Dieciklen®
If any of the following conditions/diseases or risk factors are present, the potential risks and expected benefits of using the drug 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/diseases or risk factors appear when using this drug, you should consult your doctor, who may decide whether to discontinue the drug.
Thrombosis
Thrombosis 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 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 when restarting 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, however, 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, for example, the veins and arteries of the liver, mesentery, kidneys, brain or retina.
Symptoms of deep vein thrombosis
include the following: unilateral swelling of the lower extremity or along a vein in the lower extremity, pain and discomfort in the lower extremity only in an upright position or when walking, local increase in temperature in the affected lower extremity, redness or discoloration of the skin on the lower extremity.
Symptoms of pulmonary embolism
are as follows: 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; cardiopalmus. 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).
If the above symptoms occur in women taking COCs, you should immediately consult your doctor.
The risk of developing 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 quit smoking if they want to take Diecyclen®);
- 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 stop using COCs (in the case of a planned operation, at least 4 weeks in advance) and not resume it until two weeks have passed after complete restoration of motor activity; if the use of Diecyclen® has not been discontinued in advance, antithrombotic therapy should be considered;
— air flight lasting more than 4 hours;
— for obesity (body mass index >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 quit smoking if they want to take Diecyclen®);
- 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, SLE, hemolytic uremic syndrome, chronic inflammatory bowel disease (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 and severity of migraine attacks during the use of COCs (which may be a harbinger of cerebrovascular accident) is a reason for the immediate discontinuation of these drugs.
There is no consensus regarding the potential role of varicose veins and superficial thrombophlebitis in the development of VTE.
Tumors
The most significant 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, 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 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 breast cancer diagnoses in women taking or previously taking COCs is small compared with the overall risk of this disease. 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. Women who are taking or have previously taken COCs are diagnosed with earlier stages of breast cancer than women who have never taken 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 with hypertriglyceridemia or 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 COCs, Diecyclen® should be discontinued and treatment of arterial hypertension initiated. The drug can be continued if normal blood pressure values are achieved with antihypertensive therapy.
The drug should be discontinued in case of acute and chronic liver dysfunction until all indicators of liver function return to normal. Relapses of cholestatic jaundice that occurred for the first time during pregnancy or the period preceding it during the use of COCs also require discontinuation of the drug.
The use of COCs may cause the onset 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; SLE; hemolytic-uremic syndrome; chorea; herpes during pregnancy; hearing impairment 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 ultraviolet radiation while using COCs.
The disappearance of acne symptoms is usually observed after 3-4 months of therapy.
Women should be warned that Diecyclen® does not protect them from HIV infection and other sexually transmitted diseases.
Decrease in efficiency
The contraceptive effectiveness of COCs may be reduced, for example, in case of missing pills, in the case of gastrointestinal disorders (vomiting, diarrhea) or simultaneous use of other medications.
Cycle irregularity
While taking any COC, irregular bleeding may occur (“spotting” or “breakthrough” bleeding), especially in the first months of taking the pills. Bleeding usually stops as the body adapts to Diecyclen® (usually after three cycles of taking the tablets). If bleeding continues and its severity increases, you should consult a specialist.
Absence of another bleeding “oooContraindications”, “With caution”);
- with local compaction in the mammary gland;
- if she plans to use other medications (see section “Interaction with other medications”);
- if long-term immobilization is expected (for example, a plaster cast is applied to the leg), hospitalization or surgery is planned (you must consult a doctor 4-6 weeks before);
- if unusually heavy uterine bleeding occurs;
- if a woman forgot to take a pill in the first week of taking the package (blister) and had sexual intercourse a week before;
- if a woman has not had withdrawal bleeding twice in a row or she suspects that she is pregnant (you cannot start taking pills from the next package (blister) until she consults with your doctor).
DIECYCLENE
Pharmacokinetics
Ethinyl estradiol
Absorption:
When taken orally, it is quickly and completely absorbed. The maximum concentration of estradiol in the blood plasma (about 67 pg/ml) is achieved after 1.5-4 hours. After absorption and the “first pass” effect through the liver, ethinyl estradiol is metabolized, its absolute bioavailability when administered orally is about 44%.
Distribution:
Ethinyl estradiol binds significantly to serum albumin (approximately 98%) and induces the synthesis of sex hormone binding globulin (SHBG) in plasma. The volume of distribution of ethinyl estradiol is approximately 2.8-8.6 l/kg.
Metabolism:
Ethinyl estradiol undergoes presystemic conjugation both in the mucous membrane of the small intestine and in the liver. The main route of metabolism is aromatic hydroxylation with the formation of a variety of hydroxylated and methylated derivatives in the form of free metabolites, glucuronide metabolites and sulfates. The clearance rate from plasma is approximately 2.3-7 ml/min/kg.
Excretion from the body:
Up to 30-50% of ethinyl estradiol metabolites are excreted by the kidneys, 30-40% through the intestines. The half-life of estradiol (T1/2) does not exceed 10 hours after a single dose of 1 tablet and increases to 15 hours after 3 cycles of taking the drug.
Equilibrium concentration
ethinyl estradiol in blood plasma when taken regularly
achieved in the second half of the cyclic dosing of the drug
Dienogest
Suction:
When taken orally, it is quickly and almost completely absorbed. The maximum concentration of dienogest in the blood serum (about 51 pg/ml) is achieved after 2.5 hours. The absolute bioavailability of dienogest is 96%, the equilibrium concentration in the blood plasma with continuous use is achieved after 4 days.
Distribution:
90% of the total plasma concentration of dienogest is bound to serum albumin, but not to SHBG or corticosteroid binding globulin. 10% of the total concentration of dienogest in the blood plasma is found in unbound form. The volume of distribution of dienogest is about 37-45 liters.
Metabolism:
Metabolized primarily by hydroxylation, but also by hydrogenation, conjugation and aromatization to form inactive metabolites. After taking a single dose, the total clearance of dienogest is about 3.6 l/h.
Removal:
After taking a dose of 0.1 mg/kg, the ratio of dienogest excretion in the form of metabolites by the kidneys and through the intestines is 3:1. Only a small amount of unchanged dienogest is excreted by the kidneys. The half-life (T1/2) of dienogest is approximately 8.5-10.8 hours. After oral administration, 86% of the dose of dienogest is excreted within 6 days; a significant part of it is excreted in the first 24 hours after administration, mainly by the kidneys.
Equilibrium concentration.
Induction of globulin synthesis by ethinyl estradiol does not affect the pharmacokinetics of dienogest. With daily use of the drug, the concentration of dienogest in the serum increases by 1.5 times.
