Lindynette 30
If any of the conditions, diseases or risk factors listed below currently exist, the potential risks and expected benefits of using COCs, including the combination of gestodene + ethinyl estradiol, should be carefully weighed in each individual case and discussed with the woman before starting to take 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 taking the drug.
Risk of developing venous and arterial thromboembolism (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, PE, myocardial infarction, cerebrovascular disorders). These diseases are rare.
The increased risk of developing VTE associated with the use of COCs is due to the presence of estrogen in its composition. COCs containing levonorgestrel, norgestimate or norethisterone as a progestogen component are associated with the lowest risk of VTE. When using other COCs, such as the combination of gestodene + ethinyl estradiol, the risk of developing VTE is twice as high.
The choice of a COC with a higher risk of VTE should only be made after consultation with the woman to ensure that she fully understands the risk of VTE associated with the contraceptive, the effect of the drug on her existing risk factors and that the risk of developing VTE maximum in the first year of taking such drugs. An increased risk is also observed when COC use is resumed (after a break between doses of the drug of 4 weeks or more). The increased risk of developing VTE is present primarily during the first 3 months.
VTE can be life-threatening or lead to death (in 1-2% of cases). VTE, manifested as DVT and/or PE, can occur with all COCs.
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 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 in the affected 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).
ATE can lead to stroke, vascular occlusion, or myocardial infarction.
Symptoms of a stroke
: sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, severe or prolonged headache for no apparent reason, one- or two-sided loss of vision; problems with speech and understanding; sudden disturbance in gait, dizziness, loss of balance or coordination; sudden loss of consciousness or fainting with or without a seizure.
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, radiating to the back, jaw, upper limb, epigastric region; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; fast or irregular heartbeat. ATE can be life-threatening and lead to death.
In women with a combination of several risk factors or high severity of one of the factors, the possibility of their mutual reinforcement should be considered. In such cases, the degree of increase in risk may be higher than with a simple summation of factors. In this case, taking the combination of gestodene + ethinyl estradiol is contraindicated.
The risk of developing thrombosis (venous and/or arterial) and thromboembolism or cerebrovascular disorders increases:
-with age;
- in women who smoke (with an increase in the number of cigarettes or an increase in age, the risk increases, especially over the age of 35);
- if there is a family history (for example, VTE or ATE in close relatives or parents aged less than 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 COCs;
- for obesity (with a BMI more than 30 kg/m2);
- with dyslipoproteinemia;
- for arterial hypertension;
- for migraine;
- for diseases of the heart valves;
- with atrial fibrillation;
- in case of prolonged immobilization, serious surgery, any operation on the lower extremities, in the pelvic area or extensive trauma.
In these cases, the use of COCs should be stopped (in the case of planned surgery, at least four weeks before it) and not resumed for two weeks after the woman has fully regained mobility.
Temporary immobilization (eg, air travel 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 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 and severity of migraine (which may precede cerebrovascular events) during the use of COCs is grounds 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 risk-benefit ratio, it should be taken into account that adequate treatment of the relevant condition/disease may reduce the associated risk of thrombosis.
Tumors
The most significant risk factor for the development of cervical cancer (CC) is persistent human papillomavirus infection. 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 findings are related to screening for cervical pathology or to sexual behavior patterns (less use of barrier methods of contraception, greater number of sexual partners).
A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of developing breast cancer diagnosed in women currently taking COCs (relative risk 1.24). The increased risk gradually disappears within 10 years of stopping these drugs. Due to the fact that breast cancer is rare in women under 40 years of age, the increase in the incidence of breast cancer in women who are currently taking COCs or 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 breast cancer in women using COCs (they are diagnosed with earlier clinical forms of breast cancer than women not taking COCs), the biological effects of COCs, or a combination of both of these factors.
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. In case of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding, this should be taken into account when making a differential diagnosis.
Other states
Depressed mood and depression are known adverse reactions when using hormonal contraceptives. Depression can be a serious disorder and is a known risk factor for suicidal behavior and suicide. Women should be advised to contact their doctor if mood changes or depressive symptoms occur, including soon after starting treatment.
In women with hypertriglyceridemia (or a family history of this condition), the risk of developing pancreatitis may increase while taking COCs.
Although slight increases in blood pressure have been described in many women taking COCs, clinically significant increases have rarely been reported. However, if a persistent clinically significant increase in blood pressure develops during the use of COCs, the COC should be discontinued and treatment of arterial hypertension should be initiated. COC use 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: cholestatic jaundice and/or pruritus associated with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; chorea; herpes during pregnancy; hearing loss associated with otosclerosis. Cases of Crohn's disease and ulcerative colitis have also been described with the use of COCs.
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 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, in patients with diabetes mellitus using low-dose COCs, as a rule, no dose adjustment of hypoglycemic drugs is required. 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 COCs.
Effect on liver function tests
In clinical studies involving patients receiving hepatitis C viral therapy (a combination of drugs containing ombitasvir, paritaprevir, ritonavir, dasabuvir, with or without ribavirin), increases in ALT activity more than 5 times the upper limit of normal were recorded more often in patients using ethynyl-containing COCs.
If a course of therapy with this combination of drugs is necessary, a patient using the contraceptive drug gestodene + ethinyl estradiol should be switched to alternative methods of contraception (non-hormonal or contraceptives containing only gestagen) before starting the course of treatment. You can resume taking the combination of gestodene + ethinyl estradiol no earlier than 2 weeks after the end of the course of therapy with antiviral drugs.
Laboratory tests
The use of drugs such as gestodene + ethinyl estradiol may affect the results of some laboratory tests, including biochemical indicators of liver, thyroid, kidney and adrenal function, the concentration of transport proteins in plasma (for example, transcortin, lipid / lipoprotein fractions, parameters of carbohydrate metabolism, coagulation and fibrinolysis). These changes usually remain within normal physiological values.
Reduced efficiency
The effectiveness of COCs may be reduced in the following cases: in case of missed pills, gastrointestinal disorders or as a result of drug interactions.
Effect on bleeding pattern
While taking COCs, irregular bleeding may occur (“spotting” and/or “breakthrough” 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.
Some women may not develop bleeding during a break in taking pills. “ooContraindications” and “With caution.”
-Local compaction in the mammary gland.
-Concomitant use of other medications.
-If prolonged immobilization is expected (for example, a cast is applied to the lower extremity), 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 drug 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.
This medicine contains lactose (in the form of lactose monohydrate) and sucrose. Patients with rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome, as well as rare congenital forms of fructose intolerance or sucrase-isomaltase deficiency should not take this drug.
In 1860, the German pathologist Carl von Rokitansky first described changes in the myometrium corresponding to adenomyosis. This term is now commonly used to describe the benign invasion of endometrial stromal and glandular cells into the myometrium, leading to an increase in the size of the uterus due to hypertrophy and hyperplasia of adjacent myocytes [1, 2].
According to various sources, the prevalence of adenomyosis varies widely - from 5 to 70% [3], which is apparently due to the methodology of diagnosis. Histopathologically, adenomyosis is detected in 20–30% of cases during hysterectomies [4–9]. In at least 70% of patients, the diagnosis is made before menopause, which is typical for hormone-dependent diseases of the genital organs [9]. In addition, there is an opinion about the existence of ethnic groups among which adenomyosis is more common [8]. Regardless of the true prevalence of this disease, it is one of the most serious due to the scale of the impact it has on the female genital area.
With severe adenomyosis, the patient is often offered a hysterectomy. It is known that, even despite the development of new approaches to preoperative preparation and postoperative management of patients, removal of the uterus is accompanied by a decrease in the quality of life of women [10]. This forces scientists to look for alternative ways to solve the problem. Radical surgical approaches are not acceptable for patients who want to preserve their reproductive potential.
Today, drug therapy is used much more widely, aimed at relieving the symptoms of the disease or temporary regression of foci of adenomyosis. Nonsteroidal anti-inflammatory drugs (NSAIDs), combined oral contraceptives (COCs), gestagens, danazol, and gonadotropin-releasing hormone agonists (GnRH agonists) are used [10]. Each group of drugs has its own advantages and disadvantages. NSAIDs effectively relieve pain, but do not affect the intensity of bleeding and do not have a pathogenetic effect on the heterotopic endometrium [11]. GnRHa therapy has a positive effect on the pregnancy rate in subsequent natural cycles or in vitro fertilization cycles of women with endometriosis [12]. Moreover, the frequent combination of endometriosis and uterine fibroids allows the use of GnRH agonists to simultaneously reduce the size of fibroids [13, 14]. However, GnRH therapy is characterized by the development of hypoestrogenic disorders [15] and cannot be prescribed for a long period.
The effectiveness of danazol is not inferior to GnRHa, but its use is associated with the development of serious side effects [16], which significantly complicates its use in modern practice. COCs are known for their good tolerability profile and the possibility of long-term use in the treatment of endometriosis [17], however, they are not without drawbacks, because have no registered indication for the treatment of endometriosis. A number of conditions and diseases (see table) limit the widespread use of COCs (Medical criteria for the acceptability of contraception in the Russian Federation, 2012):
- women over 35 years of age who smoke or quit smoking less than a year ago;
- history/current history of deep vein thrombosis, pulmonary embolism;
- arterial hypertension (uncorrected);
- presence of thrombogenic mutations;
- the first 6 months after childbirth while maintaining breastfeeding;
- cholestasis while taking COCs;
- surgery with prolonged immobilization;
- complicated valvular heart defects;
- diabetes mellitus with a disease duration of more than 20 years or in the presence of vascular complications;
- acute hepatitis (at the time of initiation of therapy).
Progestins are a group of drugs that have antigonadotropic properties, which suppress hormonal stimulation of endometrioid cells. Under the influence of gestagens, a decrease in proliferative activity in foci of endometriosis also occurs [18]. Drugs in this group can be prescribed for a long time and have a much smaller list of contraindications than gestagens combined with estrogens.
In recent years, the effectiveness of dienogest at a dose of 2 mg per day for patients with genital forms of endometriosis has been actively studied. Among the works devoted to this topic, very little attention is paid to the issue of using dienogest for adenomyosis [19–21]. We analyzed the results of treatment of 42 women with a diffuse form of adenomyosis by prescribing dienogest at a dose of 2 mg per day continuously for 12–14 months. The age of the women averaged 38±4.9 years. The main diagnosis of adenomyosis in each patient was confirmed by transvaginal ultrasound and magnetic resonance imaging. In half of the cases (47.6%; n=20), the patients previously underwent hysteroscopy for benign hyperplastic processes of the endometrium, in which expansion of the cavity was noted (45%), unevenness of the uterine walls (40%), increased vascular pattern of the uterus (15% ) and narrowing in the area of the orifices of the fallopian tubes (5%). The remaining 22 (52.4%) patients previously underwent laparoscopy for diseases of the uterine appendages (tumor-like formations of the ovaries - 91%, hydrosalpinx - 9%). During the operation, the uterus of all patients had a spherical shape; in 32%, endometrioid heterotopias were present on the pelvic peritoneum and/or uterosacral ligaments. In our observations, we encountered both normal and “marbled” coloration of the serous cover of the uterus, and this sign did not correlate in any way with the degree of endometrioid damage.
In the structure of complaints, menorrhagia occupied first place (74%). Intermenstrual bleeding from the genital tract bothered 4 (9.5%) women. Clinical and laboratory examination revealed mild anemia in 11 patients and moderate anemia in 9 (26 and 21.4%, respectively). Dysmenorrhea occurred in 28.6% of patients. The patients underwent a complete clinical and laboratory examination before the start of therapy and after a year of treatment, incl. biochemical blood test and indicators of the blood coagulation system, measurement of blood pressure, body weight, ultrasound, MRI. After 1 and 3 months from the start of taking dienogest, an additional assessment of the biochemical profile of the blood, hemoglobin level and coagulation parameters was carried out. At each visit, patients assessed their pain using a psychometric visual analogue scale, the intensity and number of days of bleeding, and the presence of adverse events.
Analysis of the results showed that by the end of the first, third and twelfth months of treatment 41.7; 66.7 and 91.7% of patients, respectively, noted a significant reduction in pain. By the end of the third month of treatment, all women noted normalization of the volume of menstrual blood loss. An increase in hemoglobin to a level of ≥ 120 g/l over the same period occurred in 16 of 20 (80%) patients. By the end of the 12th month of treatment, hemoglobin levels returned to normal in all patients.
Dienogest at a dose of 2 mg showed its metabolic neutrality. There were no statistically significant changes in glucose, low-density lipoprotein, very low-density lipoprotein, high-density lipoprotein, cholesterol, or triglyceride levels throughout the follow-up period. Indicators of the blood coagulation system (clotting time, activated partial thromboplastin time, prothrombin index, fibrinogen concentration, thrombin time and soluble fibrin-monomer complex, as well as blood pressure also remained within normal values. During control ultrasound examinations after treatment with dienogest 2 mg/ days for 12 months, a positive change was noted in all patients. The homogeneity of the myometrial structure increased, the “cellularity and reticulation” of the myometrium disappeared, the clarity of the boundaries between the myo- and endometrium increased. The least changes affected the “picket fence” symptom, apparently due to the irreversibility of fibrous -sclerotic changes in the wall of the uterus. In 95% of cases, a decrease in the size of the uterus by 54–102 cm3 was noted.
By the end of the year of taking the drug, an increase in body weight was recorded in 7.1% of patients, on average by 2.2% of the initial body weight. Complaints of periodic headaches were made by 9.5% of patients, and increased oiliness of the facial skin and acne – by 2.3%. Breakthrough bleeding in the first three months of treatment was noted by 30.9% of patients. By the end of the first year of treatment – 9.5%. Mostly they had the character of scanty discharge (“spotting”, 87%), and the duration of each episode was 5±3.2 days. Interestingly, a similar number of women complained of intermenstrual bleeding before treatment. Patients often noted amenorrhea, which can be regarded as a favorable result of treatment. After a year of dienogest therapy, 35.7% of women had no menstrual-like reactions, as well as breakthrough bleeding. Our observations have shown that when prescribing dienogest therapy (2 mg) to patients with a diffuse form of adenomyosis, not only is there an improvement in their well-being and clinical manifestations of the disease, but there are also reliable instrumental and laboratory markers of the safety and effectiveness of therapy.
Further full-scale studies will make it possible to evaluate the place of dienogest in the treatment of combined hyperplastic diseases of the myometrium, compare its effectiveness with other groups of drugs, and justify the optimal duration of treatment for various forms of the disease.
