Estrogel transdermal gel 0.0006/g 80g N1 dispenser bottle

Estrogel transdermal gel 0.0006/g 80g N1 dispenser bottle

Action

The active ingredient of the drug Estrogel® - 17beta-estradiol - is chemically and biologically identical to endogenous human estradiol.
It has an estrogenic effect on the main target organs: ovaries, endometrium, vaginal epithelium, mammary glands, urethra, hypothalamus, pituitary gland, liver - similar to the action of endogenous estrogens in the follicular phase of the menstrual cycle.

Replenishes estrogen deficiency in women during menopause and reduces the severity of menopausal disorders, including hot flashes, increased sweating at night, atrophic changes in the genitourinary tract (atrophic vulvovaginitis, dyspareunia, urinary incontinence), psycho-emotional disorders.

The clinical effectiveness of Estrogel® in the treatment of menopausal symptoms is comparable to that of oral estrogens.

Estradiol helps reduce the concentration of total cholesterol without changing the cholesterol/HDL ratio.

It has a procoagulant effect, increases the synthesis in the liver of vitamin K-dependent blood clotting factors (II, VII, IX, X), reduces the concentration of antithrombin III.

Estradiol prevents bone loss associated with natural menopause or oophorectomy.

Estrogen deficiency during postmenopause is associated with a decrease in bone mineral density (BMD). The effect of estrogen on BMD is dose-dependent and appears to last as long as hormone replacement therapy (HRT) is administered. After stopping HRT, BMD begins to decrease at the same rate as before it began. Data from the randomized, placebo-controlled Women's Health Initiative (WHI) trial and a meta-analysis of clinical trials showed that HRT with estrogens alone or estrogens plus progestins in healthy postmenopausal women reduces the risk of hip, vertebral and other osteoporotic fractures. There is also limited evidence that HRT can prevent bone fractures in women with low BMD and/or established osteoporosis.

Pharmacokinetics

Absorption and distribution

When the gel is applied topically to a large surface of the skin, the alcohol evaporates and approximately 10% of estradiol is absorbed through the skin into the vascular system, regardless of the patient’s age. Daily use of 2.5 g or 5 g of Estrogel® over an area of ​​400-750 cm2 leads to a gradual increase in the concentration of estradiol and estrone and ensures their equilibrium concentration in the blood plasma after approximately 3-5 days in a ratio characteristic of the beginning of the middle follicular phase of menstruation cycle. When using the drug Estrogel® in 17 postmenopausal women once a day by applying it to the back surface of one arm from wrist to shoulder for 14 days, the maximum concentration (Cmax) of estradiol and estrone in the blood plasma on the 12th day of use was 117 pg/ml and 128 pg/ml, respectively. The average concentration of estradiol and estrone in the blood plasma over a 24-hour period after administration of 2.5 g of Estrogel® on the 12th day of administration was 76.8 pg/ml and 95.7 pg/ml, respectively.

Metabolism and excretion

Estradiol is metabolized mainly in the liver to estriol, estrone and their conjugated metabolites (glucuronides, sulfates). These metabolites undergo enterohepatic recirculation. After cessation of treatment, estradiol concentrations return to baseline levels after approximately 76 hours.

Instructions for use ESTROGEL (OESTROGEL)

• For women using estrogen-only

-from 0 to 3 (average 1.5) over 5 years of therapy

-from 3 to 7 (average 5) for 10 years of therapy.

• For women using HRT containing estrogens and gestagens

-from 5 to 7 (average 6) over 5 years of therapy

-from 18 to 20 (average 19) for 10 years of therapy.

According to estimates from the WHI study, it was shown that when followed for 5.6 years in women aged 50 to 79 years using HRT containing estrogens and progestins

(CEE + MPA) is associated with the development of 8
additional
cases of invasive breast cancer per 1000 women per year.

Based on calculations based on the results of the study, the following was shown:

• Per 1000 women in the placebo group

-invasive breast cancer will be diagnosed in 16 women over 5 years.

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• Per 1000 women from the group where combined estrone and progestogen-based HRT (CEE + MPA) was used, the number of additional
  cases of invasive breast cancer will be:

-From 0 to 9 (average 4) cases during 5 years of therapy.

In general, the number of additional cases of breast cancer is approximately the same regardless of a woman's age at the time she starts using HRT (women aged 45 to 65 years).

Endometrial hyperplasia

• The risk of endometrial hyperplasia and carcinoma is increased by estrogen monotherapy over a long period. Adding progestogen for at least 12 days per cycle in women without a hysterectomy significantly reduces this risk.
• Intermenstrual bleeding is possible during the first months of treatment. If they appear after several months of therapy or persist after stopping treatment, it is necessary to find the cause, which may require an endometrial biopsy to exclude malignant transformation.
• Monotherapy with estrogens can cause malignant transformation of residual foci of endometriosis. Therefore, in women with endometriosis after hysterectomy, when the absence of residual endometriosis cannot be guaranteed, the addition of progestins to estrogen replacement therapy is recommended.

Ovarian cancer

According to some epidemiological studies, long-term use of HRT (for a minimum of 5-10 years), including estrogen monotherapy in women after hysterectomy, is associated with an increased risk of developing ovarian cancer. It remains unknown whether the risk of developing ovarian cancer with long-term use of combination replacement therapy differs from that with estrogen monotherapy.

Venous thromboembolic complications

The use of HRT is associated with an increased relative risk of episodes of venous thromboembolism (VTE), i.e. deep vein thrombosis and pulmonary embolism. A controlled randomized trial and multiple epidemiological studies have shown a 2- to 3-fold increase in the risk of developing VTE in women receiving treatment compared with women not receiving treatment. In untreated women, the incidence of venous thromboembolic events over a 5-year period is estimated to be approximately 3 per 1000 women aged 50 to 59 years and 8 per 1000 women aged 60 to 69 years. In healthy women treated for 5 years, the estimated number of additional cases of VTE over a 5-year period is 2 to 6 (average: 4) per 1000 patients aged 50 to 59 years and 5 to 15 cases (average: :

• 9) per 1000 patients aged 60 to 69 years. The development of VTE is more likely during the first year of HRT.

Generally recognized risk factors for VTE are a personal or family history of VTE, severe obesity (BMI > 30 kg/m2), systemic lupus erythematosus. There is no consensus regarding the role of varicose veins in the development of venous thrombosis.

Patients with a history of VTE and patients with thrombophilia represent a high-risk group for the development of VTE. The use of HRT may increase this risk. Patients with a personal or family history of severe VTE or a history of repeated spontaneous miscarriages should be evaluated to exclude a thrombophilic predisposition. Until a thorough assessment of thrombophilic factors and initiation of anticoagulant therapy, HRT is considered contraindicated in this group of patients. Women already receiving anticoagulants require special attention and assessment of the risk-benefit ratio of HRT.

The risk of VTE may temporarily increase with prolonged immobilization, severe trauma, or major surgery. As in all patients, special attention should be paid to VTE prevention in the postoperative period. Because Prolonged immobilization is a consequence of elective surgical interventions, especially in the abdominal cavity or during orthopedic operations on the lower extremities; as a preventive measure, temporary cessation of HRT for a period of 4-6 weeks before surgery should be considered. HRT can be resumed only after the patient’s mobility has been completely restored.

If VTE develops after starting treatment, it should be interrupted. Patients should be informed to seek immediate medical attention if possible symptoms of thromboembolism (eg, painful swelling of the legs, sudden chest pain, or shortness of breath) occur.

Cardiac ischemia

Controlled randomized trials have shown no cardiovascular benefits with combination therapy of conjugated estrogens and medroxyprogesterone acetate (MPA). Two important clinical trials (WHI and HERS - Heart and Esrogen/Progestin Replacement Study) showed an increased risk of mortality from cardiovascular complications during the first year of treatment in the absence of overall benefits in relation to of cardio-vascular system. For other types of HRT, there is currently only limited evidence from randomized controlled trials assessing the effects on cardiovascular disease morbidity and mortality. There is no definitive evidence that these results apply to other types of HRT.

Cerebral vascular complications

In a large clinical randomized trial (WHI study), the secondary endpoint found an increased risk of ischemic cerebral vascular complications in healthy women during combination therapy with conjugated estrogens and MPA. In untreated women, the estimated incidence of cerebral vascular complications over a 5-year period is approximately 3 per 1000 women aged 50 to 59 years and 11 per 1000 women aged 60 to 69 years. In women treated with conjugated estrogens and MPA, the number of additional cases is estimated to be 0 to 3 (mean = 1) per 1000 women aged 50 to 59 years and 1 to 9 cases (mean = 4) per 1,000 women aged 50 to 59 years. 1000 women aged 60 to 69 years. There is no clear evidence that this increased risk applies to other types of HRT.

Other states

The use of estrogens can lead to salt and fluid retention, which therefore requires careful monitoring in patients with cardiac or renal failure. Careful monitoring is necessary in patients with end-stage renal failure who have a tendency to increase estrogen levels in the blood plasma.

Careful monitoring is necessary in women with previously diagnosed hypertriglyceridemia, because When using estrogen monotherapy or hormone replacement therapy, rare cases of a pronounced increase in triglyceride levels have been described, which can lead to the development of pancreatitis.

Estrogens increase thyroid hormone binding globulin (TBG) levels, which may lead to an increase in total circulating thyroid hormone levels as determined using PBI (protein bound iodine), T4 (chromatography or radioimmunoassay), and T3 (radioimmunoassay). analysis). The binding of T3 by polymers decreases, indicating an increase in TSH levels. The concentrations of free T3 and T4 do not change. Levels of other proteins, such as cortisol transport protein (CTP), sex hormone binding protein (SHB), may increase, which may lead to corresponding increases in circulating levels of corticosteroids and sex hormones. The concentrations of free or biologically active hormones do not change. It is also possible to increase the level of other plasma proteins (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

There is no convincing evidence of improvements in cognitive function with HRT. The WHI study shows a trend toward a possible increased risk of dementia in women on long-term HRT use who initiate combination therapy with conjugated estrogens and medroxyprogesterone acetate over the age of 65 years. It remains unknown whether these observations apply to younger postmenopausal women or when using other types of HRT.

Use in elderly people (over 65 years of age)

Experience with this type of treatment in women over 65 years of age is limited.

There is no reason to impose any restrictions on the duration of therapy, however, to continue treatment of postmenopausal symptoms, the minimum effective dose should be used for the minimum period of time. A thorough assessment of risks and benefits should be performed at least once a year; Hormone replacement therapy should be continued only as long as the benefits outweigh the risks associated with the therapy.

Use for liver dysfunction and/or history of cholestatic jaundice

Estrogen metabolism may be decreased in women with impaired liver function. For women with a history of cholestatic jaundice associated with previous estrogen use or pregnancy, caution should be exercised, and in case of relapse, the drug should be discontinued.

Use for renal impairment

There are no data from clinical studies.

Use in pediatrics

Estrogel is not indicated for use in children.

Impact on the ability to drive vehicles and operate machinery

The effect of estrogens has not been studied.

Oestrogel®

When treating postmenopausal symptoms, HRT should only be started if symptoms are present that adversely affect quality of life. A detailed assessment of the risks and benefits should be carried out at least once a year and HRT should only be prescribed if the benefits outweigh the risks.

Data regarding the risks associated with HRT for the treatment of premature menopause are limited. However, given the low absolute risk of HRT in younger women, the benefit-risk ratio may be more favorable in these women than in older women.

Before starting or re-prescribing HRT, it is necessary to obtain a complete personal and family history. A medical examination should be conducted to identify possible contraindications and observe the necessary precautions when taking the drug (including examination of the pelvic organs and mammary glands). During treatment, periodic examinations are recommended. The frequency and methods included in it are determined for each specific case individually. Tests, 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 taking HRT medications, a thorough assessment of all the benefits and risks of therapy should be carried out.

Conditions that require monitoring

If any of the following conditions are present, previously encountered and/or aggravated during pregnancy or previous hormonal therapy, the patient should be under constant medical supervision.

It should be taken into account that these conditions may, in rare cases, recur or worsen during treatment with Estrogel®, in particular:

• uterine fibroids or endometriosis;
• risk factors for the development of thromboembolic diseases;
• risk factors for estrogen-dependent tumors (presence of first-degree relatives with breast cancer);
• arterial hypertension;
• liver diseases (for example, liver adenoma);
• diabetes mellitus with or without diabetic angiopathy;
• cholelithiasis;
• migraine and/or severe headache;
• systemic lupus erythematosus;
• history of endometrial hyperplasia;
• epilepsy;
• bronchial asthma;
• otosclerosis;
• hereditary angioedema.

Reasons for immediate discontinuation of therapy

Therapy should be discontinued if contraindications are found and/or in the following situations:

• jaundice or worsening liver function;
• marked increase in blood pressure;
• new attacks of migraine-like headache;
• pregnancy.

Hyperplasia and endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and cancer increases when taking estrogens for a long time. The risk of developing endometrial cancer in women using estrogen only is reported to be 2- to 12-fold higher than in women not using estrogen, depending on the duration of treatment and dose of estrogen. After stopping treatment, the increased risk may persist for at least 10 years.

The addition of a progestin in the last 12 days of the month/28 days of the cycle or continuous combined estrogen-progestin therapy in women with a non-removed uterus reduces the increased risk of endometrial hyperplasia and cancer associated with estrogen-only HRT.

During the first months of treatment, breakthrough bleeding and spotting may occur. If breakthrough bleeding or spotting appears after a period of treatment or continues after discontinuation of treatment, it is necessary to conduct an examination to identify the causes of their occurrence, including an endometrial biopsy to exclude endometrial malignancy.

The use of drugs for HRT containing only estrogen can lead to precancerous or malignant transformation of residual foci of endometriosis. Therefore, in women who have undergone hysterectomy for endometriosis, consideration should be given to adding a progestin to estrogen replacement therapy for the prevention of endometrial cancer if they are known to have residual endometriosis.

Mammary cancer

Available data suggest an increased risk of breast cancer in women receiving combined estrogen-progestin drugs and possibly also estrogen-only HRT drugs; this risk depends on the duration of HRT use.

The use of HRT drugs containing only estrogen

The WHI study found no increased risk of breast cancer in women who had a hysterectomy and used estrogen-only HRT.

Observational studies in most cases report a small increase in the risk of diagnosing breast cancer, which is significantly lower than in women using combined estrogen-progestin drugs.

The use of combined estrogen-progestin drugs for HRT

The WHI study and epidemiological studies provide concordant evidence of an increased risk of breast cancer in women receiving combined estrogen-progestin drugs for HRT; an increase in risk was detected after approximately 3 years of treatment.

The additional risk begins to appear after several years of treatment, but returns to baseline within a few (not more than five) years after stopping treatment.

HRT, in particular combined estrogen-progestin drugs, leads to increased density of mammographic images, which may interfere with radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much less common than breast cancer. Long-term (at least 5-10 years) use of estrogen-only HRT drugs is associated with a slight increase in the risk of developing ovarian cancer. Some studies, including the WHI study, have found that long-term use of combination HRT drugs may carry a similar or less significant risk.

Venous thromboembolism

In women receiving HRT, there is an increase in the risk of developing VTE, in particular deep vein thrombosis or pulmonary embolism, compared with women who did not receive HRT, by 1.3-3 times. The likelihood of developing VTE is higher in the first year of HRT than in subsequent years.

Patients with known thrombophilic disorders may have an increased risk of developing VTE, and HRT may further increase this risk. Therefore, HRT is contraindicated in such patients.

The main risk factors for the development of VTE: individual or family history, estrogen use, old age, major surgery, prolonged immobilization, severe obesity (body mass index more than 30 kg/m2), pregnancy and the postpartum period, systemic lupus erythematosus, 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, major trauma, or major surgery. Taking HRT medications should be stopped 4-6 weeks before planned abdominal surgery or orthopedic surgery on the lower extremities. Treatment can be resumed after complete restoration of motor ability.

In women who do not have a history of VTE but have first-degree relatives who experienced thrombosis at a young age, screening can be offered after a detailed discussion of its limitations (screening detects only some thrombophilic disorders).

If the patient has a thrombophilic disorder that has been demonstrated by thrombosis in family members, or if there are “severe” defects (such as antithrombin deficiency, protein S or protein C deficiency, or a combination of defects), HRT is contraindicated.

In women already receiving chronic anticoagulant treatment, a careful assessment of the benefit-risk ratio of HRT is required.

If VTE develops after starting treatment, the drug should be discontinued.

Patients should be instructed to contact their physician immediately if potential symptoms of thromboembolism (tenderness and/or swelling of the lower extremity, sudden chest pain, shortness of breath) occur.

Cardiac ischemia

Randomized controlled trials have not provided data on the preventive effect against myocardial infarction in women with or without coronary artery disease who received HRT with combined estrogen-progestin drugs or estrogen alone.

The use of HRT drugs containing only estrogen

There is no evidence from randomized controlled trials of an increased risk of coronary artery disease in patients who have undergone hysterectomy and are receiving estrogen-only HRT medications.

The use of combined estrogen-progestin drugs for HRT

When using 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 CAD is largely dependent on age, the number of additional cases of CAD due to the use of estrogens in combination with progestins in healthy women approaching menopause is extremely small, but increases with age.

Ischemic stroke

HRT with combined estrogen-progestin drugs and estrogen alone is associated with an almost 1.5-fold increase in the risk of ischemic stroke. The relative risk does not change with age or with time since menopause. However, since baseline risk of stroke is largely dependent on age, the overall risk of stroke in women taking HRT will increase with age.

Other states

• Estrogens cause fluid retention in the body. Patients with heart or kidney failure should be under constant medical supervision.
• Careful monitoring is necessary when carrying out HRT in women with a history of hypertriglyceridemia, since in this condition, during estrogen therapy, rare cases of a sharp increase in the concentration of triglycerides in the blood plasma, leading to the development of pancreatitis, have been described.
• Estrogens increase the concentration of thyroxine-binding globulin, leading to an increase in the total concentration of circulating thyroid hormones. The concentrations of free T3 and T4 do not change.

The content of other proteins, such as corticosteroid binding globulin and sex hormone binding globulin, may increase, which may lead to an increase in the total concentration of circulating corticosteroids and sex hormones. The concentrations of free or biologically active hormones do not change. It is also possible to increase the content of other blood plasma proteins (angiotensinogen (renin substrate), alpha-1-antitrypsin, ceruloplasmin).

Chloasma

In some cases, chloasma may develop, especially in women with a history of chloasma during pregnancy. Women who are prone to developing chloasma should minimize exposure to sunlight or ultraviolet radiation while using HRT.

Effect on cognitive function

HRT does not improve cognitive function. The WHI study showed a trend towards a possible increased risk of dementia in women who started long-term HRT with combined estrogen-progestin drugs or estrogen alone after the age of 65 years.

The drug Estrogel® should be used:

• the woman herself
• morning or evening, on clean skin.

The drug Estrogel ® does not leave stains.