Madinet film-coated tablets blister pack No. 21

Instructions for Madinet film-coated tablets blister No. 21

Composition

active ingredients: 1 film-coated tablet contains ethinylestradiol 0.03 mg and chlormadinone acetate 2 mg;

excipients: lactose monohydrate, corn starch, maltodextrin, magnesium stearate;

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

Dosage 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. ATX code G03A A15.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Continuous use of Madinet® for 21 days suppresses the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary gland and, as a result, suppresses ovulation. There is proliferation of the endometrium and its secretory transformation. The consistency of cervical mucus also changes. This makes it difficult for sperm to pass through the cervical canal and leads to impaired motility. There are also changes in the endometrium, making the endometrium unsuitable for implantation.

The minimum dose of chlormadinone acetate that provides complete suppression of ovulation is 1.7 mg. The dose required for endometrial transformation is 25 mg per cycle.

Chlormadinone acetate is a progestogen with antiandrogenic properties. Its mechanism of action is based on the ability to replace androgens at specific receptors.

Clinical efficacy

In clinical trials using tablets with the same combination of active ingredients, 1,655 women were studied over 2 years, and more than 22,000 menstrual cycles were recorded, with 12 pregnancies. In 7 women, errors in use, concomitant diseases causing nausea or vomiting, or concomitant use of medicines known to reduce the contraceptive effect of hormonal contraceptives were recorded during the conception period.

Pharmacokinetics

Chlormadinone acetate (XMA)

Absorption

XMA is rapidly and almost completely absorbed after oral administration. The systemic bioavailability of XMA is high, as it is not subject to first-pass metabolism in the liver. The maximum plasma concentration (Cmax) is reached within 1-2 hours after oral administration of XMA.

Distribution

More than 95% of HMA is bound to plasma proteins, mainly albumin. HMA does not bind to sex hormone-binding globulin or cortisol-binding globulin. HMA accumulates mainly in adipose tissue.

Biotransformation

Various reduction and oxidation processes and 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-XMA with biological half-lives that do not differ significantly from unmetabolized XMA. The 3-hydroxymetabolites show antiandrogenic activity similar to XMA. In urine, the metabolites are found mainly in the form of conjugates. After enzymatic cleavage, the main metabolite is 2α-hydroxy-XMA, along with 3-hydroxymetabolites and dihydroxymetabolites.

Breeding

XMA is eliminated from plasma with a mean half-life of approximately 34 hours (after a single dose) and approximately 36-39 hours (after multiple doses). After oral administration, XMA and its metabolites are excreted in approximately equal amounts by both the kidneys and the intestines.

Ethinylestradiol (EE)

Absorption

EE is rapidly and almost completely absorbed after oral administration, with Cmax achieved after 1.5 hours. Due to presystemic binding and the effect of first-pass metabolism in the liver, absolute bioavailability is only approximately 40% and is subject to strong interindividual 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.

Biotransformation

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

Breeding

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

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

Chlormadinone acetate has been shown to be embryolethal in rabbits, rats and mice. Teratogenicity was also observed in rabbits at embryotoxic doses and in mice at the lowest dose tested (1 mg/kg/day). The relevance of these findings to human use has not been established.

In the course of conventional preclinical safety studies, which studied the chronic toxicity, genotoxicity and oncogenic potential of the drug, no special risks for humans were identified, except for those already described in other sections of the instructions for medical use of the drug.

Indication

Hormonal contraception.

Before prescribing Madinet®, the woman should be assessed for the presence of individual risk factors, especially those related to the risk of venous thromboembolism (VTE), and the risk of VTE when taking the drug should be compared with the risk when taking other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special Instructions for Use").

Contraindication

Combined hormonal contraceptives (CHCs) should not be used in the presence of the diseases listed below. If one of these conditions occurs while taking CHCs, Madinet® should be discontinued immediately:

Hypersensitivity to the active substances or to any other component of the drug.

Loss of control over diabetes.

Uncontrolled hypertension or significant elevation of blood pressure (values consistently above 140/90 mm Hg).

Presence or risk of venous thromboembolism (VTE):

current or history of VTE (when taking anticoagulants) (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE);

Known hereditary or acquired predisposition to VTE, in particular resistance to activated protein C (including factor V Leiden mutation); antithrombin III deficiency, protein C deficiency, protein S deficiency;

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

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

Presence or risk of arterial thromboembolism (ATE):

ATE is present either in history (e.g., myocardial infarction) or prodromal states (angina);

cerebrovascular diseases: current or history of stroke or prodromal conditions (transient ischemic attack (TIA));

known hereditary or acquired predisposition to the development of ATE, in particular hyperhomocysteinemia and the presence of antibodies to phospholipids (anticardiolipin antibodies, lupus anticoagulant);

history of migraine with focal neurological symptoms;

high risk of ATE due to the presence of multiple risk factors (see section "Special warnings and precautions for use") or the presence of one of the risk factors:

diabetes mellitus accompanied by vascular complications;

severe arterial hypertension;

severe dyslipoproteinemia.

Hepatitis, jaundice, liver dysfunction (until liver function tests normalize).

Generalized itching, cholestasis, particularly during previous pregnancy or estrogen therapy.

Dubin-Johnson syndrome, Rotor syndrome, bile secretion disorders.

Liver tumors in history or present.

Severe epigastric pain, liver enlargement or symptoms of intra-abdominal bleeding (see section "Adverse reactions").

New-onset or recurrent porphyria (all three forms, especially acquired porphyria).

History or current malignant hormone-dependent tumors, such as tumors of the mammary glands or uterus.

Severe lipid metabolism disorders.

History or current pancreatitis accompanied by severe hypertriglyceridemia.

Migraine symptoms that have occurred for the first time, as well as more frequent and extremely severe headaches.

Acute sensory disorders, such as vision or hearing impairment.

Movement disorders (including paresis).

Increased epileptic seizures.

Severe depression.

Otosclerosis that progressed during previous pregnancies.

Amenorrhea of unknown etiology.

Endometrial hyperplasia.

Vaginal bleeding of unknown etiology.

Meningioma or history of meningioma.

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section “Interaction with other medicinal products and other types of interactions”).

A contraindication is the presence of one or more serious risk factors for the development of venous or arterial thrombosis (see section "Special warnings and precautions for use").

Interaction with other medicinal products and other types of interactions

Note: The information for the concomitant medicinal product should be consulted for potential interactions.

Pharmacodynamic interactions

In clinical trials, transaminase (ALT) elevations greater than 5 times the upper limit of normal (ULN) have been observed in patients treated with hepatitis C virus (HCV) medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin. This occurred at a significantly higher frequency in women using ethinylestradiol-containing medicinal products, including combined hormonal contraceptives (CHCs). In addition, ALT elevations have also been observed in women using ethinylestradiol-containing medicinal products, such as CHCs, in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.3).

Therefore, patients taking Madinet® should switch to an alternative method of contraception (e.g. progestogen-only contraception or non-hormonal methods) before starting therapy with these combination drugs. Madinet® can be resumed 2 weeks after completing therapy with these combination regimens.

Pharmacokinetic interactions

Effect of other drugs on Madinet®

Interaction with drugs that induce microsomal enzymes is possible, as a result of which the clearance of sex hormones may increase, which, in turn, will lead to breakthrough bleeding and/or loss of contraceptive effectiveness.

Therapy

Enzyme induction is possible after a few days of administration. Maximum enzyme induction is usually observed within a few weeks. After drug withdrawal, enzyme induction may persist for up to 4 weeks.

Short-term treatment

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

If therapy with an enzyme-inducing drug is started during the period of taking the last COC tablets from the current package, then taking the tablets from the next COC package should be started immediately after the tablets in the previous package are finished, without taking a break in taking the tablets.

Long-term treatment

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

The following interactions have been documented based on published scientific data.

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

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

all medications that increase gastrointestinal motility (e.g. metoclopramide) or impair absorption (e.g. activated charcoal).

Active substances with inconsistent effects on PDA clearance

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

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

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

active substances that inhibit the sulfation of ethinylestradiol in the intestinal wall, such as ascorbic acid or paracetamol;

atorvastatin (increases the AUC of ethinylestradiol by 20%);

active substances that inhibit the activity of liver enzymes, such as antifungal agents that are imidazole derivatives (e.g. fluconazole), indinavir or troleandomycin.

Effect of Madinet® on other medicines:

inhibition of liver enzyme activity and, accordingly, an increase in the serum concentration of such active substances as diazepam (and other benzodiazepines metabolized by hydroxylation), cyclosporine, theophylline and prednisolone;

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

This may also apply to medications that have been used recently.

You should study the instructions for medical use of the medicinal product prescribed by your doctor to identify possible interactions with Madinet®.

Laboratory studies

The use of contraceptive steroids may affect the results of certain laboratory tests, including biochemical indicators of liver, thyroid, adrenal and renal function; as well as the level of plasma transport proteins, such as corticosteroid-binding globulin and lipid/lipoprotein fractions, as well as parameters of carbohydrate metabolism, coagulation and fibrinolysis. Changes usually occur within the normal range of laboratory values.

Application features

Special warnings.

Smoking increases the risk of serious cardiovascular adverse reactions with combined hormonal contraceptives (CHCs). This risk increases with age, depends on the number of cigarettes smoked, and is particularly high in women over 35 years of age. Women over 35 years of age who smoke should consider using other methods of contraception.

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

If one of the diseases or risk factors listed below is present, the use of Madinet® should be discussed with the woman.

If these diseases or risk factors appear for the first time or progress during use of the drug, the woman is advised to consult a doctor to determine whether she should stop using Madinet®.

Thromboembolism or other vascular diseases

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

Thrombosis of other blood vessels, such as hepatic, mesenteric, renal, retinal veins and arteries, has been reported very rarely in women using CHCs.

Risk of venous thromboembolism.

Combined hormonal contraceptives (CHCs) increase the risk of venous thromboembolism (VTE) in users compared with non-users. Products containing levonorgestrel, norgestimate or norethisterone are associated with a low risk of VTE. Other CHCs containing chlormadinone/ethinylestradiol, such as Madinet®, may have a 1.25-fold increased risk compared with products containing levonorgestrel. The decision to use any product other than those known to have a low risk of VTE should only be made after discussion with the woman to ensure that she understands the risk of VTE with Madinet®, her risk factors that influence this risk, and that the risk of VTE is highest in women during the first year of use. There is also evidence that the risk is increased when CHCs are restarted after a break of 4 weeks or more.

In women who were not using CHCs and were not pregnant, about two in a thousand would develop VTE in a year. However, the risk for any particular woman may be much higher, depending on her underlying risk factors (see below).

Epidemiological studies in women using low-dose CHCs (<50 μg ethinylestradiol) have shown that out of 10,000 women, 6–12 developed VTE within 1 year.

It is estimated that out of 10,000 women using CHCs containing chlormadinone, 6–9 will develop VTE in one year; this compares with around 6 in women using CHCs containing levonorgestrel.

Number of VTE cases per 10,000 women per year

The number of VTEs per year with low-dose CHCs is lower than the number in women during pregnancy or in the postpartum period.

VTE can be fatal in 1–2% of cases.

Risk factors for developing VTE.

The risk of venous thromboembolic complications in women using CHCs may be increased by the presence of additional risk factors, especially if there are several of the risk factors listed in Table 1.

Madinet® is contraindicated if a woman has several risk factors that place her at high risk of developing venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor for VTE, a situation may arise in which the risk is increased to a greater extent than when the individual factors are summed up: in this case, the overall risk of VTE should be taken into account.

If the benefit/risk balance is considered negative during the assessment, CHCs should not be prescribed (see section “Contraindications”).

Factors contributing to the development of VTE. Table 1

Basically, the risk of development increases with increasing body mass index.

This is especially important to consider if other risk factors are also present.

There is no consensus on whether there is a relationship between superficial thrombophlebitis and varicose veins or the etiology of venous thromboembolism.

It should also be taken into account that the risk of thromboembolic complications increases during pregnancy and especially in the first 6 weeks after delivery (see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

If symptoms occur, a woman should seek urgent medical attention and inform her doctor that she is taking CHCs.

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 that can only be felt when standing or walking;

increased sensation of warmth in the affected leg; red or discolored skin on the leg.

Symptoms of pulmonary embolism (PE) may include:

sudden attack of shortness of breath for an unknown reason or rapid breathing;

sudden cough, which may be accompanied by hemoptysis;

sharp chest pain;

severe headache or dizziness;

fast 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 symptoms (e.g., respiratory tract infections).

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

If the occlusion occurs in the vessels of the eye, symptoms can range from painless blurred vision, which may progress, to vision loss. Sometimes vision loss can occur immediately.

Risk of arterial thromboembolism (ATE).

Epidemiological studies have shown that the use of CHCs increases the risk of arterial thromboembolism or cerebrovascular accident (e.g. transient ischemic attack, stroke). Arterial thromboembolism can be fatal.

Risk factors for developing ATE

The risk of arterial thromboembolic events (myocardial infarction) or acute cerebrovascular accident (stroke) is increased in women using CHCs with the risk factors described in Table 2. Madinet® is contraindicated if a woman has one serious or several risk factors for ATE that place her at high risk of developing arterial thrombosis (see section "Contraindications"). It is possible that if a woman has more than one risk factor, this leads to an increased likelihood of an 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").

Factors of ATE development. Table 2.

Symptoms of ATE

If symptoms occur, a woman should seek urgent medical attention and inform her doctor that she is taking CHCs.

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 problems walking, dizziness, loss of balance or coordination;

sudden confusion, problems with speech or perception;

sudden vision problems in one or both eyes;

an unexpectedly severe or prolonged headache with no known cause;

loss of consciousness or fainting, with or without seizures.

Temporary symptoms indicate a transient ischemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

pain, discomfort, pressure, heaviness, a feeling of squeezing or bursting in the chest, arm, or behind the breastbone;

discomfort with irradiation to the back, jaw, throat, arm, stomach;

feeling full, upset stomach, or constipation;

sweating, nausea, vomiting and dizziness;

severe weakness, restlessness, or shortness of breath;

fast or irregular heartbeat.

Patients taking COCs should be informed that if they experience possible symptoms of thrombosis, they should consult a doctor. If thrombosis is suspected or confirmed, Madinet® 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 is controversial because it is unclear to what extent other factors influence the results (e.g., differences in the number of sexual partners or the use of barrier contraceptive methods) (see also the section on Medical Examination).

A meta-analysis of 54 epidemiological studies showed that the relative risk of developing breast cancer is slightly higher in women who use CHCs (RR = 1.24). This increased risk gradually decreases within 10 years after stopping CHCs. However, these studies have not confirmed a causal relationship between the disease and taking the drug. The observed increased risk may be explained by the fact that breast cancer is diagnosed at an earlier stage in women who use CHCs than in those who do not use them, by the biological action of CHCs, or by a combination of both factors.

With prolonged use of oral contraceptives, benign, very rarely malignant liver tumors have been observed, which in some cases can lead to life-threatening bleeding in the abdominal cavity. If severe acute pain in the upper abdomen appears that does not go away on its own, if the liver is enlarged or signs of intraperitoneal bleeding appear, the possibility of developing a liver tumor should be considered, and Madinet® should be discontinued.

Meningioma.

Meningiomas (single and multiple) have been reported in association with the use of chlormadinone acetate, particularly at high doses and over long periods (several years). Patients should be monitored for signs and symptoms of meningiomas in accordance with clinical practice. If a patient is diagnosed with a 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 undesirable effects of hormonal contraceptives (see section 4.8). Depression can be severe and is a known risk factor for suicidal behaviour and suicide. Women should be advised to contact their doctor if they experience mood changes and depressive symptoms, including shortly after starting treatment.

Many women taking oral contraceptives experience a slight increase in blood pressure. Clinically significant increases in blood pressure are rare. The relationship between the use of oral contraceptives and arterial hypertension has not been confirmed to date. If a clinically significant increase in blood pressure is observed while taking Madinet®, the drug should be discontinued and hypertension should be treated. As soon as blood pressure normalizes after antihypertensive therapy, Madinet® can be resumed.

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

In women with a history of herpes gestationis, a recurrence of this disease is possible while taking CHCs.

The use of CHCs may affect peripheral insulin resistance or glucose tolerance. Therefore, diabetic patients taking oral contraceptives should be carefully monitored.

In rare cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid exposure to the sun and ultraviolet radiation while taking oral contraceptives.

Precautions

Taking medications containing estrogen or estrogen/progestin may adversely affect certain diseases/conditions. Cases in which close medical supervision is necessary:

epilepsy;

multiple sclerosis;

tetany;

migraine (see section "Contraindications");

asthma;

heart or kidney failure;

minor chorea;

diabetes mellitus (see section "Contraindications");

liver disease (see section "Contraindications");

dyslipoproteinemia (see section "Contraindications");

autoimmune diseases, including systemic lupus erythematosus;

adiposity;

arterial hypertension (see section "Contraindications");

endometriosis;

varicose veins;

thrombophlebitis (see section "Contraindications");

blood clotting disorders (see section "Contraindications");

mastopathy;

uterine fibroids;

herpes in pregnant women;

depression;

chronic inflammatory bowel diseases (Crohn's disease, ulcerative colitis, see the "Adverse Reactions" section).

Medical examination

Before initiating or reinstituting Madinet®, a complete personal and family medical history should be taken, a physical examination should be performed, and pregnancy should be ruled out. Blood pressure should be measured and a physical examination should be performed, taking into account the contraindications (see section 4.3) and warnings described in this section.

The woman should be warned about the risk of venous and arterial thrombosis, including when using Madinet® compared with other CHCs, the symptoms of VTE and ATE, known risk factors, and what to do in case of suspected thrombosis.

The woman should carefully read the instructions for medical use of the medicinal product and follow the specified recommendations. The frequency and type of examinations should be based on the developed practical recommendations, adapted for each specific woman.

It is worth informing the woman that taking oral contraceptives does not protect against HIV infection (AIDS), as well as other sexually transmitted diseases.

Decreased efficiency

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

Impact on menstrual cycle control

Breakthrough bleeding and minor spotting

The use of all oral contraceptives can lead to irregular vaginal bleeding (breakthrough bleeding and light spotting), especially during the first cycles of taking the drug. Therefore, a medical evaluation of irregular cycles should be carried out only after an adaptation period of about three cycles. If, while taking the drug