Divigel

Divigel is a medicine used to eliminate disorders caused by menopause. It has a strong estrogenic effect.

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Indications Divigel

It is used when performing HRT in women with signs of estrogen deficiency, which has a variety of etiologies.

In addition, it is prescribed for menopause, which can develop due to the natural aging of the body and the onset of menopause, or menopause of surgical origin (this includes menopause that occurs due to ovariectomy, as well as radiation castration).

At the same time, Divigel is used to prevent the occurrence of osteoporosis during the post-menopausal stage and as a supporting substance during pregnancy and its stable course after IVF.

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Release form

The drug is released in the form of a transdermal gel contained in multilayer sachets with a volume of 0.5 or 1 g. There are 28 sachets inside the box.

Pharmacodynamics

The severity of the medicinal effect of the drug used depends on the activity of estradiol. The drug acts by compensating for the deficiency of the female sex hormone, and also by stimulating the activity of estrogen endings located inside target cells.

Estradiol is able to diffuse into the target cell, then move into the cell nucleus and form a compound with specific estrogen endings. As a result, the R-L complex is created.

Estrogen endings are located inside a variety of tissues, but most of them are located inside the female reproductive organs: the uterus, mammary glands, liver, ovaries with vagina, HGS and bones.

The formed R-L complex has the following properties:

• interacts with estrogen-effector components of the genome, as well as a specific protein located inside cells;
• promotes the stimulation of binding of matrix RNA (informational), as well as proteins;
• helps release cytokines;
• helps increase the activity of growth factors.

Like other estrogens, estradiol provokes feminization of the body. For example, the active element of the drug, 17-β-estradiol, has the following effect:

• stimulates the development of female genitalia, connective tissues where specific components of various organs of the female genital system (stroma) are located, and along with this, the ducts of the mammary glands;
• promotes the development of pigmentation in the genital areas and nipples;
• stimulates the formation of secondary sexual characteristics of a feminine type;
• helps the development and growth of bone epiphyses;
• creates conditions for timely rejection of the uterine endometrium;
• helps regulate the frequency of menstruation;
• suppresses the production of maternal milk, as well as bone resorption;
• has procoagulant activity;
• increases the rate of restoration of an adequate number of leukocytes during conditions that were caused by radiation damage and manifested in the form of suppression of hematopoietic processes within the bone marrow.

With increased estradiol levels, endometrial hyperplasia develops. In addition, the production of some transport proteins is stimulated (globulin, which synthesizes thyroxine, circulating in the blood, transferrin, and also globulins, synthesizing corticosteroids and androgens). Stimulation of fibrinogen production also occurs.

An increase in estradiol levels is accompanied by the following effects:

• blood levels of thyroxine, iron and copper, etc. increase;
• the production of factors responsible for blood clotting and dependent on vitamin K within the liver tissue is potentiated;
• the amount of antithrombin 3, a specific protein contained within the blood coagulation system, decreases;
• the degradation of internal adrenaline and noradrenaline catecholamines is prevented (this effect develops when estradiol competes for the active endings of the COMT enzyme).

Other important properties of estradiol are:

• prevention of atherosclerosis;
• promoting an increase in blood HDL levels;
• lowering blood LDL levels;
• a decrease in blood cholesterol levels with a simultaneous increase in triglyceride levels.

The drug changes the characteristics of the sensitivity of the endings in relation to progesterone, the properties of sympathetic regulation of smooth muscle tone, and at the same time stimulates the transport of the liquid plasma part to the tissue area and the processes of compensatory retention of sodium ions with liquid.

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Pharmacokinetics

After oral administration, a significant amount of estradiol undergoes metabolic processes within the intestinal microflora (intestinal walls together with the lumen) and liver before penetrating into the bloodstream. Under the influence of this effect, a non-physiological increase in plasma estrone levels occurs. Long-term therapy leads to the accumulation of estrone together with estrone sulfate.

There is little information about the consequences of the accumulation of estradiol metabolic products over a long period. It has only been revealed that the use of estrogens results in increased protein binding (for example, renin). This factor causes a significant increase in blood pressure values.

Divigel has an alcohol base. After the epidermis is treated with the medicine, the alcohol evaporates rather quickly, and estradiol, which is the active component of the medicine, passes through the skin, penetrating into the circulatory system.

When treating an epidermal area with the gel, the area of which is approximately the size of 1-2 palms (about 200-400 cm ² ), the volume of absorbed estradiol does not change. Absorption values decrease if the size of the treated area increases.

A small portion of estradiol remains within the subcutaneous layer, from where it is later gradually released into the bloodstream. Due to transdermal application, the initial hepatic phase of metabolism does not develop, due to which the change in plasma estrogen levels is not of decisive importance.

The metabolic processes of 17-β-estradiol are similar to the metabolism of naturally produced estrogens. After passing into the bloodstream, the component is almost entirely synthesized with the transport protein. The level of bioavailability of orally administered estradiol is almost 100%.

Excretion of estradiol biological breakdown products is mainly carried out through the kidneys in the form of glucuronides with sulfates. A small amount of estrone together with estradiol and estriol is recorded in the urine.

When performing medicinal procedures with the application of Divigel, the ratio of estradiol/estrone values fluctuates in the range of 0.4-0.7. The level of bioavailability of the drug is approximately 82%.

After treatment of the epidermis with a gel in a portion of 1 mg 17-β-estradiol (1 g of gel substance), the plasma Cmax value is 157 picomoles/l. The mean intraplasmic level over the dosing interval is 112 picomoles/l. Free mean intraplasmic values are 82 picomoles/l.

There is no accumulation of the drug.

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Dosing and administration

The drug Divigel can be used in cyclic and long-term treatment.

Initially, the usual dosage prescribed is 1 mg of estradiol per day (1 g of gel), but sometimes the dosage may differ depending on the severity of the disease.

After completing 2-3 treatment cycles using the drug, the initial dose can be adjusted taking into account changes in the clinical picture of an individual woman.

The most suitable dosage is selected individually; usually it is 0.5-1.5 mg of the substance per day.

The attending physician should select the day of the cycle on which to start taking the medication.

People with an intact uterus should additionally be prescribed gestagenic substances during Divigel therapy. They should be used for 10-12 days per cycle.

After the completion of the cycle of using the gestagen, the woman should have a period of menstruation. If the patient experiences prolonged or extraordinary uterine bleeding, it is necessary to determine the cause of their occurrence.

It is important to take into account that during postmenopause the duration of one menstrual cycle can be extended up to 3 months.

The medicinal gel should be applied to the epidermis in the area of the lower part of the anterior abdominal wall, shoulders with forearms, lower back, or alternately treat the buttocks once a day (recommended at the same time). It is necessary to alternate the treatment areas daily.

The optimal area is considered to be the size of 1-2 palms. The applied gel must dry (this requires a maximum of 2-3 minutes). It is forbidden to rinse or wash the area treated with gel for the next hour.

In cases where a woman has forgotten to carry out the treatment with the medicine, it is necessary to carry out the procedure immediately after it is remembered (in this case, the period when the gel can be applied is a maximum of 12 hours from the time of using the medicine according to the schedule). In a situation where the period of absence is more than 12 hours, the treatment is postponed until the time of the next scheduled procedure.

With irregular use of the drug (with frequent skipping of doses), menstrual-like bleeding from the uterus of a breakthrough nature may develop.

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Use Divigel during pregnancy

Divigel should not be prescribed during breastfeeding or pregnancy.

If pregnancy occurs during therapy, the use of the gel should be stopped immediately. However, the final decision regarding the need for further use of the drug after pregnancy has been established should be made by the attending physician.

Epidemiological studies have shown that no fetotoxic or teratogenic effects occur with accidental use of estrogen in early pregnancy.

Contraindications

Main contraindications:

• the presence of strong sensitivity to estradiol or other auxiliary elements contained in the composition of the drug;
• suspected, established, or existing history of breast cancer;
• history of, suspected or already established malignant tumors of an estrogen-dependent nature inside the uterus, ovaries or endometrium;
• the presence of benign tumors located inside the reproductive system or mammary glands (for example, uterine fibroids) in women under 60 years of age;
• uterine bleeding of unknown etiology, as well as a predisposition to its occurrence;
• hyperplastic endometrial processes;
• neoplasms in the pituitary gland;
• diffuse connective tissue lesions;
• the presence of inflammatory genital pathologies in a woman (for example, endometritis or salpingo-oophoritis);
• climacteric stage, during which an increase in estrogen levels is observed;
• thromboembolic venous lesions that are spontaneous (this also includes pathologies present in the anamnesis);
• diseases in which deep vein thrombosis is observed (this list also includes diseases present in the anamnesis);
• thrombophlebitis (acute or history);
• congenital diseases in which increased blood bilirubin levels are observed (this includes constitutional hyperbilirubinemia, enzymopathic jaundice or Rotor syndrome);
• the presence of liver neoplasms (including liver carcinoma or hemangioma);
• diseases in which a disorder of blood circulation inside the brain develops (for example, hemorrhagic or ischemic stroke);
• sickle cell anemia;
• diseases associated with disorders of fat metabolism;
• diabetes mellitus (also with complications in the form of angiopathy or retinopathy);
• intrahepatic cholestasis or severe stage of cholestatic pruritus (including those aggravated by previous pregnancy or use of steroids);
• diseases associated with the middle ear, arising from pathological bone growth inside it (also exacerbation of this disorder during pregnancy).

The gel should be used with extreme caution in the following situations:

• in case of asthma, epileptic seizures or migraine attacks;
• with persistently elevated blood pressure values;
• in case of insufficiency associated with liver, cardiac or renal function;
• in case of edema syndrome or coronary heart disease;
• in hematoporphyria;
• for mastopathy.

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Side effects Divigel

Sometimes the medication causes the appearance of individual side effects:

• problems associated with the functioning of the PNS and CNS: migraine attacks, headaches and dizziness, as well as chorea and depression;
• disorders affecting the function of the cardiovascular system: thrombophlebitis and increased blood pressure;
• digestive disorders: vomiting, colic in the stomach, bloating and nausea, and in addition pain in the epigastric region;
• Reproductive organ damage: vaginal bleeding of irregular form (metrorrhagia), scanty vaginal discharge, increase in the size of uterine leiomyoma, as well as significant proliferation of the endometrium (usually occurs when the drug is not combined with progesterone). In addition, carcinoma of the uterine body may develop (often in patients with an intact uterus and menopause), changes associated with libido and Stein-Leventhal syndrome (in case of prolonged use of the drug);
• signs associated with the endocrine system: increased tension, engorgement or enlargement of the mammary glands, decreased tolerance to carbohydrates and the appearance of extra pounds;
• disorders associated with the biliary tract and liver: cholelithiasis, intrahepatic cholestasis or attacks of hematoporphyria;
• EBV imbalance: fluid and calcium retention with sodium, which is why swelling may occur with prolonged use of the gel;
• local allergic reactions: rashes, contact dermatitis, hyperemia of the epidermis and severe irritation;
• other symptoms: visual disturbances, which manifest themselves in the form of changes in its curvature, and in addition to this, melasma, the formation of chloasma and thrush.

Overdose

In case of exceeding the standard dose of the drug, the following pathological manifestations may occur: flatulence, breast tenderness, bloating in the pelvic area, vomiting, a feeling of strong irritability or anxiety, as well as metrorrhagia or nausea.

If any of these signs occur, symptomatic measures must be taken. Often, negative symptoms disappear after reducing the dosage or stopping the drug.

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Interactions with other drugs

When estradiol is combined with certain drugs, the following drug effects develop:

• increasing the activity of hypolipidemic substances;
• reducing the medicinal effect of products containing male sex hormones;
• reduction of therapeutic properties of antidiabetic drugs;
• weakening the medicinal effect of diuretics;
• decrease in the medicinal activity of antihypertensive drugs;
• reducing the effect of anticoagulants.

The processes of estradiol metabolism are accelerated in case of combination with anxiolytics, barbiturates, anesthetic drugs, opioids, some anticonvulsants (for example, phenytoin or carbamazepine), as well as with inducers of liver microsomal enzymes and medications, the active element of which is the herb of common St. John's wort.

A decrease in blood estradiol levels occurs when combined with phenylbutazone, as well as some antibiotics (such as ampicillin, rifampicin, nevirapine, etc.). This reaction is caused by changes in the intestinal microflora.

The effects of estradiol can be enhanced by using it with thyroid medications and folic acid medications.

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Storage conditions

Divigel must be stored in places closed to small children. Temperature values - maximum 25°C.

Shelf life

Divigel is approved for use within a 36-month period from the date of manufacture of the therapeutic product.

Reviews

Divigel receives good reviews from medical professionals. The drug stabilizes the regularity of menstruation, eliminates sleep disorders and other symptoms that occur after the onset of menopause, and at the same time prevents the occurrence of osteoporosis and sclerosis.

Among the advantages of the drug, doctors also highlight the fact that it does not lead to an increase in blood pressure, which is different from oral estradiol-containing substances.

The use of the gel during IVF helps to stabilize the course of pregnancy, and in addition, maintains an optimal hormonal balance in the body.

Comments from women who have used Divigel show that although the medication has high therapeutic efficacy, it also quite often leads to the appearance of negative symptoms (usually bloating and nausea).

Some patients who used the gel at the stage of conception planning say that the substance inhibits ovulation, but after discontinuing the drug, pregnancy usually occurs quite quickly.