Material and methods
A total of 40 women aged 18 to 35 years took part in the study. Before prescribing Bonade, the patients were examined: examined by a gynecologist with examination of smears for flora and oncocytology, ultrasound examination of the genitals, general blood and urine tests, and biochemical blood tests. The survey excluded thrombosis and thromboembolism, cerebrovascular disorders, migraine with focal neurological symptoms, diabetes mellitus, pancreatitis with severe hypertriglyceridemia, and liver failure. If multiple or severe risk factors for venous or arterial thrombosis were identified (damage to the heart valves, atrial fibrillation, cerebrovascular disease or coronary artery disease, uncontrolled arterial hypertension, smoking, obesity), women were not included in the study. Patients took the drug Bonade orally, 1 tablet per day, without chewing and with a small amount of water, at the same time every day. The tablets were taken for 21 days according to the schedule indicated on the blister, then after a 7-day break the next package of Bonade was started. Observations were carried out over 3 months.
Bonade®
If any of the conditions, diseases or risk factors listed below are present, the ratio of the expected benefit to the possible risk of using the dienogest + ethinyl estradiol combination should be carefully assessed in each individual case and discussed with the woman before starting the drug. If any of these conditions, diseases or risk factors worsen, intensify, or appear for the first time, a woman should consult her doctor to decide whether to stop using the drug.
Risk of developing VTE and PTE
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.
An increased risk is present after initial use of COCs or resumption of use after a break of 4 weeks or more. Medicines containing levonorgestrel, norgestimate or norethisterone as a progestogen component have the lowest risk of developing VTE. It is not yet known whether the risk of developing VTE is higher when taking BONADE® compared to these drugs. The choice in favor of the drug BONADE® can only be made after consultation with the woman to ensure that she fully understands the risk of VTE associated with the use of the drug; the effect of the drug on her existing risk factors and the fact that the risk of developing VTE is maximum in the first year of using such drugs.
VTE can be life-threatening or lead to death (in 1-2% of cases).
It is extremely rare when using COCs that thrombosis of other blood vessels occurs, for example, hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels.
Symptoms of deep vein thrombosis:
unilateral swelling or swelling along the vein, pain or discomfort in the lower limb only in an upright position or when walking, local increase in temperature, redness or discoloration of the skin of the lower limb.
Symptoms of pulmonary embolism
: difficulty or rapid breathing; sudden cough, including with hemoptysis; sharp pain in the chest, which may intensify with deep inspiration; sense of anxiety; severe dizziness; fast or irregular heartbeat. Some of these symptoms (eg, shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more common and less severe conditions (eg, respiratory tract infection).
Arterial thromboembolism can lead to stroke, vascular occlusion, or myocardial infarction.
Symptoms of a stroke include:
sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, problems with speech and understanding; sudden unilateral or bilateral vision loss; sudden disturbance in gait, dizziness, loss of balance or coordination; sudden, severe or prolonged headache for no apparent reason; loss of consciousness or fainting with or without convulsions.
Other signs of vascular occlusion:
sudden pain, swelling and slight cyanosis of the extremities, “acute” abdomen.
Symptoms of myocardial infarction
: pain, discomfort, pressure, heaviness, a feeling of compression or fullness in the chest or behind the sternum with irradiation to the back, jaw, left upper limb, epigastric region; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; fast or irregular heartbeat. Arterial thromboembolism can be life-threatening or fatal.
In women with a combination of several risk factors or high severity of one of them, the possibility of their mutual reinforcement should be considered. In such cases, the degree of increase in the risk of blood clots may be higher than with a simple summation of factors. In this case, taking the drug is contraindicated.
The risk of developing thrombosis (venous and/or arterial) and thromboembolism or cerebrovascular disorders increases:
- with age;
- in smokers (with an increase in the number of cigarettes or an increase in age, the risk increases, especially in women over 35 years old);
in the presence of:
— obesity (body mass index 30 kg/m2 or more);
- family history (for example, venous or arterial thromboembolism ever in close relatives or parents under the age of 50 years). In the case of a hereditary or acquired predisposition, the woman should be examined by an appropriate specialist to decide on the possibility of taking the drug;
- prolonged immobilization, extensive surgery, any operation on the lower extremities or major trauma. In these cases, the drug must be stopped (in the case of a planned operation, at least four weeks before it) and not resumed for two weeks after the end of immobilization.
Temporary immobilization (eg, air travel lasting more than 4 hours) may also be a risk factor for the development of venous thromboembolism, especially in the presence of other risk factors;
- dislipoproteinemia;
- arterial hypertension;
- migraine;
— diseases of the heart valves;
- atrial fibrillation.
The possible role of varicose veins and superficial thrombophlebitis in the development of VTE remains controversial.
The increased risk of thromboembolism in the postpartum period should be taken into account.
Peripheral circulatory disorders may also occur in diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell anemia.
An increase in the frequency or severity of migraine while taking the drug (which may precede cerebrovascular events) is grounds for immediate discontinuation of COC use.
Biochemical indicators indicating a hereditary or acquired predisposition to venous or arterial thrombosis include the following: resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
When assessing the balance of benefit and risk, it should be taken into account that adequate treatment of the relevant condition can reduce the associated risk of thrombosis. It should also be taken into account that the risk of thrombosis and thromboembolism during pregnancy is higher than when taking low-dose COCs (<0.05 mg ethinyl estradiol).
Tumors
The most significant risk factor for the development of cervical cancer (CC) is persistent papillomavirus infection (HPV). There are reports of a slight increase in the risk of developing CC with long-term use of COCs. However, the connection with taking COCs has not been proven. Controversy remains regarding the extent to which these data are related to screening for cervical pathology or to women's sexual behavior (lower use of barrier methods of contraception, number of sexual partners).
A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of developing breast cancer (BC) diagnosed in women who are currently using COCs (relative risk 1.24). The increased risk gradually disappears within 10 years after stopping COC use. Due to the fact that breast cancer is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses in women who are currently taking COCs or have recently taken them is insignificant in relation to the overall risk of this disease. Its connection with COC use has not been proven. The observed increase in the risk of developing breast cancer may be due not only to earlier diagnosis of breast cancer, but also to the biological effect of sex hormones or a combination of these two factors. In women who have ever used COCs, earlier stages of breast cancer are detected. than in women who have never used them.
In rare cases, during the use of COCs, the development of benign, and in extremely rare cases, malignant liver tumors, which in some cases led to life-threatening intra-abdominal bleeding, was observed. If severe abdominal pain, liver enlargement, or signs of intra-abdominal bleeding occur, this should be taken into account when making a differential diagnosis.
Low mood and depression
Decreased mood and depression are well-known adverse reactions when using hormonal contraceptives. Depression can be serious and is a known risk factor for suicidal behavior and suicide. Women should be advised to consult a doctor if mood changes or symptoms of depression occur, including soon after starting to take the drug.
Other states
Women with hypertriglyceridemia (or a family history of this condition) may have an increased risk of developing pancreatitis while taking COCs.
Although slight increases in blood pressure (BP) have been observed in many women taking COCs, clinically significant increases have rarely been observed. However, if a persistent clinically significant increase in blood pressure develops while taking a COC, you should stop taking the COC and begin treatment for hypertension. The drug can be continued if normal blood pressure values are achieved with antihypertensive therapy.
The following conditions have been reported to develop or worsen both during pregnancy and while taking COCs, but their relationship with COC use has not been proven: jaundice and/or pruritus associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; chorea; gestational herpes; hearing loss associated with otosclerosis.
Cases of worsening the course of endogenous depression, epilepsy, Crohn's disease and ulcerative colitis during the use of COCs have also been described.
In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.
Acute or chronic liver dysfunction may require discontinuation of COCs until all liver function tests return to normal. Recurrence of cholestatic jaundice, which developed for the first time during a previous pregnancy or previous use of sex hormones, requires discontinuation of COC use.
Although COCs may have an effect on insulin resistance and
Glucose tolerance, and the need to adjust the dose of hypoglycemic drugs in patients with diabetes mellitus using low-dose COCs (<0.05 mg ethinyl estradiol), as a rule, do not arise. However, women with diabetes mellitus should be carefully monitored while taking COCs.
Chloasma can sometimes develop, especially in women with a history of pregnancy chloasma. Women with a tendency to chloasma should avoid prolonged exposure to the sun and exposure to ultraviolet radiation while taking the drug.
Laboratory tests
Taking the combination of dienogest + ethinyl estradiol may affect the results of some laboratory tests, including liver, kidney, thyroid, adrenal function, plasma transport protein concentrations, carbohydrate metabolism, blood coagulation and fibrinolysis parameters. Changes usually do not go beyond normal values.
Reduced efficiency
The effectiveness of the drug may be reduced in the following cases: missed pills, gastrointestinal disorders or as a result of drug interactions.
Frequency and severity of menstrual-like bleeding
While taking the drug, irregular bleeding may occur (“spotting” spotting and/or “breakthrough” uterine bleeding), especially during the first months of use. Therefore, any irregular bleeding should be assessed only after an adaptation period of approximately 3 cycles of dosing. If irregular bleeding recurs or develops after previous regular cycles, careful evaluation should be performed to rule out malignancy or pregnancy.
No regular menstrual bleeding
Some women may not develop bleeding during a break in taking pills. “ooContraindications” and “With caution”;
— local compaction in the mammary gland;
- simultaneous use of other medications;
- if prolonged immobility is expected (for example, a cast is applied to the lower limb), hospitalization or surgery is planned (at least four weeks before the proposed operation);
- unusually heavy bleeding from the vagina;
- missed a pill in the first week of taking the package and had sexual intercourse seven days or less before;
- absence of regular menstrual-like bleeding two times in a row or suspicion of pregnancy (you should not start taking pills from the next package before consulting your doctor).
You should stop taking the tablets and consult your doctor immediately if there are possible signs of thrombosis, myocardial infarction or stroke: unusual cough; unusually severe pain behind the sternum, radiating to the left arm; unexpected shortness of breath, unusual, severe and prolonged headache or migraine attack; partial or complete loss of vision or double vision; slurred speech; sudden changes in hearing, smell, or taste; dizziness or fainting; weakness or loss of sensation in any part of the body; severe abdominal pain; severe pain in the lower limb or sudden swelling of any of the lower limbs.
Results and discussion
During the first 2 months, the most common side effects were (see figure):
Tolerability of the drug Bonade. Gastrointestinal tract - gastrointestinal tract.
- irregular bleeding, spotting - in 3 (7.5%) women;
- disorders of the gastrointestinal tract in the form of abdominal pain, bloating, nausea, diarrhea - in 4 (10%) women, which cannot exclude pathology from the gastrointestinal tract;
— pregnancy occurred in 1 (2.5%) patient as a result of missing the next pill dose.
The frequency of side effects when taking the drug Bonade is comparable to the frequency of adverse reactions to drugs of a similar group and corresponds to those stated by the manufacturer in the instructions for medical use of the drug Bonade.
At a repeat visit to the gynecologist after 1, 2 and 3 months, the patients were examined with a smear taken for flora, a general blood test, urine test, and a biochemical blood test. Ultrasound examination of the pelvic organs was carried out 3 months after the start of taking the drug Bonade. Noteworthy is the fact that microscopy of smears did not reveal vulvovaginal infections or bacterial vaginosis, which indicates the constancy of the vaginal biocenosis when taking the drug Bonade. A general analysis of blood and urine revealed no pathological changes. Biochemical parameters of transferases were normal in all patients. Ultrasound examination of the genitals did not reveal significant differences before and during use of the drug Bonade. All observed women noted a decrease in the amount of blood loss. Relief of premenstrual syndrome was noted by 44 (97.7%) patients. Pregnancy occurred in 1 (2.5%) patient.
Bonade, 63 pcs., 2 mg+0.03 mg, film-coated tablets
If any of the following conditions or risk factors are present, the potential risks and expected benefits of therapy should be carefully assessed and discussed with the woman before she decides to start taking the drug. If the symptoms of an existing disease intensify, the disease worsens, or the first signs of these conditions or risk factors appear when using this drug, you should consult your doctor, who may decide whether to discontinue the drug.
Thrombosis.
This is the formation of a blood clot (thrombus) that can block a blood vessel. When a blood clot breaks off, thromboembolism develops. Sometimes thrombosis develops in the deep veins of the lower extremities (deep vein thrombosis), vessels of the heart (myocardial infarction), brain (stroke) and extremely rarely - in the vessels of other organs. The risk of deep vein thrombosis in women taking COCs is higher than in those not taking 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 greatest in the first year of taking such drugs, mainly during the first 3 months. An increased risk is present after initial use of COCs or upon resumption of use of the same or different COCs (after a dosing interval 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 not taking COCs, although this risk remains lower than the risk of VTE in 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.
It is extremely rare when using COCs that thrombosis occurs in other blood vessels, such as the veins and arteries of the liver, mesentery, kidneys, brain or retina. Symptoms of deep vein thrombosis (DVT) include the following: unilateral swelling of the lower extremity or along a vein in the lower extremity, pain or discomfort in the lower extremity only when standing or walking, localized warmth in the affected lower extremity, redness or discoloration of the skin on lower limb.
Symptoms of pulmonary embolism include: difficulty or rapid breathing; sudden cough, incl. with hemoptysis; sharp pain in the chest, which may intensify with deep inspiration; sense of anxiety; severe dizziness; fast or irregular heartbeat. Some of these symptoms (eg shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more or less serious events (eg respiratory tract infection).
If the above symptoms occur in women taking COCs, you should immediately consult your doctor.
The risk of VTE increases:
- with age;
- when smoking (with heavy smoking and with increasing age, the risk further increases, especially in women over 35 years of age. Women over 35 years of age should be strongly advised to stop smoking if they want to take BONADE®);
- with a burdened family history (i.e., if there is a history of cases of venous thromboembolism at a relatively young age in parents or close relatives). If a hereditary predisposition is suspected, a woman should consult a specialist before deciding on any hormonal contraception;
- with prolonged immobilization, major surgery, any operation on the lower extremities or major trauma. In these situations, it is necessary to discontinue use (in the case of planned surgery, at least 4 weeks in advance), and not resume it until 2 weeks have passed after complete restoration of motor activity. If BONADE® has not been discontinued in advance, antithrombotic therapy should be considered;
— air flight lasting more than 4 hours;
- for obesity (body mass index more than 30 kg/m2).
The risk of arterial thromboembolic complications or cerebrovascular accident increases:
- with age;
- when smoking (with heavy smoking and with increasing age, the risk further increases, especially in women over 35 years of age. Women over 35 years of age should be strongly advised to stop smoking if they want to take BONADE®);
- with dislipoproteinemia;
- for arterial hypertension;
- for migraine;
- for diseases of the heart valves;
- with atrial fibrillation;
- with a burdened family history (i.e., if there is a history of cases of arterial thrombosis at a relatively young age in parents or close relatives). If a hereditary predisposition is suspected, a woman should consult a specialist before deciding on any hormonal contraception. Peripheral circulatory disorders may also occur in diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (namely Crohn's disease or ulcerative colitis) and sickle cell anemia.
The increased risk of thromboembolism in the postpartum period must be taken into account. An increase in the frequency or severity of migraine attacks during use of the drug BONADE® (which may be a harbinger of 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 human papillomavirus infection. Some epidemiological studies suggest that long-term use of COCs may contribute to this risk. However, there is still ongoing debate about the extent to which this result depends on other factors, such as cervical screening tests and more free sexual behavior, and the abandonment of barrier methods of contraception.
A meta-analysis of the results of 54 epidemiological studies suggests a slightly increased relative risk of breast cancer detection in women using COCs (relative risk - 1.24). The increased risk gradually decreases over 10 years after stopping COC use. Given that breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnoses in women taking or previously taking COCs is small compared to the overall risk of breast cancer. These studies do not support a cause-and-effect relationship. The observed increase in the incidence of breast cancer in women taking COCs may be due to earlier diagnosis, biological effects of the drugs, or a combination of these factors. Breast cancer diagnosed in women who are using or have previously used COCs is usually a less clinically advanced cancer than in patients who have never used them.
Isolated 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 upper abdominal pain, liver enlargement, or signs of intra-abdominal bleeding occur in women taking COCs, you should consult your doctor immediately.
Other states.
Women who suffer from hypertriglyceridemia or have a family history of this disease may have an increased risk of pancreatitis when taking COCs.
Although small increases in blood pressure have been reported in many women taking COCs, clinically significant increases are rare. However, if a clinically significant increase in blood pressure (above 140/90 mmHg) develops while taking a COC, BONADE® should be discontinued and treatment of arterial hypertension initiated. The drug can be continued if normal blood pressure values are achieved with antihypertensive therapy.
Discontinuation of COC use may be inevitable in acute and chronic liver dysfunction until all liver function tests return to normal. Relapses of cholestatic jaundice that occurred for the first time during pregnancy or during the period preceding it using COCs also require discontinuation of the drug.
The use of COCs (which includes the drug BONADE®) can cause the appearance or worsening of conditions for which the connection with the use of these drugs is not indisputable: jaundice and/or itching associated with cholestasis, formation of gallstones, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham's chorea, herpes during previous pregnancy, hearing loss associated with otosclerosis.
Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, women with diabetes mellitus taking low-dose COCs generally do not require dose adjustments or dosing regimens of hypoglycemic agents. However, such women should be closely monitored. Crohn's disease and ulcerative colitis may be associated with COC use. Chloasma (hyperpigmentation of the facial skin) can sometimes appear, especially if it occurs during pregnancy. Women with a predisposition to chloasma should avoid direct sunlight and other UV radiation while using COCs.
The disappearance of acne symptoms is usually observed after 3–4 months of therapy.
Women should be warned that BONADE® does not protect them from HIV infections and other sexually transmitted diseases.
Reduced efficiency
The effectiveness of COCs may be reduced, for example, if you miss pills, have gastrointestinal disorders (vomiting, diarrhea), or use other medications at the same time.
Cycle irregularity
While taking any COC, irregular bleeding (spotting or breakthrough bleeding) may occur, especially in the first months of taking the pills. Bleeding usually stops as the body adapts to the drug BONADE® (usually after three cycles of taking the tablets). If bleeding continues and its severity increases, you should consult a specialist.
No further withdrawal bleeding
Some women do not experience withdrawal bleeding during a break from taking the pills. If the drug is taken according to the instructions, pregnancy is unlikely. However, if the tablets were taken irregularly, or withdrawal bleeding did not occur 2 times in a row, then pregnancy must be excluded before continuing to use the drug.
Laboratory research
The use of COCs may affect the results of laboratory tests, including biochemical indicators of the efficiency of the liver, thyroid gland, adrenal glands and kidneys, the concentration of blood plasma proteins, such as DRGs, as well as the lipid / lipoprotein composition of the blood, indicators of carbohydrate metabolism and indicators of the blood coagulation system . However, deviations usually remain within the range of normal laboratory values.
Medical checkup
Before the first prescription or resumption of taking BONADE®, it is necessary to collect a detailed medical history and conduct a medical examination, 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 (for example, transient ischemic conditions, etc.) or risk factors (for example, a family history of venous or arterial thrombosis), which may arise for the first time only while taking 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 include, first of all, the need to exclude pregnancy, check blood pressure, the condition of the mammary glands, abdominal and pelvic organs, including cytological examination of the cervical epithelium to exclude disorders of the blood coagulation system.
In case of long-term use of the drug, examination must be carried out at least once every 6 months.
You should consult your doctor as soon as possible:
- in case of any health changes, especially any conditions listed in this description of the drug (see “Contraindications” and “With caution”);
- with local compaction in the mammary gland;
- if it is necessary to use other medications (see “Interaction”);
- if long-term immobilization is expected (for example, a plaster cast is applied to the leg), hospitalization or surgery is planned (consult your doctor 4-6 weeks before);
- if unusually heavy uterine bleeding occurs;
- if the patient forgot to take the pill in the first week of taking the package (blister) and had sexual intercourse the week before;
- if the patient has not had regular withdrawal bleeding twice in a row or she suspects that she is pregnant (you should not start taking the next package (blister) without consulting your doctor).
Impact on the ability to drive vehicles and machinery.
When driving vehicles and engaging in potentially hazardous activities, you must be careful, because In rare cases, dizziness may occur while taking BONADE®.
conclusions
When choosing a contraceptive drug, one should take into account reliability, effectiveness, and a minimum of adverse reactions. Based on the results of our study, Bonade can be recommended as a contraceptive. The drug is well tolerated, with minor side effects that subside during the first months of use. If the patient adheres to taking hormonal contraceptives, consultation with a specialist is necessary for the purpose of examination, identification of contraindications, correct selection of the drug and correction of possible side effects.
There is no conflict of interest.
