AC-HELP

INSTRUCTIONS FOR MEDICAL USE OF THE DRUG DROSPIFEM^®20

Composition:

active ingredients: ethinylestradiol, drospirenone;

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

1 white placebo tablet does not contain active ingredients;

excipients:

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

Pharmaceutical form.

Film-coated tablets.

Main physical and chemical properties:

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

placebo tablets: round, biconvex tablets with an oval-shaped engraving on both sides, film-coated, white, without coating defects.

Pharmacotherapeutic group.

Sex hormones and modulators of the genital system. Hormonal contraceptives for systemic use.

Progestogens and estrogens, fixed combinations. Drospirenone and ethinylestradiol.

ATC code G03A A12.

Pharmacological properties.

Pharmacodynamics.

Pearl Index of contraceptive failures 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).

Drosiphen^®20 is a combined oral contraceptive that contains ethinylestradiol and drospirenone. At therapeutic doses, drospirenone has antiandrogenic and moderate anti-mineralocorticoid properties. It does not have estrogenic, glucocorticoid, and anti-glucocorticoid activity. Therefore, drospirenone has a pharmacological profile similar to that of 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 trial data, the moderate anti-mineralocorticoid properties of Drosiphen^®20 have a moderate anti-mineralocorticoid effect.

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

Pharmacokinetics.

Drospirenone

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

Distribution. After oral administration, the serum concentration of drospirenone decreases with a terminal half-life of approximately 31 hours. Drospirenone is bound to serum albumin, without binding to sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG). Only 3-5% of its total amount in serum is present in the free state. The increase in SHBG caused by ethinylestradiol does not affect the binding of drospirenone to serum proteins. The average volume of distribution of drospirenone is approximately 3.7 ± 1.2 l / kg.

Metabolism. Drospirenone is extensively metabolized after oral administration. The main metabolites in plasma are acidic forms of drospirenone, which are formed as a result of the opening of the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate, which is formed by hydration followed by sulfation. Drospirenone is also a substrate for oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone may weakly or moderately inhibit cytochrome P450 enzymes: CYP1A1, CYP2C9, CYP2C19, and CYP3A4.

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

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

Special patient groups:

- with impaired renal function: the equilibrium concentration of drospirenone in serum in women with mild renal impairment (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 impairment (creatinine clearance 30-50 ml / min) compared to women with normal renal function. The use of drospirenone has shown good tolerability in patients with mild and moderate renal impairment. It has been shown that taking drospirenone does not have a clinically significant effect on potassium levels in serum;

- with impaired liver function: in a study of single-dose administration, the clearance of drospirenone after oral administration decreased by approximately 50% in patients with moderate liver impairment compared to volunteers with normal liver function. A significant decrease in drospirenone clearance in volunteers with moderate liver impairment did not lead to a significant difference in potassium levels in serum. Even in the presence of diabetes and concomitant therapy with spironolactone (two factors that can provoke hyperkalemia), no increase in potassium levels in serum above the upper limit of normal was observed. It can be concluded that drospirenone is well tolerated in patients with mild or moderate liver impairment (class B according to the Child-Pugh classification).

Ethinylestradiol

Absorption. Ethinylestradiol is rapidly and completely absorbed after oral administration. The maximum serum concentration, which is 33 pg / ml, is reached within 1-2 hours after a single dose. The absolute bioavailability due to presystemic conjugation and first-pass metabolism is approximately 60%. Concurrent food intake reduces the bioavailability of ethinylestradiol by approximately 25% in some subjects, while the bioavailability remains unchanged in the rest.

Distribution. Ethinylestradiol levels in serum decrease in a biphasic manner, with a terminal phase half-life of approximately 24 hours. Ethinylestradiol is strongly but non-specifically bound to serum albumin (approximately 98.5%) and induces an increase in the concentration of SHBG and CBG in serum. 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 mainly occurs through 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 approximately 5 ml / min / kg.

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

Excretion. Ethinylestradiol is practically not excreted in its unchanged form. 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 achieved in the second half of the application 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, reproductive toxicity studies in animals showed the presence of species-specific embryotoxic and fetotoxic effects. With exposure exceeding that in users of the Drosiphen^®20 drug, some animal species showed an effect on sex differentiation.

Clinical characteristics.

Indications.

Oral contraception.

The decision to prescribe Drosiphen^®20 should be made taking into account the individual risk factors of the patient, in particular the risk factors for venous thromboembolism (VTE). The risk of VTE during treatment with Drosiphen^®20 should also be compared with the risk of VTE during treatment with other combined hormonal contraceptives (CHC) (see sections "Contraindications" and "Special warnings and precautions for use").

Contraindications.

CHC should not be used in the presence of any of the following conditions. If any of these conditions occur for the first time during CHC use, the drug should be discontinued immediately.

· Presence or risk of venous thromboembolism (VTE):

o current VTE, including during anticoagulant therapy, or in history (e.g., deep vein thrombosis or pulmonary embolism);

o inherited or acquired predisposition to venous thromboembolism, including resistance to activated protein C (e.g., factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency;

o major surgical interventions with prolonged immobilization (see section "Special warnings and precautions for 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 presence of arterial thromboembolism at the moment or in history (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);

o cerebrovascular disorders at the moment or in history, presence of prodromal symptoms (e.g., transient ischemic attack (TIA));

o inherited or acquired predisposition to arterial thromboembolism, including hyperhomocysteinemia and antiphospholipid antibodies (antibodies to cardiolipin, 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 with vascular complications;

- severe arterial hypertension;

- severe dyslipoproteinemia.

· Presence of severe liver disease at the moment or in history, until liver function tests have returned to normal.

· Renal failure of severe degree or acute renal failure.

· Presence of liver tumors at the moment or in history (benign or malignant).

· Presence of breast cancer at the moment or in history, which may be hormone-dependent (see section "Special warnings and precautions for use", subsection "Tumors").

· Vaginal bleeding of unknown etiology.

· Concurrent use with drugs containing ombitasvir / paritaprevir / ritonavir and dasabuvir, with drugs containing glecaprevir / pibrentasvir or sofosbuvir / velpatasvir / voxilaprevir (see section "Interactions with other medicinal products and other forms of interaction").

· Hypersensitivity to the active substances or to any of the excipients of the drug.

Interactions with other medicinal products and other forms of interaction.

It is necessary to familiarize yourself with the information about the medicinal product that was used concurrently to identify potential interactions.

Influence of other medicinal products on Drosiphen^®20

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

Therapy

Enzyme induction can be detected as early as a few days of treatment. Maximum enzyme induction is usually observed after several 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 contraceptive method in addition to the combined oral contraceptive (COC). The barrier method should be used throughout the entire period of concomitant therapy and for 28 days after its discontinuation.

If concomitant therapy continues after the end of the last active tablets of the COC in the package, the intake of placebo tablets should be skipped and the intake of active tablets from the next package of the COC should be started.

Long-term treatment

Women with long-term therapy with enzyme-inducing substances are recommended to use a barrier or other reliable non-hormonal contraceptive method.

The following interactions have been reported according to published data

Substances that increase the clearance of COC (decrease the effectiveness of COC due to enzyme induction), such as:

barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; antiretroviral drugs: ritonavir, nevirapine, and efavirenz; as well as possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and herbal preparations containing St. John's wort (Hypericum perforatum).

Substances with an unpredictable effect on COC clearance

When used concurrently with COC, a large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) protease inhibitors, may increase or decrease plasma estrogen or progestin concentrations. The overall effect of such changes may be clinically significant in some cases.

Therefore, when using antiretroviral drugs for HIV / HCV treatment, which are used concurrently, it is necessary to familiarize yourself with the information about the medicinal product and any other recommendations. In case of any doubts, women should additionally use a barrier contraceptive method when taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Substances that decrease the clearance of COC (enzyme inhibitors):

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

Concurrent use of potent CYP3A4 inhibitors may increase plasma estrogen or progestin concentrations, or both.

In a study of multiple doses of a combination of drospirenone (3 mg / day) / ethinylestradiol (0.02 mg / day) with concurrent use of a potent CYP3A4 inhibitor, ketoconazole, for 10 days, the AUC (0-24h) of drospirenone and ethinylestradiol increased 2.7 and 1.4 times, respectively.

When taking etoricoxib at doses of 60 to 120 mg / day with a combined hormonal contraceptive containing 0.035 mg of ethinylestradiol, an increase in plasma ethinylestradiol concentrations was found to be 1.4-1.6 times, respectively.

Influence of Drosiphen^®20 on other medicinal products. Oral contraceptives can affect the metabolism of other active substances. They can change the concentration of active substances in plasma and tissues: increase (e.g., cyclosporine) and decrease (e.g., lamotrigine).

According to in vivo interaction studies conducted in female volunteers who took omeprazole, simvastatin, and midazolam as indicator substrates, the effect of drospirenone at a dose of 3 mg with other medicinal products, the metabolism of which occurs with the participation of cytochrome P450, is unlikely.

Clinical data indicate that ethinylestradiol inhibits the clearance of CYP1A2 substrates, which leads to a weak (e.g., theophylline) or moderate (e.g., tizanidine) increase in their plasma concentrations.

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

Laboratory tests.

The use of COC can affect the results of some laboratory tests, such as biochemical indicators of liver, thyroid, adrenal, and kidney function, as well as the concentration of transport proteins in plasma, such as globulin that binds corticosteroids, and the concentration of lipid / lipoprotein fractions in plasma, indicators of carbohydrate metabolism, coagulation, and fibrinolysis. Such changes are usually within the normal range. Drospirenone increases the activity of renin and aldosterone in plasma, which is induced by its moderate anti-mineralocorticoid activity.

Pharmacodynamic interactions

During clinical trials in patients treated for hepatitis C infections with drugs containing ombitasvir / paritaprevir / ritonavir and dasabuvir, with or without ribavirin, a significant increase in transaminase levels (ALT) was found, which exceeded the upper limit of normal (ULN) 5 times more often in women who used ethinylestradiol-containing drugs, such as combined hormonal contraceptives (CHC). Additionally, an increase in ALT levels was also observed when using antiviral drugs containing glecaprevir / pibrentasvir or sofosbuvir / velpatasvir / voxilaprevir in women who used ethinylestradiol-containing drugs, such as CHC (see sections "Contraindications"). Therefore, patients taking Drosiphen^®20 should switch to an alternative contraceptive method (e.g., progestin-only contraception or non-hormonal contraceptive methods) before starting treatment with these combination drug regimens. Treatment with Drosiphen^®20 can be resumed 2 weeks after the end of treatment with these combination drug regimens.

Special warnings and precautions for use.

In the presence of any of the following conditions / risk factors, the feasibility of using Drosiphen^®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 to discontinue the use of the Drosiphen^®20 drug.

• In case of suspected or confirmed VTE or ATE, the use of the drug should be discontinued. If anticoagulant therapy is started, adequate alternative contraception should be ensured due to the teratogenic effect of anticoagulants (coumarins).

• Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any COC increases the risk of developing venous thromboembolism (VTE) in women who use them compared to those who do not receive them, however, its frequency is less than the frequency associated with pregnancy (60 cases per 100,000 pregnancies). Drugs containing levonorgestrel, norgestrel, or norethindrone are associated with a lower risk of VTE. The use of other drugs, such as Drosiphen^®20, may lead to an increased risk of VTE, which is twice as high. The decision to use drugs other than those with the lowest risk of VTE should be made only after discussing with the woman. It is necessary to make sure that she understands the risk of VTE associated with the use of the Drosiphen^®20 drug compared to other COC, the degree of influence of existing risk factors, and the actions that need to be taken in case of suspected thrombosis.

VTE risk factors

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

It is necessary to pay attention to the increased risk of thromboembolism during pregnancy, especially during the 6 weeks after childbirth (information about pregnancy or breastfeeding is provided in the section "Use during pregnancy or breastfeeding").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

Women are recommended to immediately consult a doctor and report that they are using COC if the following symptoms appear:

Symptoms of deep vein thrombosis (DVT) may be:

- unilateral swelling of the leg and / or foot or along the vein on the leg;

- pain or increased sensitivity in the leg, which can be felt only when standing or walking;

- a feeling of heat in the affected leg; redness or a change in skin color on the leg.

Symptoms of pulmonary embolism (PE) may be:

- sudden shortness of breath of unknown origin or rapid breathing;

- sudden cough, which may be accompanied by hemoptysis;

- sharp chest pain;

- severe dizziness or vertigo;

- rapid or irregular heartbeat.

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

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

If occlusion develops in the retinal veins, the symptoms may vary from painless blurring of vision, which can progress to loss of vision. Sometimes, vision loss develops almost instantly.

Risk of arterial thromboembolism (ATE).

Epidemiological studies have established a link between the use of COC and an increased risk of arterial thromboembolic complications (myocardial infarction) or the risk of cerebrovascular disorders (e.g., transient ischemic attacks, stroke). Cases of arterial thromboembolism can be fatal.

ATE risk factors

Very rare cases of thrombosis of other blood vessels, such as hepatic, renal, mesenteric vessels, cerebral vessels, or retinal vessels, have been reported in women using combined contraceptives, but their connection with COC use has not been proven.

Symptoms of ATE

Women are recommended to immediately consult a doctor and report that they are using COC if the following symptoms appear:

Symptoms of cerebrovascular disorders may be:

- sudden numbness, weakness, or paralysis of the face, arms, or legs, especially unilateral;

- sudden disturbance of gait, dizziness, loss of balance, or coordination;

- sudden confusion, speech or language disorders;

- sudden vision loss in one or both eyes;

- sudden, severe, or prolonged headache without a known cause;

- loss of consciousness or fainting with or without seizures.

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

Symptoms of myocardial infarction (MI) may be:

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

- feeling of discomfort that radiates to the back, jaw, throat, arm, or stomach;

- feeling of fullness in the stomach or digestive disorders;

- excessive sweating, nausea, vomiting, or dizziness;

- severe weakness, anxiety, or irregular heartbeat.

Tumors

The results of some epidemiological studies indicate an additional increase in the risk of cervical cancer with long-term (more than 5 years) use of COC, but this statement is still controversial, since it is not finally clarified how much the results of the studies take into account concomitant risk factors, such as a smear from the cervix and sexual behavior, and other factors, such as human papillomavirus.

Breast cancer. Drosiphen^®20 is contraindicated in women who have or have had breast cancer, as it may be hormone-dependent (see section "Contraindications").

Epidemiological studies have not found a consistent association between the use of combined oral contraceptives (COC) and the risk of breast cancer. The results of studies do not show a link between current or past use of COC and the risk of breast cancer. However, some studies report a slight increase in the risk of breast cancer in those who are currently using or have recently used COC (<6 months from the last use). A meta-analysis of 54 epidemiological studies found a moderate increase in the relative risk (RR = 1.24) of breast cancer in women using COC. This increased risk gradually disappears within 10 years after the end of COC use.

Since breast cancer in women under 40 is rare, the increase in the number of breast cancer diagnoses in women using or recently using COC is negligible compared to the overall risk of breast cancer. The results of the studies do not confirm a causal relationship. The increase in risk may be due to both earlier diagnosis of breast cancer in women using COC and the biological effect of COC, or a combination of both factors. A tendency has been noted that breast cancer detected in women who have ever taken COC is clinically less severe than in those who have never taken COC.

In isolated cases, benign and, less often, malignant liver tumors have been observed in women using COC. In some cases, these tumors caused life-threatening intra-abdominal bleeding. If complaints of severe pain in the epigastric region, liver enlargement, or signs of intra-abdominal bleeding appear during COC use, liver tumor should be considered in the differential diagnosis in women taking COC.

When using COC in higher doses (50 μg of ethinylestradiol), the risk of endometrial and ovarian cancer is reduced. The hypothesis that similar trends may apply to low-dose COC still needs to be confirmed.

Other conditions

The progestin component in Drosiphen^®20 is an aldosterone antagonist with potassium-sparing properties. In most cases, an increase in potassium levels is not expected. However, in a clinical study, in some patients with mild or moderate renal impairment and concurrent use of potassium-sparing drugs, the level of potassium in serum slightly, but not significantly, increased during drospirenone use. Therefore, it is recommended to check the potassium level in serum during the first cycle of treatment in patients with renal impairment and pre-treated hyperkalemia.

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

Although a slight increase in blood pressure has been observed in many women taking COC, clinically significant hypertension has been reported rarely. Only in rare cases is it necessary to discontinue COC use. If, during COC use, a woman with previously existing arterial hypertension has consistently elevated blood pressure values or a significant increase in blood pressure that does not adequately respond to hypotensive therapy, COC use should be discontinued. If necessary, COC use can be continued if, with the help of hypotensive therapy, normal blood pressure values are achieved.

There have been reports of the occurrence or exacerbation of the following conditions during pregnancy and COC use, but their connection with COC use has not been finally clarified: jaundice and / or itching associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham's chorea; herpes during pregnancy; hearing loss associated with otosclerosis.

Exogenous estrogens can cause or exacerbate symptoms of hereditary and acquired angioedema.

In case of acute or chronic liver function disorders, it may be necessary to discontinue COC use until liver function tests return to normal. In case of recurrent cholestatic jaundice, which first occurred during pregnancy or with previous use of sex hormones, COC use should be discontinued.

Although COC can affect peripheral insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen for women with diabetes who take low-dose COC (containing <0.05 mg of ethinylestradiol). However, women with diabetes should be under constant careful supervision throughout the entire period of COC use.

There have also been reports of worsening of the condition in epilepsy, Crohn's disease, and ulcerative colitis during COC use.

Mood changes and depression are well-known side effects of hormonal contraceptives (see section "Adverse reactions"). Depression can be severe, and this is a known risk factor for suicidal behavior and suicide. Women should consult a doctor if they experience mood changes and symptoms of depression, including soon after starting treatment.

Sometimes, chloasma may occur, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid prolonged exposure to direct sunlight or ultraviolet radiation during COC use.

Drosiphen^®20 contains lactose. Therefore, it should not be prescribed to patients with rare hereditary intolerance to galactose, hereditary lactase deficiency, or glucose-galactose malabsorption syndrome. If a lactose-free diet is followed, the amount of lactose in the drug should be taken into account.

The placebo tablets contain less than 1 mmol (23 mg) of sodium per tablet, which means they are almost sodium-free.

Medical examination / consultation.

Before starting or resuming Drosiphen^®20, it is recommended to collect a complete medical history (including family history) and rule out pregnancy. It is necessary to measure blood pressure and conduct a medical examination, taking into account contraindications (see section "Contraindications") and precautions (see section "Special warnings and precautions for use"). The woman's attention should be drawn to the information about venous and arterial thrombosis, including the risk associated with the use of Drosiphen^®20 compared to other COC, the symptoms of VTE and ATE, known risk factors, and the actions that need to be taken in case of suspected thrombosis.

The woman should carefully read the instructions for medical use and follow the given recommendations. The frequency and content of examinations should be based on established practical recommendations and adapted to the needs of a specific patient.

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

Reduced efficacy.

The efficacy of COC may be reduced in case of missed intake of active tablets (see section "Method of administration and dosage"), gastrointestinal disorders during the intake of active tablets (see section "Method of administration and dosage"), or when using other medicinal products concurrently (see section "Interactions with other medicinal products and other forms of interaction").

Disorders of the cycle.

When taking all COC, irregular bleeding (spotting or breakthrough bleeding) may be observed, especially during the first few months. Therefore, such bleeding can be considered significant only after three menstrual cycles of the adaptation period.

If irregular bleeding persists or appears after a period of regular cycles, it is necessary to consider non-hormonal causes of bleeding and take appropriate diagnostic measures, including examination to rule out the presence of tumors and pregnancy. Diagnostic measures can include curettage.

In some women, withdrawal bleeding may not occur during the placebo period.

If COC is taken according to the instructions in the section "Method of administration and dosage", the occurrence of pregnancy is unlikely. However, if COC use was not in accordance with the instructions before the first withdrawal bleeding or if withdrawal bleeding is absent for two cycles, it is necessary to rule out pregnancy before continuing COC use.

Use during pregnancy or breastfeeding.

The use of Drosiphen^®20 during pregnancy is contraindicated.

If pregnancy occurs during Drosiphen^®20 use, the drug should be discontinued immediately. The results of numerous epidemiological studies have not found an increased risk of congenital malformations in children whose mothers took COC before pregnancy or an teratogenic effect when COC was accidentally taken during pregnancy.

Animal studies have shown the presence of undesirable effects during pregnancy and breastfeeding. Based on these animal studies, it cannot be excluded that there may be undesirable effects due to the hormonal action of the active substances. However, the overall experience of COC use during pregnancy does not indicate a negative effect in humans.

The available data on the use of Drosiphen^®20 during pregnancy are too limited to draw conclusions about the negative impact of the drug on the course of pregnancy, the health of the fetus, and the newborn. Currently, there are no relevant epidemiological data.

When resuming Drosiphen^®20, it is necessary to take into account the increased risk of VTE in the postpartum period (see sections "Method of administration and dosage" and "Special warnings and precautions for use").

Breastfeeding period.

COC may affect breastfeeding, as they can reduce the amount of breast milk and change its composition. Given this, COC is not recommended until the end of breastfeeding. Small amounts of contraceptive steroids and / or their metabolites may pass into breast milk during COC use. These amounts may affect the child.

Ability to affect the reaction rate when driving vehicles or working with other mechanisms.

No studies have been conducted on the effect on the reaction rate when driving vehicles or working with other mechanisms. No effects of COC on the ability to drive a car or work with other mechanisms have been reported.

Method of administration and dosage.

Method of administration

Oral administration

Dosage

How to take the Drosiphen^®20 drug

Tablets should be taken daily at approximately the same time, if necessary, with a small amount of liquid, in the sequence indicated on the blister pack. Take 1 tablet per day for 28 days in a row, without interruption. The intake of tablets from each subsequent pack should start on the next day after the end of the previous pack. Withdrawal bleeding usually occurs on the 2nd-3rd day after starting the intake of placebo tablets and does not necessarily end before starting a new pack.

How to start taking the Drosiphen^®20 drug

If hormonal contraceptives were not used in the previous period (last month). The intake of tablets should start on the first day of the menstrual cycle (i.e., on the first day of menstrual bleeding).

Switching from another combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring, or transdermal patch). It is desirable to start taking the tablets of the Drosiphen^®20 drug on the next day after taking the last hormonally active tablet of the previous COC, but not later than the next day after the end of the tablet-free period or the intake of placebo tablets of the previous COC. When switching from a vaginal ring or transdermal patch, the intake of the Drosiphen^®20 drug should start on the day of removal of the previous device, but not later than the day when the next application of these devices is required.

Switching from a method based on the use of only progestin ("mini-pill", injections, implants) or an intrauterine system with progestin. You can start taking the drug on any day after stopping the "mini-pill" (in the case of an implant or intrauterine system, on the day of their removal, in the case of injections, instead of the next injection). However, in all cases, it is recommended to use a barrier method of contraception additionally during the first 7 days of taking the drug.

After an abortion in the I trimester of pregnancy. The use of the drug should start on the day of the operation. In this case, there is no need to use additional contraceptive methods.

After childbirth or abortion in the II trimester of pregnancy.

It is necessary to start taking the drug from the 21st to 28th day after childbirth or abortion in the II trimester of pregnancy. If the intake starts later, it is recommended to use a barrier method of contraception additionally during the first 7 days of taking the tablets. However, if sexual intercourse has already occurred, it is necessary to exclude the possibility of pregnancy or wait for the first menstruation.

If the woman is breastfeeding - see the section "Use during pregnancy or breastfeeding".

Missed tablet intake.

A missed placebo tablet can be skipped. However, they must be removed from the package to avoid accidental prolongation of the placebo phase. The instructions below apply only to missed active tablets.

If the delay in taking a tablet does not exceed 24 hours, the contraceptive effect of the drug is not reduced. The missed tablet should be taken as soon as possible. The next tablet from this package should be taken at the usual time.

If the delay in taking a missed tablet exceeds 24 hours, the contraceptive protection may be reduced. In this case, you should follow two basic rules:

1. The recommended pause in taking hormone-containing tablets should last 4 days, and the pause in taking tablets should never exceed 7 days.

2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved by continuous intake of tablets for 7 days.

Accordingly, the following recommendations should be followed:

Days 1-7

The last missed tablet should be taken as soon as the woman remembers, even if it means taking two tablets at the same time. Then, the tablets should be continued at the usual time. Additionally, a barrier method of contraception should be used for the next 7 days. If sexual intercourse occurred in the previous 7 days, the possibility of pregnancy should be considered.

Days 8-14

The last missed tablet should be taken as soon as the woman remembers, even if it means taking two tablets at the same time. Then, the tablets should be continued at the usual time. If the woman has been taking the tablets correctly for 7 days before the first missed tablet, there is no need to use additional contraceptive methods. However, if more than one tablet is missed, it is recommended to use a barrier method of contraception for the next 7 days.

Days 15-24

The likelihood of a decrease in contraceptive efficacy is significant due to the approaching placebo phase. However, if the intake schedule is followed, it is possible to avoid a decrease in contraceptive protection. If one of the following instructions is followed, there will be no need to use additional contraceptive methods, provided that the tablets were taken correctly for 7 days before the first missed tablet. If this is not the case, it is recommended to follow the first of the following instructions and use additional contraceptive methods for the next 7 days.

1. The last missed tablet should be taken as soon as the woman remembers, even if it means taking two tablets at the same time. Then, the tablets should be continued at the usual time until the end of the active tablets. The 4 placebo tablets should not be taken. It is necessary to start taking the active tablets from the next blister pack immediately. It is unlikely that the woman will experience withdrawal bleeding until the end of the active tablets from the second pack, although there may be spotting or breakthrough bleeding.

2. The intake of active tablets from the current package should be stopped. Instead of active tablets, placebo tablets should be taken for 4 days, including the days of missed tablets, and then the intake of tablets from the next blister pack should be started.

If, after missing tablets, withdrawal bleeding is absent during the placebo period, the possibility of pregnancy should be considered.

Recommendations in case of gastrointestinal disorders.

In case of severe gastrointestinal disorders (e.g., vomiting, diarrhea), incomplete absorption of the drug may occur. In this case, additional contraceptive methods should be used. If vomiting occurs within 3-4 hours after taking an active tablet, it is necessary to take another (replacement) tablet (from another package) as soon as possible. The next tablet should be taken within 24 hours of the usual time of intake. If more than 24 hours have passed, the rules specified in the section "Missed tablet intake" above should be followed.

How to postpone withdrawal bleeding.

To delay the start of withdrawal bleeding, you should continue taking the Drosiphen^®20 drug from the next blister pack without taking the placebo tablets from the current package. If desired, the intake period can be extended until the end of the active tablets from the second package. During this time, spotting or breakthrough bleeding may occur. The regular intake of Drosiphen^®20 should be resumed after taking the placebo tablets.

To change the day of withdrawal bleeding to another day of the week, it is recommended to shorten the placebo phase by the desired number of days. The shorter the pause, the higher the risk of absence of withdrawal bleeding and the occurrence of breakthrough bleeding or spotting during the intake of tablets from the next package (as in the case of delaying withdrawal bleeding).

Additional information for special populations.

Elderly patients

Drosiphen^®20 is not indicated after menopause.

Patients with impaired liver function

Drosiphen^®20 is contraindicated in women with severe liver diseases. See also sections "Contraindications" and "Pharmacokinetics".

Patients with impaired renal function

Drosiphen^®20 is contraindicated in women with severe renal impairment or acute renal failure. See also sections "Contraindications" and "Pharmacokinetics".

Children.

The drug is indicated for use on the prescription of a doctor only after the onset of regular menstruation.

Overdose

To date, there is no data on overdose with Drosphiphem^®20 tablets. As general experience with the use of COCs suggests, in case of overdose, nausea, vomiting, and slight vaginal bleeding may occur in young girls. There is no specific antidote, and treatment should be symptomatic.

Adverse Reactions

Serious adverse reactions associated with the use of COCs are also described in the "Special Instructions" section. The following adverse reactions were observed with the use of Drosphiphem^®20.

The table below lists adverse reactions by system organ class and frequency. Frequency is based on clinical trial data. The most acceptable MedDRA terms are used to describe specific reactions and their synonyms and related conditions.

*Irregular bleeding usually disappears with continued therapy.

Description of Individual Adverse Reactions

In women taking COCs, an increased risk of venous and arterial thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism, has been observed, which are described in more detail in the "Special Instructions" section.

The following serious adverse reactions have been reported in women using COCs (see also "Special Instructions"):

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumors;
• development or exacerbation of diseases whose connection with COC use has not been finally clarified: Crohn's disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes during pregnancy, Sydenham's chorea, hemolytic-uremic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic liver function disorders that may require discontinuation of COC use until liver function tests return to normal.

The frequency of breast cancer diagnosis is slightly increased among women using COCs. Since breast cancer in women under 40 is rare, the increase in the number of breast cancer diagnoses in women using or recently using COCs is small compared to the overall risk of breast cancer. The connection to COC use is unknown. See also "Contraindications" and "Special Instructions".

Interactions

Breakthrough bleeding and/or decreased contraceptive effectiveness may occur due to the interaction of other medications (enzyme inducers) with COCs (see "Interaction with Other Medicinal Products and Other Types of Interactions").

Postmarketing Data

According to the results of five studies comparing the risk of breast cancer in those who have ever taken or are taking COCs and those who have never taken COCs, no connection was found between COC use and the risk of breast cancer, with effect estimates of 0.90-1.12.

Corresponding studies of breast cancer risk with combined oral contraceptives

In three studies, the risk of breast cancer was compared in those taking COCs at the time of the study or recently (<6 months since last use) and those who never took COCs. One of these studies reported no connection between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19-1.33 with current or recent COC use. Both of these studies found an increased risk of breast cancer with prolonged use at the time of the study, with the relative risk ranging from 1.03 with less than 1 year of use to approximately 1.4 with more than 8-10 years of use.

Reporting Suspected Adverse Reactions

Reporting suspected adverse reactions during postmarketing surveillance is very important. This allows for monitoring the benefit-risk ratio of medicinal products. Healthcare professionals are encouraged to report any suspected adverse reactions using the national reporting system.

Shelf Life

4 years.

Storage Conditions

Store in a place inaccessible to children in the original packaging at a temperature not exceeding 30 °C.

Packaging

28 tablets in a blister pack (24 active tablets + 4 placebo tablets); 1, 3, or 6 blister packs in a carton.

Release Category

Prescription only.

Manufacturer

Mibe GmbH Arzneimittel.

Manufacturer's Location and Address

Münchener Straße 15, Brena, Saxony-Anhalt, 06796, Germany.