Feminat film-coated tablets 3.03 mg blister No. 28

Instructions for use Feminat film-coated tablets 3.03 mg blister No. 28

Composition

active ingredients: ethinylestradiol, drospirenone;

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

excipients: lactose monohydrate, corn starch, pregelatinized starch (corn), 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), macrogol 3350, talc, iron oxide yellow (E 172)).

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

Dosage form

Film-coated tablets.

Main physicochemical properties: round yellow tablets, film-coated, without engraving; placebo: round white tablets, film-coated, without engraving.

Pharmacotherapeutic group

Sex hormone and drugs used in genital pathology. Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combinations.

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.

Femina® is a combined oral contraceptive with ethinylestradiol and the progestogen drospirenone. In therapeutic doses, drospirenone exhibits antiandrogenic and moderate antimineralocorticoid properties. It has no estrogenic, glucocorticoid or antiglucocorticoid activity. Therefore, drospirenone has a similar pharmacological profile to natural progesterone.

The drug has 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 serum drospirenone concentration is present 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. 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 hepatic function. The observed difference 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 spironolactone therapy (two factors that can induce 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 passes into breast milk in small amounts (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, with serum ethinylestradiol levels increasing approximately 1.4-2.1-fold.

Preclinical safety data.

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with the known pharmacological action. In particular, reproductive toxicity studies in animals showed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those observed in users of the medicinal product, 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 oral contraceptives (COCs) are contraindicated in the presence of at least one of the following conditions. If any of these conditions appear for the first time during COC 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 (in particular myocardial infarction) or the presence of prodromal symptoms (in particular angina);

o current or history of cerebrovascular disease, presence of prodromal symptoms (including 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:

diabetes mellitus with vascular complications;

severe arterial hypertension;

Current or history of severe liver disease until liver function tests return 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 drug.

Suspected or confirmed pregnancy.

The drug Feminati® is contraindicated for simultaneous use with drugs containing ombitasvir, paritaprevir, ritonavir, dasabuvir, glecaprevir, pibrentasvir, sofosbuvir, velpatasvir, voxilaprevir (see sections “Special instructions for use” and “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 patient should consult the information on the medicinal product that the patient plans to use concurrently to identify potential interactions.

Effect of other medicines on Feminat®

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 pack should be started immediately after the previous placebo tablet-free period.

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 in scientific publications.

Active substances that may increase the clearance of COCs (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 perforatum).

Active substances with inconsistent effects on PDA 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 to identify potential interactions. 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 the clearance of PDA (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, progestin, or both components.

In a multiple-dose study of the combination of drospirenone (3 mg/day)/ethinyl estradiol (0.002 mg/day) and the strong CYP3A4 inhibitor ketoconazole, administered concomitantly for 10 days, the AUC(0-24h) of drospirenone and ethinyl estradiol increased 2.7- and 1.4-fold, respectively.

Etoricoxib at doses of 60 to 120 mg/day has been shown to increase plasma concentrations of ethinyl estradiol by 1.4- to 1.6-fold, respectively, when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinyl estradiol.

Effect of Femina® on other medicines

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

Clinical data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, which in turn causes a slight (e.g. theophylline) or moderate (e.g. tizanidine) increase 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 and voxilaprevir increases the risk of alanine aminotransferase (ALT) elevations (see sections 4.3 and 4.4).

Therefore, women using Feminat® 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. Use of Feminat® can be resumed 2 weeks after completion of therapy with this combination.

In patients with normal renal function, concomitant use of drospirenone and ACE inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) has not shown a significant effect on serum potassium levels. However, concomitant use of Femina® 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, the plasma concentration of transport proteins such as corticosteroid-binding globulin, the plasma concentration 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 Feminati® should take into account the woman's individual risk factors, including risk factors for venous thromboembolism (VTE), as well as the risk of VTE associated with Feminati® compared with other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special Instructions").

Warning

If any of the conditions or risk factors listed below are present, the appropriateness of using Feminati® should be discussed with the woman.

In case of exacerbation or at 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 Feminati®.

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. Products containing levonorgestrel, norgestimate or norethisterone are associated with a lower risk of VTE. The use of other products such as Feminati® may increase the risk by twofold. The decision to use these products, 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 Feminati®, 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 increases when resuming CHC use after a break of 4 weeks or more.

About two 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).

It has been estimated1 that out of 10,000 women using CHCs containing drospirenone, 9-12 will develop VTE in one year. This compares with 62 in women using CHCs containing levonorgestrel.

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 lead to fatal outcomes in 1-2% of cases.

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

1 These figures are based on all epidemiological data, 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 the arteries and veins of the liver, kidneys, mesenteric vessels, brain or retina, has been reported extremely rarely in women using CHCs.

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).

Femina® is contraindicated in women with multiple risk factors that increase the risk of venous thrombosis (see section 4.3). 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 VTE should be considered. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section 4.3).

Risk factors for developing VTE

Table 1

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 during the 6 weeks after delivery (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 unexplained shortness of breath or rapid breathing; sudden cough, possibly with blood; sudden chest pain; fainting or dizziness; and a 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 events (transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.

Risk factors for developing ATE

When using CHCs, the risk of arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 2). The use of Feminine is contraindicated if women have one serious or several 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").

Risk factors for developing ATE

Table 2

The risk increases significantly with increasing body mass index.

It especially requires attention if women have other risk factors.

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 numbness of the face, weakness or numbness of the limbs, especially on one side; sudden trouble walking, dizziness, loss of balance or coordination; sudden confusion, trouble speaking or understanding; sudden loss of vision 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 a myocardial infarction may include: pain, discomfort, a feeling of squeezing or heaviness in the chest, arm or below the breastbone; discomfort radiating to the back, jaw, throat, arm, stomach; a feeling of fullness in the stomach, indigestion or shortness of breath; increased sweating, nausea, vomiting or dizziness; extreme weakness, anxiety or shortness of breath; fast or irregular heartbeat.

Tumors

The results of some epidemiological studies indicate 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.

A meta-analysis of 54 epidemiological studies has shown 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 COC use. Since breast cancer is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses 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, the biological action of COCs, or a combination of both. There is a tendency for breast cancer diagnosed in women who have ever used COCs to be clinically less severe than in women 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 the event 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 is not known whether these findings may also apply to low-dose COCs.

Other states

The progestin component of Femina® is an aldosterone antagonist with potassium-sparing properties. In most cases of use, an increase in potassium levels is not expected. In clinical studies, 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 is recommended during the first treatment cycle in patients with renal insufficiency. 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”).

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 normotensive status has been achieved with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and COC use, but the relationship between estrogen/progestin use and the following conditions 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.

Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.

The metabolism of steroid hormones may be impaired in patients with impaired liver function. Acute or chronic disorders of liver function may require discontinuation of COC use until liver function tests return to normal and a causal relationship to COC use has been excluded.

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 that there is a need to change the therapeutic regimen in diabetic women taking low-dose COCs (<0.05 mg ethinylestradiol). However, women with diabetes should be closely monitored during COC use, especially at the beginning of treatment.

Cases of exacerbation of endogenous depression, 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.

The yellow and white tablets contain lactose monohydrate. This should be taken into account in the presence of rare hereditary conditions of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, and in the case of being on a lactose-free diet, the indicated amount of lactose should be taken into account.

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Elevated ALT levels

In clinical trials in patients treated for hepatitis C with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations greater than 5 times the upper limit of normal (ULN) were observed significantly more frequently in women using medicinal products containing ethinylestradiol.