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Active ingredients
Drospirenone + Ethinyl Estradiol
Release form
Pills
Composition
Active ingredient: drospirenone 3 mg, ethinyl estradiol 0, 03 mg. Excipients: magnesium stearate (weight - 0, 8 mg). lactose monohydrate (48 mg). corn starch (16 mg). pregelatinized corn starch (9, 6 mg). Concentration of active ingredient (mg): 3.03 mg.
Pharmacological effect
The contraceptive effect of the drug MIDIANA is based on the interaction of various factors, the most important of which are the inhibition of ovulation and endometrial changes. The drug MIDIANA is a combination oral contraceptive containing ethinyl estradiol and drospirenone. At a therapeutic dose, drospirenone also has anti-androgen and weak anti-mineralocorticoid properties. It is devoid of any 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 with combined oral contraceptives.
Pharmacokinetics
Drospirenone (3 mg) Absorption: Oral administration of drospirenone is rapidly and almost completely absorbed. The maximum concentration of the active substance in serum, equal to 37 ng / ml, is reached within 1-2 hours after a single dose. During one cycle of administration, the maximum equilibrium concentration of drospirenone in serum is about 60 ng / ml and is reached after 7-14 hours. Bioavailability ranges from 76% to 85%. Meal does not affect the bioavailability of drospirenone. Distribution: After oral administration, there is a two-phase decrease in the concentration of drospirenone in serum, which is characterized by a half-life of 1.6 ± 0.7 hours and 27.0 ± 7.5 hours, respectively. Drospirenone binds to serum albumin and does not bind to 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. An ethinyl estradiol-induced increase in SHBG does not affect the binding of drospirenone to serum proteins. The average apparent volume of distribution is 3.7 ± 1.2 l / kg.Biotpansformaiya: After oral administration, drospirenone undergoes 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 little involvement of cytochrome P450. Elimination: The metabolic clearance of serum drospirenone is 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 through the intestine in a ratio of approximately 1.2: 1.4. The half-life of excretion of metabolites by the kidneys and through the intestines is approximately 40 hours. Equilibrium concentration: During one cycle of treatment, the maximum equilibrium concentration of drospirenone in serum (approximately 60 ng / ml) 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 no increase in concentration is observed. Ethinyl estradiol (30 mcg). Absorption: Ethinyl estradiol after oral administration is rapidly and completely absorbed. The maximum serum concentration after a single dose of 30 mcg is reached in 1-2 hours and is about 100 pg / ml. For ethinyl estradiol, a significant “first pass” effect with high individual variability is expressed. Absolute bioavailability varies and is approximately 45%. Distribution: The apparent volume of distribution is about 5 l / kg, the association with plasma proteins is about 98%. Ethinyl estradiol induces the synthesis of SHBG and transcortin in the liver. With a daily intake of 30 μg of ethinyl estradiol, the plasma concentration of SHBG rises from 70 nmol / L to about 350 nmol / L. Ethinyl estradiol in small quantities passes into breast milk (approximately 0.02% of the dose). Biotransformation: Ethinyl estradiol is completely metabolized. (The rate of metabolic clearance is 5 ml / min / kg). Elimination: 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 half-life for excretion of metabolites is approximately 1 day. The elimination half-life is 20 hours.Equilibrium concentration: The state of equilibrium concentration is reached during the second half of the treatment cycle. Selected Populations Impact on renal function. The equilibrium serum concentration of drospirenone in women with a weak degree of renal failure (creatinine clearance (CK) = 50-80 ml / minute) was comparable to that in women with normal renal function (CK> 80 ml / minute). The serum concentration of drospirenone was, on average, 37% higher in women with moderate renal failure (CK = 30-50 ml / minute) compared to women with normal renal function. Drospirenone therapy was well tolerated in women with both mild and moderate renal failure. Drospirenone treatment had no clinically significant effect on serum potassium concentration. Effect on liver function: In women with moderate hepatic insufficiency (class B, Child-Pugh classification), the average plasma concentration curve did not correspond to that in women with normal liver function. The values of the maximum concentration (Stah) 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 liver failure, compared with people with normal liver function. After a single dose, total clearance (C1 / F) in volunteers with moderate hepatic insufficiency was reduced by about 50% compared with people with normal liver function. The marked decrease in the clearance of drospirenone in volunteers with moderate hepatic impairment does not lead to any significant differences in serum potassium concentration. Even with diabetes mellitus and simultaneous treatment with spironolactone (two factors that can trigger hyperkalemia in a patient), there was no increase in serum potassium above the upper limit of normal. It can be concluded that the combination of drospirenone / ethinyl estradiol is well tolerated by patients with moderate hepatic impairment (Child-Pugh class B).
Indications
Contraception. Additional benefits for patients with puffiness, hormone-dependent fluid retention or weight gain, with seborrhea and acne
Contraindications
Median pills can not be prescribed for the following conditions, and also requires cancellation when they are first developed while taking this drug: hypersensitivity to the components. Thrombosis of deep veins, arteries or pulmonary embolism by thrombus, as well as hereditary or acquired predisposition to them. Myocardial infarction. Various thrombosis precursors: transient ischemic attack (TIA) or angina pectoris. Atrial fibrillation, uncontrollable arterial hypertension. Complicated damage to the valves of the heart. Cerebrovascular diseases. Surgical intervention with a long term immobilization (immobilization). Smoking after 35 years. Renal, liver failure, liver tumor. Risk factors for arterial thrombosis: severe hypertension and dyslipoproteinemia, diabetes mellitus. Hyperhomocysteinemia. Pancreatitis, severe hypertriglyceridemia. Deficiencies: antithrombin iii, protein c or s. Severe forms and exacerbations of liver diseases until complete normalization of liver tests. Suspected or established hormone-dependent malignant diseases of the reproductive system. Bleeding from the vagina of unknown origin. Migraine. Pregnancy or suspicion, breastfeeding. Lactase enzyme deficiency, galactosemia, glucose-galactose malabsorption. Caution should be used for obesity, dyslipoproteinemia, controlled arterial hypertension, chloasma, the postpartum period.
Precautionary measures
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 cancel the combined oral contraceptive.
Use during pregnancy and lactation
During pregnancy and lactation, the use of the drug MIDIANA is contraindicated.If the pregnancy occurred on the background of hormonal contraception, immediate withdrawal of the drug is necessary. The few data available on unintentionally negligently taking combined oral contraceptives indicate the absence of a teratogenic effect and an increased risk for children and women during childbirth. Combined oral contraceptives affect lactation, 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 can affect the baby. The use of combined oral contraceptives is possible after complete cessation of breastfeeding.
Dosage and administration
Take the pill inside, you can drink water (small amount), every day (starting from the 1st day of the natural menstrual cycle, that is, menstrual bleeding) at about the same time in the sequence indicated on the blister: one tablet 3 weeks, then a 7-day interval is necessary for the onset of menstrual bleeding. When replacing with another combined oral contraceptive, vaginal ring or transdermal patch, it is preferable to start using Midiana the next day after consuming the last pill or on the day of removing any previously used drug. You can switch to taking Midiana pills with a mini-pill on any day, on the day of removing the implant or other intrauterine contraceptive, on the day of the next injection, while it is desirable to use additional barrier methods of contraception in the first week. If the pregnancy was interrupted in the 1st trimester, then start taking immediately without additional contraceptive measures, if the pregnancy is interrupted in the 2nd trimester or a child is born, then start taking in 3-4 weeks. A longer interval requires the use of additional barrier methods of contraception in the first week. If sexual intercourse occurred, you must first completely eliminate the pregnancy or wait for the 1st menstruation. Scheme of taking missed pills. In case of a delay in taking the pill within 12 hours, the contraceptive protection of the drug will decrease, so it is recommended to take the pill immediately and continue further intake in the usual way.If the delay is more than 12 hours, then in the further tactics of taking the drug, you should use 2 simple rules: It is impossible to stop taking the contraceptive for more than 1 week. To achieve adequate inhibition of the hypothalamic-pituitary system of the functioning of the ovaries, a 7-day continuous intake of the drug is required. In daily practice, the following recommendations will come in handy: In the first week, take the last missed dose as soon as possible, up to taking 2 pills at the same time. In the future, the pills are taken at the usual set time, however, it is recommended to additionally use barrier methods of contraception for 7 days, otherwise the likelihood of pregnancy is possible, and it directly depends on the number of missed pills and proximity to the 7-day break of the drug. In the second week, take the last missed dose as soon as possible and continue as usual. If the previous 7 days of intake were correct, then you can not use barrier contraceptives, but if more than 1 tablet is missed, then without them, sex is not desirable. In the third week, the probability of a decrease in the contraceptive effect is significantly increased, this is due to the upcoming 7-day skipping of taking pills. To prevent a decrease in contraceptive action, you can correct the schedule for taking the drug. If the previous 7 days the course is not interrupted, then you can do without barrier contraception, otherwise - it is necessary and we must act in one of two ways. First: you should take the drug as soon as possible and continue as usual, then you need to start a new package without a break between the packages (most often there is no withdrawal bleeding, but there may be spotting or complications such as breakthrough uterine bleeding). Second: stop taking the pills from the current packaging for 7 days for withdrawal bleeding, including missed days of administration, then continue with the new packaging. In order to delay the withdrawal bleeding, it is necessary not to stop taking the drug, that is, not to take a break between the packages. Delay may be until the end of the 2nd package, however, with a lengthening of the cycle, spotting bleeding from the vagina or complications such as breakthrough uterine bleeding may occur. Next, resume receiving, starting with a new pack after the standard 7-day interval.In order to postpone the onset of withdrawal bleeding to another day, it is necessary to shorten the nearest break to as much as necessary. Remember that the smaller the interval, the greater the risk of the absence of withdrawal bleeding and spot bleeding (or complications such as breakthrough uterine bleeding) in taking the 2nd package. If taking Median pills is accompanied by severe reactions from the gastrointestinal tract, for example, vomiting or diarrhea, this means that the drug may not be completely absorbed, therefore it is recommended to use other contraceptive measures. If a vomiting attack occurs after taking the pill after 3-4 hours, then a new pill should be taken as soon as possible. If possible, take a new pill within 12 hours after the usual prescribed time of admission. If more than 12 hours have passed, then you need to act in accordance with the rules of admission. If you do not plan to change the normal mode of administration, then take an additional one or more pills from the following package.
Side effects
The incidence of side effects is: ≥ one in 100 to
Overdose
Information about the overdose of drospirenone and ethinyl estradiol-containing drugs is not available.However, nausea, vomiting and bloody vaginal discharge / bleeding may occur. There is 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: Effect on liver metabolism: Some drugs due to induction of microsomal enzymes capable of increasing the clearance of hormones (phenytoin, barbiturates, primidone, carbamazepine and rifampicin; maybe the same effect oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin and vegetable means on the basis of Hypericum perforatum (Hypericum perforatum). It was reported about the possible action of HIV protease inhibitors (for example, ritonavir) and non-nucleoside inhibitors of reverse oh transcriptase (eg, nevirapine) and their combinations on metabolism in the liver. Effects on enterohepatic hepatitis Clinical observations show that simultaneous use with some antibiotics, such as penicillins and tetracyclines, reduces the enterohepatic recirculation of estrogens, which can lead to a decrease in estradiol concentrations: Women taking any of the above classes of drugs should use a barrier method of contraception in addition to the drug MIDIANA or Take any other contraceptive method. 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 Midiana, the following package should be started without the usual interruption in the intake.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 on other drugs. Oral contraceptives can affect the metabolism of other medicines. In addition, their concentrations in plasma and tissues may change, both increasing (for example, cyclosporine) and decreasing (for example, lamotrigine). Based on the results of in vitro inhibition studies and in vivo interaction studies in female volunteers taking omeprazole, simvastatin, and midazolam as substrate indicators, 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 who receive oral contraceptives simultaneously with other drugs that increase the concentration of potassium in the blood serum: angiotensin converting enzyme inhibitors (ACE), angiotensin II receptor antagonists, some nonsteroidal anti-inflammatory drugs (eg indometacin) , 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 Hormone contraceptives can affect the results of individual laboratory tests, including biochemical indicators of liver, thyroid, adrenal glands and kidney function, as well as the concentration of transport plasma proteins such as corticosteroid binding globulin and lipid / lipoprotein fractions, carbohydrate metabolism, coagulation fibrinolysis. Changes usually occur within laboratory norms. Due to its small anti-mineralocorticoid activity, drospirenone increases renin activity and plasma aldosterone concentrations.
special instructions
The frequency of venous thromboembolism (VTE) using a low-dose estrogen combination oral contraceptive (<50 µg ethinyl estradiol, such as Midian) is about 20 to 40 cases per 100,000 women per year, which is slightly higher than for women who do not use hormonal contraceptives (5 to 10 cases per 100,000 women), but lower than women during pregnancy (60 cases per 100,000 pregnancies). An additional risk of VTE is noted during the 1st 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, such as hepatic, mesenteric, renal, cerebral and retinal vessels, both arteries and veins, have been taken in those taking oral hormonal contraceptives. The causal relationship to the occurrence of these side effects with the use of combined oral contraceptives has not been proven. The presence of one of the serious risk factors or multiple risk factors for arterial or venous disease, respectively, may be contraindicated. Women using combined oral contraceptives should immediately consult 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). The increased risk of thromboembolism in the postpartum period should be considered. Other diseases that are associated with severe vascular disease include diabetes mellitus, SLE, 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 during the use of combined oral contraceptives (which may precede cerebrovascular impairment) may be grounds for immediate discontinuation of these drugs.Tumors: The most significant risk factor for cervical cancer is infection with human papillomavirus. Some epidemiological studies have reported an increased risk of cervical cancer with long-term use of combined oral contraceptives, but there are conflicting opinions about the extent to which these findings relate to concomitant factors, such as testing for cervical cancer 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) for 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 cancers in women who have ever taken combined oral contraceptives were less clinically pronounced than women who had never taken them. In rare cases, against the background of the use of combined oral contraceptives, the development of benign liver tumors was observed; and even more rare - 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 the possibility of a woman taking combined oral contraceptives, severe pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding. Other conditions: The progesterone component in Midian's preparation is an aldosterone antagonist capable of retaining potassium.In most cases, there is no increase in potassium concentration. However, in a clinical study 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 1st cycle of taking the drug in patients with renal insufficiency and the values of potassium concentration before treatment for VGN, as well as the simultaneous 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 ruled out while taking combined oral contraceptives. Although a small increase in blood pressure has been described in many women taking combined oral contraceptives, clinically significant increases have been rare. Only in rare cases is it necessary to immediately discontinue the use of combined oral contraceptives. If during the reception of combined oral contraceptives in patients with arterial hypertension, the values of blood pressure are constantly increased or do not decrease when taking antihypertensive drugs, the use of combined oral contraceptives should be stopped. If necessary, taking combined oral contraceptives can be continued if normal blood pressure values are achieved with the help of antihypertensive therapy.