Divigel, gel 0.1%, 0.5g, 28pcs

Composition

>

of 1 g of gel contains:

Active ingredient:

estradiol 1 mg;

Auxiliary substances:

carbomers (carbopol 974 P);

trollamine;

propylene glycol;

ethyl alcohol (96%);

purified water – up to 1.0 g

Pharmacological action

Pharmaceutical group:

estrogen.

Pharmaceutical action:

Divigel is an estrogenic drug for external use.

The active ingredient, synthetic 17b-estradiol, is chemically and biologically identical to endogenous human estradiol (produced in women from the first menstrual period until menopause) produced by the ovaries. In the cells of organs affected by hormones, estrogens form a complex with specific receptors (found in various organs – in the uterus, vagina, urethra, mammary gland, liver, hypothalamus, pituitary gland), the receptor-ligand complex interacts with estrogen-effector elements of the genome and specific intracellular proteins that induce the synthesis of i-RNA, proteins and the release of cytokines and growth factors.

It has a feminizing effect on the body. It stimulates the development of the uterus, fallopian tubes, vagina, stroma and ducts of the mammary glands, pigmentation in the area of the nipples and genitals, the formation of secondary sexual characteristics in the female type, the growth and closure of the epiphysis of long tubular bones. Promotes timely rejection of the endometrium and regular bleeding, causes endometrial hyperplasia in high concentrations, suppresses lactation, inhibits bone resorption, stimulates the synthesis of a number of transport proteins (thyroxine-binding globulin, transcortin, transferrin, a protein that binds sex homones), fibrinogen.

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.

Increases blood concentrations of thyroxine, iron, copper, etc. It has an anti-atherosclerotic effect, increases HDL, reduces LDL and cholesterol (the level of triglycerides increases).

Modulates the sensitivity of progesterone receptors and sympathetic regulation of smooth muscle tone, stimulates the transfer of intravascular fluid to tissues, and causes compensatory sodium and water retention. In high doses, it inhibits the degradation of endogenous catecholamines by competing for active catechol-O-methyltransferase receptors.

After menopause, the body produces only a small amount of estradiol (from estrone found in the liver and in adipose tissue). A decrease in the content of estradiol produced in the ovaries is accompanied in many women by vasomotor and thermoregulatory instability (“hot flashes” of blood to the skin of the face), sleep disorders, as well as progressive atrophy of the genitourinary system. Due to estrogen deficiency, osteoporosis develops (mainly in the spine).

After ingestion, a larger amount of estradiol is metabolized in the lumen (microflora) and intestinal wall, as well as in the liver before entering the bloodstream (which leads to unphysiologically high concentrations of estrone in plasma, and with long – term therapy-to the accumulation of estrone and estrone sulfate). The consequences of accumulating these metabolites in the body over a long period of time are not yet clear. It is known that oral use of estrogens causes an increase in protein synthesis (including renin), which leads to an increase in blood pressure.

Divigel is an alcohol-based gel for external use. When applied to the skin, alcohol quickly evaporates and estradiol penetrates through the skin, entering the circulatory system. Applying Divigel to an area of 200-400 cm2 (the size of one or two palms) does not affect the amount of absorbed estradiol. However, if Divigel is applied over a large area, the degree of absorption is significantly reduced. To some extent, estradiol is retained in the subcutaneous tissues, from where it is gradually released into the bloodstream.

Transdermal application avoids the first stage of hepatic metabolism, so that fluctuations in the concentration of estrogen in blood plasma when using Divigel are insignificant.

Pharmacokinetics:  

Metabolism is similar to that of natural estrogens. In the blood, it almost completely binds to the carrier protein. It undergoes the “first pass” effect through the liver, where it is metabolized to less active products-estrone and estriol. It is released by bile into the lumen of the small intestine and reabsorbed. Finally loses its activity as a result of oxidation in the liver. Excreted mainly by the kidneys in the form of sulfates and glucuronides, small amounts of estradiol, estrone and estriol are also found in the urine.

During treatment with Divigel, the estradiol/estrone ratio remains at the level of 0.4-0.7. The bioavailability of Divigel is 82%. Transdermal application of Divigel in a dose of 1.0 mg of estradiol (1.0 g of Divigel, respectively) creates a maximum concentration of Cmax in blood plasma of approximately 157 picomol/l.

The corresponding average concentration of Ssr for the dosing interval is 112 picomol/l. The corresponding average free concentration of Cmin in blood plasma is 82 picomol/l. It doesn’t accumulate.

Indications

Hormone replacement therapy for symptoms of estrogen deficiency;

treatment of menopausal syndrome associated with natural or artificial menopause, which developed as a result of surgical intervention.

Use during pregnancy and lactation

Divigel is contraindicated for use during pregnancy and lactation.

Contraindications

• breast cancer (diagnosed, suspected or history);
• diagnosed or suspected estrogen-malignant tumors of the ovaries, uterus, endometrium;
• benign and malignant neoplasms of the genital organs (cancer of the cervix and uterine body, uterine, vulvar cancer, ovarian cancer) in women under the age of 60 years;
• benign tumors of the breast in women up to the age of 60 years;
• vaginal bleeding of unknown etiology and a tendency to uterine bleeding;
• endometrial hyperplasia;
• pituitary tumors;
• diffuse connective tissue diseases;
• inflammatory diseases of female genital organs (oophoritis, endometritis);
• hyperestrogenia stage of menopause;
• spontaneous thromboembolic venous disease (including in history);
• deep vein thrombosis, pulmonary embolism (including in the anamnesis);
• thrombosis and acute thrombophlebitis (including in the anamnesis);
• congenital hyperbilirubinemia (Gilbert syndrome, Dubin-Johnson, Rotor);
• liver tumors (hemangioma, liver cancer);
• cerebrovascular disease (ischemic stroke, hemorrhagic stroke);
• diabetes mellitus, retinopathy, angiopathy;
• sickle cell disease;
• fat metabolism disorders;
• cholestatic jaundice or severe cholestatic pruritus (including strengthening their manifestations during pregnancy or in patients receiving steroid medications);
• otosclerosis (including exacerbation during pregnancy);
• hypersensitivity to estradiol and/or other components of the drug.

With caution:  bronchial asthma, migraine, epilepsy, hypertension, heart failure, CHD, hepatic and / or renal failure, edematous syndrome, endometriosis, fibrocystic mastopathy, porphyria. Experience with use in women over 65 years of age is limited.

Divigel should not be applied to the mammary glands, face, genital area, or irritated skin areas.

Side effects

From the central nervous system and peripheral nervous system:  headache, migraine, dizziness, depression, chorea.

From the cardiovascular system:  increased blood pressure, thrombophlebitis.

From the digestive system:  nausea, vomiting, stomach cramps, flatulence, epigastric pain, cholestatic jaundice, cholelithiasis.

Allergic reactions:  at the site of application – rash, skin irritation, skin hyperemia, contact dermatitis.

From the side of the reproductive system:  metrorrhagia, scanty spotting, increased uterine leiomyoma, endometrial hyperplasia (when prescribed without a combination with progesterone), endometrial carcinoma (in women with an intact uterus after menopause), ovarian sclerosis with prolonged use, changes in libido.

From the endocrine system:  engorgement (tension and / or enlargement) of the mammary glands, weight gain, decreased tolerance to carbohydrates.

From the side of metabolism:  sodium, calcium and water retention (edema) with prolonged use; attacks of porphyria.

Other services:  visual impairment (changes in the curvature of the cornea), chloasma, melasma, vaginal candidiasis.

Interaction

Estradiol increases the effectiveness of lipid-lowering drugs; weakens the effect of male sex hormone preparations; hypoglycemic, diuretic, antihypertensive drugs and anticoagulants; reduces glucose tolerance (dose adjustment of hypoglycemic drugs).

The metabolism of estradiol is accelerated when taken simultaneously with barbiturates, tranquilizers (anxiolytics), opioid analgesics, anaesthetics, some antiepileptic drugs (carbamazepine, phenytoin), inducers of microsomal liver enzymes; herbal preparations containing St. John’s wort (St. John’s wort).

The concentration of estradiol in the blood also decreases with the simultaneous use of phenylbutazone and certain antibiotics (ampicillin, rifampicin, rifabutin) and antiviral drugs (nevirapine, efavirenz), which is associated with changes in the intestinal microflora.

The effect of estradiol increases against the background of taking folic acid and thyroid medications.

How to take, course of use and dosage

of Divigel is prescribed for long-term and cyclical therapy. The initial dose is usually 1 g of gel (equivalent to 1 mg of estradiol) per day, but is determined by the severity of symptoms. Depending on the clinical picture, the dose can be changed individually after 2-3 cycles from 500 mg to 1.5 g of gel per day (which corresponds to 500 mcg to 1.5 mg of estradiol per day).

Patients with an intact (non-operated) uterus during treatment with Divigel are recommended to prescribe a progestogen (for example, medroxyprogesterone acetate, norethisterone, norethisterone acetate or dihydrogesterone) for 10-12 days in each cycle. After a course of gestagen use, menstrual-like bleeding should occur. In case of extraordinary or prolonged uterine bleeding, it is necessary to determine the cause of their occurrence.

In postmenopausal patients, the cycle duration can be extended to 3 months.

The gel is applied 1 time / day on the clean skin of the lower part of the anterior wall of the abdomen, lumbar region, shoulders, forearms, or alternately on the right or left buttocks, alternating daily application sites. The area of application should be equal in size to 1-2 palms. After applying the drug, wait a few minutes until the gel dries (2-3 minutes).

The place of application of the gel should not be rinsed for 1 h. Avoid accidental contact with Divigel in the eyes. Wash your hands immediately after applying the gel.

If you miss the next application of the gel, you should do it as soon as possible, but not later than within 12 hours from the moment of applying the drug according to the scheme. If more than 12 hours have passed, then the use of Divigel should be postponed until the next time. With irregular use of the drug (missed doses), menstrual-like uterine breakthrough bleeding may occur.

Overdose

Symptoms: breast or pelvic pain, bloating, anxiety, irritability, nausea, vomiting, and in some cases, metrorrhagia.

Treatment: conducting symptomatic therapy.

Symptoms disappear when the dose is reduced or the drug is discontinued.

Special instructions

Before starting or re-prescribing hormone replacement therapy, it is necessary to collect a complete personal and family history. A medical examination should be performed to identify possible contraindications and follow the necessary precautions when using the drug (including the pelvic organs and mammary glands).

In the course of treatment, it is recommended to conduct periodic examinations, the frequency and set of methods included in it are determined for each specific case individually. Studies, including mammography, should be conducted in accordance with accepted standards and taking into account individual clinical characteristics in each individual case.

During HRT, all benefits and risks of therapy should be carefully evaluated.

The patient should be constantly monitored by a doctor for any of the following diseases or conditions that were previously observed and/or worsened during pregnancy or previous hormone therapy: leiomyoma (uterine fibromyoma), endometriosis; a history of thromboembolic diseases or risk factors for their occurrence; risk factors for estrogen-dependent tumors (1st degree hereditary breast cancer); arterial hypertension; liver function disorders (adenoma); diabetes mellitus with or without vascular lesions; cholelithiasis; migraine and/or (severe) headache; systemic lupus erythematosus; a history of endometrial hyperplasia; epilepsy; bronchial asthma; otosclerosis. It should be borne in mind that against the background of treatment with Divigel, in rare cases, relapse or exacerbation of these diseases is possible.

Therapy should be stopped immediately if contraindications are found and/or in the following situations: jaundice or deterioration of liver function; marked increase in blood pressure; new attacks of migraine-like headache; pregnancy.

When taking estrogens for a long time, the risk of developing endometrial hyperplasia and carcinoma increases. To reduce the risk, it is necessary to combine estrogen therapy in women with an unoperated uterus with progesterones for at least 12 days during the treatment cycle.

If breakthrough bleeding and/or scanty spotting occurs after several months of taking Divigel, studies should be conducted to determine the causes of their occurrence. Studies may include an endometrial biopsy (to rule out endometrial malignancy).

Women with uterine removal due to endometriosis (especially in cases of residual endometriosis) are recommended to add progesterone to estrogen-dependent therapy, due to premalignant or malignant transformation of endometriosis foci during estrogen stimulation.

Prolonged use of HRT increases the risk of developing breast cancer. According to epidemiological studies, among women aged 50 to 70 years,45 cases out of 1000 are diagnosed with breast cancer. It was found that among women taking or recently taking HRT, the total number of additional cases of breast cancer in the corresponding period is 1-3 (on average – 2) additional cases per 1000 people receiving HRT for 5 years; 3-9 (on average – 6) cases per 1000 people receiving HRT for 10 years and 5-20 (on average – 12) cases per 1000 women receiving HRT for 15 years. An increase in this risk was found mainly in women with a thin or normal build. Overweight women (high predisposition to breast cancer) HRT does not additionally increase the risk of breast cancer.

An additional risk of developing breast cancer appears with increasing duration of HRT and returns to baseline within approximately 5 years after discontinuation of treatment.

Combined oestrogen-progestogen HRT causes a similar or higher risk compared to oestrogen therapy.

In women who received HRT, the risk of developing thromboembolic venous diseases (deep vein thrombosis of the lower extremities and pulmonary veins) is increased by 2-3 times compared to women who did not receive HRT. The probability is higher in the first year of HRT than in subsequent years.

The main risk factors for thromboembolic complications: individual or family history, severe obesity (body mass index more than 30 kg / m2), systemic lupus erythematosus.

Patients with a history of thromboembolism or recent spontaneous miscarriages should be further investigated to rule out a predisposition to thrombophlebitis. The use of HRT in this case should be initiated after a complete assessment of the risk factors for thrombophlebitis and the start of anticoagulant therapy. The risk increases with prolonged immobilization, extensive injuries, or extensive surgery. HRT should be discontinued 4-6 weeks before planned abdominal surgery or orthopedic surgery on the lower extremities. Treatment can be resumed after full recovery of motor ability. If thromboembolic symptoms develop (sudden chest pain, dyspnoea), HRT may need to be discontinued.

Estrogens cause fluid retention in the body. Patients with impaired renal function should be constantly monitored by a doctor due to increased levels of estradiol and its metabolites in the blood.

Estrogens increase insulin sensitivity and increase its excretion. Patients with diabetes mellitus in the first months of HRT are shown to constantly monitor their blood glucose levels.

Taking estrogens increases the risk of surgically confirmed gallstone disease.

In rare cases of a sharp increase in the level of triglycerides in the blood against the background of taking estrogens, pancreatitis may develop.

Estrogens increase the level of thyroid-binding globulin, increasing the level of total circulating thyroid hormones.

Avoid getting the gel on the mammary glands and mucous membranes of the vulva and vagina.

Influence on the ability to drive motor vehicles and manage mechanisms

Divigel therapy does not affect the ability to engage in potentially dangerous activities that require increased attention and speed of psychomotor reactions.

Product form

Transdermal gel

Storage conditions

At a temperature not exceeding 25 °C

Shelf life

3 years

Active ingredient

Estradiol

Conditions of release from pharmacies

By prescription

Dosage form

gel for external use

Purpose

For postmenopausal women, For adults as prescribed by a doctor, For women in the menopausal period

Indications

Osteoporosis, Menopause