Oestrogel transdermal gel 600 g/g – 80 g pump

Active substance formulation Estrozhel ^® – 17β-estradiol is chemically and biologically identical to endogenous human estradiol.

It exerts estrogenic effects on the major target organs: ovary, endometrium, epithelium of the vagina, mammary glands, urethra, hypothalamus, pituitary, liver – similar to the effect of endogenous estrogens in the follicular phase of the menstrual cycle.

Fills deficit of estrogen in women during menopause and reduce the severity of menopausal disorders, including “hot flashes”, sweating at night, atrophic changes in the urinary tract (atrophic vulvovaginitis, dyspareunia, urinary incontinence), psycho-emotional disorders.

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

Estradiol contributes to lower the total cholesterol concentration, without changing the ratio of cholesterol / HDL.

Has procoagulant action, increases the synthesis of hepatic vitamin K-dependent coagulation factors (II, VII, IX, X), reduces the concentration of antithrombin III.

Estradiol prevents bone loss associated with natural menopause or ovariectomy.

estrogen deficiency in post-menopausal associated with reduced bone mineral density (MPLS). The effect of estrogen on the MPLS is dose-dependent and proceeds apparently, as long as held hormone replacement therapy (HRT). After the cancellation of HRT MPLS starts to decrease at the same rate as before the beginning of it.

These randomized, placebo-controlled study “Women’s Health Initiative” (WHI) and meta-analysis of clinical studies have shown that HRT only estrogen or estrogen plus progestin in healthy postmenopausal women reduce the risk of fractures of the hip, spine, and other osteoporotic fractures. There is also limited evidence that HRT can prevent bone fractures in women with low bone mineral density and / or established osteoporosis.

Active substance:
Estradiol

Manufacturer

Bezen Menyufekchuring Beldzhium, Belgium

Prescribing

For women in menopause, Adults prescribed by a doctor, for postmenopausal women

Composition

Excipients:

Carbomer (Carbopol 980) – 5 mg,

trolamine (triethanolamine) – 5 mg,

Ethanol – 400 mg

Purified water – q.s. up to 1 year

Indications

At menopause, estrogen deficiency From
– Hormone replacement therapy for estrogen deficiency symptoms, the treatment of menopausal symptoms associated with natural or surgical menopause;

– prevention of osteoporosis in postmenopausal women at high risk of fractures in case of intolerance or contraindications to the use of other drugs for the prevention of osteoporosis
.

Contraindications

– breast cancer (diagnosed, suspected or history);

– diagnosed or suspected estrogen-dependent malignant tumors of the genital organs (eg endometrial cancer) or the presence of their history;

– bleeding from the genital tract of unknown etiology;

– untreated endometrial hyperplasia;

– identifying acquired or inherited predisposition to venous or arterial thrombosis, including antithrombin III deficiency, protein C deficiency, protein deficit S);

– venous thrombosis and thromboembolism present or in history (including thrombosis and deep vein thrombophlebitis, pulmonary embolism);

– active or recently transferred arterial thromboembolic disease (including angina, myocardial infarction);

– Acute liver disease or having a history of liver disease, if the results of liver function tests have not returned to normal;

– congenital hyperbilirubinemia (Gilbert syndrome, Dubin-Johnson syndrome, Rotor);

– benign or malignant liver tumors in the present or in history;

– cholestatic jaundice or severe cholestatic pruritus (including during a previous pregnancy or while taking sex hormones);

– pregnancy;

– Lactation (breastfeeding);

– porphyria;

-. Hypersensitivity to estradiol and / or any of the excipients of the drug

Be wary: use in patients with such diseases and conditions such as: uterine fibroids; endometriosis; endometrial hyperplasia in history; the presence of risk factors for estrogen dependent tumors (breast cancer in a first relative relationship line); the presence of risk factors for thromboembolic disorders; arterial hypertension; liver disease (including hepatic adenoma) under normal liver function tests indicators; 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; coronary artery disease; sickle cell anemia; chloasma in history; hypertriglyceridemia in history; pancreatitis; hereditary angioedema.

Experience of treating women older than 65 years is limited.

Side effects

The following are the possible side effects of HRT. The frequency of side effects is defined as follows: often (> 1/100; < 1/10), rare (> 1/1000; < 1/100), rare (> 1/10 000; < 1 / 1000).

Immune system: rare – anaphylactic reactions (in women with a history of allergic reactions).

On the part of metabolism and nutrition: rare – impaired glucose tolerance.

Mental Disorders: rare – depression, mood swings; rarely – changes in libido.

From the nervous system: common – headache; rarely – headache, dizziness; rarely – worsening of epilepsy.

With the cardiovascular system: rare – venous thromboembolism; rarely – increased blood pressure.

From the digestive tract: often – nausea, stomach pain; infrequently – flatulence, vomiting.

On the part of the liver and biliary tract: rare – abnormal liver function test parameters.

Skin and subcutaneous tissue disorders: rare – itchy skin; rarely – skin discoloration, acne.

From the genital and breast: often – swelling of the breast, breast pain, breast enlargement, dysmenorrhea, menorrhagia, metrorrhagia, Leucorrhœa, endometrial hyperplasia; infrequently – benign tumors of the mammary glands, increase in uterine size, uterine fibroids, vaginitis, candida vaginitis; rarely – galactorrhea.

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

Other adverse reactions, detected during therapy with estrogen-progestin preparations:

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

The risk of breast cancer

In women using combined estrogen-progestin drugs over 5 years, there is an increase in breast cancer diagnosis risk 2-fold. When estrogen HRT only the risk of developing breast cancer is much lower than with HRT combined estrogen-progestin therapy. The magnitude of the risk of developing breast cancer depends on the duration of HRT.

The risk of endometrial cancer

In postmenopausal women with an intact uterus

The incidence of endometrial cancer is about 5 cases per 1000 women with an intact uterus, who have not performed HRT.

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

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

The addition of a progestogen for at least 12 days cycle to estrogen therapy alone can prevent this increased risk. In the WHI study during ZGG (sequential or continuous), combined estrogen-progestin drugs were found in the increased risk of endometrial cancer (RR 1.0 (0.8-1.2)) for five years.

Ovarian Cancer

Prolonged estrogen HRT only and combined estrogen-progestin drugs was associated with a small increased risk of developing ovarian cancer. In the WHI study with the use of HRT in 1 extra case of ovarian cancer for 2500 women diagnosed within five years.

The risk of venous thromboembolism

In women receiving hormone replacement therapy, there is an increased risk of venous thromboembolism (VTE), in particular deep vein thrombosis or pulmonary embolism, compared with women not receiving HRT in 1.3-3 times. The probability of VTE is higher in the first year of HRT than in subsequent years.

Storage conditions

List B. The drug should be stored in reach of children at a temperature not higher than 25 ° C.

Active substance

Estradiol

Interaction

Use of the drug Estrozhel ^® , together with surfactants (e.g., sodium lauryl sulphate) or other agents which modify the structure or the barrier function of the skin, can reduce its effectiveness. It is therefore necessary to avoid concomitant use of the drug with strong detergents or detergents (e.g., containing benzalkonium or benzethonium chloride), skin care products with a high content of ethanol (astringent, sun) and a keratolytic agent (e.g. salicylic or lactic acid).

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

Accelerated metabolism of estradiol while the use of 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 a strong inhibitor, when combined with sexual hormones, in contrast, exhibit inducing properties.

When transdermal administration avoids the effect of “first pass” through the liver thus, the effect of drugs for transdermal application of HRT with estrogens, perhaps to a lesser extent than after oral application depends on the action of microsomal liver enzyme inducers.

Accelerated metabolism of estradiol while the use of tranquilizers (anxiolytics), narcotic analgesics, agents for anesthesia. The concentration of estradiol in blood plasma is also reduced while the application of certain antibiotics (penicillins and tetracyclines).

The action of estradiol is enhanced in patients receiving folic acid and thyroid hormone drugs.

In clinical practice, enhanced metabolism of estrogens may lead to a weakening effect and changes in the nature of uterine bleeding.

Estradiol increases the effectiveness of lipid-lowering drugs.

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

Special conditions

In the treatment of the symptoms of post-menopausal hormone replacement therapy should be initiated only with the symptoms that adversely affect quality of life. Followed by at least 1 time per year to carry out a detailed assessment of the risks and benefits of HRT and appoint only if the benefit outweighs the risk.

Data concerning the risks associated with HRT in the treatment of premature menopause is limited. However, given the low absolute risk of HRT in younger women, the ratio of profit and risk in these women may be more favorable than in older women.

Before the start or re-appointment of HRT should provide a complete personal and family history. It is necessary to carry out a medical examination in order to identify possible contraindications and complying with the necessary precautions while taking the drug (including examination of the pelvic organs and mammary glands). In the course of treatment recommended for periodic examinations. The frequency and methods included in it, are determined for each case individually. Investigations including mammography, should be carried out in accordance with accepted standards and adapt to the individual clinical needs of each individual case.

During the application of patient HRT need to conduct a thorough evaluation of all the benefits and risks of therapy.

The states that require monitoring

If any of the following conditions are present, have met earlier and / or exacerbate during pregnancy or previous hormone treatment, 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 Estrozhel ^® , in particular:

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

Reasons for immediate discontinuation of therapy

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

• jaundice or deterioration in liver function;
• marked increase in blood pressure;
• newly emerging attacks migraine headaches;
• pregnancy.

hyperplasia and endometrial cancer

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

The addition of progestogen in the last 12 days of the month / 28 day cycle or continuous combined estrogen-progestogen therapy in women with a uterus unremoved mitigates the increased risk of endometrial hyperplasia and cancer associated with HRT use only estrogen.

During the first months of treatment may experience breakthrough bleeding and spotting. If breakthrough bleeding or spotting appears after some time of treatment or continued after discontinuation of treatment, it is necessary to conduct a survey to determine the cause, including endometrial biopsy to exclude endometrial malignancy.

Use of HRT containing estrogen alone can lead to premalignant or malignant transformation residual foci of endometriosis. Thus, women who have undergone hysterectomy because of endometriosis, it is necessary to provide for the addition of a progestogen to estrogen replacement therapy for the prevention of endometrial cancer, if it is known that they have residual endometriosis.

Breast Cancer

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

The use of HRT containing estrogen alone

In the WHI study found no increased breast cancer risk in women who had undergone hysterectomy and applying drugs for HRT containing estrogen alone.

In observational studies, in most cases, it reported a slight increase in the risk of diagnosis of breast cancer, which is significantly lower than in women using combined estrogen-progestin preparations.

The use of combined estrogen-progestin HRT

In the WHI study and epidemiological studies received matching data of an increased risk of breast cancer in women receiving combined estrogen-progestogen HRT; increased risk was detected after about 3 years of treatment.

Additional risk begins to manifest after several years of treatment, but returned to baseline within a few (at most 5) years after stopping treatment.

HRT, especially combined estrogen-progestin medications increases the density of mammographic images which can prevent X-ray detection of breast cancer.

Ovarian Cancer

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of HRT containing estrogen only, is associated with a slight increase in the risk of developing ovarian cancer. In some studies, including WH1 study found that long-term use of combined HRT may cause the same or even less significant risk.

Venous thromboembolism

In women taking HRT, there is an increased risk of VTE, in particular deep vein thrombosis or pulmonary embolism, compared with women not receiving HRT in 1.3-3 times. The probability of VTE is higher in the first year of HRT than in subsequent years.

Patients with known thrombophilic disorders may be at increased risk of VTE and HRT may increase it further. Therefore, HRT is contraindicated in these patients.

The main risk factors for VTE: personal or family history, use of oestrogens, older age, major surgery, prolonged immobilization, severe obesity (BMI over 30 kg / m ² ), pregnancy and the postpartum period, systemic lupus erythematosus , malignant neoplasms.

There is no consensus about the possible role of varicose veins in VTE development.

VTE risk increases with prolonged immobilization, major trauma or major surgical interventions. Receiving HRT should be discontinued for 4-6 weeks before planned surgery on abdominal organs or orthopedic surgery of the lower extremities. Treatment can be resumed after the full recovery of motor abilities.

Women without a history of VTE but with relatives of the first line of kinship undergoing thrombosis at young age, screening may be offered after a detailed discussion of its limitations (at screening identified only a few thrombophilic disorders).

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

Women already receiving continuous treatment with anticoagulants requires careful assessment of potential advantages and risks of HRT.

If, after the start of treatment of VTE develops, the drug should be discontinued. Patients should be pointed out the need to immediately contact a doctor if symptoms of thromboembolism potential pain and / or swelling of the lower limbs, sudden chest pain, shortness of breath).

Coronary Heart Disease

In randomized controlled trials are not received on the preventive effect of the data in relation to myocardial infarction in women with or without coronary artery disease treated with HRT combined estrogen-progestin drugs or only estrogen.

The use of HRT containing estrogen alone

In randomized controlled trials, no evidence of increase in risk of CHD in patients who have undergone a hysterectomy and receiving HRT containing estrogen alone.

The use of combined estrogen-progestin HRT

With combined estrogen-progestin HRT has been a slight increase in the relative risk of CHD. Since the original absolute risk of coronary heart disease is largely dependent on the age, the number of additional cases of coronary heart disease due to the use of estrogen plus progestin in healthy women approaching menopause, extremely small, but increases with age.

An ischemic stroke

HRT combined estrogen-progestin therapy and estrogen only associated with increased risk of ischemic stroke by almost 1.5 times. The relative risk does not change with age and, depending on the time elapsed since the onset of menopause. However, as the baseline risk of stroke is largely dependent on the age, the overall risk of stroke in women receiving HRT will increase with age.

Other conditions

Estrogen causes fluid retention in the body. Patients with cardiac or renal failure should be under constant medical supervision.

Should be closely monitored during the use of HRT in women with a history of hypertriglyceridemia, because in this state, on the background of estrogen therapy are described rare cases of a sharp increase in plasma concentrations of triglycerides, leading to the development of pancreatitis.

Estrogens increase the concentration of thyroxine binding globulin, resulting in an increase in the total concentration of circulating thyroid hormones. The concentrations of free T ₃ and T ₄ are not changed.

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

Chloasma

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. Women with a tendency to develop chloasma, against the use of hormone replacement therapy should minimize exposure to sun or ultraviolet radiation.

The effect on cognitive function

HRT has no effect on the improvement of cognitive function. The WHI study showed a trend toward a possible increase in the risk of dementia in women who began HRT long-term combined estrogen-progestin drugs or estrogen only at the age of 65 years.

Effects on ability to drive vehicles and mechanisms

Effect of estrogen on the ability to drive and explore mechanisms.

Recommendations for use

Estrozhel ^® topically administered continuously or cyclically. The dose and duration of treatment is determined individually.

Typically, the initial dose of 2.5 g of gel 1 time / day, which corresponds to 1.5 mg of estradiol. For most patients, the dose is effective in relieving the symptoms of menopause. If, after one month of therapy efficacy is not achieved, possibly increasing the daily dose to a maximum – 5 g of gel, corresponding to 3 mg of estradiol.

For the beginning and continuation of treatment of menopausal symptoms should use the lowest effective dose for the minimum period of time.

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

In applying the drug in a tube for determining the daily dose using a plastic applicator dispenser 1 dose applicator corresponds to 2.5 g of gel (equivalent to 1.5 mg of estradiol).

In applying the drug vial in a single press on the pump dispenser is released gel 1.25 g (corresponding to 0.75 mg of estradiol) equal to half the daily dose. The average daily dose of 2.5 g of gel (2 clicking on a pump-dispenser).

Use of the drug Estrozhel ^® without the addition of a progestogen only possible in patients with hysterectomy.

Patients with intact (neudalennnoy) uterus during treatment with Estrozhel ^® is recommended to assign the progestogen.

During the menopausal transition and must be treated for at least 3 consecutive weeks, then a break must be followed by a 1-week, while orally administered progestin for 12-14 days last month.

During perimenopause treatment can be carried out from 1 to 25 day of the month at the same time with oral progestogen. During the week-long break may occur menstrualnopodobnye bleeding due to a decrease in the content of sex hormones. It is recommended to use only the progestogen, the reception of which is allowed in conjunction with estrogen.

In post-menopausal estrogen therapy in combination with gestagens carried out continuously.

Prolonged estrogen monotherapy is indicated in women after hysterectomy. In women who have undergone hysterectomy, the addition of progestogen in the absence of a history of endometriosis is not recommended.

Depending on the clinical symptoms after 2-3 treatment cycles performed dose adjustment:

• When prompted hyperestrogenia symptoms such as feeling of tension in the breasts, feeling of fullness in the abdomen and pelvis, anxiety, nervousness, aggressiveness, dose reduction is necessary;
• for symptoms of hypoestrogenism, such as remaining “hot flashes”, dryness of the vaginal mucosa, headache, sleep disturbance, fatigue, tendency to depression, the dose should be increased.

In women, not previously used preparations for hormone replacement therapy, and women who are entering the drug Estrozhel ^® a combined preparation for HRT a continuous reception mode, treatment with Estrozhel ^® , you can start on any day convenient for the patient. In women who are entering the drug Estrozhel ^® with continuous sequential HRT schemes, treatment should be started after the completion of the previous scheme.

If the patient has forgotten to put the gel should be done as soon as possible but not later than 12 hours after applying the drug. If more than 12 hours, applying the preparation Estrozhel ^® is postponed until next time. When the irregular application of the drug (missed doses) may occur breakthrough bleeding and spotting.

Dosing

The gel is applied by patients on their own, in the morning or in the evening, a thin layer to clean, dry skin of the abdomen, the lumbar region, shoulder or forearm to complete absorption. The area of ​​application should not be less than 2 square palms.

Do not place massaging gel application. Avoid getting gel on mammary glands and mucous membranes of the vulva and vagina.

Application deemed to be correct and effective, if the gel is absorbed completely within 2-3 minutes.

If sticky consistency is preserved for more than 5 minutes after the application, so too little gel coated surface of the skin.

The drug is Estrozhel ^® non-staining.

Hands should be washed immediately after gel application.

Use of the drug in a tube. It should open the tube and pierce the metal membrane tubes with a small punch, which is located in the upper portion of the cover tube. The desired dose is removed from the tube by the line applicator.

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

Use of the drug in the vial. It is necessary to remove the cap from the bottle and pushed hard on the pump dispenser, turn the other hand to collect the gel. The dose that is released by the first pressing, may be inaccurate. It is recommended to discard. The vial 64 is designed for pressing. After 64 strokes the amount of gel, which is released at the touch, can be smaller than necessary. Therefore, do not use the vial after 64 taps on the pump dispenser.

Pregnancy and lactation

Estrozhel contraindicated during pregnancy and lactation.

Overdose

About the symptoms of acute overdose have been reported. Breast pain or excessive production of cervical secretions may be indicative of too high a dose of the drug.

The symptoms of overdose of estrogen may be nausea and withdrawal bleeding.

Treatment: No specific antidote; you must stop the drug and symptomatic therapy.