Bonadea^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Haupt Pharma Munster, GmbH (Germany)

Quality Control Release

ZENTIVA, k.s. (Czech Republic)

ATC Code

G03AA (Progestogens and estrogens (fixed combinations))

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Dienogest (Rec.INN registered by WHO)

Dosage Form

Bonadea®

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

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex.

Excipients: lactose monohydrate – 57.17 mg, corn starch – 12 mg, povidone 30LP – 3 mg, sodium starch glycolate – 5 mg, magnesium stearate – 800 mcg.

Film coating composition: aquapolish white 014.17 MS (hypromellose – 48%, hydroxypropylcellulose – 12%, talc – 20%, hydrogenated cottonseed oil – 5%, titanium dioxide – 15%) – 9 mg.

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

Clinical-Pharmacological Group

Monophasic oral contraceptive with antiandrogenic properties

Pharmacotherapeutic Group

Contraceptive agent (estrogen + progestagen)

Pharmacological Action

A low-dose monophasic oral combined estrogen-progestogen contraceptive drug. The action of Bonadea^® is based on the combined action of various factors, the most important of which is the suppression of ovulation and an increase in the viscosity of cervical mucus.

The progestogenic component of Bonadea^®, Dienogest, is a derivative of norethisterone and has antiandrogenic activity. Dienogest also has a favorable effect on the lipid profile by increasing HDL levels.

In women taking combined oral contraceptives (COCs), the cycle becomes more regular, painful menstruation is less common, and the intensity and duration of bleeding are reduced.

Pharmacokinetics

Dienogest

Absorption

After oral administration, Dienogest is rapidly and almost completely absorbed. C_max in plasma (51 ng/ml) is reached after 2.4±1.4 hours. Bioavailability in combination with ethinylestradiol is about 96%.

Distribution

Dienogest binds to serum albumin (90%) and does not bind to specific transport proteins – sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG). Any influence on the physiological transport of endogenous steroids is unlikely. The ethinylestradiol-induced increase in SHBG concentration does not affect the binding of dienogest to serum proteins.

Steady-state concentration. SHBG concentration does not influence the pharmacokinetics of dienogest. After daily dose administration, the plasma concentration of the drug increases approximately 1.5-fold, and C_ss is reached after approximately 4 days.

Metabolism

Dienogest is metabolized primarily by hydroxylation, but also by hydrogenation, conjugation, and aromatization to form inactive metabolites.

Elimination

The total clearance after a single dose is 3.6 L/h.

The T_1/2 of dienogest is 8.5-10.8 hours. A negligible amount of dienogest is excreted unchanged by the kidneys. Metabolites are excreted by the kidneys and bile in a 3:1 ratio. The T_1/2 of metabolites is 14.4 hours.

Ethinylestradiol

Absorption

After oral administration, Ethinylestradiol is rapidly and completely absorbed. C_max in plasma (67 ng/ml) is reached within 1.5-4 hours. During absorption and first-pass metabolism through the liver, Ethinylestradiol is metabolized, resulting in an average oral bioavailability of 44%.

Distribution

Ethinylestradiol is almost completely (98%), although non-specifically, bound to albumin. Ethinylestradiol induces the synthesis of SHBG. The apparent V_d of ethinylestradiol is 2.8-8.6 L/kg.

Steady-state concentration. C_ss is reached during the second half of the treatment cycle, when serum drug levels become twice as high compared to a single dose.

Metabolism

Ethinylestradiol undergoes presystemic conjugation both in the small intestinal mucosa and in the liver. The main metabolic pathway is aromatic hydroxylation, followed by conjugation with glucuronic and/or sulfuric acids.

Elimination

The metabolic clearance rate from plasma is 2.3-7 ml/min/kg. The plasma concentration of ethinylestradiol decreases in a biphasic manner: the first phase is characterized by a T_1/2 of about 1 hour, the second – 10-20 hours.

It is not excreted unchanged. Ethinylestradiol metabolites are excreted by the kidneys and liver in a 4:6 ratio, with a T_1/2 of about 24 hours.

Indications

• Contraception;
• Treatment of mild to moderate acne in women requiring contraception, when other treatment methods have been ineffective (topical treatment or systemic antibiotics).

ICD codes

Dosage Regimen

Bonadea^® is taken orally, 1 tablet/day, without chewing and with a small amount of water, at the same time each day. The tablets are taken for 21 days without a break according to the scheme indicated on the blister. Each blister contains 21 tablets. Each tablet is marked with the day of the week on which it should be taken. For the next 7 days, no tablets are taken. During this period, withdrawal bleeding should begin. It usually starts 2-3 days after taking the last Bonadea^® tablet.

After a 7-day break, on the 8th day, start taking tablets from a new pack (if the pack contains 21 tablets) or blister (if the pack contains 63 tablets), even if the bleeding has not yet stopped. This means that the woman will always start a new pack (blister) on the same day of the week, and each month the withdrawal bleeding will occur on approximately the same day of the month.

How to start taking Bonadea^®

If no hormonal contraceptives were used in the previous month, Bonadea^® should be started on the 1st day of the natural menstrual cycle (i.e., the 1st day of menstrual bleeding). Take the tablet marked with the corresponding day of the week. For example, if the period starts on a Friday, take the tablet marked for Friday. Then, continue taking the tablets on the following days in the established order. It is also permissible to start from day 2-5 of the cycle, but in this case, it is recommended to additionally use a barrier method of contraception (condom) during the first 7 days of taking tablets from the first pack (blister).

When switching from other COCs, a contraceptive vaginal ring, or a contraceptive patch, you can start taking Bonadea^® the day after taking the last tablet from the previous COC pack (i.e., without a break in intake). If the previous pack also contained inactive tablets (without active substance), you can start using Bonadea^® the day after taking the last active tablet. You can also start later, but in no case later than the next day after the usual break in use (7-day break for products containing 21 tablets) or after taking the last inactive tablet (for products containing 28 tablets per pack).

In case of using a contraceptive patch or a contraceptive vaginal ring, taking Bonadea^® should be started on the day of their removal, but no later than the day when a new ring should be inserted or a new patch applied.

When switching from progestogen-only oral contraceptives (“mini-pills”), you can stop taking the “mini-pills” on any day and start using Bonadea^® the next day, at the same time. During the first 7 days of taking the tablets, it is also necessary to additionally use a barrier method of contraception.

When switching from an injectable contraceptive, an implant, or intrauterine contraceptives (IUD) releasing a progestogen, start using Bonadea^® on the day the next injection is due or on the day of removal of the implant or intrauterine contraceptive. During the first 7 days of taking the tablets, it is also necessary to additionally use a barrier method of contraception.

Immediately after childbirth, the doctor may recommend waiting until the end of the first normal menstrual cycle before starting Bonadea^®. Sometimes, on the doctor’s recommendation, you can start using the drug earlier.

After spontaneous miscarriage or abortion in the first trimester of pregnancy, you should consult a doctor. Usually, it is recommended to start using the drug immediately.

Taking missed tablets

If the delay in taking the next tablet is less than 12 hours, the contraceptive effect of Bonadea^® is maintained. The patient should take the tablet as soon as she remembers. The next tablet should be taken at the usual time.

If the delay in taking the tablets is more than 12 hours, contraceptive protection may be reduced. The more tablets are missed in a row, and the closer this miss is to the start or end of intake, the higher the risk of pregnancy.

In this regard, the following rules can be followed:

• If more than 1 tablet from the pack (blister) is missed, you should consult a doctor;
• If 1 tablet is missed in the first week of using the drug, take the missed tablet as soon as possible, as soon as the patient remembers (even if this means taking two tablets at the same time). The next tablet should be taken at the usual time. It is necessary to additionally use a barrier method of contraception for the next 7 days. If sexual intercourse occurred during the week before the missed tablet, the possibility of pregnancy must be considered. You should consult a doctor immediately;
• If 1 tablet is missed in the second week of taking the drug, take the missed tablet as soon as possible, as soon as the patient remembers (even if this means taking 2 tablets at the same time). The next tablet should be taken at the usual time. If the woman has taken the tablets correctly for the 7 days preceding the first missed tablet, the contraceptive effect of Bonadea^® is maintained, and the woman does not need to use additional contraceptive measures. Otherwise, and also if 2 or more tablets are missed, it is necessary to additionally use barrier methods of contraception for 7 days;
• If 1 tablet is missed in the third week of taking the drug, but during the 7 days preceding the first missed tablet, all tablets were taken correctly, there is no need to use additional contraceptive methods if the woman adheres to either of the following two options:

1. Take the missed tablet as soon as possible, as soon as the patient remembers (even if this means taking 2 tablets at the same time). The next tablet should be taken at the usual time. The next pack (blister) must be started immediately after finishing the tablets from the current pack (blister), so there will be no break between packs (blisters). Withdrawal bleeding is unlikely until the tablets from the second pack (blister) are finished, but spotting or breakthrough bleeding may occur on the days of taking the drug.

2. Stop taking the tablets from the current pack (blister), take a break for 7 or fewer days (including the day of the missed tablet) and then start taking tablets from a new pack (blister).

The absence of expected withdrawal bleeding after the break in taking the tablets may mean that the woman is pregnant. In this case, the woman must consult a doctor before she starts taking tablets from a new pack (blister).

By following these rules, a woman can always start taking tablets from the next pack (blister) on the day of the week she usually does.

In situations where it is recommended to stop taking Bonadea^®, or when its reliability may be reduced, you should refrain from sexual intercourse or use non-hormonal contraceptive methods (e.g., condom or other barrier methods). The rhythm or temperature method should not be used. These methods may be unreliable because taking COCs leads to changes in basal temperature and cervical mucus.

Discontinuation of the drug

You can stop taking Bonadea^® at any time. In case of discontinuation due to a desire to become pregnant, it is usually recommended to wait for the first normal menstruation and only then try to get pregnant. This method makes it easier to determine the due date.

Recommendations in case of gastrointestinal disorders

In case of vomiting or diarrhea, the active substances of Bonadea^® may not be fully absorbed. If vomiting continues 3-4 hours after taking the contraceptive tablet, the result may be the same as missing a tablet. You should proceed as recommended in case of a missed tablet. In case of severe diarrhea, you should consult your doctor.

Delaying the onset of withdrawal bleeding

You can delay the onset of withdrawal bleeding by starting to take tablets from the next pack (if the pack contains 21 tablets) or blister (if the pack contains 63 tablets) immediately after finishing the current pack (blister). You can take the tablets for as long as necessary, or until the tablets in the pack (blister) run out. If it is necessary for withdrawal bleeding to begin, you should stop taking the tablets. While taking Bonadea^® tablets from a new pack (blister), heavy or spotting bleeding may occur. The use of tablets from the next pack (blister) should be started after the usual 7-day interval.

Changing the day of onset of withdrawal bleeding

If a woman takes the tablets strictly following all recommendations, withdrawal bleeding occurs on approximately the same days every 4 weeks. If it is necessary to change these days, the next tablet-free interval should be shortened (but in no case extended). For example, bleeding starts on Fridays, but it is necessary for it to start on Tuesdays (3 days earlier), then you should start taking tablets from a new pack (blister) 3 days earlier than usual. If the tablet-free interval is too short, bleeding may not occur at all during this interval. However, while taking tablets from a new pack (blister), heavy or spotting bleeding may occur.

Special patient groups

Children and adolescents: Bonadea^® is indicated only after menarche.

Elderly patients: Bonadea^® is not indicated after menopause.

The drug is contraindicated in women with severe liver disease until liver function tests return to normal.

Bonadea^® has not been specifically studied in women with impaired renal function. Available data do not suggest a change in the dosage regimen in such patients.

Adverse Reactions

When using Bonadea^®, irregular bleeding (spotting or breakthrough uterine bleeding) may occur, especially during the first months of use.

Other undesirable effects may be observed during the use of Bonadea^®, although their occurrence is not necessary in all patients.

Side effects identified during the use of the active substances of Bonadea^® are presented with distribution by frequency of development and by organ systems. The frequency of side effects was classified as follows: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000) and frequency unknown (based on available data it is impossible to estimate the frequency of adverse reactions).

Infections and infestations uncommon – vaginitis, vulvovaginitis, vaginal candidiasis or other fungal vulvovaginal infections; rare – salpingo-oophoritis (adnexitis), urinary tract infections, cystitis, mastitis, cervicitis, fungal infections, oral herpes, influenza, bronchitis, sinusitis, upper respiratory tract infections, viral infection.

Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon – ovarian cyst; rare – uterine adnexa cyst, uterine fibroid, breast lipoma, breast cysts, fibrocystic mastopathy.

Blood and lymphatic system disorders rare – anemia.

Immune system disorders: rare – allergic reactions.

Endocrine disorders rare – virilism.

Metabolism and nutrition disorders: uncommon – increased appetite; rare – anorexia.

Psychiatric disorders uncommon – depressed mood; rare – mental disorders, depression, insomnia, sleep disorders, aggression; frequency unknown – decreased libido, increased libido.

Nervous system disorders common – headache; uncommon – dizziness, migraine; rare – ischemic stroke, cerebrovascular disorders, dystonia.

Eye disorders rare – dryness of the eye mucosa, irritation of the eye mucosa, oscillopsia; frequency unknown – contact lens intolerance (discomfort when wearing them).

Ear and labyrinth disorders rare – sudden hearing loss, tinnitus, vertigo, hearing impairment.

Cardiac and vascular disorders: uncommon – increase/decrease in BP; rare – cardiovascular disorders, tachycardia, venous and arterial thrombosis and thromboembolism, thrombophlebitis, increased diastolic pressure, orthostatic circulatory dystonia, flushing, varicose veins, venous diseases, pain along the veins.

Respiratory, thoracic and mediastinal disorders rare – bronchial asthma, hyperventilation.

Gastrointestinal disorders uncommon – abdominal pain, discomfort, bloating, nausea, vomiting, diarrhea; rare – gastritis, enteritis, dyspepsia.

Skin and subcutaneous tissue disorders uncommon – acne, alopecia, rash, including macular rash, pruritus (including generalized pruritus); rare – allergic dermatitis, atopic dermatitis, neurodermatitis, eczema, psoriasis, hyperhidrosis, chloasma, hyperpigmentation, seborrhea, dandruff, hirsutism, skin reaction – cellulitis, spider veins; frequency unknown – urticaria, erythema nodosum, erythema multiforme.

Musculoskeletal and connective tissue disorders rare – back pain, musculoskeletal discomfort, myalgia, pain in extremities.

Reproductive system and breast disorders common – breast pain, discomfort; uncommon – changes in the duration and volume of withdrawal bleeding, including heavy withdrawal bleeding, scanty withdrawal bleeding and absence of withdrawal bleeding, breakthrough bleeding, including vaginal bleeding and metrorrhagia, breast enlargement, breast engorgement and fullness, breast swelling, painful withdrawal bleeding, vaginal discharge, pelvic pain; rare – cervical epithelial dysplasia, dyspareunia, galactorrhea; frequency unknown – breast discharge.

General disorders and administration site conditions uncommon – fatigue, asthenia, malaise, changes in body weight (increase, decrease and fluctuations in body weight); rare – chest pain, peripheral edema, influenza-like symptoms, increased body temperature, irritability; frequency unknown – fluid retention.

Investigations rare – hypertriglyceridemia, hypercholesterolemia.

The following serious adverse events have been reported in women using COCs (which include the drug Bonadea^®):

• Venous thromboembolic disorders;
• Arterial thromboembolic disorders;
• Stroke;
• Increased BP;
• Hypertriglyceridemia;
• Impaired glucose tolerance or effect on peripheral insulin resistance;
• Liver tumors (benign and malignant);
• Impaired liver function tests;
• Chloasma;
• In women with hereditary angioedema, exogenous estrogens may cause or exacerbate symptoms of angioedema;
• Onset or worsening of conditions for which the association with the use of COCs (which include the drug Bonadea^®) is not indisputable: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea; herpes during a previous pregnancy; hearing loss associated with otosclerosis; Crohn’s disease; ulcerative colitis; cervical cancer;
• Visual impairment;
• Dizziness;
• Pancreatitis;
• Cholecystitis;
• The frequency of diagnosis of breast cancer in women using COCs (which include the drug Bonadea^®) is very slightly increased. Breast cancer is rarely observed in women under 40 years of age, the excess frequency is insignificant relative to the overall risk of breast cancer. A causal relationship between the occurrence of breast cancer and the use of COCs has not been established.

Due to the interaction of other drugs (inducers of microsomal enzymes) with COCs, breakthrough bleeding and/or a decrease in the contraceptive effect may occur.

If adverse effects not listed in the instructions occur, the woman should inform her doctor.

Contraindications

The drug Bonadea^® is contraindicated in the presence of any of the conditions/diseases listed below. If any of these conditions develops for the first time during its use, the drug should be immediately discontinued

• Thrombosis (venous and arterial) and thromboembolism currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction);
• Conditions preceding thrombosis (including angina pectoris) currently or in history;
• Cerebrovascular disease: stroke, transient ischemic attacks currently and in history;
• Multiple or pronounced risk factors for venous or arterial thrombosis, including complicated lesions of the heart valves, atrial fibrillation, diseases of the cerebral vessels or coronary arteries of the heart, severe dyslipoproteinemia; uncontrolled arterial hypertension, major surgery, prolonged immobilization, surgical interventions on the lower extremities and pelvic organs, neurosurgical interventions, smoking at the age over 35 years;
• Congenital or acquired predisposition to arterial or venous thrombosis (resistance to activated protein C (including factor 5 Leiden), antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, presence of antiphospholipid antibodies, (anticardiolipin, lupus anticoagulant));
• Migraine with focal neurological symptoms currently or in history;
• Diabetes mellitus with vascular complications;
• Pancreatitis with severe hypertriglyceridemia currently or in history;
• Hepatic insufficiency and severe liver diseases (until normalization of liver enzyme parameters), including Rotor and Dubin-Johnson syndromes;
• Liver tumors (benign or malignant) currently or in history;
• Identified hormone-dependent malignant neoplasms (including of the genital organs or mammary glands) or suspicion of them;
• Vaginal bleeding of unknown origin;
• Pregnancy or suspicion of it;
• Period of lactation (breastfeeding);
• Hypersensitivity to any of the components of the drug Bonadea^®;
• Galactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose);
• Obesity (BMI over 30 kg/m²);
• Extensive trauma.

The drug Bonadea^® is not intended for use in men.

With caution

The potential risk and expected benefit of using COCs should be carefully weighed in each individual case in the presence of the following diseases/conditions and risk factors

• Risk factors for thrombosis and thromboembolism: smoking; obesity (BMI less than 30 kg/m²); dyslipoproteinemia, arterial hypertension; migraine without focal neurological symptoms; uncomplicated heart valve defects; hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at a young age in any of the immediate relatives);
• Other diseases in which peripheral circulatory disorders may be noted: diabetes mellitus; oncological diseases, SLE; hemolytic-uremic syndrome; Crohn’s disease and ulcerative colitis; sickle cell anemia; superficial phlebitis;
• Hereditary angioedema;
• Hypertriglyceridemia;
• Diseases that first appeared or worsened during pregnancy or against the background of previous use of sex hormones (for example, jaundice, cholestasis, gallbladder diseases, otosclerosis with hearing impairment, porphyria, herpes during pregnancy, Sydenham’s chorea);
• Postpartum period.

Use in Pregnancy and Lactation

The drug Bonadea^® should not be used during pregnancy. If pregnancy is detected during the use of the drug Bonadea^®, it should be discontinued immediately and a doctor should be consulted. However, extensive epidemiological studies have not revealed an increased risk of developmental defects in children born to women who received sex hormones before pregnancy or who took sex hormones inadvertently in early pregnancy.

Taking COCs may reduce the amount of breast milk and change its composition, so their use is not recommended until breastfeeding is discontinued.

Use in Hepatic Impairment

The drug is contraindicated in hepatic insufficiency, severe liver diseases (until normalization of liver enzyme parameters), liver tumors (benign or malignant) currently or in history.

Use in Renal Impairment

The drug Bonadea^® has not been specifically studied in women with impaired renal function. Available data do not suggest a change in the dosage regimen in such patients.

Pediatric Use

Children and adolescents the drug Bonadea^® is indicated only after menarche.

Geriatric Use

The drug Bonadea^® is not indicated after menopause.

Special Precautions

In the presence of any of the conditions or risk factors listed below, the potential risk and expected benefit of therapy should be carefully assessed and discussed with the woman before she decides to start taking the drug. If symptoms of an existing disease worsen, the disease exacerbates, or the first signs of these conditions or risk factors appear during the use of this drug, it is necessary to consult a doctor who may decide to discontinue the drug.

Thrombosis

The risk of deep vein thrombosis in women taking COCs is higher than in those who do not take them, but not as high as during pregnancy.

The results of epidemiological studies indicate a relationship between the use of COCs and an increased risk of thrombosis and thromboembolic diseases such as myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism when taking COCs. These complications are rare.

The risk of developing venous thromboembolism (VTE) is highest in the first year of using such drugs, mainly during the first 3 months. An increased risk exists when initially using COCs or when resuming the use of the same or different COCs (after a break in taking the drug of 4 weeks or more).

The overall risk of VTE in patients taking low-dose COCs (<50 mcg ethinyl estradiol) is 2-3 times higher than in non-pregnant patients who do not take COCs, however, this risk remains lower compared to the risk of VTE during pregnancy and childbirth.

In very rare cases, venous or arterial thromboembolism can be fatal.

VTE, manifested as deep vein thrombosis and/or pulmonary embolism, can occur with the use of any COC.

Very rarely, when using COCs, thrombosis occurs in other blood vessels, for example, in the veins and arteries of the liver, mesentery, kidneys, brain or retina.

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

Symptoms of pulmonary embolism (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 (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more or less severe events (e.g., respiratory infection).

If women taking COCs develop the symptoms listed above, they should immediately consult a doctor.

The risk of VTE increases

• With age;
• With smoking (with heavy smoking and with increasing age, the risk additionally increases, especially in women over 35 years of age. Women over 35 years of age should be strongly advised to quit smoking if they wish to take the drug Bonadea^®;
• With a burdened family history (i.e., if there is a history of venous thromboembolism at a relatively young age in parents or close relatives). If a hereditary predisposition is suspected, before deciding on any hormonal contraception, a woman should consult a specialist;
• With prolonged immobilization, major surgery, any surgery on the lower extremities or extensive trauma. In these situations, it is necessary to stop use (in case of planned surgery at least 4 weeks in advance), and not resume it until two weeks after full restoration of motor activity. If the use of the drug Bonadea^® was not stopped in advance, the issue of antithrombotic therapy should be considered;
• During a flight lasting more than 4 hours;
• With obesity (BMI over 30 kg/m²).

The risk of arterial thromboembolic complications or cerebrovascular accident increases

• With age;
• With smoking (with heavy smoking and with increasing age, the risk additionally increases, especially in women over 35 years of age. Women over 35 years of age should be strongly advised to quit smoking if they wish to take the drug Bonadea^®;
• With dyslipoproteinemia;
• With arterial hypertension;
• With migraine;
• With heart valve diseases;
• With atrial fibrillation;
• With a burdened family history (i.e., if there is a history of arterial thrombosis at a relatively young age in parents or close relatives). If a hereditary predisposition is suspected, before deciding on any hormonal contraception, a woman should consult a specialist.

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

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

An increase in the frequency or severity of migraine attacks during the use of the drug Bonadea^® (which may be a precursor to cerebrovascular accident) is a reason for immediate discontinuation of the drug.

There is no consensus regarding the potential role of varicose veins and superficial thrombophlebitis in the development of VTE.

Tumors

The most important risk factor for cervical cancer is persistent papillomavirus infection. Some epidemiological studies show that long-term use of COCs may contribute to an increase in this risk. However, there is still debate about how much this result depends on other factors, such as cervical screening and more liberal sexual behavior and refusal of barrier methods of contraception.

A meta-analysis of the results of 54 epidemiological studies indicates a slightly increased relative risk of detecting breast cancer in women using COCs (relative risk 1.24). The increased risk gradually decreases over 10 years after stopping COC use. Given the fact that breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed breast cancers in women taking or previously taking COCs is small compared to the overall risk of breast cancer. These studies do not confirm a causal relationship. The reason for the observed increase in the number of detected breast cancers in women taking COCs may be earlier diagnosis, the biological effect of the drugs, or a combination of these factors. Breast cancer diagnosed in women taking or previously taking COCs is usually less clinically advanced than in patients who have never used them.

Individual cases of benign liver tumors and, much less frequently, malignant liver tumors have been diagnosed in women taking COCs. In rare cases, such tumors have caused life-threatening intra-abdominal bleeding. If severe pain in the upper abdomen, liver enlargement or signs of intra-abdominal bleeding occur in women taking COCs, it is necessary to immediately consult a doctor.

Other conditions

Women suffering from hypertriglyceridemia or having a family history of this disease may have an increased risk of pancreatitis when using COCs.

Although many women taking COCs have experienced a slight increase in BP, clinically significant increases are rare. However, if a clinically significant increase in BP (above 140/90 mm Hg) develops during COC use, the use of the drug Bonadea^® should be discontinued and treatment for arterial hypertension should be initiated. Use of the drug may be continued if normal BP values are achieved with antihypertensive therapy.

Discontinuation of COCs may be inevitable in acute and chronic liver dysfunction until all liver function parameters return to normal. Recurrences of cholestatic jaundice that first occurred during pregnancy or during a previous period of COC use also require discontinuation of the drug.

The use of COCs (which include the drug Bonadea^®) may cause the appearance or worsening of conditions for which the association with the use of these drugs is not indisputable: jaundice and/or pruritus associated with cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham’s chorea, herpes during a previous pregnancy, hearing loss associated with otosclerosis.

Although COCs may affect peripheral insulin resistance and glucose tolerance, women with diabetes taking low-dose COCs generally do not require dose adjustment or changes in the dosing regimen of hypoglycemic drugs. Nevertheless, such women should be under close observation.

Crohn’s disease and ulcerative colitis may be associated with COC use.

Chloasma (hyperpigmentation of the facial skin) may sometimes appear, especially if it was observed during pregnancy. Women with a predisposition to chloasma during the use of COCs should avoid direct sunlight and exposure to other UV radiation.

Disappearance of acne symptoms is usually noted after 3-4 months of therapy.

Women should be warned that the drug Bonadea^® does not protect them from HIV infections and other sexually transmitted diseases.

Reduced Efficacy

The efficacy of COCs may decrease, for example, in case of missed tablet intake, in case of gastrointestinal disorders (vomiting, diarrhea) or simultaneous use of other medicinal products.

Cycle Irregularity

During the use of any COC, irregular bleeding (spotting or “breakthrough” bleeding) may occur, especially during the first months of taking the tablets. Bleeding usually stops as the body adapts to the drug Bonadea^® (usually after 3 cycles of tablet intake). If bleeding continues and its severity increases, a specialist should be consulted.

Absence of Scheduled Withdrawal Bleeding

Some women do not experience withdrawal bleeding during the tablet-free interval. If the drug was taken as directed, pregnancy is unlikely. However, if the tablets were taken irregularly, or withdrawal bleeding did not occur twice in a row, pregnancy must be ruled out before continuing the use of the drug.

Laboratory Tests

The use of COCs may affect the results of laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, the concentration of plasma proteins, for example, corticosteroid-binding globulin, as well as the lipid/lipoprotein composition of the blood, parameters of carbohydrate metabolism and parameters of the blood coagulation system. However, deviations usually remain within the range of normal laboratory values.

Medical Examination

Before the first prescription or resumption of Bonadea^® use, a detailed history must be taken and a medical examination performed, taking into account contraindications, special instructions and precautions. The examination must be repeated regularly. Regular medical examination is also necessary due to the presence of contraindications (e.g., transient ischemic conditions, etc.) or risk factors (e.g., a family history of venous or arterial thrombosis) that may occur for the first time only during the use of COCs. The frequency and nature of such examinations should be based on approved practical methods, adapted to the specific patient, but in general they should primarily include ruling out pregnancy, determining blood pressure, the condition of the breasts, abdominal and pelvic organs, including cytological examination of the cervical epithelium, and ruling out disorders of the blood coagulation system.

In case of long-term use of the drug, examination should be performed at least once every 6 months.

A woman should consult a doctor as soon as possible

• In case of any changes in health, especially any conditions listed in the instructions for use;
• In case of a local lump in the breast;
• When other medicinal products are prescribed;
• If prolonged immobilization is expected (e.g., application of a plaster cast to the lower limb), hospitalization or surgery is planned (consultation with a doctor is necessary 4-6 weeks before it);
• In case of unusually severe uterine bleeding;
• If a woman forgot to take a tablet in the first week of taking the pack (blister) and had sexual intercourse within the week before that;
• If there was no scheduled withdrawal bleeding twice in a row or if pregnancy is suspected (the next pack (blister) should not be started until consultation with a doctor).

Effect on Ability to Drive and Operate Machinery

Caution must be exercised when driving vehicles and engaging in potentially hazardous activities, because during the use of the drug Bonadea^®, dizziness may rarely occur.

Overdose

No information on serious side effects from overdose has been reported.

Symptoms nausea, vomiting, and minor vaginal bleeding or spotting may occur.

Treatment there is no specific antidote, symptomatic treatment should be carried out.

Drug Interactions

It is necessary to take into account the prescribing information of concomitant drugs to identify potential drug interactions.

Effect of Other Medicinal Products on Bonadea^®

Interaction with medicinal products that induce hepatic microsomal enzymes is possible, which may increase the clearance of sex hormones, which, in turn, can lead to breakthrough uterine bleeding and/or a decrease in the contraceptive effect.

Enzyme induction can be observed after just a few days of treatment. Maximum induction of hepatic enzymes is usually achieved within a few weeks. After discontinuation of the drug, induction may persist for approximately 4 weeks.

Women who receive treatment with such drugs for a short course in addition to Bonadea^® are advised to use a barrier method of contraception or choose another non-hormonal method of contraception. The barrier method of contraception should be used throughout the period of taking the concomitant drugs, as well as for 28 days after their discontinuation. If the use of inducing drugs continues longer than the tablet cycle in the Bonadea^® pack, tablet intake from a new pack should be started without a break in tablet intake.

For women receiving long-term treatment with drugs that induce hepatic microsomal enzymes, the use of another reliable non-hormonal method of contraception is recommended.

Substances that Increase the Clearance of Bonadea^® (Weakening Efficacy Due to Induction of Hepatic Enzymes)

Barbiturates, bosentan, carbamazepine, phenytoin, primidone, modafinil, rifampicin and drugs for the treatment of HIV infection, such as ritonavir, nevirapine and efavirenz, and possibly felbamate, griseofulvin, barbexaclone, topiramate, oxcarbazepine, and preparations containing St. John’s wort (Hypericum perforatum).

Substances with Variable Effects on the Clearance of Bonadea^®

Drugs that increase gastrointestinal motility (e.g., metoclopramide) may reduce the plasma concentration of ethinylestradiol.

Active substances that inhibit the sulfation of ethinylestradiol in the intestinal wall (e.g., ascorbic acid and paracetamol) may increase the plasma concentration of ethinylestradiol.

Concomitant use of atorvastatin increases the AUC of ethinylestradiol by 20%.

Drugs that inhibit the activity of hepatic microsomal enzymes, such as imidazole derivative antifungals (e.g., fluconazole), indinavir or troleandomycin may increase the plasma concentration of ethinylestradiol. When the combination of dienogest and ethinylestradiol is used concomitantly, many HIV or hepatitis C virus protease inhibitors and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentration of estrogen or progestogen. In some cases, this effect may be clinically significant.

When Bonadea^® is used concomitantly with a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor, an additional barrier method of contraception should be used throughout the use of these drugs and for 7 days after the end of therapy.

Effect of Bonadea^® on Other Medicinal Products

COCs may affect the metabolism of some other drugs, leading to an increase (e.g., cyclosporine) or decrease (e.g., lamotrigine) in their plasma and tissue concentrations.

The combination of dienogest and ethinylestradiol may affect the metabolism of other medicinal products

• Inhibit the activity of hepatic microsomal enzymes and thus increase the plasma concentration of drugs such as benzodiazepines (e.g., diazepam), cyclosporine, theophylline and corticosteroids (e.g., prednisolone);
• Induce glucuronidation in the liver and thus reduce the plasma concentration of drugs such as clofibrate, paracetamol, morphine and lorazepam.

During the use of Bonadea^®, adjustment of the dose of hypoglycemic drugs may be necessary, as the drug may affect peripheral insulin resistance and glucose tolerance.

Effect on Laboratory Tests

The use of COCs may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, the concentrations of transport proteins in plasma, e.g., CBG, lipoprotein fractions, parameters of carbohydrate metabolism and the blood coagulation system. Usually these changes remain within normal values.

Storage Conditions

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

Shelf Life

Shelf life – 3 years.

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.