Meridjen

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MÉRIGEN® (MERIGEN)

Composition:

Active substances: drospirenone, ethinylestradiol;

1 tablet contains drospirenone 3 mg; ethinylestradiol 0.03 mg;

Excipients: lactose monohydrate; hydroxypropylcellulose; potassium polycriline; sodium lauryl sulfate; magnesium stearate; coating: film-coating mixture Opadry II Yellow 85F32771: (polyethylene glycol (macrogol); titanium dioxide (E 171); partially hydrolyzed polyvinyl alcohol; talc; yellow iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: cylindrical, biconvex tablets, film-coated, pale yellow in color.

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

ATC code G03A A12.

Pharmacological properties.

Pharmacodynamics.

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

The overall Pearl Index (contraceptive failures + user 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.

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

According to clinical study data, the moderate antimineralocorticoid properties of the drug result in a moderate antimineralocorticoid effect.

Pharmacokinetics.

Drospirenone

Absorption. Orally administered drospirenone is rapidly and completely absorbed. Peak serum concentration of approximately 38 ng/mL is reached about 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 about 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 total drospirenone concentration in serum exists as free steroid. The increase in SHBG levels induced by ethinylestradiol does not affect drospirenone binding to serum proteins. The mean apparent volume of distribution of drospirenone is 3.7 ± 1.21 L/kg.

Metabolism. After 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-dihydrodrospirenone-3-sulfate, formed by 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.

Excretion. 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 terminal half-life and 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. It is known that after a single dose, oral clearance of drospirenone is reduced in subjects with moderate hepatic impairment compared to volunteers with normal liver function. The observed alteration in drospirenone clearance in subjects with moderate hepatic impairment did not result in any clinically significant differences regarding serum potassium concentrations. Even in the presence of 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 subjects with mild to moderate hepatic impairment (Child-Pugh class B).

Ethnicity. No clinically significant 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. After administration of 30 µg, peak serum concentration of 100 pg/mL is reached within 1–2 hours. Ethinylestradiol undergoes extensive first-pass effect, which depends on individual differences.

Absolute bioavailability is about 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 synthesis in the liver of SHBG and corticosteroid-binding globulins. With administration of 30 µg ethinylestradiol, plasma concentration of SHBG increases from 70 to about 350 nmol/L. Ethinylestradiol is excreted in small amounts in breast milk (0.02% of dose).

Metabolism. Ethinylestradiol is extensively metabolized in the gastrointestinal tract and during first-pass through the liver. Ethinylestradiol is mainly metabolized via aromatic hydroxylation, forming a large number of hydroxylated and ethylated metabolites, which are present as free metabolites and conjugates with glucuronides and sulfates. Metabolic plasma clearance of ethinylestradiol is about 5 mL/min/kg. In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and also, based on mechanism of action, an inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Excretion. 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 reached during the second half of the treatment cycle, and serum levels of ethinylestradiol increase approximately 1.4–2.1 times.

Preclinical safety data.

Available information indicates that in laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with known pharmacological actions. In particular, reproductive toxicity in animals indicates species-specific embryotoxic and fetotoxic effects. At exposures exceeding those in users, ethinylestradiol and drospirenone affected sexual differentiation in certain animal species.

Environmental risk assessment studies have shown that ethinylestradiol and drospirenone may potentially pose a threat to the aquatic environment (see section "Special precautions").

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

Combined hormonal contraceptives (CHCs) must not be used if any of the conditions listed below are present. If any of these conditions occur for the first time during CHC use, the medication should be discontinued immediately.

• Presence or risk of venous thromboembolism (VTE):
  • Current venous thromboembolism, including patients receiving 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 multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
  • Current or past arterial thromboembolism (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 severe liver disease until liver function tests return to normal range.
• Severe renal insufficiency or acute renal failure.
• Current or past benign or malignant liver tumors.
• Known or suspected hormone-dependent malignancies (e.g., of the genital organs or breasts).
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the medicinal product.
• Suspected or confirmed pregnancy.

Concomitant use of Merіjen® with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or with medicinal products containing glecaprevir/pibrentasvir, sofosbuvir/velpatasvir/voxilaprevir is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Special precautions.

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.

Carefully review information on any concurrently administered medicinal product to identify potential interactions.

• Effect of other medicinal products on Merіjen®

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

Therapy

Enzyme induction may be observed within a few days of starting treatment. Maximum enzyme induction is generally reached after several weeks. After discontinuation of the inducing agent, 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 duration of treatment with the enzyme-inducing agent 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 one, without the usual tablet-free interval.

Long-term treatment

For women on long-term therapy with enzyme-inducing substances, a barrier method or another appropriate non-hormonal contraceptive method is recommended.

The following interactions have been reported based on published data.

Active substances that increase COC clearance (reducing COC efficacy via enzyme induction), for example:

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

Active substances with variable effects on COC clearance:

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

Therefore, information on the medical product used for HIV/HCV treatment should be reviewed to identify potential interactions and other recommendations. In case of any doubt, 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.

Repeated doses of the combination drospirenone/ethinylestradiol and the strong CYP3A4 inhibitor ketoconazole, administered concomitantly for 10 days, have been shown to increase AUC(0-24h) values of drospirenone and ethinylestradiol.

Etoricoxib at doses of 60 to 120 mg/day has demonstrated increased plasma concentrations of ethinylestradiol when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

• Effect of Merіjen® on other medicinal products

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

Interactions in healthy female volunteers using omeprazole, simvastatin, and midazolam as substrate markers have shown that clinically significant interaction of drospirenone at a dose of 3 mg with other active substances metabolized by cytochrome P450 is unlikely.

Literature data indicate that ethinylestradiol inhibits the clearance of CYP1A2 substrates, leading to mild (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Pharmacodynamic interactions

Clinical data from studies involving patients receiving antiviral hepatitis C (HCV) treatment regimens containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, have shown increased transaminase levels (ALT) more than 5 times above the upper limit of normal (ULN). This occurred significantly more frequently in women using medicinal products containing ethinylestradiol, including combined hormonal contraceptives (CHCs). Additionally, increased ALT levels were also observed in women taking ethinylestradiol-containing medicinal products, such as CHCs, during treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Contraindications").

Therefore, women using Merіjen® should temporarily switch to an alternative contraceptive method (e.g., progestogen-only contraceptives or non-hormonal methods) before starting therapy with the above-mentioned drug combinations. Use of Merіjen® may be resumed 2 weeks after completion of treatment with these combinations.

In patients with normal renal function, concomitant use of drospirenone with angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) did not show a significant effect on serum potassium levels. However, concomitant use of Merіjen® 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. The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function; plasma concentrations of transport proteins such as corticosteroid-binding globulin; plasma levels of lipid/lipoprotein fractions; carbohydrate metabolism parameters; and coagulation and fibrinolysis parameters. Such changes are usually within normal ranges.

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

Special Warnings and Precautions

The decision to prescribe the medicinal product Meriжен® should be based on individual risk factors currently present in a woman, including risk factors for venous thromboembolism (VTE), as well as the VTE risk associated with Meriжен® compared to other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special Warnings and Precautions").

Warnings

• If any of the conditions or risk factors listed below are present, the appropriateness of using Meriжен® should be discussed with the woman.
• Women should be advised to contact their physician if they experience an exacerbation or the first signs of any of the mentioned conditions or risk factors, to determine whether discontinuation of Meriжен® is necessary.
• Combined hormonal contraceptives (CHCs) should be discontinued if a suspected or confirmed venous or arterial thromboembolism (VTE or ATE) occurs. If anticoagulant therapy is initiated, an alternative effective contraceptive method should be provided, due to the teratogenic effects of anticoagulants (coumarins).
• Circulatory disorders.

Risk of Venous Thromboembolism (VTE)

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

In 2 out of 10,000 women who are not taking CHCs and are not pregnant, VTE develops over one year. However, for any individual woman, the risk may be significantly higher depending on her individual risk factors (see below).

It has been established¹ 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 per 10,000 women using CHCs containing levonorgestrel.

In both cases, the annual incidence of VTE was lower than that typically expected during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

Number of VTE cases per 10,000 women per year

¹ These estimates are based on published data from epidemiological studies, taking into account the relative risks associated with different CHCs compared to CHCs containing levonorgestrel.

² Average of 5–7 cases per 10,000 woman-years, calculated from the relative risk of using CHCs containing levonorgestrel compared to non-use of CHCs (approximately 2.3–3.6 cases).

Thrombosis in other blood vessels—such as hepatic, renal, mesenteric, cerebral, or retinal veins and arteries—has been reported very rarely in women using CHCs.

Factors increasing the risk of VTE

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

The use of Meriжен® is contraindicated in women with multiple risk factors that may 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 the 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").

Table 1.

Risk factors for VTE

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 (for information on pregnancy and lactation, see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (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 leg and/or foot swelling, or swelling along a vein in the leg;
• Pain or increased sensitivity in the leg, which may occur only when standing or walking;
• Feeling of warmth in the affected leg, redness, or skin discoloration.

Symptoms of PE may include:

• Sudden unexplained shortness of breath or rapid breathing;
• Sudden cough, possibly with blood;
• Sudden chest pain;
• Near-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 studies indicate that the 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

The risk of arterial thromboembolic complications or cerebrovascular complications increases in women using COCs who have risk factors (see Table 2). The use of Merihen® is contraindicated in women who have 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 risks associated with each individual factor, so the overall risk should be considered. If the benefit-risk ratio is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 2.

Risk factors for ATE

ATE Symptoms

Women should be advised to seek immediate medical attention and inform their doctor if they experience any of the symptoms listed below while taking COCs.

Symptoms of cerebrovascular disorders may include:

• sudden facial numbness, weakness or numbness of limbs, especially on one side;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, speech or comprehension disturbances;
• sudden vision deterioration in one or both eyes;
• sudden, severe or prolonged headache without a known cause;
• loss of consciousness or fainting, with or without seizures.

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

Symptoms of myocardial infarction may include:

• chest pain, discomfort, tightness or heaviness in the chest, arm or below the sternum;
• discomfort radiating to the back, jaw, throat, arm or stomach;
• stomach fullness, indigestion or suffocation;
• excessive sweating, nausea, vomiting or dizziness;
• extreme weakness, anxiety or shortness of breath;
• rapid or irregular heartbeat.

Tumors

According to published data, there is evidence of an additional increased risk of cervical cancer with long-term use of COCs (> 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.

Published data from a meta-analysis based on 54 epidemiological studies indicate a slight increase in relative risk (RR = 1.24) of breast cancer among women using COCs. This increased risk gradually disappears within 10 years after discontinuation of COCs. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among current or recent COC users is minimal in relation 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 COC users, a biological effect of COCs, or a combination of both factors. There is a trend indicating that breast cancer diagnosed in women who have ever used COCs tends to be less clinically advanced than in those who have never used COCs.

In rare cases, benign and even more rarely malignant liver tumors have been observed in women using COCs, which in some cases have led to life-threatening intra-abdominal hemorrhage. In case of complaints of severe epigastric pain, liver enlargement or signs of intra-abdominal bleeding, liver tumor should be considered in differential diagnosis during COC use.

Use of COCs at high doses (50 mcg ethinylestradiol) reduces the risk of endometrial and ovarian cancer. It remains to be confirmed whether these data apply to low-dose COCs as well.

Other Conditions

The progestin component of the medicinal product Meriжен® is an aldosterone antagonist with potassium-sparing properties. In most cases, increased serum potassium levels are not expected during use. However, in some patients with mild to moderate renal impairment and concomitant use of potassium-sparing medicinal products, serum potassium levels may slightly, but not significantly, increase 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 be advised to maintain serum potassium levels not exceeding the upper limit of normal before starting treatment, especially when using potassium-sparing medicinal products concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Women with hypertriglyceridemia or a family history of this condition are at increased risk of developing pancreatitis while using COCs.

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

The following conditions have been reported to occur or worsen during pregnancy and with COC use, although their causal relationship to estrogen/progestin use has not been definitively established: jaundice and/or cholestasis-related pruritus, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham's chorea, herpes gestationis, hearing loss associated with otosclerosis.

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate angioedema symptoms.

Metabolism of steroid hormones may be impaired in patients with liver function disorders.

Acute or chronic liver dysfunction may require discontinuation of COCs until liver function tests return to normal and a causal relationship with COCs is excluded.

COC use should be discontinued in case of recurrence of cholestatic jaundice and/or pruritus related to cholestasis previously experienced during pregnancy or prior use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence to suggest a need for changes in therapeutic regimen in diabetic women using low-dose COCs (< 0.05 mg ethinylestradiol). However, women with diabetes should be carefully monitored during COC use, especially at the beginning of treatment.

Exacerbations of epilepsy, Crohn's disease, and ulcerative colitis have also been reported during COC 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 doctor 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 COC use.

Consultations/Medical Examination

Before initiating or resuming use of the medicinal product Meriжен®, a complete medical history (including family history) should be taken, 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"). Women should be informed about venous and arterial thrombosis, including the risk associated with use of Meriжен® compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take in case of suspected thrombosis.

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 established medical practice guidelines, taking into account individual characteristics of each woman.

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

Reduced Efficacy

The efficacy of COCs may be reduced in case of missed tablet intake (see section "Dosage and Administration"), gastrointestinal disturbances (see section "Dosage and Administration"), or concomitant use of 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 COC use, especially during the first few months. If such bleeding persists beyond three menstrual cycles, it should be considered clinically significant.

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

In some women, withdrawal bleeding may not occur during the tablet-free interval. If COCs have been taken according to instructions in section "Dosage and Administration", pregnancy is unlikely. However, if COCs 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 COC use.

One tablet of the medicinal product contains 46 mg of lactose. In patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, or those on a lactose-free diet, this lactose content should be taken into account.

Use during Pregnancy or Breastfeeding

Pregnancy. The medicinal product is contraindicated during pregnancy.

If pregnancy occurs during use of Meriжен®, treatment must be discontinued immediately. However, results of epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers used COCs before pregnancy, nor a teratogenic effect from unintentional COC use during pregnancy.

Animal studies have shown adverse effects during pregnancy and lactation (see section "Pharmacological Properties"). Based on these animal studies, adverse effects due to the hormonal activity of the active substances cannot be excluded. However, overall experience with COC use during human pregnancy does not indicate an adverse effect in humans.

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

When resuming use of Meriжен®, the increased risk of VTE in the postpartum period should be considered (see sections "Special Precautions" and "Dosage and Administration").

Breastfeeding. COCs may affect breastfeeding by reducing the quantity and altering the composition of breast milk. Therefore, COCs are not recommended during breastfeeding. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during COC use, which may affect the infant.

Effect on ability to drive and use machines

No studies on the effect on the ability to drive or use machines have been conducted. There have been no reports of impaired ability to drive or operate machinery in women taking combined oral contraceptives.

Method of Administration and Dosage

Method of Administration: Oral.

Dosage

How to take the medicinal product MerihenÒ

Tablets should be taken regularly at approximately the same time each day, swallowing with a small amount of liquid if necessary, in the order indicated on the blister pack. The medicinal product should be taken as one tablet daily for 21 consecutive days. Treatment with the next pack should be started after a 7-day tablet-free interval, during which withdrawal bleeding usually occurs. This bleeding typically begins on days 2–3 after the last tablet has been taken and may continue until the start of the next pack.

How to start using the medicinal product MerihenÒ

• No previous use of hormonal contraceptives (last month)

Begin taking tablets on the first day of the natural cycle (i.e., the first day of menstrual bleeding).

• Switching from combined oral contraceptives (COCs), vaginal ring, or transdermal patch

It is recommended to take the first tablet of MerihenÒ the day after the last active tablet (containing the active ingredient) was taken. However, it should not be later than the day after the tablet-free interval or the hormone-free period of the previous COC. When switching from a vaginal ring or transdermal patch, start taking MerihenÒ on the day of removal of the device, but no later than the day when the next application of these products would be due.

• Switching from a progestogen-only method (‘mini-pill’, injections, implants) or an intrauterine system containing progestogen

MerihenÒ may be started on any day after discontinuation of the ‘mini-pill’ (in the case of an implant or intrauterine system – on the day of removal; in the case of injections – 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 medicinal product.

• After first-trimester abortion

Treatment may be started immediately. In this case, additional contraceptive methods are not required.

• After childbirth or second-trimester abortion

It is recommended to start taking MerihenÒ on days 21–28 after childbirth or second-trimester abortion. If starting later, an additional barrier method of contraception should be used for the first 7 days of tablet intake. However, if sexual intercourse has already occurred, possible pregnancy should be ruled out or the woman should wait for the onset of the first menstruation before starting the medicinal product.

For breastfeeding women, see section "Use during pregnancy or breastfeeding".

What to do if a tablet is missed

If the delay in taking any tablet does not exceed 12 hours, contraceptive protection is not reduced. The missed tablet should be taken as soon as possible. The next tablet from the pack 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, two main rules should be followed:

1. The tablet-free interval must never exceed 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved only with continuous tablet intake over 7 days.

Accordingly, the following practical recommendations should be observed:

Week 1

Take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. Then continue taking tablets at the usual time. Additionally, use a barrier method of contraception (e.g., condoms) for the next 7 days. If sexual intercourse occurred in the previous 7 days, consider the possibility of pregnancy. The greater the number of missed tablets and the closer the gap in intake, the higher the risk of pregnancy.

Week 2

Take the last missed tablet as soon as remembered, even if two tablets have to be taken at the same time. Then continue taking tablets at the usual time. If tablets were taken correctly in the 7 days before the missed dose, no additional contraceptive methods are needed. However, if more than one tablet is missed, it is recommended to use a barrier method of contraception for the next 7 days.

Week 3

The risk of reduced efficacy increases as the 7-day tablet-free interval approaches. However, following one of the regimens below can help avoid reduced contraceptive protection. If one of the following options is followed, additional contraceptive methods are not required, provided tablets were taken correctly during the 7 days before the missed dose. If this is not the case, follow the first option below and use additional barrier methods for the next 7 days.

1. Take the last missed tablet as soon as remembered, even if two tablets must be taken at the same time. Then continue taking tablets at the usual time. Start the next pack immediately after finishing the current one, without any break between packs. Withdrawal bleeding is unlikely to occur before finishing the second pack, although breakthrough bleeding or spotting may occur during tablet intake.
2. Alternatively, stop taking tablets from the current pack. In this case, the break in using the medicinal product should not exceed 7 days, including the days of missed tablets; treatment should then be resumed with the next pack.

If withdrawal bleeding does not occur during the first planned tablet-free interval after missed tablets, pregnancy should be considered.

Recommendations in case of gastrointestinal disorders

In case of severe gastrointestinal disturbances (such as vomiting or diarrhea), incomplete absorption of the medicinal product may occur; therefore, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking the tablet, a new (replacement) tablet should be taken as soon as possible. The next tablet should, if possible, be taken within 12 hours according to the usual dosing schedule. If more than 12 hours have passed, the recommendations described above under "What to do if a tablet is missed" should be followed. If a woman does not wish to change her tablet-taking schedule, she should take additional tablet(s) from the next pack.

How to delay withdrawal bleeding

To delay withdrawal bleeding, continue taking tablets from a new pack of MerihenÒ without interruption. The duration of intake may be extended at will up to the end of tablets in the second pack. Breakthrough bleeding or spotting may occur during this time. Usually, treatment with MerihenÒ is resumed after a 7-day tablet-free interval.

To shift the timing of withdrawal bleeding to another day of the week, it is recommended to shorten the tablet-free interval by the desired number of days. It should be noted that the shorter the interval, the more frequently absence of withdrawal bleeding and breakthrough bleeding or spotting may occur during intake of tablets from the second pack (similar to delaying withdrawal bleeding).

Additional Information for Special Patient Groups

Elderly patients. The product is not indicated after menopause.

Patients with hepatic impairment. MerihenÒ is contraindicated in women with severe hepatic impairment (see sections "Contraindications" and "Pharmacological Properties").

Patients with renal impairment. MerihenÒ is contraindicated in women with severe renal impairment or acute renal failure (see sections "Contraindications" and "Pharmacological Properties").

Children.

MerihenÒ is indicated for use only after the onset of the first menstruation. There are no data indicating differences in safety and efficacy in this patient group compared to women aged 18 years and older.

Overdose.

There are currently no data on overdose with MerihenÒ tablets. Based on general experience with COCs, overdose may result in nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may occur in girls even before menarche in cases of accidental or unintentional ingestion of the medicinal product. 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 use of the medicinal product Merihen® (see Table 3).

Table 3.

Adverse reactions observed during use of the medicinal product Merihen®.

Description of individual adverse reactions

An increased risk of developing venous or arterial thrombotic/thromboembolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis, and pulmonary embolism, has been observed in women taking COCs, as described in more detail in the section "Special precautions".

The following serious adverse reactions have been observed in women using COCs, which are also described in the section "Special precautions":

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumours;
• development or exacerbation of diseases 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;
• in women with hereditary predisposition to angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

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

Other adverse reactions associated with combined oral contraceptives are also listed in the sections "Contraindications" and "Special precautions" (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, urticaria).

The frequency 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".

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 suspected adverse reactions

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

21 tablets in a blister; 1 blister with a cardboard blister holder in a carton.

Prescription status. Prescription only.

Manufacturer.

1. JSC "KYIV VITAMIN PLANT".
2. Sindea Pharma, S.L.

Manufacturer's address and site of operations.

1. 38 Kopilivska Street, Kyiv, 04073, Ukraine.

Website: www.vitamin.com.ua

2. Poligono Industrial Emilian Revilla Sans. Avenida de Agreda, 31, Olvega, 42110 Soria, Spain