Midiana

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİDIANA (MIDIANA)

Composition:

Active substances: drospirenone, ethinylestradiol;

1 tablet contains drospirenone 3 mg, ethinylestradiol 0.03 mg;

Excipients: lactose monohydrate, maize starch, pregelatinized starch, povidone K 25, magnesium stearate;

Coating: Opadry II White (polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, lecithin (soy)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex film-coated tablets, with "G63" engraved on one side and the other side unmarked. Diameter – approximately 6 mm.

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

ATC code G03A A12.

Pharmacological properties.

Pharmacodynamics.

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

Midiana, film-coated tablets, is a combined oral contraceptive containing ethinylestradiol and the progestogen drospirenone. At therapeutic doses, drospirenone also possesses antiandrogenic and mild antimineralocorticoid properties. It lacks any estrogenic, glucocorticoid, or antiglucocorticoid activity. This gives drospirenone a pharmacological profile very similar to that of the natural hormone progesterone.

The mild antimineralocorticoid properties of Midiana tablets result in a mild antimineralocorticoid effect.

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

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

Pharmacokinetics.

Drospirenone

Absorption

Following oral administration, drospirenone is rapidly and almost completely absorbed. Maximum active substance concentration in serum, equal to 38 ng/mL, is reached within 1–2 hours after single administration. The bioavailability of drospirenone ranges from 76% to 85%. Concomitant food intake does not affect the bioavailability of drospirenone.

Distribution

After oral administration, a decline in drospirenone serum levels is observed, characterized by an elimination half-life of 31 hours. Drospirenone binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG).

Only 3–5% of the total serum concentration of the active substance represents free hormone. The ethinylestradiol-induced increase in SHBG does not affect the binding of drospirenone to serum proteins. The mean apparent volume of distribution is 3.7±1.2 L/kg.

Biological transformation

After oral administration, drospirenone undergoes extensive metabolism. Most metabolites in plasma are represented by acidic forms of drospirenone formed via opening of the lactone ring, and 4,5-dihydrodrospirenone-3-sulfate, formed by reduction followed by sulfation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4. In vitro, the drug has demonstrated the ability to inhibit the activity of this isoenzyme, as well as the cytochrome P450 isoenzymes 1A1, 2C9, and 2C19.

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 in feces and urine in a ratio of approximately 1.2:1.4. The elimination half-life for metabolites excreted in urine and feces is approximately 40 hours.

Steady-state concentration

During one treatment cycle, the maximum steady-state concentration of drospirenone in serum (approximately 70 ng/mL) is reached after 8 days of administration. The serum concentration of drospirenone increases approximately threefold due to the existing relationship between the terminal half-life and the dosing interval used.

Ethinylestradiol

Absorption

Ethinylestradiol is rapidly and completely absorbed after oral administration. Maximum serum concentration after single oral dose is reached within 1–2 hours and is approximately 33 pg/mL. Absolute bioavailability, due to presystemic conjugation and first-pass liver metabolism, is approximately 60%. Concomitant food intake reduced ethinylestradiol bioavailability by approximately 25% in some studied women, while no changes were observed in others.

Distribution

After oral administration, a biphasic decline in ethinylestradiol serum levels is observed, characterized by an elimination half-life of approximately 24 hours. Ethinylestradiol is strongly but non-specifically bound to plasma proteins (approximately 98.5%) and induces an increase in serum levels of SHBG and CBG. The expected volume of distribution of ethinylestradiol is approximately 5 L/kg.

Biological transformation

Ethinylestradiol undergoes extensive metabolism in the gut and first-pass metabolism in the liver. Ethinylestradiol is metabolized primarily via aromatic hydroxylation, but a wide spectrum of hydroxylated and methylated metabolites are formed, present as free metabolites and conjugates with glucuronides and sulfates. The metabolic clearance rate of ethinylestradiol is approximately 5 mL/min/kg. In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, as well as an inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Elimination

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

Steady-state concentration

Steady-state concentration is achieved during the second half of the treatment cycle, with serum levels of ethinylestradiol accumulating by a factor of approximately 1.4–2.1.

Special population groups

Effect on renal function

Steady-state serum levels of drospirenone in women with mild renal impairment (creatinine clearance 50–80 mL/min) were comparable to those in women with normal renal function (>80 mL/min). Serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CLcr = 30–50 mL/min) compared to women with normal renal function. Treatment with drospirenone was well tolerated in women with both mild and moderate renal impairment.

Treatment with drospirenone had no clinically significant effect on serum potassium concentration.

Effect on hepatic function

Oral clearance in volunteers with moderate hepatic impairment was approximately 50% lower compared to individuals with normal liver function.

This reduction in drospirenone clearance in volunteers with moderate hepatic impairment does not lead to any clinically significant changes in serum potassium concentration.

Even in patients with diabetes and concomitant treatment with spironolactone (two factors that may provoke hyperkalemia), no increase in serum potassium concentration above the upper limit of normal was observed.

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

Ethnic groups

No clinically significant differences in the pharmacokinetics of drospirenone or ethinylestradiol were observed between women of European and Asian ethnicity.

Clinical characteristics.

Indications.

Oral contraception.

Contraindications.

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

• Hypersensitivity to the active substances or to any of the excipients of the medicinal product (see section "Composition");
  • Hypersensitivity to peanuts or soya;
  • Presence or risk of venous thromboembolism (VTE):
• Venous thromboembolism – current VTE, including VTE due to anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
• Known hereditary or acquired predisposition to venous thromboembolism, 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 venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions");
• Presence or risk of arterial thromboembolism (ATE):
• Arterial thromboembolism – current or past arterial thromboembolism (e.g., myocardial infarction) or prodromal state (e.g., angina pectoris);
• Cerebrovascular disorders – current or past stroke, presence of prodromal state (e.g., transient ischaemic attack (TIA));
• Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinaemia and presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• History of migraine with focal neurological symptoms;
• High risk of arterial thromboembolism due to the presence of multiple risk factors (see section "Special precautions") or due to the presence of any of the following serious risk factors:
  • Diabetes mellitus with vascular complications;
  • Severe arterial hypertension;
  • Severe dyslipoproteinaemia;
• Current or past severe liver disease until liver function tests have returned to normal;
• Severe renal insufficiency or acute renal failure;
• Current or past hepatic tumours (benign or malignant);
• Known or suspected hormone-dependent malignant neoplasms (e.g., of genital organs or breasts);
• Vaginal bleeding of unknown etiology;
• Suspected or confirmed pregnancy.

Concomitant use of the medicinal product Midiana with medicinal products containing ombitasvir/paritaprevir/ritonavir, dasabuvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir is contraindicated (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Information regarding any concomitantly used medicinal product should be reviewed to identify potential interactions.

Pharmacodynamic interactions

Concomitant use of medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir may increase the risk of elevated alanine aminotransferase (ALT) levels (see sections "Contraindications" and "Special precautions"). Therefore, before initiating treatment with these medicinal products, patients using Midiana should switch to an alternative method of contraception (e.g., progestogen-only contraceptives or non-hormonal methods). Use of Midiana may be resumed 2 weeks after completion of treatment with these medicinal products.

Pharmacokinetic interactions

Effect of other medicinal products on Midiana

Interactions are possible with medicinal products that induce microsomal enzymes. This may lead to increased clearance of sex hormones, which in turn may result in breakthrough bleeding and/or loss of contraceptive efficacy.

Therapy

Enzyme induction may be observed within a few days of starting treatment. Maximum enzyme induction is generally observed after several weeks. After discontinuation of treatment, 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 contraceptive method in addition to COCs. The barrier method should be used throughout the treatment period with the relevant medicinal product and for an additional 28 days after discontinuation. If treatment is initiated during the period of taking the last tablets from the COC pack, the next pack of COC tablets should be started immediately after the previous one, 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 documented according to published data.

Substances increasing COC clearance (reduced COC efficacy due to enzyme induction), for example:

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

Substances with variable effects on COC clearance

When used concomitantly with COCs, numerous 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 oestrogen or progestins. The overall effect of these changes may be clinically significant in some cases.

Therefore, information regarding the medical use of the medicinal product for treatment of HIV/HCV, taken concomitantly, should be reviewed to identify potential interactions and any 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.

Substances decreasing COC clearance (enzyme inhibitors)

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

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

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

Etoricoxib at doses of 60 mg/day to 120 mg/day demonstrated an increase in ethinylestradiol plasma concentrations by 1.4 to 1.6 times, respectively, when used concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

Effect of Midiana on other medicinal products

Combined oral contraceptives may affect the metabolism of other drugs. As a result, plasma and tissue concentrations of active substances may change—either increased (e.g., cyclosporine) or decreased (e.g., lamotrigine).

Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin, or midazolam as marker substrates, 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, resulting in mild (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Other forms of interaction

In patients with normal renal function, concomitant use of drospirenone with angiotensin-converting enzyme (ACE) inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) did not show a significant effect on serum potassium levels. However, concomitant use of aldosterone antagonists or potassium-sparing diuretics has not been studied. In such cases, serum potassium levels should be monitored during the first cycle of treatment (see also section "Special precautions").

Laboratory tests

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

Drospirenone increases plasma renin and aldosterone activity, which is caused by its mild anti-mineralocorticoid activity.

Special precautions for use

The decision to prescribe the drug Midiana should be made taking into account the individual risk factors of the woman at the time, including risk factors for venous thromboembolism (VTE), as well as the VTE risk associated with the use of Midiana compared to other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions for use").

Warning

• If any of the conditions or risk factors listed below are present, the need for using Midiana should be discussed with the woman.
• In case of exacerbation or first signs of any of the mentioned conditions or risk factors, women are advised to consult a physician and determine whether discontinuation of Midiana is necessary.
• In suspected or confirmed arterial or venous thrombosis, CHCs should be discontinued. If anticoagulant therapy is initiated, an alternative effective contraception should be provided due to the teratogenic effect of anticoagulants (coumarins).

Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any CHC increases the risk of venous thromboembolism (VTE) compared to non-use. The use of contraceptives containing levonorgestrel, norgestimate, or norethisterone is associated with a lower risk of VTE. The use of other medicinal products, such as Midiana, may double the risk. The decision to use a product not belonging to the group with the lowest VTE risk should only be made after discussion with the woman. It is essential to ensure that she understands the VTE risk associated with Midiana, how her individual risk factors may influence this risk, 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 CHC use after a break of 4 weeks or more.

Among women who do not use CHCs and are not pregnant, the incidence of VTE is approximately 2 cases per 10,000 women per year. However, in any individual woman, the risk level may be significantly higher depending on her underlying major risk factors (see below).

It has been established¹ that among 10,000 women using CHCs containing drospirenone, 9–12 women will develop VTE within one year. This compares with approximately 6 cases among women using CHCs containing levonorgestrel.

In both cases, the annual number of VTE cases was lower than that usually expected during pregnancy or in the postpartum period.

VTE can be fatal 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 different CHCs compared to CHCs containing levonorgestrel.

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

Very rare cases of thrombosis in other vessels, such as arteries and veins of the liver, kidneys, retina, or mesenteric vessels, have been reported in women using CHCs.

Risk factors for VTE

The risk of venous thromboembolic complications during CHC use may be substantially increased in women with additional risk factors, especially when multiple risk factors are present (see Table 1).

Midiana is contraindicated in women with multiple risk factors that place them in a high-risk group for venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of risks associated with each individual factor; therefore, the overall risk of VTE should be considered. CHCs should not be prescribed if the benefit-risk balance is unfavorable (see section "Contraindications").

Table 1

Risk factors for VTE

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

Particular attention should be paid to the increased risk of thromboembolism during pregnancy, especially during the first 6 weeks postpartum (see section "Use during pregnancy or breastfeeding").

Signs and symptoms of VTE (venous thromboembolism: deep vein thrombosis and pulmonary embolism)

If any of the symptoms listed below occur, women should seek immediate medical attention and inform their physician that they are taking COCs.

Symptoms of deep vein thrombosis (DVT) may include:

• Unilateral swelling of the leg and/or foot, or along a vein in the leg;
• Pain or increased sensitivity in the leg, which may occur only when standing or walking;
• A feeling of warmth in the affected leg;
• Redness or change in skin color of the leg.

Symptoms of pulmonary embolism (PE) may include:

• Sudden unexplained shortness of breath or rapid breathing;
• Sudden onset of cough, which may be accompanied by hemoptysis;
• Sudden chest pain;
• Presyncope 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 serious conditions (e.g., respiratory tract infections).

Other signs of vascular occlusion may include sudden pain, swelling, and mild cyanosis of a limb.

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

Risk of arterial thromboembolism (ATE)

Epidemiological studies have shown that the use of any combined oral contraceptives (COCs) is associated with an increased risk of arterial thromboembolism (e.g., myocardial infarction) or cerebrovascular events (e.g., transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.

ATE risk factors

When using COCs, the risk of developing arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 2). The drug Midiana is contraindicated if a woman has 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; therefore, the overall risk of ATE should be considered. COCs should not be prescribed if the benefit-risk ratio is unfavorable (see section "Contraindications").

Table 2

ATE risk factors

ATE Symptoms

If any of the symptoms listed below occur, women should seek immediate medical attention and inform their doctor that they are taking COCs.

Symptoms of cerebrovascular disorders may include:

• sudden numbness or weakness of the face, arm, or leg, especially on one side of the body;
• sudden trouble walking, dizziness, loss of balance or coordination;
• sudden confusion, trouble speaking or understanding speech;
• sudden vision changes in one or both eyes;
• sudden severe or prolonged headache with no known cause;
• loss of consciousness or fainting, with or without seizures.

Transient symptoms may indicate a transient ischaemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

• pain, discomfort, pressure, heaviness, squeezing, or fullness in the chest, arm, or behind the breastbone;
• discomfort radiating to the back, jaw, throat, arm, or stomach;
• feeling of fullness, indigestion, or choking;
• excessive sweating, nausea, vomiting, or dizziness;
• extreme weakness, restlessness, or shortness of breath;
• rapid or irregular heartbeat.

Tumours

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

A meta-analysis of data from 54 epidemiological studies indicates a slight increase in relative risk (RR=1.24) of breast cancer in women using 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 diagnosed cases among women currently or recently using COCs is minimal in relation to the overall risk of breast cancer. These study results 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. There is a tendency for breast cancer diagnosed in women who have ever used COCs to be less clinically advanced than in those who have never used COCs.

In rare cases, benign and, more rarely, malignant liver tumours have been observed in women using COCs. In some cases, these tumours have led to life-threatening intra-abdominal haemorrhage. In the differential diagnosis of women taking COCs who present with severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of a liver tumour should be considered.

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

Malignant tumours may be life-threatening or result in death.

Other conditions

Depressed mood and depression are common adverse reactions associated with the use of hormonal contraceptives (see section "Adverse Reactions"). Depression can be severe and is a known risk factor for suicidal behaviour and suicide. Women should be advised to seek medical advice if mood changes or symptoms of depression occur, even if these arise soon after starting treatment.

The progestogenic component of Midiana is an aldosterone antagonist with potassium-sparing properties. In most cases, an increase in serum potassium levels is not expected during use. However, in a clinical study, 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 medicinal products during treatment with drospirenone. Therefore, monitoring of serum potassium levels is recommended during the first cycle of treatment in patients with renal impairment, and serum potassium levels should be maintained no higher than the upper limit of normal before starting treatment, especially when potassium-sparing medicinal products are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

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

Although a slight increase in blood pressure has been reported in many women using COCs, clinically significant hypertension is rare. Only in these rare cases is immediate discontinuation of COCs required. In women with pre-existing hypertension or in whom blood pressure cannot be adequately controlled with antihypertensive therapy, COCs should be discontinued. If appropriate, COC use may be resumed after normotension is achieved with antihypertensive therapy.

The following conditions have been reported to occur or worsen during pregnancy and COC use, but their association with COC use has not been definitively established: cholestasis-related jaundice and/or pruritus; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.

Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.

Acute or chronic liver dysfunction may require discontinuation of COCs until liver function parameters return to normal. COC use should be discontinued if cholestatic jaundice and/or cholestasis-related pruritus, which previously occurred during pregnancy or prior use of sex hormones, recurs.

Although combined hormonal contraceptives may affect peripheral insulin resistance and glucose tolerance, there are no data indicating a need to change the therapeutic regimen in women with diabetes who use low-dose COCs (containing <0.05 mg ethinylestradiol). However, women with diabetes should be carefully monitored during COC use, particularly at the beginning of treatment.

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

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

Excipients

This medicinal product contains 48.17 mg lactose monohydrate per tablet.

This medicinal product should not be used in patients with rare hereditary conditions of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

One tablet of this medicinal product contains 0.07 mg of soy lecithin. This product should not be used in patients with hypersensitivity to peanut or soy.

Medical examination/consultation

Before starting or resuming use of Midiana, a full medical and family history should be taken, a medical examination performed, and pregnancy excluded. Blood pressure should be measured, and a physical examination conducted, taking into account contraindications (see section "Contraindications") and warnings (see section "Special precautions for use"). It is important to inform women about the risk of venous and arterial thrombosis, including the risk associated with using Midiana compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take in case of suspected thrombosis.

Patients should be advised to read the patient information leaflet carefully 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.

Women should be informed that oral contraceptives do not protect against HIV infection (AIDS) or 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 control

Irregular bleeding (spotting or breakthrough bleeding) may occur during COC use, particularly during the first months of treatment. Therefore, evaluation of irregular bleeding may only be meaningful after three adaptation cycles.

If irregular bleeding persists or occurs after several normal cycles, non-hormonal causes should be considered and appropriate diagnostic measures undertaken (curettage if necessary) to exclude malignancy or pregnancy.

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

Elevated ALT levels

During clinical trials in patients receiving treatment for hepatitis C virus (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, marked increases in ALT levels exceeding the upper limit of normal by more than 5 times were observed. This occurred more frequently in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives (COCs). Increased ALT levels were also observed with antiviral medicinal products containing glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding

Pregnancy

Midiana is contraindicated during pregnancy.

If pregnancy occurs while taking Midiana, treatment should be stopped immediately. However, results of epidemiological studies do not indicate an increased risk of congenital malformations in children born to women who used COCs before pregnancy, nor do they indicate teratogenic effects from inadvertent COC use during pregnancy.

Animal studies have shown adverse effects during pregnancy and lactation (see section "Pharmacological properties"). Based on these data, adverse effects related to the hormonal influence of the combined active substances cannot be excluded. However, the overall experience with COC use during pregnancy does not indicate an adverse effect in humans.

Data on the use of Midiana during pregnancy are too limited to draw conclusions regarding any negative effect of Midiana on pregnancy outcome, fetal or neonatal health. To date, there are no relevant epidemiological data.

When resuming use of Midiana, the increased risk of VTE in the postpartum period should be considered (see sections "Special precautions for use" and "Dosage and administration").

Breastfeeding 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, and these amounts may affect the infant.

Ability to influence reaction speed when driving or operating machinery

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

Method of Administration and Dosage

Orally.

Dosing

Tablets should be taken daily at approximately the same time, swallowed with a small amount of liquid if necessary, in the order indicated on the blister pack. One tablet should be taken daily for 21 consecutive days. Each subsequent pack should be started after a 7-day tablet-free interval, during which withdrawal bleeding usually occurs. This bleeding typically begins 2–3 days after the last tablet and may not cease before starting tablets from the next pack.

How to Start Treatment with Midiana

If hormonal contraceptives have not been used previously (in the past month)

Treatment with Midiana should begin on the first day of the woman’s natural cycle (i.e., the first day of menstrual bleeding).

Switching from another combined hormonal contraceptive (combined oral contraceptives, vaginal ring, or transdermal patch)

It is recommended that the woman start taking Midiana tablets the day after taking the last active tablet of the previous combined oral contraceptive; in such cases, Midiana should not be started later than the day following the usual tablet-free interval or the intake of inactive tablets of the previous contraceptive. When switching from a vaginal ring or transdermal patch, Midiana should preferably be started on the day of removal of the previous method; in such cases, Midiana should not be started later than the planned switch date.

Switching from a progestogen-only method (progestogen-only pills, injections, implant) or an intrauterine system containing progestogen (IUS)

A woman may start taking Midiana at any time after discontinuation of progestogen-only pills (in the case of an implant or intrauterine system – on the day of removal; in the case of injection – instead of the next scheduled injection). However, in all cases, it is recommended to use an additional barrier method of contraception during the first 7 days of taking Midiana.

After first-trimester abortion

Treatment should be started immediately on the same day following the procedure. In this case, there is no need to use additional contraceptive methods.

After childbirth or second-trimester abortion

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

Women should be advised to start taking Midiana on days 21–28 after childbirth or second-trimester abortion. If the woman starts later, she should be advised to use an additional barrier method of contraception during the first 7 days of tablet intake. However, if sexual intercourse has already occurred, pregnancy should be ruled out before starting the combined oral contraceptive, or the woman should wait for her first menstrual period.

What to Do If a Tablet Is Missed

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 possible. The next tablet from the pack should be taken at the usual time.

If the delay in taking the missed tablet exceeds 12 hours, contraceptive protection may be reduced.

In case of a missed tablet, two main rules should be followed:

1. The tablet-free interval must never exceed 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved by continuous tablet intake for 7 days.

Accordingly, the following practical recommendations should be followed:

Week 1

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

Week 2

The woman should take the last missed tablet as soon as she remembers, even if two tablets must be taken at the same time. She should then continue taking tablets at the usual time. If the woman has taken tablets correctly for the 7 days prior to the missed dose, no additional contraceptive methods are needed. Otherwise, or if more than one tablet is missed, a barrier method of contraception should be used for 7 days.

Week 3

The risk of reduced contraceptive efficacy is significant due to the upcoming 7-day tablet-free interval. However, by following one of the regimens below, a reduction in contraceptive protection can be avoided. If one of the following options is followed, no additional contraceptive methods are required, provided tablets were taken correctly for the 7 days prior to the missed dose. Otherwise, the first of the following options should be followed, and additional contraceptive methods should be used for the next 7 days.

1. The woman should take the last missed tablet as soon as she remembers, even if two tablets must be taken at the same time. She should then continue taking tablets at the usual time. Tablets from a new pack should be started immediately after finishing the previous pack, i.e., there should be no break between packs. Withdrawal bleeding is unlikely to occur before finishing the second pack, although breakthrough bleeding or spotting may occur during tablet intake.
2. The woman may also be advised to stop taking tablets from the current pack. In this case, the tablet-free interval should not exceed 7 days, including the days of missed tablets; tablet intake should resume with a new pack.

If a woman misses tablets and does not experience withdrawal bleeding during the first usual tablet-free interval, pregnancy should be considered.

Recommendations in Case of Gastrointestinal Disorders

In case of severe gastrointestinal disturbances (vomiting, diarrhea), incomplete absorption of the drug may occur; in such cases, additional contraceptive methods should be used.

If vomiting occurs within 3–4 hours after taking a tablet, a new tablet should be taken as soon as possible to replace the previous one. The replacement tablet should be taken within 12 hours of the usual intake time, if possible. If more than 12 hours have passed, the rules for missed tablets described in the section "What to Do If a Tablet Is Missed" should be followed. If the woman does not wish to change her usual dosing schedule, she should take an additional tablet(s) from another pack.

How to Change the Timing of Withdrawal Bleeding

To delay the onset of menstruation, the woman should continue taking Midiana tablets from a new pack without interruption. The duration of intake may be extended up to the end of the second pack if desired. Breakthrough bleeding or spotting may occur during this time. Normal Midiana intake should resume after a 7-day tablet-free interval.

To shift the timing of menstruation to another day of the week, it is recommended to shorten the tablet-free interval by the desired number of days. It should be noted that the shorter the interval, the more likely it is that withdrawal bleeding will not occur, and breakthrough bleeding or spotting may be observed during intake of tablets from the second pack (as in the case of delaying withdrawal bleeding).

Special Patient Populations

Elderly patients

Not applicable. Midiana is not indicated after menopause.

Patients with hepatic impairment

Midiana is contraindicated in women with liver function disorders (see section "Contraindications").

Patients with renal impairment

Midiana film-coated tablets are contraindicated in women with severe renal insufficiency or acute renal failure (see section "Contraindications").

Children

Midiana is indicated for use 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 data on combined overdose of drospirenone and ethinylestradiol.

Based on general experience with combined oral contraceptives, symptoms that may occur in such cases include nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may even occur in girls before the onset of the first menstruation if they accidentally take the medication. No specific antidotes are available; treatment should be symptomatic.

Adverse reactions.

Serious adverse effects associated with the use of COCs are described in the section "Special precautions".

The following adverse reactions have been reported during the use of the drug Midiana.

The table below lists adverse reactions by MedDRA System Organ Classes (SOC) and frequency according to WHO recommendations.

Description of individual adverse reactions

An increased risk of arterial or venous thrombotic/thromboembolic complications, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism, has been observed in women using COCs. More detailed information is provided in the section «Special precautions for use».

The following serious adverse reactions have been reported in women using COCs, also described in the section «Special precautions for use»:

• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• arterial hypertension;
• liver tumors;
• occurrence or worsening of diseases whose relationship with oral contraceptive use has not been definitively established: Crohn’s disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, hemolytic-uremic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic disturbances in liver function, which may require discontinuation of COC use until normalization of liver function tests;
• exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

The frequency of breast cancer diagnosis is slightly increased among women taking COCs. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases of breast cancer among women currently or recently using COCs is small relative to the overall risk of breast cancer. The relationship with COC use is unknown. For detailed information, see sections «Contraindications» and «Special 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»).

Reporting suspected adverse reactions

Reporting suspected adverse reactions during post-marketing surveillance is very important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report suspected adverse reactions.

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging to protect from light. Keep out of reach of children.

Packaging. 21 tablets in a blister; 1 or 3 blisters together with a cardboard holder for blister storage in a carton.

Prescription status. Prescription only.

Manufacturer. Gedeon Richter Plc., Hungary.

Manufacturer's address and location of manufacturing site.

H-1103 Budapest, Dózsa György út 19-21, Hungary.