Merijen film-coated tablets 3 mg/0.03 mg blister No. 21

Instructions for Merijen film-coated tablets 3 mg/0.03 mg blister No. 21

Composition

active ingredients: drospirenone, ethinylestradiol;

1 tablet contains drospirenone 3 mg; ethinylestradiol 0.03 mg;

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

Dosage form

Film-coated tablets.

Main physicochemical properties: cylindrical tablets with a biconvex surface, covered with a pale yellow film coating.

Pharmacotherapeutic group

Sex hormones and drugs used in genital pathology. Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combinations. Drospirenone and ethinyl estradiol.

ATX code G03A A12.

Pharmacological properties

Pharmacodynamics.

The Pearl contraceptive failure index for 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 various factors, the most important of which are the suppression of ovulation and changes in cervical secretion.

The drug Merijen® is a combined oral contraceptive with ethinylestradiol and the progestogen drospirenone. In therapeutic doses, drospirenone exhibits antiandrogenic and moderate antimineralocorticoid properties. It does not have estrogenic, glucocorticoid and antiglucocorticoid activity. Therefore, drospirenone has a similar pharmacological profile to natural progesterone.

According to clinical studies, the moderate antimineralocorticoid properties of the drug lead to a moderate antimineralocorticoid effect.

Pharmacokinetics.

Drospirenone

Absorption: Orally administered drospirenone is rapidly and completely absorbed. Peak serum concentrations of 38 ng/ml are reached approximately 1–2 hours after a single oral dose. Bioavailability is approximately 76–85%. Concomitant food intake does not affect the bioavailability of drospirenone.

Distribution: After oral administration, serum drospirenone concentrations decline with a mean terminal half-life of approximately 31 hours. Drospirenone is bound to serum albumin but not to sex steroid binding globulin (SSGB) or corticoid binding globulin (CBG). Only 3–5% of the total drospirenone concentration is present in serum as free steroid. The increase in SSGB induced by ethinylestradiol does not affect serum protein binding of drospirenone. 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, which is formed as a result of the opening of the lactone ring, as well as 4,5-dihydro-drospirenone-3-sulfate, which is formed by hydration with subsequent sulfation. Drospirenone is also the subject of oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone can weakly or moderately inhibit the 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 small amount of drospirenone is excreted unchanged. The metabolites of drospirenone are excreted in the feces and urine in a ratio of approximately 1.2:1.4. The half-life of metabolites in urine and feces is about 40 hours.

Steady-state concentration: During a treatment cycle, the maximum steady-state serum concentration of drospirenone of approximately 70 ng/ml is reached after approximately 8 days of treatment. The serum concentration of drospirenone increased approximately 3-fold due to the ratio of the terminal half-life to the dosing interval.

Special categories of patients

Effects on hepatic impairment. It is known that after a single dose, the oral clearance of drospirenone was reduced in subjects with moderate hepatic impairment compared to volunteers with normal liver function. The observed deviation in drospirenone clearance in subjects with moderate hepatic impairment did not result in any apparent differences in serum potassium concentrations. Even in the presence of diabetes mellitus and concomitant therapy with spironolactone (two factors that can provoke hyperkalemia), no increase in serum potassium concentrations 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 difference in the pharmacokinetics of drospirenone or ethinyl estradiol was observed between Japanese and Caucasian women.

Ethinylestradiol

Absorption: Ethinylestradiol is rapidly and completely absorbed after oral administration. After administration of 30 mcg, peak serum concentrations of 100 pg/ml are reached within 1-2 hours. Ethinylestradiol is subject to extensive first-pass metabolism, which varies between individuals.

Absolute bioavailability is about 45%.

Distribution. The expected volume of distribution of ethinylestradiol is approximately 5 l/kg and plasma protein binding is approximately 98%. Ethinylestradiol induces hepatic synthesis of GH and corticosteroid-binding globulin. With 30 μg of ethinylestradiol, plasma GH concentrations increase from 70 to approximately 350 nmol/l. Ethinylestradiol is excreted in small amounts in breast milk (0.02% of the dose).

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

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

Steady-state concentration: Steady-state concentration is reached during the second half of the therapy cycle and serum ethinylestradiol levels increase approximately 1.4-2.1-fold.

Preclinical safety data.

There is information that in laboratory animals the effects of drospirenone and ethinylestradiol were limited to those associated with the known pharmacological action. In particular, reproductive toxicity in animals shows species-specific embryotoxic and fetotoxic effects. At exposures exceeding those observed in users of ethinylestradiol and drospirenone, effects on sexual differentiation were observed in some animal species.

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

Indication

Oral contraception.

Contraindication

Combined hormonal contraceptives (CHCs) should not be used if any of the following conditions are present. If any of these conditions appear for the first time during CHC use, the drug should be discontinued immediately.

• Presence or risk of venous thromboembolism (VTE).

o venous thromboembolism at present, in particular due to anticoagulant therapy, or in history (e.g. deep vein thrombosis (DVT) or pulmonary embolism (PE));

o known hereditary or acquired predisposition to venous thromboembolism, such as resistance to activated protein C (including factor V Leiden mutation), antithrombin-III deficiency, protein C deficiency, protein S deficiency;

o major surgical interventions with prolonged immobilization (see section "Peculiarities of use");

o high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special warnings and precautions for use").

• Presence or risk of arterial thromboembolism (ATE).

o the presence of arterial thromboembolism at present or in history (e.g. myocardial infarction) or the presence of prodromal symptoms (e.g. angina);

o current or history of cerebrovascular disease, presence of prodromal symptoms (e.g. transient ischemic attack (TIA));

o known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);

o migraine with focal neurological symptoms in history;

o high risk of arterial thromboembolism due to the presence of multiple risk factors (see section "Special warnings and precautions for use") or due to the presence of one serious risk factor, such as:

• severe arterial hypertension;
• severe dyslipoproteinemia.
• Current or history of severe liver disease until liver function tests have returned to normal.
• Severe renal failure or acute renal failure.
• Presence of liver tumors at present or in history (benign or malignant).
• Known or suspected malignant tumors (e.g., genital or mammary) that are sex hormone-dependent.
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the components of the medicinal product.
• Suspected or confirmed pregnancy.

The simultaneous use of the drug Merijen® with drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with drugs containing glecaprevir/pibrentasvir, sofosbuvir/velpatasvir/voxilaprevir is contraindicated (see section “Interaction with other medicinal products and other types of interactions”).

Special safety precautions

This medicinal product may pose a risk to the environment (see section 5.1). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other types of interactions

The information for the concomitant medicinal product should be consulted to identify potential interactions.

• The effect of other drugs on the drug Merijen®

Interactions are possible with drugs that induce microsomal enzymes. This will lead to an increase in the clearance of sex hormones, which in turn causes changes in the pattern of menstrual bleeding and/or loss of contraceptive effectiveness.

Therapy

Enzyme induction can be detected after a few days of treatment. Maximum enzyme induction is generally observed after a few weeks. After discontinuation of treatment, enzyme induction may persist for about 4 weeks.

Short-term treatment

Women taking enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method should be used throughout the entire period of treatment with the drug and for 28 days after stopping its use. If therapy is started during the last COC tablet-free period, the next COC tablet-free period should be started immediately after the previous one without the usual tablet-free interval.

Long-term treatment

For women on long-term therapy with active substances that induce liver enzymes, a barrier or other appropriate non-hormonal method of contraception is recommended.

The following interactions have been reported based on published data.

Active substances that increase COC clearance (reduced COC efficacy due to enzyme induction), for example:

barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; medicines used for HIV infection: ritonavir, nevirapine and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate and herbal medicines containing St. John's wort extract (Hypericum perfiratum).

Active substances with variable effects on COC clearance:

When used concomitantly with COCs, a large number of 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 estrogen or progestins. The cumulative effect of such changes may be clinically significant in some cases.

Therefore, the prescribing information for the concomitant HIV/HCV medicinal product should be consulted for potential interactions and any other recommendations. In case of any doubt, women should additionally use a barrier method of contraception during treatment with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Active substances that reduce COC clearance (enzyme inhibitors)

The clinical significance of the potential interaction with enzyme inhibitors remains unclear.

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

It is known that multiple doses of the combination of drospirenone/ethinyl estradiol and the strong CYP3A4 inhibitor ketoconazole, administered concomitantly, for 10 days increased the AUC(0-24h) values of drospirenone and ethinyl estradiol.

Etoricoxib at doses of 60 to 120 mg/day has been shown to increase plasma concentrations of ethinyl estradiol when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinyl estradiol.

• The effect of the drug Merijen® on other drugs

Interactions in female volunteers using omeprazole, simvastatin and midazolam as marker substrates showed that clinically significant interactions of drospirenone at a dose of 3 mg with other active substances induced by cytochrome P450 are unlikely.

Literature data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, which in turn causes a weak (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentrations.

Pharmacodynamic interactions

Available information from clinical trials involving patients treated with hepatitis C virus (HCV) medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin has shown elevations in transaminases (ALT) greater than 5 times the upper limit of normal (ULN). This occurred at a significantly higher frequency in women taking ethinylestradiol-containing medicinal products, including combined hormonal contraceptives (CHCs). In addition, ALT elevations have also been observed in women taking ethinylestradiol-containing medicinal products, such as CHCs, with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.3).

Therefore, women using the drug Merijen® should temporarily switch to an alternative method of contraception (e.g. progestogen-only contraceptives or non-hormonal methods) before starting therapy with this combination of drugs. The use of the drug Merijen® can be resumed 2 weeks after completing therapy with this combination.

In patients with normal renal function, concomitant use of drospirenone and angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) has not shown a significant effect on serum potassium levels. However, concomitant use of Merijen® and aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium levels should be monitored during the first treatment cycle (see also section "Special warnings and precautions for use").

Other forms of interaction

Laboratory tests. The use of contraceptive steroids may affect the results of some laboratory tests, such as biochemical parameters of liver, thyroid, adrenal and renal function, plasma concentrations of transport proteins such as corticosteroid-binding globulin, plasma concentrations of lipid/lipoprotein fractions, and parameters of carbohydrate metabolism, coagulation and fibrinolysis. These changes are usually within normal limits.

Drospirenone increases plasma renin and aldosterone activity, which is induced by its moderate antimineralocorticoid activity.

Application features

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

Warning

• If any of the conditions or risk factors listed below are present, the appropriateness of using the drug Merijen® should be discussed with the woman.
• In the event of exacerbation or the first manifestations of any of the above conditions or risk factors, women are advised to consult a doctor and determine the need to discontinue taking the drug Merijen®.
• In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. If anticoagulant therapy is initiated, alternative adequate contraception should be provided due to the teratogenic effects of anticoagulants (coumarins).
• Circulatory disorders.

Risk of developing venous thromboembolism (VTE)

The use of any CHC increases the risk of venous thromboembolism (VTE) in women who use it compared with those who do not use it. Medicines containing levonorgestrel, norgestimate or norethisterone are associated with a lower risk of VTE. The use of other medicines such as Merijene® may lead to a twofold increase in the risk. The decision to use medicines other than those with the lowest risk of VTE should only be made after discussion with the woman. It is necessary to ensure that she is aware of the risk of VTE associated with the use of Merijene®, the extent of the influence of her existing 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 may increase when resuming CHC use after a break of 4 weeks or more.

About 2 in 10,000 women who are not taking CHCs and are not pregnant will develop a VTE in a year. However, the risk for an individual woman may be much higher depending on the risk factors she has (see below).

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

VTE can be fatal in 1–2% of cases.

Number of VTE cases per 10,000 women in one year

1 These figures are based on literature data from epidemiological studies, taking into account the relative risks associated with the use of different CHCs compared with the use of CHCs containing levonorgestrel.

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

Thrombosis in other blood vessels, such as arteries and veins of the liver, kidneys, mesenteric vessels, brain or retina, has been reported extremely rarely in women using CHCs.

Risk factors for developing VTE

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

The use of the drug Merijen® is contraindicated in women with multiple risk factors that may increase the risk of developing venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk of developing VTE should be taken into account. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 1.

Risk factors for developing VTE

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

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 contact their doctor immediately if they experience the following symptoms and to inform them that they are using CHCs.

Symptoms of DVT may include:

• unilateral swelling of the leg and/or foot or areas along a vein in the leg;
• pain or increased sensitivity in the leg that may only be felt when standing or walking;
• a feeling of heat in the affected leg, redness or discoloration of the skin on the leg.

Symptoms of PE may include:

• sudden shortness of breath of unknown etiology or rapid breathing;
• sudden cough, possibly with blood;
• sudden chest pain;
• fainting or dizziness;
• fast or irregular heartbeat.

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

Other manifestations of vascular occlusion may include sudden pain, swelling, acute abdomen, and slight blueness of the limb.

In the case of occlusion of the vessels of the eye, the initial symptom may be blurred vision, which is not accompanied by pain, and which can progress to loss of vision. Sometimes the loss of vision develops almost instantly.

Risk of developing arterial thromboembolism (ATE)

Epidemiological studies have shown that the use of any CHC is associated with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular complications (transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.

When using CHCs, the risk of developing arterial thromboembolic complications or cerebrovascular complications is increased in women with risk factors (see Table 2). The use of the drug Merijen® is contraindicated if women have one serious or multiple risk factors for ATE that may increase the risk of developing arterial thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk should be taken into account. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 2.

Risk factors for developing ATE

Symptoms of ATE

Women should be advised to contact their doctor immediately if they experience the symptoms listed below and to inform them that they are using CHCs.

Symptoms of a cerebrovascular accident may include:

• sudden facial numbness, weakness or numbness of the limbs, especially on one side;
• sudden trouble walking, dizziness, loss of balance or coordination;
• sudden confusion, impaired speech or understanding;
• sudden vision loss in one or both eyes;
• sudden, severe, or prolonged headache with no known cause;
• loss of consciousness or fainting with or without seizures.

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

Symptoms of myocardial infarction may include:

• pain, discomfort, a feeling of tightness or heaviness in the chest, arm, or below the breastbone;
• a feeling of discomfort radiating to the back, jaw, throat, arm, stomach;
• feeling of fullness in the stomach, indigestion or heartburn;
• increased sweating, nausea, vomiting, or dizziness;
• extreme weakness, anxiety, or shortness of breath;
• fast or irregular heartbeat.

Tumors

According to the literature, it is known that there is an additional increase in the risk of developing cervical cancer with long-term use of COCs (> 5 years), but this statement remains controversial, since it is not yet clear to what extent the results of the studies take into account concomitant risk factors, such as sexual behavior, and other factors, such as human papillomavirus infection.

According to published data, a meta-analysis based on 54 epidemiological studies indicates a small increased relative risk (RR = 1.24) of developing breast cancer in women who use COCs. This increased risk gradually disappears within 10 years after stopping COCs. Since breast cancer is rare in women under 40 years of age, the increase in the number of cases diagnosed with breast cancer in women who are current or recent users of COCs is small in relation to the overall risk of breast cancer. The results of these studies do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in women who use COCs, to the biological action of COCs, or to a combination of both. There is a trend for breast cancer detected in women who have ever used COCs to be clinically less severe than in those who have never used COCs.

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

High-dose COCs (50 mcg ethinylestradiol) reduce the risk of endometrial and ovarian cancer. It remains to be confirmed whether these findings can also be extended to low-dose COCs.

The progestin component of the drug Merijhen® is an aldosterone antagonist with potassium-sparing properties. In most cases of use, an increase in potassium levels is not expected. In some patients with mild to moderate renal insufficiency and concomitant use of potassium-sparing drugs, serum potassium levels increased slightly, but not significantly, during the use of drospirenone. Therefore, monitoring of potassium levels during the first cycle of treatment in patients with renal insufficiency is recommended. These patients are also recommended to maintain serum potassium levels not above the upper limit of normal before starting the drug, especially when concomitantly using potassium-sparing drugs (see section “Interaction with other medicinal products and other forms of interaction”).

Women with hypertriglyceridemia or a family history of this disorder are at risk of developing pancreatitis when using COCs.

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant increases in blood pressure have been observed in isolated cases. Immediate discontinuation of COCs is only necessary in these isolated cases. In the case of persistent hypertension or failure to control blood pressure with antihypertensive drugs, women taking COCs should discontinue their use. If appropriate, COC use can be resumed after achieving normotensive status with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and COC use, but the relationship to estrogen/progestin use is not conclusive: 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.

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

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

Acute or chronic liver function disorders may require discontinuation of COC use until liver function tests return to normal and a causal relationship to COC use has been ruled out.

If cholestatic jaundice and/or itching associated with cholestasis recurs, which previously occurred during pregnancy or previous use of sex hormones, COC use should be discontinued.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence to suggest that diabetic women taking low-dose COCs (<0.05 mg ethinylestradiol) should be monitored closely during COC use, especially at the beginning of treatment.

Cases of exacerbation of epilepsy, Crohn's disease and ulcerative colitis have also been observed during the use of COCs.

Depressed mood and depression are well-known side effects that can occur with hormonal contraceptives (see section 4.8). Depression can be a serious condition and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to seek medical advice if they experience mood changes or symptoms of depression, including shortly after starting treatment.

Chloasma may occasionally occur, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid exposure to direct sunlight or ultraviolet radiation while using COCs.

Consultations/medical examination