Divigel

Divigel - a medicine used to eliminate disorders caused by menopause. It has a powerful estrogenic effect.

[1]

Indications Divygelya

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 during menopause of surgical origin (this includes menopause due to ovariectomy, and besides radiation castration).

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

[2], [3],

Release form

The release of the medication is carried out in the form of a transdermal gel contained in multi-layer sachets having a volume of 0.5 or 1 g. Inside the box - 28 sachets.

Pharmacodynamics

The severity of the drug effect of the drug used depends on the activity of estradiol. The drug acts by compensating for the lack of a female sex hormone, as well as stimulating the activity of estrogen endings located inside the target cells.

Estradiol is able through diffusion to pass into the target cell, then moving inside the cell nucleus and forming a compound with specific endpoints of estrogen. As a result, an R-L complex is being created.

Estrogenic endings are located within a variety of tissues, but most of them reside within the female genital organs: the uterus, mammary glands, liver, ovaries with vagina, HGS, and bones.

Formed complex Р-Л possesses the following properties:

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

Like the rest of the estrogen, estradiol provokes feminization of the body. For example, the active drug element, 17-β-estradiol, has the following effects:

• stimulates the development of the female genitalia, connective tissues, where the specific components of the various organs of the female genital system (the stroma) are located, and with it the breast ducts;
• contributes to the development of pigmentation in the areas of the genitals and nipples;
• stimulates the formation of sexual characteristics of a secondary nature of the feminine type;
• helps the development and growth of bone epiphyses;
• creates conditions for the timely rejection of the uterine endometrium;
• helps to regulate the frequency of menstruation;
• inhibits breast milk production as well as bone resorption;
• possesses procoagulant activity;
• increases the recovery rate of an adequate number of leukocytes during conditions that were caused by radiation damage, and manifested in the form of suppression of hematopoietic processes inside the bone marrow.

With increased estradiol, endometrial hyperplasia develops. In addition, the production of certain transporter proteins (a globulin that synthesizes thyroxin circulating inside the blood, transferrin, and also globulins that synthesize corticosteroids and androgens) is stimulated. Fibrinogen production is also stimulated.

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

• blood counts of thyroxine, iron with copper, etc., increase;
• production within the liver tissues of the factors responsible for blood coagulation and dependent on vitamin K is potentiated;
• the number of antithrombin 3 contained within the blood coagulation system, which is a specific protein, is reduced;
• degradation of the internal adrenaline and noradrenaline catecholamines is prevented (this effect develops when estradiol competes for the active end of the enzyme COMT).

Other important properties of estradiol are:

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

The drug changes the sensitivity characteristics of the endings with respect to progesterone, the properties of the 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 the liquid.

[4], [5], [6]

Pharmacokinetics

After oral use, a significant amount of estradiol, even before penetration into the bloodstream, undergoes metabolic processes inside the intestinal microflora (intestinal walls along with the lumen) and the liver. Under the influence of this effect, a non-physiological increase in plasma parameters of estrone occurs. Prolonged therapy leads to the accumulation of estrone along with estrone sulphate.

Information about the consequences of the accumulation of the metabolic products of estradiol over a long period is not enough. It was revealed only that as a result of the use of estrogens, there is an increase in protein binding (for example, renin). This factor causes a significant increase in blood pressure values.

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

When processing the epidermis with a gel, whose area is approximately the same as the size of 1-2 palms (about 200-400 cm ² ), the volume of absorbed estradiol does not change. Absorption values are reduced in the case of increasing the size of the treated area.

A small part of estradiol remains inside the subcutaneous layer, from which it is later gradually released into the bloodstream region. Due to transdermal application, the initial hepatic exchange phase does not develop, which is why the change in plasma estrogen level is not critical.

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 completely synthesized with a transferring protein. The level of bioavailability of orally taken estradiol is almost 100%.

The excretion of the products of biological decomposition of estradiol is mainly carried out through the kidneys under the guise of glucuronides with sulfates. A small amount of estrone along with estradiol and estriol is recorded inside the urine.

When performing medical procedures with application of Divigel, the ratio of estradiol / estrone values ranges from 0.4-0.7. The level of bioavailability of drugs is approximately 82%.

After treatment of the epidermis with a gel in a portion of 1 mg of 17-β-estradiol (1 g of gel substance), the plasma value of Cmax is 157 pmol / l. The average plasma level for the dosing line is 112 pmom / L. The free mean intraplasma values are 82nd pmol / l.

Accumulation of the drug does not occur.

[7], [8], [9]

Dosing and administration

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

Initially, the use of 1 mg of estradiol per day is usually prescribed (amounts to 1 g of gel), but sometimes the dosage may vary depending on the severity of manifestations of the disease.

At the end of 2-3 treatment cycles with the use of the drug, the initial portion can be adjusted taking into account changes in the clinical picture of an individual woman.

The most appropriate dosage is selected individually; it usually equals 0.5-1.5 mg of a substance per day.

The attending doctor must choose the day of the cycle on which to start the use of the medication.

People with uterus of the intact type during therapy with Divigel need to prescribe progestogen substances. It is necessary to use them for 10-12 days per cycle.

At the end of the cycle of using gestogen, a woman should go through a period of menstruation. When a patient has prolonged or extraordinary bleeding from the uterus, it is necessary to determine the cause of their occurrence.

It is necessary to take into account that during menopause the duration of one cycle of menstruation can be extended up to 3 months.

Drug gel must be applied to the epidermis in the area of the lower region of the anterior abdominal wall, shoulders with forearms, lower back or alternately process the buttocks 1 times per day (recommended at the same time). It is required to alternate daily processing sites.

The best fit is considered to be the area that is similar in size to the area 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 treatment area with gel for the next hour.

In cases where a woman has forgotten to carry out the treatment with a medicine, it is necessary to perform the procedure immediately after she is remembered (the period when the gel can be applied is 12 hours maximum since the use of the drug on a schedule). In a situation when the pass section was more than 12 hours, the processing is postponed until the next scheduled procedure.

With the occasional use of medication (with frequent skipping portions), menstrual-like bleeding from the uterus, which has a breakthrough character, may develop.

[13]

Use Divygelya during pregnancy

You can not assign Divigel during breastfeeding or pregnancy.

When pregnancy occurs during therapy, it is necessary to immediately cancel the use of the gel. But the final verdict regarding the need for further use of drugs after the establishment of pregnancy must make the attending doctor.

Epidemiological tests have revealed that with the occasional use of estrogen at an early stage of pregnancy, no fetotoxic or teratogenic effect develops.

Contraindications

Main contraindications:

• the presence of strong sensitivity towards estradiol or other auxiliary elements contained in the composition of the drug;
• suspected, established or existing breast cancer;
• present in history, suspected or already established malignant estrogen-dependent tumors within the uterus, ovaries or endometrium;
• the presence of benign tumors, which are located within the reproductive system or mammary glands (for example, uterine fibroids), in women under 60 years of age;
• bleeding from the uterus, having an unknown etiology, but also a predisposition to their appearance;
• hyperplastic endometrial processes;
• neoplasms in the pituitary gland;
• diffuse lesions of connective tissues;
• the presence of pathologies of inflammatory genitalia in a woman (for example, endometritis or salpingo-oophoritis);
• climacteric stage in which there is an increase in the rate of estrogen;
• thromboembolic lesions of the veins, which are spontaneous (this includes pathologies that are in history);
• diseases in which there is a thrombosis in the area of the deep veins (in this list, and diseases present in the history);
• thrombophlebitis (acute or present in history);
• congenital diseases, in which there are increased blood levels of bilirubin (this includes constitutional hyperbilirubinemia, the enzymopathic form of jaundice or Rotor syndrome);
• the presence of hepatic neoplasms (among them, liver carcinoma or hemangioma);
• diseases in which a circulatory disorder develops inside the brain (for example, a hemorrhagic or ischemic form of a stroke);
• sickle cell anemia;
• diseases associated with the metabolism of fat;
• diabetes mellitus (also with complications in the form of angiopathy or retinopathy);
• intrahepatic cholestasis or a pronounced stage of cholestatic itching (among those, and enhanced previous pregnancy or the use of steroids);
• diseases associated with the middle ear, arising from pathological bone growth inside it (also exacerbation of this disorder during pregnancy).

Extremely carefully the gel must be applied in the following situations:

• with BA, seizures of epilepsy or migraine attacks;
• with steadily increased blood pressure values;
• in case of insufficiency associated with hepatic, cardiac or renal function;
• with edema syndrome or ischemic heart disease;
• with hematoporphyria;
• with mastopathy.

[10], [11], [12]

Side effects Divygelya

Sometimes the medication leads to the appearance of separate side signs:

• problems associated with the work of the PNS and the central nervous system: migraine attacks, headaches and dizziness, as well as chorea and depression;
• disorders affecting the function of the cardiovascular system: thrombophlebitis and an increase in blood pressure values;
• digestive disorders: vomiting, stomach cramps, bloating and nausea, and in addition to this pain in the epigastric zone;
• lesions of the reproductive organs: vaginal bleeding, having an irregular shape (metrorrhagia), scanty vaginal discharge, an increase in the size of uterine leiomyoma, as well as significant growth of the endometrium (usually occurs when the drug is not combined with progesterone). In addition, uterine carcinoma may develop (often in patients with uterus of the intact type and menopause), changes associated with libido and Stein-Leventhal syndrome (in case of prolonged use of drugs);
• signs associated with the endocrine system: increased stress, engorgement or increase in the size of the mammary glands, a decrease in the level of tolerance for carbohydrates and the appearance of extra kg;
• disorders associated with the system of gastrointestinal diseases and the liver: cholelithiasis, intrahepatic cholestasis or episodes of hematoporphyria;
• imbalance in EBV: fluid and calcium retention with sodium, which can cause puffiness during prolonged use of the gel;
• local allergic manifestations: rash, contact form of dermatitis, hyperemia of the epidermis and severe irritation;
• other symptoms: visual disorders that manifest themselves in the form of a change in its curvature, and in addition to this melasma, the formation of chloasm and thrush.

Overdose

If the standard dose of the drug is exceeded, the following pathological manifestations may occur: flatulence, tenderness of the mammary glands, swelling in the pelvic area, vomiting, feeling of strong irritability or anxiety, and also metrorrhagia or nausea.

If any of these symptoms occur, symptomatic interventions are required. Often, negative symptoms disappear after lowering the dosage or withdrawing the medication.

[14]

Interactions with other drugs

The combination of estradiol with some drugs leads to the development of the following drug effects:

• increased activity of lipid-lowering substances;
• reduction of medicinal effects of drugs that contain male-type sex hormones;
• reduction of therapeutic properties of antidiabetic drugs;
• the weakening of the drug effects of diuretic drugs;
• a decrease in the medicinal activity of antihypertensive drugs;
• reducing the effects of anticoagulants.

Estradiol metabolism is accelerated when combined with anxiolytics, barbiturates, anesthetic drugs, opioids, some anticonvulsants (for example, phenytoin or carbamazepine), and in addition with enzyme inducers of liver microsomes and medicines, whose active element is herb of St. John's wort.

Lowering blood values of estradiol occurs when combined with phenylbutazone, as well as with some antibiotics (such as ampicillin, rifampicin, nevirapine, etc.). Such a reaction is caused by changes in the intestinal microflora.

It is possible to increase the effect of estradiol by using it together with thyroid medications and folic acid medications.

[15], [16]

Storage conditions

Divigel is required to be kept in the places closed from penetration of small children. Temperature values - maximum 25 ° С.

Shelf life

Divigel is allowed to apply within the 36-month period from the moment the therapeutic product is manufactured.

Reviews

Divigel receives good reviews from medical professionals. The drug stabilizes the regularity of menstruation, eliminates sleep disorders and other manifestations 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 differs from oral estradiol-containing substances.

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

Comments of women who used Divigel show that, although the drug has a 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 planning stage of conception, say that the substance inhibits ovulation, but after the abolition of drugs, pregnancy usually occurs fairly quickly.