Gestoden, Ethinyl estradiol

Pharmacological properties

Lindynette 20 and Lindynette 30 - a combined oral contraceptive. blocks the action of gonadotropins. the primary effect is manifested by inhibition of ovulation. the use of the drug leads to a change in the characteristics of cervical mucus, which complicates the penetration of sperm into the uterine cavity and affects the endometrium, thereby reducing the possibility of implantation of a fertilized egg. all this helps prevent pregnancy.

Oral contraceptives, in addition to preventing pregnancy, have a number of positive properties.

Regulatory effect on the menstrual cycle. The monthly cycle becomes regular, the frequency of dysmenorrhea decreases. Blood loss and iron loss during menstruation are reduced.

Effects associated with inhibition of ovulation. The incidence of functional ovarian cysts and ectopic pregnancy is reduced.

Other effects. The incidence of fibroadenomas and fibrocysts in the mammary glands, inflammatory processes in the pelvic organs, the risk of endometrial cancer, and the skin condition with acne are reduced.

Pharmacokinetics Guestoden. Suction. Gestoden is rapidly and almost completely absorbed after oral administration. C_max in blood plasma 1 h after administration, it is 2-4 ng / ml. Bioavailability is about 99%.

Distribution. In blood plasma, gestodene binds to albumin and sex hormone-binding globulin. About 1–2% of the steroid is in free form, 50–75% specifically binds to globulin. By increasing the level of sex hormone-binding globulin in the blood, ethinyl estradiol increases the gestodene fraction associated with it and decreases its fraction associated with albumin. The average distribution volume of gestodene is 0.7–1.4 l / kg body weight.

Gestoden metabolism is carried out along the pathway characteristic of all steroids. The average plasma clearance is 0.8–1.0 ml / min / kg body weight.

Selection. The level of gestoden in the blood plasma decreases two-phase. T_½ in the terminal phase - 12–20 hours

It is excreted only in the form of metabolites: 60% - with urine, 40% - with feces. T_½ metabolites - about 24 hours

Stage of saturation. The pharmacokinetics of gestodene depends on the level of sex hormone binding globulin. The concentration in the blood of a globulin that binds sex hormones increases by 3 times under the action of ethinyl estradiol. With daily intake, the level of gestoden in the blood plasma rises 3-4 times and is balanced in the second half of the cycle.

Ethinyl estradiol. Suction. After oral administration, ethinyl estradiol is rapidly and almost completely absorbed. C_max in blood plasma is achieved 1–2 hours after administration and is 30–80 pg / ml. Bioavailability due to presystemic conjugation and metabolism is about 60%.

Distribution. Ethinyl estradiol completely but non-specifically binds to albumin (about 98.5%) and induces an increase in the level of globulin that binds sex hormones in the blood plasma. The average volume of distribution is 5–18 l / kg body weight.

Metabolism. Ethinyl estradiol is mainly metabolized by aromatic hydroxylation, resulting in the formation of hydroxylated and methylated metabolites present in the form of free metabolites or in the form of conjugates (glucuronides and sulfates). The clearance of ethinyl estradiol from blood plasma is about 5–13 ml / min / kg body weight.

Selection. The concentration in the blood plasma decreases two-phase. T_½ in the second phase - 16-24 hours. Ethinyl estradiol is excreted only in the form of metabolites with urine and bile in a ratio of 2: 3. T_½ metabolites - about 24 hours

Stage of saturation. The equilibrium concentration is established by the 3-4th day of administration, and the level of ethinyl estradiol in blood plasma is 20% higher than after a single dose.

Indications

Oral contraception.

Application

The drug should be taken within 21 days, 1 tablet per day (if possible at the same time). then take a 7-day break. during the 7-day break, menstrual bleeding appears due to drug withdrawal. usually bleeding begins on the 2nd or 3rd day after taking the last pill and may not end before taking the pill from the next pack. the day after a 7-day break, they start taking tablets from the next package containing 21 tablets.

The first dose of the drug. Lindynette 20 and Lindynette 30 should begin to be taken from the 1st day of the menstrual cycle.

You can start taking pills from the 2nd to the 5th day of menstruation, but in this case, you must use additional non-hormonal contraceptives during the first 7 days of taking the tablets during the first cycle.

Switching to Lindynette 20 or Lindynette 30 with another combined oral contraceptive. The first pill, Lindynette 20 or Lindynette 30, should be taken after taking the last pill from a previous package of another oral hormonal contraceptive on the 1st day of menstrual bleeding, but no later than one day after a break in taking tablets (or using a placebo) from the previous package of oral contraceptives.

Switching to taking Lindynette 20 or Lindynette 30 with preparations containing only a progestogen (mini-pill, injection, implant or intrauterine system). With mini-drank you can go on taking Lindynette 20 or Lindynette 30 on any day of the cycle. From the implant, you can switch to Lindynette 20 or Lindynette 30 the next day after removal of the implant or intrauterine system; after the use of injection solution - on the day when it is necessary to conduct another injection, instead of injection.

In such cases, in the first 7 days it is necessary to apply additional methods of contraception.

Taking Lindynette 20 or Lindynette 30 after an abortion in the first trimester of pregnancy. After an abortion, you can take the drug immediately; in this case, there is no need for an additional method of contraception.

Taking the drug Lindynette 20 or Lindynette 30 after childbirth or after an abortion performed in the II trimester of pregnancy. Information on the use of the drug during lactation is described in the section "Use during pregnancy and lactation."

Women who do not breast-feed should start taking the drug 21–28 days after birth or abortion in the second trimester of pregnancy. If a woman decides to take pills later than 21–28 days after giving birth or abortion, then additional contraceptive methods must be used in the first 7 days.

If there was sexual contact after childbirth or abortion, pregnancy should be excluded before taking the drug or wait for the first menstruation.

Skipping the drug. If the break in admission was less than 12 hours, then the effectiveness of the drug will not decrease. If the drug was missed, the missed tablet should be taken immediately as soon as it turns out. The next tablet from this package should be taken at the usual time.

If the interval in taking the drug was more than 12 hours, its effectiveness may be reduced. In this case, two basic rules must be followed:

1. A break in taking pills can never be more than 7 days.

2. Adequate inhibition of the hypothalamus-pituitary-ovary system is achieved by continuous use of the drug for 7 days.

Accordingly, in everyday life should be guided by the following recommendations:

1st week. A woman should take the last missed pill as soon as possible, even if she has to take two tablets at the same time. After that, she continues to take pills at the usual time.In addition, over the next 7 days it is necessary to use a barrier method of contraception, such as a condom. If sexual intercourse took place in the previous 7 days, the possibility of pregnancy should be considered. The more missed pills and the closer the pass to the 7-day break in taking the drug, the higher the risk of pregnancy.

2nd week. A woman should take the last missed pill as soon as possible, even if she has to take two tablets at the same time. After that, she continues to take pills at the usual time. If a woman took the pill correctly for 7 days before skipping, there is no need to use additional contraceptives. Otherwise, or when skipping more than one tablet, it is recommended to additionally use the barrier method of contraception for 7 days.

3rd week. The probability of a decrease in the contraceptive effect is significant due to the upcoming 7-day break in the use of the drug. However, if you follow the pill regimen, you can avoid a decrease in contraceptive protection. If you adhere to one of the options below, then there will be no need to use additional contraceptives provided that the dragee is correctly taken for 7 days before the pass. If this is not the case, it is recommended that you stick to the first of the options below and use additional methods of contraception over the next 7 days.

1. A woman should take the last missed pill as soon as possible, even if she has to take two tablets at the same time. After that, she continues to take pills at the usual time. Reception of tablets from a new package should be started immediately after the previous one, that is, there should be no interruption in taking the drug. It is unlikely that menstrual bleeding will begin before the end of taking the tablets from the second package, although spotting or spotting bleeding may occur.

2. You may also be advised to stop taking the tablets from the current package. In the second case, the break in taking the drug should be 7 days, including days of skipping pills; taking the drug should start from the next package.

If you missed taking pills and there is no menstrual bleeding during the first usual break in taking the drug, you should consider the likelihood of pregnancy.

Vomiting measures. If vomiting begins within 3-4 hours after taking the drug, its active components are not completely absorbed. This situation should be regarded as a missed drug and act accordingly. If the patient does not want to violate the regimen, missed tablets should be taken from an additional package.

Delay or accelerate the onset of menstruation. To delay menstruation, the drug should be continued from the new package without interruption. Menstruation can be delayed as much as necessary, until the end of taking the last pill from the second package. With a delay in menstruation, breakthrough or spotting bleeding may occur. Regular intake of Lindynette 20 or Lindynette 30 can be restored after a typical 7-day break.

In order to accelerate the onset of menstruation, a 7-day break in taking the drug is reduced by the desired number of days. The shorter the break in taking the drug, the more likely that menstrual bleeding will not occur, and breakthrough or spotting bleeding will appear when taking the drug from the next package.

Contraindications

Pregnancy or suspected pregnancy bleeding from the genitals of an unknown etiology; history or references to arterial or venous thromboembolic diseases (e.g. deep vein thrombophlebitis, pulmonary thromboembolism, cerebrovascular disorders, myocardial infarction); the presence of a risk of arterial or venous thromboembolism (bleeding disorders, heart disease, atrial fibrillation); history of thrombosis prodromal symptoms (transient cerebral ischemic attack,angina pectoris); cardiovascular disorders (pathology of the valve (s) of the heart, arrhythmias); heavy ag; the presence of a benign or malignant tumor or severe liver disease; the presence in the history of malignant tumors of the uterus or mammary glands; diagnosed or suspected malignant tumors of the endometrium or other estrogen-dependent neoplasms; vascular ophthalmopathy; a history of herpes in pregnancy; sickle cell anemia; hyperlipidemia; diabetic angiopathy; migraine with focal neurological symptoms; pancreatitis now or in history, if it is associated with severe hypertriglyceridemia; a history of cholestatic jaundice or itching during pregnancy; the progression of otosclerosis during a previous pregnancy; Dubin-Johnson syndrome, rotor syndrome; hypersensitivity to any of the components of the drug.

Side effects

In the first period of taking the drug in 10-30% of women, such side effects can be noted: breast engorgement, poor health, spotting bleeding. these side effects are usually mild and disappear after 2–4 cycles.

Other possible adverse reactions

In women taking oral contraceptives, vaginitis, fluid retention, mood changes, headache, nausea, vomiting, acne, a change in the menstrual cycle, tension of the mammary glands, changes in body weight and libido are possible.

The use of oral contraceptives is associated with an increased risk of developing the following conditions:

• arterial and venous thrombotic and thromboembolic complications, including myocardial infarction, stroke, venous thrombosis and pulmonary embolism;
• cervical intraepithelial neoplasia and cervical cancer;
• mammary cancer;
• benign tumors of the liver (focal nodular hyperplasia).

Infections and infestations: vulvovaginal candidiasis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): breast cancer, hepatocellular carcinoma, liver adenoma.

On the part of the blood and lymphatic system: hemolyticouremic syndrome.

On the part of the immune system: anaphylactic reactions, urticaria, angioedema, severe allergic reactions with respiratory failure and circulatory symptoms, exacerbation of systemic lupus erythematosus, exacerbation of porphyria.

Disorders of nutrition and metabolism: fluid retention, decreased or increased appetite, bloating, decreased glucose tolerance, hyperlipidemia, hypertriglyceridemia, ischemic colitis, inflammatory bowel disease (Crohns disease, ulcerative colitis).

Mental disorders: mood changes, depression, decreased or increased libido, irritability, nervousness.

From the side of the nervous system: migraine, headache, dizziness, exacerbation of chorea, optic neuritis (can lead to partial or complete loss of vision), stroke (LLT).

From the side of the organ of vision: intolerance to contact lenses, retinal artery thrombosis.

From the side of the organ of hearing and balance: otosclerosis.

From the side of the heart: myocardial infarction.

From the cardiovascular system: hypertension, thrombosis, embolism.

From the digestive tract: nausea, vomiting, abdominal pain, pancreatitis.

From the liver and biliary tract: gallbladder disease, gallstone disease *, hepatocellular damage (including hepatitis and impaired liver function).

* The use of combined oral contraceptives can aggravate the course of an existing gallbladder disease and accelerate the development of the disease in women who have not previously noted symptoms of the disease.

On the part of the skin and subcutaneous tissue: acne, chloasma (LLT melasma), hirsutism, alopecia, erythema nodosum, erythema multiforme.

From the reproductive system and mammary glands: breakthrough bleeding, spotting between menstruation, pain in the mammary glands, engorgement of the mammary glands.

Laboratory indicators: decrease or increase in body weight, decrease in folate levels.

Serious and other adverse events are described in the SPECIAL INSTRUCTIONS section.

special instructions

Circulatory system diseases. oral contraceptives increase the risk of myocardial infarction. it is higher in women smokers who have additional risk factors (ag, hypercholesterolemia, obesity and diabetes).

Smoking significantly increases the risk of cardiovascular complications that may occur with oral contraceptives. This risk increases with age, therefore, women over the age of 35 years and those who smoke a lot, significantly increases the risk of cardiovascular complications. Women who take oral contraceptives are advised to stop smoking.

Lindynette 20 and Lindynette 30 should be prescribed with caution to women at risk for cardiovascular disease.

The use of oral contraceptives increases the risk of developing cerebrovascular diseases (ischemic and hemorrhagic stroke) and venous thromboembolic disorders.

An increase in blood pressure has been reported in women taking oral contraceptives. Increased blood pressure is more often observed in older women, as well as with prolonged use.

The data obtained indicate that the incidence of hypertension increases depending on the amount of estrogen.

For women who have previously noted high blood pressure or diseases accompanied by high blood pressure or who have had kidney disease, another method of contraception should be recommended. If, despite this, a woman with hypertension wants to take oral contraceptives, her condition needs strict control and with a significant increase in blood pressure, the drug should be discontinued.

In most women, blood pressure after discontinuation of the drug returns to normal, and in the future, an increased risk of hypertension is uncharacteristic.

Venous and arterial thrombosis and thromboembolism. The use of combined oral contraceptives is associated with an increased risk of venous and arterial thrombotic and thromboembolic complications. For each particular combination of estrogen / progestogen, a dosing regimen should be applied that contains the minimum amount of estrogen and progestogen and at the same time provides a low failure rate that meets the needs of the patient.

Venous thrombosis and thromboembolism. The use of any combined oral contraceptives (CPC) leads to an increased risk of venous thromboembolic diseases (VTZ).

The additional risk of developing VTZ increases in the first year of using CPC in women who have not yet taken such drugs. This risk is much lower than the risk of VTZ of pregnant women. Of the 100,000 pregnant women, approximately 60 have VTZ, and 1–2% of all cases of VTZ have a fatal outcome.

The incidence of VTZ in women taking 50 μg or less of ethinyl estradiol in combination with levonorgestrel is about 20 cases per 100 thousand women per year. The incidence of VTZ in women taking gestoden in combination is about 30–40 cases per 100 thousand women per year.

The risk of thromboembolism (arterial and / or venous) is increased:

• with age;
• when smoking (excessive smoking and age, especially over 35 years old, are additional risk factors);
• with a burdened family history (for example, diseases of a father or brother, sister at a young age). If there is an inborn tendency to thromboembolic diseases, it is necessary to consult a specialist before using the drug;
• for obesity (body mass index 30 kg / m²);
• with impaired fat metabolism (dyslipoproteinemia);
• with hypertension;
• with migraine;
• with diseases of the heart valves;
• with atrial fibrillation;
• with prolonged immobilization, heavy operations, operations on the lower extremities, severe injuries. Due to the fact that the risk of thromboembolic diseases increases in the postoperative period, it is proposed to stop taking the drug 4 weeks before surgery and start taking 2 weeks after remobilization of the patient.

Since the period immediately after childbirth is associated with an increased risk of thromboembolism, taking Lindynette 20 or Lindynette 30 should not begin earlier than on the 28th day after childbirth or abortion in the second trimester of pregnancy.

Arterial thrombosis and thromboembolism. When taking Lindynette 20 or Lindynette 30, the risk of developing arterial thrombotic and thromboembolic complications increases. The described complications include myocardial infarction and cerebrovascular disorders (ischemic and hemorrhagic stroke, transient ischemic attack). The risk of developing arterial thrombotic and thromboembolic complications is higher in women with additional risk factors.

Lindynette 20 or Lindynette should be prescribed with caution to 30 women with a risk of developing thrombotic and thromboembolic complications.

Women suffering from migraine and taking PDA (especially for migraines with aura) are characterized by an increased risk of stroke.

The use of the drug should be stopped immediately if such signs of thromboembolism appear: chest pain radiating to the left arm, unusually intense pain in the lower extremities, swelling of the legs, stitching pain when inhaling or coughing, hemoptysis.

Biochemical indicators indicating a tendency to thromboembolic diseases: resistance to activated protein C (APC), hyperhomocysteinemia, deficiency of antithrombin III, protein C and protein S, the presence of antiphospholipid antibodies (anticardiolipin, lupus anticoagulant).

Tumors Some studies have reported more frequent cases of cervical cancer in women who have been taking oral contraceptives for a long time, but the results are mixed. The likelihood of developing cervical cancer depends on sexual behavior and other factors (such as the human papillomavirus).

Cases of breast cancer in women taking oral contraceptives have been reported clinically at an earlier stage than in women not taking these drugs.

There are few reports of the development of a benign liver tumor in women who have been taking hormonal contraceptives for a long time.

An association has been established between the occurrence of benign liver tumors and the administration of oral contraceptives, although such benign tumors are rarely detected. When these tumors rupture, intra-abdominal bleeding is noted, which can lead to death.

In women taking oral contraceptives for a long time, the development of a malignant tumor of the liver was occasionally noted.

In patients with a history of cholestatic jaundice or itching during pregnancy, as well as in patients who have previously taken combined oral contraceptives, the risk of developing these diseases is higher. In the event that such patients take Lindynette 20 or Lindynette 30, careful monitoring of their condition is necessary, and if the disease recurs, the use of the drug must be stopped.

Other conditions. With the use of oral contraceptives, retinal vascular thrombosis can sometimes develop. The drug should be discontinued in case of loss of vision (full or partial), exophthalmos, diplopia, with swelling of the optic nerve nipple or irregularities in the vessels of the retina and undergo an additional medical examination.

According to studies, the relative risk of gallstone formation increases with age in women taking oral contraceptives or drugs containing estrogen. Recent studies have shown that the risk of gallstone disease is low when using drugs containing hormones in a low dose.

If there is or an increase in the severity of migraine attacks, the appearance of a constant or repeated unusually intense headache, the drug should be discontinued.

Lindynette 20 or Lindynette 30 tablets should be stopped immediately if itching occurs or when an epileptic seizure develops.

Effect on carbohydrate and lipid metabolism. In women taking Lindynette 20 or Lindynette 30, a decrease in carbohydrate tolerance may be noted. Therefore, women with diabetes taking Lindynette 20 or Lindynette 30 should be closely monitored.

In some women, when using an oral contraceptive, an increase in the level of triglycerides in the blood was detected. A number of progestogens lower HDL. Due to the fact that estrogen increases the level of HDL cholesterol in plasma, the effect of Lindynette 20 or Lindynette 30 on lipid metabolism depends on the balance between estrogens and progestogen and on the dose and form of progestogen.

Careful monitoring of the condition of women with hyperlipidemia is needed, who, despite this, decided to take contraceptives.

In women with hereditary hyperlipidemia, taking the drug with estrogen, there was a sharp increase in the level of triglycerides in the blood plasma, which could lead to the development of pancreatitis.

Menstrual irregularities. When using the drug Lindynette 20 or Lindynette 30, especially in the first 3 months, irregular (breakthrough) bleeding may appear. If such bleeding is present for a rather long time or appears after regular cycles have formed, their cause is usually non-hormonal; it is necessary to conduct an appropriate gynecological examination to exclude pregnancy or malignant neoplasms. If a non-hormonal cause is excluded, you should switch to another drug.

In some cases, menstrual bleeding drug withdrawal within a 7-day break does not appear. If the regimen for the use of the drug is violated before the absence of bleeding, or if there is no bleeding after taking the last tablet from the second package, pregnancy should be excluded before continuing with the drug.

Conditions requiring special care

Medical checkup. Before using Lindynette 20 or Lindynette 30, you should collect a detailed family history and undergo a general medical and gynecological examination. These studies should be repeated regularly. During a physical examination, you need to measure blood pressure, examine the mammary glands, palpate the stomach, conduct a gynecological examination with the study of a cytological smear, as well as laboratory tests.

A woman must be warned that the drug does not protect her from sexually transmitted infections, in particular from AIDS.

Liver function. In acute or chronic dysfunction of the liver, the use of the drug should be discontinued until the liver enzymes normalize. With a violation of the activity of liver enzymes, the metabolism of steroid hormones can be disrupted.

Affective disorder. It is advisable for women who develop depression when taking contraceptives to discontinue the drug and temporarily switch to another method of contraception until the cause of the depression is determined. Women who have previously experienced depression should be closely monitored, and when a relapse occurs, the use of an oral contraceptive should be discontinued.

Folate level. With the use of oral contraceptives, the level of folic acid in the blood may decrease. This is of clinical significance only when conception occurs shortly after completion of an oral contraceptive course.

Chloasma.The occurrence of chloasma is especially characteristic of women with a history of pregnant chloasma. Women prone to chloasma should avoid exposure to the sun, as well as the effects of ultraviolet radiation while taking PDAs.

Other In addition to the above conditions, it is necessary to pay special attention to the condition of a woman in the presence of the following diseases: otosclerosis, multiple sclerosis, epilepsy, small chorea, intermittent porphyria, tetanic conditions, renal failure, obesity, systemic lupus erythematosus, uterine fibroids.

Under the influence of oral contraceptives, the level of some laboratory parameters (indicators of the function of the liver, kidneys, adrenal glands, thyroid gland, blood coagulation and fibrinolytic factors, lipoproteins and transport proteins) may change. Despite this, the indicators remain within normal limits.

Patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactase malabsorption syndrome should not use the drug.

Patients with rare hereditary forms of fructose intolerance, sucrose-isomaltase deficiency or glucose-galactose malabsorption syndrome should not use the drug.

Use during pregnancy and lactation. Before taking Lindynette 20, pregnancy should be excluded.

If pregnancy has occurred during the period of use of the drug, it is necessary to immediately stop taking oral contraceptives.

Extensive epidemiological studies have not identified an increased risk of congenital malformations in newborns born to women who took oral contraceptives before pregnancy, nor teratogenic effects (in particular, heart disease and limb developmental abnormalities) in cases where oral contraceptives were inadvertently taken in the early stages pregnancy.

The use of hormonal contraceptives during breastfeeding is not recommended, since these drugs penetrate into milk in a small amount, reduce its excretion and change the composition.

Children. The drug is not used in children.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Studies on the possible effect of the drug on the ability to drive vehicles or work with other mechanisms have not been conducted.

Interactions

The interaction between ethinyl estradiol and the drugs used simultaneously can lead to an increase or decrease in the level of ethinyl estradiol in the blood plasma.

A decrease in the level of ethinyl estradiol in the blood plasma can lead to an increase in the number of breakthrough bleeding and menstrual irregularities, sometimes a decrease in the contraceptive effect of the drug Lindynette 20 or Lindynette 30 is also noted. Therefore, with the simultaneous use of ethinyl estradiol and drugs that reduce the level of ethinyl estradiol in the blood plasma, in addition to taking Lindynette 20 or Lindynette 30 is recommended to use non-hormonal methods of contraception (for example, condoms, spermicides). In the event that prolonged use of drugs containing such active substances is necessary, the possibility of refusing to use hormonal contraceptives as the main method of contraception should be considered.

After stopping the use of drugs that reduce the concentration of ethinyl estradiol in the blood, it is recommended to use additional non-hormonal methods of contraception for at least 7 days. After stopping the use of drugs that can induce the induction of microsomal liver enzymes and lead to a decrease in the concentration of ethinyl estradiol in the blood plasma, it is recommended to use additional non-hormonal methods of contraception for a longer period. Sometimes, depending on the dose, duration of treatment and the rate of excretion of the drug that caused the induction of enzymes, it may take weeks before the induction of liver enzymes completely stops.

Active substances that can reduce the concentration of ethinyl estradiol in blood plasma:

• any active substance that shortens the passage through the digestive tract and, therefore, reduces absorption;
• substances that induce microsomal liver enzymes, such as rifampicin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, griseofulvin, topiramate, some protease inhibitors, modafinil, carbamazepine, oxx