Milanda

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MILENDA (MILANDA)

Composition:

Active substances: drospirenone; ethinylestradiol;

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

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: flat, round, film-coated tablets of yellow color.

Pharmacotherapeutic group.

Sex hormones and drugs used in disorders of the genital system. Hormonal contraceptives for systemic use.

Progestogens and estrogens, fixed combinations. Drospirenone and ethinylestradiol.

ATC code G03A A12.

Pharmacological Properties

Pharmacodynamics

The Pearl Index for contraceptive failures of the drug is 0.09 (upper two-sided 95% confidence interval [CI] – 0.32).

The overall Pearl Index (contraceptive failures + user 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 several factors, the most important of which are inhibition of ovulation and changes in cervical secretion.

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

According to clinical study data, the moderate antimineralocorticoid properties of Milanda result in a moderate antimineralocorticoid effect.

Pharmacokinetics

Drospirenone

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

Distribution. After oral administration, drospirenone serum concentrations decline with a mean terminal half-life of approximately 31 hours. Drospirenone binds to serum albumin but does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 3–5% of the total drospirenone concentration in serum exists as free steroid. The increase in SHBG levels induced by ethinylestradiol does not affect drospirenone binding to serum proteins. 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, formed by opening of the lactone ring, and 4,5-dihydrodrospirenone-3-sulfate, formed via hydration followed by sulfation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone may weakly or moderately inhibit cytochrome P450 enzymes: CYP1A1, CYP2C9, CYP2C19, and CYP3A4.

Elimination. Metabolic clearance of drospirenone from serum is 1.5±0.2 mL/min/kg. Only a negligible amount of drospirenone is excreted unchanged. Drospirenone metabolites are excreted in feces and urine in a ratio of approximately 1.2:1.4. The elimination half-life of metabolites in urine and feces is approximately 40 hours.

Steady-state concentration. During the treatment cycle, the maximum steady-state concentration of drospirenone in serum—approximately 70 ng/mL—is reached after about 8 days of treatment. Serum drospirenone concentration increases by approximately 3-fold due to the relationship between the terminal half-life and the dosing interval.

Special patient populations

Effect of renal impairment. At steady state during drospirenone therapy, serum drospirenone concentrations were similar in women with mild renal impairment (creatinine clearance 50–80 mL/min) and in women with normal renal function. In women with moderate renal impairment (creatinine clearance 30–50 mL/min), serum drospirenone concentrations were on average 37% higher than in women with normal renal function. Drospirenone therapy was well tolerated in women with mild to moderate renal impairment. Drospirenone therapy showed no clinically significant effect on serum potassium concentration.

Effect of hepatic impairment. In a single-dose study, oral clearance of drospirenone was reduced by approximately 50% in subjects with moderate hepatic impairment compared to healthy volunteers. This observed deviation in drospirenone clearance in subjects with moderate hepatic impairment did not result in any apparent differences in serum potassium concentration. Even in the presence of diabetes mellitus and concomitant use of spironolactone (two factors that may predispose to hyperkalemia), serum potassium concentration did not exceed the upper limit of normal. Thus, drospirenone is well tolerated in subjects with mild to moderate hepatic impairment (Child-Pugh class B).

Ethnic origin. No clinically significant differences in the pharmacokinetics of drospirenone or ethinylestradiol were observed between Japanese women and Europeans.

Ethinylestradiol

Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. Following a 30 µg dose, peak plasma concentration of 100 pg/mL is reached within 1–2 hours. Ethinylestradiol undergoes extensive first-pass metabolism, which varies depending on individual differences.

Absolute bioavailability is approximately 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 sex hormone-binding globulin (SHBG) and corticosteroid-binding globulins. Administration of 30 µg ethinylestradiol increases plasma SHBG concentration from 70 to approximately 350 nmol/L.

A small amount of ethinylestradiol is excreted into breast milk (0.02% of the dose).

Metabolism. Ethinylestradiol is extensively metabolized in the gastrointestinal tract (GI tract) and during first-pass through the liver. Ethinylestradiol is primarily metabolized via aromatic hydroxylation, forming a large number of hydroxylated and ethylated metabolites, which exist as free metabolites and as conjugates with glucuronides and sulfates. 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 mechanism of action, an inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Elimination. Ethinylestradiol is not excreted unchanged in significant amounts. Ethinylestradiol metabolites are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is approximately 1 day. The elimination half-life of metabolites is 20 hours.

Steady-state concentration. Steady-state concentration is achieved during the second half of the treatment cycle; plasma ethinylestradiol levels increase by approximately 1.4–2.1 times.

Preclinical safety data

In laboratory animals, the effects of drospirenone and ethinylestradiol were limited to those associated with known pharmacological actions. In particular, animal studies on reproductive toxicity revealed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those in users of Milanda, effects on sexual differentiation were observed in certain animal species. Environmental risk assessment studies indicated that ethinylestradiol and drospirenone may potentially pose a risk to the aquatic environment (see section "Special precautions for safety").

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

Combined hormonal contraceptives (CHCs) must not be used if any of the following conditions are present. If any of these conditions occur for the first time during CHC use, the drug should be discontinued immediately.

• Presence or risk of venous thromboembolism (VTE):
  • Current VTE, including anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
  • known hereditary or acquired predisposition to VTE, such as activated protein C resistance (including factor V Leiden mutation), antithrombin-III deficiency, protein C deficiency, protein S deficiency;
  • major surgery with prolonged immobilization (see section "Special precautions");
  • high risk of VTE due to multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
  • current ATE or history of ATE (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);
  • current or past cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • known hereditary or acquired predisposition to ATE, such as hyperhomocysteinemia or antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • high risk of ATE due to multiple risk factors (see section "Special precautions") or due to a single serious risk factor, such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Current or past severe liver disease until liver function parameters have returned to normal limits.
• Current or past hormone-sensitive breast cancer (see section "Special precautions", subsection "Malignant neoplasms").
• Severe or acute renal failure.
• Current or past liver tumors (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms (e.g., of the genital organs).
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the drug.
• Suspected or confirmed pregnancy.

Milanda must not be used concomitantly with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Special safety measures.

This medicinal product may pose a risk to the environment (see section "Pharmacological properties"). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

The information on concomitantly administered medicinal products should be reviewed to identify potential interactions.

• Effect of other medicinal products on Milanda.

Interactions are possible with medicinal products that induce microsomal enzymes. This may lead to increased clearance of sex hormones, resulting in changes in the pattern of menstrual bleeding and/or loss of contraceptive efficacy.

Therapy

Enzyme induction may be observed within a few days of treatment. Maximum enzyme induction generally occurs after several weeks. After discontinuation of the inducing drug, enzyme induction may persist for approximately 4 weeks.

Short-term treatment

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another non-hormonal contraceptive method in addition to COCs. The barrier method should be used throughout the duration of treatment with the enzyme-inducing drug and for an additional 28 days after discontinuation. If treatment is initiated during the period of taking the last tablets of the COC pack, the next pack of COC tablets should be started immediately after the previous pack, without the usual tablet-free interval.

Long-term treatment

Women undergoing long-term therapy with enzyme-inducing substances are advised to use a barrier method or another appropriate non-hormonal contraceptive method.

The following interactions have been reported according to published data.

Active substances that increase COC clearance (reduced COC efficacy due to enzyme induction), e.g.:

barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; drugs used in HIV infection: ritonavir, nevirapine, and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and herbal medicinal products containing St. John's wort (Hypericum perforatum).

Active substances with variable effects on COC clearance

When used concomitantly with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) inhibitors, may either increase or decrease plasma concentrations of estrogens or progestins. The net effect of these changes may be clinically significant in some cases.

Therefore, information on the medical use of the medicinal product for HIV/HCV treatment taken concomitantly should be reviewed to identify potential interactions and other recommendations. In case of any doubts, women should additionally use a barrier method of contraception during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Active substances that decrease COC clearance (enzyme inhibitors)

The clinical significance of potential interactions with enzyme inhibitors remains unclear.

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

In a multiple-dose study of the combination drospirenone (3 mg/day)/ethinylestradiol (0.02 mg/day) and the strong CYP3A4 inhibitor ketoconazole administered concomitantly for 10 days, the AUC(0-24h) of drospirenone and ethinylestradiol increased by 2.7 and 1.4 times, respectively.

Etoricoxib at doses of 60 to 120 mg/day demonstrated an increase in ethinylestradiol plasma concentrations by 1.4–1.6 times, respectively, when co-administered with a CHC containing 0.035 mg ethinylestradiol.

• Effect of Milanda on other medicinal products.

Oral contraceptives may affect the metabolism of certain active substances. Consequently, 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 substrate markers, clinically significant interaction of drospirenone at a dose of 3 mg with other active substances metabolized by cytochrome P450 is unlikely.

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

Pharmacodynamic interactions

During clinical trials involving patients receiving medicinal products for the treatment of hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, elevated transaminases (ALT) more than 5 times above the upper limit of normal (ULN) were observed. This occurred significantly more frequently in women using medicinal products containing ethinylestradiol, including combined hormonal contraceptives (CHCs). Additionally, in patients receiving treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, increased ALT levels were observed in women taking ethinylestradiol-containing medicinal products, such as CHCs (see section "Contraindications").

Therefore, women using Milanda must use an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods) before starting therapy with the specified combination of medicinal products. Milanda may be resumed 2 weeks after completion of therapy with the specified combination.

In patients with normal renal function, concomitant use of drospirenone with angiotensin-converting enzyme (ACE) inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) showed no significant effect on serum potassium levels. However, concomitant use of Milanda with aldosterone antagonists or potassium-sparing diuretics has not been studied. In such cases, serum potassium levels should be monitored during the first treatment cycle (see also section "Special precautions").

Other forms of interaction

Laboratory tests

Use of contraceptive steroids may affect the results of certain laboratory tests, such as biochemical parameters of liver, thyroid, adrenal, and kidney function, plasma concentrations of transport proteins such as corticosteroid-binding globulin, plasma concentrations of lipid/lipoprotein fractions, carbohydrate metabolism parameters, coagulation, and fibrinolysis. Such changes are usually within normal ranges.

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

Special precautions for use

The decision to prescribe the drug Milanda should be made taking into account individual risk factors currently present in a woman, including risk factors for venous thromboembolism (VTE), as well as the VTE risk associated with the use of Milanda compared to other combined oral contraceptives (COCs) (see sections "Contraindications" and "Special precautions for use").

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 case of exacerbation or first signs of any of the listed conditions or risk factors, women are advised to consult a physician to determine whether discontinuation of Milanda is necessary.
• If venous or arterial thromboembolism (VTE or ATE) is suspected or confirmed, COCs should be discontinued. If anticoagulant therapy is initiated, an alternative effective contraceptive method should be provided due to the teratogenic effects of anticoagulants (coumarins).
• Circulatory disorders.

Risk of venous thromboembolism (VTE)

The use of any COC increases the risk of VTE in women who use them compared to non-users. Products containing levonorgestrel, norgestimate, or norethisterone are associated with a lower VTE risk. The use of other medicinal products, such as Milanda, may double the risk. The decision to prescribe products other than those with the lowest VTE risk should be made only after discussing the matter with the woman. It is essential to ensure that she understands the VTE risk associated with the use of Milanda, the extent to which her individual risk factors contribute, and that the risk of VTE is highest during the first year of use. According to some data, the risk of VTE may increase when resuming COC use after a break of 4 weeks or longer.

Among 10,000 women who do not use COCs and are not pregnant, approximately 2 will develop VTE within one year. However, in individual women, the risk may be significantly higher depending on their specific risk factors (see below).

It has been established¹ that among 10,000 women using COCs containing drospirenone, 9–12 women will develop VTE within one year. This compares to a rate of 6 among women using COCs containing levonorgestrel.

In both cases, the annual number of VTE events was lower than typically expected during pregnancy or the postpartum period.

VTE may result in fatal outcomes in 1–2% of cases.

Number of VTE cases per 10,000 women per year

¹ These estimates are based on all available epidemiological data, taking into account relative risks associated with the use of different COCs compared to COCs containing levonorgestrel.

² Average of 5–7 cases per 10,000 woman-years, based on the relative risk of using COCs containing levonorgestrel compared to non-COC users (approximately 2.3–3.6 cases).

Very rare cases of thrombosis in other blood vessels, such as hepatic, renal, mesenteric, cerebral, or retinal veins and arteries, have been reported in women using COCs.

Risk factors for VTE

The risk of venous thromboembolic complications in women using COCs may be substantially increased in the presence of additional risk factors, especially multiple ones (see Table 2).

The use of Milanda is contraindicated in women with multiple risk factors that may increase the risk of venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may exceed the sum of risks associated with each individual factor; therefore, the overall VTE risk should be considered. If the benefit-risk ratio is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 2

Risk factors for VTE

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

Particular 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 seek immediate medical attention and inform their physician that they are taking COCs if any of the symptoms listed below occur.

Symptoms of DVT may include: unilateral swelling of the leg and/or foot or along a vein in the leg; pain or tenderness in the leg, which may occur only when standing or walking; warmth 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 hemoptysis; sudden chest pain; syncope or dizziness; rapid or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are nonspecific and 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 mild cyanosis of a limb.

In occlusion of ocular vessels, initial symptoms may include blurred vision without pain, which may progress to vision loss. In some cases, vision loss develops almost instantaneously.

Risk of arterial thromboembolism (ATE)

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

Risk factors for ATE

When using COCs, the risk of developing arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 3). Use of the drug Milanda is contraindicated in women who 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 increase in 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, COCs should not be prescribed (see section "Contraindications").

Table 3

Risk factors for ATE

ATE Symptoms

Women should be advised to seek immediate medical attention and inform their doctor if they are taking COCs should any of the symptoms listed below occur.

Symptoms of cerebrovascular disorders may include: sudden facial numbness, weakness or numbness of the limbs, especially on one side; sudden difficulty walking, dizziness, loss of balance or coordination; sudden confusion, speech disturbances or difficulty understanding speech; sudden vision impairment in one or both eyes; sudden, severe or prolonged headache without a known cause; loss of consciousness or fainting, with or without seizures.

Transient nature of symptoms may indicate a transient ischemic attack (TIA).

Symptoms of myocardial infarction may include: chest pain, discomfort, pressure or heaviness in the chest, arm, or below the sternum; discomfort radiating to the back, jaw, throat, arm, or stomach; sensation of stomach fullness, indigestion, or heartburn; excessive sweating, nausea, vomiting, or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeat.

Malignant Neoplasms

Results from some epidemiological studies suggest an increased risk of cervical cancer with long-term use of COCs (>5 years); however, this assertion remains controversial, as it is not fully established to what extent study results account for confounding risk factors such as sexual behavior and other factors, including human papillomavirus infection.

A meta-analysis based on 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of developing breast cancer in women using COCs. This increased risk gradually disappears within 10 years after discontinuation of COCs. Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among women currently or recently using COCs is minimal relative to the overall risk of breast cancer. These studies do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in COC users, a biological effect of COCs, or a combination of both factors. There is a tendency for breast cancer diagnosed in women who have ever used COCs to be clinically less advanced than in those who have never used COCs.

In rare cases, benign and even more rarely malignant liver tumors have been observed in women taking COCs, which in some instances led to life-threatening intra-abdominal bleeding. In cases of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of a liver tumor related to COC use should be considered in differential diagnosis.

Use of COCs at high doses (50 mcg ethinylestradiol) reduces the risk of endometrial and ovarian cancer. It remains to be confirmed whether these findings also apply to low-dose COCs.

Breast Cancer. (Warnings issued by the FDA Center for Drug Evaluation and Research (CDER))

Drospirenone/ethinylestradiol is contraindicated in women with current or past history of breast cancer, as breast cancer may be hormone-sensitive (see section "Contraindications").

Epidemiological studies have not shown a consistent association between use of combined oral contraceptives (COCs) and risk of breast cancer. Studies do not show a link between current or past use of COCs and risk of breast cancer. However, some studies report a slight increase in breast cancer risk among current or recent users (within 6 months of last use) and among past users (see section "Adverse Reactions", subsection "Post-marketing data").

Other Conditions

The progestin component of Milanda has aldosterone antagonist properties with potassium-sparing effects. In most cases, hyperkalemia is not expected during use. During clinical trials, slight but non-significant increases in serum potassium levels were observed in some patients with mild to moderate renal impairment who were also taking potassium-sparing medications during drospirenone use. Therefore, monitoring of serum potassium levels is recommended during the first treatment cycle in patients with renal impairment. These patients should also maintain serum potassium levels at or below the upper limit of normal before starting Milanda, especially when concomitantly using potassium-sparing medications (see section "Interaction with other medicinal products and other forms of interaction").

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

Although minor increases in blood pressure have been reported in many women taking COCs, clinically significant hypertension occurs only rarely. Immediate discontinuation of COCs is required only in these rare cases. In cases of persistent hypertension or inability to control blood pressure with antihypertensive therapy, women taking COCs should discontinue use. If appropriate, COC use may be resumed after normotension is achieved with antihypertensive treatment.

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

Exogenous estrogens may induce or exacerbate symptoms of angioedema.

Metabolism of steroid hormones may be impaired in patients with hepatic dysfunction. Acute or chronic liver disorders may require discontinuation of COCs until liver function tests return to normal and a causal relationship with COCs is ruled out.

COC use should be discontinued in case of recurrence of cholestatic jaundice and/or cholestatic pruritus previously experienced during pregnancy or prior use of sex hormones.

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

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

Depressed mood and depression are well-known adverse effects that may occur during use of hormonal contraceptives (see section "Adverse Reactions"). Depression can be a serious condition and is a well-known risk factor for suicidal behavior and suicide. Women should be advised to consult a physician if mood changes or symptoms of depression occur, including soon after starting treatment.

Chloasma may occasionally occur, particularly in women with a history of chloasma gravidarum. Women prone to chloasma should avoid direct sunlight or ultraviolet radiation during COC use.

One tablet of the drug contains 46 mg of lactose. In patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, or those on a lactose-free diet, this lactose content should be taken into account.

Consultations/Medical Examination

Before initiating or resuming use of Milanda, a complete medical history (including family history), a full physical examination, and exclusion of pregnancy are recommended. Blood pressure should be measured and a medical examination performed, considering contraindications (see section "Contraindications") and special precautions (see section "Special Precautions for Use"). Women should be informed about venous and arterial thrombosis, including the risk associated with Milanda compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take if thrombosis is suspected.

Patients are advised to carefully read the package leaflet and follow the recommendations provided.

The frequency and nature of follow-up examinations should be based on current medical practice guidelines, taking into account individual patient characteristics.

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

Reduced Efficacy

The efficacy of COCs may be reduced in case of missed tablet intake (see section "Dosage and Administration"), gastrointestinal disorders (see section "Dosage and Administration"), or concomitant use of other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Cycle Disturbances

Irregular bleeding (spotting or breakthrough bleeding) may occur during COC use, especially during the first few months. If such bleeding persists beyond three menstrual cycles, it should be considered clinically significant.

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

In some women, withdrawal bleeding may not occur during the tablet-free interval. If COCs have been taken according to instructions in section "Dosage and Administration", pregnancy is unlikely. However, if COC intake has been irregular prior to the absence of the first withdrawal bleed, or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be ruled out before continuing COC use.

Use during Pregnancy or Breastfeeding

Pregnancy. The drug is contraindicated during pregnancy. If pregnancy occurs during use of Milanda, treatment must be discontinued immediately. However, results of epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers used COCs before pregnancy, nor teratogenic effects from inadvertent COC use during pregnancy.

Animal studies have shown adverse effects during pregnancy and lactation (see section "Pharmacological Properties"). Based on animal studies, adverse effects due to the hormonal action of active substances cannot be excluded. However, overall clinical experience with COC use during pregnancy does not indicate adverse effects in humans.

Available data on use of the drug during pregnancy are too limited to draw conclusions regarding any negative impact of Milanda on pregnancy outcome, fetal or newborn health. To date, there are no relevant epidemiological data.

When resuming use of Milanda, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and Administration", "Special Precautions for Use").

Lactation Period. COCs may affect breastfeeding, as they can reduce the quantity and alter the composition of breast milk. Therefore, COCs are not recommended during breastfeeding. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during COC use, which may affect the infant.

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted on the effect on the ability to drive or operate machinery. There have been no reports of impaired ability to drive or operate machinery in women taking combined oral contraceptives.

Method of Administration and Dosage

Administer orally.

Dosing

Tablets should be taken regularly at approximately the same time each day, swallowed with a small amount of liquid if necessary, in the order indicated on the blister pack. The medication is taken as one tablet daily for 21 consecutive days. After each 21-day cycle, a new pack should be started following a 7-day break during which withdrawal bleeding usually occurs. This bleeding typically begins on the 2nd or 3rd day after taking the last tablet and may not cease before starting tablets from the next pack.

Initiating Treatment with Milanda

• No prior use of hormonal contraceptives (previous month)

Begin taking tablets on the first day of the natural cycle (i.e., the first day of menstrual bleeding).

• Transition from combined oral contraceptives (COCs), vaginal ring, or transdermal system

It is recommended to take the first tablet of Milanda the day after the last active tablet (containing active ingredient) is taken, but no later than the day after the tablet-free interval begins. When switching from a vaginal ring or transdermal patch, start Milanda on the day of device removal, but no later than the day the next application would have been due.

• Transition from a progestogen-only method ("mini-pill", injection, implant) or intrauterine system containing progestogen

Milanda may be started at any time after discontinuation of the "mini-pill" (in the case of an implant or intrauterine system – on the day of removal; in the case of an injection – instead of the next scheduled injection). However, in all such cases, it is recommended to use an additional barrier method of contraception during the first 7 days of Milanda use.

• After first-trimester abortion

Treatment may be started immediately. In this case, additional contraceptive methods are not required.

• After childbirth or second-trimester abortion

It is recommended to start Milanda between days 21 and 28 after childbirth or second-trimester abortion. If initiation is delayed beyond this period, an additional barrier method of contraception should be used during the first 7 days of tablet intake. However, if sexual intercourse has already occurred, pregnancy should be ruled out or the first menstrual period awaited before starting Milanda.

For breastfeeding women, see section "Use during pregnancy or breastfeeding".

Missed tablet instructions

If the delay in taking any tablet does not exceed 12 hours, contraceptive protection is not reduced. The missed tablet should be taken as soon as remembered. The next tablet should be taken at the usual time.

If the delay in taking a tablet exceeds 12 hours, contraceptive protection may be reduced. In such cases, two main principles should be followed:

1. The interval between tablet intakes must never exceed 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian axis is achieved only with continuous tablet intake over 7 days.

Accordingly, the following practical recommendations should be observed:

• Week 1

Take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. Continue taking tablets at the usual time. Additionally, use a barrier method of contraception (e.g., condom) for the next 7 days. If sexual intercourse occurred in the previous 7 days, consider the possibility of pregnancy. The greater the number of missed tablets and the closer the missed dose is to the tablet-free interval, the higher the risk of pregnancy.

• Week 2

Take the last missed tablet as soon as remembered, even if two tablets must be taken at the same time. Continue taking tablets at the usual time. If tablets were taken correctly during the 7 days prior to the missed dose, no additional contraceptive methods are required. However, if more than one tablet is missed, a barrier method of contraception should be used for 7 days.

• Week 3

The risk of reduced efficacy increases as the 7-day tablet-free interval approaches. However, following one of the regimens below can prevent reduced contraceptive protection. If tablets were taken correctly during the 7 days before the missed dose, no additional contraceptive methods are required when following one of the options below. Otherwise, follow the first option and use additional precautions for the next 7 days.

1. Take the last missed tablet as soon as remembered, even if two tablets must be taken simultaneously. Continue taking tablets at the usual time. Begin tablets from the next pack immediately after finishing the current one—there should be no break between packs. Withdrawal bleeding is unlikely to occur before completing tablets from the second pack, although breakthrough bleeding or spotting may occur during tablet intake.
2. Alternatively, stop taking tablets from the current pack. In this case, the total break (including missed days) should not exceed 7 days; then start tablets from the next pack.

If withdrawal bleeding does not occur during the first scheduled tablet-free interval after a missed tablet, pregnancy should be considered.

Gastrointestinal disturbances

In cases of severe gastrointestinal disturbances (such as vomiting or diarrhea), incomplete absorption of the drug may occur; therefore, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking the tablet, take another (replacement) tablet as soon as possible. The next tablet should, if possible, be taken within 12 hours according to the usual schedule. If more than 12 hours have passed, follow the recommendations outlined above under "Missed tablet instructions". If a woman wishes to maintain her usual tablet schedule, she should take additional tablet(s) from the next pack.

Delaying withdrawal bleeding

To delay withdrawal bleeding, continue taking tablets from a new pack without interruption. The duration may be extended up to the end of the second pack, if desired. Breakthrough bleeding or spotting may occur during this time. Usually, Milanda is resumed after a 7-day tablet-free interval.

To shift the timing of withdrawal bleeding to another day of the week, shorten the tablet-free interval by the desired number of days. Note that the shorter the break, the more likely it is that withdrawal bleeding will not occur and that breakthrough bleeding or spotting may occur during intake of tablets from the second pack (similar to delaying withdrawal bleeding).

Additional information for special patient groups

Elderly patients

The drug is not indicated after menopause.

Patients with hepatic impairment

Milanda is contraindicated in women with severe hepatic impairment (see sections "Contraindications" and "Pharmacological properties").

Patients with renal impairment

Milanda is contraindicated in women with severe renal impairment or acute renal failure (see sections "Contraindications" and "Pharmacological properties").

Children

Milanda is indicated only after the onset of the first menstruation. Based on epidemiological data collected from over 2000 adolescents under 18 years of age, there is no evidence of differences in safety and efficacy in this patient group compared to women aged 18 years and older.

Overdose

There are currently no clinical data on overdose with Milanda tablets. Based on general experience with combined oral contraceptives (COCs), overdose may result in nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may occur in girls even before menarche in cases of accidental or unintentional ingestion. There is no specific antidote; treatment should be symptomatic.

Side effects.

For serious side effects in women using COCs, see also section "Special precautions". The side effects listed below were observed during the use of the drug Milanda (see Table 4).

Table 4

Side effects observed during the use of the drug Milanda

Description of individual adverse reactions

An increased risk of venous or arterial thrombotic/thromboembolic events, including myocardial infarction, stroke, transient ischaemic attack (TIA), venous thrombosis, and pulmonary embolism, has been observed in women taking combined oral contraceptives (COCs), as described in more detail in the section "Special warnings and precautions for use".

The following serious adverse reactions have been observed in women taking COCs, which are also described in the section "Special warnings and precautions for use":

• Venous thromboembolic disorders;
• Arterial thromboembolic disorders;
• Arterial hypertension;
• Liver tumours;
• Development or worsening of conditions for which a causal relationship with COC use has not been definitively established: Crohn’s disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, haemolytic uraemic syndrome, cholestatic jaundice;
• Chloasma;
• Acute or chronic disorders of liver function, which may require discontinuation of COC use until liver function tests return to normal;

Adverse reactions observed in patients taking COCs: emotional lability, depression; loss of libido; venous and arterial thromboembolic events, including occlusion of deep peripheral veins, thrombosis and embolism of pulmonary vessels, myocardial infarction, stroke (including haemorrhagic stroke, ischaemic stroke, TIA); erythema.

Other adverse reactions associated with the COC class are also listed in the sections "Contraindications" and "Special warnings and precautions for use" (including hearing loss associated with otosclerosis, hypertriglyceridaemia and increased risk of pancreatitis, gallstone formation, changes in glucose tolerance or effects on peripheral insulin resistance, jaundice and/or pruritus associated with cholestasis, hypersensitivity reactions including rash, urticaria).

The incidence of breast cancer diagnosis is slightly increased among women using COCs. Since breast cancer is rare in women under the age of 40, the increase in diagnosed cases of breast cancer among women currently or recently using COCs is small relative to the overall risk of breast cancer. The causal relationship with COC use is unknown. See also sections "Contraindications" and "Special warnings and precautions for use".

Interactions

Breakthrough bleeding and/or reduced contraceptive efficacy may occur due to interactions between other medicinal products (enzyme inducers) and oral contraceptives (see section "Interaction with other medicinal products and other forms of interaction").

Post-marketing data. (Warning issued by the Center for Drug Evaluation and Research (CDER), FDA.)

Five studies comparing the risk of breast cancer between women who had ever used (currently or in the past) COCs and those who had never used COCs reported no association between COC use and breast cancer risk, with effect estimates ranging from 0.90 to 1.12.

Three studies compared the risk of breast cancer between women currently using or recently using COCs (<6 months since last use) and those who had never used COCs. One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19–1.33 with current or recent use. Both of these studies also found an increased risk of breast cancer with long-term use, with relative risk ranging from 1.03 for less than one year of COC use to approximately 1.4 for more than 8–10 years of use.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is very important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

21 tablets in a blister with a calendar scale. 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Laboratorios Leon Farma S.A.

Manufacturer’s address and place of business.

C/La Vallina s/n, Polígono Industrial Navatejera, Villacarramba, 24193 León, Spain.

Marketing Authorisation Holder.

Zentiva, k.s.

Address of the Marketing Authorisation Holder.

Dolní Měcholupy, U Kabelovny 130, 102 37 Prague 10, Czech Republic.

If any adverse effects, side effects or lack of therapeutic effect occur, please report to Zentiva Ukraine LLC, 5I Brovarskyi Avenue, Kyiv, 02660, Ukraine, tel./fax +38 044 517-75-00, e-mail: [email protected].