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Active ingredients
Drospirenone + Ethinyl Estradiol
Release form
Pills
Composition
In 1 tablet: ethinyl estradiol 30 mcg; drospirenone 3 mg. Adjuvants: lactose monohydrate - 48.17 mg, corn starch - 16.8 mg, pregelatinized corn starch - 9.6 mg, povidone K25 - 1.6 mg, magnesium stearate - 0.8 mg.
Pharmacological effect
Combined oral contraceptive preparation containing ethinyl estradiol and drospirenone. The contraceptive effect is based on the interaction of various factors, the most important of which are inhibition of ovulation and changes in the endometrium. At a therapeutic dose, drospirenone also has anti-androgenic and weak anti-mineralocorticoid properties. It does not have estrogenic, glucocorticoid and antiglucocorticoid activity. This provides drospirenone with a pharmacological profile similar to natural progesterone. There is evidence of a reduction in the risk of endometrial and ovarian cancer when using combined oral contraceptives.
Pharmacokinetics
Drospirenone Absorption: When taken orally, drospirenone is rapidly and almost completely absorbed. Cmax of the active substance in serum, equal to 37 ng / ml, is achieved within 1-2 h after a single dose. Bioavailability ranges from 76% to 85%. Food intake does not affect the bioavailability of drospirenone. Distribution: During one cycle of intake, Cssmax in serum in serum is about 60 ng / ml and is reached in 7-14 hours. A 2-3-fold increase in the concentration of drospirenone is noted. A further increase in the serum concentration of drospirenone is noted after 1-6 cycles of administration, after which there is no increase in concentration. After oral administration, a two-phase decrease in the concentration of drospirenone in serum is observed, which is characterized by T1 / 2 1.6 ± 0.7 h and 27.0 ± 7.5 h, respectively. Drospirenone is bound it does not bind to serum albumin and sex hormone binding globulin (SHBG) and corticosteroid binding globulin (transcortin). Only 3-5% of the total serum concentration of the active substance is a free hormone. The ethinyl estradiol-induced increase in SHBG does not affect the binding of drospirenone to serum proteins. The average apparent Vd is 3.7 ± 1.2 l / kg. Metabolism: After oral administration, drospirenone undergoes a significant metabolism.Most plasma metabolites are represented by the acid forms of drospirenone, obtained by opening the lactone ring, and 4.5-dihydro-drospirenone-3-sulfate, which are formed without involving the cytochrome P450 system. According to in vitro studies, drospirenone is metabolized with an insignificant participation of cytochrome P450. Excretion: The rate of metabolic clearance of drospirenone in serum is 1.5 ± 0.2 ml / min / kg. Drospirenone is displayed only in trace amounts in unchanged form. The metabolites of drospirenone are excreted by the kidneys and through the intestine in a ratio of approximately 1.2: 1.4. T1 / 2 with excretion of metabolites by the kidneys and through the intestine is approximately 40 hours. Pharmacokinetics in special clinical cases: Css serum drospirenone in women with a weak degree of renal failure (CC 50-80 ml / min) was comparable to that in women with normal function kidney disease (CC> 80 ml / min). The serum concentration of drospirenone was, on average, 37% higher in women with moderate renal failure (CK 30–50 ml / min) compared with women with normal renal function. Drospirenone therapy was well tolerated in women and with weak and moderate renal failure. Drospirenone treatment did not have a clinically significant effect on serum potassium concentration. In women with moderate hepatic insufficiency (Child-Pugh class B), the average plasma concentration did not match such in women with normal liver function. The Cmax values observed in the absorption and distribution phases were the same. During the end of the distribution phase, the decrease in the concentration of drospirenone was about 1.8 times higher in volunteers with moderate hepatic insufficiency compared with people with normal liver function. After a single dose, total clearance (Cl / F) in volunteers with moderate hepatic insufficiency was approximately 50% reduced compared with people with normal liver function. The marked decrease in clearance of drospirenone in volunteers with moderate hepatic insufficiency does not lead to any significant differences in the concentration of potassium in the serum. Even in diabetes mellitus and the simultaneous treatment with spironolactone (two factors that can trigger hyperkalemia in a patient), there was no increase in the concentration of potassium I am in serum above VGN.It can be concluded that the combination of drospirenone / ethinyl estradiol is well tolerated by patients with mild hepatic impairment (Child-Pugh class B). Ethinyl estradiol. Absorption: Ethinyl estradiol after oral administration is rapidly and completely absorbed. Cmax after a single dose of 30 μg is achieved in 1-2 hours and is about 100 pg / ml. For ethinyl estradiol expressed a significant effect of the first passage with a high individual variability. Absolute bioavailability varies and is approximately 45%. Distribution: The state of equilibrium concentration is reached during the second half of the treatment cycle. The apparent Vd is about 5 l / kg, the association with plasma proteins is about 98%. Ethynyl estradiol induces the synthesis of HSPG and transcortin in the liver. With daily intake of 30 mcg of ethinyl estradiol, the plasma concentration of SHBG rises from 70 nmol / l to about 350 nmol / l. Ethinyl estradiol in small amounts passes into breast milk (approximately 0.02% of the dose). Metabolism: Ethinyl estradiol is completely metabolized. The metabolic clearance rate is 5 ml / min / kg. Excretion: Ethinyl estradiol is practically not excreted unchanged. Ethinyl estradiol metabolites are excreted by the kidneys and through the intestine at a ratio of 4: 6. The T1 / 2 metabolite is approximately 1 day. Elimination T1 / 2 is 20 h.
Indications
Contraception.
Contraindications
Median drug; Should not be assigned in the presence of any of the conditions listed below. If any of these conditions develop for the first time while taking the drug, immediate withdrawal is required.— Presence of vein thrombosis at present or in history (deep vein thrombosis, pulmonary embolism) - Presence of artery thrombosis at present or in history ( for example, myocardial infarction) or previous conditions (for example, angina pectoris and transient ischemic attack) - complicated lesions of the cardiac valve apparatus, atrial fibrillation, uncontrolled arterial hypertension; - a serious surgeon cal interference with prolonged immobilization, - smoking at the age of 35 years; - hepatic impairment; - cerebrovascular disease at present or in history - the existence of serious or multiple risk factors for arterial thrombosis (diabetes with vascular complications, severe hypertension,severe dyslipoproteinemia); hereditary or acquired susceptibility to venous or arterial thrombosis, such as resistance to APS (activated protein C), deficiency of antithrombin III, deficiency of protein C, deficiency of protein S, hyperhomocysteinemia, and the presence of antiphospholipid antibodies (in your own language). ); - pancreatitis, including in history if severe hypertriglyceridemia was noted - severe liver disease (before normalization of liver tests) now or in history; - severe chronic renal failure or acute renal failure; - liver tumors (benign or malignant), now or in anamnesis - hormone-dependent malignant diseases of the reproductive system (genitals, mammary glands) or suspicion of them; - bleeding from the vagina of unknown origin; - migraine with focal neurological mptomatikoy history - hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption, - pregnancy or suspected it - lactation; - hypersensitivity to the drug or any of its components.
Precautionary measures
With caution: - risk factors for thrombosis and thromboembolism (smoking under 35 years old, obesity); - dyslipoproteinemia; - controlled arterial hypertension; - migraine without focal neurological symptoms; - uncomplicated valvular heart disease; - hereditary thrombosis predisposition myocardial infarction or cerebral circulation at a young age in someone from the next of kin); - diseases that can cause disturbances in the peripheral circulation (diabetes mellitus beta, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn's disease, ulcerative colitis, sickle cell anemia, phlebitis of superficial veins); - hereditary angioedema; - hypertriglyceridemia; - liver disease; - diseases that first appeared or worsened during pregnancy or against the background of previous intake of sex hormones (including jaundice and / or itching associated with cholestasis, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes during pregnancy in history, minor chorea (Sydenhem disease), chloasm , Postpartum).
Use during pregnancy and lactation
During pregnancy and lactation, use of the drug Midiana; contraindicated.If the pregnancy has occurred on the background of hormonal contraception, immediate withdrawal of the drug is necessary. The few evidence of unintentional use of combined oral contraceptives suggests that there is no teratogenic effect and an increased risk for children and women during childbirth. Combined oral contraceptives affect lactation and can decrease the composition of breast milk. Small amounts of hormonal contraceptives or their metabolites are found in milk during hormonal contraception and can affect the baby. The use of combined oral contraceptives is possible after complete cessation of breastfeeding.
Dosage and administration
Tablets should be taken every day at about the same time, if necessary, with a small amount of liquid, in the order indicated on the blister pack. It is necessary to take 1 tab. / Day for 21 days in a row. Taking pills from each subsequent package should begin after a 7-day interval in taking the pills, during which menstrual-like bleeding usually occurs. It usually starts 2-3 days after taking the last pill and may not end by the start of the next pack. If hormonal contraceptives have not been used before (last month), combined oral contraceptives start on the 1st day of the woman’s natural menstrual cycle (i.e. on the 1st day of menstrual bleeding). In case of replacement of another combined oral contraceptive, vaginal ring or transdermal patch, it is preferable to start taking the drug Midiana; the day after taking the last active pill of the previous combined oral contraceptive; in such cases, taking the drug Midiana; It should not begin later than the day after the usual interruption in taking the pills or taking the inactive pills of her previous combined oral contraceptive. When replacing the vaginal ring or transdermal patch, take the oral contraceptive Midiana; it is advisable to start on the day of removal of the previous remedy; in such cases, taking the drug Midiana; should start no later than the day of the scheduled replacement procedure. In case of replacement of the method using only progestins (mini-pili, injection forms,implants) or intrauterine contraceptives with progestin release: a woman can go with a mini-drink on any day (from an implant or an intrauterine contraceptive on the day of its removal, from an injection form from the day when the next injection was to be given). 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 termination of pregnancy in the first trimester, the woman can start taking it immediately. If this condition is met, there is no need for additional contraceptive measures. After delivery or termination of pregnancy in the second trimester, it is advisable for the woman to start taking the drug Midiana; on the 21-28th day after birth or termination of pregnancy in the II trimester. If reception is started later, you must use an additional barrier method of contraception during the first 7 days of taking the pills. In case of sexual intercourse, pregnancy should be excluded or the first menstruation should be avoided before taking the drug. Acceptance of missed pills. If the delay in taking the pill is less than 12 hours, the contraceptive protection does not decrease. A woman needs to take a pill as soon as possible, the following pills are taken at the usual time. If the delay in taking the pills is more than 12 hours, contraceptive protection can be reduced. Tactics for skipping the drug is based on the following two rules: 1) pills should not be stopped for more than 7 days, 2) to achieve adequate suppression of the hypothalamic-pituitary-ovarian system, you need 7 days of continuous pills. Week 1. You must take the last pill as soon as possible, even if it means taking two pills at the same time. The next pill is taken at the usual time. Additionally, a barrier method of contraception should be used over the next 7 days. If sexual contact occurred within 7 days before the tablet was missed, the likelihood of pregnancy should be considered. The more pills are missed and the closer this pass to the 7-day break in taking the drug, the higher the risk of pregnancy. Week 2. You need to take the last missed pill as soon as possible, even if it means taking two pills at the same time. The next pill is taken at the usual time. If a woman has taken the pills correctly for the previous 7 days, there is no need to use additional contraceptives.However, if she missed more than 1 pill, additional contraceptive measures should be used in the next 7 days. Week 3. The probability of a decrease in the contraceptive effect is significant due to the upcoming 7-day break in the pill. However, by adjusting the schedule for taking the pills, it is possible to prevent a decrease in contraceptive protection. If you follow any of the following two tips, you will not need additional methods of contraception if during the previous 7 days before you skip a pill a woman took all the pills correctly. If this is not the case, she should follow the first of the two methods and also use additional contraceptive measures for the next 7 days. You must take the last missed pill as soon as possible, even if it means taking two pills at the same time. The next pill is taken at the usual time. Taking the pills from the new package should be started as soon as the current package is finished, that is, without a break between taking two packages. Most likely, the withdrawal bleeding will not be until the end of the second package, but there may be spotting or breakthrough uterine bleeding on the days of taking the pills. A woman may be advised to stop taking the pills from this package. Then you need to stop taking the pills for 7 days, including the days when she forgot to take the pills, and then start taking the pills from the new package. In case of severe reactions from the gastrointestinal tract (such as vomiting or diarrhea), absorption may be incomplete, and additional contraceptive measures must be taken. In case of vomiting within 3-4 hours after taking the pill, take a new pill as soon as possible. A new pill, if possible, must be taken within 12 hours after the usual time taken. If more than 12 hours are missed, if possible, you should follow the rules for taking the drug as indicated in the section Receiving the missed pills. .To delay the day of the onset of withdrawal bleeding, it is necessary to continue taking the drug Midiana; from new packaging without interruption in reception.Delay is possible until the end of the pills in the second package. During the lengthening of the cycle, spotting bleeding from the vagina or breakthrough uterine bleeding may occur. Resume Median; from the new pack follows the usual 7-day break. To transfer the day of the onset of withdrawal bleeding to another day of the week on a regular schedule, shorten the next break in taking the pills by as many days as necessary. The shorter the interval, the higher the risk that there will be no bleeding, and while taking the pills from the second package there will be spotting bleeding and breakthrough uterine bleeding (as well as in the case of delaying the onset of withdrawal bleeding).
Side effects
The following adverse reactions have been reported during the simultaneous use of drospirenone and ethinyl estradiol: Organ systems Frequenciesfrequently (≥1 / 100, <1/10) Infrequently (≥1 / 1000, <1/100) Rarely (≥10,000, <1000) .So side of the nervous system; headache, emotional lability, depression, decreased libido, increased libido. From the endocrine system; menstrual disorders, intermenstrual bleeding, pain in the mammary glands, discharge from the mammary glands. On the part of the sense organs; hearing loss, poor tolerance to contact lenses. From the digestive system; nausea, abdominal pain, vomiting, diarrhea On the part of the skin and subcutaneous tissue; acne, eczema, skin rash, urticaria, erythema nodosum, erythema multiforme, pruritus, chloasma, especially if there is a history of pregnant chloasma. From the side of the cardiovascular system; migraine increase or decrease in blood pressure thrombosis (venous and arterial), thromboembolism. Systemic disorders; weight gain; fluid retention; weight loss. From the immune system; bronchospasm. From the reproductive system and mammary glands; acyclic vaginal bleeding (spotting or breakthrough uterine bleeding), engorgement, tenderness, enlargement of mammary glands, vaginal candidiasis, vaginitis of discharge from the mammary glands, increase of vaginal discharge.
Overdose
Information about the overdose of drospirenone and ethinyl estradiol is not available. However, nausea, vomiting and bloody vaginal discharge / bleeding are possible. Treatment: No specific antidote. Symptomatic treatment should be carried out.
Interaction with other drugs
The interaction between oral contraceptives and other drugs can lead to breakthrough uterine bleeding and / or a decrease in contraceptive reliability. The literature describes the following types of interactions. Effects on metabolism in the liver: Some drugs (phenytoin, barbiturates, primidone, carbamazepine and rifampicin), due to the induction of microsomal enzymes, can increase the clearance of sex hormones. Perhaps the same effect of oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin and herbal remedies based on Hypericum perforatum. It was reported about the possible effect of HIV protease inhibitors (for example, ritonavir) and non-nucleoside reverse transcriptase inhibitors (for example, neviracin). Liver effects. Enteric-hepatic recirculation. Clinical observations show that simultaneous use with some antibiotics, such as penicillins and tetracyclines, reduces intestinal estrogenic recirculation of estrogens, which can lead to a decrease in ethinyl estradiol concentration. Women taking any of the above drugs should use a barrier method of contraception in addition to Midiana; or switch to any other method of contraception. Women who receive ongoing treatment with drugs containing active substances that affect liver microsomal enzymes must, in addition, use a non-hormonal method of contraception within 28 days after their withdrawal. Women taking antibiotics (except rifampicin or griseofulvin) should temporarily use a barrier method of contraception in addition to the combined oral contraceptive, both during the administration of the drug, and within 7 days after its cancellation. If the concomitant use of the drug is started at the end of taking the package of the drug Midiana; the next package should be started without the usual interruption in reception. The main metabolism of drospirenone in human plasma is carried out without the involvement of the cytochrome P450 system. Inhibitors of this enzyme system, therefore, do not affect the metabolism of drospirenone. The effect of the drug Midiana; other drugs Oral contraceptives may affect the metabolism of other drugs.In addition, their plasma and tissue concentrations may change: both increase (for example, cyclosporin) and decrease (for example, lamotrigine). Based on the results of in vitro inhibition studies and in vivo interaction studies in female volunteers who take omeprazole, simvastatin and midazolam as a substrate indicator, the effect of drospirenone at a dose of 3 mg on the metabolism of other active substances is unlikely. Other interactions: There is a theoretical possibility of increasing the concentration of serum potassium in women, gender teaching oral contraceptives simultaneously with other drugs that increase the concentration of potassium in the blood serum: ACE inhibitors, angiotensin II receptor antagonists, some NSAIDs (for example, indomethacin), potassium-sparing diuretics and aldosterone antagonists. However, in a study evaluating the interaction of an ACE inhibitor with the combination of drospirenone + ethinyl estradiol in women with moderate arterial hypertension, there was no significant difference between serum potassium concentrations in women who received enalapril and placebo. Laboratory studies: Acceptance of hormonal contraceptives may affect the results of individual laboratory tests , including biochemical indicators of liver, thyroid, adrenal and kidney function, as well as the concentration of transport plasma proteins, such as corticosteroid binding globulin and lipid / lipoprotein fractions, carbohydrate metabolism, blood coagulation and fibrinolysis. Changes usually occur within laboratory norms. Due to its small anti-mineralocorticoid activity, drospirenone increases renin activity and plasma plasma aldosterone concentrations.
special instructions
If any of the conditions / risk factors listed below are present, then the potential risk and the expected benefits of using the combined oral contraceptive in each individual case should be carefully weighed in and discussed with the woman before she decides to start taking the drug. In the event of weighting, aggravation, or the first manifestation of any of these conditions or risk factors, the woman should consult with her physician.who may decide to discontinue the combined oral contraceptive. Circulatory system disorders Frequency of venous thromboembolism (VTE) when using a combination of low dose estrogen oral contraceptives (<50 μg of ethinyl estradiol, such as Midian’s;) is about 20 to 40 cases per 100,000 women per year, which is slightly higher than in women who do not use hormonal contraceptives (from 5 to 10 cases per 100,000 women), but lower than in women during pregnancy (60 cases per 100,000 of adherence). The additional risk of VTE is noted during the first year of use of the combined oral contraceptive. VTE is fatal in 1-2% of cases. Epidemiological studies have also found a link between the use of a combined oral contraceptive 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 taken in oral hormonal contraceptives. The causal relationship to the occurrence of these side effects with combined oral contraceptives has not been proven. Symptoms of venous or arterial thrombosis / thromboembolism or cerebrovascular disease may include: - unusual unilateral pain and / or edema of the extremity; - sudden severe chest pain, with or without irradiation in the left hand; - sudden shortness of breath; - sudden attack of cough; - any unusual, severe, prolonged headache; - sudden partial or complete loss of vision; - diplopia; speech or aphasia; - dizziness; - loss of consciousness with or without a convulsive seizure; - weakness or a very significant loss of sensitivity, suddenly appearing from one half or in one part of the body; - movement disorders; - acute abdomen symptom complex.Risk of complications associated with VTE, when taking a combined oral contraceptive, increases: - with age - with a family history (venous or arterial thromboembolism in close relatives or parents at a relatively young age); if hereditary predisposition is expected, the woman should consult a specialist before prescribing a combined oral contraceptive - after prolonged immobilization, serious surgery, any surgery on the legs or an extensive injury.In these situations, it is recommended to stop taking the drug (in the case of a planned operation, at least four weeks before it) and not to resume taking it within two weeks after the end of immobilization. Additionally, it is possible to prescribe antithrombotic therapy if oral hormonal contraceptives are not discontinued at the recommended time; with obesity (BMI over 30 mg / m2). The risk of arterial thrombosis and thromboembolism when taking a combined oral contraceptive increases: with age; in smokers (women over 35 years old are strictly not recommended to smoke if they want to use the combined oral contraceptives); with dyslipoproteinemia; with hypertension; with migraine; with valvular heart disease; for atrial fibrillation. The presence of one of the serious risk factors or multiple risk factors for diseases of the arteries or veins, respectively, may be a contraindication. Women who use combined oral contraceptives should immediately see a doctor if symptoms of a possible thrombosis occur. In cases of suspected thrombosis or confirmed thrombosis, the combined oral contraceptive should be discontinued. It is necessary to choose an adequate method of contraception due to the teratogenicity of anticoagulant therapy (coumarins). You should take into account the increased risk of thromboembolism in the postpartum period. Other diseases that are associated with severe vascular disease include diabetes, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory inflammation, chronic inflammatory disease, chronic inflammatory inflammation. Crohn's disease or ulcerative colitis) and sickle cell anemia. Increase in the frequency and severity of migraine during the use of combined oral These contraceptives (which may precede cerebrovascular disorders) may be grounds for immediate discontinuation of these drugs. Tumors: The most significant risk factor for cervical cancer is infection with the human papilloma virus. Some epidemiological studies have reported an increased risk of developing cervical cancer with long-term use of combined oral contraceptives,however, controversial views remain on the extent to which these findings relate to concomitant factors, such as a cervical cancer test or the use of barrier methods of contraception. A meta-analysis of 54 epidemiological studies has shown that there is a slightly increased relative risk (RR = 1.24) development of breast cancer diagnosed in women who at the time of the study used combined oral contraceptives. Excessive risk gradually decreases over 10 years after discontinuation of combined oral contraceptives. Since breast cancer is rare in women younger than 40 years, an increase in the number diagnosed in recent years in women taking or taking combined oral contraceptives, breast cancer is small relative to the overall risk of developing breast cancer. These studies do not confirm a causal relationship between taking 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 effect of combined oral contraceptives, or a combination of both. Breast tumors in women who have ever taken combined oral contraceptives were less clinically pronounced than women who had never taken them. In rare cases, the use of combined oral contraceptives resulted in the development of benign liver tumors, and in even rarer cases, malignant . In some cases, these tumors caused life-threatening intra-abdominal bleeding. In the differential diagnosis of a liver tumor, it is necessary to take into account when a woman takes the combined oral contraceptives, severe pain in the upper abdomen, an enlarged liver or signs of intra-abdominal bleeding. Other conditions: Progesterone component in the preparation of Midiana; is an aldosterone antagonist, with the ability to retain potassium. In most cases, there is no increase in potassium concentration.However, in a clinical trial in some patients with mild or moderate renal insufficiency and the simultaneous prescription of potassium-retaining drugs, when receiving drospirenone, the serum potassium concentration slightly, but increased. Thus, it is recommended to check the concentration of potassium in the blood serum in the first cycle of taking the drug in patients with renal insufficiency and the values of the concentration of potassium before treatment for VGN, as well as with simultaneous use