Zoely pills 2.5 mg + 1.5 mg №28

Composition

For pills containing active ingredients

1 pill contains:

Active substances: Nomegestrol acetate 2.50 mg, estradiol hemihydrate 1.55 mg (equivalent to 1.50 mg of estradiol).

Excipients: 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: Opadry 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 pills that do not contain active ingredients (placebo)

1 pill contains:

Excipients: 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: Opadry 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 dye yellow oxide 0.016 mg, iron dye black oxide 0 00024 mg

Packaging

28 pcs.

Mechanism of action

Nomegastrol acetate is a highly selective progestogen that is derived from the natural steroid hormone Progesterone. Nomegestrol acetate has a pronounced affinity for the human progesterone receptor, has antigonadotropic activity, antiestrogenic activity mediated by progesterone receptors, moderate antiandrogenic activity and does not possess estrogenic, androgenic, glucocorticoid and mineralocorticoid activity. Zoeli&№174; contains 17β-estradiol, a natural estrogen identical to endogenous human 17β-estradiol (E2). Unlike ethinyl estradiol, which is part of other combined oral contraceptives (CEC), E2 does not have an ethynyl group in the 17α position. When using the drug Zoeli&№174;, 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 the subsection “Pharmacokinetics”). The contraceptive effect of Zoeli&№174; is due to a combination of various factors, the most important of which are the suppression of ovulation and the change in the viscosity of the cervical secretions.

In two randomized open comparative studies of efficacy and safety, more than 3,200 women aged 18–50 years took Zoeli&№174; for 13 consecutive cycles and more than 1,000 women took the combination of drospirenone (3 mg) / ethinyl estradiol (30 μg) according to the regimen 21 / 7. In the group taking the drug Zoeli&№174;, an increase in body weight was reported in 8.6% of women (in the comparison group - 5.7%), irregular bleeding of "withdrawal" (mainly the absence of bleeding of "withdrawal") 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 the section “Side Effects”). An assessment of the development of acne when taking Zoeli&№174; showed that in the majority of women (73.1%) there were no changes in the state compared to the state before the start of treatment, in 16.8% of women there was an improvement in the condition and in 10.1% of women there was appearance or worsening of acne. In the clinical study of the drug Zoeli&№174;, conducted in the European Union, Asia and Australia, the following Pearl index indicators were calculated for the age group 18–35 years: method inefficiency - 0.40 (upper limit of 95% confidence interval 1.03); the inefficiency of the method and the patient's error - 0.38 (the upper limit of the 95% confidence interval of 0.97).

In a clinical study of the drug Zoeli&№174;, conducted in the United States of America, Canada and Latin America, the following Pearl index indicators were calculated for the age group of 18–35 years: method inefficiency - 1.22 (upper limit of 95% confidence interval 2.18); the inefficiency of the method and patient error - 1.16 (upper limit of the 95% confidence interval 2.08).

In a randomized open-label study, 32 women received Zoeli&№174; for 6 cycles. After stopping Zoeli&№174;, ovulation was restored an average of 20.8 days after the last pill, with the earliest date of ovulation being recorded on the 16th day.

Folic acid is an important vitamin in early pregnancy. While taking Zoeli&№174;, the concentration of folic acid in the blood plasma does not change and remains at a basic level for 6 consecutive months of taking the drug.In a randomized open comparative study of 2 years duration when taking Zoeli&№174; by women aged 21-35 years, there was a lack of a clinically significant effect of Zoeli&№174; on bone mineral density.

A randomized open comparative multicenter study was conducted to assess the effect of Zoeli&№174; on blood coagulation parameters, lipid profile, carbohydrate metabolism, adrenal and thyroid function, and also androgen concentration. Sixty women aged 18–50 years took Zoeli&№174; for 6 consecutive cycles. In clinical studies it was found that when taking the drug Zoeli&№174; insulin resistance and glucose tolerance did not change, and there were no clinically significant effects on lipid metabolism and hemostasis. Taking Zoeli&№174; increased the concentration of thyroxin-binding globulin and corticosteroid-binding globulin (CGC) protein carriers. When taking Zoeli&№174;, the concentration of sex hormone-binding globulin (GSPH) slightly increased, and the concentrations of androstenedione, dehydroepiandrosterone, total and free testosterone significantly decreased. In a clinical study, a group of women (n = 32) after 13 cycles of taking Zoeli&№174; did not show any pathological changes in the histological examination of the endometrium.

Nomegestrol acetate

Suction

Nomegastrol acetate is rapidly absorbed after oral administration. After a single dose, the maximum plasma concentration is about 7 ng / ml and is reached after 2 hours. The absolute bioavailability after a single dose is 63%. Food does not have a clinically significant effect on the bioavailability of nomegastrol acetate.

Distribution

Nomegastrol acetate actively binds to albumin (97-98%), but does not bind to SHBG or CGC. The apparent volume of distribution of nomegestrol acetate in the equilibrium state is 1,645 &№177; 576 l.

Metabolism

Nomegestrol acetate is metabolized to several inactive hydroxylated metabolites by the action of liver cytochrome P450 isoenzymes, mainly CYP3A4 and CYP3A5; it is also possible to participate in the metabolism of isoenzymes CYP2C8 and CYP2C19.

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

Removal

Elimination half-life (t_1/2) in the equilibrium state is 46 hours (from 28 to 83 hours). The half-life of metabolites is not installed. Nomegastrol acetate is excreted by the kidneys and through the intestines. Approximately 80% of the dose is excreted by the kidneys and through the intestines for 4 days. Nomegestrol acetate is almost completely excreted within 10 days. Excretion through the intestine exceeds renal excretion.

Linearity

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

Equilibrium state

SHBG has no effect on the pharmacokinetics of nomegastrol acetate. The equilibrium state is reached in 5 days. The average concentration in the equilibrium state is 4 ng / ml. The maximum concentration of nomegastrol 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 the glycoprotein R.

Estradiol (E2)

Suction

Estradiol undergoes a pronounced metabolism during the "first passage" through the liver after ingestion. Absolute bioavailability is about 1%. Eating 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 unbound form.

Metabolism

Exogenous estradiol is actively biotransformed after oral administration. The metabolism of exogenous and endogenous estradiol is similar. Estradiol quickly turns into several metabolites in the intestine and liver (mainly in estrone), which are subsequently conjugated and subjected to enterohepatic recirculation. 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 the isoenzymes of cytochrome P450, mainly CYP1A2, CYP1A2 (outside the liver), CYP3A4, CYP3A5, CYP1B1 and CYP2C9.

Removal

Estradiol is rapidly eliminated from the blood. Due to metabolism and enterohepatic recirculation, there is a large pool of circulating sulphates and estrogen glucuronides. As a result, the elimination half-life of estradiol, adjusted for the baseline, varies widely and is 3.6 &№177; 1.5 hours after intravenous administration. Equilibrium state The maximum concentration of estradiol in the blood plasma is about 90 pg / ml and is reached 6 hours after administration. The average concentration in the blood plasma is 50 pg / ml. These estradiol concentrations correspond to those in the initial and late phases of the menstrual cycle.

Pharmacokinetics in Special Groups

Children

The pharmacokinetics of nomegastrol acetate (the primary goal) after a single dose of Zoeli&№174; was inside the oral administration was comparable in healthy adolescent girls after menarche and in adult women. The concentration of estradiol (secondary goal) in adolescent girls compared with adult women was comparable in the first 24 hours and lower than in adult women after 24 hours. The clinical significance of this result is unknown.

Renal dysfunction

The effect of kidney disease on the pharmacokinetics of Zoeli&№174; has not been studied.

Liver dysfunction

The effect of liver disease on the pharmacokinetics of Zoeli&№174; has not been studied. However, in patients with impaired liver function, the metabolism of sex hormones may worsen.

Ethnic groups

Pharmacokinetics of the drug in representatives of ethnic groups has not been specifically studied.

Contraception.

KOC should not be used in the presence of any of the conditions / diseases listed below. There are no epidemiological data on the use of COC containing 17β-estradiol, however, contraindications to the use of the drug Zoeli&№174; correspond to contraindications to the use of contraceptives containing ethinyl estradiol. In case of any of these conditions / diseases during the period of use of the drug Zoeli&№174;, you should immediately stop taking the drug.

• Deep vein thrombosis or pulmonary thromboembolism, including a history.
• Arterial thrombosis (myocardial infarction) or prodromal conditions (transient ischemic attack, angina), including a history.
• Acute disorders of cerebral circulation, including a history.
• Migraine with focal neurological symptoms, including a history.
• Severe or multiple risk factors for venous or arterial thrombosis (see section "Special Instructions"), such as: diabetes mellitus with vascular symptoms; uncontrolled arterial hypertension; severe dyslipoproteinemia; obesity (body mass index more than 30 kg / m^₂); prolonged immobilization; extensive surgery, any operation on the lower limbs or a serious injury; complicated heart defects; atrial fibrillation; smoking over the age of 35 years.
• Hereditary or acquired susceptibility to the development of venous or arterial thrombosis, for example, resistance of activated protein C, deficiency of antithrombin III, deficiency of proteins C and S, hyperhomocysteinemia and antiphospholipid antibodies (antibodies to cardiolipin, lupus anticoagulant).
• Pancreatitis with severe hypertriglyceridemia, including a history of.
• Severe liver disease, including a history of, to normalize the performance of the liver.
• Liver tumors (malignant or benign), including a history of.
• Known or suspected hormone-dependent malignant tumors (for example, of the genital organs or the mammary gland).
• Established or suspected pregnancy, breastfeeding period.
• Hypersensitivity to any active or excipient.
• Lactase deficiency, lactose intolerance , glucose-galactose malabsorption.
• Bleeding from the vagina of unknown etiology.
• Postmenopause.

There are no data on the efficacy and safety of the drug Zoeli&№174; in
adolescent girls under the age of 18 years. Available information on pharmacokinetics is presented in the Pharmacokinetics section.

Carefully: If any of the following conditions, diseases, risk factors are present, the benefits of using Zoeli&№174; and the possible risks for each individual woman should be evaluated. This should be discussed with the woman before she starts taking Zoeli&№174;.Additional information is provided in the “Special Instructions” section. In cases of deterioration, exacerbation or the first occurrence of any of these conditions, diseases, risk factors, a woman should consult a doctor to decide whether it is possible to continue using Zoeli&№174;. Diabetes without vascular disease; severe depression or a history of the disease; systemic lupus erythematosus; Crohn's disease; ulcerative colitis; abnormal liver function; hypertriglyceridemia, including family history; risk factors for coronary heart disease (obesity, arterial hypertension); family history of venous thrombosis, arterial embolism in brothers, sisters, or parents at a young age (see section "Special Instructions").

Pregnancy

Use of the drug Zoeli&№174; is contraindicated during pregnancy. In the event of pregnancy with the use of the drug Zoeli&№174; should stop taking the drug.

Most epidemiological studies have not revealed an increase in the risk of congenital malformations in children whose mothers before pregnancy took COCs containing ethinyl estradiol. If accidentally taken at the beginning of pregnancy, COC containing ethinyl estradiol, there was no teratogenic effects. There is limited experience with the use of the drug Zoeli&№174; in pregnant women, which indicates the absence of an undesirable effect of the drug on the condition of the fetus or newborn.

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

The drug Zoeli&№174; is intended to prevent unwanted pregnancy. If a woman wants to stop taking Zoeli&№174; to become pregnant, you should take into account that ovulation is restored on average 20.8 days after the last dose of Zoeli&№174; was taken (see Pharmacological Properties section, Pharmacodynamics section).

Breastfeeding period

COCs can affect lactation, as they cause changes in the amount and composition of breast milk. Consequently, the use of COC is not recommended until complete cessation of breastfeeding (an alternative method of contraception should be selected).Small amounts of contraceptive sex hormones and / or their metabolites can be eliminated with breast milk, but there is no evidence of their undesirable effect on the health of the newborn.

The drug is intended for oral administration.

How to take Zoeli&№174;

The pills are taken daily at the same time of the day, regardless of the meal, in the order indicated on the package, if necessary with a small amount of water. You should take one pill per day for 28 consecutive days. Reception should begin with white pills containing active ingredients. White pills containing active ingredients are taken within the first 24 days. Over the next 4 days, take yellow pills that do not contain active ingredients (placebo). Taking pills from each subsequent package should be started the next day after taking the last pill from the previous package, regardless of the presence or absence of "withdrawal" bleeding. “Cancellation” bleeding usually starts 2-3 days after taking the last white pill and may not stop by the start of taking the pills from the next pack. Additional information is provided in the section "Special Instructions" subsection "Changes in the nature of menstruation."

Special patient groups

Renal dysfunction

Data on the use of patients with renal insufficiency are not available, but the effect of renal failure on the excretion of nomegestrol acetate and estradiol is unlikely.

Liver dysfunction

The effect of liver disease on the pharmacokinetics of Zoeli&№174; has not been studied. However, since patients with impaired liver function may deteriorate the metabolism of sex hormones, the use of Zoeli&№174; in this group of patients is not recommended until normalization of liver function indicators (see the section “Contraindications”).

How to start taking Zoeli&№174;

In the previous cycle, hormonal contraceptives were not used.

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

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

It is advisable for a woman to start taking Zoeli&№174; the next day after taking the last pill containing the active ingredients, but no later than the next day after completing the usual interval between cycles or taking placebo tablets. If a woman used a vaginal ring or a transdermal patch, then it is advisable to start taking Zoeli&№174; on the day of their removal, but not later than on the day when you should insert a new ring or stick another patch.

Transition from drugs containing progestogen only (tablets, implants, injectable forms, or hormone-containing intrauterine systems (IUDs))

A woman can stop taking pills containing only progestogen on any given day, and the next day, start taking Zoeli&№174;. Implant or IUD can be removed any day. In this case, taking Zoeli&№174; should be started on the day of their removal. If a woman received injections, then taking Zoeli&№174; is started on the day when the next injection should have been made. In all these cases, the woman is recommended to additionally use a barrier method of contraception during the first 7 days of taking pills containing active ingredients.

After abortion in the first trimester

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

After childbirth or second trimester abortion

For breastfeeding women, see the section “Use during pregnancy and during breastfeeding”.

A woman should start taking the drug between the 21st and 28th day after birth or abortion in the second trimester. At a later start of the drug is recommended to use an additional barrier method of contraception during the first 7 days of taking the pills. However, if after childbirth or abortion you have already had sex, before you start taking Zoeli&№174; you must exclude pregnancy or wait for the first menstrual period.

What to do if you miss pills

The following recommendations only concern not to take white pills containing active ingredients.

If a woman takes another pill with a delay of less than 12 hours, the contraceptive effect does not decrease. A woman should take a pill as soon as possible as soon as she remembers. Subsequent pills must be taken at the usual time.

If a woman takes an active pill more than 12 hours late, then the contraceptive effect may be reduced. When you skip taking pills, it is advisable to follow two rules:

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

Recommendations for skipping pills

If you miss one white pill containing the active ingredientsbut

Contraceptive effect is not reduced. A woman should take the last white pill she missed as soon as she remembers, even if she has to take two pills at the same time. Then the pills should be taken as usual. Additional contraceptive measures are not required.

If you miss two or more white pills

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

Days 1-7

A woman should take the last white pill she missed as soon as she remembers, even if she has to take two pills at the same time. Then the pills should be taken as usual. At the same time during the first week of continuous use of white pills, you must use the barrier method of contraception. If during the previous 7 days there was sexual intercourse, then you should consider the possibility of pregnancy.

Days 8-17

A woman should take the last white pill she missed as soon as she remembers, even if she has to take two pills at the same time. Then the pills should be taken as usual.However, over the next 7 days of taking white pills, you must use a barrier method of contraception.

Days 18-24

The risk of reducing the contraceptive effect increases with the onset of the start of the yellow placebo pill. However, a change in the pill regimen avoids a reduction in contraceptive action. 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. You can not simultaneously take more than two white pills containing active ingredients. Over the next 7 days of taking the white pills, you should use a barrier method of contraception, and the next pack should be started immediately after the end of the white pills from the previous pack, that is, a woman should not take yellow placebo pills. In this case, “withdrawal” bleeding usually occurs while taking the yellow pills from the next pack, but during the taking of the white pills, “breakthrough” bleeding or spotting may occur.

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 miss the yellow placebo pill

Contraceptive effect is not reduced. A woman may not take yellow pills from the last (fourth) row of blisters. However, missed pills should be discarded to avoid an unintended increase in the duration of the placebo phase.

Recommendations for gastrointestinal disorders

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

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

How to move or delay the onset of menstrual bleeding

To delay the onset of menstrual bleeding, a woman should continue to take white pills from another package without taking yellow pills. White pills from the second package can be continued until they run out. After completion of taking the yellow pills from the second pack, you must resume taking Zoeli&№174; in the usual way. With an extended regimen, "breakthrough" bleeding or "spotting" discharge may occur.

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

The safety of Zoeli&№174; was evaluated during seven multicenter clinical studies with a duration of up to two years. The study included 3490 women aged 18–50 years (a total of 35028 cycles).

Tolerability of Zoeli&№174; is good, the safety profile is similar to that of other COCs. The table lists the possible adverse effects that have been reported when using 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),
• "Rarely" (<1/1000),

in accordance with MedDRA (synonyms or related states are not listed, but must also be considered).

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

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

Nervous system disorders: often - migraine, headache; rarely - a violation of attention.

Violations by the organ of vision: rarely - intolerance to contact lenses, dry eye mucosa

Vascular disorders: infrequently - "tides".

Violations of the gastrointestinal tract: often nausea; infrequently - abdominal distension; rarely, dry mouth.

Violations of the skin and subcutaneous tissues: very often - acne¹; infrequently - hyperhidrosis, alopecia, itching, dry skin, seborrhea; rarely - chloasma, hypertrichosis.

Disorders of the musculoskeletal system and connective tissue: Infrequently - a feeling of heaviness.

Violations of the genital and breast organs: very often, irregular “withdrawal” bleeding; often - abundant acyclic bleeding, abundant menstrual-like bleeding, breast tenderness, pain in the pelvic region; infrequently - scanty menstrual bleeding, breast engorgement, galactorrhea, uterine muscle spasm, premenstrual-like syndrome, breast lumps, dyspareunia, dryness of the vulvar and vaginal mucosa; rarely - an unpleasant smell from the vagina, discomfort in the vaginal area.

General disorders and disorders at the site of administration: infrequently - irritability, swelling; rarely - feeling of hunger.

Laboratory and instrumental data: often - weight gain; infrequently - an increase in liver enzyme activity.

¹ - Acne is not a spontaneous reported, but a requested phenomenon, since the evaluation was carried out at each visit during the study.

In addition to the above adverse events, with the use of the drug Zoeli&№174;, hypersensitivity reactions have been reported (incidence has not been established).

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

If any of the following conditions, diseases, risk factors are present, the benefits of using Zoeli&№174; and the possible risks for each individual woman should be evaluated. This should be discussed with the woman before she starts taking Zoeli&№174;. In cases of deterioration, exacerbation or the first occurrence of any of these conditions, diseases, risk factors, a woman should consult a doctor to decide whether it is possible to continue using Zoeli&№174;.

The data below was obtained during epidemiological studies with COC use containing ethinyl estradiol. The drug Zoeli&№174; contains 17β-estradiol, however, special instructions regarding the administration of combined contraceptives containing ethinyl estradiol are also considered applicable to the drug Zoeli&№174;.

Vascular disorders

• The use of any COC is accompanied by an increased risk of venous thrombosis and embolism, which is the highest during the first year after the start of COC administration.
• The results of epidemiological studies demonstrate that the frequency is