starting any hormonal contraceptives, you should consult a specialist.

Other conditions that have been associated with adverse vascular events include diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), and sickle cell anemia.

It is necessary to take into account the increased risk of thromboembolic complications in the postpartum period.

An increase in the frequency or severity of migraine (which may precede the development of a cerebrovascular complication) is grounds for immediate discontinuation of Zoely®.

Women taking combined oral contraceptives should consult a doctor if possible symptoms of thrombosis occur. In cases of suspected or confirmed thrombosis, the combined oral contraceptive should be discontinued. In this case, adequate contraception should be started, given the teratogenicity of anticoagulant therapy (coumarins).

Tumors

The most significant risk factor for developing cervical cancer is persistent infection with human papillomavirus (HPV). Epidemiological studies have shown that long-term use of ethinyl estradiol-containing combination contraceptives increases this risk, but it is unclear to what extent this effect is due to other factors, such as more frequent cervical examination or sexual behavior patterns, including the use of barrier contraceptives. , or is a combination of these factors.

When using combined oral contraceptives in higher doses (50 mcg ethinyl estradiol), the risk of developing endometrial and ovarian cancer is reduced. It remains unclear whether this applies to combined oral contraceptives containing 17β-estradiol.

A meta-analysis of 54 epidemiological studies in women receiving ethinyl estradiol-containing combined oral contraceptives found a small increase in the relative risk of developing breast cancer (relative risk = 1.24). The increased risk gradually disappears within 10 years after stopping combined oral contraceptives. Breast cancer rarely develops in women under 40 years of age, so the additional incidence of breast cancer in women who take or have taken combined oral contraceptives is small compared to the overall risk of breast cancer. Breast cancer diagnosed in women using combined oral contraceptives is clinically less severe than cancer diagnosed in women who have never used these drugs. The risk of breast cancer is slightly increased during use of combined oral contraceptives, which may be due to earlier diagnosis, drug exposure, or a combination of these two factors.

In rare cases, women taking combined oral contraceptives have developed benign liver tumors and, even more rarely, malignant tumors. In some cases, these tumors have led to life-threatening intra-abdominal bleeding. If intense pain in the upper abdomen, liver enlargement, or symptoms of intra-abdominal bleeding occur in women taking combined oral contraceptives, it is necessary to exclude a liver tumor.

Other states

Women with hypertriglyceridemia or a corresponding family history have an increased risk of developing pancreatitis when taking combined oral contraceptives.

Many women receiving combined oral contraceptives experienced a slight increase in blood pressure, although clinically significant increases in blood pressure were rare. The connection between taking combined oral contraceptives and the development of arterial hypertension has not been established. However, if persistent arterial hypertension develops while taking a combined oral contraceptive, then it is advisable to discontinue the combined oral contraceptive and prescribe antihypertensive therapy. If blood pressure is adequately controlled with antihypertensive drugs, it is possible to resume taking the combined oral contraceptive. In clinical studies lasting up to 1 year, no clinically significant changes in blood pressure were detected when using Zoely®.

During pregnancy and during the use of combined oral contraceptives, the development or worsening of the following conditions has been noted, although their relationship with the use of contraceptives has not been definitively established: jaundice and/or itching associated with cholestasis, formation of gallstones, porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham's chorea, gestational herpes, hearing loss associated with otosclerosis, (hereditary) angioedema.

In acute and chronic liver dysfunction, it may be necessary to discontinue combined oral contraceptives until liver function tests normalize. If cholestatic jaundice recurs, first observed during pregnancy or with previous use of sex steroids, it is necessary to stop taking combined oral contraceptives.

There is no need to change the regimen of low-dose combined oral contraceptives (containing less than 0.05 mg ethinyl estradiol) in women with diabetes. However, it is necessary to carefully conduct periodic examinations of women with diabetes mellitus taking combined oral contraceptives, especially during the first months. Zoely® has no effect on insulin resistance of peripheral tissues and glucose tolerance in healthy women.

Worsening of depression, Crohn's disease, and ulcerative colitis has been associated with use of combined oral contraceptives.

Chloasma sometimes developed, especially in women with a history of this disease. Women who are predisposed to developing chloasma should avoid sun exposure or exposure to ultraviolet light while taking combined oral contraceptives.

Medical examinations/consultations

Before prescribing the drug, you should carefully review the woman’s medical history (including family history) and exclude pregnancy.

It is necessary to measure blood pressure and, if indicated, conduct a physical examination, taking into account contraindications and precautions. The interval between control medical examinations is determined in each case separately, but not less than once every 6 months.

Women should be informed that combined oral contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Reduced efficiency

The effectiveness of combined oral contraceptives may be reduced by missed pills, gastrointestinal distress while taking active pills, or concomitant therapy.

Changes in the nature of menstruation

As with all combined oral contraceptives, breakthrough bleeding or spotting may occur, especially in the first few months. Therefore, examination for irregular bleeding is justified only after an adaptation period (approximately 3 cycles). If irregular bleeding persists or occurs after previous regular cycles, it is necessary to assume non-hormonal causes and conduct diagnostic tests to exclude a malignant tumor or pregnancy. A diagnostic curettage may be required.

In clinical studies in women taking Zoely®, the incidence of bleeding-related side effects was low. Withdrawal bleeding was mild, short-lived (average 3-4 days), and often less painful.

Some women taking Zoely® reported no withdrawal bleeding while taking the yellow placebo tablets, even though they were not pregnant. In these cases, the absence of withdrawal bleeding was not associated with a higher incidence of irregular bleeding in subsequent cycles. The nature of menstrual-like bleeding at the beginning of taking Zoely® (cycles 2-4) allows us to predict the nature of menstrual-like bleeding in subsequent cycles.

If there is no withdrawal bleeding when taking Zoely® in accordance with the recommended dosage regimen, then the likelihood of pregnancy is low. However, if a woman has not taken the drug in accordance with these recommendations or there are no two withdrawal bleedings in a row, then pregnancy must be excluded.

Lab tests

Data obtained with combined oral contraceptives have shown that the use of these drugs may affect the results of some laboratory tests, including biochemical indicators of liver, thyroid, adrenal and kidney function, plasma concentrations of transport proteins, for example, corticosteroid hormones, on lipid/lipoprotein fractions, indicators of carbohydrate metabolism, blood clotting and fibrinolysis. Usually these changes remain within normal limits.

Use in pediatrics

There are no data on the effectiveness and safety of the drug in children and adolescents under 18 years of age.

Impact on the ability to drive vehicles and operate machinery

Zoely® does not affect the ability to drive vehicles or operate machinery.

Side effects

As practice has shown, the Zoely contraceptive is generally well-tolerated, and the safety of use is at the level of other combination drugs with similar effects. Below are possible negative effects that have been observed while taking Zoely.

Metabolism:

• weight gain;
• fluid retention;
• increase or decrease in appetite.

CNS:

• decreased or increased libido ;
• depression;
• migraine;
• attention disorder;
• headache.

Organs of vision:

• dry eyeballs;
• intolerance to wearing contact lenses.

Vascular system:

• tides.

Digestive system:

• bloating;
• nausea;
• increased activity of liver enzymes;
• dry mouth.

Skin and subcutaneous tissues:

• acne;
• alopecia;
• hyperhidrosis;
• itching;
• seborrhea;
• dry skin;
• hypertrichosis;
• chloasma.

Musculoskeletal system:

• feeling of heaviness.

Genital organs and mammary glands:

• withdrawal bleeding;
• menorrhagia;
• pain in the pelvic area;
• hypomenorrhea;
• engorgement of the mammary glands;
• metrorrhagia;
• galactorrhea;
• premenstrual syndrome;
• uterine spasm;
• lumps in the mammary glands;
• dryness of the vagina and vulva;
• dyspareunia;
• discomfort in the vaginal area;
• unpleasant odor from the vagina.

Are common:

• edema;
• irritability;
• hunger.

Side effects observed with the use of COCs (combined oral contraceptives) that contain ethinyl estradiol:

• increase in blood pressure;
• arterial and venous thromboembolism ;
• chloasma;
• hormone-dependent tumors ( breast cancer, liver tumors ).

The incidence of breast cancer diagnosis in women using COCs is slightly higher than that in women using other methods and means of contraception.

The connection between breast cancer and COC use has not been established.

Instructions for use of Zoely (Method and dosage)

The instructions for Zoely recommend taking the tablets orally at the same time every day, without taking into account food intake. The tablets are taken in the sequence indicated on the blister and washed down with water.

For all women, recommendations for using Zoely are the same. For 28 days you need to take 1 tablet every day in a row. In the first 24 days, take white tablets containing active ingredients, after which, over the next 4 days, take yellow tablets ( placebo ), which do not contain active ingredients.

The initial tablet from each subsequent blister (or package) must be taken the next day after the final tablet from the previous blister. The drug is taken regardless of the absence or presence of withdrawal bleeding , which is usually observed 24-36 hours after consuming the last white tablet and can continue until the next blister is used.

Start of use

For women who have not previously taken hormonal contraceptives, it is best to start taking Zoely on the first day of the menstrual cycle . In this case, additional contraception will not be needed. It is allowed to start using it from the 2nd to 5th day of the cycle, but during the week, it is necessary to use additional contraceptive barrier methods.

When switching from other contraceptives with combined hormonal action (other COCs, patches , vaginal rings ), in the case of using other COCs, it is recommended to start taking Zoely on the next day after the last active tablet ( not placebo ) and no later than the next day after the end of the usual range between cycles or taking placebo . If you have previously used a transdermal patch or vaginal ring , it is advisable to start switching to Zoely tablets on the day of their removal (removal), but no later than during the next recommended application of the patch or insertion of the ring.

With correct and constant use of previous contraceptive methods and guaranteeing the absence of pregnancy, it is possible to switch to Zoely any day. Under no circumstances should you exceed the recommended hormone-free period of the previous contraceptive method.

In case of switching from contraceptives containing one progestogen ( implants , tablets, injections or IUD - intrauterine system ) with previous use of other tablets, you can switch to Zoely on any day, the next day after stopping taking tablets with progestogen. When switching from injection forms, taking Zoely tablets is replaced by the next recommended injection. The IUD or implant is removed on any convenient day, on which Zoely is started. In all of the above cases, it is recommended to use additional barrier contraceptives for a week.

After an abortion in the first trimester , you can begin using Zoely immediately after the end of the procedure, and no additional contraceptive measures are required.

After an abortion in the second trimester or childbirth, you should start using the drug between 21 and 28 days. barrier contraceptives for a week . In case of previous sexual intercourse, it is necessary to exclude possible pregnancy before using it.

If you miss taking pills

If you miss another active (white) tablet, the following recommendations are given.

If the next dose is less than 12 hours late, take the required tablet without adjusting the order and time of taking subsequent tablets.

If you are more than 12 hours late, two rules are followed:

• Active tablets should be taken for at least 7 days in a row;
• The greater the number of active tablets missed and the closer the time of placebo , the higher the possibility of pregnancy.

If you miss the first tablet, take it as soon as possible, even if you take the next 2 tablets at the same time. In the future, continue with the usual regimen of use, without additional measures.

If you miss 2 or more tablets and there is no withdrawal bleeding during the placebo , pregnancy .

If you miss a cycle during the 1st – 7th day, you should take the last missed tablet as soon as possible, even if you take 2 subsequent tablets at the same time. In the future, continue the usual regimen of use, using barrier contraception , during the first week. If you have sexual intercourse at this time, pregnancy .

If you miss during the 8th - 17th day of the cycle, you should take the last missed tablet as soon as possible, even if you take 2 subsequent tablets at the same time. In the future, continue the usual regimen of use, using barrier contraception , during the first week.

If you miss during the 18th - 24th day of the cycle, you should take the last missed tablet as soon as possible, even if you take 2 subsequent tablets at the same time. You cannot take more than 2 active tablets at the same time. During the first week barrier contraception , and the first active tablet from the next blister should be taken after the last active tablet from the previous one, that is, the last phase of taking placebo . With this regimen, withdrawal bleeding most often occurs during the next placebo spotting or breakthrough bleeding may occur during the current cycle

If you are unsure about the number of missed pills, you need to use barrier contraceptives for at least a week of continuous use of the current pills.

placebo pills does not reduce the contraceptive effect.

In case of gastrointestinal painful conditions, such as diarrhea or vomiting, the absorption process of Zoely may be affected, and therefore it is necessary to resort to auxiliary contraceptive measures.

If vomiting within 3–4 hours after swallowing the tablet, this dose is considered to be a missed dose. If this painful condition continues for several days, you should use the recommendations described above. If you do not want to change the typical regimen of use, you can take an additional active tablet or a tablet from another blister.

To delay the moment of menstrual-like bleeding, you need to start taking white tablets from the next blister, immediately after finishing them from the previous blister, that is, exclude taking placebo . The white tablets from the second blister can be taken in full. After taking the placebo from the second blister, resume the usual regimen of taking Zoely. , spotting and/or breakthrough bleeding may occur . To shift the day of onset of menstrual-like bleeding , you can reduce the placebo (by a maximum of 4 days). A shorter break increases the risk of no withdrawal bleeding and the development of spotting and breakthrough bleeding.

Pharmacokinetics

Nomegestrol acetate

Suction. Nomegestrol acetate is rapidly absorbed after oral administration. After a single dose, Cmax in plasma is about 7 ng/ml and is achieved after 2 hours. Absolute bioavailability after a single dose is 63%. Food does not have a clinically significant effect on the bioavailability of nomegestrol acetate.

Distribution. Nomegestrol acetate binds actively to albumin (97–98%), but does not bind to SHBG or DSG. The apparent Vss of nomegestrol acetate is (1645±576) l.

Metabolism. Nomegestrol acetate is metabolized to several inactive hydroxylated metabolites under the influence of liver cytochrome P450 isoenzymes, mainly CYP2C8, CYP2C19, CYP3A4 and CYP3A5, with possible participation in the metabolism of CYP2C8 and CYP2C19 isoenzymes. Nomegestrol acetate and its hydroxylated derivatives undergo pronounced phase 2 metabolism with the formation of glucuronide and sulfate conjugates. Clearance at steady state is 26 l/h.

Excretion. T1/2 at steady state is 46 hours (from 28 to 83 hours). T1/2 of metabolites has not been established. Nomegestrol acetate is excreted by the kidneys and intestines (approximately 80% of the dose is excreted within 4 days). Nomegestrol acetate is almost completely eliminated within 10 days. Excretion through the intestines exceeds excretion by the kidneys.

Linearity. Linearity of pharmacokinetics depending on the dose was observed in the range of 0.625–5 mg (assessed in women of reproductive and postmenopausal age).

Equilibrium state. SHBG does not affect the pharmacokinetics of nomegestrol acetate. The equilibrium state is achieved after 5 days. The average Css is 4 ng/ml. Cmax of nomegestrol acetate in plasma is about 12 ng/ml and is achieved 1.5 hours after taking the drug.

Interactions. In vitro, nomegestrol acetate does not have a significant inducing or inhibitory effect on cytochrome P450 isoenzymes and does not interact with glycoprotein P.

Estradiol (E2)

Suction. 17β-estradiol undergoes extensive first-pass metabolism after oral administration. Absolute bioavailability is approximately 1%. Food intake does not have a clinically significant effect on the bioavailability of E2.

Distribution. 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.

Metabolism. Exogenous E2 is actively biotransformed after oral administration. The metabolism of exogenous and endogenous E2 is similar. E2 is rapidly converted to several metabolites in the intestine and liver (mainly estrone), which are subsequently conjugated and undergo enterohepatic circulation. There is a dynamic equilibrium between E2, estrone and estrone sulfate due to the activity of various enzymes, including estradiol dehydrogenases, sulfotransferases and arylsulfatases. Oxidation of estrone and E2 occurs under the influence of cytochrome P450 isoenzymes, mainly CYP1A2, CYP1A2 (outside the liver), CYP3A4, CYP3A5, CYP1B1 and CYP2C9.

Excretion. E2 is quickly eliminated from the blood. Due to metabolism and enterohepatic circulation, there is a large pool of circulating estrogen sulfates and glucuronides. As a result, T1/2 E2, adjusted to the initial value, varies widely and amounts to (3.6 ± 1.5) hours after i.v. administration.

Equilibrium state. Cmax E2 in serum is about 90 pg/ml and is achieved 6 hours after administration. The average serum concentration is 50 pg/ml. This E2 concentration corresponds to that in the initial and late phases of the menstrual cycle.

Special patient groups

Children. The pharmacokinetics of nomegestrol acetate (primary target) following a single oral dose of Zoely® were comparable in healthy postmenarchean adolescent girls and adult women. Concentrations of E2 (secondary target) in adolescent girls compared with adult women were comparable during the first 24 hours and lower than in adult women after 24 hours. The clinical significance of this finding is unknown.

Renal dysfunction. The effect of renal disease on the pharmacokinetics of Zoely® has not been studied.

Liver dysfunction. The effect of liver disease on the pharmacokinetics of Zoely® has not been studied. However, in patients with impaired liver function, the metabolism of sex hormones may deteriorate.

Ethnic groups. The pharmacokinetics of the drug in representatives of ethnic groups has not been specifically studied.

Interaction

In order to completely exclude possible interactions, you should carefully read the instructions for them in the instructions for use of drugs used in parallel.

Interaction of COCs, including Zoely, with other drugs may cause bleeding and/or a decrease in contraceptive effectiveness. Below are generalized interactions of other drugs with COCs.

Hepatic metabolism

Interaction with inducers of microsomal liver enzymes is possible, which can cause an increase in the clearance of PG ( sex hormones). There is definitely an interaction with barbiturates, Phenytoin, Primidone, Rifampicin, Carbamazepine . Interaction with Griseofulvin, Topiramate, Oxcarbazepine, Felbamate and St. John's wort preparations is possible. Also, agents that inhibit HIV proteases ( Ritonavir , etc.) and non-nucleoside reverse transcriptase inhibitors ( Nevirapine , etc.), as well as their combinations, have an effect on hepatic metabolism.

When taking microsomal enzyme inducers , as well as for 28 days after their discontinuation, it is necessary to use barrier contraception. In case of long-term therapy with these drugs, the issue of prescribing another contraceptive method should be considered.

Inhibitors of microsomal enzymes , such as ketoconazole , can lead to increased plasma concentrations of PG.

Antibiotics

When used together with antibiotics such as tetracyclines and ampicillin , a decrease in the effectiveness of COCs containing ethinyl estradiol . The mechanism of this interaction is not fully understood. reliable data on the interaction of COCs containing 17β-estradiol and antibiotics. Women who are undergoing antibiotic therapy (except for the use of Griseofulvin and Rifampicin ) should use additional barrier contraceptives throughout the entire period of treatment, as well as 7 days after. If the period of additional barrier contraception covers the end of taking the active pills, it is recommended to skip the placebo and immediately proceed to taking the active pills from another blister.

Other drugs

COCs can affect the metabolism of other drugs, increasing their plasma and tissue concentrations, as in the case of Cyclosporine , or decreasing, as in the case of Lamotrigine .

Use during pregnancy and breastfeeding

The use of Zoely® is contraindicated during pregnancy. If pregnancy occurs while using Zoely®, you should stop taking the drug.

Most epidemiological studies have not found an increased risk of birth defects in children whose mothers took COCs containing ethinyl estradiol before pregnancy. No teratogenic effects were observed with the occasional use of COCs containing ethinyl estradiol at the beginning of pregnancy.

There is limited experience with the use of Zoely® in pregnant women, which indicates the absence of undesirable effects of the drug on the condition of the fetus or newborn.

Reproductive toxicity has been reported in laboratory animal studies of the nomegestrol acetate/estradiol combination.

Zoely® is intended to prevent unwanted pregnancy. If a woman wants to stop taking Zoely® in order to become pregnant, it should be taken into account that ovulation is restored on average 20.8 days after the last dose of Zoely® tablet (see Pharmacodynamics).

COCs may affect lactation because they cause changes in the quantity and composition of breast milk. Therefore, the use of COCs is not recommended until breastfeeding has completely stopped (an alternative method of contraception should be selected). Small amounts of contraceptive sex hormones and/or their metabolites can be excreted in breast milk, but there is no data on their undesirable effects on the health of the newborn.

special instructions

The data below were obtained during epidemiological studies of COCs containing ethinyl estradiol . The drug Zoely includes 17β-estradiol , however, the special instructions described apply to it as well.

Vascular disorders

An association has been observed between taking COCs and the risk of thromboembolism , as well as venous and arterial thrombosis ( myocardial infarction, deep vein thrombosis, stroke, pulmonary embolism). Against the general background, these conditions rarely develop, but during the first year of taking COCs, the risk of developing these complications is highest. You should know that 1-2% of cases of embolism and venous thrombosis .

With the development of thrombosis, the following may occur:

• pain and/or swelling of the legs;
• sudden shortness of breath ;
• sharp pain in the chest, with or without rebound, in the left arm;
• unexpected cough ;
• sudden loss of vision (partial or complete), uncharacteristic severe prolonged headaches;
• diplopia;
• dizziness;
• speech disorder;
• collapse (possibly with convulsions);
• weakness;
• movement disorders;
• sudden severe numbness on one side of the body;
• acute abdomen syndrome.

Risk factors for embolism and venous thrombosis :

• advanced age;
• hereditary predisposition (family history of these diseases);
• obesity;
• thrombophlebitis;
• phlebeurysm;
• serious injury;
• major surgery;
• long-term immobilization.

Risk factors for arterial thrombosis :

• smoking;
• advanced age;
• dyslipoproteinemia;
• arterial hypertension;
• obesity;
• migraine;
• atrial fibrillation;
• heart valve disease;
• hereditary predisposition.

It is worth remembering the increased risk of thromboembolic exacerbations in the postpartum period.

For any of these disorders, you should consult your doctor before taking Zoely tablets. In cases of suspected thrombosis or its diagnosis, while using COCs, the tablets should be discontinued. For conditions requiring hospitalization (serious trauma, major surgery, prolonged immobilization), it is better to stop using COCs (one month before a planned operation), with resumption of use 14 days after normal resumption of motor functions.

Also, consultation with a doctor will be required for such diseases as:

• diabetes;
• uremic hemolytic syndrome;
• systemic lupus erythematosus;
• ulcerative colitis;
• Crohn's disease;
• sickle cell anemia.

Increased migraine is an indication for immediate discontinuation of Zoely.

Tumors

Long-term use of ethinyl estradiol-containing COCs , according to research results, increases the risk of developing cervical cancer , however, the question of other exposure factors remains open. It is not fully understood whether COC use, more frequent cervical testing, sexual intercourse (including barrier contraception), or a combination of these leads to an increased risk.

reliable information about the effect of Zoely on the development of ovarian and endometrial .

A slight increase in the relative risk (RR) of breast cancer (RR = 1.24). This risk decreases over 10 years after discontinuation of COCs. This increase is possibly due to earlier detection, the effects of COCs, or a combination of both.

Sometimes, when taking COCs, the development of liver tumors (benign) was detected, and even less often - malignant. In rare cases, these tumors, due to intra-abdominal bleeding, became a threat to the patient’s life. If an enlarged liver, intense abdominal pain, or symptoms of intra-abdominal bleeding are detected, a possible liver tumor should be excluded.

Other states

Taking COCs with hypertriglyceridemia or a family history of it slightly increases the risk of pancreatitis .

increase in blood pressure was often observed , which was rarely clinically significant. The connection between COC use and the formation of arterial hypertension . However, if it develops, it is worth stopping the use of COCs and considering prescribing adequate antihypertensive therapy. When blood pressure is stabilized with the use of antihypertensive drugs, it is possible to resume the use of COCs. According to the results of clinical studies, taking Zoely for up to 12 months did not lead to clinically significant blood pressure disorders.

During the use of COCs and during pregnancy, complications or development were noted: itching and/or jaundice , cholelithiasis, gestational herpes, porphyria, hemolytic uremic syndrome, systemic lupus erythematosus, Sydenham's chorea, angioedema , as well as hearing loss.

Liver pathologies may require discontinuation of COCs until the liver condition is completely normalized.

In case of recurrence of cholestatic jaundice, which was first diagnosed during pregnancy or previous steroids

glucose tolerance and insulin resistance . However, while taking them, it is necessary to conduct careful periodic examinations, especially for women with diabetes .

ulcerative colitis, Crohn's disease and was observed .

chloasma developed , especially when this disease was mentioned in the anamnesis. In this case, it is better to avoid prolonged exposure to the sun, solarium and other exposure to ultraviolet radiation.

Conducting consultations and examinations

Before prescribing a COC, it is necessary to obtain an understanding of the woman’s personal and family history, and also to exclude possible pregnancy. Measure blood pressure and, if indicated, prescribe a physical examination , taking into account all contraindications. The frequency of control examinations in each case is determined separately, but at least twice a year.

Women should receive full information about the action and side effects of COCs, and also be informed that this method of contraception does not prevent HIV infection and other sexually transmitted diseases.

Reduced efficiency

The effectiveness of COCs may be reduced if active tablets are missed, as well as gastrointestinal disorders.

Menses

The use of COCs, especially in the first months, may be accompanied by spotting or breakthrough bleeding . In this regard, it is advisable to conduct a study of these manifestations after the adaptation period (3 months). If these symptoms persist after three cycles of taking COCs, their non-hormonal nature should be assumed and diagnostics should be prescribed to exclude possible tumors or pregnancy . may be performed .

When studying the drug Zoely, bleeding developed rarely and was short-lived, mild and slightly painful. In some cases, the absence of proper withdrawal bleeding was observed when taking placebo, without diagnosing pregnancy, which indicates its low probability even in the absence of withdrawal bleeding. If two bleedings are missed, when taking the drug in accordance with the instructions, a possible pregnancy must be excluded.

Zoely®

If any of the following conditions, diseases, or risk factors are present, the benefits of using Zoely® and the possible risks for each individual woman should be assessed. This should be discussed with the woman before she starts taking Zoely®.

In cases of deterioration, exacerbation, or the first occurrence of any of these conditions, diseases, or risk factors, a woman should consult a doctor to decide on the possibility of further use of the drug Zoely®.

The data below were obtained from epidemiological studies with the use of CHCs containing ethyttestradiol. Zoely® contains 17β-estradiol, however, the special instructions regarding the use of combined contraceptives containing ethinipestradiol are considered applicable to Zoely®.

Vascular disorders

— The use of COCs is accompanied by an increased risk of developing VTE compared to the risk of developing VTE in patients not using COCs. The greatest additional risk of VTE is observed in the first year of COC use. The risk also increases when starting to use a COC or when restarting the same or a different COC after a break of 4 weeks or more. Epidemiological studies demonstrate that the incidence of VTE in patients without known risk factors taking low-dose (<50 mcg ethinyl estradiol) COCs ranges from 3 to 12 cases per 10,000 woman-years (WY). For comparison, the same parameter in non-pregnant patients who do not take CHCs is from 1 to 5 cases per 10,000 YL, and in pregnant women - from 5 to 20 cases per 10,000 YL (pregnancy data are based on the actual duration of pregnancy in standard studies; Based on the assumption that pregnancy lasts 9 months, the risk ranges from 7 to 27 cases per 10,000 YL). In postpartum women, the risk of developing VTE ranges from 40 to 65 cases per 10,000 women. VTE can be fatal in 1-2% of cases. There is no data on the effect of Zoely® on the risk of venous thrombosis and embolism compared to other CHCs.

— Epidemiological studies have established a connection between the use of CGCs and an increased risk of arterial thromboembolism (myocardial infarction, transient ischemic attacks).

- Thrombosis of other vessels, including hepatic, mesenteric, renal, cerebral arteries and veins, or retinal vessels, was extremely rare in patients taking CHCs.

— Symptoms of venous and arterial thrombosis or acute cerebrovascular accident may include the following conditions: sudden pain and/or swelling of the lower limb; sudden intense chest pain, radiating or not radiating to the left arm; sudden shortness of breath; sudden cough; unusual severe or prolonged headache; sudden partial or complete loss of vision; diplopia; speech impairment or aphasia; dizziness; collapse, with or without focal convulsions; weakness or severe numbness that suddenly appears on one side of the body; movement disorders; "acute belly"

— The risk of developing venous thromboembolism increases with the presence of the following risk factors:

• Age.
• Family history of disease (venous thrombosis and embolism in siblings or parents aged <50 years). If a hereditary predisposition is suspected, then before starting any hormonal contraceptives, you should consult a specialist.
• Prolonged immobilization, major surgery, any surgery on the lower extremities or serious trauma. In these cases, you should stop taking the drug (at least 4 weeks before planned surgery) and resume it only 2 weeks after complete restoration of motor activity. If the use of COCs has not been discontinued in advance, the need to use antithrombotic agents should be considered (see also section "Contraindications").
• Obesity (body mass index more than 30 kg/m2).
• Air travel longer than 4 hours may temporarily increase the risk of developing a blood clot, especially in women with other risk factors.

— There is no sufficient information about the role of thrombophlebitis of superficial veins and varicose veins in the etiology of venous thrombosis.

— The risk of developing complications of arterial thromboembolism or acute cerebrovascular accident increases in the presence of the following risk factors:

• Age.
• Smoking (the risk increases even more with heavy smoking, especially in women over 35 years of age). Women over 35 years of age should be strongly advised to stop smoking if they wish to take COCs.
• Dyslipoproteinemia.
• Obesity (body mass index more than 30 kg/m2).
• Arterial hypertension.
• Migraine.
• Heart valve disease.
• Atrial fibrillation.
• Family history of disease (arterial thrombosis in siblings or parents aged <50 years). If a hereditary predisposition is suspected, then before starting any hormonal contraceptives, you should consult a specialist.

— Other conditions that have been associated with adverse vascular events include diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), and sickle cell disease.

— It is necessary to take into account the increased risk of thromboembolic complications in the postpartum period.

— An increase in the frequency or severity of migraine when using COCs (which may precede the development of a cerebrovascular complication) is grounds for immediate discontinuation of Zoely®.

Women taking COCs should consult a doctor if possible symptoms of thrombosis appear. In cases of suspected or confirmed thrombosis, COC use should be discontinued. In this case, adequate contraception should be started, given the teratogenicity of anticoagulant therapy (coumarins).

Tumors

— The most significant risk factor for developing cervical cancer is persistent infection with human papillomavirus (HPV). Epidemiological studies have shown that long-term use of ethinyl estradiol-containing combination contraceptives increases this risk, but it is unclear to what extent this effect is due to other factors, such as more frequent cervical examination or sexual behavior patterns, including the use of barrier contraceptives. , or a combination of these factors. A cause-and-effect relationship with COC use has not been proven.

- When using COCs in higher doses (50 mcg ethinyl estradiol), the risk of developing endometrial and ovarian cancer is reduced. It remains unclear whether this applies to COCs containing 17β-estradiol.

— A meta-analysis of 54 epidemiological studies in women receiving COCs containing ethinyl estradiol found a small increase in the relative risk (RR) of developing breast cancer (RR = 1.24). The increased risk gradually disappears within 10 years after stopping COC use. Breast cancer rarely develops in women under 40 years of age, so the additional incidence of breast cancer in women who take or have taken COCs is small compared to the overall risk of developing breast cancer. Women who use COCs are diagnosed with earlier stages of breast cancer than women who have never used them.

— Another epidemiological study conducted in Denmark involving 1.8 million women, with a follow-up of an average of 10.9 years, found an increased RR of breast cancer in women who took long-term COCs compared with women who never used COCs (overall RR = 1.19; RR ranged from 1.17 [for 1 year to less than 5 years of use] to 1.46 [for more than 10 years of use]). The observed difference in absolute risk (number of breast cancer cases among women who had never used COCs compared with women who were taking or had recently taken COCs) was small: 13 cases per 100,000 woman-years.

— Epidemiological studies do not provide evidence of a connection. The observed increased risk may be due to earlier diagnosis of breast cancer in women taking COCs, the biological effects of COCs, or a combination of both.

- In rare cases, women taking COCs have developed benign liver tumors and, even more rarely, malignant ones. In some cases, these tumors have led to life-threatening intra-abdominal bleeding. If intense pain in the upper abdomen, liver enlargement, or symptoms of intra-abdominal bleeding occur in women taking COCs, it is necessary to exclude a liver tumor.

Hepatitis C

In clinical trials of the drug combination for the treatment of hepatitis C virus ombitasvir/paritaprevir/ritonavir with or without dasabuvir, increases in ALT levels greater than 5 times the upper limit of normal were observed significantly more often in women using drugs containing ethinyl estradiol, such as KGC. In women using drugs containing estrogens other than ethinyl estradiol, such as estradiol, the rate of increase in ALT activity was similar to that in women not using any estrogens. However, due to the limited number of women taking estrogens other than ethinyl estradiol, caution should be exercised when co-administering the drug with the ombitasvir/paritaprevir/ritonavir drug combination with or without dasabuvir (see Interactions with Other Drugs section). ).

Other states

- Women with hypertriglyceridemia or a corresponding family history have an increased risk of developing pancreatitis when taking COCs.

- Many women receiving COCs experienced a slight increase in blood pressure, but clinically significant increases in blood pressure were rare. The connection between taking COCs and arterial hypertension has not been established. However, if persistent arterial hypertension develops while taking COCs, then it is advisable to stop taking COCs and prescribe antihypertensive therapy. If blood pressure is adequately controlled with antihypertensive drugs, it is possible to resume taking COCs. In clinical studies lasting up to two years, no clinically significant changes in blood pressure were detected when using Zoely®.

— During pregnancy and during the use of COCs, the development or worsening of the following conditions was noted, although their connection with the use of contraceptives has not been definitively established: jaundice and/or itching associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham's chorea (minor chorea); herpes during pregnancy; hearing loss associated with otosclerosis.

— In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

- In acute and chronic liver dysfunction, it may be necessary to discontinue COCs until liver function tests normalize. If cholestatic jaundice recurs, first observed during pregnancy or during previous use of sex hormones, it is necessary to stop taking COCs.

— Despite the fact that COCs may have an effect on insulin resistance and glucose tolerance, there is no need to change the dosage regimen of hypoglycemic drugs in patients with diabetes mellitus taking COCs containing less than 0.05 mg of ethinyl estradiol. However, it is necessary to carefully conduct periodic examinations of women with diabetes mellitus taking COCs, especially during the first months. Zoely® has no effect on insulin resistance of peripheral tissues and glucose tolerance in healthy women (see section “Pharmacological properties”, subsection “Pharmacodynamics”).

- Crohn's disease, ulcerative colitis and worsening depression were associated with COC use.

- Sometimes chloasma developed, especially in women with a history of this disease. Women who are predisposed to developing chloasma should avoid sun exposure or exposure to ultraviolet light while taking COCs.

Medical examinations/consultations

Before prescribing or resuming taking Zoely®, you should carefully review the woman’s medical history (including family history) and exclude pregnancy.

It is necessary to measure blood pressure and, if indicated, conduct a physical examination, taking into account contraindications and precautions. The interval between control medical examinations is determined in each individual case, but not less than once every 6 months.

Women should be informed that COCs do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Reduced efficiency

The effectiveness of COCs may be reduced in case of missed tablets (see section "Method of administration and dosage"), gastrointestinal disorders while taking tablets containing active ingredients (see section "Method of administration and dosage") or in case of concomitant therapy, which reduces the concentration of nomegestrol acetate in the blood plasma (see section “Interaction with other drugs”).

Changes in the nature of menstruation

When taking any COC, you may experience breakthrough bleeding or spotting, especially in the first few months. Therefore, examination for irregular bleeding is justified only after an adaptation period (approximately 3 cycles). In 15-20% of women using Zoely®, acyclic bleeding was observed after this adaptation period.

If irregular bleeding persists or occurs after previous regular cycles, it is necessary to assume non-hormonal causes and conduct diagnostic tests to exclude a malignant tumor or pregnancy. A diagnostic curettage may be required.

Women taking Zoely® experienced breakthrough bleeding/spotting in subsequent cycles. In 4.6% of women, there was no bleeding “oooo Method of administration and dose”, there was no “withdrawal” bleeding in a row, then it is necessary to exclude pregnancy.

Zoely's analogs

Level 4 ATC code matches:
Ovidon

Rigevidon

Non-Ovlon

Mercilon

Yarina Plus

Yarina

Miniziston 20 fem

Novinet

Microgynon

Janine

Lindineth

Cyclo-Proginova

Regulon

Logest

Midiana

Belara

Femoden

Jess Plus

Jess

Analogues of Zoely are represented by the following contraceptive drugs:

• Claira;
• Trisiston;
• Trigestrel;
• Tri-regol;
• Triquilar.

Zoely or Klaira - which is better?

Despite some differences in the composition of the active ingredients, nomegestrol + estradiol in Zoely and dienogest + estradiol valerate in Qlaira , the mechanism of action of both drugs is almost the same. Both drugs are microdosed, however, Klaira , in each group of tablets (different in color), contains a different mass fraction of active substances, while in Zoely the dosage in each active tablet is the same. These contraceptives practically repeat each other, both in contraindications and side effects. In this regard, it is not possible to give a definite answer which of these drugs is better.

Oral contraceptives of hormonal action are selected individually and the best suitable drug can be prescribed only after undergoing many tests and undergoing some research. We should not forget about chronic diseases, a history of painful conditions (both personal and family) and many other factors that can also affect the choice of contraceptive.

Whenever you choose between Zoely and Claira , you should remember that these drugs, if you strictly follow the recommendations for their use, are highly effective and cause fewer side effects compared to other contraceptives. But the choice of COCs should be purely individual.

Modern contraception: trends and development. Zoely - a safe oral contraceptive

Over the past 50 years of the existence of GC, scientists and pharmaceutical companies around the world have been looking for new formulas of “ideal” synthetic components, determining their optimal composition, dosage, form and mode of administration, ultimately wanting to offer women a drug that provides the best protection and the minimum amount of unwanted side effects. effects. The history of GK is associated with the names of such scientists as L. Haberland, G. Pincus, J. Rock, M. Sanger and some others, thanks to whose developments in 1961 (Searle) received a license for the first contraceptive pill Enovid, containing 5 mg norethinodrel and 75 mcg mestranol. From then until the end of 2010, we witnessed incremental changes in the dosage and composition of the contraceptive pill, leading to the existence of a portfolio of safe and effective brands of combined oral contraceptives (COCs). This path was accompanied by small and large upheavals, controversy and certain waves of fear about GC, which exist to this day and are often associated with the lack of scientifically based coverage of this topic in the media. So, in the 1990s. The results of some studies on the risk of thromboembolic complications of COCs were widely and uncritically disseminated by the media, which led to a wave of fear about birth control pills. Many women interrupted their GC, which led to an increase in the incidence of unplanned pregnancy and, consequently, abortion [5, 17]. And only a few modern women understand that there is a very big difference between the original birth control pills and the currently existing forms of GC. Their evolution occurred by searching for COCs that cause the fewest side effects. She was facilitated by advances in the study of hormonal mechanisms and findings about the endocrine and metabolic effects of COCs. The main source of information for a patient wishing to use COCs is her gynecologist. “A woman wants - this is a powerful argument.” Detailed counseling should begin with clarification of the patient's expectations and preferences. Most myths about GCs are the result of the patient’s misunderstanding of certain mechanisms of their action, and the result of this is refusal to use them. The main myths about modern GC are the possibility of infertility, amenorrhea, weight gain, acne, and hirsutism. Modern women have the following requirements for GCs: high contraceptive effectiveness, even if the dosage regimen is violated, safety (“no chemicals”), positive non-contraceptive effects, absence of side effects, ease of use. Currently, a new monophasic COC – ZOELY®, which is registered in Russia under the trade name Zoely® (“MSD Pharmaceuticals”), has been introduced to the global pharmaceutical market. The drug contains nomegestrol acetate (NOMAC) 2.5 mg in combination with 17β-estradiol (E2) 1.5 mg. In this article we will try to dispel some myths about GC using the example of this drug, which is currently the highest link in the evolutionary development of COCs. A distinctive feature of this drug is that both components in it are as close as possible to the natural hormones produced in a woman’s body. It contains estrogen - 17b-estradiol, identical in structure to natural, and a highly selective progestogen - a derivative of progesterone - nomegestrol acetate (NOMAC), the structure of which is similar to endogenous progesterone. The new progestogen made it possible to carry out long-term attempts to use an estrogenic component in COCs, close to natural estradiol. Previously, all attempts to replace ethinyl estradiol with 17β-estradiol and other estrogens ended in failure due to poor control of the menstrual cycle [3, 15]. Unlike its predecessors, Zoeli has a fairly long half-life (46 hours), which ensures high reliability of contraception (even if the woman forgot to take the pill on time). This allows the patient not to doubt its effectiveness, even with a slight violation of the dosage regimen. In a study by D. Mansour, C. Verhoeven et al. (2001) when comparing two COCs in the group with NOMAC/E2, skipping one active tablet at any time or two tablets between days 8 and 17 of the cycle was allowed without the need for additional use of condoms; in the DRSP/EE group, only one active pill was allowed to be missed in the second week (days 8–14 of the cycle), all other missed active pills required additional use of condoms [9]. High antigonadotropic activity provided by the progestin component, a pronounced property to suppress ovulation and the ability to increase the viscosity of cervical mucus ensure the effectiveness of contraception. The question of the timing of possible pregnancy after discontinuation of the drug is very important for patients in connection with the myth about the possibility of infertility. In a study by S. Christin-Maitre, D. Serfary et al. (France, 2010) showed restoration of ovulation and endometrial thickness within the first cycle after stopping the drug in 72% of patients, as indicated by a progesterone level > 3 ng/ml measured on the 20th day of the menstrual cycle or later (the second measurement was carried out several days later if progesterone levels were <3 ng/ml) [6]. Similar results regarding cervical mucus, endometrial thickness and ovulation recovery were observed in a comparative study of NOMAC/E2 and DRSP/EE [8]. It is assumed that in the remaining patients, restoration of ovulation occurred in the 2nd–3rd cycle after stopping the drug. Some time ago, there was a myth that menstruation every 28 days was a sign of normal female reproductive function, which resulted in the imitation of a 28-day menstrual cycle, achieved by taking contraceptives for 21 days, followed by an interval of 7 days without taking the drug . The modern rhythm of women's lives and scientific research have changed the view of the cyclicity of menstruation. In 1999, a study was conducted in Holland in which women were asked about their views on the frequency of menstruation and changes they would like to make to their pattern (shorter, less heavy, less painful or no periods at all). Women who prefer monthly menstruation accounted for less than a third of respondents, 9% would like not to menstruate at all. Regarding the new innovative COC, according to a large randomized trial, it was noted that when taking NOMAC/E2 tablets (n=1591) for contraception for 13 bleeding cycles, withdrawal symptoms were shorter than when using drospirenone/EE tablets (3 mg/ 30 g) (n = 535) (3–4 days vs. 4–5 days, respectively). Interim bleeding rates were similar (about 15%), but more women did not experience withdrawal bleeding with NOMAC/E2 (about 10% versus 0.5%, respectively), reflecting the greater progestational effect of NOMAC [2]. For this reason, women taking NOMAC/E2 should be informed about the possibility of “invisible periods” before starting a course of contraception, which is not a side effect, but rather an additional benefit of the drug. Concerns about the increased risk of thromboembolism due to the estrogen content of COCs led to a gradual reduction in the dose of ethinyl estradiol from 50 to 30, 20 and even 15 mcg. This dose reduction was also accompanied by a reduction in side effects such as breast engorgement, nausea and flatulence. But even with such small doses of hormones, COCs still have a prothrombotic effect. In a double-blind randomized study by P. Gaussem, M. Alhenc-Gelas (France, 2011), when using Zoely, side effects in relation to hemocoagulation markers (prothrombin 1+2, antithrombin, protein C, D-dimer, plasminogen and plasminogen activator inhibitor 1 and fibrinolysis) were recorded less frequently than when using LNG/EE in the 21+7 mode. None of the drugs had an effect on platelet aggregation. The findings suggest that Zoeli may have a lower risk of venous thrombosis compared with LNG/EE; Further epidemiological studies are needed to confirm this [7]. Therefore, a thorough history taking is necessary, including heredity for cardiovascular and thromboembolic factors, and taking into account all possible risks. There is another myth that using COCs can lead to cancer. There is some evidence of a protective effect of COCs against ovarian and endometrial cancer and, to a lesser extent, colon cancer. The birth control pill also reduces the likelihood of developing benign breast diseases. However, to date there is no clear information about the relationship between the risk of breast cancer (BC) and COCs [1]. This problem is also important because breast cancer is currently one of the most common malignant diseases in women and is the main cause of death among the female population. Of particular interest here is the comparison of NOMAC with those progestogens that have already been shown to influence the development of breast cancer, such as medroxyprogesterone acetate, which was used in the Women's Health Initiative study [18], or norethisterone, which was used in several non-experimental studies [ 14]. Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in tissues of people with breast cancer and is a predictor of the risk of developing progesterone-dependent cancer. MCF-7 cells (primary breast cancer cells) were transfected with a PGRMC1-expressing plasmid and stimulated with estradiol (10–12 and 10–10 M concentrations). In addition, NOMAC, progesterone, medroxyprogesterone acetate and norethisterone (each at a concentration of 10–7 M) were added sequentially or simultaneously. Research has shown that women who have breast cancer cells with increased PGRMC1 activity may be more susceptible to its development if treated with estrogen in combination with certain types of synthetic progestogens [13]. In a laboratory study, NOMAC did not have a proliferative effect on MCF-7 cells and was more consistent with natural progesterone than other progestogens used for GC and hormone therapy [12]. NOMAC is also capable of altering estrogen metabolism through inhibition of sulfatase, 17β-hydroxysteroid dehydrogenase and aromatase in both normal and cancer breast cells, thereby reducing the supply of estradiol to these cells [16]. All of these reactions lead to a reduction in estrogenic activity in both benign and malignant breast cells. Since the presence of estrogen in the mammary gland is considered a precondition for the additional proliferative effect of the progestogen [16], the described action of NOMAC may even lead to a reduction in risk. Thus, Zoely, which contains nomegestrol acetate (NOMAC) in combination with 17β-estradiol (E2), will likely not have a significant effect on the mammary glands, and we should see this in clinical trial endpoints. An important criterion for the safety of COCs is its effect on metabolic parameters. A. Basdevant et al. reported that NOMAC at a dose of 5 mg/day. does not have a significant effect on fasting blood glucose or insulin levels, nor on the levels of total cholesterol, HDL or LDL, fibrinogen or plasminogen in women after six cycles of use [4]. In addition, NOMAC has no or minimal effect on the production of nitric oxide (NO), vasoprotective or antithrombotic factors [10]. Zoely has a positive effect of E2 on NO formation [19, 20]. Modern COCs can be prescribed not only for contraceptive purposes, but also for therapeutic or prophylactic purposes, which is related to the mechanism of action of the drug and is not always realized by the patient. Additional benefits of the drug include the treatment and prevention of functional ovarian cysts, pelvic inflammatory diseases requiring hospitalization, ectopic pregnancy and iron deficiency anemia. Either solely for the treatment of the following symptoms or in combination with the purpose of contraception, birth control pills may also be prescribed to treat certain gynecological conditions such as dysmenorrhea, irregular or excessive bleeding, acne, hirsutism and pain associated with endometriosis. These positive health effects cannot be exaggerated. The high selectivity of NOMAC, due to its belonging to the class of progesterone derivatives, provides it with a targeted effect on progesterone receptors, and therefore Zoeli is devoid of estrogenic, androgenic, glucocorticoid or mineralocorticoid activity. Effective suppression of ovulation allows the drug to occupy its niche in the prevention of hormonally dependent diseases of the reproductive system, which will ultimately preserve reproductive health and improve the quality of life of our patients. Thus, the innovative COC containing analogues of natural estrogen and gestagen (1.5 mg 17β-estradiol and 2.5 mg nomegestrol acetate) is the contraceptive of choice for women of any age - from menarche to menopause, since it meets all the requirements for modern hormonal contraceptives. The effectiveness of Zoely is more than 99%, the half-life is 46 hours, it provides predictable cycle control, short and less heavy withdrawal bleeding, and a convenient continuous monophasic regimen of use 24/4. Literature 1. Savelyeva I.S. Mammary glands and hormonal contraception // Gynecology. 2000. No. 1. P. 32–51. 2. Agren UM, Anttila M., Mäenpää-Liukko K. et al. Effects of a monophasic combined oral contraceptive nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism // Eur. J. Contracept. Reprod. Health Care. 2011. Vol. 16. P. 444–457. 3. Astedt B., Jeppsson S., Liedholm P. et al. Clinical trial of a new oral contraceptive pill containing the natural estrogen 17beta-oestradiol // Br. J. Obstet. Gynaecol. 1979. Vol. 86. P. 732–736. 4. Basdevant A., Palissier C., Degrelle H. et al. Effects of nomegestrol acetate (5 mg/d) on hormonal, metabolic and hemostatic parameters in premenopausal women // Contraception. 1991. Vol. 44. P. 599–605. 5. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM et al. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen // Lancet. 1995. Vol. 346. P. 1593–1596. 6. Christin-Maitre S., Serfaty D., Chabbert-Buffet N. et al. Comparison of a 24-day and a 21-day pill regimen for the novel combined oral contraceptive, nomegestrol acetate and 17b-estradiol (NOMAC/E2): a double-blind, randomized study // Hum. Reprod. 2011. Vol. 26. No. 6. P. 1338–1347, 7. Gaussem P., Alhenc-Gelas M. et. al. Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17β-estradiol, compared with those of levonorgestrel/ethinyl estradiol // Thromb. Haemost. 2011. Vol. 105. 8. Ingrid JM Duijkers, Klipping Ch., Grob P. et al. Effects of a monophasic combined oral contraceptive nomegestrol acetate and 17β-oestradiol on ovarian function in comparison to a monophasic combined oral contraceptive containing drospirenone and ethinylestradiol // Eur. J. Contracept. Reproduct. Health Care. 2010. P. 1–12. 9. Mansour D., Verhoeven C., Sommer W. et al. Efficacy and tolerability of a monophasic combined oral contraceptive nomegestrol acetate and 17β-oestradiol in a 24/4 regimen, in comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a 21/7 regimen // Eur. J. Contracept. Reproduct. Health Care. 2011. Early Online. P. 1–14. 10. Mueck AO, Sitruk–Ware R. Nomegestrol acetate, a novel progestogen for oral contraception // Steroids. 2011. Vol. 76. P. 531–539. 11. Mueck AO, Ruan X. Benefits and risks during HRT – main safety issue breast cancer // Horm. Mol. Biol. Clin. Invest. 2011. Vol. 5. P.105–116. 12. Ruan X., Neubauer H., Yang Y. et al. Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells // Climacteric. 2012. 13. Ruan X., Schneck H., Schultz S. Nomegestrol acetate sequentially or continuously combined to estradiol did not negatively affect membrane-receptor associated progestogenic effects in human breast cancer cells // Gynecol. Endocrinol. 2012. P.1–4. 14. Seeger H., Mueck AO Are the progestins responsible for breast cancer risk during hormone therapy in the postmenopause? Experiment. vs. clinical data // J. Steroid. Biochem. Mol. Biol. 2008. Vol. 109. P. 11–15. 15. Serup J., Bostofte E., Larsen S. et al. Natural oestrogens for oral contraception // Lancet. 1979. Vol. 2. P. 471–472. 16. Shields–Botella J., Chetrite G., Meschi S., Pasqualini JR Effect of nomegestrol acetate on estrogen biosynthesis and transformation in MCF-7 and T47–breast cancer cells // J. Steroid. Biochem. Mol. Biol. 2005. Vol. 93. P.1–13. 17. WHO Venous thromboembolic disease and combined oral contraceptives: Results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception // Lancet. 1995. Vol. 346. P. 1575–1582. 18. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women // JAMA. 2002. Vol. 288. P. 321–333. 19. Zerr-Fouineau M., Chataigneau M., Blot C., Schini-Kerth VB Progestins overcome inhibition of platelet aggregation by endothelial cells by down-regulating endothelialNOsynthase via glucocorticoid receptors // FASEB J. 2007. Vol. 21. P. 265–273. 20. Zerr-Fouineau M., Jourdain M., Boesch C. et al. Certain progestins prevent the enhancing effect of 17-estradiol on NO-mediated inhibition of platelet aggregation by endothelial cells // Arterioscler. Thromb. Vasc. Biol. 2009. Vol. 29. P. 586–593.

Reviews about Zoely

The pharmaceutical industry produces many hormonal contraceptives for oral use. Considering Zoely's birth control pills, reviews from gynecologists, subject to all the rules for taking the pills, are mostly positive. Naturally, any doctor in his practice has encountered many side effects of medications, and Zoely cannot do without them. Although, compared to many other COCs, Zoely tablets exhibit fewer side effects, and those that are detected are less pronounced.

Reviews of Zoely among women using this drug are purely positive, and this suggests that the active and auxiliary composition of the tablets is completely suitable for their body. Negative reviews are found among women who tried this contraceptive and eventually abandoned its use due to various side effects.

Each organism is individual and has its own set of characteristics, therefore, when choosing a contraceptive, you need to rely on the experience of a gynecologist, as well as undergo all the tests recommended by him. In this case, you have a much better chance of choosing exactly “your” contraceptive, which will not only protect you from unwanted pregnancy, discomfort into your life .

Zoely price, where to buy

The price of Zoely on the Russian pharmaceutical market ranges from 800 to 1100 rubles.

You can buy Zoely birth control pills in Moscow at an average cost of 850 rubles.

• Online pharmacies in RussiaRussia

ZdravCity

• Zoely tablets p.p.o.
  2.5 mg + 1.5 mg placebo 28 pcs. Delpharm Lille S.A.S./Merck Sharp and Dome B.V./N.V.Organon RUB 1,205 order