Estrogel gel 600 mcg/g 80 g

Excipients: 

carbomer (carbopol 980) - 5 mg, 

trolamine (triethanolamine) - 5 mg, 

ethanol - 400 mg, 

purified water - qs up to 1 g.

The active substance of the drug Estrozhel ^®  - 17β-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, hypotolamus, pituitary, liver - similar to the action of endogenous estrogens in the follicular phase of the menstrual cycle.

It replenishes the estrogen deficiency in women during menopause and reduces the severity of menopausal disorders, including flushing, night sweats, atrophic changes in the urogenital tract (atrophic vulvovaginitis, dyspareunia, urinary incontinence), and psychoemotional disorders.

The clinical efficacy of Estrozhel ^®  in the treatment of menopausal symptoms is comparable to that of oral estrogen.

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

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

Estradiol prevents bone loss associated with natural menopause or ovariectomy.

Estrogen deficiency in the postmenopausal period is associated with a decrease in bone mineral density (BMD). The effect of estrogen on MPCM is dose-dependent and, apparently, continues until hormone replacement therapy (HRT) is performed. After the abolition of HRT, the MPCM begins to decline at the same rate as before it began.

The data from a randomized, placebo-controlled study of Women's Health Initiatives (WHI) and a meta-analysis of clinical trials showed that HRT alone with estrogens or estrogens in combination with gestagens 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.

Estrozhel ^{® is}  prescribed externally, continuously or in a cyclic mode. Doses and duration of therapy are set individually.

Typically, 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 alleviating the symptoms of menopause. If after one month of therapy the effectiveness is not achieved, it is possible to increase the daily dose of the drug to a maximum of 5 g of gel, which corresponds to 3 mg of estradiol.

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

For the prevention of osteoporosis in women during the postmenopausal period, the minimum effective dose in most patients is 2.5 g of the drug Estrozhel ^® 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 vial, one press of the metering 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 metering pump).

The use of the drug Estrozhel ^®  without the addition of gestagen is possible only in patients with a removed uterus.

Patients with an intact (non-removed) uterus during treatment with Estrozhel ^{® are}  recommended to prescribe gestagen.

During the menopausal transition, treatment should be carried out for at least 3 consecutive weeks, then a break of 1 week should follow, and gestagen should be given orally for the last 12-14 days of the month.

During the period of perimenopause, treatment can be carried out from 1 to 25 days of the month simultaneously with oral administration of gestagen. During a week-long break, menstrual 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.

In the postmenopausal period, estrogen treatment in combination with progestogens is carried out in a continuous mode.

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

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

• when symptoms of hyperestrogenism appear, such as a feeling of tension in the mammary glands, a feeling of overflow in the abdomen and pelvis, a sense of anxiety, nervousness, aggressiveness, a dose reduction is necessary;
• with symptoms of hypoestrogenism, such as persistent flushing, dryness of the vaginal mucosa, headache, sleep disturbances, asthenia, tendency to depression, the dose should be increased.

For women who have not previously used preparations for HRT, and for women switching to Estrozhel ^®  with a combined preparation for HRT with a continuous regimen, treatment with Estrozhel ^®  can be started on any day convenient for the patient. In women switching to Estrozhel ^®  with a continuous sequential HRT regimen, treatment should be started after completion of the previous regimen.

If the patient forgot to apply the gel, it should be done as soon as possible, but no later than within 12 hours from the time of application of the drug. If more than 12 hours have passed, the application of the drug Estrozhel ^®  should be postponed until the next time. With irregular use of the drug (missed doses), breakthrough bleeding and spotting spotting may occur.

Mode of application

The gel is applied by patients on their own, in the morning or in the evening, with a thin layer on clean, dry skin of the abdomen, lumbar region, shoulders or forearms until completely absorbed. The application area 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, it means that the skin is too small on the gel.

The drug Estrozhel ^®  does not leave spots.

Wash your hands immediately after applying the gel.

The use of the drug in a tube. You should open the tube and pierce the metal membrane of the tube with a small punch, which is located at the top of the tube cover. The required dose is extracted from the tube according to the applicator line.

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

The use of the drug in a bottle. It is necessary to remove the cap from the bottle and press the dispensing pump strongly, substituting the other hand to collect the gel. The dose that is released upon first pressing may be inaccurate. It is recommended to throw it away. The bottle is designed for 64 clicks. After 64 clicks, the amount of gel that is released with one click may be less than necessary. Therefore, it is not recommended to use the bottle after 64 clicks on the metering pump.

Carefully: the drug should be used for diseases and conditions such as: uterine fibroids; endometriosis; 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 disease (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; Ischemic heart disease; sickle cell anemia; a history of chloasma; history of hypertriglyceridemia; pancreatitis hereditary angioedema.

Experience in treating women over 65 is limited.

Possible side effects of HRT are described below. The frequency of side effects is determined as follows: often (> 1/100; <1/10), infrequently (> 1/1000; <1/100), rarely (> 1/10000; <1/1000).

On the part of 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 - a change in libido.

From the nervous system:  often - headache; infrequently - migraine, dizziness; rarely - exacerbation of epilepsy.

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

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

On the part of the liver and biliary tract:  rarely - a deviation from the norm of indicators of liver function tests.

On the part of the skin and subcutaneous tissues:  infrequently - skin itching; rarely - discoloration of the skin, acne.

From the genitals and mammary gland:  often - breast edema, pain in the mammary glands, enlargement of the mammary glands, dysmenorrhea, menorrhagia, metrorrhagia, leukorrhea, endometrial hyperplasia; infrequently - benign mammary tumors, an increase in the size of the uterus, uterine fibroids, vaginitis, candidal vaginitis; rarely - galactorrhea.

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

Other adverse reactions identified with estrogen-progestogen therapy:

• gallbladder disease;
• on the part of the skin and subcutaneous tissues: chloasma, erythema multiforme, erythema nodosum, thrombocytopenic purpura;
• increased risk of dementia over the age of 65.

Breast cancer risk

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

Endometrial cancer risk

In postmenopausal women with an intact uterus

The incidence of endometrial cancer is about 5 cases for every 1000 women with an intact uterus who are not undergoing HRT.

In women with an intact uterus, HRT alone with estrogens is not recommended, as this increases the risk of developing endometrial cancer.

Depending on the duration of the use of estrogen alone and its dose, the increased risk of endometrial cancer in epidemiological studies ranged from 5 to 55 additional cases diagnosed in every 1000 women aged 50 to 65 years.

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

Ovarian cancer

Long-term HRT only with estrogens and combined estrogen-progestogen drugs was associated with a slight increase in the risk of ovarian cancer. In a WHI study on HRT for five years, 1 additional case of ovarian cancer per 2500 women was identified.

The risk of venous thromboembolism

Women receiving HRT have an increased risk of venous thromboembolism (VTE), in particular, deep vein thrombosis or pulmonary embolism, compared with women who have not received HRT, by 1.3-3 times. The likelihood of developing VTE is higher in the first year of HRT than in subsequent years.

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

The use of any concomitant drugs that have a damaging effect on the skin (e.g., cytotoxic) should be avoided.

The metabolism of estradiol is accelerated while it is used 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 perforated.

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

With transdermal administration, the effect of the "first passage" through the liver can be avoided, thus, the effect of HRT preparations during transdermal administration of estrogens, possibly to a lesser extent than with oral administration, depends on the action of inducers of microsomal liver enzymes.

The metabolism of estradiol is accelerated with simultaneous use with tranquilizers (anxiolytics), narcotic analgesics, and drugs for anesthesia. The concentration of estradiol in blood plasma also decreases with the simultaneous use of 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 effect and changes in the nature of uterine bleeding.

Estradiol increases the effectiveness of lipid-lowering drugs.

Estradiol weakens the effect of drugs of male sex hormones, hypoglycemic, diuretic, antihypertensive drugs and anticoagulants.

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

Symptoms of an estrogen overdose include nausea and withdrawal bleeding.

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

Suction and distribution

With topical application of the gel on a large surface 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 Estrozhel ^®  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 their C _ss  in blood plasma after about 3-5 days in a ratio characteristic of the beginning of the middle of the follicular phase menstrual cycle. 

When using the drug Estrozhel ^®  in 17 postmenopausal women 1 time / day by applying on the back surface of one arm from the wrist to the shoulder for 14 days, the _{max max of}  estradiol and estrone in 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 time interval after the use of the drug Estrozhel ^®  in a dose of 2.5 g 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 discontinuation of treatment, the concentration of estradiol returns to its original level after about 76 hours.

In the treatment of postmenopausal symptoms, HRT should only be started if there are symptoms that adversely affect the quality of life. A detailed risk and benefit assessment should be carried out at least once a year and HRT should be prescribed only if the benefit exceeds the risk.

Data on the risks associated with HRT for treating premature menopause are limited. However, given the low absolute risk of HRT in young women, the benefit-risk ratio of such women is perhaps more favorable than that of older women.

Before starting or re-appointing HRT, you need to collect a complete personal and family history. A medical examination should be performed to identify possible contraindications and the necessary precautions when taking the drug (including examination of the pelvic organs and mammary glands). In the process of treatment, it is recommended to conduct a periodic examination. The frequency and methods included in it are determined individually for each particular case. Research, including mammography, should be carried out in accordance with accepted standards and adapted to the individual clinical needs of each individual case.

During the patient’s use of HRT preparations, a thorough assessment of all the benefits and risks of therapy should be carried out.

States that require observation

If any of the following conditions are present, met earlier and / or worsened during pregnancy or prior hormone therapy, the patient should be under constant medical supervision. It should be borne in mind that these conditions can, in rare cases, recur or worsen during treatment with Estrozhel ^® , in particular:

• uterine fibroids 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 (e.g., 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 discontinuing therapy immediately

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

• jaundice or impaired liver function;
• marked increase in blood pressure;
• relapses of migraine-like headache;
• pregnancy.

Hyperplasia and endometrial cancer

In women with an intact uterus, the risk of hyperplasia and endometrial cancer increases with estrogen for a long time. According to reports, the risk of developing endometrial cancer in women using estrogen-only increases 2-12 times compared with women not using estrogen, depending on the duration of treatment and the dose of estrogen. After discontinuation of treatment, an increased risk may persist for at least 10 years.

The addition of gestagen in the last 12 days of the month / 28 days of the cycle or continuous combined estrogen-progestogen therapy in women with an unexplained uterus reduces the increased risk of developing hyperplasia and endometrial cancer associated with HRT only with estrogens.

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

The use of preparations for HRT containing only estrogen can lead to precancerous or malignant transformation of the residual foci of endometriosis. Thus, in women who underwent hysterectomy 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.

Mammary cancer

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

The use of estrogen-only HRT preparations

The WHI study found no increased risk of developing breast cancer in women who underwent a hysterectomy and used HRT products containing only estrogen.

In observational studies, in most cases, a slight increase in the risk of diagnosing breast cancer is reported, which is significantly lower than in women using combined estr