Midiana, 21 pcs., 3 mg+30 mcg, film-coated tablets

Midiana®

If any of the conditions, diseases or risk factors listed below currently exist, the potential risks and expected benefits of using COCs, including the combination of drospirenone + ethinyl estradiol, should be carefully weighed in each individual case and discussed with the woman before starting to take the drug. If any of these conditions, diseases or risk factors worsen, intensify or appear for the first time, a woman should consult her doctor to decide whether to stop taking the drug.

Risk of developing VTE and ATE

The results of epidemiological studies indicate a relationship between the use of COCs and an increased incidence of venous and arterial thrombosis and thromboembolism (such as DVT, PE, myocardial infarction, cerebrovascular disorders). These diseases are rarely reported.

The increased risk of developing VTE associated with the use of COCs is due to the presence of estrogen in its composition.

Drugs containing levonorgestrel, norgestimate, or norethisterone as a progestogen component are associated with the lowest risk of VTE.

When using other COCs, such as the combination of drospirenone + ethinyl estradiol, the risk of developing VTE is twice as high. The choice of a COC with a higher risk of VTE should only be made after consultation with the woman to ensure that she fully understands the risk of VTE associated with the contraceptive, the effect of the drug on her existing risk factors and that the risk of developing VTE maximum in the first year of taking such drugs. An increased risk is also observed when COC use is resumed (after a break between doses of the drug of 4 weeks or more). The increased risk of developing VTE is present primarily during the first 3 months.

VTE can be life-threatening or lead to death (in 1-2% of cases). VTE, manifested as DVT and/or PE, can occur with all COCs.

It is extremely rare when using COCs that thrombosis of other blood vessels occurs, for example, hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels.

Symptoms of DVT:

unilateral swelling of the lower limb or along the vein, pain or discomfort only in an upright position or when walking, local increase in temperature, redness or discoloration of the skin in the affected lower limb.

Symptoms of pulmonary embolism:

difficulty or rapid breathing; sudden cough, including with hemoptysis; sharp pain in the chest, which may intensify with deep inspiration; sense of anxiety; severe dizziness; fast or irregular heartbeat. Some of these symptoms (eg, shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more common and less severe conditions (eg, respiratory tract infection).

ATE can lead to stroke, vascular occlusion, or myocardial infarction.

Symptoms of a stroke:

sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, severe or prolonged headache for no apparent reason, unilateral or bilateral loss of vision; problems with speech and understanding; sudden disturbance in gait, dizziness, loss of balance or coordination; sudden loss of consciousness or fainting with or without a seizure.

Other signs of vascular occlusion:

sudden pain, swelling and slight cyanosis of the extremities, “acute” abdomen.

Symptoms of myocardial infarction:

pain, discomfort, pressure, heaviness, a feeling of compression or fullness in the chest or behind the sternum, radiating to the back, jaw, upper limb, epigastric region; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; fast or irregular heartbeat. ATE can be life-threatening and lead to death.

In women with a combination of several risk factors or high severity of one of the factors, the possibility of their mutual reinforcement should be considered. In such cases, the degree of increase in risk may be higher than with a simple summation of factors. In this case, the combination of drospirenone + ethinyl estradiol is contraindicated.

The risk of developing thrombosis (venous and/or arterial) and thromboembolism or cerebrovascular disorders increases:

-with age;

- in women who smoke (with an increase in the number of cigarettes or an increase in age, the risk increases, especially over the age of 35);

- if there is a family history (for example, VTE or ATE in close relatives or parents aged less than 50 years). In the case of a hereditary or acquired predisposition, the woman should be examined by an appropriate specialist to decide on the possibility of taking COCs;

- for obesity (with a BMI more than 30 kg/m2);

- with dyslipoproteinemia;

- for arterial hypertension;

- for migraine;

- for diseases of the heart valves;

- with atrial fibrillation;

- in case of prolonged immobilization, serious surgery, any operation on the lower extremities, in the pelvic area or extensive trauma. In these cases, the use of COCs should be stopped (in the case of planned surgery, at least four weeks before it) and not resumed for two weeks after the woman has fully regained mobility.

Temporary immobilization (eg, air travel lasting more than 4 hours) may also be a risk factor for the development of VTE, especially in the presence of other risk factors.

The possible role of varicose veins and thrombophlebitis of superficial veins in the development of VTE remains controversial.

The increased risk of thromboembolism in the postpartum period should be taken into account.

Peripheral circulatory disorders may also occur in diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell anemia.

An increase in the frequency and severity of migraine (which may precede cerebrovascular events) during the use of COCs is grounds for immediate discontinuation of these drugs.

Biochemical indicators indicating a hereditary or acquired predisposition to the development of venous or arterial thrombosis include: resistance to activated protein C, hyperhomocysteipemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When assessing the risk-benefit ratio, it should be taken into account that adequate treatment of the relevant condition/disease may reduce the associated risk of thrombosis.

Tumors

The most significant risk factor for the development of cervical cancer (CC) is persistent human papillomavirus infection. There are reports of a slight increase in the risk of developing CC with long-term use of COCs. However, the connection with taking COCs has not been proven. Controversy remains regarding the extent to which these findings are related to screening for cervical pathology or to sexual behavior patterns (less use of barrier methods of contraception, greater number of sexual partners).

A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of developing breast cancer diagnosed in women currently taking COCs (relative risk 1.24). The increased risk gradually disappears within 10 years of stopping these drugs. Due to the fact that breast cancer is rare in women under 40 years of age, the increase in the incidence of breast cancer in women who are currently taking COCs or have recently taken it is insignificant in relation to the overall risk of this disease. Its connection with COC use has not been proven. The observed increase in risk may also be a consequence of earlier diagnosis of breast cancer in women using COCs (they are diagnosed with earlier clinical forms of breast cancer than women not taking COCs), the biological effects of COCs, or a combination of both of these factors.

In rare cases, during the use of COCs, the development of benign, and in extremely rare cases, malignant liver tumors, which in some cases led to life-threatening intra-abdominal bleeding, was observed. In case of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding, this should be taken into account when making a differential diagnosis.

Other states

Depressed mood and depression are known adverse reactions when using hormonal contraceptives. Depression can be a serious disorder and is a known risk factor for suicidal behavior and suicide. Women should be advised to contact their doctor if mood changes or depressive symptoms occur, including soon after starting treatment.

Drospirenone is an aldosterone antagonist with potassium-sparing properties. In most cases, there should be no increase in plasma potassium concentration. In clinical studies in some patients with mild to moderate renal impairment and concomitant use of potassium-sparing drugs, plasma potassium concentrations were slightly increased while taking drospirenone. Therefore, it is necessary to monitor the concentration of potassium in the blood plasma during the first cycle of taking the drug in patients with renal failure and when the initial potassium concentration is at the upper limit of normal, especially when taking potassium-sparing drugs concomitantly.

In women with hypertriglyceridemia (or a family history of this condition), the risk of developing pancreatitis may increase while taking COCs. Although slight increases in blood pressure (BP) have been described in many women taking COCs, clinically significant increases have rarely been reported. However, if a persistent clinically significant increase in blood pressure develops while using a COC, the COC should be discontinued and treatment of arterial hypertension should be initiated. COC use can be continued if normal blood pressure values ​​are achieved with antihypertensive therapy.

The following conditions have been reported to develop or worsen both during pregnancy and while taking COCs, but their relationship with COC use has not been proven: cholestatic jaundice and/or pruritus associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; chorea; herpes during pregnancy; hearing loss associated with otosclerosis. Cases of Crohn's disease and ulcerative colitis have also been described with the use of COCs.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

Acute or chronic liver dysfunction may require discontinuation of COCs until liver function tests return to normal. Recurrence of cholestatic jaundice, which developed for the first time during a previous pregnancy or previous use of sex hormones, requires discontinuation of COC use.

Although COCs may have an effect on insulin resistance and glucose tolerance, in patients with diabetes mellitus using low-dose COCs, as a rule, no dose adjustment of hypoglycemic drugs is required. However, women with diabetes mellitus should be carefully monitored while taking COCs.

Chloasma can sometimes develop, especially in women with a history of pregnancy chloasma. Women with a tendency to chloasma should avoid prolonged exposure to the sun and exposure to ultraviolet radiation while taking COCs.

Effect on liver function tests

In clinical studies involving patients receiving hepatitis C viral therapy (a combination of drugs containing ombitasvir, paritaprevir, ritonavir, dasabuvir, with or without ribavirin), increases in ALT activity more than 5 times the upper limit of normal were recorded more often in patients using ethynyl-containing COCs.

If a course of therapy with this combination of drugs is necessary, a patient using the combination of drospirenone + ethinyl estradiol should be switched to alternative methods of contraception (non-hormonal or progestogen-only contraceptives) before starting treatment. You can resume taking the combination of drospirenone + ethinyl estradiol no earlier than 2 weeks after the end of the course of therapy with antiviral drugs.

Laboratory tests

The use of drugs such as drospirenone + ethinyl estradiol may affect the results of some laboratory tests, including biochemical indicators of liver, thyroid, kidney and adrenal function, the concentration of transport proteins in the blood plasma (for example, transcortin, lipid / lipoprotein fractions, parameters of carbohydrate metabolism, coagulation and fibrinolysis). These changes usually remain within normal physiological values.

Drospirenone increases plasma renin activity and aldosterone concentrations, which is associated with its antimineralocorticoid effect.

Reduced efficiency

The effectiveness of COCs may be reduced in the following cases: in case of missed pills, gastrointestinal disorders or as a result of drug interactions.

Effect on bleeding pattern

While taking COCs, irregular bleeding may occur (“spotting” and/or “breakthrough” bleeding), especially during the first months of use. Therefore, any irregular bleeding should be assessed only after an adaptation period of approximately three drug cycles.

If irregular bleeding recurs or develops after previous regular cycles, careful evaluation should be performed to rule out malignancy or pregnancy.

Some women may not develop withdrawal bleeding during a break from taking the pills; pregnancy should be ruled out before continuing to take it.

Medical examinations

Before starting or resuming taking the drug drospirenone + ethinyl estradiol, it is necessary to familiarize yourself with the woman’s life history and family history, conduct a thorough general medical examination (including measuring blood pressure, determining BMI) and gynecological examination (with mandatory examination of the mammary glands and cytological examination of the cervical epithelium), and exclude pregnancy. The scope of additional studies and the frequency of follow-up examinations are determined individually. Typically, follow-up examinations should be carried out at least once every 6 months.

It must be remembered that the drug does not protect against HIV infection (AIDS) and other sexually transmitted diseases!

You should stop taking the tablets and consult your doctor immediately if there are possible signs of thrombosis, myocardial infarction or stroke: unusual cough; unusually severe pain behind the sternum, radiating to the left arm; unexpected shortness of breath, unusual, severe and prolonged headache or migraine attack; partial or complete loss of vision or double vision; slurred speech; sudden changes in hearing, smell, or taste; dizziness or fainting; weakness or loss of sensation in any part of the body; severe abdominal pain; severe pain in the lower limb or sudden swelling of any of the lower limbs.

Midiana

Use during pregnancy and breastfeeding

During pregnancy and lactation, the use of Midiana® is contraindicated.
If pregnancy occurs while taking hormonal contraception, immediate discontinuation of the drug is necessary. The limited available data on unintentional use of combined oral contraceptives suggests no teratogenic effect and an increased risk for children and women during childbirth.

Combined oral contraceptives affect lactation and can reduce the amount and change the composition of breast milk. Small amounts of hormonal contraceptives or their metabolites are found in milk during hormonal contraception and may affect the baby. The use of combined oral contraceptives is possible after complete cessation of breastfeeding.

special instructions

If any of the conditions/risk factors listed below currently exist, the potential risks and expected benefits of using a combined oral contraceptive should be carefully weighed on an individual basis and discussed with the woman before she decides to start taking the drug. If any of these conditions or risk factors worsen, intensify, or appear for the first time, a woman should consult her doctor, who may decide whether it is necessary to discontinue the combined oral contraceptive.

Circulatory system disorders

The incidence of venous thromboembolism (VTE) when using low-dose estrogen combination oral contraceptives (<50 mcg ethinyl estradiol, such as Midiana®) is approximately 20 to 40 cases per 100,000 women per year, which is slightly higher than in women not using hormonal contraceptives (5 to 10 cases per 100,000 women), but lower than in women during pregnancy (60 cases per 100,000 pregnancies).

An additional risk of VTE is observed during the first year of combined oral contraceptive use. VTE is fatal in 1-2% of cases.

Epidemiological studies have also found an association between combined oral contraceptive use and an increased risk of arterial thromboembolism. Extremely rare cases of thrombosis of other blood vessels, for example, hepatic, mesenteric, renal, cerebral and retinal vessels, both arteries and veins, have been described in patients taking oral hormonal contraceptives. The cause-and-effect relationship between the occurrence of these side effects and the use of combined oral contraceptives has not been proven.

Symptoms of venous or arterial thrombosis/thromboembolism or cerebrovascular disease may include:

• unusual unilateral pain and/or swelling of the limb;
• sudden severe chest pain, with or without radiation to the left arm;
• sudden shortness of breath;
• sudden attack of coughing;
• any unusual, severe, prolonged headache;
• sudden partial or complete loss of vision;
• diplopia;
• slurred speech or aphasia;
• dizziness;
• loss of consciousness with or without a seizure;
• weakness or very significant loss of sensation that suddenly appeared on one side or in one part of the body;
• movement disorders;
• symptom complex “acute abdomen”.

The risk of complications associated with VTE when taking a combined oral contraceptive increases:

• with age;
• in the presence of a family history (venous or arterial thromboembolism in close relatives or parents at a relatively young age); if a hereditary predisposition is suspected, the woman needs to consult a specialist before prescribing a combined oral contraceptive;
• after prolonged immobilization, major surgery, any leg surgery or major trauma. In these situations, it is recommended to stop taking the drug (in the case of planned surgery, at least four weeks before it) and not to resume taking it for two weeks after the end of immobilization. Additionally, antithrombotic therapy may be prescribed if oral hormonal contraceptives have not been discontinued within the recommended time frame;
• for obesity (BMI more than 30 mg/m2).

The risk of arterial thrombosis and thromboembolism increases when taking a combined oral contraceptive:

• with age;
• in smokers (women over 35 years of age are strictly not recommended to smoke if they want to use combined oral contraceptives);
• with dyslipoproteinemia;
• with arterial hypertension;
• for migraines;
• for diseases of the heart valves;
• with atrial fibrillation.

The presence of one of the serious risk factors or multiple risk factors for arterial or venous disease, respectively, may be a contraindication.

Women using combined oral contraceptives should contact their doctor immediately if symptoms of possible thrombosis occur. In cases of suspected or confirmed thrombosis, the combined oral contraceptive should be discontinued. It is necessary to select an adequate method of contraception due to the teratogenicity of anticoagulant therapy (coumarins).

The increased risk of thromboembolism in the postpartum period should be taken into account.

Other diseases that are associated with severe vascular pathology include diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis), and sickle cell disease.

An increase in the frequency and severity of migraine during use of combined oral contraceptives (which may precede cerebrovascular events) may be grounds for immediate discontinuation of these drugs.

Tumors

The most significant risk factor for developing cervical cancer is infection with the human papillomavirus. Some epidemiological studies have reported an increased risk of cervical cancer with long-term use of combined oral contraceptives, but there remains controversy regarding the extent to which these findings are attributable to confounding factors such as testing for cervical cancer or use of barrier methods of contraception.

A meta-analysis of 54 epidemiological studies demonstrated that there is a slightly increased relative risk (RR=1.24) of developing breast cancer diagnosed in women who were using combined oral contraceptives at the time of the study. The excess risk decreases gradually over 10 years after stopping combined oral contraceptives. Because breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnosed in recent years in women taking or taking combined oral contraceptives is small relative to the overall risk of developing breast cancer. These studies do not support a causal relationship between combined oral contraceptives and breast cancer. The observed increased risk may be due to earlier diagnosis of breast cancer in women using combined oral contraceptives, a biological effect of combined oral contraceptives, or a combination of both. Breast tumors in women who had ever taken combined oral contraceptives were clinically less severe than in women who had never taken them.

In rare cases, the development of benign liver tumors has been observed during the use of combined oral contraceptives, and in even more rare cases, malignant ones. In some cases, these tumors caused life-threatening intra-abdominal bleeding. In the differential diagnosis of a liver tumor, it should be taken into account when a woman taking combined oral contraceptives experiences severe pain in the upper abdomen, liver enlargement, or signs of intra-abdominal bleeding.

Other states

The progesterone component in Midiana® is an aldosterone antagonist with the property of retaining potassium. In most cases, there is no increase in potassium concentration. However, in a clinical study in some patients with mild to moderate renal impairment and concomitantly prescribed potassium-retaining medications, serum potassium concentrations were slightly increased when taking drospirenone. Therefore, it is recommended to check the serum potassium concentration in the first cycle of dosing in patients with renal failure and pre-treatment potassium concentration values ​​for ULN, as well as during concomitant use of drugs that retain potassium in the body.

In women with hypertriglyceridemia or a family history of hypertriglyceridemia, an increased risk of pancreatitis cannot be excluded when taking combined oral contraceptives. Although slight increases in blood pressure have been described in many women taking combined oral contraceptives, clinically significant increases have rarely been reported. Only in rare cases is it necessary to immediately stop taking combined oral contraceptives. If, while taking combined oral contraceptives in patients with arterial hypertension, blood pressure values ​​are constantly elevated or do not decrease when taking antihypertensive drugs, the use of combined oral contraceptives should be stopped. If necessary, combined oral contraceptives can be continued if normal blood pressure values ​​are achieved with antihypertensive therapy.

The following conditions develop or worsen both during pregnancy and when taking combined oral contraceptives, but their relationship with taking combined oral contraceptives has not been proven: jaundice and/or itching associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham's chorea; history of herpes during pregnancy; hearing loss associated with otosclerosis.

In women with hereditary angioedema, exogenous estrogens may cause or worsen symptoms of angioedema. For acute or chronic liver dysfunction, it may be necessary to discontinue use of combined oral contraceptives until liver function tests return to normal. Recurrent cholestatic jaundice and/or itching caused by cholestasis, which develops for the first time during pregnancy or previous use of sex hormones, requires discontinuation of combined oral contraceptives.

Although combined oral contraceptives may have an effect on peripheral insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in diabetic patients using low-dose combined oral contraceptives (containing <50 mcg ethinyl estradiol). However, women with diabetes should be closely monitored by a doctor, especially when starting to take combined oral contraceptives.

An increase in endogenous depression, epilepsy, Crohn's disease and ulcerative colitis has also been reported with the use of combined oral contraceptives. Chloasma can sometimes develop, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid prolonged exposure to the sun and ultraviolet radiation while taking combined oral contraceptives.

1 tablet contains 48.17 mg of lactose. Patients with hereditary galactose intolerance, lactase deficiency or glucose/galactose malabsorption who are on a lactose-free diet should not take the drug.

Medical examination

Before starting to use hormonal contraceptives, you must consult with your gynecologist and undergo an appropriate medical examination. Further observation and frequency of medical examinations are carried out on an individual basis, but at least once every 6 months.

STDs and HIV infection

Midiana®, like other combined oral contraceptives, does not protect against HIV infection and other sexually transmitted diseases.

Reduced efficiency

The effectiveness of combined oral contraceptives may be reduced if pills are missed, gastrointestinal disorders occur, or if other medications are taken at the same time.

Reduced cycle control

While taking combined oral contraceptives, irregular bleeding (spotting or breakthrough uterine bleeding) may occur, especially during the first months of use. Therefore, assessing any irregular bleeding is only meaningful after an adaptation period of approximately 3 cycles.

If irregular bleeding recurs or develops after previous regular cycles, non-hormonal causes should be considered and adequate diagnostic measures taken to exclude malignancy or pregnancy. These may include diagnostic curettage.

Some women may not develop withdrawal bleeding during a break from combined oral contraceptives. If combined oral contraceptives are taken according to the instructions for taking the drug, then pregnancy is unlikely. However, if combined oral contraceptives have not previously been taken regularly or if there are no consecutive withdrawal bleeds, pregnancy should be ruled out before continuing to take combined oral contraceptives.

Impact on the ability to drive vehicles and operate machinery

There have been no studies examining the effect of the drug on driving ability.

Instructions for use MIDIANA®

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

In case of worsening of the condition or the first identified episode of any of these conditions or risk factors, the woman should be notified of the need to contact her doctor to decide on the further use of Midiana®.

Risk of venous thromboembolism (VTE)

The use of any combined hormonal contraceptive increases the risk of developing VTE compared to no treatment. Drugs containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. For other drugs, for example, Midiana®, this risk may be 2 times higher. The decision to use a drug that does not belong to the group of drugs with the lowest risk of developing VTE should be made only after discussing with the woman in a form accessible to her the risk of VTE while using the drug Midiana®, the influence of her existing risk factors on the level of this risk and notifications that the risk of VTE is highest in the first year of use of the drug. There is evidence that the risk increases when combined hormonal contraceptives are reused after a break of 4 weeks or more.

Among women not using combined hormonal contraceptives and who are not pregnant, the incidence of VTE is approximately 2 cases per 10,000 women per year. However, any individual woman may have a significantly higher risk level, depending on her underlying risk factors.

The estimated incidence1 of VTE among women using combined hormonal contraceptives containing drospirenone is 9–12 cases per 10,000 women per year, which is comparable to 62 cases in women using combined hormonal contraceptives containing levonorgestrel.

In both cases, the reported number of VTE cases per year is less than the expected number of cases during pregnancy or the postpartum period.

In 1-2% of cases, VTE is fatal.

Among women using combined hormonal contraceptives, extremely rare cases of thrombosis of other blood vessels, such as the hepatic, mesenteric, renal or retinal veins and arteries, have been described.

1 Incidence rates were derived from a pool of data from epidemiological studies using relative risks for different drugs compared with levonorgestrel-containing combined hormonal contraceptives.

2 The median range of 5–7 cases per 10,000 women is based on a relative risk of approximately 2.3–3.6 for combined hormonal contraceptives containing levonorgestrel compared with non-drug-related events.

Risk factors for developing VTE

When using combined hormonal contraceptives, the risk of developing venous thromboembolic complications may be significantly increased in women with additional risk factors, especially those with multiple risk factors (see Table 1).

Midiana® is contraindicated in women with multiple risk factors that place her at high risk of developing venous thrombosis. If a woman has multiple risk factors, it is possible that the increase in risk is greater than the sum of the individual factors, in which case the overall risk of developing VTE should be taken into account. Combined hormonal contraceptives should not be prescribed if the benefit/risk ratio is assessed as negative.

Table 1. Risk factors for developing VTE

There is no consensus regarding the possible role of varicose veins and superficial thrombophlebitis in the occurrence or progression of venous thrombosis.

The increased risk of thromboembolism during pregnancy and especially in the first 6 weeks of the postpartum period should be taken into account (for information on use during pregnancy and breastfeeding, see the section "Pregnancy and lactation").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

If appropriate symptoms occur, the woman should urgently seek medical help, and should notify the health care professional that she is using a combined hormonal contraceptive.

Symptoms of deep vein thrombosis (DVT):

• unilateral swelling of the lower limb and/or foot or the presence of swelling along the vein in the lower limb;
• pain or tenderness in the lower extremity that may only be felt when standing or walking;
• increased temperature of the affected lower limb, redness or discoloration of the skin of the lower limb.

Symptoms of pulmonary embolism (PE):

• sudden onset of unexplained shortness of breath or rapid breathing;
• sudden cough, which may be associated with hemoptysis;
• sharp chest pain;
• severe dizziness;
• fast or irregular pulse.

Some of these symptoms (eg, shortness of breath, cough) are nonspecific and for this reason may be misinterpreted as more common or less severe conditions (eg, respiratory tract infections).

Other signs of vascular occlusion may include:

• sudden pain, swelling and slight blue discoloration of the limb.

With retinal vascular occlusion, symptoms may range from blurred vision without pain to progressive vision loss. Sometimes there may be a sudden loss of vision.

Risk of developing arterial thromboembolism (ATE)

Epidemiological studies have found that the use of combined hormonal contraceptives is associated with a high risk of arterial thromboembolism (myocardial infarction) or cerebrovascular disease (eg, transient ischemic attack, stroke). Arterial thromboembolic complications can be fatal.

Risk factors for developing ATE

The risk of developing arterial thromboembolic complications or cerebrovascular accidents during the use of combined hormonal contraceptives increases in the presence of risk factors (see Table 2). Midiana® is contraindicated in women with one serious or multiple risk factors for the development of ATE, on the basis of which she can be classified as a high-risk group for the development of arterial thrombosis. If a woman has multiple risk factors, it is possible that the increase in risk is greater than the sum of the individual factors, in which case the magnitude of the overall risk should be considered. Combined hormonal contraceptives should not be prescribed if the benefit/risk ratio is assessed as negative.

Table 2. Risk factors for developing ATE.

Symptoms of ATE

If appropriate symptoms occur, the woman should urgently seek medical help, and should notify the health care professional that she is using a combined hormonal contraceptive.

Symptoms of acute cerebrovascular accident:

• sudden numbness or weakness of the muscles of the face, upper or lower extremities, especially on one side of the body;
• sudden disturbance in gait, dizziness, loss of balance or coordination;
• sudden onset of confusion, difficulty speaking or understanding;
• severe visual impairment in one or both eyes;
• sudden onset of severe or prolonged headache without a known cause;
• loss of consciousness or fainting with or without convulsions.

Transient symptoms indicate that this phenomenon is a transient ischemic attack (TIA).

Symptoms of myocardial infarction may include:

• pain, discomfort, feeling of pressure, heaviness, compression or fullness in the chest, upper limb or below the sternum;
• discomfort radiating to the back, lower jaw, throat, arm, stomach;
• feeling of fullness in the stomach, indigestion, or choking;
• sweating, nausea, vomiting, or dizziness;
• a state of extreme weakness, anxiety or shortness of breath;
• fast or irregular pulse.

The presence of one of the major risk factors or multiple risk factors for arterial or venous disease, respectively, may also be a contraindication. Anticoagulant therapy should be considered. Women using combined hormonal contraceptives should contact their doctor immediately if they experience symptoms of possible thrombosis. In cases of suspected or confirmed thrombosis, the use of combined hormonal contraceptives should be discontinued. It is necessary to select an adequate method of contraception due to the teratogenicity of anticoagulant therapy (coumarin derivatives).

The increased risk of thromboembolism in the postpartum period should be taken into account (for more information, see the section "Pregnancy and lactation").

Other diseases that are associated with severe vascular pathology include diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis), and sickle cell disease.

An increase in the frequency or severity of migraines during use of combined hormonal contraceptives (which may precede cerebrovascular events) may be grounds for immediate discontinuation of combined hormonal contraceptives.

Tumors

The most significant risk factor for developing cervical cancer is having an infection with the human papillomavirus (HPV). Some epidemiological studies have reported an increased risk of cervical cancer with long-term CHC use (>5 years), but there remains controversy regarding the extent to which these findings are attributable to confounding factors such as cervical cancer screening or barrier use. methods of contraception.

A meta-analysis of data from 54 epidemiological studies demonstrated that there is a slightly increased relative risk (RR=1.24) of developing breast cancer diagnosed in women who were using combined hormonal contraceptives at the time of the study. The excess risk gradually decreases over 10 years after stopping combined hormonal contraceptives. Because breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnoses in recent years among women who have previously used or are currently using combined hormonal contraceptives is small relative to the overall risk of developing breast cancer. These studies do not support a causal relationship between the use of combined hormonal contraceptives and the development of breast cancer. The observed increased risk may be due to earlier diagnosis of breast cancer in women using combined hormonal contraceptives, a biological effect of combined hormonal contraceptives, or a combination of both.

Among women who had ever used combined hormonal contraceptives, there was a trend toward less clinical severity of diagnosed breast cancer cases than among women who had never used combined hormonal contraceptives.

In rare cases, the development of benign liver tumors has been observed during the use of combined hormonal contraceptives, and in even more rare cases, malignant ones. In some cases, these tumors caused life-threatening intra-abdominal bleeding. In the differential diagnosis, a liver tumor should be considered when a woman using combined hormonal contraceptives experiences severe pain in the upper abdomen, liver enlargement, or signs of intra-abdominal bleeding.

Malignant tumors can be life-threatening or fatal.

Other states

The progesterone component of Midiana® is an aldosterone antagonist with potassium-sparing properties. In most cases, there is no increase in serum potassium levels. However, in a clinical study in some patients with mild to moderate renal impairment and concomitant use of potassium-sparing medications, a small increase in serum potassium occurred when taking drospirenone. Thus, it is recommended to monitor serum potassium levels in the first cycle of taking the drug in patients with renal failure and in patients with pre-treatment potassium levels at the ULN level, as well as in cases of simultaneous administration of drugs that retain potassium in the body.

In women with hypertriglyceridemia or a family history of this disorder, an increased risk of pancreatitis cannot be excluded when using combined hormonal contraceptives.

Although slight increases in blood pressure have been described in many women using combined hormonal contraceptives, clinically significant increases have been reported rarely. Only in these rare cases is immediate cessation of combined hormonal contraceptives justified. If, during the use of combined hormonal contraceptives in cases of pre-existing arterial hypertension, blood pressure values ​​​​are constantly elevated, or significantly elevated blood pressure cannot be controlled with the use of antihypertensive drugs, the combined hormonal contraceptives should be discontinued. If necessary, the use of combined hormonal contraceptives can be continued if normal blood pressure values ​​are achieved during antihypertensive therapy.

The following conditions have been noted to develop or worsen both during pregnancy and during the use of combined hormonal contraceptives, but their relationship with the use of combined hormonal contraceptives has not been proven:

• jaundice and/or itching associated with cholestasis;
• gallbladder stones;
• porphyria;
• systemic lupus erythematosus;
• hemolytic-uremic syndrome;
• Sydenham's chorea;
• herpes during pregnancy;
• hearing loss associated with otosclerosis.

In women with hereditary angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

Acute or chronic liver dysfunction may require discontinuation of combined hormonal contraceptives until liver function tests return to normal.

Recurrent cholestatic jaundice and/or itching caused by cholestasis, which develop for the first time during pregnancy or previous use of sex hormones, requires discontinuation of the use of combined hormonal contraceptives.

Although combined hormonal contraceptives may have an effect on peripheral insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in diabetic patients using low-dose combined hormonal contraceptives (containing <0.05 mg ethinyl estradiol). However, women with diabetes should be monitored closely, especially when starting combined hormonal contraceptives.

Worsening of the course of endogenous depression, epilepsy, Crohn's disease and ulcerative colitis has also been reported with the use of combined hormonal contraceptives.

Chloasma can sometimes develop, especially in women with a history of chloasma during pregnancy. Women who are prone to developing chloasma should avoid prolonged sun exposure or exposure to ultraviolet radiation while using combined hormonal contraceptives.

One tablet of Midiana® contains 48.17 mg of lactose monohydrate. The drug should not be taken by patients with rare hereditary diseases such as lactose intolerance or glucose-galactose malabsorption.

One tablet of Midiana® contains 0.070 mg of soy lecithin. This drug should not be taken by patients with hypersensitivity to peanuts or soy.

Medical examination

Before starting or re-prescribing Midiana®, a thorough medical history (including family history) should be taken and pregnancy should be excluded. Blood pressure should be measured and an objective examination should be performed, guided by information on contraindications and special instructions and precautions. It is important to draw women's attention to the risk of venous and arterial thrombosis, including the risk of using Midiana® compared to other combined hormonal contraceptives, the symptoms of VTE and ATE, as well as established risk factors and actions taken in case of suspected thrombosis.

It is necessary that the woman carefully read the “Instructions for medical use of the drug” and follow the recommendations presented in it. The frequency and type of examinations should be based on developed practical recommendations with their adaptation for each individual woman.

The woman should be warned that oral contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Reduced efficiency

The effectiveness of combined hormonal contraceptives may be reduced by missed pills, gastrointestinal disorders, or concomitant use of other medications.

Cycle control

While taking combined hormonal contraceptives, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. For this reason, assessment of any irregular bleeding is only meaningful after an adaptation period of approximately three cycles.

If irregular bleeding recurs or develops after previous regular cycles, non-hormonal causes should be excluded, with appropriate diagnostic measures carried out to exclude malignancy or pregnancy. These may include diagnostic curettage.

Some women may not develop withdrawal bleeding during a break from oral contraceptives. If combined hormonal contraceptives are taken as directed in the Dosage Regimen section, it is unlikely that the woman will become pregnant. However, if before the first absence of withdrawal bleeding, combined hormonal contraceptives were not taken in accordance with the instructions or there are no two withdrawal bleedings in a row, then pregnancy should be excluded before continuing to take the combined hormonal contraceptive.

Impact on the ability to drive vehicles and operate machinery

No studies have been conducted to study the effect on the ability to drive vehicles and operate machinery.