Divigel gel transdermalny 0,1% 500mg N28
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Active ingredients
Estradiol
Release form
Gel
Composition
Active ingredient: Estradiol Concentration of active ingredient (mg): 1 mg
Pharmacological effect
Estrogen preparation for external use. The active ingredient of the drug Divigel - synthetic 17β-estradiol, chemically and biologically identical to endogenous human estradiol, produced in the body of women by the ovaries, from the first menstruation until menopause. Estrogens form a complex with specific receptors found in cells of various target organs - in the uterus, vagina, urethra, breast, liver, hypothalamus, pituitary. The receptor ligand complex interacts with the estrogen effector elements of the genome and specific intracellular proteins that induce the synthesis of mRNA, proteins and the release of cytokines and growth factors. It has a feminizing effect on the body. Stimulates the development of the uterus, fallopian tubes, vagina, stroma and ducts of the mammary glands, pigmentation in the nipples and genitals, the formation of secondary sexual characteristics of the female type, growth and closure of the epiphysis of the long bones. Promotes timely rejection of the endometrium and regular bleeding, in high concentrations causes endometrial hyperplasia, suppresses lactation, inhibits bone resorption, stimulates the synthesis of a number of transport proteins (thyroxin-binding globulin, transcortin, transferrin, globulin that binds sex hormones), fibrinogen. It has procoagulant action, induces synthesis of vitamin K-dependent coagulation factors in the liver (II, VII, IX, X), reduces the concentration of antithrombin III. Increases blood concentrations of thyroxine, iron, copper. It has anti-atherosclerotic effect, increases HDL content, reduces LDL and cholesterol, increases the concentration of triglycerides. Modulates receptor sensitivity to progesterone and the sympathetic regulation of smooth muscle tone, stimulates the transfer of intravascular fluid into the tissue and causes a compensatory delay of sodium and water. In high doses, it prevents the degradation of endogenous catecholamines, competing for active catechol-O-methyltransferase receptors. After menopause, only a small amount of estradiol (from estrone found in the liver and in adipose tissue) is formed in the body.A decrease in the content of estradiol produced in the ovaries is accompanied in many women by vasomotor and thermoregulation instability (flushing to the skin of the face), sleep disorders, and progressive atrophy of the urogenital system. Osteoporosis (mainly the spine) develops due to estrogen deficiency. After ingestion, a larger amount of estradiol is metabolized in the lumen (microflora) and intestinal wall, as well as in the liver (which leads to non-physiologically high concentrations of estrone in plasma, and during long-term therapy to the accumulation of estrone and estrone sulfate). . The consequences of the accumulation of these metabolites in the body for a long time have not yet been clarified. It is known that oral administration of estrogen causes an increase in protein synthesis (including renin), which leads to an increase in blood pressure.
Pharmacokinetics
Absorption and distributionDrug Divigel is a gel for external use on an alcohol-containing basis. When applying the gel to the skin, the alcohol evaporates quickly and estradiol penetrates the skin, entering the systemic circulation. Application of the drug Divigel on the area of 200-400 cm2 (size of one or two palms) does not affect the amount of absorbed estradiol. However, if Divigel is applied over a large area, the degree of absorption is significantly reduced. To some extent, estradiol is delayed in the subcutaneous tissues, from which there is a gradual release into the bloodstream. The bioavailability of estradiol when using the drug Divigel is 82%. With the transdermal administration of Divigel at a dose of 0.5, 1 and 1.5 mg of estradiol (0.5, 1 and 1.5 g of Divigel), Cmax in the blood plasma is 143, 247 and 582 pmol / l, respectively. The average concentrations (Caverage) during the interval between application of the drug are 75, 124 and 210 pMol / l, respectively. Cmin are 92, 101 and 152 pmol / l, respectively. Against the background of the use of the drug Divigel, the estradiol / estrone ratio remains at a level from 0.4 to 0.7, whereas with the use of oral estrogens it usually decreases to <0.2. Not cumulative. Metabolism and excretion: Transdermal application avoids the first stage of hepatic metabolism, thanks to which fluctuations of estrogen concentration in the blood plasma when using the drug Divigel are insignificant. Does not accumulate.
Indications
Hormone replacement therapy for estrogen deficiency symptoms; treatment of menopausal syndrome associated with natural or artificial menopause, developed as a result of surgical intervention.
Contraindications
Hypersensitivity to estradiol and / or any other ingredient of the drug. Breast cancer (diagnosed, suspect or history). Diagnosed or suspected estrogen-dependent malignant tumors of the ovaries, uterus, endometrium. Benign tumors of the genitals and mammary glands (cancer of the cervix, uterus, uterine fibroids, vulvar cancer, ovarian cancer) in women under 60 years old. Vaginal bleeding of unknown etiology and a tendency to uterine bleeding. Endometrial hyperplasia. Pituitary tumors. Diffuse s disease tkani.Vospalitelnye connective diseases of the female reproductive organs (oophoritis, endometritis) .Giperestrogennaya climacteric stage perioda.Spontannye thromboembolic venous disease, including a history. Deep vein thrombosis, pulmonary embolism, including a history. Thrombophlebitis and acute thrombophlebitis, including a history. Congenital hyperbilirubinemia (Gilbert, Dubin-Johnson, Rotor syndromes). Liver tumors (hemangioma, liver cancer). Brain brain. ischemic stroke, hemorrhagic stroke). Sugar diabetes, retinopathy, angiopathy. Sperphoid cell anemia. Disorders of fat metabolism. Cholestatic jaundice or severe cholestatic itching (including increased manifestations during the previous pregnancy tee or on the background of taking steroids). Otoskleroz (including its exacerbation during pregnancy).
Precautionary measures
Do not exceed the recommended dose. With caution, Divigel should be used for uterine myoma, endometriosis, the presence of risk factors for thromboembolic disorders, the presence of risk factors for estrogen-dependent tumors (breast cancer in first-line relatives), hypertension, and liver diseases (including liver adenoma) with normal liver function tests, diabetes mellitus with or without diabetic angiopathy, cholelithiasis, migraine or severe headache, systemic lupus erythematosus, hyp endometrial epiderma in history, epilepsy,bronchial asthma, otosclerosis, heart failure, renal failure, coronary artery disease, sickle cell anemia, history of chloasma, history of hypertriglyceridemia, hereditary angioedema.
Use during pregnancy and lactation
The drug Divigel is not indicated for use during pregnancy. If during the treatment with the drug Divigel comes pregnancy, treatment should be stopped immediately. The results of most epidemiological studies conducted to date regarding the accidental effect of estrogen on the fetus do not indicate the presence of teratogenic or fetotoxic effect. Divigel is not indicated for use during breastfeeding .
Dosage and administration
Divigel - gel for transdermal application. Divigel can be used for long and cyclic therapy. The usual starting dose is 1.0 mg of estradiol (1.0 g of gel, respectively) per day, but the choice of the initial dose may be based on the severity of symptoms. Depending on the clinical picture, the dose can be changed after 2-3 cycles individually from 0.5 g to 1.5 g per day, which corresponds to 0.5 to 1.5 mg of estradiol per day. Patients with “intact” (non-operated ) during treatment with Divigel, it is recommended to administer a gestagen (for example, medroxyprogesterone acetate, norethisterone, norethysterone acetate or dihydrogestrone) for 10-12 days in each cycle. After the course application of progestogen, menstrual bleeding should occur. In case of extraordinary or prolonged uterine bleeding, it is necessary to determine the cause of their occurrence. In postmenopausal patients, the cycle time can be increased to 3 months. The gel is usually applied 1 time per day to the clean skin of the lower part of the anterior abdominal wall, lumbar region, shoulders, forearm, or alternately on the right or left buttocks, alternating daily application sites. The area of application should be equal in size to 1-2 palms. After applying the drug should wait a few minutes until the gel dries (2-3 minutes). The place of application of the gel can not be rinsed for 1 hour. Divigel's accidental eye contact should be avoided.Hands should be washed immediately after applying the gel. If the patient has forgotten to apply the gel, this should be done as soon as possible, but no later than 12 hours after the application of the drug on a schedule. If more than 12 hours have passed, the application of Divigel should be postponed until the next time. With the occasional use of the drug (missed doses), menstrual-like uterine bleeding "breakthrough" may occur.
Side effects
From the central and peripheral nervous system: headache, migraine, dizziness, depression, chorea, from the cardiovascular system: increased blood pressure, thrombophlebitis, from the alimentary system: nausea, vomiting, stomach cramps, flatulence, epigastric pain ; allergic reactions at the site of application: rash, skin irritation, skin flushing at the site of application of the gel, contact dermatitis; from the reproductive system: irregular vaginal bleeding (metrorrhagia) or scanty edematous secretions, increase in the size of uterine leiomyoma, endometrial hyperplasia (when administered without combination with progesterone), endometrial carcinoma (in women with an intact uterus after menopause), ovarian sclerosis with prolonged use, changes in libido; from the endocrine system: engorgement (tension and / or an increase in the mammary glands, an increase in body weight, a decrease in tolerance to carbohydrates, a dysfunction of the liver and biliary system: cholestatic jaundice, cholelium-thiase, bouts of porphyria, and water and salt ene: delay Na +, Ca2 + and water (edema) after prolonged use; Other: vision disturbance (change in curvature of the cornea), chloasma, melasma, vaginal candidiasis.
Overdose
In transdermal use, overdose is unlikely. Symptoms: breast pain, anxiety, irritability, nausea, vomiting, and in some cases metrorrhagia. Treatment: symptomatic therapy. Gel should be washed off the skin. Symptoms disappear when the dose is reduced or when the drug is withdrawn.
Interaction with other drugs
Estradiol metabolism is accelerated with simultaneous use with barbiturates, tranquilizers (anxiolytics), narcotic analgesics, anesthetics,some antiepileptic drugs (carbamazepine, phenytoin), inducers of liver microsomal enzymes; herbal preparations containing St. John’s wort hormones, on the contrary, exhibit inducing properties. The effect of estradiol increases with the use of folic acid and thyroid gland hormone preparations. nsdermal administration can avoid the effect of the first passage through the liver, thus, the effect of drugs for hormone therapy during transdermal application of estrogens, perhaps to a lesser extent than oral administration, depends on the effect of inducers of microsomal liver enzymes. In clinical practice, increased estrogen metabolism can lead to weakening of the effect and changes in the nature of uterine bleeding. Estradiol increases the effectiveness of lipid-lowering drugs. Estradiol weakens the effect of male drugs O hormone, hypoglycemic, diuretic, antihypertensive drugs and anticoagulants.
special instructions
In the treatment of postmenopausal symptoms, HRT should be initiated only if there are symptoms that adversely affect the quality of life. It should be at least once a year to conduct a detailed assessment of the risks and benefits and to appoint HRT only if the benefit exceeds the risk. Data on the risks associated with conducting HRT for the treatment of early menopause are limited. However, given the low absolute risk of HRT in young women, the balance of benefits and risks in such women is probably more favorable than in older women. Before starting or re-prescribing HRT, you need to have a full personal and family history. A medical examination should be conducted to identify possible contraindications and to observe necessary precautions when taking the drug (including examination of the pelvic organs and mammary glands).In the course of treatment, it is recommended that periodic examinations be recommended; periodic examinations are recommended; the frequency and methods included in it are determined individually for each specific case. Studies, including mammography, should be carried out in accordance with accepted standards and adapted to the individual clinical needs of each individual case. While the patient is receiving drugs for hormone therapy, a thorough assessment of all the benefits and risks of therapy should be made. Conditions that require observation If any of the following conditions are present, met before and / or exacerbated during pregnancy or prior hormone therapy, the patient must be under constant medical supervision but. It should be taken into account that these conditions may, in rare cases, recur or worsen during treatment with Divigel, in particular, uterine myoma or endometriosis; risk factors for thromboembolic disease; risk factors for estrogen-dependent tumors (presence of first-line relatives with breast cancer); arterial hypertension; liver disease (eg, liver adenoma); diabetes mellitus with or without diabetic angiopathy; cholelithiasis; migraine and / or severe headache; systemic lupus erythematosus; endometrial hyperplasia in history; epilepsy; bronchial asthma; otosclerosis; hereditary angioedema. Causes for immediate cessation of therapy Therapy should be stopped if contraindications are found and / or in the following situations: jaundice or deterioration of liver function; pronounced increase in blood pressure; newly occurring episodes of migraine-like headache, pregnancy. Hyperplasia and endometrial cancer The risk of hyperplasia and endometrial cancer is increased when estrogen is taken for a long time. According to available data, the risk of endometrial cancer in women who use only estrogen, increases by 2-12 times in comparison with women who do not use estrogen, depending on the duration of treatment and dose of estrogen. After cessation of treatment, the increased risk may persist for at least 10 years. To reduce the risk, it is necessary to combine estrogen therapy in women with an unremoved uterus with gestagens for at least 12 days during the treatment cycle or to take combined estrogen-gestagen preparations continuously. Breakthrough bleeding and spotting may be observed during the first months of treatment.If breakthrough bleeding or spotting appear after a certain period of treatment or continue after discontinuation of treatment, an examination should be carried out to identify their causes, including endometrial biopsy (to prevent endometrial malignancy). The use of estrogen-containing drugs may lead to precancerous or malignant transformation of residual foci of endometriosis. Thus, women who have had a hysterectomy for endometriosis should consider adding progestogens to estrogen replacement therapy in order to prevent endometrial cancer, if it is known that they have residual endometriosis foci. Breast cancer The available data generally indicate an increased risk of breast cancer glands in women receiving combined estrogen-progestin drugs and, possibly, also drugs for hormone therapy containing only estrogen; this risk depends on the duration of HRT use. The use of combined estrogen-progestin drugs for hormonal hormone therapy in a randomized, placebo-controlled study (the WHI Women's Health Initiative study) and coincidental data on increasing the risk of breast cancer in women receiving combined estrogen-gestagenic drugs for HRT; an increase in risk was found after about 3 years of treatment. The use of drugs for hormone therapy containing only estrogen In the WHI study, there was no increase in the risk of developing breast cancer in women undergoing hysterectomy and using drugs for hormone therapy containing only estrogen. In observational studies in most cases it is reported a slight increase in the risk of diagnosing breast cancer, which is significantly lower than in women using a combination of estrogen and progestogen. Additional risk begins to manifest itself after several years of treatment, but returns to its original level within a few (not more than five) years after stopping treatment. HRT, in particular, with combined estrogen-progestin preparations, leads to an increase in the density of mammography images, which can interfere with radiographic detection of breast cancer glands. Ovarian cancer Ovarian cancer is less common than breast cancer.Epidemiological data obtained from a large meta-analysis indicate a slightly increased risk in women taking estrogen mono-drugs or combined estrogen-gestagen HRT; the risk becomes apparent within 5 years of use and decreases with time after discontinuation. Some other studies, including the WHI study, suggest that combination HRT may be associated with a similar or slightly lower risk. arteries, compared with women who did not receive HRT, 1.3-3 times. The probability is higher in the first year of HRT than in subsequent years. The main risk factors are: personal or family history, estrogen use, serious operations, prolonged immobilization, severe obesity (BMI over 30 kg / m2), systemic lupus erythematosus, old age, pregnancy and the postpartum period, malignant neoplasms. There is no consensus on the possible role of varicose veins in the development of VTE. The risk of VTE increases with prolonged immobilization, extensive injuries or extensive surgical interventions. Reception of drugs for HRT should be stopped 4-6 weeks before the planned surgery on the abdominal organs or orthopedic operations on the lower limbs. Treatment can be resumed after full recovery of motor ability. For women who do not have VTE in history, but have first-line relatives who have had thrombosis at a young age, screening can be offered after a detailed discussion of its limitations (only some thrombophilic disorders are detected during screening). If a thrombophilic disorder is detected, manifested by thrombosis in family members, as well as in the presence of severe defects (such as an antithrombin deficiency, protein S or protein C, or a combination of defects), HRT is contraindicated. the ratio of benefits and risks of HRT. If VTE develops after starting treatment, the drug should be discontinued.Patients should be told to immediately contact a physician if potential symptoms of thromboembolism appear (pain and / or swelling of the lower extremity, sudden chest pain, shortness of breath). IBSV randomized controlled studies have not obtained data on the preventive effect on myocardial infarction in women with or without IHD, which received combined estrogen-progestin drugs for hormone replacement therapy or estrogen alone. Use of combined estrogen-progestin drugs for hormone replacement therapy. When using the combined estrogen-progestin drugs for HRT, there is a slight increase in the relative risk of coronary artery disease. Since the initial absolute risk of coronary artery disease largely depends on age, the number of additional cases of coronary artery disease associated with the use of estrogen in combination with gestagens in healthy women approaching menopause is extremely small, but increases with age. The use of estrogen-only drugs. In randomized controlled studies, there was no evidence of an increased risk of coronary artery disease in patients undergoing hysterectomy and receiving drugs for hormone therapy containing only estrogen. Ischemic insult with combined estrogen-progestin drugs and only estrogen associated with an increased risk of ischemic stroke almost 1.5 times. The relative risk does not change with age and depending on the time elapsed after the onset of menopause. However, since the initial risk of stroke largely depends on age, the overall risk of stroke in women receiving HRT will increase with age. Impaired kidney function Estrogens cause fluid retention in the body. Patients with heart or kidney failure should be under constant medical supervision. Diabetes mellitus Estrogens increase insulin sensitivity and increase its excretion. Patients with diabetes mellitus in the first months of HRT are constantly monitored for glucose concentration in the blood. Gallstone disease. Estrogen administration increases the risk of cholelithiasis.since in this state, during estrogen therapy, rare cases of sharp increases in plasma triglyceride concentrations are described, leading to the development of pancreatitis. Effects on thyroid function. Estrogens increase thyroxin binding globulin concentration, leading to an increase in the total concentration of circulating thyroid hormones. especially in women with a history of chloasma during pregnancy. Women with a tendency to develop chloasma, while using HRT, should minimize the effects of solar or ultraviolet radiation. Effects on cognitive function. HCT does not improve cognitive function. There is a slight increase in the risk of developing dementia at the onset of HRT over the age of 65. The drug Divigel is not a contraceptive; it is necessary to use adequate non-hormonal methods of contraception while taking the drug. The effect on the ability to drive and control mechanisms is not affected.