Evorel Gel 500 microgram Transdermal gel

Theramex🇬🇧 Electronic Medicines Compendium

Approval Date: N/A
Approval ID: 0f22186299a5acd1
Company: Theramex
Type: Standard

Approval Details

Approval Id: 0f22186299a5acd1
Drug Approval Emc Name: Evorel Gel 500 microgram Transdermal gel
Drug Name: Evorel Gel 500 microgram Transdermal gel
Company Name: Theramex
Company Address: Theramex HQ UK Ltd, 50 Broadway, 5th Floor, London, SW1H 0BL, UK
Company Website: www.theramex.com
Company Medical Info Direct Line: 0333 0096795
Company Medical Info Email: [email protected]
Atc Code: G03CA03
Legal Category: Prescription only medicine
Authorisation Holder: 7. Marketing authorisation holder Theramex HQ UK Limited 5th Floor, 50 Broadway London, SW1H 0BL United Kingdom
Authorisation Number: 8. Marketing authorisation number(s) PL 49105 / 0020
Authorisation Date: 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 04 March 2026 Date of latest renewal:
Instruction Authorisation Holder: 7. Marketing authorisation holder Theramex HQ UK Limited 5th Floor, 50 Broadway London, SW1H 0BL United Kingdom
Instruction Authorisation Number: 8. Marketing authorisation number(s) PL 49105 / 0020
Instruction Authorisation Date: 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 04 March 2026 Date of latest renewal:
Instruction Composition: 2. Qualitative and quantitative composition 1 g of gel contains 1.0325 mg of estradiol hemihydrate, corresponding to 1.0000 mg of anhydrous estradiol. Each dose delivers 0.5 g of gel, i.e. 0.5 mg of estradiol (as 0.516 mg of estradiol hemihydrate). Excipient with known effect: Propylene glycol (6.0 mg). For the full list of excipients, see section 6.1.
Instruction Dosage Form: 3. Pharmaceutical form Transdermal gel Clear, translucent, colourless-to-slight yellowish and odourless gel
Instruction Clinical Particulars: 4. Clinical particulars 4.1 Therapeutic indications Hormone Replacement Therapy (HRT) for estrogen deficiency symptoms in postmenopausal women. The experience treating women older than 65 years is limited. 4.2 Posology and method of administration Posology Two therapeutic regimens can be used: 1) Cyclic: for 24 to 28 days, followed by a 2 to 7 days treatment free period. The progestogen should be administered at least during the last 12 days of the estradiol treatment in non-hysterectomised women. Withdrawal bleeding may occur during this period. 2) Continuous: with no treatment free period. In non-hysterectomised women the progestogen should be administered for at least 12 days per month. Withdrawal bleeding may occur when the progestogen is withdrawn. Continuous, non-cyclic, treatment may be recommended in cases where marked symptoms of estrogen deficiency recur during the treatment-free period. In women with an intact uterus the addition of a progestogen for at least 12 to 14 days per cycle is essential to help prevent any endometrial hyperplasia induced by the estrogen. For more detailed information, please refer to section "Special warnings and precautions for use" – Endometrial hyperplasia). In hysterectomised women, unless there is a previous diagnosis of endometriosis, the addition of a progestogen is not recommended. Menopausal and postmenopausal symptoms Each metered dose (1 pump actuation) from the dispenser is 0.5 g of Evorel Gel. One pump (0.5 g) of Evorel Gel once daily (0.5 mg Estradiol) is the usual starting dose for 24 to 28 days. This starting dose can be adapted per the patients' individual needs. The average dose is three pumps (1.5 g) of Evorel Gel per day, which in the majority of women will provide effective relief of symptoms. If after one month's treatment effective relief is not obtained, the dosage may be increased accordingly to a maximum of six pumps (3 g) of Evorel Gel daily (3 mg Estradiol). The lowest effective dose should be used for maintenance therapy. For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used. Use with progestogen In women with an intact uterus the addition of a progestogen for at least 12 to 14 days per cycle is essential to help prevent any endometrial hyperplasia induced by the estrogen. In hysterectomised women, unless there is a previous diagnosis of endometriosis, the addition of a progestogen is not recommended. Initiation of treatment Women who have never taken HRT and are post-menopausal or have very infrequent menstrual cycles: treatment with Evorel Gel can be started on any day. Switching from a continuous oestrogen-progestogen combined HRT: treatment with Evorel Gel can be started on any day of the cycle. Switching from a cyclic or continuous sequential HRT treatment: finish the therapeutic sequence before beginning treatment with Evorel Gel. Method of Administration It may be necessary to prime the pump when beginning a new bottle. The pump must be pressed several times until gel comes out of the pump. The first dose may not be accurate and should be discarded. The pump may need to be reprimed after first use. The correct dose of gel should be dispensed and applied to clean, dry, intact areas of skin e.g. on the arms and shoulders, or inner thighs, preferably after washing in the morning or evening. The area of application should be at least 2 times the size of the hand. Evorel Gel should NOT be applied on or near the breasts or on the vulval region. A frequent change in application sites is recommended. It is not necessary to rub Evorel Gel in, however, it should be allowed to dry for 2 minutes before covering the skin with clothing. The gel should be applied by the patient herself, not by anyone else. Women should cover the application site with clothing if another person may come into contact with the area of skin after the gel dries. Skin contact, particularly with a male partner, should be avoided. The site of application should not be washed for 60 minutes. Wash hands with soap and water after applying the gel. Patients should be informed that children should not come in contact with the area of the body where Evorel was applied on (see section 4.4). For people not being treated with Evorel Gel: In the event of contact with an application area, which has not been washed or is not covered with clothing, wash the area of skin onto which Evorel Gel may have been transferred as soon as possible, using soap and water. If the patient forgets to apply a dose and it is more than 12 hours until the next dose, the missed dose should be applied and normal dosing resumed the next day. If the next dose is less than 12 hours away, it is best just to wait and apply the next dose normally. Patients should be advised not to apply two doses at the same time. Forgetting a dose may increase the likelihood of break-through bleeding and spotting. The individual dose can be adjusted to individual needs. Individual doses may range from 0.5 g to 3 g of gel. The average dose is 1.5 g of gel per day, i.e. 3 consecutive doses. 4.3 Contraindications • Known, past or suspected breast cancer. • Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer). • Undiagnosed genital bleeding. • Untreated endometrial hyperplasia. • Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism). • Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4). • Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction). • Acute liver disease, or a history of liver disease as long as liver functions have failed to return to normal. • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Porphyria. 4.4 Special warnings and precautions for use For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk. Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women. Medical examination/follow-up Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see “Breast cancer” below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual. Conditions which need supervision If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with EVOREL GEL, in particular: • Leiomyoma (uterine fibroids) or endometriosis. • Risk factors for thromboembolic disorders (see below). • Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer. • Hypertension. • Liver disorders (e.g. liver adenoma). • Diabetes mellitus with or without vascular involvement. • Cholelithiasis. • Migraine or (severe) headache. • Systemic lupus erythematosus. • A history of endometrial hyperplasia (see below). • Epilepsy. • Asthma. • Otosclerosis. Reasons for immediate withdrawal of therapy Therapy should be discontinued in case a contra-indication is discovered and in the following situations: • Jaundice or deterioration in liver function. • Significant increase in blood pressure. • New onset of migraine-type headache. • Pregnancy. Endometrial hyperplasia and carcinoma • In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years. • The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT. • For oral doses of estradiol > 2 mg, conjugated equine estrogens > 0.625 mg and patches > 50 µg/day the endometrial safety of added progestogens has not been demonstrated. • Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy. • Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis. Breast cancer The overall evidence shows an increased risk of breast cancer in women taking combined estrogen- progestogen or estrogen-only HRT, that is dependent on the duration of taking HRT. Combined oetrogen-progestogen therapy • The randomised placebo-controlled trial Women's Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestogen for HRT that becomes apparent after about 3 (1-4) years (see Section 4.8). Estrogen – only therapy • The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen- only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is lower than that found in users of estrogen-progestogen combinations (see section 4.8). Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more. HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer. Ovarian cancer Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies including the WHI trial suggest that the use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8). Venous thromboembolism • HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8). • Generally recognised risk factors for VTE include, use of estrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE. • As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised. • Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. • If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea). • Patients with a history of VTE or known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients. • In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated. Coronary artery disease (CAD) There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen or estrogen-only HRT. Combined oetrogen-progestogen therapy • The relative risk of CAD during use of combined estrogen+progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen+progestogen use is very low in healthy women close to menopause, but will rise with more advanced age. Estrogen–only therapy • Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy. Ischaemic stroke Combined estrogen-progestogen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8). Other conditions • Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. • Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition. • Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema. • Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). • HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65 ALT elevation During clinical trials with the hepatitis C virus (HCV) combination regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol- containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing estrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, caution is warranted for co-administration with the following combination drug regimens ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. See section 4.
Instruction Pharmacology: 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: ESTROGENS (Genitourinary system and sex hormones) ATC code: G03CA03 Mechanism of action Natural estrogen by transdermal route The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms Clinical Trial Information Clinical efficacy, safety and acceptability Evorel Gel was evaluated in an open, randomised phase 3 study of 277 postmenopausal women, 145 women were treated with Evorel Gel and 132 with comparator for a period of 3 months. Rapid and dramatic decrease in daily frequency and intensity of hot flushes was reported. No statistical significant difference for efficacy between Evorel Gel and comparator were reported. Evorel Gel (n=145) Comparator (n=132) Before 4 weeks 3 months Before 4 weeks 3 months Number of hot flushes 10.5 ± 0.4 2.7 ± 0.3 1.4 ± 0.2 10.7 ± 0.5 2.4 ± 0.3 1.6 ± 0.3 Kupperman Index 22.7 ± 0.6 9.3 ± 0.6
Instruction Pharmaceutical Particulars: 6. Pharmaceutical particulars 6.1 List of excipients Ethanol 96 per cent, Purified water, Propylene glycol, Diethylene glycol monoethyl ether (Transcutol), Carbomer (Carbopol 1382), Trolamine, Disodium edetate. 6.2 Incompatibilities Not applicable 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not refrigerate or freeze . 6.5 Nature and contents of container An aluminium bag placed in an opaque white polypropylene bottle containing 50 g of gel, with a dosing pump. Box of one or three bottles of 50g. The pump delivers pushes of 0.5 g of gel corresponding to 0.5 mg of estradiol. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Instruction Content: ## Composition 2. Qualitative and quantitative composition 1 g of gel contains 1.0325 mg of estradiol hemihydrate, corresponding to 1.0000 mg of anhydrous estradiol. Each dose delivers 0.5 g of gel, i.e. 0.5 mg of estradiol (as 0.516 mg of estradiol hemihydrate). Excipient with known effect: Propylene glycol (6.0 mg). For the full list of excipients, see section 6.1. ## Pharmaceutical Form 3. Pharmaceutical form Transdermal gel Clear, translucent, colourless-to-slight yellowish and odourless gel ## Clinical Particulars 4. Clinical particulars 4.1 Therapeutic indications Hormone Replacement Therapy (HRT) for estrogen deficiency symptoms in postmenopausal women. The experience treating women older than 65 years is limited. 4.2 Posology and method of administration Posology Two therapeutic regimens can be used: 1) Cyclic: for 24 to 28 days, followed by a 2 to 7 days treatment free period. The progestogen should be administered at least during the last 12 days of the estradiol treatment in non-hysterectomised women. Withdrawal bleeding may occur during this period. 2) Continuous: with no treatment free period. In non-hysterectomised women the progestogen should be administered for at least 12 days per month. Withdrawal bleeding may occur when the progestogen is withdrawn. Continuous, non-cyclic, treatment may be recommended in cases where marked symptoms of estrogen deficiency recur during the treatment-free period. In women with an intact uterus the addition of a progestogen for at least 12 to 14 days per cycle is essential to help prevent any endometrial hyperplasia induced by the estrogen. For more detailed information, please refer to section "Special warnings and precautions for use" – Endometrial hyperplasia). In hysterectomised women, unless there is a previous diagnosis of endometriosis, the addition of a progestogen is not recommended. Menopausal and postmenopausal symptoms Each metered dose (1 pump actuation) from the dispenser is 0.5 g of Evorel Gel. One pump (0.5 g) of Evorel Gel once daily (0.5 mg Estradiol) is the usual starting dose for 24 to 28 days. This starting dose can be adapted per the patients' individual needs. The average dose is three pumps (1.5 g) of Evorel Gel per day, which in the majority of women will provide effective relief of symptoms. If after one month's treatment effective relief is not obtained, the dosage may be increased accordingly to a maximum of six pumps (3 g) of Evorel Gel daily (3 mg Estradiol). The lowest effective dose should be used for maintenance therapy. For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used. Use with progestogen In women with an intact uterus the addition of a progestogen for at least 12 to 14 days per cycle is essential to help prevent any endometrial hyperplasia induced by the estrogen. In hysterectomised women, unless there is a previous diagnosis of endometriosis, the addition of a progestogen is not recommended. Initiation of treatment Women who have never taken HRT and are post-menopausal or have very infrequent menstrual cycles: treatment with Evorel Gel can be started on any day. Switching from a continuous oestrogen-progestogen combined HRT: treatment with Evorel Gel can be started on any day of the cycle. Switching from a cyclic or continuous sequential HRT treatment: finish the therapeutic sequence before beginning treatment with Evorel Gel. Method of Administration It may be necessary to prime the pump when beginning a new bottle. The pump must be pressed several times until gel comes out of the pump. The first dose may not be accurate and should be discarded. The pump may need to be reprimed after first use. The correct dose of gel should be dispensed and applied to clean, dry, intact areas of skin e.g. on the arms and shoulders, or inner thighs, preferably after washing in the morning or evening. The area of application should be at least 2 times the size of the hand. Evorel Gel should NOT be applied on or near the breasts or on the vulval region. A frequent change in application sites is recommended. It is not necessary to rub Evorel Gel in, however, it should be allowed to dry for 2 minutes before covering the skin with clothing. The gel should be applied by the patient herself, not by anyone else. Women should cover the application site with clothing if another person may come into contact with the area of skin after the gel dries. Skin contact, particularly with a male partner, should be avoided. The site of application should not be washed for 60 minutes. Wash hands with soap and water after applying the gel. Patients should be informed that children should not come in contact with the area of the body where Evorel was applied on (see section 4.4). For people not being treated with Evorel Gel: In the event of contact with an application area, which has not been washed or is not covered with clothing, wash the area of skin onto which Evorel Gel may have been transferred as soon as possible, using soap and water. If the patient forgets to apply a dose and it is more than 12 hours until the next dose, the missed dose should be applied and normal dosing resumed the next day. If the next dose is less than 12 hours away, it is best just to wait and apply the next dose normally. Patients should be advised not to apply two doses at the same time. Forgetting a dose may increase the likelihood of break-through bleeding and spotting. The individual dose can be adjusted to individual needs. Individual doses may range from 0.5 g to 3 g of gel. The average dose is 1.5 g of gel per day, i.e. 3 consecutive doses. 4.3 Contraindications • Known, past or suspected breast cancer. • Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer). • Undiagnosed genital bleeding. • Untreated endometrial hyperplasia. • Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism). • Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4). • Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction). • Acute liver disease, or a history of liver disease as long as liver functions have failed to return to normal. • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Porphyria. 4.4 Special warnings and precautions for use For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk. Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women. Medical examination/follow-up Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see “Breast cancer” below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual. Conditions which need supervision If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with EVOREL GEL, in particular: • Leiomyoma (uterine fibroids) or endometriosis. • Risk factors for thromboembolic disorders (see below). • Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer. • Hypertension. • Liver disorders (e.g. liver adenoma). • Diabetes mellitus with or without vascular involvement. • Cholelithiasis. • Migraine or (severe) headache. • Systemic lupus erythematosus. • A history of endometrial hyperplasia (see below). • Epilepsy. • Asthma. • Otosclerosis. Reasons for immediate withdrawal of therapy Therapy should be discontinued in case a contra-indication is discovered and in the following situations: • Jaundice or deterioration in liver function. • Significant increase in blood pressure. • New onset of migraine-type headache. • Pregnancy. Endometrial hyperplasia and carcinoma • In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years. • The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT. • For oral doses of estradiol > 2 mg, conjugated equine estrogens > 0.625 mg and patches > 50 µg/day the endometrial safety of added progestogens has not been demonstrated. • Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy. • Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis. Breast cancer The overall evidence shows an increased risk of breast cancer in women taking combined estrogen- progestogen or estrogen-only HRT, that is dependent on the duration of taking HRT. Combined oetrogen-progestogen therapy • The randomised placebo-controlled trial Women's Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestogen for HRT that becomes apparent after about 3 (1-4) years (see Section 4.8). Estrogen – only therapy • The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen- only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is lower than that found in users of estrogen-progestogen combinations (see section 4.8). Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more. HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer. Ovarian cancer Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies including the WHI trial suggest that the use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8). Venous thromboembolism • HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8). • Generally recognised risk factors for VTE include, use of estrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE. • As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised. • Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. • If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea). • Patients with a history of VTE or known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients. • In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated. Coronary artery disease (CAD) There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen or estrogen-only HRT. Combined oetrogen-progestogen therapy • The relative risk of CAD during use of combined estrogen+progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen+progestogen use is very low in healthy women close to menopause, but will rise with more advanced age. Estrogen–only therapy • Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy. Ischaemic stroke Combined estrogen-progestogen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8). Other conditions • Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. • Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition. • Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema. • Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). • HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65 ALT elevation During clinical trials with the hepatitis C virus (HCV) combination regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol- containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing estrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, caution is warranted for co-administration with the following combination drug regimens ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. See section 4. ## Pharmacological Properties 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: ESTROGENS (Genitourinary system and sex hormones) ATC code: G03CA03 Mechanism of action Natural estrogen by transdermal route The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms Clinical Trial Information Clinical efficacy, safety and acceptability Evorel Gel was evaluated in an open, randomised phase 3 study of 277 postmenopausal women, 145 women were treated with Evorel Gel and 132 with comparator for a period of 3 months. Rapid and dramatic decrease in daily frequency and intensity of hot flushes was reported. No statistical significant difference for efficacy between Evorel Gel and comparator were reported. Evorel Gel (n=145) Comparator (n=132) Before 4 weeks 3 months Before 4 weeks 3 months Number of hot flushes 10.5 ± 0.4 2.7 ± 0.3 1.4 ± 0.2 10.7 ± 0.5 2.4 ± 0.3 1.6 ± 0.3 Kupperman Index 22.7 ± 0.6 9.3 ± 0.6 ## Pharmaceutical Particulars 6. Pharmaceutical particulars 6.1 List of excipients Ethanol 96 per cent, Purified water, Propylene glycol, Diethylene glycol monoethyl ether (Transcutol), Carbomer (Carbopol 1382), Trolamine, Disodium edetate. 6.2 Incompatibilities Not applicable 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not refrigerate or freeze . 6.5 Nature and contents of container An aluminium bag placed in an opaque white polypropylene bottle containing 50 g of gel, with a dosing pump. Box of one or three bottles of 50g. The pump delivers pushes of 0.5 g of gel corresponding to 0.5 mg of estradiol. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Company Detail Path: /organization/laboratoire-theramex

Active Ingredients

Approved

Quick Info

Agency

UK EMC

Country

🇬🇧

Approval ID

0f22186299a5acd1

Type

Standard

Back to UK EMC Approvals