Midiana, 63 pcs.

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

Midiana® is a combination oral contraceptive containing ethinylestradiol and drospirenone. At a therapeutic dose, drospirenone also has antiandrogenic and mild anti-mineralocorticoid properties.

It is devoid of any estrogenic, glucocorticoid and antiglucocorticoid activity. This provides drospirenone with a pharmacological profile similar to that of natural progesterone.

There is evidence for a reduced risk of endometrial and ovarian cancer with combined oral contraceptives.

Pharmacokinetics

Drospirenone

Intake. When taken orally, drospirenone is rapidly and almost completely absorbed. Cmax of active substance in serum is 37 ng/ml, Tmax is 1-2 h after a single dose. During 1 cycle of administration the maximum Css of drospirenone in serum is about 60 ng/ml and is reached after 7-14 hours. Bioavailability ranges from 76 to 85%. Food intake does not affect the bioavailability of drospirenone.

Distribution. After oral administration, there is a biphasic decrease in serum concentration of drospirenone, characterized by a T1/2 (1.6±0.7) and (27±7.5) h, respectively. Drospirenone binds to serum albumin and does not bind to sex hormone-binding globulin (hSPH) and corticosteroid-binding globulin (transcortin). Only 3-5% of the total serum concentration of the active ingredient represents free hormone. The ethinylestradiol-induced increase in hGHG does not affect the binding of drospirenone by serum proteins. Mean apparent Vd is (3.7±1.2) l/kg.

Biotransformation. After oral administration drospirenone undergoes significant metabolism. Most metabolites in plasma are represented by acidic forms of drospirenone, obtained by opening the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate, which are formed without involvement of the cytochrome P450 system. According to in vitro studies, drospirenone is metabolized with negligible involvement of cytochrome P450.

Elimination. The metabolic clearance rate of drospirenone in serum is (1.5±0.2) ml/min/kg. Drospirenone is excreted only in trace amounts unchanged. Drospirenone metabolites are excreted by the kidneys and through the intestine at a ratio of about 1.2:1.4. T1/2 for excretion of metabolites by the kidneys and through the intestine is approximately 40 h.

Css. During the 1st cycle of treatment, the maximum Css (approximately 60 ng/ml) of drospirenone in serum is reached after 7-14 h. There is a 2-3-fold increase in drospirenone concentration. A further increase in serum concentration of drospirenone is observed after 1-6 cycles of administration, after which no increase in concentration is observed.

Ethinylestradiol

Intake. Ethinylestradiol is quickly and completely absorbed after oral administration. Cmax after a single dose of 30 mcg is about 100 pg/ml, Tmax is 1-2 hours. For ethinylestradiol a significant first pass effect with high individual variability is expressed. Absolute bioavailability varies and is approximately 45%.

Distribution. The apparent Vd is about 5 l/kg and the binding to plasma proteins is about 98%. Ethinylestradiol induces the synthesis of hGH and transcortin in the liver. Daily administration of 30 mcg of ethinylestradiol increases plasma HGH concentration from 70 to about 350 nmol/L. Ethinylestradiol passes into breast milk in small amounts (about 0.02% of the dose).

Biotransformation. Ethinylestradiol is completely metabolized. The metabolic clearance rate is 5 ml/min/kg.

Elimination. Ethinylestradiol is practically not excreted unchanged. Metabolites of ethinylestradiol are excreted by the kidneys and through the intestine at a ratio of 4:6. The T1/2 for excretion of metabolites is approximately 1 day. The elimination T1/2 is 20 h.

Css. The Css state is reached during the 2nd half of the treatment cycle.

Particular populations

The effect on renal function. Serum Css of drospirenone in women with mild renal impairment (creatinine Cl 50-80 ml/min) was comparable to that in women with normal renal function (creatinine Cl >80 ml/min). Serum drospirenone concentrations were 37% higher, on average, in women with moderate renal impairment (creatinine Cl 30-50 ml/min) compared to those in women with normal renal function. Drospirenone therapy was well tolerated by women with mild to moderate renal impairment.

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

The effect on liver function. In women with moderate hepatic impairment (class B according to Child-Pugh classification) the curve of average plasma concentration did not correspond to that in women with normal liver function. The Cmax values observed during the absorption and distribution phase were similar. During the end of the distribution phase, the decrease in drospirenone concentration was approximately 1.8 times greater in volunteers with moderate hepatic impairment compared to those with normal liver function.

After a single dose, total clearance in volunteers with moderate hepatic impairment was approximately 50% lower compared to those with normal liver function.

The observed decrease in drospirenone clearance in volunteers with moderate hepatic impairment does not result in any significant difference in serum potassium concentration. Even with diabetes mellitus and concomitant treatment with spironolactone (two factors that can provoke hyperkalemia in a patient) there was no increase in serum potassium concentration above the IOP.

It can be concluded that the drospirenone/ethinylestradiol combination is well tolerated in patients with moderate hepatic impairment (Child-Pugh class B).

Indications

Preventing pregnancy.

Active ingredient

Composition

Active ingredients:

ethinylestradiol 30 mcg,

drospirenone 3 mg,

Associates:

Lactose monohydrate,

Corn starch,

Pregelatinized corn starch,

Povidone K25,

Magnesium stearate,

Shell:

Opadray II white 85G18490 (polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, soy lecithin).

How to take, the dosage

The tablets should be taken at approximately the same time each day, if necessary with a small amount of liquid, in the sequence indicated on the blister pack. One tablet/day should be taken for 21 consecutive days. Taking pills from each subsequent package should be started after a 7-day interval in the intake of pills, during which menstrual bleeding usually occurs. It usually begins 2 to 3 days after taking the last pill and may not end by the time the next package begins.

If hormonal contraceptives have not been used previously (in the last month), the combined oral contraceptive starts on day 1 of a woman’s natural menstrual cycle (that is, on day 1 of her menstrual bleeding).

In case of replacement of another combined oral contraceptive, vaginal ring, or transdermal patch, it is preferable to start Midiana the day after taking the last active pill of the previous combined oral contraceptive; in such cases, Midiana should not be started later than the day after a normal pill interruption or taking inactive pills of her previous combined oral contraceptive. When replacing a vaginal ring or transdermal patch, the Midiana oral contraceptive should preferably be started on the day of removal of the previous product; in such cases, Midiana should be started no later than the day of the intended replacement procedure.

In case of progestin-only replacement methods (mini-pills, injectable forms, implants) or intrauterine contraceptives with progestin release: a woman may switch from a mini-pill on any day (from an implant or intrauterine contraceptive – on the day of its removal, from an injectable form – from the day when the next injection should have been made). However, in all these cases, it is advisable to use an additional barrier method of contraception during the first 7 days of taking the pills.

After a pregnancy termination in the first trimester, a woman can start taking the pills immediately. No additional contraceptive measures are necessary if this condition is met.

After giving birth or terminating a pregnancy in the second trimester, it is preferable for women to start Midiana on day 21-28 after giving birth or terminating a pregnancy in the second trimester. If administration is started later, it is necessary to use an additional barrier method of contraception during the first 7 days of taking the pills. If you have sexual intercourse before starting the drug, pregnancy must be excluded or you must wait for your first menstrual period.

Missed pills

If the pill is taken less than 12 hours late, contraceptive protection is not reduced. The woman needs to take the pill as soon as possible, and the next pills are taken at the usual time.

If the delay in taking the pills is more than 12 hours, contraceptive protection may be reduced. Tactics for missed pills are based on the following two rules:

1) the pills should not be discontinued for more than 7 days;

2) 7 days of continuous pills are needed to achieve adequate suppression of the hypothalamic-pituitary-ovarian system.

Week 1

The last missed pill should be taken as soon as possible, even if this means taking two pills at the same time. The next pill is taken at the usual time. Additionally, a barrier method of contraception must be used for the next 7 days. If sexual intercourse occurred during the 7 days before skipping the pill, the possibility of pregnancy must be considered. The more pills you miss and the closer this skip is to the 7-day break in medication, the greater the risk of pregnancy.

Week 2

The last pill you missed should be taken as soon as possible, even if that means taking two pills at once. The next pill is taken at the usual time. If the woman has taken the pills correctly in the previous 7 days, there is no need to use additional contraception. However, if she missed more than 1 pill, it is necessary to use additional contraceptive measures in the next 7 days.

Week 3

The likelihood of a reduction in contraceptive effect is significant because of the upcoming 7-day break in pills. However, by adjusting your pill schedule, you can prevent a decrease in contraceptive protection. If either of the following two tips are followed, no additional contraceptive methods will be needed if the woman has taken all pills correctly in the preceding 7 days before missing the pill. If not, she should follow the first of the two ways and also use additional contraception for the next 7 days.

1. The last missed pill should be taken as soon as possible, even if it means taking two pills at the same time. The next tablet is taken at the usual time. The pills from a new pack should be started as soon as the current pack is finished, that is, without a break between the two packs. It is most likely that you will not have a bleeding discontinuation until the end of the second pack, but you may have a mucosal bleeding or breakthrough uterine bleeding on the days you take the pills.

2. A woman may be advised to stop taking the pills in this package. Then she should stop taking the pills for 7 days, including the days she forgot to take the pills, and then start taking the pills from the new package.

If the pills are missed and there is no bleeding cancellation at the first free interval, pregnancy must be ruled out.

Gastrointestinal disorders

In case of severe gastrointestinal reactions (such as vomiting or diarrhea), absorption may be incomplete and additional contraceptive measures should be used.

If vomiting occurs within 3 to 4 hours after taking the tablet, a new replacement tablet should be taken as soon as possible. If possible, the new tablet should be taken within 12 h after the usual time of ingestion. If more than 12 hours are missed, if possible, the rules for taking the drug, specified in the section “Taking missed pills”, should be followed.

If a patient does not want to change her normal medication regimen, she should take an additional tablet, (or more pills) from another package.

How to delay a bleeding withdrawal

To delay the day a bleeding withdrawal begins, you must continue taking Midiana from the new pack without interruption. Postponement is possible until the pills in the second pack are finished.

When your cycle is prolonged, you may experience a vaginal discharge or breakthrough uterine bleeding. You should resume taking Midiana from the new pack after the usual 7-day break. To postpone the start day of bleeding to another day of the week of the usual schedule, shorten the nearest break in your pills by as many days as necessary. The shorter the interval, the greater the risk that there will be no bleeding cancellation and that you will experience oozing and breakthrough uterine bleeding while taking pills from the second pack (just like delaying the start of a bleeding cancellation).

Interaction

Interactions between oral contraceptives and other medications may result in uterine bleeding breakthroughs and/or decreased contraceptive reliability. The following interactions have been described in the literature.

The effect on liver metabolism

Some drugs (phenytoin, barbiturates, primidone, carbamazepine and rifampicin) due to induction of microsomal enzymes can increase the clearance of sex hormones. The same effect of oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin, and the herbal remedy St. John’s wort is possible.

Possible effects of HIV protease inhibitors (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine) and their combinations on liver metabolism have been reported.

The effect on intestinal-hepatic recirculation

Clinical observations indicate that concomitant use with certain antibiotics, such as penicillins and tetracyclines, reduces intestinal-hepatic recirculation of estrogen, which may lead to decreased concentrations of ethinylestradiol.

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 ingredients that affect microsomal liver enzymes must use an additional non-hormonal contraceptive method within 28 days of 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 while taking the drug and for 7 days after its withdrawal.

If concomitant use of the drug is started at the end of a package of Midiana, the next package should be started without the usual interruption of intake. The main metabolism of drospirenone in human plasma occurs without the involvement of the cytochrome P450 system. Inhibitors of this enzyme system thus do not affect the metabolism of drospirenone.

The effect of Midiana on other drugs

The oral contraceptives may affect the metabolism of other drugs. In addition, their plasma and tissue concentrations may change: both increased (e.g., cyclosporine) and decreased (e.g., lamotrigine).

Based on the results of in vitro inhibition studies and in vivo interaction studies in female volunteers taking omeprazole, simvastatin and midazolam as indicator-substrates, the effect of drospirenone at 3 mg on the metabolism of other active substances is unlikely.

Other interactions

There is a theoretical possibility of increased serum potassium concentration in women receiving oral contraceptives concomitantly with other drugs that increase serum potassium concentration: ACE inhibitors, angiotensin II receptor antagonists, some NSAIDs (such as indomethacin), potassium-saving diuretics, and aldosterone antagonists. However, in a study evaluating the interaction of an ACE inhibitor with drospirenone+ethinylestradiol combination in women with moderate arterial hypertension, no significant difference was found between serum potassium concentrations in women receiving enalapril and placebo.

Laboratory studies

. Taking hormonal contraceptives may affect the results of selected laboratory tests, including biochemical measures of liver, thyroid, adrenal, and renal function, as well as concentrations of plasma transport proteins such as corticosteroid-binding globulin and lipid/lipoprotein fractions, carbohydrate metabolism, blood clotting, and fibrinolysis measures. Changes usually occur within laboratory norms.

Due to its small anti-mineralocorticoid activity, drospirenone increases renin activity and plasma aldosterone concentrations.

Special Instructions

If any of the conditions/risk factors listed below are currently present, the potential risks and expected benefits of the combined oral contraceptive should be carefully weighed on a case-by-case 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 first appear, the woman should consult her doctor, who may decide if the combined oral contraceptive should be discontinued.

Circulatory system disorders

The incidence of venous thromboembolism (VTE) with the combined oral contraceptive with low-dose estrogen (< 50 mcg of ethinylestradiol, such as Midiana) is about 20 to 40 cases per 100,000 women per year, which is slightly higher than for women not using hormonal contraceptives (5 to 10 cases per 100,000 women) but lower than for women during pregnancy (60 cases per 100,000 pregnancies).

An additional risk of VTE is noted 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. Very rare cases of thrombosis of other blood vessels, such as hepatic, mesenteric, renal, cerebral, and retinal vessels, both arteries and veins, have been described in those taking oral hormonal contraceptives. A causal 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 irrigation to the left arm;

– sudden shortness of breath;

– sudden onset of coughing;

– any unusual, severe, prolonged headache;

– sudden partial or total loss of vision;

– diplopia;

– slurred speech or aphasia;

– dizziness;

– loss of consciousness with or without a seizure;

– weakness or very significant loss of sensation, suddenly appearing from one half or in one part of the body;

– motor disturbances;

– “acute abdominal” symptom.

The risk of VTE-related complications when taking the combined oral contraceptive increases:

– with age;

– if there is a family history (venous or arterial thromboembolism in close relatives or parents at a relatively young age); If a hereditary predisposition is suspected, a woman needs to consult a specialist before prescribing a combined oral contraceptive;

After prolonged immobilization, major surgery, any leg surgery, or extensive 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 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;

In obesity (BMI over 30 mg/m2).

The risk of arterial thrombosis and thromboembolism increases with combined oral contraceptive use:

– with age;

– in smokers (women over the age of 35 are strictly advised not to smoke if they want to use combined oral contraceptives);

– In dyslipoproteinemia;

– In arterial hypertension;

– In migraine;

– In heart valve disease;

– In atrial fibrillation.

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

Women using combined oral contraceptives should consult a physician 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 choose an adequate method of contraception due to teratogenicity of anticoagulant therapy (coumarins).

The increased risk of thromboembolism in the postpartum period should be considered.

Other conditions 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 anemia.

An increase in the frequency and severity of migraines during use of combined oral 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 papillomavirus. Some epidemiological studies have reported an increased risk of cervical cancer with long-term use of combined oral contraceptives, but conflicting opinions remain about the extent to which these findings relate to comorbidities, such as cervical cancer screening or use of barrier methods of contraception.

A meta-analysis of 54 epidemiologic studies demonstrated that there is a slightly increased relative risk (OR = 1.24) of developing breast cancer diagnosed in women who were using combined oral contraceptives at the time of the study. The excess risk gradually decreased over a 10-year period after discontinuation of the combined oral contraceptives. Because breast cancer rarely occurs in women younger than 40 years of age, the increase in breast cancer diagnosed in recent years in women who have taken or are taking combined oral contraceptives is small in relation to the overall risk of developing breast cancer. These studies do not support a causal relationship between taking the combined oral contraceptives and breast cancer. The observed increase in risk may be a consequence of 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, development of benign liver tumors has been observed during the use of combined oral contraceptives, and in even rarer cases, malignant tumors. In some cases, these tumors have caused life-threatening intra-abdominal bleeding. In the differential diagnosis of a liver tumor we should consider when a woman taking combined oral contraceptives presents with severe upper abdominal pain, liver enlargement, or signs of intra-abdominal bleeding.

Other conditions

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 insufficiency and concomitant administration of potassium retarding drugs, serum potassium concentration slightly but increased when taking drospirenone. Thus, it is recommended to check serum potassium concentration in the first cycle of the drug in patients with renal insufficiency and values of potassium concentration before treatment with IHN, as well as during concomitant use of potassium retarding drugs.

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 small increases in BP have been described in many women taking combined oral contraceptives, clinically significant increases have rarely been reported. Only in rare cases is immediate discontinuation of combined oral contraceptives necessary. If during the use of combined oral contraceptives in patients with arterial hypertension, BP values are constantly elevated or do not decrease while taking hypotensive drugs, the combined oral contraceptives should be discontinued. The combined oral contraceptives may be continued if normal BP is achieved with hypotensive therapy.

The following conditions develop or worsen both during pregnancy and while taking combined oral contraceptives, but their association with taking combined oral contraceptives has not been proven: Jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea; a history of herpes during pregnancy; hearing loss associated with otosclerosis.

In women with hereditary angioedema, exogenous estrogens may cause or exacerbate symptoms of angioedema. Acute or chronic liver dysfunction may require discontinuation of combined oral contraceptives until liver function returns to normal. Recurrent cholestatic jaundice and/or cholestasis-induced pruritus that develops for the first time during pregnancy or previous use of sex hormones requires discontinuation of combined oral contraceptives.

While combined oral contraceptives may affect 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 ethinylestradiol). Nevertheless, women with diabetes mellitus should be closely monitored by a physician, especially at the beginning of combined oral contraceptives.

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

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

Medical evaluation

Preferral with an attending gynecologist and appropriate medical examinations should be consulted before starting hormonal contraceptives. Further follow-up and the frequency of medical examinations are done 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 or other sexually transmitted diseases.

The effectiveness of combination oral contraceptives may decrease if pills are missed, if you have gastrointestinal problems, or if you are taking other medicines at the same time.

Contraindications

Midiana® should not be prescribed for any of the conditions listed below. If any of these conditions develop for the first time while taking the drug, the drug should be stopped immediately.

Side effects

The use of combined oral contraceptives may cause irregular bleeding (spotting or breakthrough bleeding), especially during the first months of use.

There have been other adverse effects with combined oral contraceptives in women, and the relationship to their use has not been confirmed, but has not been disproven.

The digestive system: frequently – nausea, abdominal pain; infrequently – vomiting, diarrhea.

CNS disorders: frequently – asthenic syndrome, headache, decreased mood, mood swings, nervousness; infrequently – migraine, decreased libido; rarely – increased libido.

Or vision: rare – contact lens intolerance (discomfort when wearing contact lenses).

As to the sexual system: often – pain in the mammary glands, mammary gland engorgement, menstrual irregularities, candidiasis of the vagina, uterine bleeding; infrequent – hypertrophy of the mammary glands; rarely – vaginal discharge, discharge from the breasts.

The skin and its appendages: common – acne; infrequent – rash, urticaria; rare – erythema multiforme.

Others: frequently – weight gain; infrequently – fluid retention; rarely – weight loss, hypersensitivity reactions.

As with other combined oral contraceptives in rare cases development of thrombosis and thromboembolism is possible.
In women with hereditary angioedema estrogen administration can cause or aggravate its symptoms.

Overdose

There are no reports of overdose of drospirenone and ethinylestradiol. However, nausea, vomiting and bloody discharge/bleeding from the vagina are possible.

Treatment: There is no specific antidote. Symptomatic treatment should be given.

Pregnancy use

The use of Midiana is contraindicated during pregnancy and lactation. If pregnancy occurs against the background of hormonal contraception, immediate discontinuation of the drug is necessary.

There are few data on unintended use of combined oral contraceptives that show no teratogenic effects and increased risks to children and women during childbirth.

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

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