Divigel, transdermal gel 0.1%, 0.5 g bags 28 pcs.

Pharmaceutical group:

estrogen.

Pharmic 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 their first menstruation until menopause), produced by the ovaries. In the cells of the organs targeted by the hormones, estrogens form a complex with specific receptors (found in various organs – the uterus, vagina, urethra, breast, liver, hypothalamus, pituitary), the receptor-ligand complex interacts with estrogen-effector elements of the genome and specific intracellular proteins, inducing the synthesis of i-RNA, proteins and the release of cytokines and growth factors.

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

It has procoagulant effect, increases the synthesis in the liver of vitamin K-dependent clotting factors (II, VII, IX, X), reduces the concentration of antithrombin III.

Enhances concentrations of thyroxine, iron, copper, etc. in the blood. Has anti-atherosclerotic effect, increases HDL, reduces LDL and cholesterol (triglyceride levels increase).

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

After menopause, only small amounts of estradiol (from estrone in the liver and adipose tissue) are produced in the body. The decrease of estradiol produced in ovaries is accompanied in many women by vasodilatory and thermoregulatory instability (“rushes” of blood to the face), sleep disorders, and progressive atrophy of the genitourinary system.
Osteoporosis (mainly of the spine) develops as a consequence of estrogen deficiency.

After ingestion, more estradiol is metabolized in the lumen (microflora) and intestinal wall as well as in the liver (which leads to unphysiologically high plasma concentrations of estrone and estrone sulfate cumulation during long-term therapy) before it enters the bloodstream. The consequences of the accumulation of these metabolites in the body over a long period of time have not yet been elucidated. Oral estrogen use is known to increase protein synthesis (including renin), which leads to increased BP.

Divigel is an alcohol-based gel for external use. When applied to the skin, the alcohol quickly evaporates and estradiol penetrates through the skin and enters the bloodstream. Applying Divigel to an area of 200-400 cm2 (the size of one or two palms) does not affect the amount of estradiol absorbed. However, if Divigel is applied over a larger 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 plasma estrogen concentrations when using Divigel are small.

Pharmacokinetics:

The metabolism is similar to that of natural estrogen. In the blood is almost completely bound to the carrier protein. Subjected to the “first pass” effect through the liver, where it is metabolized to less active products – estrone and estriol. It is excreted by bile into the lumen of the small intestine and reabsorbed. It finally loses its activity as a result of oxidation in the liver. It is 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 is maintained at 0.4 to 0.7. The bioavailability of Divigel is 82%.
Transdermal application of Divigel at a dose of 1.0 mg estradiol (1.0 g Divigel, respectively) produces a maximum plasma Cmax concentration of approximately 157 picomol/L.

The corresponding mean Csr concentration over the dosing interval is 112 picomoles/L. The corresponding mean free plasma Cmin concentration is 82 picomol/L.
Does not cumulate.

Indications

Hormone replacement therapy for symptoms of estrogen deficiency;

The treatment of menopausal syndrome associated with natural or artificial menopause resulting from surgery.

Active ingredient

Composition

1 g gel contains:

Active substance:

estradiol 1 mg;

Associates:

carbomers (carbopol 974 P);

trolamine;

Propylene glycol;

Ethyl alcohol (96%);

Purified water – up to 1.0 g.

How to take, the dosage

Divigel is prescribed for long-term and cyclic therapy. The initial dose is usually 1 g of gel (corresponding 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 after 2-3 cycles individually 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 are recommended to receive gestagen (e.g. medroxyprogesterone acetate, norethisterone, norethisterone acetate or dihydrogesterone) for 10-12 days per cycle during Divigel treatment. After a course of gestagen administration, menstrual-like bleeding should occur. If you have unscheduled or prolonged uterine bleeding it is necessary to establish the cause of its occurrence.

In postmenopausal patients, the cycle time may be extended up to 3 months.

The gel is applied once a day to clean skin on the lower front of the abdomen, lumbar region, shoulders, forearms, or alternately on the right or left buttocks, alternating locations daily. The area of application should be equal in size to 1-2 palms. After application, you should wait a few minutes until the gel dries (2-3 minutes).

The area where the gel was applied must not be rinsed for 1 hour. Accidental contact of Divigel in the eyes should be avoided. Hands should be washed immediately after applying the gel.

If another application of the gel is missed, it should be done as soon as possible, but no later than 12 hours from the time of application according to the regimen. If more than 12 hours have passed, Divigel should be postponed until the next time. Menstrual-like uterine breakthrough bleeding may occur if the drug is used irregularly (missed doses).

Interaction

Estradiol increases the effectiveness of hypolipidemic drugs; weakens the effect of male sex hormone drugs; hypoglycemic, diuretic, hypotensive drugs and anticoagulants; reduces glucose tolerance (dose correction of hypoglycemic drugs).

The metabolism of estradiol is accelerated with concomitant administration with barbiturates, tranquilizers (anxiolytics), opioid analgesics, anesthetics, some antiepileptics (carbamazepine, phenytoin), inducers of microsomal liver enzymes; herbal products containing St. John’s wort (Saint John’s wort).

The concentration of estradiol in blood is also reduced with concomitant use of phenylbutazone and some antibiotics (ampicillin, rifampicin, rifabutin) and antiviral drugs (nevirapine, efavirenz), which is associated with changes in the gut microflora.

The action of estradiol is increased against a background of taking folic acid and thyroid drugs.

Special Instructions

A complete personal and family history should be taken before starting or re-prescribing hormone replacement therapy. A medical examination should be performed to identify possible contraindications and to take the necessary precautions when using the drug (including pelvic organs and breasts).

In the course of treatment, periodic examinations are recommended; the frequency and set of methods included are determined on a case-by-case basis. Examinations, including mammography, should be performed according to accepted norms and taking into account individual clinical features on a case-by-case basis.

The benefits and risks of therapy should be carefully evaluated at the time of the ZGT.

The patient should be kept under constant medical supervision if any of the following diseases or conditions have been previously observed and/or exacerbated by pregnancy or prior hormone therapy Leiomyoma (uterine fibroid), endometriosis; history of or risk factors for thromboembolic disease; risk factors for estrogen-dependent tumors (1st degree of heredity for breast cancer); arterial hypertension liver dysfunction (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 noted that during treatment with Divigel in rare cases there may be a relapse or exacerbation of these diseases.

The therapy should be stopped immediately if contraindications are found and/or in the following situations: jaundice or deterioration of liver function; marked rise in BP; new attacks of migraine-like headache; pregnancy.

The risk of developing endometrial hyperplasia and carcinoma increases if estrogen is taken for a long period of time. To reduce the risk, estrogen therapy in women with a non-operated uterus should be combined with progesterone therapy for at least 12 days during the treatment cycle.

If breakthrough bleeding and/or scanty bleeding occurs after several months on Divigel, investigations should be performed to determine the cause. Studies may include an endometrial biopsy (to rule out endometrial malignization).

Women with a removed uterus due to endometriosis (especially in cases of residual endometriosis) are advised to add progesterone to estrogen-dependent therapy, due to the premalignant or malignant transformation of endometriosis foci during estrogen stimulation.

The risk of developing breast cancer increases with prolonged use of ZGT. According to epidemiological researches among women at the age of 50-70 years old 45 cases out of 1000 are diagnosed with breast cancer. It has been found that among women who are on or have recently taken MHT, the cumulative number of additional breast cancers during the relevant period is 1-3 (on average, 2) additional cases per 1,000 people on MHT for 5 years; 3-9 (on average, 6) cases per 1,000 people on MHT for 10 years; and 5-20 (on average, 12) cases per 1,000 women on MHT for 15 years. An increase in this risk was found mainly in women of thin or normal build. In women with full build (high predisposition to breast cancer) MGT does not additionally increase the risk of developing breast cancer.

The additional risk of developing breast cancer appears with increasing duration of MHT and returns to baseline within about 5 years after stopping treatment.

The combined estrogen-progestogen MHT causes a similar or higher risk than estrogen therapy.

In women who received OGT, the risk of venous thromboembolic disease (deep vein thrombosis of the lower extremities and pulmonary veins) is 2-3 times higher compared to women who did not receive OGT. The likelihood is higher in the first year of MHT than in subsequent years.

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

Patients with a history of thromboembolism or recent spontaneous miscarriage should have further investigations to rule out a predisposition to thrombophlebitis. The use of ZGT in this case should be initiated after a full assessment of risk factors for thrombophlebitis and initiation of anticoagulant therapy. The risk increases with prolonged immobilization, extensive trauma or extensive surgical interventions. ZGT should be discontinued 4-6 weeks before planned abdominal surgery or orthopedic surgery on lower extremities. Treatment may be resumed after full restoration of motor ability. If thromboembolic symptoms develop (sudden chest pain, dyspnea), withdrawal of ZHT may be necessary.

Estrogens cause fluid retention in the body. Patients with impaired renal function should be kept under constant medical supervision due to elevated levels of estradiol and its metabolites in the blood.

Estrogens increase insulin sensitivity and excretion. Patients with diabetes in the first months of ZGT should have their blood glucose levels constantly monitored.

The administration of estrogens increases the risk of surgically confirmed cholelithiasis.

In rare cases of acute increase of triglycerides in blood against a background of taking estrogens development of pancreatitis is possible.

Estrogens increase thyroid-binding globulin levels by increasing total circulating thyroid hormone levels.

Please avoid contact of the gel with the mammary glands and the mucous membranes of the vulva and the vagina.

Impact on driving and operating machinery

Divigel therapy has no effect on the ability to engage in potentially hazardous activities requiring increased attention and rapid psychomotor reactions.

Contraindications

Side effects

CNS and peripheral nervous system disorders: headache, migraine, dizziness, depression, chorea.

Cardiovascular system: increase in BP, thrombophlebitis.

Digestive system disorders: nausea, vomiting, stomach cramps, flatulence, epigastric pain, cholestatic jaundice, cholletithiasis.

Allergic reactions: in the place of application – rash, skin irritation, skin hyperemia, contact dermatitis.

Reproductive system disorders: metrorrhagia, scanty bloody discharge, increased size of uterine leiomyoma, endometrial hyperplasia (when prescribed without combination with progesterone), endometrial carcinoma (in women with intact uterus after menopause), ovarian sclerosis in long-term use, changes in libido.

Endocrine system disorders: breast engorgement (tension and/or increase), weight gain, decreased carbohydrate tolerance.

Metabolic disorders: retention of sodium, calcium and water (edema) with prolonged use; attacks of porphyria.

Others: visual impairment (change in curvature of the cornea), chloasma, melanoderma, vaginal candidiasis.

Overdose

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

Treatment: conducting symptomatic therapy.

The symptoms disappear with dose reduction or with discontinuation of the drug.

Pregnancy use

Divigel is contraindicated in pregnancy and lactation.