Dropifem 20 film-coated tablets 3.02 mg blister No. 28

Instructions for use: Dropifem 20 film-coated tablets 3.02 mg blister No. 28

Composition

active ingredients: ethinylestradiol, drospirenone;

1 active pink tablet contains 0.02 mg of ethinylestradiol and 3 mg of drospirenone;

1 white placebo tablet contains no active ingredients;

excipients:

1 active tablet contains lactose monohydrate, corn starch, maltodextrin, magnesium stearate, Opadry 10A240000 pink (hypromellose, talc, titanium dioxide (E 171), polysorbate 80, iron oxide red (E 172));

1 placebo tablet contains lactose monohydrate, corn starch, maltodextrin, magnesium stearate, white film-coating mixture (hypromellose, lactose monohydrate, titanium dioxide (E 171), macrogol 4000, sodium citrate)).

Dosage form

Film-coated tablets.

Main physicochemical properties:

active tablets: round tablets, film-coated, pink in color, without coating defects;

Placebo tablets: round tablets with double-sided oval embossing, coated with a white film coating without coating defects.

Pharmacotherapeutic group

Sex gland hormones and drugs used in genital pathology. Hormonal contraceptives for systemic use.

Progestogens and estrogens, fixed combinations. Drospirenone and ethinylestradiol.

ATX code G03A A12.

Pharmacological properties

Pharmacodynamics.

Pearl contraceptive failure index for the drug: 0.41 (upper two-sided 95% confidence interval (CI): 0.85).

Overall Pearl Index (contraceptive failures + patient errors) for the drug: 0.80 (upper two-sided 95% confidence interval (CI): 1.30).

Drospirenone® 20 is a combined oral contraceptive containing ethinylestradiol and 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 contraceptive effect of the drug is based on the interaction of various factors, the most important of which are the suppression of ovulation and changes in cervical secretion.

According to clinical studies, moderate antimineralocorticoid properties of Drospifem® 20 have a moderate antimineralocorticoid effect.

In a tricyclic clinical trial of ovulation suppression comparing drospirenone 3 mg/ethinylestradiol 0.02 mg in a 24-day regimen with a 21-day regimen, the 24-day regimen was associated with greater suppression of follicular development. After intentional dosing errors during the third cycle of therapy, a greater majority of women on the 21-day regimen experienced ovarian activity, including ovulation, compared with women on the 24-day regimen. Ovarian activity returned to pre-treatment levels during the post-therapy cycle in 91.8% of women on the 24-day regimen.

Pharmacokinetics.

Drospirenone

Absorption. When taken orally, drospirenone is rapidly and almost completely absorbed. The maximum serum concentration of 38 ng/ml is reached approximately 1-2 hours after a single dose. Bioavailability is 76-85%. Simultaneous food intake does not affect the bioavailability of drospirenone.

Distribution. After oral administration, serum concentrations of drospirenone decline with a terminal half-life of 31 hours. Drospirenone binds to serum albumin, but does not bind to sex steroid binding globulin (SSGB) or corticoid binding globulin (CBG). Only 3-5% of its total serum concentration is present in the free state. The increase in SSGB induced by ethinylestradiol does not affect the binding of drospirenone to serum proteins. The mean volume of distribution of drospirenone is 3.7±1.2 l/kg.

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

Elimination. The metabolic clearance rate of drospirenone from serum is 1.5±0.2 ml/min/kg. Drospirenone is excreted unchanged only in very small amounts. Metabolites are excreted in urine and feces in a ratio of approximately 1.2 to 1.4. The elimination half-life of metabolites in urine and feces is approximately 40 hours.

Steady state. During the administration cycle, the maximum steady-state concentration of drospirenone in serum is approximately 70 ng/ml and is reached after approximately 8 days of administration. Serum levels of drospirenone increased approximately 3-fold as a result of the ratio of the terminal half-life to the dosing interval.

with impaired renal function: the steady-state concentration of drospirenone in serum in women with mild renal insufficiency (creatinine clearance 50-80 ml/min) was comparable to that in women with normal renal function. The level of drospirenone in serum was on average 37% higher in women with moderate renal insufficiency (creatinine clearance 30-50 ml/min) compared to that in women with normal renal function. The use of drospirenone has been shown to be well tolerated in patients with mild and moderate renal insufficiency. It has been shown that taking drospirenone has no clinically significant effect on the concentration of potassium in serum;

with impaired liver function: in a single-dose study, the oral clearance of drospirenone was reduced by approximately 50% in subjects with moderate hepatic impairment compared with volunteers with normal liver function. The marked reduction in drospirenone clearance in volunteers with moderate hepatic impairment did not result in a clear difference 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).

Ethinylestradiol

Absorption. Ethinylestradiol is rapidly and completely absorbed after oral administration. Peak serum concentrations of 33 pg/ml are reached within 1-2 hours after a single dose. Absolute bioavailability due to presystemic conjugation and first-pass metabolism is approximately 60%. Concomitant food intake reduces the bioavailability of ethinylestradiol in approximately 25% of subjects, with unchanged bioavailability in the remainder.

Distribution: Serum ethinylestradiol levels decline in a biphasic manner, with a terminal phase with a half-life of approximately 24 hours. Ethinylestradiol binds strongly but nonspecifically to serum albumin (approximately 98.5%) and induces an increase in serum concentrations of GH and CSH. The apparent volume of distribution is approximately 5 l/kg.

Metabolism: Ethinylestradiol is extensively metabolized in the gastrointestinal tract and during the first pass through the liver. This occurs mainly by hydroxylation of the aromatic ring with the formation of a wide range of hydroxylated and methylated metabolites, which are present in the free state and as conjugates with glucuronides and sulfates. The metabolic clearance of ethinylestradiol is about 5 ml/min/kg.

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2, and an inhibitor of CYP3A4/5, CYP2C8 and CYP2J2.

Excretion. Ethinylestradiol is practically not excreted unchanged. Ethinylestradiol metabolites are excreted in urine and bile in a ratio of 4:6. The half-life of metabolites is approximately 1 day.

Steady state. Steady state is reached in the second half of the dosing cycle, when the serum level of ethinylestradiol increases 2-2.3 times.

Preclinical safety data.

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with the known pharmacological action. In particular, studies on reproductive toxicity in animals showed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those observed in users of the drug Drospirenone® 20, effects on sexual differentiation were observed in some animal species.

Indication

Oral contraception.

The decision to prescribe Drosophila 20 should take into account the individual patient's existing risk factors, in particular those for venous thromboembolism (VTE). The risk of VTE with Drosophila 20 should also be compared with that with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).

Contraindication

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 hereditary or acquired predisposition to venous thromboembolism, in particular 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 current or history of cerebrovascular disease, presence of prodromal symptoms (e.g. transient ischemic attack (TIA));

o hereditary or acquired predisposition to arterial thromboembolism, in particular hyperhomocysteinemia and antibodies to phospholipids (anti-cardiolipin 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;

severe dyslipoproteinemia.

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).

Current or history of breast cancer, which may be hormone-sensitive (see section “Special warnings and precautions for use”, subsection “Tumors”).

Vaginal bleeding of unknown etiology.

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section “Interaction with other medicinal products and other types of interactions”).

Hypersensitivity to the active substances or to any of the components of the drug.

Interaction with other medicinal products and other types of interactions

The information on the medicinal product being used concurrently should be consulted to identify potential interactions.

Effect of other drugs on Drospifem® 20

Interactions are possible with drugs that induce microsomal enzymes. This may lead to increased clearance of sex hormones, which in turn may cause breakthrough bleeding and/or loss of contraceptive efficacy.

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 combined oral contraceptive (COC). The barrier method should be used throughout the duration of concomitant therapy and for 28 days after its discontinuation.

If concomitant therapy is continued after the last active COC tablet in the pack has been taken, the placebo tablet period should be skipped and the active tablet period from the next COC pack should be started.

Long-term treatment

Women on long-term therapy with active substances that induce liver enzymes are recommended to use a barrier or other reliable non-hormonal method of contraception.

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 perforatum).

Active substances with inconsistent 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.

In a multiple-dose study of the combination drospirenone (3 mg/day)/ethinyl estradiol (0.02 mg/day) with concomitant use of the strong CYP3A4 inhibitor ketoconazole for 10 days, the AUC(0-24h) of drospirenone and ethinyl estradiol increased 2.7- and 1.4-fold, respectively.

Effect of Drospifem® 20 on other medicinal products. Oral contraceptives may affect the metabolism of other active substances. They may change the concentration of active substances in plasma and tissues: increase (such as cyclosporine) and decrease (such as lamotrigine).

According to in vivo interaction studies conducted with female volunteers taking omeprazole, simvastatin and midazolam as indicator substrates, the effect of drospirenone at a dose of 3 mg with other drugs metabolized by cytochrome P450 is unlikely.

Clinical data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, resulting in a mild (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentrations.

Other forms of interaction. In patients with renal insufficiency, the simultaneous use of drospirenone and ACE inhibitors or non-steroidal anti-inflammatory drugs does not have a significant effect on serum potassium levels. However, the simultaneous use of the drug Drospifem® 20 and aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, it is necessary to study the serum potassium level during the first cycle of taking the drug (see also the section "Special instructions").

Laboratory tests

The use of COCs 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.

Pharmacodynamic interactions

In clinical trials in patients treated for hepatitis C (HCV) infection with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, significant elevations of transaminases (ALT) exceeding 5 times the upper limit of normal (ULN) occurred more frequently in women using ethinylestradiol-containing medicinal products such as combined hormonal contraceptives (CHCs). In addition, elevations of ALT have also been observed with the antiviral medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir in women using ethinylestradiol-containing medicinal products such as CHCs (see sections 4.3 and 4.4). Therefore, patients taking Drospirenone 20 should switch to an alternative method of contraception (e.g. progestogen-only contraception or non-hormonal methods of contraception) before starting treatment with these combination drug regimens. Treatment with Drospirenone 20 can be resumed 2 weeks after the end of treatment with these combination drug regimens.

Application features

If any of the conditions/risk factors listed below are present, the appropriateness of using Drospifem® 20 should be discussed with the woman.

In case of exacerbation or occurrence of any of these conditions or risk factors, it is recommended to consult a doctor to determine whether the use of Drospifem® 20 should be discontinued.

In case of suspected or confirmed VTE or ATE, the drug 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 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, but the incidence is lower than the incidence associated with pregnancy (60 cases per 100,000 pregnancies). Medicines containing levonorgestrel, norgestimate or norethisterone are associated with a lower risk of VTE. The use of other medicines, such as Drospirenone, 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 Drospirenone, 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.

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).

About 2 in 10,000 women who are not using CHCs and are not pregnant will develop a VTE during the 1-year follow-up period. However, for any individual woman, the risk may be much higher depending on risk factors (see below).

It has been estimated that out of 10,000 women using a CHC containing drospirenone, 9-12 will develop a VTE in 1 year. 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.

This compares with a rate of 6 in women using levonorgestrel-containing CHCs. On average, 5-7 cases per 10,000 woman-years based on the calculation of the relative risk of using levonorgestrel-containing CHCs compared to that in women not using CHCs (about 2.3-3.6 cases).

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

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 during the 6 weeks after delivery (for information on pregnancy or breastfeeding, see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

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

Symptoms of deep vein thrombosis (DVT) may include:

unilateral swelling of the leg and/or foot or areas along a vein on 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 pulmonary embolism (PE) may include:

sudden shortness of breath of unknown etiology or rapid breathing;

sudden cough, which may be accompanied by hemoptysis;

sharp chest pain;

severe dizziness or vertigo;

fast or irregular heartbeat.

Some of the above symptoms (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as manifestations of more common and less severe conditions (e.g., respiratory infection).

Other signs of vascular occlusion may include: sudden pain in the limb, swelling, acute abdomen, and slight cyanosis of the skin of the extremities.

If the occlusion develops in the retinal veins, symptoms can range from painless blurred vision that can progress to vision loss. Sometimes, vision loss develops almost instantly.

Risk of arterial thromboembolism (ATE).

Epidemiological studies have associated the use of CHCs with an increased risk of arterial thromboembolic events (myocardial infarction) or cerebrovascular accidents (e.g. transient ischemic attacks, stroke). Cases of arterial thromboembolism can be fatal.

The risk of arterial thromboembolic complications or cerebrovascular accidents with CHC use is increased in women with existing risk factors (see table). Drospirenone 20 is contraindicated in women with one serious or a combination of several risk factors for ATE, which puts them at very high risk of 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 considered. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Risk factors for developing ATE

Extremely rare cases of thrombosis of other blood vessels, such as arteries and veins of the liver, kidneys, mesenteric vessels, cerebral vessels or retina, have been reported in women using combined contraceptives, but their relationship to CHC use has not been proven.

Symptoms of ATE

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

Symptoms of cerebral circulation disorders 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 temporary nature of the symptoms may indicate a transient ischemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

pain, discomfort, feeling of compression, heaviness, feeling of fullness in the chest, arm or behind the sternum;

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;

severe 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 (more than 5 years) use of COCs, but this statement is still controversial, since it is not yet clear to what extent the results of the studies take into account concomitant risk factors, such as cervical smears and sexual behavior, and other factors, such as human papillomavirus.

Breast cancer: Drospirenone/ethinylestradiol is contraindicated in women with current or past breast cancer, as breast cancer may be hormone-sensitive (see Contraindications).

Epidemiological studies have not found a consistent association between the use of combined oral contraceptives (COCs) and the risk of breast cancer. The results of the studies do not show an association between current or past use of COCs and the risk of breast cancer. However, some studies have reported a slightly increased risk of breast cancer among current or recent users (< 6 months since last use) and long-term users of COCs (see section “Adverse reactions”, subsection “Post-marketing data”).

Since breast cancer is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses in women who use or have recently used COCs is small in relation to the overall risk of breast cancer. The results of the studies do not prove a cause-and-effect 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 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. In some cases, these tumors have caused life-threatening intra-abdominal bleeding. In the event of complaints of severe epigastric pain, liver enlargement or signs of intra-abdominal bleeding, the possibility of a liver tumor in women using COCs should be considered in the differential diagnosis.

The risk of endometrial and ovarian cancer is reduced with higher doses of COCs (50 μg ethinylestradiol). The hypothesis that similar trends may apply to low-dose COCs remains to be confirmed.

Other states

The progestin component of Drospirenone 20 is an aldosterone antagonist with potassium-sparing properties. In most cases, an increase in potassium levels is not expected. In a clinical study, however, in some patients with mild to moderate renal insufficiency and concomitant use of potassium-sparing medicinal products, serum potassium levels increased slightly, but not significantly, while taking drospirenone. Therefore, it is recommended to check serum potassium during the first treatment cycle in patients with renal insufficiency and pre-treated with serum potassium in the upper range, and especially during concomitant use of potassium-sparing medicinal products (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 observed in many women taking COCs, clinically significant increases in blood pressure have been reported rarely. Only in rare cases is immediate discontinuation of COC use necessary. If, during the use of COCs in a woman with pre-existing hypertension, blood pressure values remain persistently elevated or if a significant increase in blood pressure does not respond adequately to antihypertensive therapy, COC use should be discontinued. If necessary, COC use may be continued if normal blood pressure values are achieved with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and COC use, but the relationship to COC use is not conclusive: jaundice and/or pruritus associated with cholestasis; gallstones; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.

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

In acute or chronic liver dysfunction, it may be necessary to discontinue COC use until liver function tests return to normal. In the event of recurrence of cholestatic jaundice, which first occurred during pregnancy or during 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 a change in the therapeutic regimen is necessary for diabetic women taking low-dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be closely monitored throughout the duration of COC use.

Worsening of epilepsy, Crohn's disease, and ulcerative colitis has also been reported with COC use.

Mood swings and depression are well-known side effects of hormonal contraceptives (see section 4.8). Depression can be serious and is a known risk factor for suicidal behaviour and suicide.