Madinet®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MADI NET®

Composition:

Active substances: 1 film-coated tablet contains ethinylestradiol 0.03 mg and chloromadinone acetate 2 mg;

Excipients: lactose monohydrate, maize starch, maltodextrin, magnesium stearate;

pink film-coating mixture: hypromellose, polyethylene glycol 400, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round film-coated tablets, pink in color, without coating defects.

Pharmacotherapeutic group. Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combinations. ATC code G03A A15.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Continuous use of Minedronate® for 21 days suppresses the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary gland and, as a result, inhibits ovulation. Endometrial proliferation and its secretory transformation are observed. Cervical mucus consistency is also altered, which hinders spermatozoa penetration through the cervical canal and impairs their motility. Additionally, changes occur in the endometrium, rendering it unsuitable for implantation.

The minimal dose of chloromadinone acetate that ensures complete suppression of ovulation is 1.7 mg. The dose required for endometrial transformation is 25 mg per cycle.

Chloromadinone acetate is a progestogen with antiandrogenic properties. Its mechanism of action is based on its ability to displace androgens from specific receptors.

Clinical efficacy

During clinical studies using tablets with the same combination of active substances over a period of 2 years, 1,655 women were investigated, and more than 22,000 menstrual cycles were evaluated, with 12 pregnancies reported. In 7 women, conception occurred during periods of application errors, concomitant diseases causing nausea or vomiting, or concomitant use of medicinal products known to reduce the contraceptive efficacy of hormonal contraceptives.

Pharmacokinetics

Chlormadinone acetate (CMA)

Absorption

CMA is rapidly and almost completely absorbed after oral administration. The systemic bioavailability of CMA is high, as it does not undergo significant first-pass metabolism in the liver. Maximum plasma concentration (Cmax) is reached within 1–2 hours after oral administration of CMA.

Distribution

Over 95% of CMA is bound to plasma proteins, primarily to albumin. CMA does not bind to sex hormone-binding globulin or to cortisol-binding globulin. CMA accumulates predominantly in adipose tissue.

Biological transformation

Various processes of reduction and oxidation, as well as conjugation with glucuronides and sulfates, lead to the formation of a large number of metabolites. The main metabolites in human plasma are 3α- and 3β-hydroxy-CMA, with biological half-lives not significantly different from those of unchanged CMA. The 3-hydroxy metabolites exhibit antiandrogenic activity similar to that of CMA. In urine, metabolites are primarily present in conjugated form. After enzymatic cleavage, the main metabolite is 2α-hydroxy-CMA, along with 3-hydroxy metabolites and dihydroxy metabolites.

Elimination

CMA is eliminated from plasma with a mean elimination half-life of approximately 34 hours (after a single dose) and approximately 36–39 hours (after multiple dosing). After oral administration, CMA and its metabolites are excreted in approximately equal amounts via the kidneys and through the intestine.

Ethinylestradiol (EE)

Absorption

EE is rapidly and almost completely absorbed after oral administration; Cmax is reached within 1.5 hours. Due to presystemic binding and first-pass metabolism in the liver, absolute bioavailability is only about 40% and is subject to high individual variability (20–65%).

Distribution

Plasma concentrations of EE reported in the literature vary widely. Approximately 98% of EE is bound to plasma proteins, almost exclusively to albumin.

Biological transformation

Like natural estrogens, EE undergoes biotransformation by the cytochrome P-450 system via hydroxylation of the aromatic ring. The main metabolite is 2-hydroxy-EE, which is further transformed into other metabolites and conjugates. EE undergoes presystemic metabolism both in the mucosa of the small intestine and in the liver. In urine, glucuronides are primarily found, whereas sulfates are present in bile and plasma.

Elimination

The mean elimination half-life of EE from plasma is approximately 12–14 hours. EE is excreted via the kidneys and through the intestine in a ratio of 2:3. EE sulfate, excreted in bile, undergoes enterohepatic recirculation after hydrolysis by intestinal bacteria.

Safety preclinical data

Estrogens have low acute toxicity. Due to pronounced differences between species of experimental animals, as well as differences between animals and humans, results of estrogen studies in animals have limited predictive value for humans. Ethinylestradiol is a synthetic estrogen commonly used in oral contraceptives. Laboratory animal studies have shown that even at relatively low doses, this substance has embryolethal effects; developmental abnormalities of the urogenital organs and signs of feminization were observed in male fetuses. These effects are considered species-specific.

Chlormadinone acetate has been shown to have embryolethal effects when administered to rabbits, rats, and mice. Teratogenic effects were also observed at embryotoxic doses in rabbits and at the lowest tested doses (1 mg/kg/day) in mice. The significance of these findings for human use has not been established.

In standard preclinical safety studies investigating chronic toxicity, genotoxicity, and oncogenic potential, no specific risks for humans were identified other than those already described in other sections of the product information.

Clinical characteristics.

Indications.

Hormonal contraception.

Before prescribing Madinette®, the presence of individual risk factors in women should be assessed, particularly those related to the risk of venous thromboembolism (VTE), as well as comparing the VTE risk during use of this drug with that associated with other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions").

Contraindications.

Combined hormonal contraceptives (CHCs) must not be used in the presence of the following conditions. If any of these conditions occur during CHC use, Madinette® should be discontinued immediately:

• Hypersensitivity to the active substances or to any other component of the medicinal product.
• Poorly controlled diabetes mellitus.
• Uncontrolled arterial hypertension or marked increase in blood pressure (values persistently exceeding 140/90 mm Hg).
• Presence or risk of venous thromboembolism (VTE):
  • Current VTE (while on anticoagulant therapy) or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
  • Known hereditary or acquired predisposition to VTE, including activated protein C resistance (including factor V Leiden mutation); deficiency of antithrombin III, protein C, or protein S;
  • 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 or past ATE (e.g., myocardial infarction) or prodromal conditions (angina pectoris);
  • Cerebrovascular disorders: current or past stroke or prodromal conditions (transient ischemic attack (TIA));
  • Known hereditary or acquired predisposition to ATE, including hyperhomocysteinemia and presence of 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 presence of one of the following risk factors:
  • Diabetes mellitus with vascular complications;
  • Severe arterial hypertension;
  • Severe dyslipoproteinemia.
• Hepatitis, jaundice, or impaired liver function (until liver function tests normalize).
• Generalized pruritus, cholestasis, particularly during previous pregnancy or estrogen therapy.
• Dubin-Johnson syndrome, Rotor syndrome, or impaired bile excretion.
• History of or current liver tumors.
• Severe epigastric pain, hepatomegaly, or symptoms of intra-abdominal bleeding (see section "Adverse reactions").
• Porphyria, either newly occurring or recurrent (all three forms, especially acquired porphyria).
• History of or current malignant hormone-dependent tumors, such as breast or uterine tumors.
• Severe lipid metabolism disorders.
• History of or current pancreatitis associated with severe hypertriglyceridemia.
• New onset of migraine symptoms, or increased frequency and intensity of headaches.
• Acute sensory disturbances, such as visual or auditory disturbances.
• Motor disturbances (including paralysis).
• Worsening of epileptic seizures.
• Severe depression.
• Otosclerosis that worsened during previous pregnancies.
• Amenorrhea of unknown etiology.
• Endometrial hyperplasia.
• Vaginal bleeding of unknown origin.
• Meningioma or history of meningioma.
• Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or with medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Contraindications include the presence of one serious or multiple risk factors for venous or arterial thrombosis (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Note: Information regarding concomitantly administered medicinal products should be reviewed to identify potential interactions.

Pharmacodynamic interactions

During clinical studies in patients receiving treatments for hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, increased transaminase levels (ALT) more than 5 times the upper limit of normal (ULN) were observed. This occurred 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 products, such as CHCs (see section "Contraindications").

Therefore, women taking Madinette® should switch to an alternative method of contraception (e.g., progestogen-only contraception or non-hormonal methods) prior to initiating therapy with these combination regimens. Use of Madinette® may be resumed 2 weeks after completion of such combination therapies.

Pharmacokinetic interactions

Effect of other medicinal products on Madinette®

Interactions are possible with medicinal products that induce microsomal enzymes, which may increase the clearance of sex hormones, leading to breakthrough bleeding and/or loss of contraceptive efficacy.

Therapy

Enzyme induction may occur within a few days of starting treatment. Maximum enzyme induction is usually observed within several weeks. After discontinuation of the inducing agent, enzyme induction may persist for up to 4 weeks.

Short-term treatment

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another contraceptive method in addition to combined oral contraceptives. The barrier method should be used throughout the entire period of treatment with the enzyme-inducing drug and for an additional 28 days after discontinuation of such therapy.

If therapy with an enzyme-inducing agent is initiated during the period of taking the last tablets in the current oral contraceptive pack, the next pack should be started immediately after finishing the previous pack, without a break.

Long-term treatment

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

The following interactions have been documented according to published scientific data.

Active substances that increase the clearance of COCs (reduced COC efficacy due to enzyme induction), e.g.: barbiturates, bosentan, carbamazepine, barbexaclon, phenytoin, primidone, modafinil, rifampicin, rifabutin, the HIV drug ritonavir, nevirapine and efavirenz, and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate, and products containing St. John's wort (Hypericum perforatum).

Medicinal products/active substances that may reduce serum concentrations of ethinylestradiol:

• All medicinal products that enhance gastrointestinal motility (e.g., metoclopramide) or impair absorption (e.g., activated charcoal).

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) protease inhibitors, may 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 should be reviewed to identify potential interactions and any additional 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.

Medicinal products/active substances that may increase serum concentrations of ethinylestradiol:

• Active substances that inhibit sulfation of ethinylestradiol in the intestinal wall, such as ascorbic acid or paracetamol;
• Atorvastatin (increases AUC of ethinylestradiol by 20%);
• Active substances that inhibit hepatic enzyme activity, such as antifungal agents derived from imidazole (e.g., fluconazole), indinavir, or troleandomycin.

Effect of Madinette® on other medicinal products:

• Inhibition of hepatic enzyme activity, thereby increasing serum concentrations of active substances such as diazepam (and other benzodiazepines metabolized via hydroxylation), cyclosporine, theophylline, and prednisolone;
• Induction of hepatic glucuronidation, thereby decreasing serum concentrations of substances such as lamotrigine, clofibrate, paracetamol, morphine, and lorazepam.

The need for insulin and oral antidiabetic agents may change, as the drug affects glucose tolerance (see section "Special precautions").

This may also apply to medicinal products recently initiated.

The package leaflet of the prescribed medicinal product should be reviewed to identify possible interactions with Madinette®.

Laboratory tests

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

Special precautions.

Special warnings.

Smoking increases the risk of serious cardiovascular side effects associated with the use of combined hormonal contraceptives (CHCs). This risk increases with age, depends on the number of cigarettes smoked, and is particularly high in women aged 35 years and older. Women aged 35 years and older who smoke should consider using alternative contraceptive methods.

The use of CHCs is associated with an increased risk of serious disorders such as myocardial infarction, thromboembolism, stroke, or liver tumors. Other risk factors, such as arterial hypertension, hyperlipidemia, obesity, and diabetes mellitus, significantly increase the risk of complications and mortality.

If any of the diseases or risk factors listed below are present, the use of Minedronette® should be discussed with the woman.

If these conditions or risk factors develop for the first time or worsen during treatment, the woman should consult a physician to determine whether Minedronette® should be discontinued.

Thromboembolism or other vascular disorders

Epidemiological studies have shown an association between the use of hormonal contraceptives and an increased risk of venous or arterial thromboembolic disorders, such as myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. These conditions are rare.

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

Risk of venous thromboembolism (VTE).

The use of combined hormonal contraceptives (CHCs) increases the risk of venous thromboembolism (VTE) in users compared to non-users. Products containing levonorgestrel, norgestimate, or norethisterone are associated with a low level of VTE risk. Other CHCs containing cyproterone acetate/ethinylestradiol, such as Minedronette®, may have a 1.25-fold higher risk compared to products containing levonorgestrel. The decision to use any product other than those known to have a low VTE risk should be made only after discussion with the woman to ensure she understands the risk of VTE associated with Minedronette®, how her individual risk factors affect this risk, and that the risk of VTE is highest during the first year of use. In addition, data indicate that the risk increases when restarting CHC use after a break of 4 weeks or more.

In women who do not use CHCs and who are not pregnant, approximately 2 out of 1000 will develop VTE over one year. However, in any individual woman, the risk may be considerably higher depending on her underlying risk factors (see below).

Epidemiological studies in women using low-dose CHCs (<50 µg ethinylestradiol) have shown that 6–12 out of 10,000 women will develop VTE within one year.

It is estimated that 6–9 out of 10,000 women using CHCs containing cyproterone acetate will develop VTE within one year; this compares with approximately 6 out of 10,000 women using CHCs containing levonorgestrel.

Number of VTE cases per 10,000 women per year

The number of VTE cases per year in women using low-dose CHCs is lower than the number observed during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

Risk factors for VTE development.

The risk of venous thromboembolic complications in women using CHCs may increase if additional risk factors are present, especially when multiple risk factors listed in Table 1 are present.

Minedronette® is contraindicated if a woman has multiple risk factors that place her in a high-risk group for venous thrombosis (see section "Contraindications"). If a woman has more than one VTE risk factor, the situation may arise where the overall risk is greater than the sum of individual risks; in such cases, the total VTE risk should be considered.

If the benefit-risk balance is considered unfavorable, CHCs should not be prescribed (see section "Contraindications").

Risk factors for VTE development. Table 1

There is no consensus regarding the relationship between superficial thrombophlebitis and varicose veins or the etiology of venous thromboembolism.

It should also be noted that the risk of thromboembolic complications increases during pregnancy and particularly during the first 6 weeks postpartum (see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

If any symptoms 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 tenderness, which may only be felt when standing or walking;
• Increased warmth in the affected leg; red or discolored skin on the leg.

Symptoms of pulmonary embolism (PE) may include:

• Sudden onset of unexplained shortness of breath or rapid breathing;
• Sudden cough, which may be accompanied by hemoptysis;
• Sharp chest pain;
• Severe headache 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 infection).

Other signs of vascular occlusion may include sudden pain, swelling, and mild bluish discoloration of the extremities.

If occlusion occurs in ocular vessels, symptoms may range from painless blurred vision, which may progress, to sudden vision loss. Sometimes, vision loss may occur immediately.

Risk of arterial thromboembolism (ATE).

Epidemiological studies have shown that the use of COCs is associated with an increased risk of arterial thromboembolism or cerebrovascular disorders (e.g., transient ischemic attack, stroke). Arterial thromboembolism can be fatal.

ATE risk factors

The risk of developing arterial thromboembolic complications (myocardial infarction) or acute cerebrovascular events (stroke) increases in women using COCs who have risk factors described in Table 2. Minedette® is contraindicated in women who have one serious or multiple risk factors for ATE that place them in a high-risk category for arterial thrombosis (see section "Contraindications"). It is likely that if a woman has more than one risk factor, this leads to a higher probability of increased overall risk of ATE compared to when these factors act individually. If the benefit-risk balance is considered negative, COCs should not be prescribed (see section "Contraindications").

ATE risk factors. Table 2.

Symptoms of ATE

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

Symptoms of acute cerebral circulation disorders may include:

• sudden weakness or numbness of the face, arm, or leg, especially on one side of the body;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, speech or comprehension difficulties;
• sudden vision problems in one or both eyes;
• sudden, severe or prolonged headache without a known cause;
• loss of consciousness or fainting, with or without seizures.

Transient symptoms may indicate a transient ischemic 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 abdomen;
• feeling of fullness, indigestion, or constipation;
• sweating, nausea, vomiting, and dizziness;
• severe weakness, restlessness, or shortness of breath;
• rapid or irregular heartbeat.

Patients taking COCs should be informed that they should contact their physician if they experience possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, Madinette® should be discontinued.

Tumors

Some epidemiological studies suggest that long-term use of oral contraceptives is a risk factor for cervical cancer in women infected with human papillomavirus (HPV). However, this issue remains controversial, as it is unclear to what extent other factors may influence the results (e.g., differences in the number of sexual partners or use of barrier contraception methods) (see also section "Medical Examination").

A meta-analysis of 54 epidemiological studies showed a slightly increased relative risk of breast cancer in women taking COCs (RR = 1.24). This increased risk gradually decreases over 10 years after discontinuation of COCs. However, these studies did not confirm a causal relationship between the disease and drug use. The observed increased risk may be explained by earlier diagnosis of breast cancer in women using COCs compared to non-users, as well as by the biological effect of COCs or a combination of both factors.

Rarely, benign and very rarely malignant liver tumors have been observed with long-term use of oral contraceptives, which in some cases may lead to life-threatening intra-abdominal hemorrhage. In the presence of severe acute upper abdominal pain that does not resolve spontaneously, hepatomegaly, or signs of intraperitoneal bleeding, the possibility of a liver tumor should be considered, and Madinette® should be discontinued.

Meningioma

Cases of meningioma (single and multiple) have been reported in association with the use of chlormadinone acetate, particularly at high doses and over prolonged periods (several years). Patients should be monitored for signs and symptoms of meningioma according to clinical practice. If a patient is diagnosed with meningioma, any treatment containing chlormadinone acetate should be discontinued as a precautionary measure.

There is some evidence that the risk of meningioma may decrease after discontinuation of chlormadinone acetate treatment.

Other diseases

Depressed mood and depression are known adverse effects of hormonal contraceptives (see section "Adverse Reactions"). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should be advised to contact their physician if they experience mood changes or depressive symptoms, including soon after starting treatment.

Many women taking oral contraceptives experience a slight increase in blood pressure. Clinically significant elevation of blood pressure is rare. The relationship between oral contraceptive use and arterial hypertension has not been confirmed to date. If clinically significant hypertension occurs during Madinette® use, the drug should be discontinued and antihypertensive treatment initiated. Once blood pressure normalizes after antihypertensive therapy, Madinette® may be resumed.

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

Women with a history of herpes gestationis may experience recurrence of this condition during COC use.

Women with a personal or family history of hypertriglyceridemia during COC use have an increased risk of pancreatitis. Acute or chronic liver dysfunction may require discontinuation of COCs until liver function tests normalize. COC use should be discontinued in case of recurrence of cholestatic jaundice first diagnosed during pregnancy or sex hormone use.

COCs may affect peripheral insulin resistance or glucose tolerance. Therefore, careful monitoring is required in diabetic patients taking oral contraceptives.

Chloasma may rarely occur, particularly in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid sun exposure and ultraviolet radiation during oral contraceptive use.

Precautionary measures

The use of drugs containing estrogen or estrogen/progestin may adversely affect certain diseases/conditions. Cases requiring careful medical monitoring include:

• epilepsy;
• multiple sclerosis;
• tetany;
• migraine (see section "Contraindications");
• asthma;
• cardiac or renal failure;
• chorea minor;
• diabetes mellitus (see section "Contraindications");
• liver disease (see section "Contraindications");
• dyslipoproteinemia (see section "Contraindications");
• autoimmune diseases, including systemic lupus erythematosus;
• obesity;
• arterial hypertension (see section "Contraindications");
• endometriosis;
• varicose veins;
• thrombophlebitis (see section "Contraindications");
• coagulation disorders (see section "Contraindications");
• mastopathy;
• uterine fibroids;
• herpes gestationis;
• depression;
• chronic inflammatory bowel diseases (Crohn's disease, ulcerative colitis, see section "Adverse Reactions").

Medical examination

Before initiating or resuming Madinette®, a complete personal and family medical history should be obtained, a clinical examination performed, and pregnancy excluded. Blood pressure should be measured, and a physical examination conducted, paying attention to contraindications (see section "Contraindications") and warnings described in this section.

The woman should be informed about the risk of venous and arterial thrombosis, including the risk with Madinette® compared to other COCs, symptoms of VTE and ATE, known risk factors, and what to do in case of suspected thrombosis.

The woman should carefully read the package leaflet and follow the instructions provided. The frequency and type of examinations should be based on established clinical guidelines adapted to each individual woman.

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

Reduced efficacy

Missed tablet intake (see section "Irregular tablet intake"), vomiting or gastrointestinal disturbances, including diarrhea, prolonged use of certain concomitant medications (see section "Interaction with other medicinal products and other forms of interaction"), or in very rare cases metabolic disorders may reduce the contraceptive efficacy of the drug.

Effect on menstrual cycle control

Breakthrough bleeding and spotting

Use of all oral contraceptives may lead to irregular vaginal bleeding (breakthrough bleeding and spotting), especially during the first cycles of use. Therefore, medical evaluation of irregular cycles should only be performed after an adaptation period of approximately three cycles. If breakthrough bleeding persists or appears anew during Madinette® use despite previously regular cycles, an evaluation should be performed to exclude pregnancy or disease. After excluding pregnancy or disease, Madinette® may be continued or switched to another medication.

Intermenstrual bleeding may indicate reduced contraceptive efficacy (see sections "Irregular tablet intake", "Recommendations in case of vomiting or diarrhea", "Interaction with other medicinal products and other forms of interaction").

Absence of withdrawal bleeding

Withdrawal bleeding usually occurs after 21 days of active tablet intake. Occasionally, especially during the first months of use, withdrawal bleeding may be absent. However, this does not necessarily indicate reduced contraceptive efficacy. If withdrawal bleeding is absent after one cycle during which the patient did not miss any tablets, the 7-day tablet-free interval was not extended, and there was no vomiting or diarrhea, the likelihood of fertilization is low, and Madinette® may be continued. If Madinette® was taken irregularly before the first missed withdrawal bleed, or if withdrawal bleeding is absent for two consecutive cycles, pregnancy should be excluded before continuing the medication.

Medicinal products of plant origin containing St. John's wort (Hypericum perforatum) should not be taken concomitantly with Madinette® (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding

Pregnancy

Madinette® is contraindicated during pregnancy. Pregnancy should be excluded before starting treatment. If pregnancy occurs during Madinette® use, treatment should be discontinued immediately. Epidemiological studies do not provide clinical evidence of teratogenic or fetotoxic effects from inadvertent estrogen use during pregnancy in combination with other progestogens at doses similar to those in Madinette®. Although animal studies have shown evidence of reproductive toxicity, clinical data from over 330 identified pregnancies in women showed no embryotoxic effect of chlormadinone acetate.

The increased risk of VTE in the postpartum period should be considered when resuming Madinette® use (see sections "Special instructions" and "Dosage and administration").

Breastfeeding period

Estrogens may affect lactation, as they may alter the quantity and composition of breast milk. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk and affect the infant. Therefore, Madinette® should not be used during breastfeeding.

Ability to influence reaction speed when driving vehicles or operating machinery

There are no data on negative effects of combined hormonal contraceptives on the ability to drive vehicles or operate machinery.

Dosage and Administration

Dosage

Take 1 tablet daily at approximately the same time each day (preferably in the evening) for 21 consecutive days, followed by a 7-day break. A withdrawal bleed resembling menstruation is expected to occur 2–4 days after taking the last tablet. After the 7-day break, continue taking tablets from the next pack of Mадінет®, regardless of whether bleeding has stopped.

Administration

The tablet should be pressed out of the blister pack according to the day-of-the-week marking and swallowed whole, with a small amount of liquid if necessary. Subsequent tablets should be taken in the direction indicated by the arrow on the blister pack.

Starting the tablets

If hormonal contraceptives have not been used previously (during the previous menstrual cycle)

Begin taking tablets on the first day of the woman’s natural cycle, i.e., the first day of menstrual bleeding. If the first tablet is taken on the first day of menstruation, contraceptive protection begins immediately and continues throughout the 7-day tablet-free interval.

Alternatively, tablets may be started on days 2–5 of the menstrual cycle, regardless of whether bleeding has ceased. However, in this case, additional barrier methods of contraception must be used for the first 7 days of tablet intake.

If menstruation began more than 5 days ago, wait until the next menstrual period before starting Mадінет®.

Switching from another hormonal contraceptive to Mадінет®

Switching from another combined oral contraceptive (COC)

Begin taking Mадінет® the day after the last active tablet or placebo tablet of the previous COC, without any gap between packs.

Switching from progestogen-only pills ("mini-pills")

Take the first Mадінет® tablet the day after discontinuing the progestogen-only pills. Use additional barrier contraception for the first 7 days of treatment.

Switching from injectable hormonal contraceptives or implants

Mадінет® may be started the day after implant removal or on the day the next scheduled injection would have been given. Use additional barrier contraception for the first 7 days of treatment.

After miscarriage or first-trimester abortion

Mадінет® may be started immediately after a miscarriage or first-trimester abortion. In this case, additional contraceptive methods are not required.

After childbirth or after second-trimester miscarriage or abortion

Non-breastfeeding women may start taking Mадінет® 21–28 days after childbirth. In this case, additional contraceptive methods are not required.

If treatment is started later than 28 days after childbirth, additional barrier contraception must be used for the first 7 days.

If sexual intercourse has already occurred, pregnancy must be ruled out before starting treatment, or wait until the onset of the first menstrual period.

Breastfeeding period (see section "Use during pregnancy or breastfeeding")

Mадінет® is not recommended for breastfeeding women.

After discontinuing Mадінет®

After stopping Mадінет®, the menstrual cycle typically resumes within about a week.

Irregular tablet intake

If a patient forgets to take a tablet but the delay in intake does not exceed 12 hours, there is no need to use additional contraceptive methods. Women should continue taking tablets as usual.

If the missed dose interval exceeds 12 hours, contraceptive protection may be reduced. In such cases, follow these two main principles:

1. The interval between tablet intakes must never exceed 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian system is achieved by taking tablets continuously for 7 days.

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 thereafter. Additionally, use a barrier method of contraception (e.g., condoms) for the next 7 days. If a tablet was missed during the first week of the cycle and sexual intercourse occurred in the previous 7 days (including the period of missed intake), consider the possibility of pregnancy. The greater the number of missed tablets and the closer the missed doses are to the tablet-free interval, the higher the risk of pregnancy.

If the current pack contains fewer than 7 tablets remaining, start taking tablets from the next pack of Mадінет® immediately after finishing the previous pack, i.e., without a break. Withdrawal bleeding is unlikely to occur before finishing the second pack, although breakthrough bleeding or spotting may occur. If menstruation does not occur after finishing the second pack, a pregnancy test should be performed.

Recommendations in case of vomiting or diarrhea

If vomiting occurs within 4 hours after taking the tablet or if severe diarrhea is present, absorption of the drug may be incomplete and contraceptive efficacy cannot be guaranteed. In such cases, follow the instructions for missed tablets (see above). Continue taking Mадінет®.

Delaying withdrawal bleeding

To delay menstruation, continue taking Mадінет® from a new pack without a break. Treatment may be continued, if desired, until the end of the second pack. Breakthrough bleeding or spotting may occur. Resume regular Mадінет® intake after a 7-day tablet-free interval.

To shift the onset of menstruation to another day of the week, shorten the tablet-free interval by the number of days desired. The shorter the interval, the more likely it is that withdrawal bleeding will be absent and breakthrough bleeding or spotting may occur during the intake of tablets from the second pack (as with delaying menstruation).

Elderly patients

Mадінет® is not indicated after menopause.

Children

Mадінет® is indicated only after menarche. The safety and efficacy of chlormadinone acetate and ethinylestradiol in adolescents under 16 years of age have not been established. There are no data. The drug is not intended for use in children.

Overdose

There is no information on serious toxic effects of the drug in overdose. Symptoms may include nausea, vomiting, and, particularly in young girls, slight vaginal bleeding. There is no specific antidote; symptomatic treatment is recommended. In rare cases, monitoring of water-electrolyte balance and liver function may be necessary.

Adverse reactions.

a) Clinical studies of tablet formulations with the same combination of active substances showed that the most common adverse reactions (>20%) were breakthrough bleeding, slight spotting, headache, and breast pain. The likelihood of irregular bleeding decreases with continued use of tablets containing the same active ingredients.

b) Following clinical studies involving 1629 women using tablets with the same combination of active substances, the following adverse reactions have been reported.

In addition, the following adverse reactions have been reported during post-marketing use of the active substances ethinylestradiol and chloromadinone acetate: asthenia and allergic reactions, including angioedema.

Description of selected adverse reactions.

When using COCs containing 0.03 mg ethinylestradiol and 2 mg chloromadinone acetate, the following adverse reactions have also been reported:

• In women using COCs, an increased risk of arterial and venous thrombotic and thromboembolic events has been observed, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism (see section "Special precautions").
• According to data from some studies, long-term use of COCs increases the risk of developing biliary tract diseases.
• Rarely, benign liver tumors have been reported after taking hormonal contraceptives; malignant liver tumors have been reported even more rarely. In individual cases, these tumors have led to intra-abdominal bleeding (see section "Special precautions").
• Exacerbation of chronic inflammatory bowel diseases (Crohn's disease, ulcerative colitis) (see section "Special precautions").

Information on other serious adverse reactions, such as cancers of the uterus or breast, is provided in the section "Special precautions".

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions between other medicinal products (enzyme inducers) and oral contraceptives (see section "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store out of the reach of children, in the original packaging, at a temperature not exceeding 30 °C.

Packaging. 21 tablets per blister; 1, 3, or 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. mibe GmbH & Co. KG.

Manufacturer's address and place of business.

Muenchener Strasse 15, Brehna, Saxony-Anhalt, 06796, Germany.