Estrogel transdermal gel 600mcg/g pump bottle, 80g

Composition

Auxiliary substances:  

carbomer (carbopol 980) – 5 mg,

trollamine (triethanolamine) – 5 mg,

ethanol-400 mg,

purified water-q. s. up to 1 g

Pharmacological action

The Active ingredient of Estrogel® – 17b-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, hypotamus, pituitary gland, liver – similar to the action of endogenous estrogens in the follicular phase of the menstrual cycle.

It makes up for 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), and psychoemotional disorders.

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

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

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.

Postmenopausal estrogen deficiency is associated with a decrease in bone mineral density (BMD). The effect of estrogens on BMD is dose-dependent and apparently continues as long as hormone replacement therapy (HRT) is performed. After HRT is discontinued, BMD begins to decline at the same rate as before the start of HRT.

Data from the Women’s Health Initiative (WHI) randomized placebo-controlled trial and a meta-analysis of clinical trials showed that HRT with oestrogens alone or oestrogens combined with progestogens in healthy postmenopausal women reduces the risk of hip, spine, and other osteoporotic fractures. There is also limited evidence that HRT can prevent bone fractures in women with low BMD and / or established osteoporosis.

Indications

-hormone replacement therapy for symptoms of estrogen deficiency, treatment of menopausal syndrome associated with natural or surgical menopause;- prevention of postmenopausal osteoporosis in women with a high risk of fractures if they are intolerant or have contraindications to the use of other drugs for the prevention of osteoporosis.

Use during pregnancy and lactation

Estrogel is contraindicated for use during pregnancy and lactation.

Recommendations for use

Estrogel® is prescribed externally, continuously or in a cyclic mode. The dose and duration of therapy are set individually.

Usually, the initial dose of the drug is 2.5 g of gel 1 time/day, which corresponds to 1.5 mg of estradiol. In most patients, this dose is effective in relieving menopausal symptoms. If after one month of therapy, the effectiveness is not achieved, it is possible to increase the daily dose of the drug to the maximum-5 g of gel, which corresponds to 3 mg of estradiol.

To start and continue treatment of menopausal symptoms, the minimum effective dose should be used for a minimum period of time.

For the prevention of osteoporosis in postmenopausal women, the minimum effective dose in most patients is 2.5 g of Estrogel®1 time / day.

When using the drug in a tube, a plastic applicator dispenser is used to determine the daily dose: 1 dose of the applicator corresponds to 2.5 g of gel (which corresponds to 1.5 mg of estradiol).

When using the drug in a bottle, one push on the dispenser pump releases 1.25 g of gel (which corresponds to 0.75 mg of estradiol), equal to half the daily dose. The average daily dose of the drug is 2.5 g of gel (2 clicks on the pump dispenser).

The use of Estrogel® without the addition of progestogen is possible only in patients with a removed uterus.

Patients with an intact (non-removed) uterus are recommended to be prescribed progestogen during treatment with Estrogel®.

During the menopausal transition, treatment should be carried out for at least 3 consecutive weeks, followed by a break of 1 week, while gestagen is administered orally during the last 12-14 days of the month.

During perimenopause, treatment can be carried out from the 1st to the 25th day of the month simultaneously with oral use of progestogen. During a week-long break, menstrual-like bleeding may occur due to a decrease in the content of sex hormones. It is recommended to use only those progestogens that are allowed to be taken simultaneously with estrogens.

During the postmenopausal period, treatment with estrogens in combination with progestogens is carried out on a regular basis.

Long-term estrogen monotherapy is indicated in women after Comfrey Woundwort. In women who have undergone a Comfrey Woundwort, the addition of progestogen in the absence of a history of endometriosis is not recommended.

Depending on the clinical symptoms, a dose adjustment is performed after 2-3 cycles of treatment:

• if you have symptoms of hyperestrogenism, such as a feeling of tension in the Breasts, a feeling of fullness in the abdomen and pelvis, anxiety, nervousness, aggressiveness, it is necessary to decrease the dose
• if symptoms of hypoestrogenism such as persistent congestion, dryness of the vaginal mucosa, headache, sleep disturbances, fatigue, tendency to depression, the dose should be increased.

In women who have not previously used HRT medications, and in women who switch to Estrogel® from a combined HRT drug with a continuous regimen, treatment with Estrogel® can begin on any day convenient for the patient. In women who switch to Estrogel® from a continuous sequential HRT regimen, treatment should begin after completing the previous regimen.

If the patient has forgotten to apply the gel, this should be done as soon as possible, but not later than 12 hours after applying the drug. If more than 12 hours have passed, the application of Estrogel® should be postponed until the next time. With irregular use of the drug (missed doses), breakthrough bleeding and spotting may occur.

Method of application

The gel is applied by patients independently, in the morning or evening, in a thin layer on clean, dry skin of the abdomen, lumbar region, shoulders or forearms until it is completely absorbed. The area of application should be at least 2 palms.

Do not massage the place of application of the gel. It is necessary to avoid getting the gel on the mammary glands and the mucous membrane of the vulva and vagina.

Application is considered correct and effective if the gel is completely absorbed within 2-3 minutes.

If the sticky consistency persists for more than 5 minutes after application, then the gel is covered with too small a surface of the skin.

The drug Estrogel® leaves no stains.

Wash your hands immediately after applying the gel.

Application of the drug in a tube. It is necessary to open the tube and pierce the metal membrane of the tube with a small punch, which is located in the upper part of the tube cover. The required dose is extracted from the tube using the applicator ruler.

1 dose corresponds to a column of extracted gel with a diameter corresponding to the diameter of the tube outlet, the length of which coincides with the recess on the applicator ruler. The recess has a dash that allows you to divide the daily dose in half. One tube of gel is designed for 30 doses.

Use of the drug in a bottle. It is necessary to remove the cap from the bottle and strongly press the pump dispenser, offering the other hand to collect the gel. The dose that is released at the first tap may not be accurate. It is recommended to throw it away. The bottle is designed for 64 clicks. After 64 taps, the amount of gel that is released with a single tap may be less than necessary. Therefore, it is not recommended to use the bottle after 64 taps on the pump dispenser.

Contraindications

-breast cancer (diagnosed, suspected, or in history);- diagnosed or suspected oestrogen-dependent malignant tumors of the genital organs (for example, endometrial cancer) or their presence in the anamnesis;- bleeding from the genital tract of unclear etiology; – untreated endometrial hyperplasia;- revealed acquired or hereditary predisposition to venous or arterial thrombosis, including antithrombin III deficiency, protein C deficiency, protein S deficiency); – venous thrombosis and thromboembolism at present or in history (including deep vein thrombosis and thrombophlebitis, pulmonary embolism);- active or recent arterial thromboembolic diseases (including angina pectoris, myocardial infarction);- acute liver disease or a history of liver disease, if the results of liver function tests have not returned to normal; – congenital hyperbilirubinemia (Gilbert’s syndrome, Dubin-Johnson, Rotor);- currently or a history of benign or malignant liver tumors;- cholestatic jaundice or severe cholestatic pruritus (incl.during a previous pregnancy or while taking sex hormones);- pregnancy; – lactation period (breastfeeding);- porphyria; – hypersensitivity to estradiol and/or any of the excipients of the drug.

With caution: the drug should be used for such diseases and conditions as: uterine fibroids; endometriosis; a history of endometrial hyperplasia; the presence of risk factors for estrogen-dependent tumors (breast cancer in first-line relatives); the presence of risk factors for thromboembolic disorders; arterial hypertension; liver diseases (including liver adenoma) with normal liver function tests; gallbladder diseases (including cholelithiasis); diabetes mellitus with or without diabetic angiopathy; migraine or severe headache; systemic lupus erythematosus; epilepsy; bronchial asthma; otosclerosis, chronic heart failure; renal failure; CHD; sickle cell anemia; a history of chloasma; a history of hypertriglyceridemia; pancreatitis; hereditary angioedema.

The experience of treating women over 65 years of age is limited.

Side effects

Possible side effects of HRT are described below. The frequency of side effects is defined as follows: often (>1/100; ><1/10), infrequently (>1/1000; <1/10), infrequently (><1/100), rarely (>1/10 000; <1/100), rarely (>

From the immune system: rarely – anaphylactic reactions (in women with a history of allergic reactions).

From the side of metabolism and nutrition: rarely-impaired glucose tolerance.

Mental disorders: infrequently – depression, mood swings; rarely-changes in libido.

Nervous system disorders: often – headache; infrequently-migraine, dizziness; rarely-exacerbation of epilepsy.

From the cardiovascular system: infrequently-venous thromboembolism; rarely-increased blood pressure.

From the gastrointestinal tract: often – nausea, abdominal pain; infrequently-flatulence, vomiting.

Liver and biliary tract disorders: rarely-deviation from the norm of liver function tests.

Skin and subcutaneous tissue disorders: infrequently-itching of the skin; rarely-skin discoloration, acne.

From the genitals and breast: often – breast edema, breast pain, breast enlargement, dysmenorrhea, menorrhagia, metrorrhagia, leukorrhea, endometrial hyperplasia; infrequently-benign breast tumors, enlarged uterus, uterine fibroids, vaginitis, candida vaginitis; rarely-galactorrhea.

Other services: often – changes in body weight (decrease or increase), fluid retention with peripheral edema; infrequently-asthenia.

Other adverse reactions detected during therapy with estrogen-progestogenic drugs:

• diseases of the gallbladder;
• skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, thrombocytopenic purpura;
• increased risk of dementia over the age of 65.

Risk of breast cancer

Women who use combined estrogen-progestogen drugs for more than 5 years have a 2-fold increased risk of breast cancer diagnosis. The risk of developing breast cancer is significantly lower when HRT is performed only with estrogens than when HRT is performed with combined estrogen-progestogen drugs. The magnitude of the risk of breast cancer depends on the duration of HRT.

In postmenopausal women with an intact uterus

, the incidence of endometrial cancer is about 5 cases for every 1,000 women with an intact uterus who do not undergo HRT.

In women with an intact uterus, oestrogen-only HRT is not recommended, as it increases the risk of endometrial cancer.

Depending on the duration of oestrogen-only use and its dose, the increased risk of endometrial cancer in epidemiological studies ranged from 5 to 55% of cases diagnosed in every 1,000 women aged 50 to 65 years.

Adding a progestogen for at least 12 days of the cycle to estrogen-only therapy may prevent this increased risk. In the WHI study, there was no increase in the risk of endometrial cancer during HRT (sequential or continuous) with combined estrogen-progestogen drugs for five years (RR 1.0 (0.8-1.2)).

Ovarian cancer

Long-term HRT with only oestrogens and combined oestrogen-progestogen medications was associated with a small increase in the risk of ovarian cancer. In the WHI study, one additional case of ovarian cancer per 2,500 women was identified during HRT over a five-year period.

Risk of venous thromboembolism

Women who receive HRT have a 1.3-to 3-fold increased risk of developing venous thromboembolism (VTE), particularly deep vein thrombosis or pulmonary embolism, compared to women who did not receive HRT. The probability of developing VTE is higher in the first year of HRT than in subsequent years.

Interaction

The use of Estrogel® in combination with surfactants (for example, sodium lauryl sulfate) or other substances that alter the structure or barrier function of the skin may reduce its effectiveness. Therefore, it is necessary to avoid concomitant use of the drug with strong detergents and detergents (for example, containing benzalkonium or benzetonium chloride), skin care products with a high ethanol content (astringents, sunscreens) and keratolytic agents (for example, salicylic acid or lactic acid).

Avoid the use of any concomitant medications that have a damaging effect on the skin (for example, cytotoxic).

Estradiol metabolism is accelerated when used concomitantly with inducers of microsomal liver enzymes, such as antiepileptic drugs (phenobarbital, phenytoin, carbamazepine); some antibiotics and antiviral drugs (rifampicin, rifabutin, nevirapine, efavirenz); herbal preparations containing St. John’s wort.

Ritonavir and nelfinavir, also known as strong inhibitors, when used together with sex hormones, on the contrary, show inducing properties.

When used transdermally, the “first pass” effect through the liver can be avoided, so the effect of HRT preparations with transdermal application of estrogens, perhaps to a lesser extent than with oral use, depends on the action of inducers of microsomal liver enzymes.

The metabolism of estradiol is accelerated when used simultaneously with tranquilizers (anxiolytics), narcotic analgesics, and anaesthetics. The concentration of estradiol in the blood plasma is also reduced when used simultaneously with certain antibiotics (penicillins and tetracyclines).

The effect of estradiol is enhanced by taking folic acid and thyroid hormone preparations.

In clinical practice, increased estrogen metabolism can lead to a 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 sex hormone preparations, hypoglycemic, diuretic, antihypertensive drugs and anticoagulants.

Overdose

No symptoms of acute overdose have been reported. Pain in the mammary glands or excessive production of cervical secretions may indicate that the drug dose is too high.

Symptoms of an estrogen overdose may include nausea and withdrawal bleeding.

Treatment: there is no specific antidote; it is necessary to cancel the drug and conduct symptomatic therapy.

Description

Transdermal gel is colorless, transparent, with an ethanol smell.

Functional features

Suction and distribution

When the gel is applied topically over a large area of the skin, triethanolamine evaporates and approximately 10% of estradiol is absorbed through the skin into the vascular system, regardless of the patient’s age. Daily use of the drug Estrogel® in a dose of 2.5 g or 5 g on an area of 400-750 cm%^%2 leads to a gradual increase in the concentration of estradiol and estrone and provides them with_ss in blood plasma after about 3-5 days in the ratio characteristic of the beginning of the middle follicular phase of the menstrual cycle.

When using the drug Estrogel® in 17 postmenopausal women 1 time / day by applying to the back of one arm from the wrist to the shoulder for 14 days, the_max of estradiol and estrone in blood plasma on the 12th day of use was 117 pg / ml and 128 pg/ml, respectively. The mean plasma concentrations of estradiol and estrone over the 24-hour time interval after use of Estrogel® at a dose of 2.5 g on day 12 of use were 76.8 pg / ml and 95.7 pg/ml, respectively.

Metabolism and elimination

Estradiol is mainly metabolized in the liver to estriol, estrone and their conjugated metabolites (glucuronides, sulfates). These metabolites undergo intestinal-hepatic recycling. After discontinuation of treatment, the estradiol concentration returns to its original level after approximately 76 hours.

Special instructions

When treating postmenopausal symptoms, HRT should only be initiated if there are symptoms that adversely affect the quality of life. A detailed risk and benefit assessment should be performed at least once a year, and HRT should only be prescribed if the benefit outweighs the risk.

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

Before starting or re-prescribing HRT, a complete personal and family history should be collected. A medical examination should be performed to identify possible contraindications and follow the necessary precautions when taking the drug (including pelvic and breast examinations). During treatment, it is recommended to conduct a periodic examination. The frequency and methods included in it are determined for each specific case individually. Studies, including mammography, should be conducted in accordance with accepted standards and adapted to the individual clinical needs of each individual case.

All benefits and risks of HRT therapy should be carefully evaluated when the patient is using HRT medications.

States that require monitoring

If any of the following conditions are present, have previously occurred, and / or have worsened during pregnancy or prior hormone 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 of thromboembolic diseases;
• the risk factors for estrogen-dependent tumors (in the presence of relatives of the first line of kinship with breast cancer);
• arterial hypertension;
• liver disorders (e. g. liver adenoma);
• diabetes with or without diabetic angiopathy;
• cholelithiasis;
• migraine and/or headache;
• systemic lupus erythematosus;
• endometrial hyperplasia in history;
• epilepsy;
• 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 deterioration of liver function;
• marked increase in blood pressure;
• recurrent migraine-like headaches;
• pregnancy.

Endometrial hyperplasia and cancer

In women with an intact uterus, the risk of endometrial hyperplasia and cancer increases when taking oestrogens for a long time. According to available data, the risk of developing endometrial cancer in women who use only estrogens increases 2-12 times in comparison with women who do not use estrogens, depending on the duration of treatment and the dose of estrogens. After discontinuation of treatment, the increased risk may persist for at least 10 years.

Progestogen supplementation in the last 12 days of the month/28 days of the cycle or continuous estrogen-progestogen combination 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 occurs after a certain period of treatment or continues after discontinuation of treatment, it is necessary to conduct an examination to determine the causes of their occurrence, including an endometrial biopsy to exclude endometrial malignancy.

The use of HRT preparations containing only estrogen can lead to precancerous or malignant transformation of residual endometriosis foci. Therefore, in women who have undergone a Comfrey Woundwort due to endometriosis, the addition of progestogen to estrogen replacement therapy should be considered in order to prevent endometrial cancer, if it is known that they have residual foci of endometriosis.

Breast cancer

Available evidence suggests an increased risk of breast cancer in women receiving combined oestrogen-progestogen medications and possibly also oestrogen-only HRT medications; this risk depends on the duration of HRT use.

Use of oestrogen-only HRT medications

The WHI study found no increased risk of breast cancer in women who underwent a Comfrey Woundwort and used HRT medications containing only estrogen.

In observational studies, in most cases, a small increase in the risk of breast cancer diagnosis is reported, which is significantly lower than in women using combined estrogen-progestogen drugs.

Use of combined estrogen-progestogen drugs for HRT

The WHI study and epidemiological studies found consistent data on an increased risk of breast cancer in women receiving combined estrogen-progestogen medications for HRT; an increased risk was detected after approximately 3 years of treatment.

The additional risk begins to appear after several years of treatment, but returns to the baseline level within a few (no more than 5) years after discontinuation of treatment.

HRT, in particular, combined estrogen-progestogen drugs, leads to an increase in the density of mammographic images, which can prevent X-ray detection of breast cancer.

Ovarian cancer

Ovarian cancer is significantly less common than breast cancer. Long-term (at least 5-10 years) use of HRT preparations containing only estrogen is associated with a slight increase in the risk of ovarian cancer. Some studies, including the WH1 study, have found that long-term use of combination medications for HRT may be associated with a similar or even less significant risk.

Venous thromboembolism

Women who received HRT had a 1.3-to 3-fold increased risk of developing VTE, particularly deep vein thrombosis or pulmonary embolism, compared to women who did not receive HRT. The probability 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 it. Therefore, HRT is contraindicated in such patients.

The main risk factors for VTE development are: individual or family history, use of estrogens, advanced age, serious operations, prolonged immobilization, severe obesity (BMI 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, extensive injuries, or extensive surgery. HRT medications should be discontinued 4-6 weeks prior to planned abdominal surgery or orthopedic surgery on the lower extremities. Treatment can be resumed after full recovery of motor ability.

Women who do not have a history of VTE but have first-line relatives who have experienced thrombosis at a young age may be offered screening after a detailed discussion of its limitations (only some thrombophilic disorders are detected during screening).

If the patient has a thrombophilic disorder that is manifested by thrombosis in family members, as well as in the presence of severe defects (such as a deficiency of antithrombin, protein S or protein C, or a combination of defects), HRT is contraindicated.

In women who are already receiving ongoing 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 advised to contact their doctor immediately if they experience potential symptoms of thromboembolism (soreness and / or swelling of the lower extremity, sudden chest pain, shortness of breath).

Coronary heart disease

In randomized controlled trials, no data were obtained on the preventive effect of myocardial infarction in women with or without CHD who received HRT with combined estrogen-progestogen drugs or only estrogens.

Use of oestrogen-only HRT medications

In randomized controlled trials, there were no data on an increased risk of CHD in patients who underwent a Comfrey Woundwort and received oestrogen-only HRT medications.

Use of combined estrogen-progestogen drugs for HRT

When using combined estrogen-progestogen drugs for HRT, there is a slight increase in the relative risk of CHD. Since the initial absolute risk of CHD largely depends on age, the number of additional cases of CHD due to the use of estrogens in combination with progestogens in healthy women approaching menopause is extremely small, but increases with age.

HRT with combined estrogen-progestogen drugs and estrogen alone is associated with an almost 1.5-fold increased risk of ischemic stroke. The relative risk does not change with age and depending on the time that has passed since the onset of menopause. However, since the initial risk of stroke is largely age-dependent, the overall risk of stroke in women receiving 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 performing HRT in women with a history of hypertriglyceridemia, since in this condition, against the background of estrogen therapy, rare cases of a sharp increase in the concentration of triglycerides in 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, respectively, to an increase in the total concentration of circulating glucocorticoids and sex hormones. Concentrations of free or biologically active hormones do not change. It is also possible to increase the content of other plasma proteins (angiotensinogen (renin substrate), alpha-1-antitrypsin, ceruloplasmin).

Chloasma

In some cases, chloasma may develop, especially in women who have a history of chloasma during pregnancy. Women who have a tendency to develop chloasma should minimize their exposure to sunlight or ultraviolet radiation while taking HRT.

Effects on cognitive function

HRT does not affect the improvement of cognitive function. The WHI study shows a trend towards a possible increase in the risk of dementia in women who started long-term HRT with combined estrogen-progestogen medications or estrogen alone over the age of 65.

Influence on the ability to drive vehicles and mechanisms

The effect of estrogens on the ability to drive vehicles and mechanisms has not been studied.

Storage conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 25°C.

Shelf

life is 3 years.

Active ingredient

Estradiol

Conditions of release from pharmacies

By prescription

Dosage form

gel for external use

Purpose

For postmenopausal women, For menopausal women, For adults as prescribed by a doctor

Indications

Estrogen deficiency, Menopause