- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Legal category
|• Evorel 25:||1.6 mg estradiol/patch|
|• Evorel 50:||3.2 mg estradiol/patch|
|• Evorel 75:||4.8 mg estradiol/patch|
|• Evorel 100:||6.4 mg estradiol/patch|
Evorel 50, 75 and 100 only:Prevention of osteoporosis in post-menopausal women at high risk of future fractures who are intolerant of, or contra-indicated for, other medicinal products approved for the prevention of osteoporosis. (See Section 4.4)The experience of treating women older than 65 years is limited.
AdultsEvorel is an oestrogen-only HRT patch applied to the skin twice weekly. For initiation and continuation of treatment of menopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used.
Treatment of oestrogen deficiency symptomsTherapy should be started with one Evorel 50 patch (delivering 50 micrograms of estradiol/24 hours) and the dose adjusted after the first month if necessary depending on efficacy and signs of over-oestrogenisation (eg breast tenderness). For maintenance therapy the lowest effective dose should be used; a maximum dose of 100 micrograms of estradiol/24 hours should not be exceeded.
Evorel 50, 75, 100
Prevention of post-menopausal osteoporosisTherapy should be started with Evorel 50. The dose may be adjusted depending on efficacy and signs of over-oestrogenisation (eg breast tenderness). Note, however, that the efficacy of Evorel 25 for the prevention of post-menopausal osteoporosis has not been demonstrated. For maintenance therapy, the lowest effective dose should be used. A dose of 100micrograms of estradiol/24 hours should not be exceeded.
Progestogen useFor women with an intact uterus progestogen should normally be added to Evorel for the prevention of adverse endometrial effects, eg hyperplasia and cancer. The regimen may be either cyclic or continuous sequential. Only progestogens approved for addition to oestrogen treatment may be prescribed (eg oral norethisterone, 1mg/day or medroxyprogesterone acetate, 2.5mg/day) and should be added for at least 12-14 days every month/28 day cycle.Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.
Guidance on how to start therapy:Post-menopausal women currently not on HRT may start Evorel at any time.Peri-menopausal women who are still having regular menstrual cycles and are not currently on HRT should start Evorel within 5 days of the start of bleeding. Peri-menopausal women with irregular menstrual cycles, for whom pregnancy has been excluded, can start Evorel at any time.
Switching from other HRTThe switch from another oestrogen-only therapy in post-menopausal women to Evorel may occur at any time.Women on a continuous combined regimen wishing to switch from another oestrogen to Evorel may do so at any time. Women on a cyclic or continuous sequential regimen wishing to switch from a sequential combined HRT preparation to Evorel may do so at the end of a cycle of the current therapy or after a 7 day hormone free interval.
Method of AdministrationEvorel should be applied to the skin as soon as it is removed from the wrapper. Recommended application sites are on clean, dry, healthy, intact skin and each application should be made to a slightly different area of skin on the trunk below waistline. Evorel should not be applied on or near the breasts.Evorel should remain in place during bathing and showering. Should it fall off during bathing or showering the patient should wait until cutaneous vasodilation ceases before applying a replacement patch to avoid potential excessive absorption. Should a patch fall off at other times it should be replaced immediately.Patients can be advised to use baby oil to help remove any gum/glue which may remain on their skin after patch removal.
Missed doseIf the patient forgets to change their patch, they should change it as soon as possible and apply the next one at the normal time. However, if it is almost time for the next patch, the patient should skip the missed one and go back to their regular schedule. Only one patch should be applied at a time.There is an increased likelihood of break-through bleeding and spotting when a patch is not replaced at the normal time.
ChildrenEvorel is not indicated in children.
ElderlyData are insufficient in regard to the use of Evorel in the elderly (>65 years old).
Route of administrationTransdermal use.
Medical examination/follow-upBefore initiating or re-instituting 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 mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions which need supervisionIf 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, in particular:Leiomyoma (uterine fibroids) or endometriosisA history of, or risk factors for, thrombo-embolic disorders (see below)Risk factors for oestrogen dependent tumours, eg 1st degree heredity for breast cancerHypertensionLiver disorders (eg liver adenoma)Diabetes mellitus with or without vascular involvementCholelithiasisMigraine or (severe) headacheSystemic lupus erythematosus.A history of endometrial hyperplasia (see below)EpilepsyAsthmaOtosclerosisHereditary angioedemaMastopathy
Conditions which require monitoring while on oestrogen therapy:• Oestrogens may cause fluid retention. Cardiac or renal dysfunction should be carefully observed• Disturbances or mild impairment of liver function• History of cholestatic jaundice• Pre-existing hypertriglyceridaemia. Rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition
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 hyperplasiaIn women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2 to 12 fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see Section 4.8). After stopping treatment, the risk may remain elevated for at least 10 years. Oestrogen-only therapy from 1 to 5 years in women with a uterus has been estimated to increase the risk of endometrial cancer 3-fold (from a baseline lifetime risk of about 3% for a woman aged 50 years), with effects persisting for several years after oestrogen is stopped. The addition of a progestogen for 12 14 days per cycle or continuous combined oestrogen/progestogen therapy in non-hysterectomised women greatly reduces this risk. Although progestogen treatment for at least 10 days per cycle reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer, 12-14 days per cycle is recommended to maximise endometrial protection. Such a sequential oestrogen/oestrogen-progestogen regimen results in cyclic bleeding in the majority of women. For Evorel 75 and 100 the endometrial safety of added progestogens has not been studied. 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 oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of a progestogen to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis if they are known to have residual endometriosis.
Breast cancerThe overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestogen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT. Combined oestrogen-progestogen therapy: The randomised placebo-controlled trial the (Women's Health Initiative study (WHI), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestogen for HRT that becomes apparent after about 3 years (see Section 4.8).
Oestrogen-only therapy:The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-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 oestrogen-progestogen combinations (see Section 4.8).The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment. HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancerOvarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller, risk.
Venous thrombo-embolismHRT is associated with a higher relative risk of developing venous thrombo-embolism (VTE), ie deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged 60-69 years. It is estimated that in healthy women who use combined oral HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later. Generally recognised risk factors for VTE include a personal history or family history, use of oestrogens, older age, severe obesity (BMI > 30 kg/m2), pregnancy/postpartum period , cancer and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE. Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thrombo-embolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised. 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 thrombo-embolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnoea).
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 oestrogen-progestagen or oestrogen- only HRT. Oestrogen-only: Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.. Combined oestrogen-progestogen therapy: The relative risk of CAD during use of combined oestrogen-progestogen HRT is slightly increased. The absolute risk of CAD is strongly dependent on age. The number of extra cases of CAD due to oestrogen-progestogen use is very low in healthy women close to menopause, but will rise with more advanced age
StrokeOne large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated oestrogens and medroxyprogesterone acetate (MPA). For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated oestrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products. Combined oestrogen-progestogen and oestrogen-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 or duration of use. 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.
Other conditionsOestrogens 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 unchanged. 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). Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation whilst taking HRT.
DementiaHRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.Evorel is not to be used for contraception. Women of child-bearing potential should be advised to use non-hormonal contraceptive methods to avoid pregnancy.
PregnancyEvorel is not indicated during pregnancy. If pregnancy occurs during use of Evorel, treatment should be withdrawn immediately.There are no clinical data on exposed pregnancies. Studies in animals have not shown reproductive toxicity.The results of most epidemiological studies to date relevant to inadvertent fetal exposure to combinations of oestrogens (and progestogens) indicate no teratogenic or foetotoxic effect.
LactationEvorel is not indicated during lactation.
|Infections and Infestations|
|Neoplasms benign, malignant and unspecified (including cysts and polyps)|
|Frequency not known||Endometrial cancer|
|Immune System Disorders|
|Nervous system disorders|
|Common||Migraine, Dizziness, Headache|
|Frequency not known||Cerebrovascular accident|
|Frequency not known||Myocardial infarction|
|Frequency not known||Deep vein thrombosis|
|Respiratory, Thoracic and Mediastinal Disorders|
|Frequency not known||Pulmonary embolism|
|Common||Abdominal pain, Diarrhoea, Nausea|
|Skin and subcutaneous tissue disorders|
|Frequency not known||Angioedema|
|Musculoskeletal and Connective Tissue Disorders|
|Reproductive system and breast disorders|
|Common||Breast pain, Metrorrhagia|
|Uncommon||Breast enlargement, Dysmenorrhoea|
|General disorders and administration site conditions|
|Very Common||Application site pruritus*, Application site rash*|
|Common||Pain, Application site erythema*, Application site oedema*, Application site reaction|
|Uncommon||Oedema, Generalised oedema, Oedema peripheral|
|Metabolism and nutrition disorders|
|Rare||Anxiety, Libido decreased, Libido increased|
|Rare||Contact lens intolerance|
|Skin and subcutaneous tissue|
|Musculoskeletal and connective tissue disorders|
|Reproductive system and breast disorders|
|Rare||Vaginal discharge, Premenstrual like syndrome|
|General disorders and administration conditions|
Breast CancerAccording to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users. An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years. For oestrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone. Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented below: Million Women study Estimated additional risk of breast cancer after 5 years' use
|Age range (years)||Additional cases per 1000 never-users of HRT over a 5 year period*2||Risk ratio #||Additional cases per 1000 HRT users over 5 years (95% CI)|
|Oestrogen only HRT|
|50-65||9-12||1.2||1-2 (0 - 3)|
|50-65||9-12||1.7||6 (5 - 7)|
|*2 Taken from baseline incidence rates in developed countries. # Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use. Note: since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer differs by EU country; the number of additional cases of breast cancer will also change proportionately.|
US WHI studies - additional risk of breast cancer after 5 year's use
|Age range (years)||Incidence per 1000 women in placebo arm over 5 years||Risk ratio & 95%CI||Additional cases per 1000 HRT users over 5 years (95% CI)|
|CEE oestrogen only|
|50-79||21||0.8 (0.7-1.0)||-4 (-6 - 0)*3|
|CEE + MPA oestrogen & progestagens §|
|50-79||17||1.2 (1.0-1.5)||+4 (0 - 9)|
|*3 WHI study in women with no uterus, which did not show an increase of breast cancer. § When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.|
Endometrial CancerIn women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestogen to oestrogen-only therapy greatly reduces this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).Adverse events which have been reported in association with oestrogen/ progestogen treatment :Venous thrombo-embolism, ie deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone HRT users than among non-users. For further information see Section 4.3 Contra-indications and 4.4 Special warnings and precautions for use.
Estradiol hemihydrate:The active ingredient, synthetic estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.
For Evorel 50, 75 and 100:Oestrogens prevent bone loss following menopause or ovariectomy.
Clinical trial information:Relief of menopausal symptoms was achieved to a similar degree during the first few weeks of treatment with Evorel 50 and Evorel 100.
Prevention of osteoporosis
For Evorel 50, 75 and 100:Oestrogen deficiency at menopause is associated with increasing bone turnover and decline in bone mass. The effect of oestrogens on the bone mineral density (BMD) is dose-dependent; the relationship is not linear, however. Protection appears to be effective as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women. Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestogen given to predominantly healthy women reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/ or established osteoporosis, but the evidence for that is limited. In a clinical trial of two years duration comparing Evorel 50 and 100 to placebo, the increase in lumbar spine bone mineral density (BMD) with Evorel 50 was 4.46 ± 4.04 % (mean±SD). With Evorel 100, the gain in lumbar spine bone density was 5.93 ± 4.34 %.The percentage of women who maintained or gained BMD in the lumbar spine with Evorel 50 was 84% and with Evorel 100, 92.5%.Evorel also had an effect on hip BMD. The increase in BMD in the femoral neck with Evorel 50 was 1.26 ± 2.86 % and with Evorel 100, 1.61±0.53 %. The percentage of women maintaining or gaining BMD in the femoral neck was 65 and 63.5 %, respectively. In the total hip, the increase in BMD was 2.17 ± 2.33 % with Evorel 50 and 2.82±0.51 % with Evorel 100. The percentage of women maintaining or gaining BMD in the total hip was 93 and 82.5 %, respectively.
Serum estradiol (pmol/L; mean+/-SD)
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