Divigel
Divigel: instructions for use and reviews
- 1. Release form and composition
- 2. Pharmacological properties
- 3. Indications for use
- 4. Contraindications
- 5. Method of application and dosage
- 6. Side effects
- 7. Overdose
- 8. Special instructions
- 9. Application during pregnancy and lactation
- 10. Use in childhood
- 11. In case of impaired renal function
- 12. For violations of liver function
- 13. Use in the elderly
- 14. Drug interactions
- 15. Analogs
- 16. Terms and conditions of storage
- 17. Terms of dispensing from pharmacies
- 18. Reviews
- 19. Price in pharmacies
Latin name: Divigel
ATX code: G03CA03
Active ingredient: estradiol (oestradiolum)
Manufacturer: Orion Corporation (Finland)
Description and photo update: 2019-10-09
Prices in pharmacies: from 608 rubles.
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Divigel is an estrogenic topical drug identical to endogenous human estradiol.
Release form and composition
The drug is produced in the form of a 0.1% gel for external use: a homogeneous opalescent substance (0.5 or 1 g of gel in single-dose three-layer bags of laminated aluminum, in a cardboard box 28 or 91 bags and instructions for using the Divigel).
The composition of 1 sachet of gel includes:
- Active ingredient: estradiol hemihydrate (in terms of estradiol) - 0.5 or 1 mg;
- Auxiliary components: trolamine, propylene glycol, carbomers (carbopol 974 R), ethyl alcohol (96%), purified water.
Pharmacological properties
Pharmacodynamics
Synthetic 17β-estradiol - the active component of Divigel, is biologically and chemically identical to endogenous human estradiol, which is produced in the female body by the ovaries, from the moment of the first menstruation until the onset of menopause.
Estrogens form a complex with specific receptors, which are found in cells of various target organs - in the vagina, uterus, mammary gland, urethra, pituitary gland, hypothalamus, liver. The interaction of the “receptor-ligand” complex with estrogen-effector elements of the genome and specific intracellular proteins, which induce the synthesis of mRNA and proteins, as well as the release of growth factors and cytokines, is noted.
Synthetic 17β-estradiol has a feminizing effect on the body. As a result of the use of Divigel, the stimulation of the development of the uterus, vagina, fallopian tubes, stroma and ducts of the mammary glands, pigmentation in the genital area and nipples, the formation of secondary sexual characteristics in the female type, growth and closure of the epiphyses of long tubular bones is noted.
The use of synthetic estradiol promotes timely endometrial rejection and regular bleeding. In the case of therapy in high concentrations, it leads to endometrial hyperplasia, suppression of lactation, inhibition of bone resorption, stimulation of the synthesis of a number of transport proteins (including thyroxine-binding globulin, transferrin, transcortin, globulin that binds sex hormones), fibrinogen.
Other effects of 17β-estradiol:
- Procoagulant action, decrease in the concentration of antithrombin III, increase in the synthesis of vitamin K-dependent factors of blood coagulation (II, VII, IX, X) in the liver;
- Increase in the concentration of iron, thyroxine, copper, etc in the blood;
- Anti-atherosclerotic effect, increasing the concentration of triglycerides, reducing the content of LDL (low density lipoprotein) and cholesterol, increasing HDL (high density lipoprotein);
- Modulation of the sensitivity of receptors to progesterone and sympathetic regulation of smooth muscle tone, stimulation of the transition of intravascular fluid into the tissue and compensatory water and sodium retention;
- Prevention of degradation of endogenous catecholamines, competitive effect for active receptors of catechol-O-methyltransferase (when used in large doses).
During the postmenopausal period, only a small amount of estradiol is formed in the body (from estrone found in adipose tissue and liver). A decrease in the content of estradiol produced in the ovaries in many women is accompanied by sleep disorders, thermoregulatory and vasomotor instability (manifested in the form of rush of blood to the skin of the face), as well as progressive atrophy of the mucous membrane of the urogenital system.
Due to a deficiency of estrogen, the development of osteoporosis (mainly of the spine) is noted. A large amount of estradiol after oral administration before entering the bloodstream is metabolized in the lumen (microflora) and the intestinal wall, as well as in the liver (this causes non-physiologically high plasma concentrations of estrone, and with prolonged use - cumulation of estrone and estrone sulfate). The consequences of long-term accumulation of these metabolites in the body have not yet been clarified. It has been established that oral administration of estrogens leads to an increase in the biosynthesis of proteins (including renin) and, as a consequence, to an increase in blood pressure.
Pharmacokinetics
Divigel is an alcohol-based external gel. Alcohol after application to the skin evaporates quickly, estradiol enters the circulatory system, penetrating through the skin. The application of the gel on an area of 200 to 400 cm 2 (approximately the size of one or two palms) does not affect the amount of absorbed estradiol. However, when applied to a large area, the degree of absorption of the substance is significantly reduced. Estradiol is retained to some extent in the subcutaneous tissues, from where it is gradually released into the bloodstream.
With the transdermal method of application, it is possible to avoid the first stage of hepatic metabolism, and therefore fluctuations in the plasma concentration of estradiol in the blood are insignificant.
When administered in doses of 0.5 mg, 1 mg and 1.5 mg of estradiol, the average C max (maximum concentration of the substance) in the blood plasma is 143, 247 and 582 pmol / L, respectively, the C average values (average concentrations) during the interval between doses - 75, 124 and 210 pmol / l, respectively, the average C min (minimum concentration of the substance) - 92, 101 and 152 pmol / l, respectively. The ratio of estradiol / estrone against the background of the use of Divigel remains in the range of 0.4-0.7, while during therapy with oral estrogens it usually decreases to <0.2.
The bioavailability of estradiol when used in the form of a gel is 82%.
With the transdermal route of administration, the mechanism of metabolism and excretion of estradiol is similar to that of natural estrogens. Does not cumulate.
Indications for use
Divigel is prescribed as hormone replacement therapy (HRT) for symptoms of estrogen deficiency. Also, the drug is used to treat climacteric syndrome, which is associated with artificial (resulting from surgery) or natural menopause.
Contraindications
Absolute:
- Malignant estrogen-dependent tumors of the endometrium, ovaries, uterus (suspected or diagnosed);
- Benign neoplasms of the mammary glands and genitals (uterine fibroids, cancer of the body and cervix, ovarian cancer, vulvar cancer) in women under the age of 60;
- Breast cancer (history, suspected or diagnosed);
- Vaginal bleeding of unexplained etiology, tendency to uterine bleeding;
- Endometrial hyperplasia;
- Pathological neoplasms of the pituitary gland;
- DZST (diffuse connective tissue diseases);
- Gynecological diseases of an inflammatory nature (salpingo-oophoritis, vulvitis, endometritis);
- Hyperestrogenic stage of the climacteric period;
- Pulmonary embolism, deep vein thrombosis, spontaneous thromboembolic diseases of the veins (including a history);
- Thrombophlebitis, acute thrombophlebitis (including a history);
- Liver tumors (liver cancer, hemangioma);
- Congenital hyperbilirubinemia (Gilbert's, Rotor's, Dubin-Johnson's syndromes);
- Cholestatic jaundice or severe cholestatic pruritus (including an increase in their manifestations during therapy with steroid drugs or in a previous pregnancy);
- Cerebral circulation disorders (hemorrhagic, ischemic stroke);
- Angiopathy, retinopathy, diabetes mellitus;
- Sickle cell anemia;
- Lipid metabolism disorders;
- Otosclerosis (including exacerbations during pregnancy);
- Hypersensitivity to drug components.
Relative contraindications (Divigel should be used with caution): migraine, bronchial asthma, epilepsy, heart failure, arterial hypertension, ischemic heart disease, edema, renal and / or hepatic failure, fibrocystic mastopathy, endometriosis, porphyria.
Divigel is not prescribed during pregnancy / lactation.
In women over the age of 65, experience with the drug is limited.
Divigel, instructions for use: method and dosage
Gel Divigel is intended for transdermal use, it is allowed to use the gel for long-term and cyclic therapy.
The standard starting daily dose is 1000 mg gel (1 mg estradiol) and may be adjusted according to the severity of symptoms.
Taking into account the clinical picture after 2-3 cycles, the daily dose of Divigel can be changed individually in the range from 500 mg to 1500 mg gel (0.5-1.5 mg estradiol).
It is recommended to apply the gel once a day, alternating the places of application every day, on previously cleansed skin: in the lower part of the anterior abdominal wall, in the area of the lower back, shoulders, forearms, or alternately on the left or right buttocks. The size of the application area should be equal to 1-2 palms. After application, you need to wait 2-3 minutes and let the gel dry; the place of application of the gel must not be rinsed for an hour. It is important to avoid accidental contact with the eyes. After applying the gel, wash your hands immediately.
In case of skipping the procedure, it is necessary to apply the gel as soon as possible, but no later than 12 hours from the moment of its application according to the schedule. If more than 12 hours have passed, it is recommended to postpone the procedure until the next time. In case of irregular use of Divigel (frequent missed doses), menstrual uterine bleeding (breakthrough bleeding) may occur.
Divigel Gel should not be applied to the face, breasts, genital area and irritated skin.
During therapy, patients with an unoperated (intact) uterus are recommended to simultaneously prescribe a gestagen (norethisterone, norethisterone acetate, medroxyprogesterone acetate, dihydrogesterone) in each cycle for 10-12 days (after such a course, menstrual bleeding should begin). If you experience extraordinary or prolonged uterine bleeding, you should consult a doctor to determine the cause.
In the postmenopausal period, an increase in the duration of the cycle is allowed up to 3 months.
Side effects
- Central and peripheral nervous system: migraine, dizziness, headache, chorea, depression;
- Cardiovascular system: thrombophlebitis, increased blood pressure;
- Digestive system: stomach cramps, flatulence, nausea, vomiting, pain in the epigastric region;
- Allergic reactions at the site of application: rash, skin irritation, skin flushing, contact dermatitis;
- Reproductive system: metrorrhagia (indiscriminate vaginal bleeding) or scanty spotting, endometrial hyperplasia (if administered without progesterone), an increase in uterine leiomyoma, endometrial carcinoma (in postmenopausal women with an intact uterus); with prolonged use - ovarian sclerosis, changes in libido;
- Endocrine system: breast engorgement (enlargement and / or tension), weight gain, decreased carbohydrate tolerance;
- Liver and biliary system: cholestatic jaundice, cholelithiasis, porphyria attacks;
- Water-salt metabolism: in case of prolonged use, delay of Na +, Ca 2 + and water (edema);
- Others: change in the curvature of the cornea (visual impairment), melasma, chloasma, vaginal candidiasis.
Overdose symptoms are: bloating, pain in the pelvic region and mammary glands, irritability, anxiety, nausea, vomiting; in some cases - metrorrhagia (disappear when the dose is reduced or when the drug is completely canceled). Treatment is symptomatic.
Overdose
Overdose with transdermal use of the substance is unlikely.
The main symptoms: irritability, anxiety, pain in the mammary glands, vomiting, nausea, sometimes metrorrhagia.
Therapy: symptomatic. The gel must be washed off the skin. Symptoms disappear with dose reduction or after complete withdrawal of the Divigel.
special instructions
Before starting or re-prescribing Divigel, a complete family and personal history of the patient should be collected. It is necessary to conduct a medical examination (including the breasts and pelvic organs) to identify contraindications and observe precautions when using the drug. In the process of therapy, it is recommended to carry out regular examinations: the set of methods included in it, and the frequency are determined for each patient individually. Research, incl. mammography should be carried out in accordance with accepted standards and in each case be adapted to individual clinical needs.
With HRT, it is important to conduct a thorough assessment of all the benefits and risks of therapy.
It is necessary to constantly monitor a doctor for any of the following diseases / conditions that were observed and / or exacerbated earlier during previous hormonal therapy or pregnancy: endometriosis, uterine fibroids (leiomyoma), a history of thromboembolic diseases or risk factors for their occurrence, arterial hypertension, risk factors for formation estrogen-dependent tumors (heredity of grade I breast cancer), liver dysfunction (liver adenoma), diabetes mellitus with or without vascular lesions, cholelithiasis, severe headache and / or migraine, epilepsy, systemic lupus erythematosus, history of endometrial hyperplasia, bronchial asthma, otosclerosis. It is important to consider that against the background of estradiol therapy, an exacerbation or relapse of the listed diseases is possible (in rare cases).
It is necessary to immediately interrupt therapy with Divigel if contraindications are found and / or is observed: deterioration of liver function, jaundice, marked increase in blood pressure (BP), resumption of migraine-like headache attacks, pregnancy.
The risk of developing endometrial carcinoma and hyperplasia is increased if estrogen is taken for a long time. To reduce the risk in women with a non-operated uterus, it is necessary to combine Divigel therapy with progesterone intake for at least 12 days during the cycle.
In the event of scanty bleeding and breakthrough bleeding after several months of using the gel, it is recommended to conduct studies to identify the causes of such a reaction (including endometrial biopsy - in order to exclude endometrial malignancy).
Women who have had their uterus removed due to endometriosis (especially when it comes to residual endometriosis) should include progesterone in estrogen-dependent therapy due to malignant or pre-malignant transformation of endometriosis foci in the case of estrogenic stimulation.
Long-term use of HRT increases the risk of developing breast cancer, mainly in women of normal or thin physique. For women with a full physique, in whom the predisposition to breast cancer is initially high, HRT does not increase it further.
The risk of developing breast cancer appears with an increase in the duration of use of Divigel and returns to its original state within approximately 5 years after stopping therapy.
Combined estrogen-progestogen hormone replacement therapy compared with estrogen monotherapy causes a similar or higher risk of developing various pathologies.
In patients receiving HRT, the risk of venous thromboembolism (thrombosis of the pulmonary veins and deep veins of the lower extremities) is 2-3 times higher than in women who did not receive HRT. In the first year of HRT, the likelihood of illness is higher than in subsequent years.
Major risk factors for thromboembolic complications: severe obesity with a body mass index ≥ 30 kg / m 2, a family or personal history of systemic lupus erythematosus.
If there is a history of thromboembolism or recent spontaneous miscarriages, additional research should be done to rule out a predisposition to thrombophlebitis. HRT in this case should be started after a full assessment of the risk factors for thrombophlebitis and the initiation of anticoagulant therapy. It should be borne in mind that the risk increases in the case of prolonged immobilization, with extensive injuries or extensive surgical interventions. HRT should be discontinued 4-6 weeks before planned orthopedic operations on the lower extremities or surgical operations on the abdominal organs. Therapy can be resumed after full recovery of motor ability, but if thromboembolic symptoms develop (dyspnea, sudden chest pain), it may need to be canceled.
Estrogens cause fluid retention in the body, therefore, in case of impaired renal function, constant medical supervision is necessary, since the level of estradiol and its metabolites increases in the blood.
Patients with diabetes mellitus at the beginning of HRT are shown constant control of blood glucose levels, since estrogens increase insulin sensitivity and enhance its excretion.
Taking estrogen increases the risk of surgically confirmed gallstone disease.
Occasionally, against the background of the use of Divigel, the level of triglycerides in the blood rises sharply, which can lead to the development of pancreatitis.
With HRT, an increase in the total amount of circulating thyroid hormones is possible, since estrogens increase the level of thyroid-binding globulin.
Application during pregnancy and lactation
Divigel is not indicated for use during pregnancy / lactation. In case of pregnancy, the drug should be canceled immediately.
According to the results of most epidemiological studies, there is no teratogenic or fetotoxic effect of synthetic estradiol.
Pediatric use
In children, there are no indications for the use of Divigel.
With impaired renal function
In case of renal failure, Divigel should be used under medical supervision.
For violations of liver function
- Benign / malignant liver tumors (including a burdened history), acute liver disease (including a burdened history, until the results of liver function tests return to normal values): therapy is contraindicated;
- Liver disease (including liver adenoma) with normal liver function tests: Divigel should be used with caution.
Use in the elderly
In women over 65 years of age, the experience of using Divigel is limited.
Drug interactions
Estradiol weakens the effect of diuretics, hypoglycemic and antihypertensive drugs, anticoagulants, male sex hormone preparations; increases the effectiveness of lipid-lowering drugs; reduces glucose tolerance (adjustment of the dose of hypoglycemic agents is necessary).
The metabolism of estradiol accelerates the simultaneous intake of barbiturates, tranquilizers (anxiolytics), narcotic analgesics, drugs for anesthesia, some antiepileptic drugs (carbamazepine, phenytoin), inducers of microsomal liver enzymes, herbal preparations containing the herb St. John's wort (St. John's herb).
The concentration of estradiol in the blood also decreases in the case of the simultaneous use of phenylbutazone and some antibiotics (rifampicin, rifabutin, ampicillin, nevirapine, efavirenz), which is associated with changes in the intestinal microflora.
The effect of estradiol is enhanced by taking thyroid drugs and folic acid.
Analogs
The analogue of Divigel is Estrogel.
Terms and conditions of storage
Keep out of the reach of children at a temperature not exceeding 25 ° C.
The shelf life is 3 years.
Terms of dispensing from pharmacies
Dispensed by prescription.
Reviews about Divigel
There are more positive reviews about Divigel than negative ones. The drug is considered effective and easy to use. Therapy usually does not cause allergies and other adverse reactions, sometimes weight gain and minor pain in the lower abdomen are noted. Many women are unhappy with the gel's sticky consistency. The cost is estimated from affordable to high.
The price of Divigel in pharmacies
The approximate price for Divigel (28 sachets, 1 g each) is 585–877 rubles.
Divigel: prices in online pharmacies
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Drug name Price Pharmacy |
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Divigel 0.1% gel transdermal 0.5 g 28 pcs. RUB 608 Buy |
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Divigel gel transderm. 0.1% 500mg 28 pcs. 630 RUB Buy |
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Divigel 0.1% gel transdermal 1 g 28 pcs. 828 RUB Buy |
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Divigel gel transderm. 0.1% 1g 28 pcs. 921 RUB Buy |
Maria Kulkes Medical journalist About the author
Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".
Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!
