Expiration date: 04/2025

Structure and Composition:

Tablets, film-coated. 1 tablet contains active substance:

Drospirenone 3 mg

0.03 mg ethinylestradiol

Excipients: lactose monohydrate - 48.17 mg of corn starch - 16.8 mg of pregelatinized corn starch - Povidone K25 9.6 mg - 1.6 mg of magnesium stearate - 0.8 mg

shell film: Opadry II White, Colorcon 85G18490 code - 2 mg (polyvinyl alcohol - 0.88 mg of titanium dioxide - 0.403 mg Macrogol 3,350 - 0,247 mg of talc - 0.4 mg, soy lecithin - 0.07 mg

in blisters made of PVC / PVDC / aluminum foil for 21 pcs. In the paper cartons 1 or 3 blisters.

Description pharmaceutical form:

Biconvex tablets round shape, film-coated white or almost white, engraved with «G63» on one side in the cross section of white or nearly white.

Pharmacokinetics:

Drospirenone (3 mg)

Suction. When taken orally, drospirenone is rapidly and almost completely absorbed. Cmax active substance in the serum, which is equal to 37 ng / ml, is reached in 1-2 hours after a single dose. During one cycle the maximum reception Css drospirenone in serum is about 60 ng / ml and is achieved in 7-14 hours. The bioavailability ranges from 76 to 85%. Food does not affect the bioavailability of drospirenone.

Distribution. Observed after oral administration of 2-phase reduction in serum concentration of drospirenone, characterized T1 / 2 (1,6 ± 0,7) and h (27 ± 7,5) h respectively. Drospirenone binds to serum albumin and globulin binds to sex hormone-binding (SHBG) and kortikosteroidsvyazyvayuschim globulin (transcortin). Only 5.3% of the total serum concentration of active substance is a hormone free. SHBG ethinylestradiol induced increase does not affect the binding of serum proteins drospirenone. Average apparent Vd is (3,7 ± 1,2) l / kg.

Biotransformation. After oral administration of drospirenone is subjected to significant metabolism. Most metabolites in plasma are presented acidic forms of drospirenone obtained with the disclosure of the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate, which are formed without involvement of cytochrome P450. According to in vitro studies Drospirenone is metabolized with little involvement of cytochrome P450.

Elimination. The metabolic clearance rate of drospirenone in serum of (1,5 ± 0,2) ml / min / kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted by the kidneys and the bowel in a ratio of about 1.2 / 1.4. T1 / 2 for metabolite excretion through the kidney and intestine is approximately 40 hours.

Css. During one treatment cycle maximum Css drospirenone in serum (approximately 60 ng / ml) reached after 7-14 hours. There 2.3-fold increase in the concentration of drospirenone. Further increase in the serum concentration observed after 1-6 drospirenone reception cycles, after which increasing the concentration is not observed.

Ethinyl estradiol (0.03 mg)

Suction. Ethinyl estradiol after oral administration is rapidly and completely absorbed. Serum Cmax after a single dose of 0.03 mg is achieved in 1-2 hours and is about 100 pg / ml. For ethinyl estradiol is expressed significant first pass effect with high individual variability. The absolute bioavailability is variable and is approximately 45%.

Distribution. Apparent Vd is about 5 l / kg, the connection with plasma proteins - about 98%. Ethinylestradiol induces the synthesis of SHBG in the liver and transcortin. With daily administration of 0.03 mg of ethinyl estradiol plasma concentration of SHBG increases from 70 nmol / L to about 350 nmol / l. Ethinylestradiol in small amounts into breast milk (approximately 0.02% of the dose).

Biotransformation. Ethinyl estradiol is metabolised completely. The metabolic clearance rate of 5 ml / min / kg.

Elimination. Ethinyl estradiol is excreted virtually unchanged. Ethinylestradiol metabolites are excreted by the kidneys and the bowel in a ratio of 4/6. T1 / 2 for metabolite excretion is about 1 day. An elimination T1 / 2 was 20 hours.

Css. Condition Css achieved during the second half of the treatment cycle.

Certain categories of the population

Effects on renal function. Css drospirenone in serum of women with mild renal impairment (Cl creatinine 50-80 ml / min) was comparable to that of women with normal renal function (Cl creatinine> 80 ml / min). Concentration of drospirenone in serum was on average 37% higher in women with moderate renal insufficiency (Cl creatinine 30-50 ml / min) compared to that of women with normal renal function. Therapy was well tolerated by women drospirenone and weak, and having an average degree of renal failure.

drospirenone treatment had no clinically significant effect on the potassium concentration in the serum.

The effect on the liver function. In women with moderate hepatic insufficiency (class B classification Child-Pugh) curve of the mean plasma concentration did not correspond to that of women with normal liver function. The values ??of Cmax, observed at the absorption and phase distributions are the same. During the reduction phase distribution closure drospirenone concentration was approximately 1.8 times higher in volunteers with mild hepatic impairment compared to subjects with normal hepatic function.

After a single dose total body clearance in volunteers with mild hepatic impairment was about 50% reduced compared to subjects with normal hepatic function.

The observed decrease in clearance of drospirenone in volunteers with mild hepatic failure does not result in any significant differences with respect to serum potassium concentration.

Even with diabetes and simultaneous treatment with spironolactone (two factors that can cause hyperkalemia in a patient) no increase in serum potassium concentrations above the ULN. It can be concluded that the combination of drospirenone / ethinylestradiol well tolerated in patients with moderate hepatic insufficiency (class B Child-Pugh classification).

Description of the pharmacological actions:

The contraceptive effect of Midiana the drug based on the interaction of various factors, the most important of which are inhibition of ovulation and changes in the endometrium.

The drug Midiana - a combined oral contraceptive containing ethinyl estradiol and drospirenone. The therapeutic dose of drospirenone also has weaker antimineralocorticoid and antiandrogenic properties. He is deprived of any estrogenic, glucocorticoid and antiglucocorticoid activity. This enables drospirenone pharmacological profile similar to natural progesterone.

There is evidence of a decrease in the risk of endometrial and ovarian cancer with the use of combined oral contraceptives.

Indications:

Contraception.

Contraindications:

Midiana The drug should not be given if any of the conditions listed below. If any of these conditions develop for the first time while taking the drug, required his immediate removal.

• vein thrombosis present or in history (deep venous thrombosis, pulmonary embolism)
  
• arterial thrombosis present or in history (eg myocardial infarction) or previous condition (eg angina pectoris and transient ischemic attack)
  
• complicated lesion valvular atrial fibrillation, uncontrolled hypertension
  
• major surgery with prolonged immobilization
  
• smoking at the age of 35 years
  
• liver failure
  
• cerebrovascular disease at present or in history
  
• severe or multiple risk factors for arterial thrombosis (diabetes with vascular complications, severe hypertension, severe dislipoproteinemia)
  
• hereditary or acquired predisposition for venous or arterial thrombosis, such as resistance to activated protein C, antithrombin III of failure, lack of protein C, protein deficiency the S, hyperhomocysteinemia and the presence of antiphospholipid antibodies (cardiolipin antibodies, lupus anticoagulant)
  
• pancreatitis, including history, if a marked hypertriglyceridemia
  
• severe liver disease (liver function tests before normalization) at present or in history
  
• severe chronic or acute renal failure
  
• liver tumors (benign or malignant) currently or history
  
• hormone-dependent malignant disease of the reproductive system (genitals, mammary glands), or are suspected
  
• vaginal bleeding of unknown origin
  
• migraine with focal neurological symptoms history
  
• pregnancy or suspected it
  
• lactation
  
• hypersensitivity to the drug or any of its component
  
• hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption.
  

Precautions: risk factors for thrombosis and thromboembolism - smoking before the age of 35 years, obesity, dislipoproteinemia controlled hypertension, migraine without focal neurological symptoms, uncomplicated valvular disease, a genetic predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident in a young age in any of the next of kin) diseases in which may occur peripheral circulation disorders - diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, Crohn's disease, ulcerative colitis, sickle cell anemia, phlebitis of superficial veins hereditary angioedema , hypertriglyceridemia, liver disease, first appeared or worsen during pregnancy, or on the background of the previous use of sex hormones, including jaundice and / or pruritus related to cholestasis, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes during pregnancy in history, chorea (Sydenham's disease), chloasma postpartum period.

Application of pregnancy and breastfeeding:

During pregnancy and lactation, use of the drug is contraindicated Midiana. If the pregnancy is in the background of hormonal contraception, requires the immediate withdrawal of the drug. The few data on inadvertent, inadvertently, taking combined oral contraceptives showed no teratogenic effects and increase the risk for children and women during childbirth. Combined oral contraceptives affect lactation may 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.

Side effect:

During the simultaneous use of drospirenone and ethinyl estradiol reported the following adverse reactions.

The frequency of their development: often (& ge1 / 100, <1/10), uncommon (& ge1 / 1000, <1/100), rarely (& ge1 / 10,000, <1/1000).

From the nervous system: often - headache, emotional lability, depression infrequently - decreased libido, rarely - increased libido.

From endocrine system: often - menstrual disorders, intermenstrual bleeding, pain in the breast is rare - discharge from the breast.

From the sensory organs: rarely - hearing loss, poor tolerance of contact lenses.

From the digestive system: often - nausea, abdominal pain, rarely - vomiting, diarrhea.

Skin and subcutaneous tissue: rare - acne, eczema, skin rash, urticaria, erythema nodosum, erythema multiforme, pruritus, chloasma, especially with a history of chloasma during pregnancy.

From the circulatory system: often - headache rarely - increased or decreased blood pressure, rarely - thrombosis (venous and arterial), thromboembolism.

Systemic disorders and complications often - weight gain infrequently - fluid retention rare - decrease in body Masa.

Immune system: rarely - bronchospasm.

Reproductive system and breast: often - acyclic vaginal bleeding (spotting or breakthrough uterine bleeding), bloating, pain, breast enlargement, vaginal candidiasis infrequently - vaginitis rarely - discharge from the breast, increased vaginal discharge.

Drug Interactions:

Interactions between oral contraceptives and other drugs may lead to breakthrough uterine bleeding and / or reduce the contraceptive reliability. The literature describes the following types of interactions.

Effect on the metabolism in the liver. Some drugs due to induction of microsomal enzymes are able to increase the clearance of sex hormones (phenytoin, barbiturates, primidone, carbamazepine and rifampicin may have a similar effect, oxcarbazepine, gopiramat, felbamate, ritonavir, griseofulvin and the herbal remedy St. John's wort on the basis of Hypericum perforatum).

It reported on the possible application of inhibitors of HIV protease (for example Ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine) and their combinations on hepatic metabolism.

The effect on enterohepatic recycling. Clinical observations indicate that simultaneous application of certain antibiotics such as penicillins and tetracyclines reduces the enterohepatic recirculation of estrogens that may reduce the concentration of ethinyl estradiol.

Women who take any of the above mentioned drugs should use a barrier method of contraception in addition to the drug Midiana or go to any other method of contraception. Women who receive chronic treatment with drugs containing active substances that affect the liver microsomal enzymes, within 28 days after their cancellation in addition must use non-hormonal contraceptive method. Women taking antibiotics except rifampin or griseofulvin should temporarily use a barrier method of contraception in addition to the COC as during treatment and within 7 days after its cancellation. If concomitant use of the drug began in the end of the reception package Midiana drug, following the package should be started without the usual break at the reception.

Drospirenone primary metabolism in human plasma carried out without the involvement of cytochrome P450. Inhibitors of this enzyme system thus It does not affect the metabolism of drospirenone.

Effect of the drug to other drugs Midiana. Oral contraceptives may affect the metabolism of other drugs. Moreover, their concentration may vary in plasma and tissues - either increase (e.g. cyclosporin), or decrease (eg lamotrigine). Based on the inhibition of in vitro studies and in vivo interaction female volunteers taking omeprazole, simvastatin and midazolam as substrates indicators influence drospirenone in a dose of 3 mg metabolism of other active substances is unlikely.

Other interactions. There is a theoretical possibility of increasing serum potassium concentrations in women receiving oral contraceptives concomitantly with other drugs that increase the concentration of potassium in the blood serum: ACE inhibitors, angiotensin II receptor antagonists, some NSAIDs (eg, indomethacin), potassium-sparing diuretics and aldosterone antagonists. However, in the study evaluating the interaction of an ACE inhibitor with a combination of drospirenone + ethinyl estradiol in women with moderate hypertension, showed no significant difference between serum potassium concentrations in women treated with enalapril and placebo.

Laboratory research. Hormonal contraceptives may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney, as well as the concentration of transport plasma proteins, such as kortikosteroidsvyazyvayuschy globulin and lipid / lipoprotein fractions, carbohydrate metabolism, blood coagulation and fibrinolysis. Changes usually occur within laboratory standards.

Due to its low anti-mineralocorticoid activity of drospirenone increases the activity of renin and aldosterone concentrations in blood plasma.

Dosage and administration:

Inside.

Tablets must be taken every day at about the same time, if necessary with a small amount of liquid in the sequence shown on the blister pack. It is necessary to take 1 tab. a day for 21 consecutive days. Pills of each subsequent packaging should begin after a 7-day pill interval during which usually occurs menstrualnopodobnoe bleeding. It usually begins 2-3 days after the last tablet and may not end at the beginning of the next pack.

If you have previously used hormonal contraceptives do not (last month). Admission COCs starts at the 1st day of the woman's natural menstrual cycle (ie the 1st day of menstrual bleeding).

In case of replacement of another combined oral contraceptive vaginal ring or a transdermal patch. For women taking this medication, preferably Midiana the next day after taking the last active tablet of the previous combined oral contraceptive, in such cases, the receiving PM Midiana should not start later than the day after the usual tablet-free interval or receiving inactive tablet of her previous combined oral contraceptive. When replacing a vaginal ring or transdermal patch use of oral contraceptives Midiana desirable to begin on the day of removal of the previous tool in such cases receive Midiana preparation should begin no later than the date of the intended replacement procedure.

In the case of the replacement method with the use of progestin-only (minipill, injectable form, implant) or intrauterine contraceptive devices to release progestin. A woman can go to the mini-pill any day (from an implant or IUD - the date of its removal from the injection mold - from the day when the next injection should have been made). However, in all these cases, it is desirable to use an additional barrier method of contraception during the first 7 days of taking the pills.

After the abortion I trimester. The woman may start taking immediately. Under this condition there is no need for additional measures of contraception.

After delivery or abortion in the II trimester. Woman desirable Midiana start taking the drug at 21-28 days after delivery or abortion in the II trimester. If the reception is started later, you must use an additional barrier method of contraception during the first 7 days of taking the pills. In the case of sexual intercourse before you start taking the drug should be excluded pregnant or you must wait for the first menstrual period.

Admission missed pills. If the delay in receiving the tablet is less than 12 hours, contraceptive protection is not reduced. The woman should take the tablet as soon as possible, these pills are taken at the usual time.

If the delay in receiving the tablets accounted for more than 12 hours, contraceptive protection may be reduced. Management of missed doses based on the following two simple rules: you can not stop taking the pill for more than 7 days to achieve adequate suppression of the hypothalamic-pituitary-ovarian system, you need to 7 days of continuous reception of tablets.

Accordingly, these tips may be used in daily practice.

Week 1. It is necessary to take the last missed tablet as soon as possible, even if it means taking 2 tablets. simultaneously. The next tablet is taken at the usual time. In addition to be used a barrier method of contraception for the next 7 days. If intercourse took place during the 7 days before skipping pills, you need to take into account the chance of pregnancy. The more missed tablets and the closer this pass to the 7-day break in taking the drug, the greater the risk of pregnancy.

Week 2. It is necessary to take the last missed tablet as soon as possible, even if it means taking 2 tablets. simultaneously. The next tablet is taken at the usual time. If a woman within the previous 7 days on the pill correctly, there is no need to use additional means of contraception. However, if she missed more than 1 table., Need to use additional contraceptive measures in the next 7 days.

Week 3. Probability reduce contraceptive effect is significant because of the forthcoming 7-day tablet-free interval. However, adjusting the schedule of taking the pills, you can prevent a decrease contraceptive protection.

If you follow any of these 2 tips, additional methods of contraception is not required if within the preceding 7 days before skipping pills she took all the pills correctly. If not, it must follow the first of the two methods and also use additional contraceptive measures during the next 7 days.

1. It is necessary to take the last missed tablet as soon as possible, even if it means taking 2 tablets at the same time. The next tablet is taken at the usual time. Taking the pills from a new pack must be started as soon as the current pack, ie without interruption between the intake of 2 packages. Most likely withdrawal bleeding will not be until the end of the 2nd package, but there may be spotting or breakthrough uterine bleeding in the days of taking the pills.

2. The woman may be advised to discontinue tablet-taking from the package. Then, you must stop taking the tablets for 7 days, including the days she forgot to take the pill, and then begin taking pills from a new package.

When you miss a pill and in the absence in the 1st free from bleeding dosing interval of cancellation is necessary to exclude pregnancy.

Tips in case of gastrointestinal disorders. In case of severe reactions on the part of the digestive tract (such as vomiting or diarrhea), absorption may not be complete, and it is necessary to use additional contraceptive measures.

If vomiting occurs within 3-4 hours after taking the pill you need a new one, replacing a tablet soon as possible. The new tablet should be taken, if possible within 12 hours after receiving the usual time. If you missed more than 12 hours, as far as possible it is necessary to observe the rules of the drug.

Admission missed pills. If the patient does not want to change the normal operation of the drug, she should take an extra tablet (or more tablets) from a new package.

How to delay withdrawal bleeding. To delay the start date of withdrawal bleeding should continue receiving Midiana preparation of the new packaging without interruption in reception. Deferment possible until the end of the tablets in the 2nd pack.

During elongation cycle may experience spotting from the vagina or breakthrough uterine bleeding. Resume Midiana the drug from a new package follows the usual 7-day break.

To move the start date of withdrawal bleeding to another day of the week normal schedules should shorten the next tablet-free interval for as many days, on how many it is necessary. The shorter the interval, the higher the risk that withdrawal bleeding will not, and while taking tablets from the 2nd package will be marked spotting and breakthrough uterine bleeding (as well as in the case of delaying the onset of withdrawal bleeding).

Overdose:

Data on overdose drospirenon- etinilestradiolsoderzhaschih and drugs are not available.

Symptoms: may cause nausea, vomiting and bleeding / bleeding from the vagina.

Treatment: No specific antidote should be symptomatic treatment.

Precautionary measures:

If any of the conditions / risk factors mentioned below are currently available, you should carefully weigh the potential risks and expected benefits of the combined oral contraceptive in each individual case and discussed with the woman before she decides to start taking the drug. In the case of aggravation, or amplification of the first manifestations of any of these conditions or risk factors, the woman should consult with your doctor, who can decide whether to cancel the combined oral contraceptive.

Disorders of the circulatory system. Incidence of venous thromboembolism (VTE) using a combined oral contraceptive, a low dose of estrogen (<50 micrograms ethinyl estradiol such as the drug Midiana) is from about 20 to 40 cases per 100,000 women per year, which is slightly higher than that of women do not apply hormonal contraceptives (5 to 10 cases per 100,000 women), but lower than for women during pregnancy (60 cases per 100,000 pregnancies).

Additional risk of VTE observed within 1 year of the combined oral contraceptive. VTE is fatal in 1-2% of cases.

Epidemiological studies have also found an association between the use of combined oral contraceptives and increased risk of thromboembolism of the arteries. We describe an extremely rare cases of thrombosis, other blood vessels, eg hepatic, mesenteric, renal, brain and retina, as the arteries and veins, those taking oral hormonal contraceptives. The causal relationship of side effects with taking the combined oral contraceptive data has not been proven.

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

• Unusual unilateral pain and / or swelling of the limbs
  
• Sudden severe pain in the chest, with or without irradiation to the left arm
  
• Sudden shortness of breath
  
• Sudden onset 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 convulsive seizure
  
• Weakness or very significant loss of sensitivity, suddenly appeared in one half of the body, or
  
• Motor disturbances
  
• A symptom of an acute abdomen.
  

The risk of complications associated with VTE while taking combined oral contraceptives increases:

• with age
  
• The presence of family history (venous or arterial thromboembolism in relatives or parents at a relatively young age), if you plan to hereditary predisposition, the woman should consult a specialist before prescribing a combined oral contraceptive
  
• After prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations, it is recommended to stop taking the drug (in the case of elective surgery - at least 4 weeks before it), and not to renew the appointment within 2 weeks after the immobilization. Additionally, you can assign antithrombotic therapy, if the use of oral hormonal contraceptives has not been terminated in the recommended time frame
  
• Obesity (body mass index> 30 kg / m2).
  

The risk of arterial thrombosis and thromboembolism while taking the combined oral contraceptive uvelichivaegsya:

• with age
  
• Smokers (women over 35 years old are strictly not recommended to smoke if they wish to use combined oral contraceptives)
  
• When dislipoproteinemia
  
• Arterial hypertension
  
• Migraine
  
• For diseases of the heart valves
  
• Atrial fibrillation.
  

The presence of one serious risk factor or multiple risk factors for venous or arterial disease may be contraindicated. Women who use combined oral contraceptives should immediately consult your doctor in case of possible symptoms of thrombosis occurs. In cases of suspected or confirmed thrombosis thrombosis receiving combined oral contraceptives should be discontinued. It is necessary to choose an adequate method of contraception due to the teratogenicity of anticoagulant therapy (coumarins).

It is necessary to take into account the increased risk of thromboembolism during the postpartum period.

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

Increased frequency and severity of migraine during use of combined oral contraceptives, which may be preceded by cerebrovascular disorders may be a reason for immediate discontinuation of these drugs.

Tumors. The most significant factor in cervical cancer risk is infection with the human papilloma virus. Some epidemiological studies have reported an increased risk of cervical cancer in long-term use of combined oral contraceptives, however, are saved conflicting opinions as to the extent to which these findings relate to the co-factors, such as the investigation of the presence of cervical cancer or the use of barrier methods of contraception.

A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are at the time of the study were used combined oral contraceptives. The excess risk gradually declines for 10 years after cessation of combined oral contraceptives. Because breast cancer is rare in women younger than 40 years, increasing the number diagnosed in recent years, women taking or taking combined oral contraceptives, breast cancer is small relative to the overall risk of developing breast cancer. These studies do not support a causal relationship between the intake of combined oral contraceptives and breast cancer. The observed increase in risk may be due to an earlier diagnosis of breast cancer in women using combined oral contraceptives, the biological effects of combined oral contraceptives or a combination of both options. Breast cancers in women who have ever treated with combined oral contraceptives, have been clinically less severe than in women, never let them take.