Divigel

General characteristics. Structure:

Active ingredients: 1 mg of oestradiol in the form of a gemigidrat.

Excipients: carbomers (карбопол 974P), троламин, propylene glycol, ethanol of 96%, the water purified.

The drug for transdermalny use intended for treatment of symptoms of the oestrogenic deficit connected with the natural or artificial menopause which developed owing to surgical intervention.

Pharmacological properties:

Pharmacodynamics. Oestrogenic drug for external use. Active ingredient - synthetic 17β-эстрадиол, chemically is also biologically identical to the endogenous human oestradiol (which is formed in an organism of women since the first periods up to a menopause), produced by ovaries. In cells of bodies to which effect of hormones is directed estrogen forms a complex with specific receptors (are found in various bodies - in a uterus, a vagina, an urethra, a mammary gland, a liver, a hypothalamus, a hypophysis); the complex a receptor ligand interacts with the estrogeneffektorny elements of a genome and specific intracellular proteins inducing synthesis i-RNK, proteins and release of cytokines and growth factors.

Exerts feminizing impact on an organism. Stimulates development of a uterus, uterine tubes, vaginas, a stroma and channels of mammary glands, pigmentation in nipples and generative organs, formation of secondary sexual characteristics on female type, growth and closing of an epiphysis of long tubular bones. Promotes timely rejection of an endometria and regular bleedings, in big concentration causes an endometria hyperplasia, suppresses a lactation, oppresses a resorption of a bone tissue, stimulates synthesis of a number of transport proteins (tiroksinsvyazyvayushchy globulin, transcortinum, transferrin, the protein connecting sexual gomona), fibrinogen. Has procoagulant effect, induces synthesis in a liver vitamin of K-dependent blood-coagulation factors (II, VII, IX, X), reduces concentration of antithrombin III.

Increases concentration in blood of thyroxine, iron, copper. Has anti-atherosclerotic effect, increases the maintenance of LPVP, reduces LPNP and cholesterol (level of triglycerides increases). Modulates sensitivity of receptors to progesterone and sympathetic regulation of a tone of smooth muscles, stimulates transition of intravascular liquid to fabrics and causes a compensatory delay of sodium and water. In high doses interferes with degradation of endogenous catecholamines, competing for active receptors of KOMT.

After a menopause in an organism only the insignificant amount of oestradiol is formed (of the estrone which is in a liver and in fatty tissue). Decrease in content of the oestradiol produced in ovaries is followed at many women by vasomotor and temperature-controlled instability (rushes of blood to face skin), frustration of a dream, and also the progressing atrophy of bodies of urinogenital system.

Owing to deficit of estrogen osteoporosis develops (mainly a backbone). After intake the bigger amount of oestradiol before getting to a blood stream, is metabolized in a gleam (microflora) and an intestines wall, and also in a liver (that results in not physiologically high concentration of estrone in plasma, and at long therapy - to cumulation of estrone and estrone of sulfate). Effects of accumulation of these metabolites in an organism are not found out for a long time yet. It is known that oral administration of estrogen causes increase in protein synthesis (including a renin) that leads to increase in the ABP.

Pharmacokinetics. Absorption and distribution. When putting gel alcohol quickly evaporates, and oestradiol gets through skin, at the same time its most part gets to a system blood stream at once, and a quantity of oestradiol is late in hypodermic cellulose and is released in a system blood stream gradually. Divigel's drawing on the area of 200-400 cm2 (the size of one or two palms) does not influence amount of the absorbed oestradiol. However if Divigel is applied on the big square, then extent of absorption considerably decreases.

Divigel's bioavailability makes 82%. At transdermalny use of Divigel in a dose of 1 mg of oestradiol (1 g of Divigel) Cmax in a blood plasma makes about 157 pmol/L, average concentration - 112 pmol/L, the minimum concentration - 82 pmol/L.

Does not kumulirut.

Metabolism and removal. Transdermalny drawing allows to avoid the first stage of hepatic metabolism, thanks to it fluctuations of concentration of estrogen in a blood plasma at Divigel's use are insignificant.

Metabolism 17β-эстрадиола is similar to metabolism of natural estrogen. In blood almost completely contacts protein carrier. Is exposed to effect of "the first passing" through a liver where it is metabolized to less active products - estrone and estriol. It is allocated with bile in a gleam of a small bowel and repeatedly absorbed. Finally loses activity as a result of oxidation in a liver.

During treatment by Divigel a ratio oestradiol/estrone remains at the level of 0.4-0.7.

Removal. It is removed generally by kidneys in the form of sulfates and glucuronides, in urine small amounts of oestradiol, estrone and estriol are also found.

Indications to use:

- replacement hormonal therapy at symptoms of deficit of estrogen;

- treatment of the menopausal syndrome connected with the natural or artificial menopause which developed owing to surgical intervention.

Route of administration and doses:

Divigel appoint for long and cyclic therapy. The initial dose, as a rule, makes 1 g of gel (that corresponds to 1 mg of oestradiol) a day, but is defined by degree of manifestation of symptoms. Depending on a clinical picture the dose can be changed after 2-3 cycles individually from 500 mg to 1.5 g of gel a day (that corresponds from 500 mkg to 1.5 mg of oestradiol a day).

Patients with the intact (not operated) uterus during treatment by Divigel are recommended to fix гестаген (for example - a medroksiprogesterona acetate, Norethisteronum, Norethisteronum acetate or дигидрогестерон) within 10-12 days in each cycle. After course use of a gestagen there has to come menstrualnopodobny bleeding. At extraordinary or long uterine bleedings it is necessary to establish the reason of their emergence surely.

At patients in the postmenopauzny period duration of a cycle can be increased up to 3 months.

Gel is applied by 1 times/days on clean skin of the lower part of a front wall of a stomach, lumbar area, shoulders, forearms or serially on the right or left buttocks, daily alternating sites of application. The area of drawing has to be equal in size to 1-2 palms. After putting drug it is necessary to wait several minutes until gel dries up (2-3 min.).

The site of application of gel cannot be rinsed during 1 h. It is necessary to avoid accidental hit of Divigel in eyes. It is necessary to wash up hands at once after putting gel.

In case of the admission of the next use of gel it is necessary to make it as soon as possible, however not later than during 12 h from the moment of putting drug according to the scheme. If there passed more than 12 h, then Divigel's use should be postponed until the following time. At irregular use of drug (the passed doses) there can be menstrualnopodobny uterine breakthrough bleedings.

Features of use:

Before the beginning or repeated purpose of replacement hormonal therapy it is necessary to collect the full personal and family anamnesis. It is necessary to conduct medical examination for the purpose of identification of possible contraindications and respect for necessary precautions at drug use (including bodies of a small pelvis and chest glands).

In the course of treatment it is recommended to conduct periodic examinations, the frequency and a set of the methods entering it are defined for each case individually. Researches, including mammography, should be conducted according to accepted standards and taking into account specific clinical features in each separate case.

During ZGT it is necessary to estimate carefully all advantages and risk of therapy.

The patient has to be under constant control of the doctor in case of any of the following diseases or states which were observed earlier and/or became aggravated at pregnancy or the previous hormonal therapy: leiomyoma (uterus fibromyoma), endometriosis; thromboembolic diseases in the anamnesis or risk factors of their emergence; risk factors of estrogenozavisimy tumors (1st degree of heredity of a breast cancer); arterial hypertension; abnormal liver functions (adenoma); a diabetes mellitus with defeats of vessels or without them; cholelithiasis; migraine and/or (severe) headache; system lupus erythematosus; an endometria hyperplasia in the anamnesis; epilepsy; bronchial asthma; otosclerosis. It must be kept in mind that against the background of treatment by Divigel the recurrence or an exacerbation of the listed diseases are in rare instances possible.

Therapy should be stopped immediately if contraindications and/or in the following situations are found: jaundice or deterioration in functions of a liver; the expressed increase in the ABP; new attacks of a migrenepodobny headache; pregnancy.

At reception of estrogen the risk of development of a hyperplasia of an endometria and carcinoma increases for a long time. For decrease in a risk degree it is necessary to combine therapy by estrogen at women with not operated uterus from progesterona of at least 12 days during a treatment cycle.

In case of developing of breakthrough bleedings and/or scanty bloody allocations after several months of reception of Divigel it is necessary to conduct researches for identification of the reasons of their emergence. Researches can include an endometria biopsy (for an endometria malignancy exception).

Addition of progesterone to estrogenozavisimy therapy, owing to premalignantny or malignantny transformation of the centers of endometriosis at oestrogenic stimulation is recommended to women with a remote uterus because of endometriosis (especially in cases of residual endometriosis).

At prolonged use of ZGT the risk of development of a breast cancer increases. According to epidemiological researches among women aged from 50 up to 70 years in 45 cases from 1000 the breast cancer is diagnosed. It is established that among the women who are accepting or recently accepting ZGT, the total quantity of additional cases of a breast cancer during the corresponding period makes 1-3 (on average - 2) additional a case on 1000 people receiving ZGT within 5 years; 3-9 (on average - 6) cases on 1000 people receiving ZGT within 10 years and 5-20 (on average - 12) cases on 1000 women receiving ZGT within 15 years. Increase in such risk is revealed generally at women of a thin or normal constitution. At women of a full constitution (high predisposition to a breast cancer) ZGT does not increase in addition risk of development of a breast cancer.

The additional risk of development of cancer of mammary glands appears with increase in duration of reception of ZGT and is returned to initial approximately within 5 years after the treatment termination.

Combined ZGT estrogen-progestagenovaya causes similar or higher risk in comparison with oestrogenic therapy.

The women receiving ZGT, risk have a development of thromboembolic diseases of veins (a deep vein thrombosis of the lower extremities and pulmonary veins), it is increased by 2-3 times in comparison with the women who were not receiving ZGT. The probability is higher in the first year of carrying out ZGT, than in the next years.

Major factors of risk of tromboembolic episodes: individual or family anamnesis, gross obesity (index of body weight more than 30 kg/sq.m), system lupus erythematosus.

Patients with instructions in the anamnesis on thromboembolisms or recent spontaneous abortions need to conduct additional researches for the purpose of an exception of predisposition to thrombophlebitis. Use of ZGT in this case has to be begun after an omnibus estimate of risk factors of development of thrombophlebitis and the beginning of anticoagulating therapy. The risk increases at a long immobilization, extensive injuries or extensive surgical interventions. ZGT should be stopped in 4-6 weeks prior to the planned surgeries on abdominal organs or orthopedic lower extremity operations. Treatment can be resumed after a complete recovery of motive ability. At development of thromboembolic symptoms (sudden thorax pains, диспноэ) cancellation of ZGT can be required.

Estrogen causes a liquid delay in an organism. Patients with renal failures have to be under constant control of the doctor owing to increase in level of oestradiol and its metabolites in blood.

Estrogen increases sensitivity to insulin and increases its removal. The sick diabetes mellitus in the first months of ZGT showed constant control of level of glucose in blood.

Reception of estrogen increases risk of developing of surgically confirmed cholelithiasis.

In rare instances of sharp increase in level of triglycerides in blood against the background of reception of estrogen development of pancreatitis is possible.

Estrogen increases the level of the tireoid-connecting globulin, increasing the level of total quantity of the circulating hormones of a thyroid gland.

It is necessary to avoid hit of gel on mammary glands and mucous membranes of a vulva and a vagina.

Influence on ability to driving of motor transport and to control of mechanisms

Therapy by Divigel does not exert impact on ability to be engaged in potentially dangerous types of activity requiring special attention and speed of psychomotor reactions.

Side effects:

From TsNS and peripheral nervous system: headache, migraine, dizzinesses, depression, chorea.

From cardiovascular system: increase in the ABP, thrombophlebitis.

From the alimentary system: nausea, vomiting, gastric gripes, a meteorism, pain in epigastric area, cholestatic jaundice, a cholelithiasis.

Allergic reactions: in a site of application - rash, irritation of skin, a dermahemia, contact dermatitis.

From reproductive system: a metrorrhagia, scanty bloody allocations, increase in the sizes of a leiomyoma of a uterus, an endometria hyperplasia (at appointment without combination with progesterone), an endometria carcinoma (at women with an intact uterus is after a menopause), a sclerosis of ovaries at prolonged use, change of a libido.

From endocrine system: a nagrubaniye (tension and/or increase) of mammary glands, increase in body weight, decrease in tolerance to carbohydrates.

From a metabolism: a delay of sodium, calcium and waters (hypostases) at prolonged use; porphyria attacks.

Others: vision disorder (change of curvature of a cornea), hloazma, melanoderma, vaginal candidiasis.

Interaction with other medicines:

Oestradiol increases efficiency of hypolipidemic means; weakens effect of drugs of male sex hormones; hypoglycemic, diuretic, hypotensive drugs and anticoagulants; reduces tolerance to glucose (dose adjustment of hypoglycemic drugs).

Metabolism of oestradiol accelerates at a concomitant use with barbiturates, tranquilizers (anxiolytics), opioid analgetics, anesthetics, some antiepileptic means (carbamazepine, Phenytoinum), inductors of microsomal enzymes of a liver; the vegetable drugs containing a grass of the St. John's Wort which is made a hole (Saint John's grass).

Concentration of oestradiol in blood also decreases at simultaneous use of phenylbutazone and some antibiotics (ampicillin, rifampicin, рифабутин) and antiviral drugs (not Virapinum, эфавиренз) that is connected with intestinal microflora changes.

Effect of oestradiol increases against the background of reception of folic acid and drugs of a thyroid gland.

Contraindications:

— the breast cancer (diagnosed, suspected or in the anamnesis);

— the diagnosed or suspected estrogenozavisimy malignant tumors of ovaries, a uterus, an endometria;

— high-quality and malignant new growths of generative organs (cancer of a neck and a body of the womb, a hysteromyoma, vulva cancer, ovarian cancer) at women aged up to 60 years;

— high-quality new growths of a mammary gland at women aged up to 60 years;

— vaginal bleedings of not clear etiology and tendency to uterine bleedings;

— endometria hyperplasia;

— hypophysis tumors;

— diffusion diseases of connecting fabric;

— inflammatory diseases of female generative organs (salpingo-oophoritis, endometritis);

— hyper oestrogenic stage of a climacteric;

— spontaneous thromboembolic diseases of veins (including in the anamnesis);

— a deep vein thrombosis, a pulmonary embolism (in т.ч.в the anamnesis);

— thrombophlebitis and acute thrombophlebitis (including in the anamnesis);

— inborn hyperbilirubinemias (Gilbert's syndromes, Cudgel Johnson, Rotor);

— liver tumors (hemangioma, liver cancer);

— disturbances of cerebral circulation (ischemic stroke, hemorrhagic stroke);

— diabetes mellitus, retinopathy, angiopatiya;

— sickemia;

— disturbances of a lipometabolism;

— cholestatic jaundice or a severe cholestatic itch (including strengthening of their manifestations during the previous pregnancy or against the background of reception of steroid drugs);

— an otosclerosis (including its aggravation during pregnancy);

— hypersensitivity to oestradiol and/or other components of drug.

With care: bronchial asthma, migraine, epilepsy, arterial hypertension, heart failure, ischemic heart disease, liver and/or renal failure, edematous syndrome, endometriosis, fibrous and cystous mastopathy, porphyria. Experience of use for women is more senior than 65 years is limited.

Divigel it is not necessary to apply on mammary glands, a face, area of genitalias, and also on the angry sites of skin.

Overdose:

Symptoms: mammary gland pains or in pelvic area, abdominal distention, uneasiness, irritability, nausea, vomiting, in certain cases - a metrorrhagia.

Treatment: performing symptomatic therapy.

Symptoms disappear at a dose decline or at drug withdrawal.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

1 g - bags multilayer (28) - packs cardboard.
1 g - a sachet (91) - packs cardboard.