FEMINATI®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FEMINATI®

Composition:

Active substances: ethinylestradiol, drospirenone;

One film-coated tablet (yellow) contains: ethinylestradiol 0.03 mg, drospirenone 3 mg;

Excipients: lactose monohydrate, maize starch, pregelatinized starch (maize), crospovidone (type B), crospovidone (type A), povidone K-30, polysorbate 80, magnesium stearate; coating: Opadry® II yellow (partially hydrogenated polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol 3350, talc, yellow ferric oxide (E 172)).

One film-coated placebo tablet (white) contains: anhydrous lactose, povidone K-30, magnesium stearate; coating: Opadry® II white (partially hydrogenated polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol 3350, talc (E 553b)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round yellow film-coated tablets, unmarked; placebo: round white film-coated tablets, unmarked.

Pharmacotherapeutic group. Sex hormones and drugs used in disorders of the reproductive system. Systemic hormonal contraceptives. Fixed combinations of progestogens and estrogens.

ATC code G03A A12.

Pharmacological properties.

Pharmacodynamics.

The Pearl Index for contraceptive failures of the drug is 0.09 (upper two-sided 95% confidence interval (CI) – 0.32).

The overall Pearl Index (contraceptive failures + patient errors) for the drug is 0.57 (upper two-sided 95% CI – 0.90).

The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of several factors, the most important of which are inhibition of ovulation and changes in cervical secretion.

Feminaté® is a combined oral contraceptive containing ethinylestradiol and the progestogen drospirenone. At therapeutic doses, drospirenone exhibits antiandrogenic and mild antimineralocorticoid properties. It has no estrogenic, glucocorticoid, or antiglucocorticoid activity. Thus, drospirenone has a pharmacological profile similar to that of natural progesterone.

The medicinal product exerts a mild antimineralocorticoid effect.

Pharmacokinetics.

Drospirenone

Absorption. Orally administered drospirenone is rapidly and completely absorbed. Peak serum concentration, amounting to 38 ng/mL, is reached approximately 1–2 hours after single oral administration. Bioavailability is approximately 76–85%. Concomitant food intake does not affect the bioavailability of drospirenone.

Distribution. After oral administration, drospirenone serum concentration declines with a mean terminal half-life of approximately 31 hours. Drospirenone binds to serum albumin but does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 3–5% of the total drospirenone concentration is present in serum as free steroid. The increase in SHBG levels induced by ethinylestradiol does not affect the protein binding of drospirenone to serum proteins. The mean apparent volume of distribution of drospirenone is 3.7 ± 1.21 L/kg.

Metabolism. Following oral administration, drospirenone is extensively metabolized. The main metabolites in plasma are the acid form of drospirenone, formed by opening of the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate, formed via hydration followed by sulfation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone may weakly or moderately inhibit cytochrome P450 enzymes: CYP1A1, CYP2C9, CYP2C19, and CYP3A4.

Elimination. The metabolic clearance of drospirenone from serum is 1.5 ± 0.2 mL/min/kg. Only a negligible amount of drospirenone is excreted unchanged. Drospirenone metabolites are excreted in feces and urine in a ratio of approximately 1.2 : 1.4. The elimination half-life of metabolites in urine and feces is about 40 hours.

Steady-state concentration. During the treatment cycle, the maximum steady-state concentration of drospirenone in serum of approximately 70 ng/mL is reached after about 8 days of treatment. Serum drospirenone concentration increased about threefold due to the relationship between the terminal half-life and the dosing interval.

Special patient populations

Effect of renal impairment. At steady state during drospirenone therapy, similar serum concentrations of drospirenone were observed in women with mild renal impairment (creatinine clearance 50–80 mL/min) and in women with normal renal function. In women with moderate renal impairment (creatinine clearance 30–50 mL/min), serum concentrations of drospirenone were on average 37% higher than in women with normal renal function. Drospirenone therapy was well tolerated in women with mild to moderate renal impairment. Drospirenone therapy showed no clinically significant effect on serum potassium concentrations.

Effect of hepatic impairment. In a single-dose study, oral clearance of drospirenone was reduced by approximately 50% in subjects with moderate hepatic impairment compared to volunteers with normal liver function. The observed difference in drospirenone clearance in subjects with moderate hepatic impairment did not result in any apparent differences regarding serum potassium concentrations. Even in patients with diabetes mellitus and concomitant therapy with spironolactone (two factors that may provoke hyperkalemia), no increase in serum potassium concentration above the upper limit of normal was observed. It can be concluded that drospirenone is well tolerated in individuals with mild to moderate hepatic impairment (Child-Pugh class B).

Ethnicity. No clinically relevant differences in the pharmacokinetics of drospirenone or ethinylestradiol were observed between Japanese women and Europeans.

Ethinylestradiol

Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. Following administration of 30 µg, peak plasma concentration of 100 pg/mL is reached within 1–2 hours. Ethinylestradiol undergoes extensive first-pass metabolism, which is subject to individual variability. Absolute bioavailability is approximately 45%.

Distribution. The expected volume of distribution of ethinylestradiol is approximately 5 L/kg, and protein binding to plasma proteins is about 98%. Ethinylestradiol induces the hepatic synthesis of SHBG and corticosteroid-binding globulins. With administration of 30 µg ethinylestradiol, plasma SHBG concentration increases from 70 to about 350 nmol/L.

Ethinylestradiol passes into breast milk in small amounts (0.02% of the dose).

Metabolism. Ethinylestradiol is extensively metabolized in the gastrointestinal tract and during first passage through the liver. Ethinylestradiol is primarily metabolized via aromatic hydroxylation, forming numerous hydroxylated and ethylated metabolites, which are present as free metabolites and conjugates with glucuronides and sulfates. The metabolic plasma clearance of ethinylestradiol is approximately 5 mL/min/kg. In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and based on its mechanism of action, an inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Elimination. Ethinylestradiol is not excreted unchanged in significant amounts. Ethinylestradiol metabolites are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is about 1 day. The elimination half-life of metabolites is 20 hours.

Steady-state concentration. Steady-state concentration is achieved during the second half of the treatment cycle; the serum level of ethinylestradiol increases approximately 1.4–2.1 times.

Preclinical safety data.

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with known pharmacological actions. In particular, reproductive toxicity studies in animals revealed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those in users of the medicinal product, effects on sexual differentiation were observed in certain animal species. Environmental risk assessment studies indicated that ethinylestradiol and drospirenone may potentially pose a threat to the aquatic environment (see section "Special precautions for environmental safety").

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

Combined oral contraceptives (COCs) are contraindicated if any of the conditions listed below are present. If any of these conditions occur for the first time during COC use, the drug should be discontinued immediately.

• Presence or risk of venous thromboembolism (VTE):
  • current venous thromboembolism, including anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
  • known hereditary or acquired predisposition to venous thromboembolism, such as activated protein C resistance (including factor V Leiden mutation), antithrombin-III deficiency, protein C deficiency, protein S deficiency;
  • major surgery with prolonged immobilization (see section "Special precautions");
  • high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
  • current arterial thromboembolism or history thereof (e.g., myocardial infarction), or presence of prodromal symptoms (e.g., angina pectoris);
  • current or past cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia or antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • high risk of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or due to a single serious risk factor such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Current or past history of severe liver disease until liver function tests return to normal range.
• Severe renal insufficiency or acute renal failure.
• Current or past history of liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms (e.g., of genital organs or mammary glands).
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the drug.
• Suspected or confirmed pregnancy.

Femynat\® is contraindicated for concomitant use with medicinal products containing ombitasvir, paritaprevir, ritonavir, dasabuvir, glecaprevir, pibrentasvir, sofosbuvir, velpatasvir, or voxilaprevir (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Special safety measures.

This medicinal product may pose a risk to the environment (see section "Pharmacological properties"). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

The information regarding any medicinal product that the patient intends to use concomitantly should be reviewed to identify potential interactions.

• Effect of other medicinal products on Femynat\®

Interactions are possible with medicinal products that induce microsomal enzymes. This may lead to increased clearance of sex hormones, resulting in changes in the pattern of menstrual bleeding and/or loss of contraceptive efficacy.

Therapy

Enzyme induction may be observed within a few days of treatment initiation. Maximum enzyme induction is generally observed after several weeks. After discontinuation of treatment, enzyme induction may persist for approximately 4 weeks.

Short-term treatment

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another contraceptive method in addition to COCs. The barrier method should be used throughout the treatment period with the relevant medicinal product and for an additional 28 days after discontinuation. If treatment is initiated during the period of taking the last tablets in the COC pack, the next pack of COCs should be started immediately after the previous placebo tablet.

Long-term treatment

Women undergoing long-term therapy with enzyme-inducing substances are advised to use a barrier method or another appropriate non-hormonal contraceptive method.

The following interactions have been reported in scientific publications.

Active substances that may increase COC clearance (reduced COC efficacy due to enzyme induction), e.g.:

barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; drugs used in HIV infection: ritonavir, nevirapine, and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and herbal medicinal products containing St. John's wort (Hypericum perforatum).

Active substances with variable effects on COC clearance

When used concomitantly with COCs, numerous combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, may either increase or decrease plasma concentrations of estrogens or progestins. The overall effect of these changes may be clinically significant in some cases.

Therefore, information regarding the medical use of the medicinal product for HIV/HCV treatment taken concomitantly should be reviewed to identify potential interactions. In case of any doubts, women should additionally use a barrier method of contraception during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Active substances that decrease COC clearance (enzyme inhibitors)

The clinical significance of potential interactions with enzyme inhibitors remains unclear.

Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of estrogen, progestin, or both components.

In a multiple-dose study combining drospirenone (3 mg/day)/ethinylestradiol (0.002 mg/day) with the strong CYP3A4 inhibitor ketoconazole, administered concomitantly for 10 days, the AUC(0–24h) of drospirenone and ethinylestradiol increased by 2.7 and 1.4 times, respectively.

Etoricoxib at doses of 60 to 120 mg/day demonstrated a 1.4- to 1.6-fold increase in ethinylestradiol plasma concentrations when administered concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

• Effect of Femynat\® on other medicinal products

Oral contraceptives may affect the metabolism of certain active substances. Therefore, plasma and tissue concentrations may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

In in vivo interaction studies in female volunteers using omeprazole, simvastatin, and midazolam as marker substrates, clinically significant interaction of 3 mg drospirenone with other active substances metabolized by cytochrome P450 is unlikely.

Clinical data indicate that ethinylestradiol inhibits the clearance of CYP1A2 substrates, resulting in weak (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Pharmacodynamic interactions

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, glecaprevir, pibrentasvir, sofosbuvir, velpatasvir, or voxilaprevir increases the risk of elevated alanine aminotransferase (ALT) levels (see sections "Contraindications" and "Special precautions").

Therefore, women using Femynat\® should temporarily switch to an alternative contraceptive method (e.g., progestogen-only contraceptives or non-hormonal methods) before starting therapy with the specified combination of medicinal products. Femynat\® may be resumed 2 weeks after completion of therapy with the specified combination.

In patients with normal renal function, concomitant use of drospirenone with ACE inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) did not show a significant effect on serum potassium levels. However, concomitant use of Femynat\® with aldosterone antagonists or potassium-sparing diuretics has not been studied. In such cases, serum potassium levels should be monitored during the first treatment cycle (see also section "Special precautions").

Other forms of interaction

Laboratory tests

Use of contraceptive steroids may affect the results of certain laboratory tests, such as biochemical parameters of liver, thyroid, adrenal, and kidney function; plasma concentrations of transport proteins such as corticosteroid-binding globulin; plasma concentrations of lipid/lipoprotein fractions; carbohydrate metabolism parameters; and coagulation and fibrinolysis parameters. Such changes are usually within normal limits.

Drospirenone increases plasma renin and aldosterone activity, induced by its moderate anti-mineralocorticoid activity.

Special precautions for use.

The decision to prescribe Femynat® should be made taking into account the individual risk factors of the woman, including risk factors for venous thromboembolism (VTE), as well as the risk of VTE associated with the use of Femynat® compared to other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions for use").

Warning

• If any of the conditions or risk factors listed below are present, the appropriateness of using Femynat® should be discussed with the woman.
• In case of exacerbation or first signs of any of the mentioned conditions or risk factors, women are advised to consult a physician and determine whether discontinuation of Femynat® is necessary.
• Combined hormonal contraceptives (CHCs) should be discontinued if VTE or arterial thromboembolism (ATE) is suspected or confirmed. If anticoagulant therapy is initiated, alternative effective contraception should be provided due to the teratogenic effect of anticoagulants (coumarins).
• Circulatory disorders.

Risk of venous thromboembolism (VTE)

The use of any CHCs increases the risk of venous thromboembolism (VTE) in women who use them compared to those who do not. Products containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. The use of other medicinal products, such as Femynat®, may double the risk. The decision to use such medicinal products, other than those with the lowest risk of VTE, should be made only after discussion with the woman. It is necessary to ensure that she understands the risk of VTE associated with the use of Femynat®, the impact of her individual risk factors, and the fact that the risk of VTE is highest during the first year of use. According to some data, the risk of VTE increases when resuming CHC use after a break of 4 weeks or longer.

Among 10,000 women who do not use CHCs and are not pregnant, 2 cases of VTE occur per year. However, in individual women, the risk may be significantly higher depending on their existing risk factors (see below).

It has been established\1\ that among 10,000 women using CHCs containing drospirenone, 9–12 women will develop VTE within one year. This compares to a rate of 6 in women using CHCs containing levonorgestrel.

In both cases, the number of VTE cases per year was lower than usually expected during pregnancy or the postpartum period.

VTE can result in fatal outcomes in 1–2% of cases.

Number of VTE cases per 10,000 women per 1 year

**

**

\1\ These estimates are based on all epidemiological study data, taking into account relative risks associated with the use of different CHCs compared to CHCs containing levonorgestrel.

\2\ On average, 5–7 cases per 10,000 woman-years, based on the calculation of relative risk of using CHCs containing levonorgestrel compared to women not using CHCs (approximately 2.3–3.6 cases).

Very rarely, thrombosis in other blood vessels—such as arteries and veins of the liver, kidneys, mesenteric vessels, cerebral vessels, or retinal vessels—has been reported in women using CHCs.

Risk factors for VTE

The risk of venous thromboembolic complications in women using CHCs may be substantially increased in the presence of additional risk factors, especially multiple ones (see Table 1).

The use of Femynat® is contraindicated in women with multiple risk factors that increase the risk of venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of risks associated with each individual factor; therefore, the overall risk of VTE should be considered. If the benefit-risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Risk factors for VTE

Table 1

There is no consensus regarding the possible influence of varicose veins and superficial thrombophlebitis on the development and progression of venous thrombosis.

Particular attention should be paid to the increased risk of thromboembolism during pregnancy, especially within 6 weeks after delivery (see section "Use in pregnancy or breastfeeding").

Symptoms of VTE (venous thromboembolism: deep vein thrombosis and pulmonary embolism)

Women should be advised to seek immediate medical attention and inform their physician that they are taking COCs if any of the symptoms listed below occur.

Symptoms of DVT may include: unilateral swelling of the leg and/or foot or a region along a vein in the leg; pain or tenderness in the leg, which may occur only when standing or walking; warmth in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of PE may include: sudden unexplained shortness of breath or rapid breathing; sudden cough, possibly with blood; sudden chest pain; syncope or dizziness; rapid or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as more common or less serious conditions (e.g., respiratory tract infections).

Other manifestations of vascular occlusion may include sudden pain, swelling, acute abdomen, and mild cyanosis of a limb.

Ocular vascular occlusion may initially present with painless blurred vision, which may progress to vision loss. In some cases, vision loss develops almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological data indicate that use of any COCs is associated with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular events (transient ischemic attack, stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE

When using COCs, the risk of developing arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 2). Use of Feminate® is contraindicated in women who have either one serious or multiple risk factors for ATE that may increase the risk of arterial thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of the risks associated with each individual factor, so the overall risk should be considered. COCs should not be prescribed if the benefit-risk balance is unfavorable (see section "Contraindications").

Risk factors for ATE

Table 2

ATE Symptoms

Women should be advised to seek immediate medical attention and inform their physician that they are taking COCs if any of the symptoms listed below occur.

Symptoms of cerebrovascular disorders may include: sudden numbness of the face, weakness or numbness of the extremities, especially on one side; sudden difficulty walking, dizziness, loss of balance or coordination; sudden confusion, speech or comprehension disturbances; sudden vision loss in one or both eyes; sudden, severe, or prolonged headache without a known cause; loss of consciousness or fainting with or without seizures.

Transient symptoms may indicate a transient ischemic attack (TIA).

Symptoms of myocardial infarction may include: chest pain, discomfort, pressure, or heaviness in the chest, arm, or below the sternum; discomfort radiating to the back, jaw, throat, arm, or stomach; a feeling of fullness, indigestion, or choking; excessive sweating, nausea, vomiting, or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeat.

Tumors

Results of some epidemiological studies suggest an increased risk of cervical cancer with long-term use of oral contraceptives (>5 years), although this remains controversial, as it is not fully established to what extent study results account for confounding risk factors such as sexual behavior and other factors, including human papillomavirus infection.

A meta-analysis of 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer among women using oral contraceptives. This increased risk gradually disappears within 10 years after discontinuation of oral contraceptive use. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among women currently or recently using oral contraceptives is minimal relative to the overall risk of breast cancer. These study results do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in women using oral contraceptives, a biological effect of COCs, or a combination of both factors. There is a tendency for breast cancer diagnosed in women who have ever used oral contraceptives to be less clinically advanced than in those who have never used them.

In rare cases, benign and even more rarely malignant liver tumors have been observed in women using oral contraceptives, which in some cases led to life-threatening intra-abdominal hemorrhage. In cases of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of a liver tumor associated with oral contraceptive use should be considered in differential diagnosis.

The use of oral contraceptives at high doses (50 mcg ethinylestradiol) reduces the risk of endometrial and ovarian cancer. It is unknown whether these data also apply to low-dose oral contraceptives.

Other conditions

The progestin component of Feminate® is an aldosterone antagonist with potassium-sparing properties. In most cases, elevated serum potassium levels are not expected. During clinical trials, slight (but not clinically significant) increases in serum potassium levels were observed in some patients with mild to moderate renal impairment who were concurrently using potassium-sparing medications during treatment with drospirenone. Therefore, monitoring of serum potassium levels is recommended during the first treatment cycle in patients with renal impairment. These patients should also maintain serum potassium levels within the upper limit of normal before initiating treatment, especially when concurrently using potassium-sparing medications (see section "Interaction with other medicinal products and other forms of interaction").

Women with hypertriglyceridemia or a family history of this condition are at risk of developing pancreatitis when using oral contraceptives.

Although a slight increase in blood pressure has been reported in many women taking oral contraceptives, clinically significant hypertension occurs only rarely. Immediate discontinuation of oral contraceptives is necessary only in these rare cases. In cases of persistent hypertension or inability to control blood pressure with antihypertensive therapy, women taking oral contraceptives should discontinue their use. If appropriate, oral contraceptive use may be resumed after normotension is achieved with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and with the use of oral contraceptives, although their relationship to estrogen/progestin 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, herpes gestationis, hearing loss associated with otosclerosis.

Exogenous estrogens may cause the onset or exacerbation of symptoms of hereditary or acquired angioedema.

Metabolism of steroid hormones may be impaired in patients with liver dysfunction. Acute or chronic liver disorders may require discontinuation of oral contraceptives until liver function tests return to normal and a causal relationship with oral contraceptives is ruled out.

Oral contraceptive use should be discontinued in cases of recurrence of cholestatic jaundice and/or pruritus associated with cholestasis that previously occurred during pregnancy or prior use of sex hormones.

Although oral contraceptives may affect peripheral insulin resistance and glucose tolerance, there are no data indicating a need to alter the therapeutic regimen in diabetic women taking low-dose oral contraceptives (<0.05 mg ethinylestradiol). However, women with diabetes should be carefully monitored during oral contraceptive use, especially at the beginning of treatment.

Exacerbations of endogenous depression, epilepsy, Crohn's disease, and ulcerative colitis have also been observed during oral contraceptive use.

Depressed mood and depression are well-known adverse reactions that may occur during use of hormonal contraceptives (see section "Adverse Reactions"). Depression can be a serious condition and is a well-known risk factor for suicidal behavior and suicide. Women should be advised to consult their physician if they experience mood changes or symptoms of depression, including soon after starting treatment.

Chloasma may occasionally occur, particularly in women with a history of chloasma of pregnancy. Women prone to chloasma should avoid direct sunlight or ultraviolet radiation during oral contraceptive use.

The yellow and white tablets contain lactose monohydrate. This should be considered in cases of rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. The lactose content should also be considered if the patient is on a lactose-free diet.

If you have been diagnosed with an intolerance to certain sugars, consult your physician before taking this medicinal product.

Elevated ALT levels

In clinical trials involving patients receiving antiviral therapy for hepatitis C with medications containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, elevations in transaminase levels (ALT) more than 5 times the upper limit of normal (ULN) were observed significantly more frequently in women using medications containing ethinylestradiol, such as combined hormonal contraceptives (CHCs). Elevated ALT levels have also been observed with other antiviral hepatitis C treatments containing glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Consultations/Medical examinations

Before initiating or resuming use of Feminate®, a complete medical and family history should be obtained, a full medical examination performed, and pregnancy excluded. Blood pressure should be measured and a medical examination conducted, taking into account contraindications (see section "Contraindications") and special precautions (see section "Special precautions for use"). Women should be informed about venous and arterial thrombosis, including the risk associated with the use of Feminate® compared to other CHCs, symptoms of VTE and ATE, known risk factors, and actions to take if thrombosis is suspected.

Patients are advised to carefully read the package leaflet and follow the recommendations provided.

The frequency and nature of follow-up examinations should be based on current medical practice guidelines, taking into account the individual characteristics of each woman.

Patients should be informed that hormonal contraceptives do not protect against HIV infection (AIDS) or any other sexually transmitted diseases.

Reduced efficacy

The efficacy of oral contraceptives may be reduced if doses are missed (see section "Dosage and administration"), in cases of gastrointestinal disorders (see section "Dosage and administration"), or when used concomitantly with other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Cycle disturbances

Irregular bleeding (spotting or breakthrough bleeding) may occur during oral contraceptive use, particularly during the first few months. If such bleeding continues after three menstrual cycles, it should be considered significant.

If irregular bleeding persists or appears after a period of regular bleeding, non-hormonal causes should be considered and appropriate diagnostic measures undertaken, including evaluation to exclude malignancy and pregnancy. Diagnostic procedures may include curettage.

Some women may not experience withdrawal bleeding during the tablet-free interval. If oral contraceptives have been taken according to the instructions in the section "Dosage and administration," pregnancy is unlikely. However, if oral contraceptives have been taken irregularly prior to the absence of the first withdrawal bleed, or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be excluded before continuing oral contraceptive use.

Use during pregnancy or breastfeeding.

Pregnancy.

This medicinal product is contraindicated during pregnancy.

If pregnancy occurs while taking Feminate®, treatment must be stopped immediately. However, results from epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers used oral contraceptives before pregnancy, nor do they indicate teratogenic effects from unintentional use of oral contraceptives during pregnancy.

Animal studies have shown adverse effects during pregnancy and lactation (see section "Pharmacological properties"). Based on data from these animal studies, adverse effects due to the hormonal action of the active substances cannot be excluded. However, the overall experience with oral contraceptive use during pregnancy does not indicate adverse effects in humans.

Available data on the use of the drug during pregnancy are too limited to draw conclusions regarding any negative impact of Feminate® on pregnancy, fetal or neonatal health. Currently, there are no relevant epidemiological data available.

When resuming use of Feminate®, the increased risk of VTE during the postpartum period should be considered (see sections "Dosage and administration," "Special precautions for use").

Breastfeeding.

Oral contraceptives may affect breastfeeding, as they may reduce the quantity and alter the composition of breast milk. Therefore, oral contraceptives are not recommended during breastfeeding. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during oral contraceptive use, which may affect the infant.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

No studies have been conducted on the influence on the ability to drive vehicles or operate machinery. There have been no reports of effects on the ability to drive vehicles or operate machinery in women taking combined oral contraceptives.

Method of Administration and Dosage

Tablets for oral use.

The tablets should be taken daily at the same time with a small amount of liquid, following the order indicated on the blister pack. Do not interrupt the use of Feminate® tablets. One tablet should be taken daily for 28 consecutive days. The next pack should be started immediately after the last tablet from the previous pack has been taken. A withdrawal bleed, similar to menstruation, usually begins on days 2–3 after starting the placebo tablets (white tablets) and may not stop before starting tablets from the next pack.

Each pack includes a blister holder, which can be used to carry the blister when needed, and a calendar scale.

The blister contains 21 active tablets (yellow) containing active ingredients and 7 placebo tablets (white) without active ingredients.

Initiating treatment with Feminate®

No hormonal contraceptives were used in the previous cycle (last month): Start taking tablets on the first day of the woman’s menstrual cycle (i.e., the first day of menstrual bleeding).

Switching from another combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring, or transdermal patch): It is recommended that the woman start taking Feminate® tablets the day after taking the last active tablet (the last tablet containing active ingredients) of her previous COC, but no later than the day after the usual hormone-free interval or after the last placebo tablet of the previous COC. When switching from a vaginal ring or transdermal patch, treatment with Feminate® should ideally begin on the day of removal of the previous product, but no later than the day when the next application of these products would have been scheduled.

Switching from a method based solely on progestogen-only contraceptives (‘mini-pill’, injections, implants) or an intrauterine system containing progestogen: The woman may start taking Feminate® at any time after discontinuing the ‘mini-pill’ (on the day of removal in the case of an implant or intrauterine system, or instead of the next scheduled injection). However, in all cases, it is recommended to use an additional barrier method of contraception during the first 7 days of taking the drug.

After first-trimester abortion: The woman may start taking the drug immediately. In this case, there is no need to use additional contraceptive methods.

After childbirth or second-trimester abortion: Women should be advised to start taking Feminate® on days 21–28 after childbirth or second-trimester abortion. If the woman starts taking tablets later, she should be advised to use an additional barrier method of contraception during the first 7 days of taking the drug. However, if sexual intercourse has already occurred, pregnancy must be ruled out or the first menstrual period must be awaited before starting the COC.

In case of breastfeeding – see section “Breastfeeding”.

Missed tablet instructions

If a white placebo tablet is missed, it may be disregarded. However, it should be removed from the pack to avoid unintentional prolongation of the placebo tablet phase.

The following instructions apply only to missed yellow tablets containing active ingredients.

If the delay in taking a tablet is less than 12 hours, the contraceptive protection is not reduced. The missed tablet should be taken as soon as possible, and subsequent tablets should be taken at the usual time.

If the delay in taking a tablet exceeds 12 hours, contraceptive protection may be reduced. In such cases, the following two main rules should be followed:

1. The interval between tablet intakes must never exceed 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved only by continuous intake of tablets for 7 days.

Accordingly, the following recommendations should be followed in daily practice:

• Week 1

The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She should then continue taking tablets at her usual time. In addition, a barrier method of contraception (e.g., condom) should be used for the next 7 days. If sexual intercourse occurred in the previous 7 days, the possibility of pregnancy should be considered. The greater the number of missed tablets and the closer the missed dose is to the placebo tablet phase, the higher the risk of pregnancy.

• Week 2

The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She should then continue taking tablets at her usual time. If the woman has taken tablets correctly for the 7 days prior to the missed dose, no additional contraceptive methods are required. However, if more than one tablet has been missed, additional contraceptive methods are recommended for the next 7 days.

• Week 3

The risk of reduced contraceptive efficacy increases as the 7-day placebo tablet period approaches.

However, by following the prescribed dosing schedule, a reduction in contraceptive protection can be avoided. If one of the following recommendations is followed, additional contraceptive methods are not required, provided that tablets were taken correctly during the 7 days preceding the first missed tablet. Otherwise, the first of these two recommendations should be followed, and additional contraceptive methods should be used for the next 7 days.

1. The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She should then continue taking tablets at her usual time until the end of the active tablets.

The 7 tablets in the last row (placebo tablets) should be disregarded. The next pack should be started immediately after the last active tablet from the previous pack has been taken. It is unlikely that withdrawal bleeding will occur before completing all active tablets from the second pack, although breakthrough bleeding or spotting may occur during tablet intake.

1. Alternatively, the woman may discontinue active tablets from the current blister pack. In this case, she should take the tablets from the last row (placebo tablets) for 7 days, including the days of missed tablets, and then continue with the next blister pack.

If a woman has missed tablets and does not experience withdrawal bleeding during the placebo tablet phase, she should consult a physician regarding the possibility of pregnancy.

Recommendations in case of gastrointestinal disturbances

In case of severe gastrointestinal disturbances (e.g., vomiting or diarrhea), incomplete absorption of the drug may occur; therefore, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking a tablet, a replacement tablet should be taken as soon as possible. The replacement tablet should be taken, if possible, within 12 hours of the usual intake time. If more than 12 hours have passed, the instructions for missed tablets described in the section "Missed tablet instructions" should be followed. If the woman does not wish to change her usual dosing schedule, she should take an additional tablet(s) from another blister pack.

How to change the timing of withdrawal bleeding

To delay withdrawal bleeding, the woman should continue taking Feminate® tablets from a new pack without taking the placebo tablets from the current pack. The duration of active tablet intake may be extended, if desired, until the active tablets in the second pack are finished. Breakthrough bleeding or spotting may occur during this period. After completing all placebo tablets, the usual Feminate® regimen should be resumed.

To shift the timing of withdrawal bleeding to another day of the week, it is recommended to shorten the placebo tablet phase by the desired number of days. The shorter this interval, the higher the risk of absence of withdrawal bleeding and the occurrence of breakthrough bleeding or spotting during intake of tablets from the next pack (similar to the case of delaying withdrawal bleeding).

Additional information for special patient groups

Elderly patients.

The drug is not indicated after menopause.

Patients with hepatic impairment. Feminate® is contraindicated in women with severe hepatic impairment (see sections “Contraindications” and “Pharmacological properties”).

Patients with renal impairment. Feminate® is contraindicated in women with severe renal impairment or acute renal failure (see sections “Contraindications” and “Pharmacological properties”).

Children. Feminate® is indicated for use only after the onset of the first menstruation. Based on epidemiological data collected in over 2000 adolescents under 18 years of age, there is no evidence indicating differences in safety and efficacy in this patient group compared to women aged 18 years and older.

Overdose.

There are currently no clinical data on overdose with Feminate® tablets. Based on experience with COCs, overdose may result in nausea, vomiting, or vaginal bleeding in young girls. Withdrawal bleeding may occur in girls, even before menarche, in cases of accidental or unintentional drug intake. There is no specific antidote; treatment should be symptomatic.

Adverse reactions.

For serious adverse reactions in women using COCs, see also section "Special precautions for use". The adverse reactions listed below were observed during the use of the medicinal product Femynity® (see Table 3).

Adverse reactions observed during the use of the medicinal product Femynity®

Table 3

Description of individual adverse reactions

Women taking COCs have been observed to have an increased risk of developing venous or arterial thrombotic/thromboembolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis, and pulmonary embolism, which are described in detail in the section "Special precautions for use".

The following serious adverse reactions have been observed in women using COCs (also described in the section "Special precautions for use"):

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumours;
• development or worsening of conditions whose relationship with COC use has not been definitively established: Crohn’s disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, haemolytic uraemic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic disorders of liver function, which may require discontinuation of COC use until liver function parameters return to normal;
• exogenous estrogens may cause the onset or exacerbation of symptoms of hereditary or acquired angioedema.

Adverse reactions observed in patients using COCs: emotional lability, depression; loss of libido; venous and arterial thromboembolic events, including occlusion of peripheral deep veins, thrombosis and pulmonary vessel embolism, myocardial infarction, stroke (including haemorrhagic stroke, ischaemic stroke, transient ischaemic attack); erythema.

Other adverse reactions associated with the class of combined oral contraceptives are also listed in the sections "Contraindications" and "Special precautions for use" (including hearing loss associated with otosclerosis, hypertriglyceridaemia and increased risk of pancreatitis, gallstone formation, changes in glucose tolerance or effects on peripheral insulin resistance, jaundice and/or pruritus associated with cholestasis, hypersensitivity reactions including rash and urticaria).

The incidence of breast cancer diagnosis is slightly increased among women using COCs. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases of breast cancer among women currently or recently using COCs is small relative to the overall risk of breast cancer. The relationship with COC use is unknown. See also sections "Contraindications" and "Special precautions for use".

Interactions

Breakthrough bleeding and/or reduced contraceptive efficacy may occur due to interactions between other medicinal products (enzyme inducers) and oral contraceptives (see section "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is important. It allows continued monitoring of the benefit-risk balance of the use of this

medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and

lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of the reach of children.

Packaging. Film-coated tablets, 0.03 mg/3 mg, № 28 (21 + 7) in a blister;

1 blister together with a calendar scale and blister holder in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Laboratorios Leon Farma, S. A.

Manufacturer's address and location of its business activity.

Calle La Vallina S/N, Poligono Industrial Navatejera, Villaquilambre, 24193, Spain.

Marketing Authorisation Holder.

TOV "VORWARTS PHARMA".

Address of the Marketing Authorisation Holder.

4 Oprytska Street, Kyiv, 03142, Ukraine.