Milanda film-coated tablets 3 mg + 0.03 mg blister No. 21

Instructions for use Miland film-coated tablets 3 mg + 0.03 mg blister No. 21

Composition

active ingredients: drospirenone; ethinylestradiol;

1 film-coated tablet contains drospirenone 3 mg and ethinylestradiol 0.03 mg;

Excipients: lactose monohydrate; corn starch; pregelatinized starch; crospovidone containing plasdon XL-10 and plasdon XL; povidone; polysorbate 80; magnesium stearate;

film coating: Opadry II yellow, containing: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, iron oxide yellow (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: flat, round tablets, coated with a yellow film coating.

Pharmacotherapeutic group

Sex gland hormones and drugs used in genital pathology. Hormonal contraceptives for systemic use.

Progestogens and estrogens, fixed combinations. Drospirenone and ethinylestradiol.

ATX code G03A A12.

Pharmacological properties

Pharmacodynamics

The Pearl contraceptive failure index for the drug is 0.09 (upper two-sided 95% confidence interval (CI) – 0.32).

The overall Pearl Index (contraceptive failures + patient errors) for the drug is 0.57 (upper two-sided 95% CI – 0.90).

The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of various factors, the most important of which are the suppression of ovulation and changes in cervical secretion.

The drug Milanda is a COC with ethinylestradiol and the progestogen drospirenone. In therapeutic doses, drospirenone exhibits antiandrogenic and moderate antimineralocorticoid properties. It has no estrogenic, glucocorticoid, or antiglucocorticoid activity. Therefore, drospirenone has a similar pharmacological profile to natural progesterone.

According to clinical studies, the moderate antimineralocorticoid properties of the drug Milanda lead to a moderate antimineralocorticoid effect.

Pharmacokinetics

Drospirenone

Absorption. Orally administered drospirenone is rapidly and completely absorbed. The maximum serum concentration of 38 ng/ml is reached approximately 1–2 hours after a single oral dose. Bioavailability is approximately 76–85%. Concomitant food intake does not affect the bioavailability of drospirenone.

Distribution: After oral administration, serum drospirenone concentrations decline with a mean terminal half-life of approximately 31 hours. Drospirenone is bound to serum albumin but not to sex steroid binding globulin (SSGB) or corticoid binding globulin (CBG). Only 3–5% of the total serum drospirenone concentration is present as free steroid. The increase in SSGB induced by ethinylestradiol does not affect serum protein binding of drospirenone. The mean apparent volume of distribution of drospirenone is 3.7±1.21 l/kg.

Metabolism. After oral administration, drospirenone is extensively metabolized. The main metabolites in plasma are the acid form of drospirenone, which is formed as a result of the opening of the lactone ring, as well as 4,5-dihydro-drospirenone-3-sulfate, which is formed by hydration with subsequent sulfation. Drospirenone is also the subject of oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone can weakly or moderately inhibit the cytochrome P450 enzymes: CYP1A1, CYP2C9, CYP2C19 and CYP3A4.

Elimination. The metabolic clearance of drospirenone from serum is 1.5±0.2 ml/min/kg. Only a small amount of drospirenone is excreted unchanged. The metabolites of drospirenone are excreted in the feces and urine in a ratio of approximately 1.2:1.4. The half-life of metabolites in urine and feces is about 40 hours.

Steady-state concentration: During a treatment cycle, the maximum steady-state concentration of drospirenone in serum, approximately 70 ng/ml, is reached after approximately 8 days of treatment. The serum concentration of drospirenone increased approximately 3-fold due to the ratio of the terminal half-life to the dosing interval.

Special categories of patients

Effects on hepatic impairment. In a single-dose study, oral clearance of drospirenone was reduced by approximately 50% in subjects with moderate hepatic impairment compared to volunteers with normal hepatic function. The observed difference in drospirenone clearance in subjects with moderate hepatic impairment did not result in any apparent differences in serum potassium concentrations. Even in the presence of diabetes mellitus and concomitant spironolactone therapy (two factors that can induce hyperkalemia), no increase in serum potassium concentrations above the upper limit of normal was observed. It can be concluded that drospirenone is well tolerated in subjects with mild to moderate hepatic impairment (Child-Pugh class B).

Ethnicity: No clinically significant difference in the pharmacokinetics of drospirenone or ethinyl estradiol was observed between Japanese and Caucasian women.

Ethinylestradiol

Absorption: Ethinylestradiol is rapidly and completely absorbed after oral administration. After administration of 30 mcg, peak serum concentrations of 100 pg/ml are reached within 1-2 hours. Ethinylestradiol is subject to extensive first-pass metabolism, which varies between individuals.

Absolute bioavailability is about 45%.

Distribution: The expected volume of distribution of ethinylestradiol is approximately 5 L/kg and plasma protein binding is approximately 98%. Ethinylestradiol induces hepatic synthesis of GHB and corticosteroid-binding globulins. When used
30 mcg of ethinylestradiol increases plasma GSH concentration from 70 to about
350 nmol/l.

Ethinylestradiol is excreted in breast milk in small amounts (0.02% of the dose).

Metabolism: Ethinylestradiol is extensively metabolized in the gastrointestinal tract (GI) and during first-pass metabolism. Ethinylestradiol is primarily metabolized by aromatic hydroxylation to form a large number of hydroxylated and ethylated metabolites, which are present as free metabolites and glucuronide and sulfate conjugates. The metabolic plasma clearance of ethinylestradiol is approximately 5 ml/min/kg. In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2, and based on the mechanism of action, an inhibitor of CYP3A4/5, CYP2C8 and CYP2J2.

Excretion. Ethinylestradiol is not excreted unchanged in significant quantities. Ethinylestradiol metabolites are excreted in urine and bile in a ratio of 4:6. The half-life of metabolites is about 1 day.

Steady-state concentration. Steady-state concentration is reached during the second half of the therapy cycle, with serum ethinylestradiol levels increasing approximately
1.4 – 2.1 times.

Preclinical safety data.

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with the known pharmacological action. In particular, reproductive toxicity studies in animals showed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those observed in users of the drug Milanda, effects on sexual differentiation were observed in some animal species.

Indication

Oral contraception.

Contraindication

Combined hormonal contraceptives (CHCs) should not be used if any of the conditions listed below are present. If any of these conditions appear for the first time during CHC use, they should be stopped immediately.

Presence or risk of venous thromboembolism (VTE): current (while on anticoagulant therapy) or history of venous thromboembolism (e.g. deep vein thrombosis (DVT), pulmonary embolism (PE)); known hereditary or acquired predisposition to venous thromboembolism, such as resistance to activated protein C (including factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency;

major surgical interventions with prolonged immobilization (see section "Special instructions for use");

high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special warnings and precautions for use").

Presence or risk of arterial thromboembolism (ATE): current or history of arterial thromboembolism (e.g. myocardial infarction) or presence of prodromal symptoms (e.g. angina); current or history of cerebrovascular accident, presence of prodromal symptoms (e.g. transient ischemic attack (TIA)); known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); history of migraine with focal neurological symptoms;

Current or history of pancreatitis associated with severe hypertriglyceridemia. Current or history of severe liver disease until liver function tests have returned to normal. Current or history of liver tumors (benign or malignant). Known or suspected malignant tumors (e.g., genital or breast) that are sex hormone dependent. Known or suspected pregnancy. Vaginal bleeding of unknown etiology. Hypersensitivity to the active substances or to any of the excipients.

The drug Sofita® is contraindicated when used concomitantly with drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir (see sections “Special instructions” and “Interaction with other medicinal products and other types of interactions”).

Interaction with other medicinal products and other types of interactions

The information for the concomitant medicinal product should be consulted to identify potential interactions.

The effect of other medicines on the drug Milanda.

Interactions are possible with drugs that induce microsomal enzymes. This will lead to an increase in the clearance of sex hormones, which also causes changes in the pattern of menstrual bleeding and/or loss of contraceptive effectiveness.

Therapy

Enzyme induction can be detected after a few days of treatment. Maximum enzyme induction is generally observed after a few weeks. After discontinuation of treatment, enzyme induction may persist for about 4 weeks.

Short-term treatment

Women taking enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method should be used throughout the entire period of treatment with the drug and for 28 days after stopping its use. If therapy is started during the last COC tablet-free period, the next COC tablet-free period should be started immediately after the previous tablet-free period without the usual interval.

Long-term treatment

For women on long-term therapy with active substances that induce liver enzymes, a barrier or other appropriate non-hormonal method of contraception is recommended.

The following interactions have been reported based on published data.

Active substances that increase COC clearance (reduced COC efficacy due to enzyme induction), for example:

barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; medicines used for HIV infection: ritonavir, nevirapine and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate and herbal medicines containing St. John's wort extract (Hypericum perfiratum).

Active substances with inconsistent effects on COC clearance

When used concomitantly with COCs, a large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, may increase or decrease plasma concentrations of estrogen or progestins. The cumulative effect of such changes may be clinically significant in some cases.

Therefore, the prescribing information for the concomitant HIV/HCV medicinal product should be consulted for potential interactions and any other recommendations. In case of any doubt, women should additionally use a barrier method of contraception during treatment with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Active substances that reduce COC clearance (enzyme inhibitors)

The clinical significance of the potential interaction with enzyme inhibitors remains unclear.

Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of estrogen or progestin, or both.

In a multiple-dose study of the combination drospirenone (3 mg/day)/ethinyl estradiol
(0.002 mg/day) and the strong CYP3A4 inhibitor ketoconazole, administered concomitantly for 10 days, increased the AUC(0-24h) of drospirenone and ethinylestradiol in
2.7 and 1.4 times respectively.

Etoricoxib at doses of 60 to 120 mg/day has been shown to increase plasma concentrations of ethinylestradiol by 1.4- to 1.6-fold, respectively, when co-administered with a CHC containing 0.035 mg ethinylestradiol.

The effect of the drug Milanda on other drugs.

Oral contraceptives may affect the metabolism of some active substances. Accordingly, plasma and tissue concentrations may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrates, it was found that a clinically significant interaction of drospirenone at a dose of 3 mg with other active substances induced by cytochrome P450 is unlikely.

Clinical data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, causing a mild (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentrations.

In patients with normal renal function, concomitant use of drospirenone and ACE inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) has not shown a significant effect on serum potassium levels. However, concomitant use of Milinda and aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium levels should be monitored during the first treatment cycle (see also section "Special warnings and precautions for use").

Laboratory tests

The use of contraceptive steroids may affect the results of some laboratory tests, such as biochemical parameters of liver, thyroid, adrenal and renal function, plasma concentrations of transport proteins such as corticosteroid-binding globulin, plasma concentrations of lipid/lipoprotein fractions, and parameters of carbohydrate metabolism, coagulation and fibrinolysis. These changes are usually within normal limits.

Drospirenone increases plasma renin and aldosterone activity, which is induced by its moderate antimineralocorticoid activity.

Application features

The decision to prescribe Milanda should take into account the woman's individual risk factors, including her current risk factors for VTE, and the risk of VTE associated with Milanda compared with other CHCs (see sections "Contraindications" and "Special Instructions").

Warning

If any of the conditions or risk factors listed below are present, the appropriateness of using Milanda should be discussed with the woman. In the event of exacerbation or at the first appearance of any of the listed conditions or risk factors, women are advised to consult a doctor and determine the need to discontinue Milanda. In the event of suspected or confirmed VTE or ATE, CHC use should be discontinued. If anticoagulant therapy is initiated, alternative adequate contraception should be provided due to the teratogenic effects of anticoagulants (coumarins). Circulatory disorders.

Risk of developing VTE

The use of any CHC increases the risk of VTE in women who use it compared with those who do not use it. Products containing levonorgestrel, norgestimate or norethisterone are associated with a lower risk of VTE. The use of other products such as Mirtazapine may lead to a twofold increase in risk. The decision to use products other than those with the lowest risk of VTE should only be made after discussion with the woman. It should be ensured that she is aware of the risk of VTE associated with Mirtazapine, the extent to which her existing risk factors are affected and that the risk of VTE is highest during the first year of use. Some data suggest that the risk of VTE may increase when CHC use is resumed after a break of 4 weeks or longer.

About 2 in 10,000 women who are not taking CHCs and are not pregnant will develop a VTE in a year. However, the risk for an individual woman may be much higher depending on the risk factors she has (see below).

It has been estimated1 that out of 10,000 women using a CHC containing drospirenone, 9 to 12 will develop a VTE in one year. This compares with 62 in women using a CHC containing levonorgestrel.

In both cases, the number of VTE cases per year was lower than would normally be expected during pregnancy or in the postpartum period.

VTE can lead to fatal outcomes in 1-2% of cases.

Risk factors for developing VTE

The risk of developing venous thromboembolic complications in women using CHCs may be significantly higher in the presence of additional risk factors, especially multiple ones (see Table 1).

The use of Milanda is contraindicated in women with multiple risk factors that may increase the risk of developing venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk of developing VTE should be considered.

If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section “Contraindications”).

Table 1. Risk factors for VTE development

There is no consensus on the possible impact of varicose veins and superficial thrombophlebitis on the development and progression of venous thrombosis.

Attention should be paid to the increased risk of thromboembolism during pregnancy, especially within 6 weeks after delivery (for information on pregnancy and lactation, see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

Women should be advised to contact their doctor immediately if they experience the following symptoms and to inform them that they are using CHCs.

Symptoms of DVT may include: unilateral swelling of the leg and/or foot or areas along a vein in the leg; pain or increased sensitivity in the leg that may only be felt when standing or walking; a feeling of heat in the affected leg; redness or discoloration of the skin on the leg.

Symptoms of PE may include: sudden unexplained shortness of breath or rapid breathing; sudden cough, possibly with blood; sudden chest pain; fainting or dizziness; and a fast or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are nonspecific or may be misinterpreted as more common or less severe conditions (e.g., respiratory tract infections).

Other manifestations of vascular occlusion may include sudden pain, swelling, acute abdomen, and slight blueness of the limb.

In the case of occlusion of the vessels of the eye, the initial symptom may be blurred vision, which is not accompanied by pain, and which can progress to loss of vision. Sometimes the loss of vision develops almost instantly.

Risk of developing arterial thromboembolism (ATE)

Epidemiological studies have shown that the use of any CHC is associated with an increased risk of ATE (myocardial infarction) or cerebrovascular events (transient ischemic attack (TIA), stroke). Arterial thromboembolic events can be fatal.

Risk factors for developing ATE

The risk of arterial thromboembolic complications or cerebrovascular events increases with the use of CHCs in women with risk factors (see Table 2). The use of MILANDA is contraindicated if women have one serious or multiple risk factors for ATE that may increase the risk of arterial thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk should be considered. If the benefit/risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 2. Risk factors for the development of ATE

Symptoms of ATE

Women should be advised to contact their doctor immediately if they experience the following symptoms and to inform them that they are using CHCs.

Symptoms of a cerebrovascular accident may include: sudden numbness of the face, weakness or numbness of the limbs, especially on one side; sudden trouble walking, dizziness, loss of balance or coordination; sudden confusion, trouble speaking or understanding; sudden loss of vision in one or both eyes; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizures.

Symptoms of a myocardial infarction may include: pain, discomfort, a feeling of squeezing or heaviness in the chest, arm or below the breastbone; discomfort radiating to the back, jaw, throat, arm, stomach; a feeling of fullness in the stomach, indigestion or shortness of breath; increased sweating, nausea, vomiting or dizziness; extreme weakness, anxiety or shortness of breath; fast or irregular heartbeat.

Tumors

The results of some epidemiological studies indicate an additional increase in the risk of developing cervical cancer with long-term use of COCs (> 5 years), but this statement remains controversial, since it is not yet clear to what extent the results of the studies take into account concomitant risk factors, such as sexual behavior, and other factors, such as human papillomavirus infection.

A meta-analysis of 54 epidemiological studies suggests a small increased relative risk (RR = 1.24) of breast cancer in women who use COCs. This increased risk gradually disappears within 10 years after stopping COCs. Since breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnoses in women who use or have recently used COCs is small in relation to the overall risk of breast cancer. The results of these studies do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in women who use COCs, the biological action of COCs, or a combination of both. There is a trend for breast cancer detected in women who have ever used COCs to be clinically less severe than in women who have never used COCs.

In isolated cases, benign and even more rarely malignant liver tumors have been observed in women using COCs, which in some cases led to life-threatening intra-abdominal bleeding. In case of complaints of severe epigastric pain, liver enlargement or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis when using COCs.

High-dose COCs (50 mcg ethinylestradiol) reduce the risk of endometrial and ovarian cancer. It remains to be confirmed whether these findings can also be applied to low-dose COCs.

Other states

The progestin component of Milanda is an aldosterone antagonist with potassium-sparing properties. In most cases, an increase in potassium levels is not expected. In clinical studies, in some patients with mild to moderate renal insufficiency and concomitant use of potassium-sparing drugs, serum potassium levels increased slightly, but not significantly, during the use of drospirenone. Therefore, monitoring of potassium levels is recommended during the first treatment cycle in patients with renal insufficiency. These patients are also recommended to maintain serum potassium levels not above the upper limit of normal before starting the drug, especially when concomitantly using potassium-sparing drugs (see section “Interaction with other medicinal products and other forms of interaction”).

Women with hypertriglyceridemia or a family history of this disorder are at risk of developing pancreatitis when using COCs.

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant increases in blood pressure have been observed in isolated cases. Immediate discontinuation of COCs is only necessary in these isolated cases. In the case of persistent hypertension or failure to control blood pressure with antihypertensive drugs, women taking COCs should discontinue their use. If appropriate, COC use can be resumed after achieving normotensive status with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and COC use, but the relationship to estrogen/progestin use is not conclusive: jaundice and/or pruritus associated with cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham's chorea, herpes gestationis, hearing loss associated with otosclerosis.

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

The metabolism of steroid hormones may be impaired in patients with impaired liver function. Acute or chronic disorders of liver function may require discontinuation of COC use until liver function tests have returned to normal and a causal relationship to COC use has been excluded.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence to suggest that diabetic women taking low-dose COCs (<0.05 mg ethinylestradiol) should be monitored closely during COC use, especially at the beginning of treatment.

Cases of exacerbation of endogenous depression, epilepsy, Crohn's disease and ulcerative colitis have also been observed during COC use.

Chloasma may occasionally occur, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid exposure to direct sunlight or ultraviolet radiation while using COCs.

1 tablet of the drug contains 46 mg of lactose. In the presence of rare hereditary conditions of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, if you are on a lactose-free diet, you should take into account the indicated amount of lactose.

Consultations/medical examination

Before initiating or reinstituting the use of , a complete medical history (including family history) and a complete physical examination are recommended, and pregnancy should be ruled out. Blood pressure should be measured and a physical examination should be performed, taking into account the contraindications (see section 4.3) and the specifics of use (see section 4.4). The woman should be informed about the information on venous and arterial thrombosis, including the risk associated with compared with other CHCs, the symptoms of VTE and ATE, known risk factors and the actions to be taken if thrombosis is suspected.

Patients are advised to carefully read the instructions for medical use of the medicinal product and follow the recommendations contained therein.

The frequency and nature of examinations should be based on existing standards of medical practice, taking into account the individual characteristics of each woman.

Patients should be advised that hormonal contraceptives do not protect against HIV infection (AIDS) or any other sexually transmitted disease.

Decreased efficiency

The effectiveness of COCs may be reduced in the event of missed tablets (see section "Method of administration and dosage"), gastrointestinal disorders (see section "Method of administration and dosage") or when other medicines are used simultaneously (see section "Interaction with other medicines and other types of interactions").

Cycle disruption

Irregular bleeding (spotting or breakthrough bleeding) may occur when taking COCs, especially during the first few months. If such bleeding continues after 3 menstrual cycles, it should be considered serious.

If irregular bleeding persists or occurs after a period of regular bleeding, non-hormonal causes of bleeding should be considered and appropriate diagnostic measures should be taken, including examination to exclude tumors and pregnancy. Diagnostic measures may include curettage.

Some women may not have a withdrawal bleed during the tablet-free interval. If COCs are taken according to the instructions in the section "Method of administration and dosage", pregnancy is unlikely. However, if COC use has been irregular until the first withdrawal bleed is absent or if withdrawal bleeds are absent for two cycles, pregnancy should be ruled out before COC use is resumed.

Ability to influence reaction speed when driving vehicles or other mechanisms

No studies have been conducted on the effects of the drug on the ability to drive or use machines. No effects on the ability to drive or use machines have been reported in women taking combined oral contraceptives.

Use during pregnancy or breastfeeding

Pregnancy. The drug is contraindicated for use during pregnancy. If pregnancy occurs during the use of the drug Milanda, its use should be discontinued immediately. However, the results of epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers took COCs before pregnancy, as well as in