INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESTRACLIN (OESTRACLIN)

Composition:

Active substance: estradiol;

1 g of gel contains 0.6 mg of estradiol as estradiol hemihydrate;

Excipients: carbomer, triethanolamine, 96% ethanol, purified water.

Pharmaceutical form. Gel.

Main physicochemical properties: colorless, semitransparent gel without visible particles.

Pharmacotherapeutic group. Sex hormones and drugs used in disorders of the reproductive system. Estrogens. Simple preparations of natural and semi-synthetic estrogens.

ATC code G03C A03.

Pharmacological Properties

Pharmacodynamics

The active ingredient of the drug, estradiol, is chemically and biologically identical to endogenous human estradiol. Estradiol compensates for the cessation of estrogen production during menopause and relieves menopausal symptoms. Estrogens prevent bone mass loss caused by menopause or oophorectomy.

Studies have shown that in women with an intact uterus, adding a progestogen for 10 or more days per cycle of estrogen use significantly reduces the risk of estrogen-induced endometrial hyperplasia.

Information on results of clinical trials

Relief of estrogen deficiency symptoms

Relief from menopausal symptoms is observed within the first few weeks of treatment.

Osteoporosis prevention

Estrogen deficiency associated with menopause is accompanied by increased bone metabolism and reduced bone mass. The effect of estrogens on bone mineral density is dose-dependent. Estrogen prevention is effective as long as treatment continues. After discontinuation of hormone replacement therapy (HRT), bone loss occurs at the same rate as in untreated women.

Evidence from the Women’s Health Initiative (WHI) study and meta-analyses of clinical trials indicates that HRT—either as monotherapy or in combination with a progestogen (mainly in healthy women)—reduces the risk of vertebral, hip, and other osteoporosis-related fractures. HRT may also prevent fractures in women with low bone mineral density and/or established osteoporosis, although evidence for this is limited.

Pharmacokinetics

Transdermal absorption is approximately 10% of the administered dose. One dose applied with the applicator (2.5 g of gel) corresponds to the release of 150 µg of estradiol.

Estradiol is temporarily stored in the stratum corneum of the epidermis.

Systemic diffusion of estradiol through the dermal vascular network occurs gradually.

The average plasma concentration of estradiol achieved in menopausal women using the amount of gel delivered by one applicator (2.5 g of gel) per day is 80 pg/mL, with an estrone/estradiol ratio similar to that observed in women of reproductive age. Topical application avoids first-pass hepatic metabolism, minimizing side effects typical of oral estrogen therapy while providing systemic estrogenization.

Clinical characteristics.

Indications.

Estreclin is intended for use in adult women for the following purposes:

• treatment of signs and symptoms of natural or surgically induced estrogen deficiency due to menopause, such as hot flushes, sleep disturbances, urogenital atrophy, mood swings, asthenia, and loss of bone mass;
• prevention of postmenopausal osteoporosis in women at high risk of bone fractures when alternative preventive measures are not tolerated or contraindicated.

Experience with use in women over 65 years of age is limited.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients;
• breast cancer (personal history or suspected);
• existing or suspected estrogen-dependent malignant tumors (e.g., endometrial cancer);
• vaginal bleeding of unknown origin;
• untreated endometrial hyperplasia;
• current or past history of idiopathic venous thromboembolism (VTE) (e.g., deep vein thrombosis, pulmonary embolism);
• known thrombophilic disorders (e.g., protein C, protein S or antithrombin deficiency);
• acute or recently occurred arterial thromboembolism (e.g., angina pectoris, myocardial infarction);
• acute liver disease or liver disease in medical history, if liver function tests have not normalized;
• porphyria.

Interaction with other medicinal products and other forms of interactions.

Metabolism of estrogens (and progestogens) may be enhanced when co-administered with enzyme inducers involved in drug metabolism, particularly cytochrome P450 enzymes, such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine), meprobamate, phenylbutazone, and anti-infective agents (e.g., rifampicin, rifabutin, nevirapine, efavirenz).

Caution should be exercised when co-administering with protease inhibitors (particularly ritonavir and nelfinavir), which are strong inhibitors of cytochrome P450 enzymes, but also have inducing properties when used concomitantly with steroid hormones.

Herbal preparations containing St John's wort (Hypericum perforatum) may also enhance the metabolism of estrogens (and progestogens).

From a clinical standpoint, enhanced metabolism of estrogens (and progestogens) may lead to reduced efficacy and changes in the pattern of vaginal bleeding.

Effect of estrogen-containing HRT on other medicinal products

It has been shown that hormonal contraceptives containing estrogens significantly reduce plasma concentrations of lamotrigine when used concomitantly, due to induction of lamotrigine glucuronidation. This may reduce seizure control efficacy. Although potential interactions between HRT and lamotrigine have not been studied, a similar interaction is expected and may lead to reduced seizure control efficacy in women taking HRT and lamotrigine concurrently.

Pharmacodynamic interactions

During clinical trials of combination therapy for hepatitis C virus (HCV) using ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elevations in transaminase levels (ALT) exceeding five times the upper limit of normal (ULN) were observed significantly more frequently in women receiving medicinal products containing ethinylestradiol, such as combined hormonal contraceptives (CHCs). In women receiving medicinal products containing estrogens other than ethinylestradiol, such as estradiol, the frequency of ALT elevations was similar to that in women not receiving estrogens. However, due to the limited number of women receiving these other estrogens, caution should be exercised when co-administering combination therapy with ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as therapy with glecaprevir/pibrentasvir (see section "Special precautions for use").

Since transdermal administration of HRT avoids the first-pass hepatic effect, enzyme inducers have less impact on estrogens than on orally administered hormones.

Special precautions for use.

HRT for the treatment of menopausal symptoms should only be initiated when these symptoms adversely affect a woman's quality of life. A careful assessment of risks and benefits of HRT should be performed at least annually, and treatment should continue only if benefits outweigh risks.

Data on risks associated with HRT in the treatment of premature menopause are limited. However, due to the low absolute risk in younger women, the benefit-risk ratio in these women is more favorable than in older women.

Before initiating or restarting HRT, the physician should obtain a full personal and family medical history and perform a complete physical examination (including breast and pelvic examination), taking into account the patient's medical history and contraindications and warnings for HRT use.

Regular medical examinations should be performed during treatment, with the scope and frequency individually tailored for each patient. Women should be informed about which changes in their breasts they should report to their physician or nurse. Regular screening, including mammography, should be performed in accordance with official clinical guidelines, adapted to each individual clinical case.

The lowest effective dose for the shortest possible duration should always be considered.

Women who have undergone hysterectomy and require postmenopausal hormone therapy should receive estrogen-only replacement therapy, unless endometriosis has been diagnosed.

Due to limited clinical experience with transdermal estradiol, caution is recommended when prescribing the drug in the following conditions:

• Cardiovascular diseases: valvular heart disease, cardiac arrhythmias, thrombosis;
• Cerebrovascular disorders;
• Vascular-related eye diseases.

Recurrence or worsening of the following conditions may occur during treatment with this medicinal product. If any of these conditions develop during treatment or have occurred previously and/or worsened during pregnancy or hormonal therapy, the patient should be under close supervision:

• Leiomyoma (uterine fibroids) or endometriosis;
• History of thromboembolic disorders or current risk factors (see below);
• Risk factors for estrogen-dependent tumors, e.g., first-degree family predisposition to breast cancer;
• Arterial hypertension;
• Hepatic disorders (e.g., hepatic adenoma);
• Renal disorders;
• Diabetes mellitus with or without vascular complications;
• Cholelithiasis;
• Migraine or (severe) headache;
• Systemic lupus erythematosus (SLE);
• History of endometrial hyperplasia (see below);
• Epilepsy;
• Bronchial asthma;
• Otosclerosis;
• Pruritus.

If worsening occurs or suspicion arises regarding the development of any of the above-listed conditions during HRT, a reassessment of the risks and benefits of HRT should be performed, and the appropriateness of continuing treatment should be determined.

Treatment must be discontinued immediately in the event of jaundice or liver dysfunction, significant increase in blood pressure, onset of migraine-like headache, pregnancy, or the occurrence of any condition listed in the section "Contraindications".

Endometrial hyperplasia and endometrial cancer

In women with an intact uterus who receive estrogen-only therapy for prolonged periods, the risk of developing endometrial hyperplasia and endometrial cancer is increased. The risk of endometrial cancer was 2−12 times higher in women taking estrogen-only therapy compared to non-users, depending on duration of treatment and estrogen dose (see section "Adverse reactions"). After discontinuation of treatment, the risk may remain elevated for at least 10 years.

Adding progestogens cyclically for at least 12 days per month/28-day cycle or using continuous combined estrogen-progestogen therapy in women with an intact uterus prevents the increased risk associated with estrogen-only HRT. Breakthrough bleeding or spotting may occur during the first months of treatment. If breakthrough bleeding or spotting occurs after some time following the initiation of treatment or persists after discontinuation of therapy, diagnostic evaluation should be performed, which may include endometrial biopsy to exclude malignant endometrial neoplasms.

Estrogen stimulation alone may lead to premalignant or malignant transformation of residual endometriosis foci. Therefore, for women who have undergone hysterectomy due to endometriosis, the addition of a progestogen to therapy should be considered, especially in the presence of residual endometriosis.

Breast cancer

The controlled clinical WHI study and other epidemiological studies have shown an increased risk of breast cancer in women receiving combined estrogen-progestogen HRT or estrogen-only HRT, depending on the duration of HRT.

Combined estrogen-progestogen therapy

The randomized placebo-controlled WHI study and meta-analysis of prospective epidemiological studies independently demonstrated an increased risk of breast cancer in women using combined estrogen-progestogen HRT, evident after approximately 3 (1−4) years (see section "Adverse reactions").

Estrogen-only monotherapy

In the WHI study, no increased risk of breast cancer was observed in women after hysterectomy receiving estrogen-only HRT. Most observational studies reported a slightly increased risk of breast cancer diagnosis, which was significantly lower than the risk in women receiving progestogens together with estrogens (see section "Adverse reactions").

Results from a large-scale meta-analysis indicate that after discontinuation of treatment, the increased risk decreases over time, and the time required to return to baseline levels depends on the prior duration of HRT. If HRT lasted more than 5 years, the risk may persist for 10 years or longer.

HRT, particularly combined estrogen-progestogen therapy, is associated with increased mammographic density on imaging, which may complicate radiological diagnosis of breast cancer.

Venous thromboembolism

HRT is associated with a 1.3−3-fold increased risk of venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. The occurrence of this event is more likely during the first year of HRT than thereafter (see section "Adverse reactions").

One randomized controlled study and several epidemiological studies have shown that the risk is 2−3 times higher in treated patients compared to untreated patients. It is estimated that in untreated women, the number of VTE cases observed over any 5-year period is approximately 3 cases per 1000 women aged 50−59 years and 8 cases per 1000 women aged 60−69 years. It is estimated that the number of additional VTE cases over any 5-year period in healthy women using HRT for 5 years is 2−6 cases (best estimate 4) per 1000 women aged 50−59 years and 5−15 cases (best estimate 9) per 1000 women aged 60−69 years. VTE development is most likely during the first year of HRT (see section "Adverse reactions").

Well-established risk factors for VTE include personal or family history, severe obesity (body mass index > 30 kg/m²), systemic lupus erythematosus (SLE), estrogen use, advanced age, major surgery, prolonged immobilization, pregnancy/postpartum period, and cancer. There is no consensus on the possible influence of varicose veins on VTE development.

Patients diagnosed with thrombophilic conditions have an increased risk of VTE, and HRT may further increase this risk. Therefore, HRT is contraindicated in these patients (see section "Contraindications").

In patients with VTE risk factors that are not contraindications, a careful assessment of the benefit-risk ratio of HRT is required.

To exclude possible predisposition to thrombophilia, it is necessary to assess personal or family history of thromboembolic events or recurrent miscarriage. HRT is contraindicated in this patient group until a thorough evaluation of thrombophilic factors and initiation of anticoagulant therapy. Before initiating treatment, a careful assessment of the benefit-risk ratio of HRT should be performed in women already receiving long-term anticoagulant therapy. Women without VTE history but with first-degree relatives who experienced thrombosis at a young age may be offered screening after thorough discussion of its limitations (screening detects only a portion of thrombophilic disorders).

If a thrombophilic disorder associated with thrombosis is identified in a family member or if the disorder is severe (e.g., antithrombin, protein S or protein C deficiency, or combination of disorders), HRT is contraindicated.

The risk of VTE may temporarily increase during prolonged immobilization and after severe trauma or major surgery. Special attention should be paid to preventive measures to avoid VTE development in patients after surgery, as in all postoperative patients. If prolonged immobilization is expected after planned surgical procedures, it is recommended to temporarily discontinue treatment 4−6 weeks before surgery, especially abdominal or orthopedic lower limb surgery. Treatment may be resumed after full restoration of patient mobility.

Treatment should be discontinued if symptoms of VTE occur. Women should be advised to seek immediate medical attention if they experience any symptoms suggestive of thromboembolic events (e.g., painful leg swelling, sudden chest pain, dyspnea).

Ischemic heart disease

Randomized controlled trials have not provided evidence that HRT (estrogen-only or combined estrogen-progestogen) protects against myocardial infarction in women with or without ischemic heart disease.

Combined estrogen-progestogen therapy

Data from randomized controlled clinical trials do not show cardiovascular benefits from long-term combined therapy with conjugated estrogens and medroxyprogesterone acetate (MPA). Two large-scale clinical trials, WHI and HERS (Heart and Estrogen/progestin Replacement Study), showed a possible increase in cardiovascular disease risk during the first year of therapy and absence of overall benefit.

In the large randomized clinical WHI study, an increased risk of stroke was observed as a secondary outcome in healthy women during long-term combined therapy with conjugated estrogens and MPA. It is estimated that the number of stroke cases over any 5-year period in untreated women not using HRT is approximately 3 cases per 1000 women aged 50−59 years and 11 cases per 1000 women aged 60−69 years. It is estimated that the number of additional cases in women taking conjugated estrogens and MPA over 5 years will be 0−3 cases (best estimate 1) per 1000 women aged 50−59 years and 1−9 cases (best estimate 4) per 1000 women aged 60−69 years.

The relative risk of ischemic heart disease slightly increases with combined estrogen-progestogen HRT. Since the baseline absolute risk of ischemic heart disease strongly depends on patient age, the number of additional cases of ischemic heart disease due to combined estrogen-progestogen therapy is very low in healthy women approaching menopause but increases in older women.

Estrogen-only monotherapy

In randomized controlled trials, no increased risk of ischemic heart disease was observed in women after hysterectomy receiving estrogen-only therapy.

To date, no randomized controlled trials have evaluated the risk of HRT-related cardiovascular diseases, mortality, or stroke events for other HRT products. For Estraklin, there are no data suggesting a different frequency of cardiovascular events or stroke.

Ischemic stroke

Treatment with combined estrogen-progestogen therapy and estrogen-only therapy is associated with up to a 1.5-fold increased risk of ischemic stroke. The relative risk does not depend on patient age or time since menopause onset. However, since the baseline risk of stroke strongly depends on age, the overall risk of stroke in women using HRT increases with age (see section "Adverse reactions").

Ovarian cancer

Ovarian cancer is less common than breast cancer.

Epidemiological data from a large meta-analysis suggest a slightly increased risk in women receiving estrogen-only or combined estrogen-progestogen HRT, evident after 5 years of treatment and decreasing over time after treatment discontinuation.

Some other studies, including WHI, suggest that combined HRT may be associated with a similar or slightly lower risk (see section "Adverse reactions").

Other conditions

Patients with renal or cardiac dysfunction should be under close supervision during treatment, as estrogens may cause fluid retention. Patients with end-stage renal failure should also be closely monitored due to the potential increase in plasma progesterone levels.

Women with existing hypertriglyceridemia should be under close supervision during estrogen or other hormonal replacement therapy, as isolated reports describe marked increases in plasma triglyceride levels, potentially leading to pancreatitis during treatment with oral estrogen preparations in such patients.

Although current data suggest that estrogens do not affect carbohydrate metabolism, women with diabetes should be monitored at the beginning of treatment until additional information is available.

HRT should not be used to improve cognitive function or prevent cognitive disorders, as efficacy for this indication has not been demonstrated. WHI study data show an increased risk of possible dementia in women who initiate continuous combined therapy with conjugated equine estrogens and MPA after age 65. It is unknown whether these findings apply to younger perimenopausal women or extend to other HRT products.

Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.

Estrogens increase levels of thyroxine-binding globulin (TBG), leading to increased levels of thyroid hormone in blood, measured as protein-bound iodine, T4 levels (measured by chromatography or radioimmunoassay), or T3 levels (measured by radioimmunoassay). Reverse T3 uptake decreases, reflecting increased TBG levels. Free T3 and T4 concentrations remain unchanged. Serum concentrations of other binding proteins, including corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG), may also change, leading to increased serum levels of corticosteroids and sex steroids, respectively. Concentrations of free or biologically active hormones remain unchanged. Levels of other plasma proteins, such as renin substrate/angiotensin, alpha-1-antitrypsin, and ceruloplasmin, may also increase.

Women should be informed that Estraklin is not a contraceptive and is not indicated for fertility restoration.

In women with an intact uterus, estrogen administration should always be accompanied by sequential progestogen administration.

Elevation of ALT levels

In clinical trials, during combined treatment of hepatitis C virus (HCV) with ombitasvir/paritaprevir/ritonavir with or without dasabuvir, ALT elevations exceeding 5 times the upper limit of normal (ULN) were significantly more frequent in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives (CHCs). Additionally, ALT elevations were observed in women using glecaprevir/pibrentasvir if they were also using ethinylestradiol-containing products, such as CHCs. In women using medicinal products containing estrogens other than ethinylestradiol, such as estradiol, the frequency of ALT elevation was similar to that in women not receiving any estrogens. However, due to the limited number of women using such other estrogens, caution should be exercised when co-administering combined HCV treatment regimens with ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as treatment regimens with glecaprevir/pibrentasvir (see section "Interaction with other medicinal products and other forms of interaction").

Possible transfer of estradiol to children

Estradiol gel may be accidentally transferred to children from the skin area where it was applied.

Post-marketing reports describe cases of breast development and breast firmness in prepubertal girls, precocious puberty, gynecomastia, and breast firmness in prepubertal boys following unintentional secondary exposure to estradiol spray/gel. In most cases, the problem resolved after cessation of exposure.

Patients should be given the following instructions:

• Patients should not allow others, especially children, to come into contact with the skin areas where the medicinal product has been applied, and if necessary, cover the application site with clothing. In case of contact, the child's skin should be washed with water and soap as soon as possible.
• Patients should consult a physician if signs or symptoms (breast development or other genital changes) appear in a child who may have been accidentally exposed to estradiol gel.

Use during pregnancy or breastfeeding.

Pregnancy

Estraklin must not be used during pregnancy. If pregnancy occurs, treatment with Estraklin must be discontinued immediately. Results from most epidemiological studies conducted to date, which reported accidental estrogen use during pregnancy, showed no teratogenic or fetotoxic effects.

Breastfeeding

Estraklin is not indicated for use during breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

Estraklin does not affect the ability to drive or operate machinery.

Method of Administration and Dosage

• Hormone replacement therapy (HRT) should be continued only if the benefit to the patient outweighs the risks.
• For the treatment of menopausal symptoms, the lowest effective dose for the shortest duration should always be used.

Dosage

Daily doses should be individually adjusted according to the physician's instructions.

The usual dosage is 2.5 g of gel per day: apply the dose measured by the applicator once daily for 21–31 days per month.

Dosing may be cyclic, in which estrogen is administered cyclically with treatment breaks: typically, this regimen consists of 21 days of treatment followed by 7 days off. Usually, a progestagen is additionally administered for 12–14 days of the cycle.

Dosing may be sequential and continuous, in which estrogen is administered continuously. Typically, a progestagen is additionally administered sequentially for at least 12–14 days of a 28-day cycle.

Dosing may be continuous and combined, in which both estrogen and progestagen are administered daily without interruption.

Dosage adjustment should be considered during the second or third treatment cycle based on the clinical signs listed below.

Excessive effect:

• breast tension;
• abdominal/pelvic bloating;
• anxiety, nervousness, aggression.

In such cases, the dose should be reduced. Apply an amount of gel corresponding to half the dose (1.25 g), as indicated on the applicator.

Insufficient effect:

• persistent hot flashes;
• vaginal dryness;
• headache and sleep disturbances;
• asthenia;
• tendency towards depression.

In such cases, the dose should be increased. Apply an amount of gel corresponding to one full dose plus half a dose (2.5 g + 1.25 g) or two full doses (2.5 g + 2.5 g), as indicated on the applicator, per day.

In particular, during the last 12–14 days of the cycle, treatment with Estraklin should be combined with oral micronized progestagen or progesterone.

The addition of progesterone is not recommended for women after hysterectomy unless they have previously been diagnosed with endometriosis.

The protective effect of progestagen against endometrial cancer has not been studied for doses exceeding 1.25 mg of estrogen per day (the standard dose of Estraklin, corresponding to 2.5 g of gel, contains 1.5 mg of estradiol, of which 10%, or 150 µg of estradiol, is absorbed).

Method of Administration

For dermal application (transdermal administration).

Apply the gel over a large skin surface area. Recommended application sites include: neck, shoulders, inner arms, abdomen, and inner thighs.

The gel must not be applied to the following areas:

• breasts (risk of swelling and pain);
• vulvovaginal mucosa (due to irritation and itching).

The gel should preferably be applied after washing, in the morning or evening. The application site should not be rubbed or massaged.

Allow the gel to dry for 1 or 2 minutes before dressing.

Estraklin is odorless and does not stain clothing. Since the gel base is a 45º mixture of water and alcohol, the product must not be applied directly to mucous membranes.

During each treatment break period, withdrawal bleeding may occur.

If a patient misses a dose by 12 hours or more before the next scheduled dose, the missed dose should be applied and the regular dosing schedule resumed. If less than 12 hours remain before the next dose, it is better to wait and apply the next dose at the usual time. Patients should be advised not to apply two doses simultaneously.

If a patient forgets to apply the medication, this may increase the likelihood of breakthrough bleeding and spotting.

Patients should be informed that children should not come into contact with areas of the body where the medication has been applied (see section "Special Warnings and Precautions for Use").

Children

The medicinal product should not be used in children.

Overdose

In cases of overdose, the following effects have been observed (see section "Method of Administration and Dosage"):

• breast tension;
• abdominal/pelvic bloating;
• anxiety, nervousness, aggression.

These symptoms usually resolve upon discontinuation of treatment or dose reduction.

There is no specific antidote. Treatment is symptomatic. The gel should be washed off.

Adverse Reactions

No adverse reactions with an incidence of 10% or higher were observed.

Other adverse reactions reported in patients using Estrakline or other estradiol-containing products in various dosage forms (excluding oral formulations) are listed below by frequency and organ system. Adverse reaction frequencies are categorized as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated based on available data).

Nervous system disorders

Common: increased or decreased libido, irritability, mood changes, migraine.

Rare: depression, dizziness, exacerbation of epilepsy.

Vascular disorders

Uncommon: arterial hypertension.

Rare: worsening of varicose veins.

Gastrointestinal disorders

Common: nausea, flatulence.

Uncommon: abdominal distension, abdominal cramps.

Rare: cholelithiasis, cholestatic jaundice.

Skin and subcutaneous tissue disorders

Uncommon: acne, pruritus.

Rare: urticaria.

Reproductive system and breast disorders

Common: unexpected bleeding, spotting, vaginal dryness, increased cervical secretion, mastodynia.

Uncommon: dysmenorrhea, endometrial hyperplasia, benign breast tumors, breast cancer.

Rare: increase in uterine fibroid size, galactorrhea.

General disorders and administration site conditions

Common: headache, eye irritation associated with contact lens use.

Uncommon: fluid and electrolyte retention, edema, weight gain or loss, dizziness, asthenia, leg cramps.

Rare cases of chloasma and melasma (which may become permanent), erythema multiforme, nodular erythema, and hepatic adenoma (which may lead to intra-abdominal hemorrhage) have been reported in women receiving estrogen therapy.

In women using HRT, venous thromboembolic disorders, including deep vein thrombosis and pulmonary embolism, occur more frequently than in women not using HRT. For additional information, see sections "Contraindications" and "Special precautions for use".

Breast cancer

A doubling or less of the risk of developing breast cancer has been reported in women who have used combined estrogen-progestogen therapy for more than 5 years. In women receiving estrogen-only therapy, the risk of breast cancer is increased to a lesser extent compared to women using combined estrogen-progestogen therapy. The level of risk depends on the duration of treatment (see section "Special precautions for use").

Estimates of absolute risk, based on results from the largest randomized placebo-controlled trial (WHI) and the largest meta-analysis of prospective epidemiological studies, are presented in Tables 1–3.

Table 1

Estimation of additional risk of developing breast cancer after 5 years of HRT use in women with a body mass index (BMI) of 27 kg/m²

* Value obtained based on a baseline incidence rate established in 2015 in England for women with a BMI of 27 kg/m².

Note: Since the baseline incidence of breast cancer varies between countries, the number of additional breast cancer cases will also change proportionally.

Table 2

Estimation of the additional risk of developing breast cancer after 10 years of HRT use in women with a BMI of 27 kg/m²

* Value obtained based on a baseline incidence rate established in 2015 in England for women with BMI of 27 kg/m².

Note: Since the baseline incidence rate of breast cancer varies across countries, the number of additional breast cancer cases will also change proportionally.

Table 3

WHI study in the US: additional risk of developing breast cancer after 5 years of treatment

CI – confidence interval

* In women without a uterus, the WHI study did not demonstrate an increased risk of breast cancer.

‡ When analysis was restricted to women who had not used HRT prior to the start of the study, no increased risk was observed during the first 5 years of treatment; after 5 years, the risk was higher compared to women not using HRT.

CEE – conjugated equine estrogens.

MPA – medroxyprogesterone acetate.

Endometrial cancer

The risk of developing endometrial cancer is approximately 5 cases per 1000 women with a uterus who do not use HRT.

In women with a uterus, estrogen-only HRT is not recommended, as it increases the risk of endometrial cancer (see section "Special precautions").

Depending on the duration of estrogen-only therapy and estrogen dose, the increased risk of endometrial cancer observed in epidemiological studies ranged from 5 to 55 additional cases per 1000 women aged 50 to 65.

Adding a progestagen to estrogen-only HRT for at least 12 days per cycle may prevent this increased risk. In the WHI study, the use of combined (sequential or continuous) HRT for five years did not increase the risk of endometrial cancer [relative risk (RR) 1.0 (0.8–1.2)].

Ovarian cancer

HRT with either estrogen-only or combined estrogen-progestagen therapy has been associated with a slightly increased risk of ovarian cancer (see section "Special precautions").

A meta-analysis of 52 epidemiological studies showed a higher risk of ovarian cancer in women who had used HRT compared to women who had never used HRT (relative risk (RR) 1.43, 95% CI, 1.31–1.56). In women aged 50–54 years who used HRT for 5 years, there was 1 additional case of ovarian cancer per 2000 women. In women aged 50–54 years not using HRT, approximately 2 cases of ovarian cancer per 2000 women were observed over a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3- to 3-fold increased risk of venous thromboembolism (VTE), such as deep vein thrombosis or pulmonary embolism. The occurrence of such events is most likely during the first year of HRT use (see section "Special precautions"). Results from the WHI study are presented in Table 4.

Table 4

WHI study: additional risk of developing VTE after 5 years of use

* Study conducted in women after hysterectomy.

Risk of ischemic heart disease

The risk of developing ischemic heart disease is slightly increased in women aged 60 years and older receiving combined estrogen-progestagen HRT (see section "Special precautions").

Risk of ischemic stroke

When using estrogen-only therapy or combined estrogen-progestagen therapy, the relative risk of ischemic stroke increases by 1.5 times. The risk of hemorrhagic stroke during HRT is not increased.

This relative risk does not depend on patient's age or duration of treatment. However, since the baseline risk increases significantly with age, the overall risk of stroke in patients receiving HRT will rise with advancing age (see section "Special precautions").

Table 5

WHI study: additional risk of ischemic stroke* after 5 years of treatment

* No differentiation was made between ischemic and hemorrhagic stroke.

Other adverse reactions reported with estrogen use, either as monotherapy or in combination with progestogens, include:

• benign or malignant estrogen-dependent neoplasms, such as endometrial cancer;
• venous thromboembolism, e.g., deep vein thrombosis of the leg or pelvic region and pulmonary embolism, worsening of varicosis, arterial hypertension (see sections "Contraindications" and "Special warnings and precautions for use");
• myocardial infarction;
• stroke;
• cutaneous and subcutaneous disorders: chloasma, erythema multiforme, nodular erythema, vasculitic purpura, contact dermatitis, pigmentary disorders, generalized pruritus, and rash;
• gallbladder disease;
• probable dementia in women aged 65 years and older (see section "Special warnings and precautions for use").

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Use within 3 months after first opening of the tube.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

80 g of gel in an aluminum tube with an internal lacquer coating, closed with a polyethylene cap. One tube with a dosing applicator in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

SEID S.A. / SEID S.A.

Manufacturer's address and place of business.

Ctra. de Sabadell a Granollers, Km. 15, Llica de Vall, Barcelona, 08185, Spain /
Ctra. de Sabadell a Granollers, Km. 15, Llica de Vall, Barcelona, 08185, Spain.