Zoely pills 2.5mg + 1.5mg, 28pcs

Composition

For tablets containing active ingredients

Active ingredients:

nomegestrol acetate 2.50 mg,

estradiol hemihydrate 1.55 mg (equivalent to 1.50 mg of estradiol).

Auxiliary substances:

microcrystalline cellulose 14.00 mg,

crospovidone 2.40 mg,

talc 0.70 mg,

magnesium stearate 0.70 mg,

colloidal silicon dioxide 0.44 mg,

lactose monohydrate 57.71 mg;

Tablet shell:

Opadray II white (1.6 mg) contains polyvinyl alcohol 0.64 mg, titanium dioxide 0.40 mg, macrogol-3350 0.32 mg, talc 0.24 mg.

For tablets that do not contain active ingredients (placebo)

Auxiliary substances:

microcrystalline cellulose 14.00 mg,

crospovidone 2.40 mg,

talc 0.70 mg,

magnesium stearate 0.70 mg,

colloidal silicon dioxide 0.44 mg,

lactose monohydrate 61.76 mg;

Tablet shell:

Opadray II yellow (2.4 mg) contains polyvinyl alcohol 0.96 mg, titanium dioxide 0.58 mg, macrogol-3350 0.48 mg, talc 0.36 mg, iron oxide yellow dye 0.016 mg, iron oxide black dye 0.00024 mg

Pharmacological action

Pharmacodynamics

Nomegestrol acetate is a highly selective progestogen derived from the natural steroid hormone progesterone. Nomegestrol acetate has a pronounced affinity for the human progesterone receptor, has antigonadotropic activity, progesterone receptor-mediated antiestrogenic activity, moderate antiandrogenic activity, and does not have estrogenic, androgenic, glucocorticoid, or mineralocorticoid activity.

Zoely® contains 17b-estradiol, a natural estrogen identical to endogenous human 17b-estradiol (E2). Unlike ethinyl estradiol, which is part of other combined oral contraceptives (COCs), E2 does not have an ethinyl 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 yellow body of the menstrual cycle (see the section “Pharmacokinetics”).

The contraceptive effect of Zoely® is due to a combination of various factors, the most important of which are ovulation suppression and changes in the viscosity of cervical secretions.

In two randomized, open-label comparative efficacy and safety studies, more than 3,200 women aged 18-50 years took Zoely® for 13 consecutive cycles and more than 1,000 women took the combination drospirenone (3 mg) / ethinyl estradiol (30 mcg) according to the 21/7 regimen.

In the Zoely® group, weight gain was reported in 8.6% of women (in the comparison group – 5.7%), irregular withdrawal bleeding (mainly no withdrawal bleeding) was reported in 10.5% of women (in the comparison group – 0.5%), acne was reported in 15.4% of women (in the comparison group – 7.9%) (see section “Side effects”).

Evaluation of the development of acne while taking Zoely® showed that the majority of women (73.1%) did not experience any changes in the condition compared to the condition before treatment,16.8% of women experienced an improvement in the condition, and 10.1% of women had the appearance or worsening of acne. In a clinical study of Zoely® conducted in the European Union, Asia and Australia, the following Perl index values were calculated for the age group of 18-35 years: method inefficiency – 0.40 (upper limit of 95% confidence interval 1.03); method inefficiency and patient error – 0.38 (upper limit of 95% confidence interval 0.97).

In a clinical study of Zoely® conducted in the United States, Canada, and Latin America, the following Perl index values were calculated for the age group of 18-35 years: method inefficiency – 1.22 (upper limit of 95% confidence interval 2.18); method inefficiency 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 taking Zoely®, ovulation was restored on average 20.8 days after the last tablet intake, with the earliest ovulation date recorded on day 16.

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,2-year comparative study, no clinically significant effect of Zoely on bone mineral density was observed when women aged 21-35 years were treated with Zoely®.

A randomized, open-label, multicenter comparative study was conducted to evaluate the effect of Zoely® on blood clotting parameters, lipid profile, carbohydrate metabolism, adrenal and thyroid function, and androgen concentrations.

Sixty 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 no clinically significant effects on lipid metabolism and hemostasis were detected. Taking Zoely® increased the concentrations of thyroxine-binding globulin and corticosteroid-binding globulin (CSG) transporter proteins. When taking Zoely®, the concentration of sex hormone binding globulin (SHBG) increased slightly, 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 during histological examination of the endometrium.

Pharmacokinetics

Nomegestrol Acetate

Suction

Nomegestrol acetate is rapidly absorbed after oral use. After a single dose, the maximum plasma concentration is about 7 ng / ml and is reached in 2 hours. Absolute bioavailability after a single dose is 63%. Food has no clinically significant effect on the bioavailability of nomegestrol acetate.

Distribution

Nomegestrol acetate actively binds to albumin (97-98%), but does not bind to SHBG or CSG. The apparent volume of distribution of nomegestrol acetate at steady state is 1645 ± 576 liters.

Metabolism

Nomegestrol acetate is metabolized to several inactive hydroxylated metabolites by liver cytochrome P 450 isoenzymes, mainly CYP3A4 and CYP3A5; it is also possible to participate in the metabolism of CYP2C8 and CYP2C19 isoenzymes.

Nomegestrol acetate and its hydroxylated derivatives undergo a pronounced phase 2 metabolism with the formation of glucuronide and sulfate conjugates. The clearance at steady state is 26 l/h.

Deduction

The half-life (t_1/2) at steady state is 46 hours (from 28 to 83 hours). The elimination half-life of the metabolites has not been established. Nomegestrol acetate is excreted by the kidneys and through the intestines. Approximately 80% of the dose is excreted by the kidneys and through the intestines within 4 days. Nomegestrol acetate is almost completely eliminated within 10 days. Intestinal excretion exceeds renal excretion.

Linearity

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

The steady state

of SHBG does not affect the pharmacokinetics of nomegestrol acetate. The equilibrium state is reached after 5 days. The average concentration at steady state is 4 ng / ml. The maximum concentration of nomegestrol acetate in plasma is about 12 ng / ml and is reached 1.5 hours after taking the drug.

In vitro interactions nomegestrol acetate has no significant inducing or inhibitory effect on cytochrome P 450 isoenzymes and does not interact with glycoprotein P.

Estradiol (E2)

Suction

Estradiol undergoes a pronounced metabolism during the” first pass ” through the liver after ingestion. Absolute bioavailability is about 1%. Food intake does not have a clinically significant effect on the bioavailability of estradiol.

Distribution

The distribution of exogenous and endogenous estradiol 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 an unbound form.

Metabolism

Exogenous estradiol is actively biotransformed after oral use. The metabolism of exogenous and endogenous estradiol is similar. Estradiol is rapidly converted to several metabolites in the intestine and liver (mainly estrone), which are subsequently conjugated and subjected to enterohepatic recycling. There is a dynamic equilibrium between estradiol, estrone, and estrone sulfate due to the activity of various enzymes, including estradiol dehydrogenase, sulfotransferase, and aryl sulfatase. The oxidation of estrone and estradiol occurs under the action of cytochrome P 450 isoenzymes, mainly CYP1A2, CYP1A2 (outside the liver), CYP3A4, CYP3A5, CYP1B1 and CYP2C9.

Deduction

Estradiol is rapidly eliminated from the blood. Due to metabolism and intestinal-hepatic recirculation, there is a large pool of circulating estrogen sulfates and glucuronides.As a result, the half-life of estradiol, adjusted for the initial value, varies widely and is 3.6 ± 1.5 hours after intravenous use. Steady state The maximum concentration of estradiol in the blood plasma is about 90 pg / ml and is reached 6 hours after use. Average plasma concentrations are 50 pg / ml. These concentrations of estradiol correspond to those in the initial and late phases of the menstrual cycle.

Pharmacokinetics in special groups

Children

The pharmacokinetics of nomegestrol acetate (primary target) after a single oral dose of Zoely® were comparable in healthy adolescent girls after menarche and in adult women. The concentration of estradiol (secondary target) in adolescent girls compared to adult women was comparable during the first 24 hours and lower than in adult women after 24 hours. The clinical significance of this result is unknown.

Impaired renal function

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

Impaired liver function

The effect of liver diseases on the pharmacokinetics of Zoely® has not been studied. However, in patients with impaired liver function, it is possible to worsen the metabolism of sex hormones.

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

Indications

Contraception.

Use during pregnancy and lactation

Pregnancy

The use of Zoely® is contraindicated during pregnancy. If pregnancy occurs when using Zoely®, the drug should be discontinued.

In most epidemiological studies, there was no increase in the risk of developing birth defects in children whose mothers took COCs containing ethinyl estradiol before pregnancy. No teratogenic effects were observed when COCs containing ethinyl estradiol were accidentally taken at the beginning of pregnancy. There is limited experience with the use of Zoely® in pregnant women, which indicates that there is no undesirable effect of the drug on the condition of the fetus or newborn.

In studies of the combination of nomegestrol acetate / estradiol in laboratory animals, reproductive toxicity was recorded.

The drug Zoely® is intended for the prevention of unwanted pregnancy. If a woman wants to stop taking Zoely® in order to become pregnant, it should be taken into account that ovulation recovers on average 20.8 days after the last intake of a tablet of Zoely® (see the section “Pharmacological properties”, subsection “Pharmacodynamics”).

Breast-feeding period

COCs can affect lactation, as they cause changes in the amount and composition of breast milk. Therefore, the use of COCs is not recommended until the complete cessation of breast-feeding (an alternative method of contraception should be chosen). Small amounts of contraceptive sex hormones and / or their metabolites can be excreted in breast milk, but there are no data on their undesirable effects on the health of the newborn.

Contraindications

COC should not be used in the presence of any of the following conditions/diseases. There are no epidemiological data on the use of COCs containing 17b-estradiol, but contraindications to the use of Zoely® correspond to contraindications to the use of contraceptives containing ethinyl estradiol. If any of these conditions/diseases occur during the use of Zoely®, the drug should be discontinued immediately.

• Deep vein thrombosis or pulmonary embolism, including in the anamnesis.
• Arterial thrombosis (myocardial infarction) or prodromal conditions (transient ischemic attack, angina pectoris), including in the anamnesis.
• Acute disorders of cerebral circulation, including in the anamnesis.
• Migraine with focal neurological symptoms, including a history.
• Expressed or multiple risk factors for venous or arterial thrombosis (see section “Special instructions”), such as: diabetes mellitus with vascular symptoms; uncontrolled hypertension; severe dislipoproteinemia; obesity (body mass index more than 30 kg/m₂); prolonged immobilization; extensive surgery, any surgery on the lower limbs or serious injury; complicated valvular heart disease; atrial fibrillation; Smoking at the age of 35 years.
• Hereditary or acquired predisposition to venous or arterial thrombosis, such as activated protein C resistance, antithrombin III deficiency, protein C and S deficiency, hyperhomocysteinemia, and antiphospholipid antibodies (cardiolipin antibodies, lupus anticoagulant).
• Pancreatitis with severe hypertriglyceridemia, including in the anamnesis.
• Severe liver diseases, including in the anamnesis, until normalization of liver function indicators.
• Liver tumors (whether malignant or benign), including a history.
• Known or suspected hormone-dependent malignancies (for example, genital or breast cancers).
• Established or expected pregnancy, breast-feeding period.
• Hypersensitivity to any active or auxiliary substance.
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
• Vaginal bleeding of unclear etiology.
• Postmenopause.

There are no data available on the efficacy and safety of Zoely ® in adolescent girls under 18 years of age. For more information on pharmacokinetics, see the section “Pharmacokinetics”.

Caution: in the presence of any of the following conditions, diseases, or risk factors, the benefits of using Zoely® and the possible risks for each individual woman should be evaluated. This should be discussed with the woman before she starts taking Zoely®. For more information, see the “Special Instructions” section. If any of these conditions, diseases, or risk factors worsen, worsen, or occur for the first time, a woman should consult a doctor to decide whether to continue using Zoely®. Diabetes mellitus without vascular damage; severe depression or a history of this disease; systemic lupus erythematosus; Crohn’s disease; ulcerative colitis; liver function disorders; hypertriglyceridemia, including a family history; risk factors for coronary heart disease (obesity, hypertension); a family history of venous thrombosis, arterial embolism in siblings or parents at a young age (see the section “Special instructions”).

Side effects

The safety of Zoely® was evaluated in seven multicenter clinical trials lasting up to two years. The study included 3,490 women aged 18-50 years (a total of 35028 cycles).

The tolerability of Zoely® is good, and the safety profile is similar to that of other COCs. The table lists possible undesirable effects that have been reported with the use of the drug.

The frequency of adverse events is indicated in terms of:

• “very often” (≥ 1/10),
• “often” ( < 1/10, ≥ 1/100),
• “infrequently” ( < 1/100, ≥ 1/1000),
• “rare” ( < 1/1000),

according to MedDRA (synonyms or related conditions are not listed, but should also be taken into account).

Metabolic and nutritional disorders: infrequently-increased appetite, fluid retention; rarely-decreased appetite.

Mental disorders: often-decreased libido, depression, mood swings; rarely-increased libido.

Disorders of the nervous system: often-migraine, headache; rarely-impaired attention.

Visual disorders: rarely-contact lens intolerance, dry eye mucosa

Vascular disorders: infrequently – “hot flashes”.

Gastrointestinal disorders: often – nausea; infrequently-bloating; rarely-dry mouth.

Skin and subcutaneous tissue disorders: very common – acne%^%1; infrequently-hyperhidrosis, alopecia, itching, dry skin, seborrhea; rarely-chloasma, hypertrichosis.

Musculoskeletal and connective tissue disorders: infrequently-feeling heavy.

Disorders of the genitals and breast: very often – irregular “withdrawal” bleeding; often – heavy acyclic bleeding, heavy menstrual – like bleeding, breast tenderness, pelvic pain; infrequently – scanty menstrual-like bleeding, breast engorgement, galactorrhea, uterine muscle spasm, premenstrual-like syndrome, seals in the mammary glands, dyspareunia, dryness of the vulvar and vaginal mucosa; rarely-unpleasant smell from the vagina, discomfort in the vaginal area.

General disorders and disorders at the injection site: infrequently-irritability, edema; rarely-hunger.

Laboratory and instrumental data: often-an increase in body weight; infrequently-an increase in the activity of liver enzymes.

1-Acne is not a spontaneously reported phenomenon, but rather a requested one, since the assessment was performed at each visit during the study.

In addition to the above-mentioned adverse events, hypersensitivity reactions have been reported with the use of Zoely® (the frequency of occurrence has not been established).

Side effects that occurred when taking COCs containing ethinyl estradiol are described in detail in the section “Special instructions”: venous and arterial thromboembolism, increased blood pressure, hormone-dependent tumors (for example, liver tumors, breast cancer), chloasma.

Interaction

To exclude possible interactions, you should read the instructions for use of concomitant medications.

Effect of other medicinal products on Zoely®

The interaction of oral contraceptives with other enzyme-inducing drugs can lead to” breakthrough ” bleeding and/or reduce the effectiveness of contraception.

Drugs that induce hepatic enzymes (and therefore increase the clearance of sex hormones) include drugs containing phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin, drugs or herbal preparations containing St. John’s wort (Hypericum perforatum), and to a lesser extent drugs containing oxcarbazepine, topiramate, felbamate and griseofulvin. HIV protease inhibitors with inducing activity (for example, ritonavir and nelfinavir) and non-nucleoside reverse transcriptase inhibitors (for example, nevirapine and efavirenz) may also affect hepatic metabolism.

During concomitant use of drugs that induce microsomal enzymes, and for 28 days after their withdrawal, a barrier method of contraception should be used. If long-term treatment with drugs that induce microsomal enzymes is necessary, the use of another method of contraception should be considered.

No drug interaction studies have been conducted for Zoely®, but two studies have been conducted on the use of a combination of nomegestrol acetate and estradiol in higher doses (nomegestrol acetate 3.75 mg + estradiol 1.5 mg) in combination with rifampicin and in combination with ketoconazole in a population of postmenopausal women. Concomitant use of rifampicin reduces the AUC0 – ∞ of nomegestrol acetate by 95% and increases the AUC0-t(last) of estradiol by 25%. Concomitant use of ketoconazole (a single dose of 200 mg) does not affect the metabolism of estradiol, but increases the maximum concentration (85%) and AUC0-∞ (115%) of nomegestrol acetate, but these changes are not clinically significant. It is assumed that similar changes may occur in the case of the use of these drugs in women of reproductive age.

Effect of Zoely® on other medicinal products

Oral contraceptives can affect the metabolism of other medications. Caution should be exercised when using Zoely® in combination with lamotrigine.

Effect of Zoely® on laboratory tests

The use of COCs may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, plasma concentrations of (transport) proteins (for example, CSG and lipid/lipoprotein fractions), carbohydrate metabolism, blood clotting and fibrinolysis. These indicators usually do not exceed the limits of normal values.

How to take, course of use and dosage

The drug is intended for oral use.

How to take Zoely®

Tablets are taken daily at the same time of day, regardless of food intake, in the order indicated on the package, if necessary, with a small amount of water. Take one tablet daily for 28 consecutive days. Reception should begin with white tablets containing active ingredients.

White tablets containing active ingredients are taken within the first 24 days. For the next 4 days, take yellow tablets that do not contain active substances (placebo). Taking tablets from each subsequent package should be started the 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 time you start taking the next pack of pills. For more information, see the section “Special instructions” subsection “Changes in the nature of menstruation”.

Special patient groups

Impaired renal function

There are no data on use in patients with renal insufficiency, but the effect of renal insufficiency on the elimination of nomegestrol acetate and estradiol is unlikely.

Impaired liver function

The effect of liver diseases on the pharmacokinetics of Zoely® has not been studied. However, since the metabolism of sex hormones may worsen in patients with impaired liver function, the use of Zoely® in this group of patients is not recommended until the liver function indicators normalize (see the section “Contraindications”).

How to start taking Zoely®

In the previous cycle, hormonal contraceptives were not used

The pill should be taken on the first day of a woman’s menstrual cycle (the first day of menstrual bleeding). In this case, the use of additional contraceptives is not required. You can start taking pills from the 2nd-5th day of the cycle. In this case, during the first 7 days of taking the tablets, it is recommended to additionally use a barrier method of contraception.

Switching from a combined hormonal contraceptive (COC, vaginal ring, or transdermal patch)

It is advisable for a woman to start taking Zoely® the day after taking the last tablet containing active ingredients, but not later than the day after completing the usual interval between cycles or taking placebo tablets. If a woman has used a vaginal ring or transdermal patch, then it is advisable to start taking Zoely® on the day of their removal, but not later than on the day when a new ring should be inserted or another patch should be applied.

Switching from progestogen-only medications (pills, implants, injectable forms, or hormone-containing intrauterine devices (IUDs))

A woman can stop taking progestogen-only pills any day and start taking Zoely®the next day. The implant or IUD can be removed on any given day. In this case, Zoely® should be started on the day of their removal. If a woman has received injections, then the drug Zoely® is started on the day when the next injection should have been made. In all these cases, a woman is recommended to additionally use a barrier method of contraception during the first 7 days of taking tablets containing active substances.

After an abortion in the first trimester

, a woman can start taking the drug immediately. In this case, there is no need for an additional method of contraception.

After giving birth or having an abortion in the second trimester

For breast-feeding women, see the section “Use during pregnancy and lactation”.

A woman should start taking the drug between the 21st and 28th day after giving birth or having an abortion in the second trimester. At a later start of taking the drug, it is recommended to use an additional barrier method of contraception during the first 7 days of taking the tablets. However, if you have already had sex after giving birth or having an abortion, you should rule out pregnancy or wait for your first menstrual period before taking Zoely®.

What to do if you miss a pill

The recommendations below apply only to skipping taking white tablets containing active ingredients.

If a woman takes another pill with a delay of less than 12 hours, the contraceptive effect is not reduced. A woman should take the pill as soon as possible, as soon as she remembers about it. Follow-up tablets should be taken at the usual time.

If a woman takes an active pill with a delay of more than 12 hours, the contraceptive effect may decrease. If you skip taking pills, it is advisable to follow two rules::

• to achieve adequate suppression of the hypothalamic-pituitary-ovarian system, white tablets containing active substances should be taken for at least 7 consecutive days;
• the more white tablets containing active substances are missed, and the closer the time of taking 4 yellow placebo tablets, the higher the risk of pregnancy.

Recommendations for skipping taking pills

If you missed taking one white tablet containing active ingredients

The contraceptive effect is not reduced. A woman should take the last missed white pill as soon as she remembers it, even if she has to take two pills at the same time. Then the pills should be taken as usual. No additional contraceptive measures are required.

If you missed taking two or more white pills

If, after skipping two or more white tablets containing active substances, there was no “withdrawal” bleeding while taking yellow placebo tablets, then pregnancy should be excluded (see also the section “Special instructions”, subsection “Changes in the nature of menstruation”).

Days 1-7

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, during the first week of continuous use of white tablets, it is necessary to use a barrier method of contraception. If sexual intercourse has taken place during the previous 7 days, then the possibility of pregnancy should be taken into account.

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, during the next 7 days of taking white tablets, it is necessary to use a barrier method of contraception.

Days 18-24

The risk of a decrease in the contraceptive effect increases with the approach to the start of taking placebo yellow tablets. However, changing the pill regimen avoids reducing the contraceptive effect. A woman should take the last missed white pill as soon as she remembers it, even if she has to take two pills at the same time. Do not take more than two white tablets containing active ingredients at the same time. During the next 7 days of taking white tablets, you should use a barrier method of contraception, and start the next package immediately after the end of the white tablets from the previous package, i. e. a woman should not take yellow placebo tablets. In this case, “withdrawal” bleeding usually occurs while taking yellow tablets from the next package, but “breakthrough” bleeding or “smearing” discharge may occur while taking white tablets.

If a woman is not sure about the number of missed pills or their color and, accordingly, does not know what recommendations she should follow, then it is necessary to use a barrier method of contraception until the woman takes white pills for 7 consecutive days.

If you missed taking yellow placebo pills

The contraceptive effect is not reduced. A woman may not take yellow pills from the last (fourth) row of the blister. However, missed pills should be discarded to avoid inadvertently increasing the duration of the placebo phase.

Recommendations for gastrointestinal disorders

In the case of gastrointestinal disorders (for example, vomiting or diarrhea), the absorption of the drug may be incomplete, so you should resort to additional contraceptive measures.

If vomiting occurs within 3-4 hours after taking the pill, then its reception should be considered missed. If you miss taking one white pill, the contraceptive effect is not reduced. If vomiting occurs again the next day or days, then follow the recommendations for skipping two or more tablets (see “Recommendations for skipping taking tablets”). If a woman does not want to change the usual pill regimen, then she should take an additional white tablet or tablets from another package.

How to delay or delay the onset of menstrual-like bleeding

To delay the onset of menstrual-like bleeding, a woman should continue taking white pills from another package without taking yellow pills. White tablets from the second package can continue to be taken until they run out. After completing the yellow tablets from the second package, it is necessary to resume taking Zoely® according to the usual scheme. With an extended reception schedule, “breakthrough” bleeding or “smearing” discharge may occur.

In order to shift the day of onset of menstrual-like bleeding to another day, you can shorten the phase of taking placebo yellow tablets (the maximum duration of taking placebo yellow tablets is 4 days). The shorter the break, the higher the risk of missing menstrual-like “withdrawal” bleeding and the occurrence of” breakthrough “bleeding or” smearing ” spotting while taking tablets from the second package (as in the case of delayed onset of menstrual-like bleeding).

Overdose

Repeated use of Zoely® in doses that are 5 times higher than recommended, and a single dose of nomegestrol acetate in doses that are 40 times higher than recommended, were not accompanied by adverse events.

Symptoms that can occur with an overdose: nausea, vomiting, spotting from the vagina.

Treatment: There are no antidotes. Further treatment should be symptomatic.

Special instructions

If you have any of the following conditions, diseases, or risk factors, you should evaluate the benefits of using Zoely® and the possible risks for each individual woman. This should be discussed with the woman before she starts taking Zoely®. If any of these conditions, diseases, or risk factors worsen, worsen, or occur for the first time, a woman should consult a doctor to decide whether to continue using Zoely®.

The following data were obtained from epidemiological studies of COCs containing ethinyl estradiol. Zoely ® contains 17b-estradiol, however, special instructions regarding the use of combined contraceptives containing ethinyl estradiol are considered applicable for Zoely®.

Vascular disorders

• The use of any COCs is associated with an increased risk of venous thrombosis and embolism, which is highest during the first year after the start of COCs.
• The results of epidemiological studies demonstrate that the incidence of venous thromboembolism (VTE) in patients with no known risk factors, taking low-dose ( For comparison, a similar parameter in patients who do not take COCs is 5-10 cases per 10,000 person-years or 60 cases per 100,000 pregnancies. VTE can be fatal in 1-2% of cases. There are no data on the effect of Zoely® on the risk of venous thrombosis and embolism compared to other COCs.
• Epidemiological studies have established a link between the use of COCs and an increased risk of arterial thromboembolism (myocardial infarction, transient ischemic attacks).
• Patients treated with COCs rarely developed thrombosis of other vessels, including 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 COCs.
• Symptoms of venous and arterial thrombosis or acute cerebrovascular accident may include the following conditions: sudden pain and/or swelling of the lower extremity, sudden intense chest pain radiating 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, accompanied or not accompanied by focal cramps, weakness or severe numbness that suddenly appears on one side of the body, movement disorders, “sharp stomach”.
• Risk factors for venous thrombosis and embolism: age; family history of diseases (venous thrombosis and embolism in siblings or parents at a young age). If a hereditary predisposition is suspected, then before taking any hormonal contraceptives, you should consult a specialist; prolonged immobilization, extensive surgery, any operation on the lower extremities or a serious injury. In these cases, it is recommended to stop taking hormonal contraceptives (at least 4 weeks before elective surgery) and resume it only 2 weeks after full recovery of motor activity. If the use of COCs has not been discontinued in advance, the need for antithrombotic agents should be considered; obesity (body mass index greater than 30 kg / m2).
• There is insufficient information on the role of superficial venous thrombophlebitis and varicose veins in the etiology of venous thrombosis.
• Risk factors for arterial thrombosis or acute cerebrovascular accident: 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 want to take COC; dyslipoproteinemia; obesity (body mass index greater than 30 kg / m2); hypertension; migraine; heart valve disease; atrial fibrillation; the presence of a family history of diseases (arterial thrombosis in siblings or parents at a young age). If a hereditary predisposition is assumed, then before starting taking any hormonal contraceptives, you should consult a specialist.
• Other conditions that have been associated with undesirable vascular disorders include diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), and sickle cell anemia.
• It is necessary to take into account the increased risk of developing thromboembolic complications in the postpartum period.
• An increase in the frequency or severity of migraines associated with the use of COCs (which may precede the development of a cerebrovascular complication) is a reason for immediate discontinuation of Zoely®.
• Women taking COCs should consult a doctor if possible symptoms of thrombosis occur. In cases of suspected or confirmed thrombosis, COCs should be discontinued. At the same time, adequate contraception should be initiated, taking into account 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 contributes to this risk, but it remains unclear to what extent this effect is associated with other factors, such as more frequent cervical examination or sexual behavior, including the use of barrier contraceptives, or with a combination of these factors. A causal relationship with the use of COCs has not been proven.
• Higher doses of COCs (50 micrograms of ethinyl estradiol) reduce the risk of endometrial and ovarian cancer. It remains unclear whether this applies to COCs containing 17b-estradiol.
• A meta-analysis of 54 epidemiological studies in women treated with COCs containing ethinyl estradiol showed a slight increase in the relative risk (RR) of developing breast cancer (RR = 1.24). The increased risk gradually disappears within 10 years after stopping taking COCs. Breast cancer rarely develops in women under the age of 40, so the additional number of breast cancer cases in women who take or have taken COCs is small compared to the overall risk of developing breast cancer. Women who use COCs are more likely to develop early-stage breast cancer than women who have never used them. During the use of COCs, the risk of developing breast cancer increases slightly, which may be due to an earlier diagnosis, the effect of the drug, or a combination of these two factors.
• In rare cases, women who took COCs developed benign liver tumors, and even less often, malignant ones. In some cases, these tumors led to life-threatening intra-abdominal bleeding. If there is intense upper abdominal pain, enlarged liver, or symptoms of intra-abdominal bleeding in women taking COCs, a liver tumor should be excluded.

Other states

• Women with hypertriglyceridemia or an appropriate family history have an increased risk of developing pancreatitis when taking COCs.
• Many women receiving COCs experienced a slight increase in blood pressure, although clinically significant increases in blood pressure were rare. The association between COCs and hypertension has not been established. However, if persistent arterial hypertension develops while taking COCs, 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 trials lasting up to two years, no clinically significant changes in blood pressure were detected with the use of Zoely®.
• During pregnancy and during the use of COCs, the following conditions were observed to develop or worsen, although their association with contraceptive use has not been definitively established: jaundice and / or pruritus associated with cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham’s chorea (small chorea), herpes during pregnancy, hearing loss associated with otosclerosis.
• In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen the symptoms of angioedema.
• In acute and chronic liver function disorders, it may be necessary to cancel COCs until liver function indicators return to normal. In case of recurrence of cholestatic jaundice, first observed during pregnancy or with previous use of sex hormones, it is necessary to stop taking COCs.
• Despite the fact that COCs can affect 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 taking COCs, especially during the first months. Zoely® has no effect on peripheral tissue insulin resistance and glucose tolerance in healthy women (see section “Pharmacological properties”, subsection “Pharmacodynamics”).
• Worsening of depression, Crohn’s disease, and ulcerative colitis was associated with COCs.
• 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 Zoely®, you should carefully read the medical history (including family history) of the woman and exclude pregnancy.

It is necessary to measure blood pressure and, if indicated, conduct a physical examination, taking into account contraindications and warnings. 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 COC may decrease in the case of skipping tablets (see the section “Dosage and use”), gastrointestinal disorders while taking active tablets (see the section “Dosage and use”), or in the case of concomitant therapy (see the section “Interaction with other medications”).

Changes in the nature of menstruation

When taking any COCs, there may be “breakthrough” bleeding or “smearing” discharge, especially in the first few months. Therefore, the examination for irregular bleeding is justified only after the adaptation period (approximately 3 cycles). Acyclic spotting after this adjustment period was observed in 15-20% of women treated with Zoely®. If irregular bleeding persists or occurs after previous regular cycles, it is necessary to assume non-hormonal causes and conduct diagnostic studies to exclude a malignant tumor or pregnancy. Diagnostic curettage may be required.

In women taking Zoely®, the duration of withdrawal bleeding averaged 3-4 days.

Some women who took Zoely® reported no withdrawal bleeding while taking placebo yellow tablets, even though they were not pregnant. In clinical trials, the absence of withdrawal bleeding was observed in 18-32% of cases (during cycles 1 to 12). In such cases, the absence of “withdrawal” bleeding was not associated with a higher frequency of “breakthrough” bleeding / “spotting” discharge in subsequent cycles. In 4.6% of women, there was no withdrawal bleeding in each of the first three cycles of using the drug. In this subgroup, there was a high percentage of women with no withdrawal bleeding in subsequent cycles (76-87%). Of the 28% of women who had no withdrawal bleeding in at least one cycle (during cycles 2,3, or 4),51-62% of patients also had no withdrawal bleeding in subsequent cycles.

If there is no withdrawal bleeding when taking Zoely® in accordance with the recommendations described in the section “Dosage and use”, then the probability of pregnancy is low. However, if the woman did not take the drug in accordance with the recommendations or if there are no two “withdrawal” bleeding in a row, then pregnancy should be excluded.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

The drug Zoely® does not affect the ability to drive vehicles and work with mechanisms.

Form of production

Film-coated tablets

Storage conditions

At a temperature of 2-30 °C

Shelf life

3 years

Active ingredient

Nomegestrol, Estradiol

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For women of childbearing age, Adults as prescribed by a doctor

Indications

For contraception