Divigel

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIVIGEL

Composition:

Active substance: estradiol;

1 sachet contains estradiol hemihydrate equivalent to 0.5 mg or 1 mg of estradiol;

Excipients: carbomer 974P, triethanolamine, propylene glycol, ethanol 96%, purified water.

Pharmaceutical form. Gel.

Main physicochemical characteristics: homogeneous opalescent gel.

Pharmacotherapeutic group. Natural and semi-synthetic estrogen preparations. Estradiol. ATC code G03C A03.

Pharmacological properties.

Pharmacodynamics.

Estradiol valerate, a synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It compensates for reduced estrogen levels in women during menopause, thereby alleviating menopausal symptoms. Estrogens prevent bone mass loss occurring during menopause or after ovariectomy.

Transdermal administration of estradiol in combination with medroxyprogesterone acetate leads to a reduction in total cholesterol levels without altering high-density lipoprotein cholesterol levels. The efficacy of Divigel in correcting decreased bone mineral density in the postmenopausal period is equivalent to that of oral estrogenic drugs.

Pharmacokinetics.

Divigel is an alcohol-based gel formulation of estradiol.

When the gel is applied to the skin, the alcohol rapidly evaporates and estradiol penetrates through the skin into the bloodstream. Application of the gel over an area of 200–400 cm² (the size of one or two palms) does not affect the amount of absorbed estradiol. However, if the drug is applied over a larger area, the absorption rate significantly decreases. A certain amount of estradiol is retained in the subcutaneous tissue, from where it gradually enters the systemic circulation. Transdermal administration avoids the first-pass hepatic metabolism. For this reason, plasma estrogen concentration fluctuations with Divigel are considerably less pronounced than with oral estrogens.

Plasma estradiol concentrations following transdermal application of Divigel were as follows:

Digivigel dose	Cmax (pmol/l)	Caverage (pmol/l)	Cmin (pmol/l)
0.5 mg	143	75	92
1 mg	247	124	101
1.5 mg	582	210	152

During treatment with the drug, the estradiol/estrone ratio remains at the level of 0.4–0.7, whereas with oral administration of estrogens it usually drops to less than 0.2. The steady-state bioavailability is 82% compared to an equivalent oral dose of estradiol valerate.

Metabolism and excretion of Divigel with transdermal application are similar to those of natural estrogens.

Clinical characteristics.

Indications.

Symptoms associated with estrogen deficiency in natural or artificial menopause.

For prevention of postmenopausal osteoporosis with high fracture risk when other medicinal products for osteoporosis prevention are contraindicated or unsuitable.

Contraindications.

Breast cancer (diagnosed, suspected, or in history).

Diagnosed or suspected estrogen-dependent malignant tumors (e.g., endometrial cancer).

Vaginal bleeding of unknown etiology.

Untreated endometrial hyperplasia.

Venous thromboembolic diseases, including history thereof (deep vein thrombosis (DVT), pulmonary embolism).

Identified increased blood coagulability (e.g., protein C, protein S or antithrombin deficiency).

Acute arterial thromboembolism, including history thereof (e.g., angina pectoris, myocardial infarction).

Acute liver diseases, including history thereof (until normalization of liver function laboratory parameters).

Hypersensitivity to the active substance or to any of the excipients.

Porphyria.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of medicinal products that are inducers of hepatic enzymes, particularly cytochrome P450, may accelerate the metabolism of estradiol. These substances include anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine) and antimicrobial agents (e.g., rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although potent inhibitors, may exhibit, on the contrary, an inducing effect when used concomitantly with steroid hormones.

Herbal medicinal products containing Hypericum perforatum (St. John's wort) may enhance estrogen metabolism. Clinically significant increased estrogen metabolism may lead to reduced efficacy of these hormones and provoke changes in menstrual cycle regularity.

Clinically significant increased metabolism of estrogens and progestogens may result in reduced effect and changes in the pattern of vaginal bleeding.

Special precautions for use.

Experience with hormone replacement therapy (HRT) in women aged 65 years and older is limited.

HRT should be used only in the presence of postmenopausal symptoms that negatively affect quality of life.

The benefit-risk balance should be carefully assessed (at least annually).

HRT may be continued as long as its benefits outweigh the risks.

Information on adverse effects associated with hormone replacement therapy for premature menopause is limited. Due to the low absolute risk of adverse reactions in younger women, the risk-benefit ratio in these women may be more favorable than in older women.

Examinations.

Before initiating or reinitiating hormone replacement therapy (HRT), the physician must obtain a complete personal and family medical history and perform a physical examination (including pelvic organs and breasts) to identify possible contraindications and necessary precautions for prescribing the drug.

Regular check-ups are recommended during treatment. The frequency and type of examinations should be determined individually for each patient. Women should be informed about which breast changes should be reported to the physician. Screening tests, including mammography, should be performed according to established guidelines and adapted to the individual clinical needs of each patient.

Conditions requiring monitoring.

If any of the conditions listed below are present, have occurred previously, and/or worsened during pregnancy or previous hormone therapy, the patient should remain under continuous medical supervision. These conditions may recur or worsen during treatment with Divigel: uterine leiomyoma (fibroids) or endometriosis, thromboembolic disorders (if previously present or at risk), risk factors for estrogen-dependent tumors (e.g., first-degree family history of breast cancer), arterial hypertension, liver disease (e.g., hepatic adenoma), diabetes mellitus with or without vascular complications, cholelithiasis, migraine or severe headache, systemic lupus erythematosus, history of endometrial hyperplasia, epilepsy, asthma, otosclerosis, hereditary angioedema (Quincke's edema).

Reasons for immediate discontinuation of therapy.

Treatment must be discontinued if contraindications are identified or if any of the following conditions occur: jaundice or worsening liver function, marked increase in blood pressure, new onset of migraine-like headaches, or pregnancy.

Endometrial hyperplasia and carcinoma.

The risk of endometrial hyperplasia and cancer increases in patients with an intact uterus who receive estrogen-only therapy over a prolonged period. A 2–12-fold increased risk of endometrial cancer has been reported in patients using estrogens compared to non-users, depending on duration of treatment and estrogen dose.

The risk may remain elevated for at least 10 years after discontinuation of treatment.

In women with an intact uterus, continuous combined estrogen-progestogen therapy or cyclic addition of a progestogen (for at least 12 days per month or over 28 days) prevents the estrogen-related risk increase.

Breakthrough bleeding or spotting may occur during the first month of treatment. If bleeding or spotting occurs some time after treatment initiation or continues after treatment discontinuation, the cause must be investigated. Endometrial biopsy should be performed when necessary to exclude malignant transformation.

Estrogen therapy without the addition of a progestogen may lead to premalignant or malignant changes in endometriotic foci. Therefore, the addition of a progestogen during estrogen therapy should be considered in patients who have undergone hysterectomy due to endometriosis, especially in those with documented endometriotic lesions.

Breast cancer.

The risk of developing breast cancer is increased both in patients receiving combined estrogen-progestogen therapy and in those receiving estrogen-only therapy.

Estrogen-progestogen combination therapy.

Randomized placebo-controlled and epidemiological studies have shown that the use of estrogen-progestogen combinations in hormone replacement therapy increases the risk of developing breast cancer. This effect becomes apparent after approximately 3 years.

Estrogen monotherapy.

In women who have undergone hysterectomy, the use of estrogens in hormone replacement therapy does not increase the risk of developing breast cancer.

Other observations indicate a slight increase in the risk of breast cancer, but this increase is considerably smaller than with estrogen-progestogen combination therapy (see section "Adverse reactions").

An apparent increase in cancer risk occurs after several years of estrogen therapy. However, the risk returns to baseline levels within a few years (no more than five) after treatment discontinuation.

HRT, particularly estrogen-progestogen combinations, increases breast tissue density, which may impair radiological detection of breast cancer.

Ovarian cancer.

Ovarian cancer is much rarer than breast cancer. Long-term use (at least 5–10 years) of estrogen-only HRT has been associated with a slight increase in the risk of ovarian cancer. According to some studies, long-term use of combined HRT may be associated with a similar or even lower risk (see section "Adverse reactions").

Venous thromboembolism.

HRT is associated with a 1.3–3-fold increased risk of venous thromboembolism, such as deep vein thrombosis or pulmonary embolism. The risk is highest during the first year of hormone replacement therapy (see section "Adverse reactions").

In patients with a predisposition to thrombosis, the risk of venous thromboembolism is significant. Since HRT may further increase this risk, it is contraindicated in such patients (see section "Contraindications").

General risk factors for venous thromboembolism include estrogen use, advanced age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus, and cancer. There is no consensus on the possible role of varicose veins in the development of venous thromboembolism.

For all surgical patients, the need for specific preventive measures to avoid postoperative thromboembolism should be considered. If prolonged immobilization is expected after elective surgery, HRT should be discontinued 4–6 weeks before surgery. Treatment should not be resumed until normal mobility is restored.

If first-degree relatives have experienced venous thromboembolism at a young age, screening for thrombophilia should be considered. Prior to screening, the woman should be informed that such testing has limited diagnostic value (only a portion of disorders leading to thrombophilia are identified). If a high predisposition to thrombosis is confirmed, a family history of thrombosis is known, or the identified disorder is severe (e.g., antithrombin, protein S and/or C deficiency, or a combination of these), HRT is contraindicated.

If a patient is on long-term anticoagulant therapy, the benefits and risks of HRT should be carefully weighed.

Treatment should be discontinued if venous thromboembolism develops during therapy. The patient should be informed about symptoms requiring immediate medical attention (e.g., painful leg swelling, sudden chest pain, dyspnea).

Ischemic heart disease.

Randomized controlled trials have not demonstrated a protective effect of estrogen-progestogen combination therapy or estrogen monotherapy in women with ischemic heart disease or in other women.

Estrogen-progestogen combination therapy.

The relative risk of ischemic heart disease slightly increases with estrogen-progestogen combination therapy. The absolute risk depends on age. The number of ischemic heart disease cases due to estrogen-progestogen combination therapy in healthy women close to menopause is very low but increases with age.

Estrogen monotherapy.

Randomized controlled trials have not shown an increased risk of ischemic heart disease in women after hysterectomy who received estrogen-only therapy.

Ischemic stroke.

Estrogen-progestogen combination therapy and estrogen monotherapy are associated with a 1.5-fold increased risk of ischemic stroke. The relative risk does not change with age or after menopause. Since stroke risk strongly depends on age, the overall risk of stroke increases with age in women receiving HRT (see section "Adverse reactions").

Other special considerations.

Estrogens may cause fluid retention; therefore, patients with cardiac or renal impairment should be closely monitored.

Patients with hypertriglyceridemia receiving HRT should be carefully observed. Several cases of marked increases in plasma triglyceride levels have been reported in such patients receiving estrogens, which may lead to pancreatitis.

Estrogens increase levels of thyroid-binding globulin (TBG), resulting in elevated levels of circulating thyroid hormones measured by protein-bound iodine, T4 concentration (column or radioimmunoassay), or T3 concentration (radioimmunoassay). The increase in T3 levels is reduced, reflecting increased TBG levels, while free T4 and T3 concentrations remain unchanged.

Concentrations of other serum-binding proteins may also increase, such as corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG), leading to increased circulating levels of corticosteroids and sex steroid hormones, respectively. Levels of free or biologically active hormones remain unchanged. Concentrations of other plasma proteins may also increase (angiotensin/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

Chloasma may rarely occur, particularly in women with a history of chloasma during pregnancy. Women prone to chloasma should minimize exposure to sunlight or ultraviolet radiation during HRT.

HRT does not improve cognitive function. There is evidence that the risk of dementia increases in women aged 65 years and older at the start and during estrogen therapy.

Divigel contains propylene glycol, which may cause skin irritation.

Divigel is not a contraceptive; therefore, appropriate contraceptive measures should be used.

Potential exposure of children to estradiol

The gel containing estradiol may accidentally enter a child's body through skin contact with the application site.

Post-marketing reports have described cases of breast enlargement in prepubertal girls and premature sexual development and gynecomastia in prepubertal boys following unintentional secondary exposure to estradiol-containing gel.
In most cases, symptoms resolved after cessation of estradiol exposure.

Patients should be instructed to:

• avoid contact of the application site with other individuals, especially children, and, if necessary, cover the application area with clothing. If a child's skin comes into contact with the application site, it should be washed immediately with soap and water;
• consult a physician if a child who may have been accidentally exposed to estradiol-containing gel shows signs or symptoms such as breast enlargement or other sexual changes.

Use during pregnancy or breastfeeding.

Divigel is not indicated during pregnancy or breastfeeding. If a patient becomes pregnant during treatment, Divigel therapy should be discontinued immediately.

According to most epidemiological studies, accidental estrogen use during pregnancy does not have teratogenic or fetotoxic effects.

Ability to affect reaction speed when driving or operating machinery.

The drug does not affect reaction speed when driving or operating machinery.

Method of Administration and Dosage.

Dosage.

Divigel is a transdermal gel intended for long-term or cyclic treatment. The usual initial dose is 1 g of gel per day, corresponding to 1 mg of estradiol. The duration of treatment and dosage are determined by the physician according to individual patient characteristics (depending on clinical condition). After 2–3 cycles, the dose may be adjusted: from 0.5 g to 1.5 g of gel per day, corresponding to 0.5–1.5 mg of estradiol daily.

For patients with an intact uterus, Divigel must be combined with progestogen therapy administered in cycles of 1 month, using, for example, medroxyprogesterone acetate, norethindrone, norethindrone acetate, or dydrogesterone for at least 12–14 days.

Progestogens are not recommended for women who have undergone hysterectomy, unless endometriosis has been diagnosed.

Patients who have not previously used hormone replacement therapy (HRT) or who are switching to Divigel from long-term combined therapy may initiate treatment with Divigel on any day. Patients switching to Divigel from continuous combined HRT may start treatment with Divigel immediately after completing the last treatment cycle.

For treatment of postmenopausal symptoms, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

If a patient forgets to apply the gel on time, treatment should be continued as usual the following day.

Irregular use of the medication may result in menstrual-like uterine bleeding.

Method of Administration.

Divigel should be applied to clean, dry skin.

The dose of Divigel should be applied once daily to the skin of the thighs or lower part of the trunk, regularly changing the application site. The application area should be approximately 1–2 palm-sized. Divigel should not be applied to the breasts, face, genital area, or to areas of irritated skin. After application, wait several minutes until the gel has dried. The application site should not be washed within one hour after application. Accidental contact of Divigel with the eyes should be avoided. Hands must be washed immediately after applying the gel.

Patients should be informed that children must not come into contact with the area of skin to which the gel containing estradiol has been applied (see section "Special Warnings and Precautions for Use").

Children. The medication must not be used in children.

Overdose.

Acute toxicity studies do not indicate a risk of acute adverse reactions following doses several times higher than the recommended dose.

In some women, nausea, headache, vomiting, or withdrawal bleeding may occur.

According to several reports, no serious adverse effects have been observed in children who have ingested oral contraceptives containing high doses of estrogens.

Treatment is symptomatic.

With transdermal administration, estradiol overdose is unlikely. There is no specific antidote. Treatment is symptomatic. The gel should be washed off.

Side effects.

Breakthrough bleeding and spotting, breast tenderness, or breast enlargement may occur during the first few months of treatment. These symptoms are usually transient and resolve during continued treatment.

The data listed below were obtained from clinical trials and post-marketing experience. Adverse reactions may occur in approximately 76% of patients. The adverse reactions observed in more than 10% of patients during clinical studies were application site reactions and breast pain.

The frequency of adverse reactions is classified as follows: common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1,000); frequency not known (cannot be estimated from the available data).

Adverse reactions observed with transdermal estradiol application.

Benign, malignant and unspecified neoplasms (including cysts and polyps).

Uncommon: benign tumors of the breast and endometrium.

Frequency not known: uterine fibroids (myoma).

Immune system disorders.

Uncommon: hypersensitivity reactions.

Frequency not known: exacerbation of hereditary angioedema.

Metabolism and nutrition disorders.

Common: edema, weight gain, weight loss.

Uncommon: increased appetite.

Frequency not known: hypercholesterolemia¹.

Psychiatric disorders.

Common: depression, nervousness, drowsiness.

Uncommon: changes in libido and mood, anxiety, insomnia, apathy, emotional lability, difficulty concentrating.

Frequency not known: euphoria¹, excitement¹.

Nervous system disorders.

Common: headache, dizziness.

Uncommon: migraine, paresthesia.

Frequency not known: tremor¹.

Eye disorders.

Uncommon: visual disturbances.

Rare: intolerance to contact lenses.

Frequency not known: dry eyes¹.

Cardiac and vascular disorders.

Common: hot flushes.

Uncommon: palpitations.

Rare: increased blood pressure, venous thromboembolism (e.g., deep vein thrombosis of the lower limbs or pelvic venous thrombosis), pulmonary embolism².

Frequency not known: cerebrovascular disorders, superficial phlebitis¹, purpura¹.

Respiratory, thoracic and mediastinal disorders.

Frequency not known: dyspnea¹, rhinitis¹.

Gastrointestinal disorders.

Common: nausea, vomiting, abdominal cramps, flatulence.

Uncommon: constipation.

Frequency not known: abdominal pain, bloating, dyspepsia¹, diarrhea¹, rectal symptoms¹.

Hepatobiliary disorders.

Rare: liver function abnormalities and impaired bile flow.

Frequency not known: cholestatic jaundice.

Skin and subcutaneous tissue disorders.

Uncommon: acne, alopecia, dry skin, nodular erythema, urticaria.

Rare: rash.

Frequency not known: contact dermatitis, eczema, nail changes¹, nodular skin changes¹, hirsutism¹.

Musculoskeletal and connective tissue disorders.

Uncommon: joint symptoms, muscle cramps.

Renal and urinary disorders.

Uncommon: increased frequency of micturition and urinary urgency.

Frequency not known: urinary incontinence¹, cystitis¹, discoloration of urine¹, hematuria¹.

Reproductive system and breast disorders.

Common: breast tenderness/pain/discomfort, breakthrough bleeding or spotting, vaginal discharge, vulvar/vaginal symptoms, menstrual disorders.

Uncommon: breast enlargement, increased breast sensitivity, endometrial hyperplasia.

Rare: painful menstruation, premenstrual syndrome.

Frequency not known: uterine symptoms¹.

General disorders and administration site reactions.

Common: irritation, itching at the application site, pain, hyperhidrosis.

Uncommon: fatigue.

Frequency not known: abnormal laboratory findings¹, asthenia¹, hyperthermia¹, influenza-like symptoms¹, malaise¹.

¹ Isolated reports. Due to the small number of participants in the studies (n = 611), the adverse reactions listed cannot be classified as uncommon or rare based on the available data.

² See sections "Contraindications" and "Special precautions for use".

Other adverse reactions observed with estrogen-progestogen combination therapy:

Estrogen-dependent benign and malignant tumors, e.g., endometrial cancer.

Development of myocardial infarction and stroke.

Gallbladder disorders.

Isolated cases of chloasma, erythema multiforme.

Development of dementia in women over 65 years of age (see section "Special precautions for use").

Risk of breast cancer.

The risk of developing breast cancer increases in women who have used estrogen-progestogen combination therapy for more than five years. The risk is significantly lower in women receiving estrogen-only therapy compared to those on estrogen-progestogen combination therapy. The level of risk depends on the duration of treatment (see section "Special precautions for use").

Risk of endometrial cancer.

Postmenopausal women with an intact uterus.

The risk of developing endometrial cancer in women with an intact uterus not using HRT is 5 per 1,000.

Estrogen-only therapy is not recommended for HRT in women with an intact uterus, as it increases the risk of endometrial cancer (see section "Special precautions for use").

According to epidemiological studies, the increased risk of endometrial cancer depends on the duration and dose of estrogen therapy and ranges from 5 to 55 additional cases per 1,000 women aged 50 to 65 years.

Adding progestogens to estrogen therapy for at least 12 days per cycle prevents this increased risk.

According to the MWS (Million Women Study), the use of combined HRT (cyclic or continuous) for 5 years does not increase the risk of endometrial cancer [(relative risk 1.0 (95% CI 0.8–1.2))].

Risk of ovarian cancer.

The use of HRT, either as monotherapy or in combination with progestogens, is associated with a slight increase in the risk of ovarian cancer.

According to studies, over 5 years of HRT, approximately 1 case of ovarian cancer per 2,000 women aged 50 to 54 was observed among those receiving HRT, compared to 2 cases per 2,000 among those not receiving HRT.

Risk of venous thromboembolism.

HRT is associated with a 1.3–3-fold increased risk of venous thromboembolism, such as deep vein thrombosis or pulmonary embolism. The risk of developing thromboembolic disease is highest during the first year of HRT.

Risk of ischemic heart disease.

The risk of ischemic heart disease is slightly increased in women aged 60 years and older who use HRT.

Risk of ischemic stroke.

The relative risk of ischemic stroke increases by 1.5-fold in women using either estrogen-only therapy or estrogen-progestogen combination therapy. The risk of hemorrhagic stroke does not increase during HRT.

The relative risk does not depend on age or duration of treatment; however, the absolute risk clearly increases with age, so the overall risk of stroke increases with age in women using HRT (see section "Special precautions for use").

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding +25°C, in a place inaccessible to children.

Packaging. 0.5 g or 1 g of gel in sachets; 28 sachets in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Orion Corporation.

Manufacturer's address.
Orionintie 1, 02200 Espoo, Finland.