Belara

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BELARA®

Composition:

Active substances: 1 film-coated tablet contains: chlormadinone acetate 2 mg, ethinylestradiol 0.03 mg;

Excipients: lactose monohydrate, maize starch, povidone K-30, magnesium stearate;

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

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: light pink, round, biconvex film-coated tablets.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Continuous administration of Belara® for 21 days suppresses the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland, thereby inhibiting ovulation. Endometrial proliferation and its subsequent secretory transformation are observed. Cervical mucus consistency is also altered, which hinders sperm penetration through the cervical canal and impairs sperm motility. Additionally, changes in the endometrium occur, rendering it unsuitable for implantation.

The minimum dose of chloromadinone acetate required to completely suppress ovulation is 1.7 mg. The dose necessary 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

In clinical studies involving 1655 women using tablets containing 0.03 mg ethinylestradiol and 2 mg chloromadinone acetate, over more than 22,000 cycles observed during a 2-year period, 12 pregnancies were recorded. In 7 of these cases, women had missed doses, suffered from concomitant illnesses associated with nausea or vomiting, or were concurrently using medications that reduce the contraceptive efficacy of hormonal preparations.

Table 1

Pharmacokinetics.

Chlormadinone acetate (CMA)

Absorption

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

Distribution

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

Biological transformation

Various processes of reduction, oxidation, and conjugation with glucuronides and sulfates lead to the formation of numerous metabolites. The main metabolites in plasma are 3α- and 3β-hydroxy-CMA, with elimination half-lives not significantly different from those of unchanged CMA. The 3-hydroxy metabolites possess antiandrogenic activity similar to that of CMA itself. In urine, metabolites are mainly present as conjugates. After enzymatic hydrolysis, the main metabolite is 2α-hydroxy-CMA, with additional formation of 3-hydroxy and dihydroxy metabolites.

Elimination

The mean elimination half-life of CMA in plasma is approximately 34 hours after a single dose and about 36–39 hours after multiple dosing. Following 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, reaching maximum plasma concentration within 1.5 hours. Due to presystemic conjugation and hepatic metabolism, absolute bioavailability is only about 40% and subject to high interindividual variability (20–65%).

Distribution

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

Biological transformation

Like natural estrogens, EE undergoes biotransformation via hydroxylation of the aromatic ring (mediated by the cytochrome P450 system). The primary metabolite is 2-hydroxy-EE, which is further transformed into other metabolites and conjugates. Ethinylestradiol undergoes presystemic conjugation both in the mucosa of the small intestine and in the liver. In urine, glucuronides are primarily found, while sulfates predominate in bile and plasma.

Elimination

The mean elimination half-life of EE in 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 following hydrolysis by intestinal bacteria.

Safety preclinical findings

Estrogens have low acute toxicity. Due to marked species differences among experimental animals and 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 compound exerts embryolethal effects; developmental abnormalities of the urogenital system and signs of feminization were observed in male fetuses. These effects are considered species-specific.

Chlormadinone acetate has been shown to exert embryolethal effects when administered to rabbits, rats, and mice. Furthermore, teratogenic effects were observed at embryotoxic doses in rabbits and at the lowest tested doses (1 mg/kg/day) in mice. The relevance of these findings to 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 beyond those already described in other sections of the product information.

Clinical characteristics.

Indications. Hormonal contraception.

Before prescribing Belara® the presence of individual risk factors in women should be assessed, especially those related to the risk of venous thromboembolism (VTE), and the VTE risk associated with taking Belara® should be compared to the risk associated with other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions").

Contraindications. CHCs must not be used in the presence of the following conditions. If any of these conditions occur during treatment with Belara®, the drug should be discontinued immediately.

• Loss of control of 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 venous thromboembolism (on anticoagulants) or history thereof (e.g., deep vein thrombosis (DVT), pulmonary embolism);
  • known hereditary or acquired predisposition to VTE, such as activated protein C resistance (including factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency;
  • major surgical interventions with prolonged immobilization (see section "Special precautions");
  • high risk of venous thromboembolism due to presence of multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
  • current arterial thromboembolism or history thereof (e.g., myocardial infarction) or prodromal states (angina pectoris);
  • cerebrovascular disorders − current or history of stroke or prodromal states (transient ischemic attack (TIA));
  • known hereditary or acquired predisposition to ATE, including hyperhomocysteinemia, antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • high risk of arterial thromboembolism due to presence of multiple risk factors (see section "Special precautions") or presence of risk factors such as diabetes mellitus with vascular complications; severe arterial hypertension, severe dyslipoproteinemia.
• Hepatitis, jaundice, liver function abnormalities until normalization of liver function parameters.
• Generalized pruritus, cholestasis, particularly during previous pregnancy or estrogen therapy.
• Dubin-Johnson syndrome, Rotor syndrome, disorders of bile excretion.
• Meningioma or history of meningioma.
• History of or current liver tumors.
• Severe epigastric pain, hepatomegaly, or symptoms of intra-abdominal hemorrhage (see section "Adverse reactions").
• Porphyria, either newly occurring or recurrent (all three forms, particularly acquired porphyria).
• History of or current malignant hormone-dependent tumors, e.g., breast or uterine tumors.
• Severe disorders of lipid metabolism.
• History of or current pancreatitis associated with severe hypertriglyceridemia.
• Migraine symptoms occurring for the first time, as well as more frequent and extremely severe headaches.
• Acute sensory disturbances, e.g., visual or auditory disturbances.
• Motor disturbances (including paralysis).
• Increased frequency or severity of epileptic seizures.
• Severe depression.
• Otosclerosis that worsened during previous pregnancies.
• Amenorrhea of unknown etiology.
• Endometrial hyperplasia.
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any other component of the medicinal product.
• Contraindications include the presence of one serious or several risk factors for venous or arterial thrombosis (see section "Special precautions").

Belara® is contraindicated for 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").

Interaction with other medicinal products and other forms of interaction.

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

Pharmacodynamic interactions

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

Therefore, women taking Belara® should switch to an alternative method of contraception (e.g., progestogen-only contraception or non-hormonal methods) prior to starting therapy with these combined regimens. Belara® may be resumed 2 weeks after completion of treatment with these combined regimens.

Pharmacokinetic interactions

Effect of other medicinal products on Belara®

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 additional method of contraception alongside combined oral contraceptives. A barrier method should be used throughout the entire period of treatment with the relevant medicinal product 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 from the current CHC pack, the next pack of CHC tablets 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 method of contraception.

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

Active substances that increase CHC clearance (reduced CHC efficacy due to enzyme induction), e.g.: barbiturates, bosentan, carbamazepine, barbexaclon, phenytoin, primidone, modafinil, rifampicin, rifabutin, and 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 ethinylestradiol serum concentrations:

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

Active substances with variable effects on CHC clearance

When co-administered with CHCs, 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 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 other recommendations. In case of any doubts, women should additionally use a barrier method of contraception during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

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

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

Effect of Belara® on other medicinal products:

• inhibition of hepatic enzyme activity and, consequently, increased serum concentrations of active substances such as diazepam (and other benzodiazepines metabolized via hydroxylation), cyclosporine, theophylline, and prednisolone;
  • induction of hepatic glucuronidation and, consequently, reduced serum concentrations of substances such as lamotrigine, clofibrate, paracetamol, morphine, and lorazepam.

The requirement 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 used.

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

Laboratory tests

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function; as well as levels of plasma transport proteins such as corticosteroid-binding globulin and lipid/lipoprotein fractions, and parameters of carbohydrate metabolism, coagulation, and fibrinolysis. 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 methods of contraception.

The use of CHCs is associated with an increased risk of serious conditions 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 Belara® should be discussed with the woman.

If these conditions or risk factors occur for the first time or worsen during treatment with Belara®, the woman is advised to consult a physician to determine whether the use of Belara® should be discontinued.

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 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 women who do not use these medicinal products. Products containing levonorgestrel, norgestimate, or norethisterone are associated with a low VTE risk. Other CHCs containing cyproterone acetate/ethinylestradiol, such as Belara, may result in approximately a 1.25-fold higher VTE risk compared to levonorgestrel-containing products. The decision to use any product other than those known to have a low VTE risk should only be made after discussion with the woman to ensure she understands the VTE risk associated with Belara®, how her individual risk factors affect this risk, and that the risk of VTE is highest during the first year of use. Additionally, data indicate that the risk increases when restarting CHC use after a break of 4 weeks or more.

In women who have not used CHCs and have not been pregnant, approximately 2 out of 1000 women 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 over one year.

It is estimated that among 10,000 women using CHCs containing cyproterone acetate, 6–9 will develop VTE over one year; this is comparable to approximately 6 women using levonorgestrel-containing CHCs.

Number of VTE cases per 10,000 women per year

The annual incidence of VTE with low-dose CHCs is lower than that observed during pregnancy or the postpartum period.

VTE may be fatal in 1–2% of cases.

Risk factors for VTE development.

The risk of venous thromboembolic complications in women using CHCs may increase in the presence of additional risk factors, especially when multiple risk factors listed in Table 2 are present.

Belara® is contraindicated if a woman has multiple risk factors placing her in a high-risk category for venous thrombosis (see section "Contraindications"). When a woman has more than one VTE risk factor, the resulting situation may lead to a greater increase in risk than the sum of individual factors; in such cases, the overall 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. Table 2

| Risk Factor | Description | |------------|-------------| | Hereditary or acquired predisposition to thrombosis | e.g., Factor V Leiden, prothrombin gene mutation, protein C, protein S, or antithrombin deficiency, antiphospholipid antibodies (lupus anticoagulant or anticardiolipin antibodies) | | Age | Risk increases with age, particularly over 35 years | | Smoking | Especially in women over 35 years of age | | Obesity (BMI >30 kg/m²) | Increased risk due to hypercoagulable state | | Prolonged immobilization | e.g., major surgery, trauma, lower limb plaster casts | | Personal or family history of VTE | Especially if idiopathic or at a young age | | Other medical conditions | such as systemic lupus erythematosus, Crohn’s disease, or sickle cell disease | | Hypertension | Increases arterial thrombosis risk | | Hyperlipidemia | Contributes to vascular pathology | | Migraine with aura | Associated with increased stroke risk | | Diabetes mellitus | Especially with vascular complications |

Note: The presence of multiple risk factors may have a multiplicative effect on overall risk.

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 in the first 6 weeks postpartum (see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

If any of these 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 occur only 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 (coughing up blood);
• 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 over time, to sudden vision loss. In some cases, 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 events (e.g., transient ischemic attack, stroke). Arterial thromboembolism can be fatal.

Risk factors for ATE development

The risk of arterial thromboembolic complications (myocardial infarction) or acute cerebrovascular events (stroke) increases in women using COCs who have risk factors as described in Table 3. Belara® is contraindicated if a woman has one serious or multiple risk factors for ATE that place her in a high-risk category for arterial thrombosis (see section "Contraindications"). It is likely that if a woman has more than one risk factor, the overall risk of developing ATE is higher than when these factors act individually. If the benefit-risk balance is considered unfavorable, COCs should not be prescribed (see section "Contraindications").

Risk factors for ATE. Table 3.

Arterial Thromboembolism (ATE) Symptoms

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

Symptoms of acute cerebrovascular events 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 if they experience possible symptoms of thrombosis, they should contact their physician. In case of suspected or confirmed thrombosis, 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 remains controversial, as it is unclear to what extent other factors 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 taking COCs compared to non-users, as well as by the biological effect of COCs or a combination of both factors.

Rare cases of 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 liver tumor should be considered, and Belara® should be discontinued.

Meningioma

Cases of meningioma (single and multiple) have been reported in association with the use of chloromadinone 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 chloromadinone acetate should be discontinued as a precautionary measure.

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

Other Conditions

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 shortly after initiating treatment.

Many women taking oral contraceptives experience a slight increase in blood pressure. Clinically significant hypertension is rare. The relationship between oral contraceptive use and hypertension has not been definitively established. If clinically significant hypertension occurs during Belara® use, the drug should be discontinued and antihypertensive treatment initiated. Once blood pressure normalizes with antihypertensive therapy, Belara® 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 while taking COCs.

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

COCs may affect peripheral insulin resistance and glucose tolerance. Therefore, careful monitoring is recommended for diabetic patients taking oral contraceptives.

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

Precautions

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 disease (Crohn’s disease, ulcerative colitis; see section "Adverse Reactions").

Medical Examination

Before initiating or resuming Belara®, 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.

Women should be informed about the risk of venous and arterial thrombosis, including when using Belara® compared to other COCs, symptoms of VTE and ATE, known risk factors, and what to do in case of suspected thrombosis.

Women 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 disorders, 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 cause irregular vaginal bleeding (breakthrough bleeding and spotting), especially during the first few cycles of treatment. Therefore, medical evaluation of irregular cycles should only be performed after an adaptation period of approximately three cycles. If breakthrough bleeding persists or newly appears during Belara® use despite a previously regular cycle, an evaluation should be performed to exclude pregnancy or pathology. After excluding pregnancy or disease, Belara® may be continued or a different drug may be considered.

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 typically occurs about 21 days after starting the medication. Occasionally, especially during the first months of treatment, withdrawal bleeding may not occur. However, this does not necessarily indicate reduced contraceptive effectiveness. If bleeding is absent after one cycle during which the patient did not miss any tablets, the seven-day tablet-free interval was not extended, and there was no vomiting or diarrhea, conception is unlikely, and Belara® may be continued. If the absence of withdrawal bleeding occurs after irregular tablet intake or if withdrawal bleeding is absent for two consecutive cycles, pregnancy should be excluded before continuing treatment.

Concomitant use of herbal preparations containing St. John’s wort (Hypericum perforatum) with Belara® is not recommended (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Excipients

The medicinal product contains 69.5 mg of lactose monohydrate. Patients with rare hereditary conditions of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this product.

If you have been diagnosed with sugar intolerance, consult your physician before taking this medicinal product.

Use during Pregnancy or Breastfeeding

Pregnancy

The drug is contraindicated during pregnancy. Pregnancy must be excluded before starting treatment. If pregnancy occurs during treatment with Belara®, the drug should be discontinued immediately. Extensive epidemiological studies have not shown evidence that estrogen use in combination with other progestogens at doses similar to those in Belara®, when inadvertently used in early pregnancy, leads to teratogenic or fetotoxic effects. Although animal studies revealed toxic effects on reproductive function (see section "Preclinical Safety Data"), data from 330 pregnant women did not show any embryotoxic effect of chloromadinone acetate on the fetus.

The increased risk of VTE in the postpartum period should be considered when resuming Belara® (see sections "Dosage and Administration," "Special Warnings").

Breastfeeding

Estrogens may affect lactation, leading to reduced quantity and altered composition of breast milk. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk and affect the infant; therefore, Belara® should not be used during breastfeeding.

Ability to Influence Reaction Speed When Operating Vehicles or Machinery
There are no data indicating that combined oral contraceptives negatively affect the ability to drive or operate machinery.

Dosage and Administration

Dosage of film-coated tablets

One film-coated tablet should be taken daily at the same time each day (preferably in the evening) for 21 consecutive days, followed by a 7-day tablet-free interval. Withdrawal bleeding, similar to menstruation, usually occurs 2–4 days after taking the last film-coated tablet. After completing the 7-day break, start the next pack of Belara® regardless of whether bleeding has stopped or not.

Remove the film-coated tablet marked with the corresponding day of the week from the blister pack and swallow it whole, with a small amount of water if needed. Tablets should be taken daily in the order indicated by the arrow on the packaging.

Starting treatment with film-coated tablets

If no hormonal contraceptives have been used previously (during the last menstrual cycle)

The first film-coated tablet should be taken on the first day of the woman’s natural cycle, i.e., the first day of the next 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.

The first film-coated tablet may alternatively be taken on days 2–5 of the menstrual cycle, regardless of whether bleeding has stopped. In this case, additional barrier contraceptive methods must be used for the first 7 days of tablet intake.

If menstruation began more than 5 days ago, the woman should be advised to wait for the onset of the next menstruation before starting Belara®.

Switching from another hormonal contraceptive to Belara®

Switching from another combined oral contraceptive

The woman should start taking Belara® the day after the 7-day break or the last placebo tablet of the previously used combined oral contraceptive.

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

The first tablet of Belara® should be taken the day after the last progestogen-only tablet. Additional barrier contraceptive methods must be used for the first 7 days.

Switching from hormonal contraceptive injections or contraceptive implants

Belara® may be started on the day of implant removal or the day the next injection was due. Additional barrier contraceptive methods must be used for the first 7 days.

After spontaneous or induced abortion in the first trimester

Treatment with Belara® may be started immediately after a first-trimester spontaneous or induced abortion. In this case, additional contraceptive measures are not required.

After childbirth, spontaneous or induced abortion in the second trimester

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

If treatment is started more than 28 days after childbirth, additional barrier contraceptive methods should be used for the first 7 days.

If the woman has already had sexual intercourse, pregnancy should be ruled out or the onset of the next menstrual cycle awaited before starting treatment.

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

Belara® is not recommended for use during breastfeeding.

After stopping Belara®

After discontinuation of Belara®, the current cycle may be prolonged by approximately 1 week.

Missed tablets

If a patient misses a tablet but takes it within the following 12 hours, no additional contraceptive measures are required. The patient should continue taking the tablets as usual.

If a tablet is missed and taken more than 12 hours later, contraceptive protection may be reduced. In case of a missed tablet, follow these two main rules:

1. The tablet intake should never be interrupted for more than 7 days.
2. A 7-day tablet-free interval is necessary to achieve sufficient suppression of the hypothalamic-pituitary-ovarian axis.

The missed tablet should be taken immediately, even if this means taking two tablets at the same time. Subsequent tablets should be taken as usual. Additional barrier contraceptive methods (e.g., condoms) must be used for the next 7 days. If tablets were missed during the first week of the cycle and sexual intercourse occurred within the 7 days prior to the missed tablets (including during the 7-day tablet-free interval), the possibility of pregnancy should be considered. The greater the number of missed tablets and the closer they are to the regular tablet-free interval, the higher the risk of pregnancy.

If fewer than 7 tablets remain in the pack, start taking tablets from a new pack of Belara® immediately after finishing the current pack—i.e., no break between packs should occur. Withdrawal bleeding may not occur until after finishing the second pack; however, breakthrough or spotting bleeding may occur during intake of the second pack. If withdrawal bleeding does not occur after finishing the second pack, a pregnancy test should be performed.

Recommendations in case of vomiting or diarrhea

If vomiting or severe diarrhea occurs within 4 hours after taking a tablet, absorption of the drug may be incomplete, and contraceptive reliability cannot be guaranteed. In this case, follow the recommendations under "Missed tablets" (see above). Continue taking Belara® as scheduled.

Postponing withdrawal bleeding

To delay withdrawal bleeding, the woman should continue taking tablets from the next pack of Belara® without a break. This can be continued at will until the second pack is finished. During intake of the second pack, slight spotting or breakthrough bleeding may occur. After the usual 7-day tablet-free interval, resume regular intake of Belara®. To shift the onset of bleeding to another day of the week, the woman may shorten the next 7-day tablet-free interval by the desired number of days. The shorter the tablet-free interval, the higher the risk of absent withdrawal bleeding and breakthrough bleeding or spotting during intake of the next pack (similar to delaying withdrawal bleeding).

Elderly patients. Belara® is not indicated for use after menopause.

Children. Belara® is indicated only after menarche. Safety and efficacy of chlormadinone acetate and ethinylestradiol in adolescents under 16 years of age have not been established. Data are lacking.

The drug must not be used in children.

Overdose.

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

Adverse reactions

During clinical studies of Belara®, it was established that the most common adverse effects (> 20%) were breakthrough bleeding, slight spotting, headache, and breast tenderness. The likelihood of irregular bleeding decreases with prolonged use of Belara®.

In a clinical study involving 1629 women, the following adverse reactions were reported after administration of Belara®.

The frequency of adverse reactions is defined as follows:

very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10,000 to <1/1000; very rare: <1/10,000; frequency not known: cannot be estimated from available data.

Infections and infestations:

uncommon: vaginal candidiasis;

rare: vulvovaginitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps):

uncommon: fibroadenoma of the breast.

Immune system disorders:

uncommon: hypersensitivity to the drug, including skin allergic reactions;

frequency not known: exacerbation of symptoms of hereditary and acquired angioedema.

Metabolism and nutrition disorders:

uncommon: changes in blood lipid levels, including hypertriglyceridemia;

rare: increased appetite.

Psychiatric disorders:

common: depressed mood, nervousness, irritability;

uncommon: decreased libido.

Nervous system disorders:

common: dizziness, migraine (and/or worsening of migraine).

Eye disorders:

common: visual disturbances;

rare: conjunctivitis, intolerance to contact lenses.

Ear and labyrinth disorders:

rare: sudden hearing loss, tinnitus.

Vascular disorders:

rare: arterial hypertension, arterial hypotension, circulatory collapse, varicose veins, venous thrombosis, venous thromboembolism (VTE) or arterial thromboembolism (ATE)*.

Gastrointestinal disorders:

very common: nausea;

common: vomiting;

uncommon: abdominal pain, bloating, diarrhea.

Skin and subcutaneous tissue disorders:

common: acne;

uncommon: pigmentation disorders, chloasma, alopecia, dry skin, hyperhidrosis, hair loss;

rare: urticarial rash, eczema, erythema, pruritus, exacerbation of psoriasis, hirsutism;

very rare: nodular erythema.

Musculoskeletal and connective tissue disorders:

common: feeling of heaviness;

uncommon: back pain, muscle disorders.

Reproductive system and breast disorders:

very common: vaginal discharge, dysmenorrhea, amenorrhea;

common: lower abdominal pain;

uncommon: galactorrhea;

rare: breast enlargement, menorrhagia, premenstrual syndrome.

General disorders and administration site conditions:

common: fatigue, edema, weight gain.

Investigations:

common: increased blood pressure.

*See section "Description of selected adverse reactions".

Adverse reactions associated with the use of ethinylestradiol and chloromadinone in the post-marketing period: asthenia and allergic reactions not related to immune system disorders.

Description of selected adverse reactions

When using combined oral contraceptives containing 0.03 mg ethinylestradiol and 2 mg chloromadinone acetate, the following adverse effects have also been reported:

• It is known that the use of combined hormonal contraceptives is associated with an increased risk of venous and arterial thrombosis and thromboembolism, including myocardial infarction, stroke, transient ischemic attack, venous thrombosis, and pulmonary embolism. This risk is described in more detail in the section "Special precautions".
• According to some studies, long-term use of COCs increases the risk of biliary tract diseases.
• Rarely, benign liver tumors have been reported after taking oral contraceptives; malignant liver tumors have been reported even more rarely. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhage (see section "Special precautions").
• Exacerbation of chronic inflammatory bowel diseases (Crohn's disease, ulcerative colitis; see section "Special precautions").

Information on other serious adverse effects, such as uterine cancer or breast cancer, is provided in the section "Special precautions".

Interactions

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

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions during the post-marketing surveillance period. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C.

Keep the medicine out of the reach of children!

Packaging. 21 film-coated tablets in a blister; 1 or 3 blisters per cardboard package.

Prescription category. Prescription only.

Manufacturer. JSC "Gedeon Richter", Hungary.

Address of manufacturer and location of its business operations.

H-1103 Budapest, Demrédi str. 19-21, Hungary.