Belara film-coated tablets No. 21

Instructions for Belara film-coated tablets No. 21

Composition

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

excipients: lactose monohydrate, corn starch, povidone K-30, magnesium stearate;

shell: hypromellose, lactose monohydrate, titanium dioxide (E 171), talc, polyethylene glycol (macrogol 6000), propylene glycol, red iron oxide (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: light pink, round, biconvex tablets, film-coated. The core is white or almost white.

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 Belara® 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

During clinical trials, in which the use of tablets containing ethinylestradiol 0.03 mg and chlormadinone acetate 2 mg was tested with the participation of 1655 women for 2 years on the example of more than 22,000 cycles, 12 pregnancies were registered. 7 women during the period of fertilization of the egg made mistakes in taking the drug, suffered from concomitant diseases accompanied by nausea or vomiting, or simultaneously took medications that reduce the contraceptive effect of hormonal drugs.

Table 1

Pharmacokinetics

Chlormadinone acetate (XMA)

Absorption

After oral administration, XMA is rapidly and almost completely absorbed. The systemic bioavailability of XMA is high, as it is not subject to primary metabolism in the liver. The maximum concentration in blood plasma is reached after 1-2 hours.

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 processes of reduction, oxidation and conjugation with glucuronides and sulfates lead to the formation of a variety of metabolites. The main metabolites in the blood plasma are 3α- and 3β-hydroxy-XMA with a half-life that does not differ significantly from that of unmetabolized XMA. The 3-hydroxy-metabolites have antiandrogenic activity similar to that of XMA itself. In the urine, the metabolites are found mainly in the form of conjugates. After enzymatic cleavage, 2α-hydroxy-XMA becomes the main metabolite, 3-hydroxymetabolites and dihydroxymetabolites are also formed.

Breeding

The mean plasma half-life of XMA is approximately 34 hours after a single dose and approximately 36–39 hours after multiple administration. 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, reaching peak plasma concentrations after 1.5 hours. Due to presystemic binding and hepatic metabolism, absolute bioavailability is only about 40% and is subject to strong individual variability (20–65%).

Distribution

Available published data on plasma concentrations of EE vary widely. Approximately 98% of ethinylestradiol is bound to plasma proteins, almost exclusively to albumin.

Biotransformation

Like natural estrogens, EE is biotransformed through hydroxylation of the aromatic ring (mediated by the cytochrome P450 system). The main metabolite is 2-hydroxy-EE, which is transformed into other metabolites and conjugates. Ethinylestradiol undergoes presystemic binding both in the mucosa of the small intestine and in the liver. Glucuronides are mainly found in the urine, and sulfates in bile and blood plasma.

Breeding

The average plasma half-life of EE 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. Because of 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; abnormalities of the genitourinary system and signs of feminization have been observed in male fetuses. These effects are considered species-specific.

Chlormadinone acetate has been shown to be embryolethal in rabbits, rats and mice. Furthermore, teratogenic effects were 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.

During 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 Belara®, the woman should be assessed for 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

CHCs should not be used in the presence of the diseases listed below. If one of these conditions occurs while taking Belara®, the drug should be discontinued immediately. Loss of control of diabetes mellitus. Uncontrolled arterial hypertension or a significant increase in blood pressure (values constantly exceeding 140/90 mm Hg); Presence or risk of venous thromboembolism: existing venous thromboembolism (on anticoagulants) or references in the medical history (e.g. deep vein thrombosis (DVT), pulmonary embolism); known hereditary or acquired predisposition to the development of VTE, such as resistance to activated protein C (including the Leiden mutation of factor V), antithrombin III deficiency, protein C deficiency, protein S deficiency;

major surgical interventions with long-term immobilization (see section "Special instructions for use")

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

Presence or risk of arterial thromboembolism (ATE): current arterial thromboembolism or history of (e.g. myocardial infarction) or prodromal conditions (angina); cerebrovascular disease - current or history of stroke or prodromal conditions (transient ischemic attack (TIA)); known hereditary or acquired predisposition to ATE, in particular hyperhomocysteinemia, antibodies to phospholipids (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 warnings and precautions for use") or the presence of risk factors such as diabetes mellitus accompanied by vascular complications; severe arterial hypertension, severe dyslipoproteinemia;

Hepatitis, jaundice, liver dysfunction until liver function tests return to normal; Generalized pruritus, cholestasis, particularly during previous pregnancy or estrogen therapy; Dubin-Johnson syndrome, Rotor syndrome, biliary disorders; History or current liver tumors;

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

New 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 disorders of lipid metabolism; History or current pancreatitis, accompanied by severe hypertriglyceridemia; New migraine symptoms, as well as more frequent and extremely severe headaches; Acute sensory disorders, such as visual or hearing impairment; Movement disorders (including paresis); Increased epileptic seizures; Severe depression; Otosclerosis that has progressed during previous pregnancies; Amenorrhea of unknown etiology; Endometrial hyperplasia; Vaginal bleeding of unknown etiology; Hypersensitivity to the active substances or to any of the other components of the drug.

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").

Belara® is contraindicated for concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).

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

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, may increase the risk of ALT elevations (see sections “Contraindications” and “Special warnings and precautions for use”). Therefore, patients taking Belara® should switch to an alternative method of contraception (e.g. progestogen-only contraceptives or non-hormonal methods) before starting therapy with the above combination medicinal products. Belara® can be resumed 2 weeks after completion of therapy.

Pharmacokinetic interactions

Effect of other medicines on Belara®

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 medicinal products 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 hepatic enzymes, such as antifungal agents that are imidazole derivatives (e.g. fluconazole), indinavir or troleandomycin.

The effect of Belara® on other medicines:

inhibition of liver enzyme activity and, consequently, an increase in serum concentrations of active substances such as diazepam (and other benzodiazepines metabolized by hydroxylation), cyclosporine, theophylline and prednisolone; induction of glucuronidation in the liver and, consequently, a decrease in 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 warnings and precautions for use").

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

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

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 Belara® 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 to discontinue use of Belara®.

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) are associated with an increased risk of venous thromboembolism (VTE) in women taking them compared with those not taking them. Products containing levonorgestrel, norgestimate or norethisterone are associated with a low risk of VTE. It is not known how Belara® affects the risk of VTE compared with products with a low risk of VTE. The decision to use any product other than those known to have a low risk of VTE should be made only after discussion with the woman to ensure that she understands the risk of VTE with Belara®, 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.

Out of 10,000 women using CHCs containing levonorgestrel, about six will develop VTE within one year.

It is not known how the risk of thromboembolic disease compares with the use of CHCs containing levonorgestrel and CHCs containing chlormadinone.

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 in the presence of additional risk factors, especially if there are several of the risk factors listed in Table 2.

Belara® 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 2

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 may 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 onset of unexplained shortness of breath or rapid breathing; sudden cough, which may be accompanied by coughing up blood; 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 3. Belara® 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 contributing to the development of ATE.

Table 3.

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 trouble walking, dizziness, loss of balance or coordination; sudden confusion, trouble speaking or understanding; sudden problems with vision in one or both eyes; a sudden 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 fullness in the chest, arm or behind the breastbone; discomfort radiating 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 any possible symptoms of thrombosis, they should consult a doctor. If thrombosis is suspected or confirmed, Belara® 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 Belara® should be discontinued.

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 Belara®, the drug should be discontinued and hypertension should be treated. As soon as blood pressure normalizes after antihypertensive therapy, Belara® can be resumed.

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

Women with a personal or family history of hypertriglyceridemia while taking CHCs are at increased risk of developing pancreatitis. In acute or chronic liver dysfunction, CHCs may need to be discontinued until liver function tests return to normal. In the event of recurrence of cholestatic jaundice, first diagnosed during pregnancy or while taking sex hormones, CHCs should be discontinued.

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");

autoimmune diseases, including systemic lupus erythematosus; obesity;

arterial hypertension (see section "Contraindications");

endometriosis; varicose veins;

thrombophlebitis (see section "Contraindications");

blood clotting disorders (see section "Contraindications");

mastopathy; uterine fibroids; herpes of pregnancy; depression;

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

Medical examination

Before initiating or reinstituting Belara®, a complete personal and family medical history should be taken, a physical examination should be performed, 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 Belara® 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 assessment of irregular cycles should be carried out only after an adaptation period of about three cycles. If breakthrough bleeding is constantly observed or appears for the first time while taking Belara®, although the cycle was previously regular, an examination should be performed to exclude pregnancy or diseases. After pregnancy or disease has been ruled out, you can continue taking Belara® or switch to another drug.

Intermenstrual bleeding may be a sign of reduced contraceptive efficacy (see sections “Irregular pill taking”, “Recommendations in case of vomiting or diarrhea”, “Interaction with other medicinal products and other types of interactions”).

Absence of withdrawal bleeding

As a rule, after 21 days of taking the drug, withdrawal bleeding occurs. Sometimes, especially during the first months of taking the drug, withdrawal bleeding may be absent. However, this does not necessarily indicate a decrease in the contraceptive effect. If bleeding is absent after one cycle of taking, during which the patient did not forget to take the pills, the seven-day break in taking the pills was not extended, the patient did not vomit or have diarrhea, then fertilization of the egg is unlikely and taking Belara® can be continued. If before the first absence of withdrawal bleeding, taking Belara® was carried out in violation of the instructions or