Zoely^® (Tablets) Instructions for Use

Marketing Authorization Holder

Zentiva, k.s. (Czech Republic)

Manufactured By

Delpharm Lille, SAS (France)

ATC Code

G03AA14 (Nomegestrol and estradiol)

Active Substances

Estradiol (Rec.INN registered by WHO)

Nomegestrol acetate (Prop.INN proposed by WHO)

Dosage Form

Zoely®

Film-coated tablets, 1.5 mg+2.5 mg: 28 or 84 pcs. incl. with a day-of-the-week sticker

Dosage Form, Packaging, and Composition

Film-coated tablets from white to almost white, round, biconvex, with an engraving “ne” on both sides; the color of the core on the cut is from white to almost white (24 pcs. in a blister).

Excipients: microcrystalline cellulose – 14 mg, crospovidone – 2.4 mg, talc – 0.7 mg, magnesium stearate – 0.7 mg, colloidal silicon dioxide – 0.44 mg, lactose monohydrate – 57.71 mg.

Shell composition Opadry II white – 1.6 mg (polyvinyl alcohol – 0.64 mg, titanium dioxide – 0.4 mg, macrogol 3350 – 0.32 mg, talc – 0.24 mg).

Tablets (placebo), film-coated yellow, round, biconvex, with an engraving “p” on both sides, the color of the core on the cut is from white to almost white (4 pcs. in a blister).

Excipients: microcrystalline cellulose – 14 mg, crospovidone – 2.4 mg, talc – 0.7 mg, magnesium stearate – 0.7 mg, colloidal silicon dioxide – 0.44 mg, lactose monohydrate – 61.76 mg.

Shell composition Opadry II yellow – 2.4 mg (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).

28 pcs. – PVC/aluminum foil blisters (1) with a day-of-the-week sticker – cardboard packs.
28 pcs. – PVC/aluminum foil blisters (3) with a day-of-the-week sticker – cardboard packs.

Clinical-Pharmacological Group

Monophasic oral contraceptive

Pharmacotherapeutic Group

Contraceptive agent (estrogen + progestagen)

Pharmacological Action

A combined hormonal contraceptive medicinal product containing the estrogen 17β-estradiol and the progestagen Nomegestrol acetate.

Estradiol (17β-estradiol) – a natural estrogen, identical to endogenous human 17β-estradiol (E2). Unlike ethinylestradiol, which is part of other combined oral contraceptives, E2 does not have an ethinyl group in the 17α-position. When used, the average E2 concentrations are comparable to those in the early follicular phase and late luteal phase of the menstrual cycle.

Nomegestrol is a highly selective progestagen, a derivative of the natural steroid hormone progesterone and structurally similar to it. Nomegestrol acetate has a pronounced affinity for the human progesterone receptor, has high antigonadotropic activity, moderate antiandrogenic activity and does not have estrogenic, androgenic, glucocorticoid or mineralocorticoid activity.

The contraceptive effect is due to a combination of various factors, the most important of which are the suppression of ovulation and changes in cervical mucus secretion. Nomegestrol acetate mainly suppresses ovulation, and E2 enhances the effects of the progestagen. After discontinuation, ovulation quickly recovers in most women.

During administration, the serum folic acid concentration does not change and remains at the baseline level for 6 consecutive months of use.

In clinical studies, the Pearl index for women aged 18 to 50 years was 0.66 (upper limit of the 95% confidence interval 1.07), and for women aged 18 to 35 years, the Pearl index was 0.75 (upper limit of the 95% confidence interval 1.23).

In clinical studies, it was found that glucose tolerance and insulin sensitivity did not change, and no clinically significant effects on lipid metabolism and hemostasis were detected. Taking the drug increased the content of carrier proteins thyroxine-binding globulin and corticosteroid-binding globulin (CBG), but to a lesser extent than the combination of levonorgestrel with ethinylestradiol. The content of sex hormone-binding globulin (SHBG) slightly increased, the content of androstenedione, dehydroepiandrosterone, total and free testosterone significantly decreased.

Pharmacokinetics

Estradiol (E2)

17β-estradiol (E2) undergoes significant first-pass metabolism after oral administration. The absolute bioavailability is approximately 5%. Food intake does not have a clinically significant effect on the bioavailability of E2.

The distribution of exogenous and endogenous E2 is similar. Estrogens are actively distributed throughout the body. Their concentrations are usually higher in 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.

C_max of E2 in serum is about 90 pg/ml and is reached 6 hours after administration. Mean serum concentrations are 50 pg/ml. These E2 concentrations correspond to those in the early and late phases of the menstrual cycle.

Exogenous E2 is actively biotransformed after oral administration. The metabolism of exogenous and endogenous E2 is similar. E2 is rapidly converted into several metabolites in the intestine and liver, mainly into estrone (E1), which are subsequently conjugated and undergo enterohepatic circulation. There is a dynamic equilibrium between E2, E1 and E1-sulfate (E1S) due to the activity of various enzymes, including E2-dehydrogenases, sulfotransferases and arylsulfatases. Oxidation of E1 and E2 occurs under the action of cytochrome P450 isoenzymes, mainly CYP1A2, CYP1A2 (extrahepatic), CYP3A4, CYP3A5, CYP1B1 and CYP2C9.

E2 is rapidly eliminated from the blood. Due to metabolism and enterohepatic circulation, there is a large pool of circulating estrogen sulfates and glucuronides. As a result, the T_1/2 of E2 varies widely and is 8.4±6.4 hours after IV administration.

Nomegestrol acetate

Nomegestrol acetate is rapidly absorbed after oral administration. After a single dose, C_max in plasma 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 nomegestrol acetate.

Dose-linear pharmacokinetics were observed in the range of 0.625-5 mg (assessed in women of reproductive and postmenopausal age).

Nomegestrol acetate is actively bound to albumin (97-98%), but does not bind to SHBG or CBG.

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

Nomegestrol acetate is metabolized to several inactive hydroxylated metabolites under the action of hepatic cytochrome P450 isoenzymes, mainly CYP2C8, CYP2C19, CYP3A4 and CYP3A5. Nomegestrol acetate and its hydroxylated derivatives undergo extensive phase 2 metabolism to form glucuronide and sulfate conjugates. The clearance at steady state is 26 L/h.

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

T_1/2 at steady state is 46 hours (from 28 to 83 hours). T_1/2 of 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. Excretion through the intestines exceeds renal excretion.

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

Indications

Contraception.

ICD codes

Dosage Regimen

Take one tablet daily at approximately the same time each day.

Follow the directional arrows on the blister pack. Take the 24 active white tablets first, then the 4 placebo yellow tablets.

Begin taking Zoely^® on the first day of your menstrual period. You may also start on day 2-5 of your cycle; in this case, use an additional barrier method of contraception for the first 7 days of tablet-taking.

When switching from another combined hormonal contraceptive, start Zoely^® the day after taking the last active tablet of your previous product. No contraceptive backup is required.

After a pregnancy or following a first-trimester abortion, start immediately. No additional contraceptive protection is needed.

After a second-trimester abortion or delivery, start between day 21 and day 28 postpartum. If started later, use a barrier method for the first 7 days. If you have already had intercourse, exclude pregnancy before starting or wait for your first menstrual period.

If a tablet is delayed for less than 12 hours, contraceptive protection is not reduced. Take the missed tablet as soon as remembered and take the next tablet at the usual time.

If a tablet is delayed for more than 12 hours, contraceptive protection may be reduced. Take the most recently missed tablet immediately, even if it means taking two tablets on the same day. Continue taking the remaining tablets at the usual time.

For missed active tablets in the third week, omit the placebo tablets from the current blister. Start a new blister pack immediately after the last active tablet. A withdrawal bleed is unlikely, but breakthrough spotting may occur.

If vomiting or severe diarrhea occurs within 3-4 hours of taking an active tablet, handle it as a missed tablet. If symptoms persist, use a non-hormonal backup method of contraception until 7 consecutive active tablets have been taken correctly.

To delay a withdrawal bleed, finish the active white tablets and immediately start a new pack, skipping the placebo tablets. Breakthrough bleeding or spotting may occur during the extension period.

Adverse Reactions

Metabolism and nutrition disorders: weight gain, increased appetite, fluid retention, decreased appetite, feeling of hunger.

Nervous system disorders: decreased libido, depression, mood swings, increased libido, migraine, headache, attention impairment, irritability.

Eye disorders: contact lens intolerance, dry eyes.

Skin and subcutaneous tissue disorders: hyperhidrosis, alopecia, pruritus, dry skin, seborrhea, acne, chloasma, hypertrichosis.

Cardiac and vascular disorders: venous and arterial thromboembolism, increased blood pressure.

Gastrointestinal disorders: abdominal bloating, increased liver enzyme activity, nausea, dry mouth.

Musculoskeletal and connective tissue disorders: feeling of heaviness.

Reproductive system and breast disorders: irregular withdrawal bleeding, metrorrhagia, menorrhagia, breast tenderness, pelvic pain, hypomenorrhea, breast engorgement, galactorrhea, uterine spasm, premenstrual syndrome, breast lumps, dyspareunia, vulvovaginal dryness, vaginal odor, vaginal discomfort.

General disorders and administration site conditions: hot flashes, edema, hormone-dependent tumors (e.g., liver tumors, breast cancer).

Contraindications

Deep vein thrombosis or pulmonary embolism, incl. in history; arterial thrombosis (myocardial infarction, cerebrovascular accident) or prodromal conditions (transient ischemic attack, angina pectoris), incl. in history; migraine with focal neurological symptoms, incl. in history; severe or multiple risk factors for venous or arterial thrombosis, such as: diabetes mellitus with vascular symptoms, severe arterial hypertension, severe dyslipoproteinemia; hereditary or acquired predisposition to the development of venous or arterial thrombosis, for example, activated protein C resistance, antithrombin III deficiency, protein C and S deficiency, hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); pancreatitis with severe hypertriglyceridemia, incl. in history; severe liver diseases, incl. in history, until liver function tests normalize; liver tumors (malignant or benign), incl. in history; known or suspected hormone-dependent malignant tumors (e.g., of the genital organs or breast); vaginal bleeding of unknown etiology; postmenopause; established or suspected pregnancy; lactation period (breastfeeding); hypersensitivity to the components of the combination.

With caution

Diabetes mellitus without vascular damage; severe depression or history of this disease; systemic lupus erythematosus; Crohn’s disease; ulcerative colitis; liver function disorders; hypertriglyceridemia, incl. in family history; risk factors for coronary artery disease (obesity, smoking at 35 years and older, arterial hypertension); prolonged immobilization or extensive surgery; family history of venous thrombosis, arterial embolism in siblings or parents at a relatively young age.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindications severe liver diseases, incl. in history, until liver function tests normalize; liver tumors (malignant or benign), incl. in history.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

If any of the conditions/diseases or risk factors listed below are currently present, the potential risk and expected benefit of using this combination should be carefully weighed.

In case of worsening, aggravation or first manifestation of any of these conditions/diseases or risk factors, the woman should consult her doctor to decide on discontinuing the drug. The data below were obtained from epidemiological studies with the use of COCs containing ethinylestradiol. This combination contains 17β-estradiol; since there is no information on estradiol-containing drugs, the information regarding the use of combined oral contraceptives (COCs) containing ethinylestradiol is also applicable to the nomegestrol + estradiol combination.

The use of COCs is associated with an increased risk of developing VTE compared with the risk of developing VTE in patients not using COCs. The greatest additional risk of developing VTE is observed in the first year of COC use. The risk also increases at the start of COC use or when resuming use of the same or another COC after a break of 4 or more weeks.

Epidemiological studies have established an association between the use of COCs and an increased risk of arterial thromboembolism (myocardial infarction, transient ischemic attacks).

The risk of developing venous thromboembolism increases in the presence of the following risk factors: age; presence of diseases in family history (venous thrombosis and thromboembolism in siblings or parents at age <50 years); prolonged immobilization, major surgery, any surgery on the lower extremities or serious trauma; obesity (body mass index over 30 kg/m²); air travel lasting more than 4 hours may temporarily increase the risk of blood clot formation, especially in women with other risk factors.

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); dyslipoproteinemia; obesity (body mass index over 30 kg/m²); arterial hypertension; migraine; heart valve disease; atrial fibrillation; presence of diseases in family history (arterial thrombosis in siblings or parents at age <50 years); other conditions that are accompanied by vascular disorders include diabetes mellitus, SLE, HUS, inflammatory bowel disease (Crohn’s disease and ulcerative colitis) and sickle cell anemia.

The increased risk of thromboembolic complications in the postpartum period should be taken into account.

An increase in the frequency or severity of migraine during the use of COCs (which may precede the development of a cerebrovascular complication) is a reason for immediate discontinuation of the contraceptive.

Epidemiological studies show an increased risk of developing cervical cancer in women infected with HPV and long-term use of COCs (> 5 years), however, to date, there is controversy regarding the degree of influence of various factors on these data, in particular, cervical screening examinations or features of a woman’s sexual behavior (number of sexual partners and use of barrier methods of contraception), as well as the cause-and-effect relationship of these factors.

According to a meta-analysis of the results of 54 epidemiological studies, a small increase (1.24) in the risk of developing breast cancer (BC) was detected in women using COCs. The increased risk gradually decreases within 10 years after discontinuation of COCs. Since BC is rare in women under 40 years of age, the increase in the number of BC cases in women currently taking COCs or having taken them recently is insignificant in relation to the overall risk of developing this disease. Its association with COC use has not been proven. The observed increase in risk may also be a consequence of earlier diagnosis of BC in women taking COCs (they are diagnosed with earlier clinical forms of BC than women who have not taken COCs), the biological effect of COCs, or a combination of both of these factors.

The occurrence of meningioma (single and multiple) has been reported with long-term use (several years) of nomegestrol monotherapy at doses of 3.75 mg or 5 mg per day and higher. If meningioma is diagnosed in a woman receiving the nomegestrol + estradiol combination, the contraceptive should be discontinued.

In women with hypertriglyceridemia or a corresponding family history, the risk of developing pancreatitis is increased when taking COCs.

In women with hypertriglyceridemia or a corresponding family history, the risk of developing pancreatitis is increased when taking COCs.

During the use of COCs, the course of endogenous depression, epilepsy, Crohn’s disease and ulcerative colitis may worsen.
In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen the symptoms of angioedema.

Acute or chronic liver dysfunction may be a reason to discontinue COCs until liver function tests normalize. Recurrence of cholestatic jaundice, observed previously during a previous pregnancy or the use of sex hormone drugs, requires discontinuation of COCs.

Although COCs may affect insulin resistance and glucose tolerance, the need to adjust the dose of hypoglycemic drugs in patients with diabetes mellitus taking low-dose COCs (< 50 mcg ethinylestradiol) is generally absent. Nevertheless, patients with diabetes mellitus should be under medical supervision and regularly monitor blood glucose levels while taking the contraceptive.

Sometimes chloasma may develop during the use of COCs, especially in women with a history of chloasma of pregnancy. Women prone to chloasma while taking COCs should avoid prolonged exposure to the sun and ultraviolet radiation.

In women with hypertriglyceridemia or a corresponding family history, the risk of developing pancreatitis is increased when taking COCs.

While taking COCs, the course of endogenous depression, epilepsy, Crohn’s disease, and ulcerative colitis may worsen.
In women with hereditary forms of angioedema, exogenous estrogens may induce or worsen the symptoms of angioedema.

Acute or chronic liver function disorders may necessitate the discontinuation of COCs until liver function tests return to normal. A recurrence of cholestatic jaundice, which occurred previously during a prior pregnancy or use of sex hormone preparations, requires the withdrawal of COCs.

Although COCs can affect insulin resistance and glucose tolerance, the need for dose adjustment of hypoglycemic drugs in patients with diabetes mellitus taking low-dose COCs (< 50 mcg ethinylestradiol) is generally not required. Nevertheless, patients with diabetes mellitus should be under medical supervision and perform regular monitoring of blood glucose concentration while taking the contraceptive.

Sometimes, chloasma may develop while taking COCs, especially in women with a history of chloasma gravidarum. Women prone to chloasma should avoid prolonged sun exposure and ultraviolet radiation during COC use.

While taking COCs, irregular bleeding (“spotting” and/or “breakthrough bleeding”) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding should be performed only after an adaptation period of approximately 3 treatment cycles.

If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be conducted to rule out malignant neoplasms or pregnancy.

In women taking the nomegestrol + estradiol combination, the duration of “withdrawal” bleeding averaged 3-4 days.

Drug Interactions

Interactions of oral contraceptives with other medicinal products may lead to breakthrough bleeding and/or reduced contraceptive efficacy. Drug interactions with combined oral contraceptives in general have been described in the literature.

Hepatic metabolism: Interaction *with inducers of microsomal liver enzymes* is possible, which may lead to an increased clearance of sex hormones. Interactions have been established, for example, with *phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly with oxcarbazepine, topiramate, felbamate, griseofulvin, and preparations containing St. John’s wort (Hypericum perforatum). HIV protease inhibitors (e.g., ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) and their combinations* have also influenced hepatic metabolism.

During concomitant use of drugs *that induce microsomal enzymes* and for 28 days after their discontinuation, barrier contraceptive methods 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.

Drugs *that inhibit microsomal enzymes (e.g., ketoconazole),* may cause an increase in the plasma concentration of sex hormones.

*Antibiotics*: A reduction in the effectiveness of oral contraceptives containing ethinylestradiol has been noted with the concomitant use of antibiotics such as *ampicillin and tetracyclines*. Women taking antibiotics (except for rifampicin and griseofulvin) should additionally use a barrier method of contraception throughout the entire period of antibiotic therapy and for 7 days after its discontinuation.

Oral contraceptives may affect the metabolism of other drugs. Accordingly, their plasma and tissue concentrations may increase *(e.g., cyclosporine) or decrease (e.g., lamotrigine).*

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.