Divigel

Divigel – oestrogenic medicine for external use, identical to endogenous human oestradiol.

Form of release and structure

Drug produce in the form of gel 0,1% for external use: homogeneous opalescent substance (on 0,5 or 1 g of gel in one-dose three-layered packages from the laminated aluminum, on 28 or 91 package in a cardboard box).

Is a part of 1 bag of gel:

• Active ingredient: гемигидрат oestradiol (in recalculation on oestradiol) – 0,5 or 1 mg;
• Auxiliary components: троламин, propylene glycol, carbomers (карбопол 974 P), alcohol (96%), the purified water.

Indications to use

Divigel appoint as the replacement hormonal therapy (RHT) at symptoms of a lack of estrogen. Also drug is used for treatment of a menopausal syndrome which is connected with artificial (being a consequence of surgical intervention) or a natural menopause.

Contraindications

Absolute:

• Malignant estrogenzavisimy tumors of an endometria, ovaries, the uterus (suspected or diagnosed);
• High-quality new growths of mammary glands and generative organs (hysteromyoma, cancer of a body and neck of uterus, ovarian cancer, vulva cancer) at women aged up to 60 years;
• Breast cancer (in the anamnesis, suspected or diagnosed);
• Bleedings vaginal obscure etiology, tendency to uterine bleedings;
• Endometria hyperplasia;
• Pathological new growths of a hypophysis;
• DDCF (diffusion diseases of connecting fabric);
• Gynecologic diseases of inflammatory character (salpingo-oophoritis, vulvitis, endometritis);
• Hyper oestrogenic stage of a climacteric;
• Pulmonary embolism, deep vein thrombosis, spontaneous clotting diseases of veins (including in the anamnesis);
• Thrombophlebitis, acute thrombophlebitis (including in the anamnesis);
• Liver tumors (liver cancer, hemangioma);
• Inborn hyperbilirubinemias (Gilbert's syndromes, Rotor, Cudgel Johnson);
• Cholestatic jaundice or severe cholestatic itch (including strengthening of their manifestations against the background of therapy by steroid drugs or in the previous pregnancy);
• Disturbances of cerebral circulation (hemorrhagic, ischemic stroke);
• Angiopatiya, retinopathy, diabetes mellitus;
• Drepanocytic anemia;
• Disturbances of lipidic exchange;
• Otosclerosis (including aggravations during pregnancy);
• Hypersensitivity to drug components.

Relative contraindications (Divigel it is necessary to apply with care): migraine, bronchial asthma, epilepsy, heart failure, arterial hypertension, coronary heart disease, edematous syndrome, renal and/or liver failure, fibrous and cystous mastopathy, endometriosis, porphyria.

At women 65 years are aged more senior experience of use of Divigel is limited.

Route of administration and dosage

Divigel is intended for transdermalny use, use of gel for long and cyclic therapy is allowed.

The standard initial daily dose makes 1000 mg of gel (1 mg of oestradiol) and can be adjusted depending on expressiveness of symptoms.

Taking into account a clinical picture after 2-3 cycles the daily dose can be changed individually in the range from 500 mg to 1500 mg of gel (0,5-1,5 mg of oestradiol).

Gel is recommended to be applied once a day, daily alternating places of application, on previously cleared skin: in the lower part of a front wall of a stomach, in a waist, shoulders, forearms or serially on the left or right buttocks. The area of drawing in size has to be equal to 1-2 palms. After application it is necessary to wait 2-3 minutes and to allow gel to dry up; within an hour the site of application of gel cannot be rinsed. It is important to avoid accidental hit of drug in eyes. After putting gel it is necessary to wash up hands at once.

In case of the admission of the procedure, it is necessary to apply as soon as possible gel, but no later than in 12 hours from the moment of its use according to the schedule. If there passed more than 12 hours, then the procedure is recommended to be postponed until the following time. In case of irregular use of drug (the frequent admission of doses) there can be menstrualnopodobny uterine bleedings (bleeding of "break").

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

Patients with not operated (intact) uterus during therapy are recommended to appoint at the same time гестаген (Norethisteronum, Norethisteronum acetate, acetate of a medroksiprogesteron, дигидрогестерон) in each cycle for 10-12 days (after such course menstrualnopodobny bleeding has to begin). When developing extraordinary or long uterine bleedings it is necessary to see a doctor to establish their reason.

In the postmenopauzny period increase in duration of a cycle up to 3 months is allowed.

Side effects

• Central and peripheral nervous system: migraine, dizzinesses, headache, chorea, depression;
• Cardiovascular system: thrombophlebitis, increase in arterial pressure;
• Alimentary system: gastric gripes, a meteorism, nausea, vomiting, pain in epigastric area;
• Allergic reactions in the place of application: rash, irritation of skin, dermahemia, contact dermatitis;
• Reproductive system: a metrorrhagia (chaotic vaginal bleedings) or scanty bloody allocations, an endometria hyperplasia (if appointment without progesterone), increase in a leiomyoma of a uterus, an endometria carcinoma (at women in a postmenopause with an intact uterus); at prolonged use – a sclerosis of ovaries, change of a libido;
• Endocrine system: a nagrubaniye (increase and/or tension) of a breast, increase in weight, decrease in tolerance to carbohydrates;
• Liver and bile-excreting system: cholestatic jaundice, cholelithiasis, porphyria attacks;
• Water salt metabolism: in case of prolonged use a delay ^{of Na+}, _Sa2 ⁺ and waters (hypostases);
• Others: change of curvature of a cornea (vision disorder), melanoderma, hloazma, vaginal candidiasis.

Symptoms of overdose are: abdominal distention, pains in pelvic area and mammary glands, irritability, uneasiness, nausea, vomiting; in certain cases – a metrorrhagia (disappear at a dose decline or at full drug withdrawal). Treatment – symptomatic.

Special instructions

Before or repeated appointment of Divigel it is necessary to collect the full family and personal anamnesis of the patient. It is necessary to conduct medical examination (including chest glands and bodies of a small pelvis) for identification of contraindications and respect for precautions when using drug. In the course of therapy it is recommended to conduct regular examinations: a set of the methods entering it and frequency are defined for each patient individually. Researches, including mammography, have to be conducted according to accepted standards and in each separate case to adapt to individual clinical requirements.

At ZGT it is important to carry out careful assessment of all advantages and risks of therapy.

Constant control of the doctor at any of the following diseases / states which were observed and/or became aggravated earlier at the previous hormonal therapy or pregnancy is necessary: endometriosis, a fibromyoma of a uterus (leiomyoma), clotting diseases in the anamnesis or risk factors of their emergence, arterial hypertension, risk factors of formation of estrogenzavisimy tumors (heredity of a breast cancer of the I degree), disturbances of work of a liver (liver adenoma), a diabetes mellitus with defeats of vessels or without them, a cholelithiasis, a severe headache and/or migraine, epilepsy, a system lupus erythematosus, data on an endometria hyperplasia in the anamnesis, bronchial asthma, an otosclerosis. It is important to consider that against the background of therapy by oestradiol the aggravation or a recurrence of the listed diseases are possible (in rare instances).

It is necessary to interrupt immediately therapy if contraindications are found and/or it is observed: deterioration in functions of a liver, jaundice, the expressed increase in the arterial pressure (AP), resuming of attacks of migrenepodobny headache, pregnancy approach.

The risk of development of a carcinoma and hyperplasia of an endometria increases in case of reception of estrogen for a long time. For reduction of a risk degree at women with not operated uterus it is necessary to combine therapy by Divigel with reception of progesteron not less than 12 days during a cycle.

At emergence of scanty bloody allocations and breakthrough bleedings after several months of use of gel carrying out researches for identification of the reasons of such reaction is recommended (including an endometria biopsy – for the purpose of an endometria malignancy exception).

Women at whom because of endometriosis the uterus is removed (especially if it is about residual endometriosis) need to include progesterone in structure of estrogenzavisimy therapy, owing to malignantny or premalignantny transformation of the centers of endometriosis in case of oestrogenic stimulation.

Long use of ZGT increases risk of development of a breast cancer generally at women of a normal or thin constitution. For women of a full constitution who have a predisposition to a breast cancer initially high ZGT does not increase it in addition.

The risk of development of a breast cancer appears with increase in duration of use of Divigel and is returned to an initial state within about 5 years after the therapy termination.

The replacement hormonal therapy combined estrogen-progestagenovaya in comparison with oestrogenic monotherapy causes similar or higher risk of development of various pathologies.

At the patients receiving ZGT, the risk of development of a thromboembolism of veins (fibrinferments of pulmonary veins and deep veins of the lower extremities) is increased by 2-3 times in comparison with the women who were not receiving ZGT. In the first year of carrying out ZGT the probability of a disease is higher, than in the next years.

Major factors of risk of tromboembolic episodes: a gross obesity with a body weight index ≥ 30 ^kg/sq.m, the family or individual anamnesis, a system lupus erythematosus.

In the presence of data in the anamnesis on a thromboembolism or recent spontaneous abortions it is necessary to conduct additional researches to exclude predisposition to thrombophlebitis. ZGT has to be in that case begun after an omnibus estimate of risk factors of emergence of thrombophlebitis and the beginning of anticoagulating therapy. It is necessary to consider that the risk increases in case of a long immobilization, at extensive injuries or extensive operative measures. ZGT needs to be stopped in 4-6 weeks prior to the planned orthopedic lower extremity operations or surgeries on abdominal organs. Therapy can be resumed after a complete recovery of motive ability, but in case of development of thromboembolic symptoms (диспноэ, sudden thorax pain) its cancellation can be required.

Estrogen causes a delay in a liquid organism therefore at a renal failure constant control of the doctor as in blood the level of oestradiol and its metabolites increases is necessary.

Constant control of level of glucose in blood as estrogen increases sensitivity to insulin is shown to patients with a diabetes mellitus at the beginning of ZGT and strengthens its removal.

Reception of estrogen increases risk of surgically confirmed cholelithiasis.

Occasionally, against the background of Divigel's use, the level of triglycerides in blood sharply increases that can lead to development of pancreatitis.

At ZGT increase in total quantity of the circulating hormones of a thyroid gland as estrogen increases the level of the tireoid-connecting globulin is possible.

Medicinal interaction

Oestradiol weakens effect of diuretics, hypoglycemic and antihypertensives, anticoagulants, drugs of male sex hormones; increases efficiency of hypolipidemic drugs; reduces tolerance to glucose (correction of a dose of hypoglycemic means is necessary).

Metabolism of oestradiol accelerates a concomitant use of barbiturates, tranquilizers (anxiolytics), narcotic 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 decreases also in case of simultaneous use of phenylbutazone and some antibiotics (rifampicin, рифабутин, ampicillin, not Virapinum, эфавиренз) that is connected with changes of intestinal microflora.

Effect of oestradiol amplifies against the background of administration of drugs of a thyroid gland and folic acid.

Terms and storage conditions

To store in the place, unavailable to children, at a temperature not above 25 °C.

Period of validity – 3 years.