Belara^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Contact Information

GEDEON RICHTER Plc. (Hungary)

ATC Code

G03AA15 (Chlormadinone and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Chlormadinone (Rec.INN registered by WHO)

Dosage Form

Belara®

Film-coated tablets, 2 mg+0.03 mg: 21 or 63 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light pink in color, round, biconvex; the color of the tablet core is white or almost white.

Excipients: povidone K30, corn starch, lactose monohydrate, magnesium stearate.

Film coating composition: hypromellose 6 mPa·s, lactose monohydrate, macrogol 6000, propylene glycol, talc, titanium dioxide, red iron oxide.

21 pcs. – blisters (1) – cardboard packs.
21 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Monophasic oral contraceptive with antiandrogenic properties

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; systemic hormonal contraceptives; progestogens and estrogens, fixed combinations

Pharmacological Action

Belara^® is a combined oral low-dose contraceptive drug (COC).

The contraceptive effect of the combination chlormadinone + Ethinylestradiol is achieved through complementary mechanisms: suppression of ovulation, increased viscosity of cervical secretion (which impedes the passage of sperm through the cervical canal), and proliferation and secretory transformation of the endometrium (preventing implantation of a fertilized egg).

The progestogen chlormadinone, which is part of the drug, has antiandrogenic properties. Its action is based on the ability to displace androgens from specific receptors, preventing and weakening the effect of endogenous and exogenous androgens.

With correct use, the Pearl Index (an indicator reflecting the pregnancy rate per 100 women per year of contraceptive use) is less than 1 (0.291-0.698, depending on how carefully the woman adheres to the drug regimen).

Clinical efficacy

During clinical studies of the use of the combination containing 2 mg chlormadinone acetate and 0.03 mg ethinylestradiol for a maximum of 2 years in 1655 women over more than 22000 cycles, 12 pregnancies were recorded. In 7 cases, the influence of the following factors during the period of egg fertilization was noted: errors in taking the drug; concomitant diseases accompanied by nausea or vomiting; or simultaneous use with drugs known to reduce the contraceptive effect.

Estrogens have low acute toxicity. Due to pronounced differences between species of experimental animals, as well as differences existing between animals and humans, the results of animal studies of estrogens have limited predictive value for humans. Ethinylestradiol, a synthetic estrogen, is often used in oral contraceptives. Laboratory studies on animals have shown that even in relatively low doses it has an embryolethal effect; in male offspring, developmental anomalies of the genitourinary system organs and signs of feminization were observed. These effects are considered species-specific.

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

Standard preclinical safety studies investigating chronic toxicity, genotoxicity, and carcinogenic potential of the drug did not reveal any special risks for humans, except for those already described in other sections of the summary of product characteristics.

Preclinical safety data

Estrogens have low acute toxicity. Due to pronounced differences between species of experimental animals, as well as differences existing between animals and humans, the results of animal studies of estrogens have limited predictive value for humans. Ethinylestradiol, a synthetic estrogen, is often used in oral contraceptives. Laboratory studies on animals have shown that even in relatively low doses it has an embryolethal effect; in male offspring, developmental anomalies of the genitourinary system organs and signs of feminization were observed. These effects are considered species-specific.

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

Standard preclinical safety studies investigating chronic toxicity, genotoxicity, and carcinogenic potential of the drug did not reveal any special risks for humans, except for those already described in other sections of the summary of product characteristics.

Pharmacokinetics

Chlormadinone acetate

Absorption

After oral administration, Chlormadinone acetate is rapidly and completely absorbed. The systemic bioavailability of chlormadinone acetate is high because it is not subject to significant first-pass metabolism in the liver. C_max is reached after 1-2 h.

Distribution

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

Metabolism

Various reduction, oxidation, and conjugation processes with glucuronides and sulfates lead to the formation of numerous metabolites. The main metabolites in plasma are 3-alpha- and 3-beta-hydroxy-Chlormadinone acetate with T_1/2 not significantly different from unmetabolized chlormadinone acetate. The 3-hydroxy metabolites have antiandrogenic activity similar to that of chlormadinone acetate itself. In urine, metabolites are found mainly in the form of conjugates. After enzymatic cleavage, the main metabolite is 2-alpha-hydroxy-Chlormadinone acetate; 3-hydroxy metabolites and dihydroxy metabolites are also formed.

Elimination

The mean T_1/2 of chlormadinone acetate from plasma is approximately 34 h (after a single dose) and about 36-39 h (with multiple applications). After oral administration, Chlormadinone acetate and its metabolites are excreted in approximately equal amounts by the kidneys and through the intestines.

Ethinylestradiol

Absorption

Ethinylestradiol is rapidly and almost completely absorbed after oral administration, reaching C_max in plasma after 1.5 h. Due to presystemic conjugation and metabolism in the liver, the absolute bioavailability is about 40% and is subject to strong individual variability (20-65%).

Distribution

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

Metabolism

Like natural estrogens, Ethinylestradiol is biotransformed via hydroxylation of the aromatic ring (via the cytochrome P450 system). The main metabolite is 2-hydroxy-Ethinylestradiol, which is transformed into other metabolites and conjugates. Ethinylestradiol undergoes presystemic conjugation, both in the small intestinal mucosa and in the liver. Glucuronides are mainly determined in urine, while sulfates are found in bile and plasma.

Elimination

The mean T_1/2 of ethinylestradiol from plasma is approximately 12-14 h. Ethinylestradiol is excreted by the kidneys and through the intestines in a ratio of 2:3. Ethinylestradiol sulfate, excreted in bile after hydrolysis by intestinal bacteria, undergoes enterohepatic recirculation.

Indications

• Oral contraception.

Before prescribing Belara^®, the presence of individual risk factors for the development of thrombosis and thromboembolism, especially venous thromboembolism (VTE), should be assessed in the woman, and the risk of VTE when taking Belara^® should be compared with other combined hormonal contraceptives (COCs) (see sections “Contraindications” and “Special Instructions”).

ICD codes

Dosage Regimen

The drug should be taken orally. The tablet marked with the corresponding day of the week should be removed from the blister pack and swallowed whole, without chewing, with a small amount of water.

One tablet should be taken daily, at the same time (preferably in the evening) for 21 consecutive days, followed by a 7-day break in taking the tablets. A withdrawal bleeding should begin 2-4 days after taking the last tablet. After the end of the 7-day break, you should start taking the drug from the next pack, regardless of whether the bleeding has stopped or not.

How to start taking Belara^®

If no hormonal contraceptive has been used in the last menstrual cycle

The drug should be started on the first day of the menstrual cycle (i.e., on the first day of menstrual bleeding), according to the day of the week indicated on the drug package. Then the tablets should be taken in order. It is permissible to start taking the drug on the 2nd-5th day of the menstrual cycle, but in this case, during the first 7 days of taking Belara^® tablets, it is recommended to additionally use a barrier method of contraception (for example, a condom).

If menstrual bleeding started more than 5 days ago, the woman should be advised to wait for the start of the next menstrual bleeding to start taking the drug.

When switching from other combined contraceptive drugs (COC, vaginal ring or transdermal patch)

It is recommended to start taking the drug on the day after taking the last tablet from the previous pack (for drugs containing 21 tablets) or on the day after taking the last hormone-containing tablet from the previous pack (for drugs containing 28 tablets per pack). Additional contraceptive measures are not required in this case. Taking Belara^® should be started on the day of removal of the vaginal ring or patch, but no later than the day when a new ring should be inserted or a new patch applied.

Switching from progestogen-only products (“mini-pill”, injectable forms, implant), or from an intrauterine therapeutic system releasing progestogen

You can switch from the “mini-pill” to Belara^® on any day (without a break), from an implant or intrauterine contraceptive with progestogen – on the day of its removal, from an injectable form – from the day when the next injection should be made. In all cases – during the first 7 days of taking Belara^® tablets, it is necessary to additionally use a barrier method of contraception (for example, a condom).

After spontaneous or medical abortion in the first trimester of pregnancy

Taking Belara^® can be started immediately. In this case, the use of additional contraceptive measures is not required.

After childbirth (in the absence of breastfeeding) or termination of pregnancy (including spontaneous) in the second trimester

It is recommended to start taking the drug on the 21st-28th day after childbirth (in the absence of breastfeeding) or immediately after termination of pregnancy (including spontaneous) in the second trimester. If the drug is started later, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets. If sexual intercourse occurred before starting the contraceptive, pregnancy must be ruled out.

After discontinuation of Belara^® the current cycle may lengthen by about one week.

Recommendations in case of a missed dose

If the delay in taking the drug was less than 12 hours, contraceptive protection is not reduced. The missed tablet should be taken as soon as possible, the next tablet is taken at the usual time. If the delay in taking the drug was more than 12 hours, contraceptive protection may be reduced.

In case of a missed tablet, it is necessary to remember

1) taking Belara^® should never be interrupted for more than 7 days;

2) 7 days of continuous drug intake are required to achieve adequate suppression of the hypothalamic-pituitary-ovarian system.

Accordingly, if the delay in taking the tablets was more than 12 hours and the interval since taking the last tablet is more than 36 hours, the woman must follow the following recommendations

• The last missed tablet must be taken immediately, even if this means taking two tablets at the same time. The next tablet is taken according to the usual schedule. For the next 7 days, it is necessary to additionally use a barrier method of contraception (for example, a condom). If sexual intercourse occurred during the week before missing the tablet, the possibility of pregnancy must be considered.

If there are less than 7 tablets left in the current pack, immediately after finishing the Belara^® tablets, you should start taking tablets from a new pack – i.e., without the usual 7-day break. Probably, the usual withdrawal bleeding will not occur until the tablets from the second pack are finished. However, while taking tablets from the new pack, breakthrough bleeding or spotting may occur. If withdrawal bleeding does not occur after finishing the tablets from the second pack, a pregnancy test should be performed.

Recommendations in case of gastrointestinal disorders

In severe gastrointestinal disorders, the absorption of the drug may be incomplete, so additional methods of contraception should be used. If vomiting occurred or there was diarrhea within 3-4 hours after taking the tablet, depending on the week of taking the drug, one should be guided by the recommendations for missed tablets indicated above.

To delay the onset of withdrawal bleeding

In order to delay the onset of withdrawal bleeding, it is necessary to continue further intake of tablets from a new pack of the drug without the usual 7-day break. Tablets from the new pack can be taken for as long as necessary, including until the pack is finished. While taking the drug from the second pack, spotting and/or breakthrough bleeding may be noted. Resumption of taking the drug from the next pack should be after the usual 7-day break.

How to change the day of onset of withdrawal bleeding

In order to move the day of onset of withdrawal bleeding to another day of the week, the woman should shorten the nearest 7-day break in taking the tablets by as many days as she wants. The shorter the break in taking the tablets, the higher the likelihood that withdrawal bleeding will not occur, and during the intake of tablets from the second pack, spotting and/or breakthrough bleeding will be observed.

Children

Belara^® is intended for use only after menarche. The efficacy and safety of the combination chlormadinone + Ethinylestradiol in adolescent girls under 18 years of age have not been established, data are lacking.

Elderly women

Belara^® is not indicated for use in the postmenopausal period.

Adverse Reactions

When taking Belara^®, the most frequently occurring adverse reactions (more than 20% of cases) are breakthrough bleeding, vaginal spotting, headache, and breast discomfort. The frequency of acyclic bleeding usually decreases with increasing duration of Belara^® use.

Within the framework of a clinical study involving 1629 women, the following adverse reactions that occurred after the use of Belara^® were reported.

The frequency of adverse reactions is indicated by system-organ classes in accordance with MedDRA according to WHO recommendations.

* see description of selected adverse reactions

In the post-registration period of use of the chlormadinone and ethinylestradiol combination, the following adverse reactions have been reported: asthenia and allergic skin reactions not associated with immune system disorders.

Description of selected adverse reactions

When using COCs, including the chlormadinone + Ethinylestradiol combination, the following adverse reactions have also been reported

• Increased risk of arterial and venous thrombosis and thromboembolism, including myocardial infarction, stroke, TIA, venous thrombosis, PE, was observed in women taking COCs (see section “Special Precautions”);
• According to some studies, long-term use of COCs increases the risk of developing biliary tract diseases;
• In rare cases, after taking COCs, cases of benign liver tumors have been registered, and even more rarely, malignant tumors have been registered, which can lead to life-threatening intra-abdominal bleeding (see section “Special Precautions”);
• Exacerbation of chronic inflammatory bowel diseases (Crohn’s disease, ulcerative colitis; see section “Special Precautions”).

Information about other serious adverse reactions, such as uterine cancer or breast cancer, is presented in the “Special Precautions” section.

Interactions

“Breakthrough” bleeding and/or contraceptive failure may be the result of the interaction of other drugs (hepatic enzyme inducers) with COCs (see section “Drug Interactions”).

Contraindications

The use of the chlormadinone + Ethinylestradiol combination is contraindicated in the presence of any of the following diseases/conditions or risk factors

• Hypersensitivity to chlormadinone and/or ethinylestradiol, or to any of the excipients in the drug;
• Venous thrombosis or VTE, including deep vein thrombosis (DVT), pulmonary embolism (PE), currently or in history;
• Arterial thrombosis or thromboembolism (ATE), including myocardial infarction, stroke or prodromal conditions (including transient ischemic attack (TIA), angina) currently or in history;
• Identified hereditary or acquired predisposition to VTE or ATE, including activated protein C resistance, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Presence of multiple high-risk factors for the development of VTE or ATE (see section “Special Precautions”) or one serious risk factor, such as:
  • Diabetes mellitus with diabetic angiopathy;
  • Severe dyslipoproteinemia;
  • Uncontrolled arterial hypertension (BP 160/100 mm Hg and above).
• Migraine with focal neurological symptoms in history;
• Newly occurring migraine attacks or the appearance of unusually severe headache;
• Major surgical intervention with prolonged immobilization;
• Pancreatitis currently or in history, accompanied by severe hypertriglyceridemia;
• Uncontrolled diabetes mellitus;
• Severe lipid metabolism disorders;
• Acute or chronic severe liver diseases (until liver function tests normalize), including in history;
• Generalized itching, cholestasis, especially during previous pregnancy or when taking sex hormones in history;
• Impaired liver excretory function, including Dubin-Johnson syndrome, Rotor syndrome;
• Liver tumors (benign and malignant), including in history;
• Meningioma currently or in history;
• Severe pain in the epigastrium, liver enlargement or symptoms of intra-abdominal bleeding;
• Hormone-dependent malignant neoplasms of the genital organs or mammary gland (including suspected ones);
• Acute sensory disturbances, for example, visual or hearing impairments;
• Motor disorders (in particular, paresis);
• Porphyria, occurring for the first time or recurrent (all 3 forms, especially – acquired);
• Otosclerosis that progressed during previous pregnancies;
• Severe depression;
• Increased frequency of seizures in epilepsy;
• Endometrial hyperplasia;
• Amenorrhea of unknown etiology;
• Genital bleeding of unknown etiology;
• Concomitant use with direct-acting antiviral drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or with drugs containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section “Drug Interactions”);
• Pregnancy (including suspected);
• Breastfeeding period;
• Age under 18 years (due to the lack of data on the efficacy and safety of using the chlormadinone + Ethinylestradiol combination in adolescent girls under 18 years of age);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

If any of these diseases/conditions or risk factors occur while using the contraceptive, the drug should be discontinued immediately.

With caution

In the presence of the following conditions/diseases/risk factors, currently or in history, the use of the chlormadinone + Ethinylestradiol combination requires careful medical supervision and assessment of the potential risk and expected benefit: epilepsy, multiple sclerosis; convulsive syndrome (tetany); migraine without focal neurological symptoms; bronchial asthma; chronic heart or renal failure; chorea minor; diabetes mellitus with uncomplicated course; chronic liver diseases with normal liver function tests; autoimmune diseases (including systemic lupus erythematosus); obesity; dyslipoproteinemia; controlled arterial hypertension; endometriosis; varicose veins, superficial phlebitis of the lower extremities; blood clotting disorders; mastopathy; uterine fibroids; gestational herpes; depression; chronic inflammatory bowel diseases (Crohn’s disease, ulcerative colitis).

Use in Pregnancy and Lactation

Pregnancy

The use of the chlormadinone + Ethinylestradiol combination during pregnancy is contraindicated. In case of using the drug Belara^®, it should be discontinued immediately. Numerous epidemiological studies have not revealed an increased risk of developmental defects in children born to women who received sex hormones before pregnancy, nor the presence of a teratogenic effect when sex hormones were taken inadvertently in early pregnancy.

Breastfeeding period

The use of the drug Belara^®, like other COCs, may reduce the amount of breast milk and change its composition, therefore, the use of the drug is contraindicated until breastfeeding is stopped. A small amount of the hormones included in the contraceptive and/or their metabolites can penetrate into breast milk and affect the child’s health.

Fertility

Clinical studies have shown that conditions favorable for conception are restored already in the first cycle after discontinuation of the drug Belara^®.

Use in Hepatic Impairment

The use of the drug is contraindicated in acute or chronic severe liver diseases (until liver function tests normalize), in the presence of liver tumors currently or in history.

The drug should be used with caution in chronic liver diseases with normal liver function tests.

Use in Renal Impairment

The drug should be used with caution in chronic renal failure.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years (due to the lack of data on the efficacy and safety of using the chlormadinone + Ethinylestradiol combination in adolescent girls under 18 years of age).

Geriatric Use

The drug Belara^® is not indicated for use in the postmenopausal period.

Special Precautions

Smoking

Smoking increases the risk of serious cardiovascular complications associated with the use of COCs. The risk increases with age, with an increase in the number of cigarettes smoked and is high in women over 35 years of age. Women over 35 years of age who smoke should use other methods of contraception.

The use of COCs is associated with an increased risk of various 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.

In the presence of one of the following diseases/conditions or risk factors, it is necessary to weigh the potential risk and expected benefit from the use of the chlormadinone + Ethinylestradiol combination, and also discuss this with the woman before she starts taking this drug.

In case of exacerbation of diseases, worsening of the condition or the appearance of the first symptoms of conditions/diseases or risk factors, the woman should immediately consult a doctor to decide on discontinuing the drug.

Thromboembolism or other vascular diseases

The results of epidemiological studies show that there is a relationship between the use of COCs and an increased risk of venous and arterial thromboembolic diseases, for example, myocardial infarction, cerebral hemorrhage; DVT and PE. These diseases develop rarely. Very rarely, in patients taking COCs, the development of thrombosis of other blood vessels has been reported, for example, hepatic, mesenteric, renal, or veins and arteries of the retina.

Risk of developing VTE and ATE. The results of epidemiological studies indicate a relationship between the use of COCs and an increased incidence of venous and arterial thrombosis and thromboembolism (such as DVT and PE, myocardial infarction, cerebrovascular disorders). These diseases are rare. The risk of developing VTE is maximum in the first year of taking such drugs. An increased risk is present after initial use of COCs or resumption of use after a break of 4 weeks or more. Data from a large prospective study involving 3 groups of patients show that this increased risk is present mainly during the first 3 months. Drugs containing levonorgestrel, norgestimate or norethisterone as a progestogenic component have the lowest risk of developing VTE. It is unknown to what extent the risk of developing VTE when taking the chlormadinone + Ethinylestradiol combination exceeds the risk of this complication when taking drugs containing levonorgestrel, norgestimate or norethisterone.

VTE can be life-threatening or fatal (in 1-2% of cases).

VTE, manifested as DVT or PE, can occur with the use of any COCs.

Symptoms of DVT unilateral swelling of the lower limb or along the vein, pain or discomfort only in an upright position or when walking, local increase in temperature, redness or discoloration of the skin of the affected lower limb.

Symptoms of PE difficult or rapid breathing; sudden cough, including with hemoptysis; acute chest pain that may worsen with deep breathing; feeling of anxiety; severe dizziness; rapid or irregular heartbeat. Some of these symptoms (for example, shortness of breath and cough) are nonspecific and may be misinterpreted as signs of other more common and less severe diseases (for example, respiratory tract infection). ATE can lead to stroke, vascular occlusion or myocardial infarction.

Symptoms of stroke sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, one- or two-sided loss of vision, gait disturbance, dizziness, loss of balance or coordination of movements, severe or prolonged headache for no apparent reason; problems with speech and understanding, loss of consciousness or fainting with or without a seizure.

Other signs of vascular occlusion sudden pain, swelling and slight bluish discoloration of the extremities, “acute abdomen” symptom complex.

Symptoms of myocardial infarction pain, discomfort, pressure, heaviness, feeling of squeezing or fullness in the chest or behind the breastbone, with radiation to the back, jaw, upper limb, epigastric region; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; rapid or irregular heartbeat.

ATE can be life-threatening or fatal.

In women with a combination of several risk factors or a high severity of one of them, the possibility of their mutual enhancement should be considered. In such cases, the degree of risk increase may be higher than with simple summation of factors. In this case, the use of the chlormadinone + Ethinylestradiol combination is contraindicated.

The risk of developing venous and/or arterial thrombosis, or thromboembolism or cerebrovascular disorders increases

• With age;
• In smokers (the risk increases to a greater extent in women over 35 years of age);
• In the presence of a family history of venous or arterial thrombosis, or thromboembolism in siblings or parents under the age of 50 (in case of a suspected hereditary predisposition, consultation with a specialist is necessary before starting COCs);
• With obesity (BMI more than 30 kg/m²);
• With dyslipoproteinemia;
• With arterial hypertension;
• With migraine;
• With heart valve diseases;
• With atrial fibrillation;
• In case of prolonged immobilization, major surgical intervention, any surgery on the lower extremities, pelvic area or neurosurgical operative intervention, extensive severe trauma. In these situations, COC use should be discontinued (in case of planned surgery, at least 4 weeks before it) and not resumed for 2 weeks after the end of immobilization.

Temporary immobilization (for example, an air flight lasting more than 4 hours) may also be a risk factor for the development of VTE, especially in the presence of other risk factors.

The question of the possible role of varicose veins and superficial thrombophlebitis in the development of VTE remains controversial.

The increased risk of thromboembolic complications in the postpartum period should be taken into account.

Peripheral circulatory disorders can also be observed in diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or ulcerative colitis) and sickle cell anemia.

An increase in the frequency and severity of migraine while taking the chlormadinone + Ethinylestradiol combination (which may precede cerebrovascular disorders) is a reason for immediate discontinuation of these drugs.

Biochemical indicators indicating a hereditary or acquired predisposition to the development of venous or arterial thrombosis include: resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When assessing the benefit-risk ratio, it should be taken into account that therapy for these conditions/diseases may reduce the associated risk of thromboembolic complications.

Women taking the chlormadinone + Ethinylestradiol combination should be informed that in case of possible symptoms of thrombosis, they should immediately consult a doctor, and the drug should be discontinued.

Tumors

The most significant risk factor for the development of cervical cancer (CC) is persistent papillomavirus infection. There are reports of a slight increase in the risk of developing CC with long-term use of COCs. The connection with COC use has not been proven. However, to date, there is controversy regarding the degree of influence of various factors on these data, in particular, cervical screening examinations or features of a woman’s sexual behavior (number of sexual partners or use of barrier methods of contraception), as well as the cause-and-effect relationship of these factors.

According to a meta-analysis of the results of 54 epidemiological studies, a slight increase (1.24) in the risk of developing breast cancer (BC) was detected in women using COCs. The increased risk gradually decreases within 10 years after discontinuation of COCs. Since BC is rare in women under 40 years of age, the increase in the number of BC cases in women currently taking COCs or who have recently taken it is insignificant in relation to the overall risk of this disease. Its connection with COC use has not been proven. The observed increase in risk may also be a consequence of earlier diagnosis of BC in women taking COCs (they are diagnosed with earlier clinical forms of BC than women who have not taken COCs), the biological effect of COCs, or a combination of both of these factors.

Very rarely, cases of benign liver tumors have been observed with the use of COCs, and even more rarely, malignant liver tumors. In some cases, these tumors have led to life-threatening intra-abdominal bleeding.

In the event of severe abdominal pain, liver enlargement, or signs of intra-abdominal bleeding, this should be considered during differential diagnosis.

Meningioma

Cases of meningioma (single and multiple) have been reported with the use of chlormadinone acetate, especially when taken in high doses and for a long time (several years). Patients should be monitored for signs and symptoms of meningioma in accordance with standard clinical practice. If a patient is diagnosed with a meningioma, as a precautionary measure, therapy with any preparations containing Chlormadinone acetate should be discontinued.

There is evidence that the risk of developing meningioma may decrease after discontinuation of chlormadinone acetate therapy.

Other conditions

Women with hypertriglyceridemia or a relevant family history have an increased risk of developing pancreatitis when taking COCs.

Although a slight increase in blood pressure has been described in many women taking COCs, clinically significant increases have been rare. However, if a persistent clinically significant increase in blood pressure develops while taking COCs, the use of the chlormadinone + Ethinylestradiol combination should be discontinued and antihypertensive therapy initiated. After normalization of blood pressure, the contraceptive may be continued.

Women with a history of gestational herpes may experience a recurrence of this condition while taking COCs.

In acute or chronic liver diseases, it may be necessary to discontinue the drug until liver function parameters normalize.

A recurrence of cholestatic jaundice, which first occurred during a previous pregnancy or previous use of sex hormones, requires discontinuation of COCs.

The use of the chlormadinone + Ethinylestradiol combination may affect peripheral insulin resistance and glucose tolerance; women with diabetes mellitus should be under close medical supervision while taking the drug.

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

Exacerbations of endogenous depression, epilepsy, Crohn’s disease, and ulcerative colitis have been reported with the use of COCs.

Depressed mood and depression are well-known adverse reactions to the use of hormonal contraceptives. Depression can be serious and is a well-known risk factor for suicidal behavior and suicide. Women should consult their doctor if they experience mood swings and depressive symptoms, including shortly after starting COCs.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

The use of preparations containing estrogen or estrogen + progestogen may adversely affect some diseases and conditions, requiring careful medical supervision

• Multiple sclerosis;
• Tetany;
• Bronchial asthma;
• Chronic heart or renal failure;
• Chorea;
• Diabetes mellitus;
• Liver diseases;
• Dyslipoproteinemia;
• Arterial hypertension;
• Endometriosis;
• Porphyria;
• Varicose veins;
• Thrombophlebitis;
• Blood clotting disorders;
• Mastopathy;
• Autoimmune diseases, including systemic lupus erythematosus;
• Gestational herpes;
• Uterine fibroids.

Medical examinations

Before starting or resuming the use of the chlormadinone + Ethinylestradiol combination, it is necessary to review the patient’s life history, family history, perform a general medical (including blood pressure measurement, BMI determination) and gynecological examination (including breast examination and cervical epithelial cytology), and rule out pregnancy. The scope of additional tests and the frequency of follow-up examinations are determined individually, at least once every 6 months. The woman should be informed that the drug does not protect against HIV infection (AIDS) and other sexually transmitted infections.

Reduced effectiveness

A missed pill (see the subsection “Recommendations in case of a missed dose”), vomiting or intestinal disorders, including diarrhea, long-term concomitant use of certain medications (see the section “Drug Interactions”) or, in very rare cases, metabolic disorders may reduce the contraceptive effectiveness of the drug.

Effect on menstrual cycle control

Breakthrough bleeding and spotting. The use of COCs may lead to vaginal bleeding (breakthrough bleeding and spotting), especially during the first cycles of taking the drug. Therefore, medical evaluation of irregular cycles should be performed only after an adaptation period of about three cycles. If breakthrough bleeding persists or first appears during the use of the chlormadinone + Ethinylestradiol combination, although the cycle was previously regular, an examination should be performed to rule out pregnancy or organic diseases. After excluding pregnancy or an organic disease, the use of the chlormadinone + Ethinylestradiol combination can be continued or the patient can be switched to another contraceptive.

Intermenstrual bleeding may be a sign of reduced contraceptive effectiveness (see the subsection “Recommendations in case of a missed dose”, “Recommendations in case of gastrointestinal disorders” and the section “Drug Interactions”).

Absence of withdrawal bleeding. As a rule, withdrawal bleeding occurs after 21 days of taking the drug. Sometimes, especially during the first months of taking the drug, withdrawal bleeding may be absent. However, this does not necessarily indicate a decrease in contraceptive effect.

If bleeding was absent after one cycle of use, during which the woman did not violate the dosing regimen (did not miss a pill, did not exceed a 7-day break in taking), and the patient did not have vomiting or diarrhea, then fertilization of the egg is unlikely and the use of the chlormadinone + Ethinylestradiol combination can be continued.

If before the first absence of withdrawal bleeding, the use of the chlormadinone + Ethinylestradiol combination occurred in violation of the instructions or withdrawal bleeding is absent for two cycles, then pregnancy should be ruled out before continuing to take the drug.

Herbal medicinal products containing St. John’s wort (Hypericum perforatum) should not be taken concomitantly with the chlormadinone + Ethinylestradiol combination (see the section “Drug Interactions”).

Excipients

This drug contains 69.5 mg of lactose monohydrate. Patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not take this drug.

Effect of the drug Belara^® on laboratory tests

Some laboratory test parameters may change while taking COCs, for example, biochemical parameters of liver, thyroid, adrenal, and kidney function, the content of transport proteins in blood plasma (e.g., corticosteroid-binding globulin, lipid and lipoprotein fractions), as well as parameters of carbohydrate metabolism, coagulation, and fibrinolysis. Usually, the changes remain within normal limits.

Effect on the ability to drive vehicles and machinery

There are no data on a negative effect of taking COCs on the ability to drive vehicles and machinery.

Overdose

There are no data on serious toxic effects of the drug in case of overdose.

The following symptoms may be observed: nausea, vomiting, and minor vaginal bleeding, especially in young girls.

Treatment there is no specific antidote; symptomatic therapy is carried out. In rare cases, monitoring of water-electrolyte balance and liver function parameters may be necessary.

Drug Interactions

In case of simultaneous use of the chlormadinone + Ethinylestradiol combination and other medicinal products, information presented in the prescribing information of these drugs should also be analyzed to identify possible drug interactions.

Pharmacodynamic interaction

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, may increase the risk of increased ALT activity.

Pharmacokinetic interaction

Effect of other medicinal products on the chlormadinone + Ethinylestradiol combination

Interaction with medicinal products that induce liver microsomal enzymes is possible, which may increase the clearance of sex hormones, which, in turn, will lead to breakthrough bleeding and/or loss of the contraceptive effect of the chlormadinone + Ethinylestradiol combination.

Risk reduction measures

Induction of liver microsomal enzymes can be observed within a few days of taking the drug. Maximum enzyme induction is usually observed within a few weeks. After discontinuation of the drug, enzyme induction may persist for up to 4 weeks.

Short-term treatment

Women who receive inducers of liver microsomal enzymes concomitantly with COCs are advised to temporarily use a barrier or other non-hormonal method of contraception. The barrier method of contraception should be used throughout the entire period of concomitant therapy and for another 28 days after discontinuation of the inducer drug. If the use of the inducer continues after taking the last COC tablet from the current package, the patient should start taking tablets from a new package, omitting the tablet-free interval.

Long-term therapy

Women receiving long-term therapy with inducers of liver microsomal enzymes are recommended to use another reliable non-hormonal method of contraception.

Known types of interactions

Substances leading to an increase in the clearance of COCs (reduction of COC effectiveness due to induction of liver microsomal enzymes), for example barbiturates, bosentan, carbamazepine, barbexaclone, phenytoin, primidone, modafinil, rifampicin, rifabutin and drugs for the treatment of HIV (ritonavir, nevirapine and efavirenz) and possibly felbamate, griseofulvin, oxcarbazepine, topiramate and preparations containing St. John’s wort (Hypericum perforatum).

Medicinal products/active substances that may reduce the concentration of ethinylestradiol in the blood serum all medicinal products that increase gastrointestinal motility (e.g., metoclopramide) or impair absorption (e.g., activated charcoal).

Substances that have different effects on the clearance of COCs when co-administered 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 the concentration of estrogens or progestogens in the blood plasma. The overall effect of such changes may in some cases be clinically significant.

To identify possible drug interactions and related recommendations, an analysis of the information presented in the prescribing information of concomitant drugs intended for the treatment of HIV infection/hepatitis C should be carried out. In case of any doubts, women receiving protease inhibitors or non-nucleoside reverse transcriptase inhibitors should use an additional barrier method of contraception.

The following medicinal products/active substances may increase the concentration of ethinylestradiol in the blood serum

• Substances that inhibit the sulfation of ethinylestradiol in the intestinal wall, for example, ascorbic acid or paracetamol;
• Atorvastatin (increases the AUC of ethinylestradiol by 20%);
• Substances that inhibit the activity of liver microsomal enzymes, such as antifungal agents derived from imidazole (e.g., fluconazole), indinavir, or troleandomycin.

Effect of the chlormadinone + Ethinylestradiol combination on other medicinal products

• By inhibiting the activity of liver microsomal enzymes and, accordingly, increasing the serum concentration of substances such as diazepam (and other benzodiazepines metabolized by hydroxylation), cyclosporine, theophylline, and prednisolone;
• By inducing glucuronidation in the liver and, accordingly, reducing the serum concentration of substances such as lamotrigine, clofibrate, paracetamol, morphine, and lorazepam.

The chlormadinone + Ethinylestradiol combination affects glucose tolerance, so the need for insulin and oral hypoglycemic agents may change.

The described interaction features may also apply to medicinal products that have been used recently.

The prescribing information for each prescribed medicinal product should be studied to identify possible interactions with the chlormadinone + Ethinylestradiol combination.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.