- estradiol hemihydrate
- norethisterone acetate
POM: Prescription only medicine
This information is intended for use by health professionals
AdultsEvorel Sequi is a continuous sequential HRT preparation. Patches are applied to the skin twice weekly. One Evorel Sequi patch should be worn at all times, without interruptions. 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.
Guidance on how to start therapy:Any previous therapy with HRT must be stopped prior to starting Evorel Sequi.Post-menopausal women currently not on HRT may start Evorel Sequi at any time.Peri-menopausal women who are still having regular menstrual cycles and are not currently on HRT should start Evorel Sequi within 5 days of the start of bleeding. Peri-menopausal women with irregular menstrual cycles, for whom pregnancy has been excluded, can start Evorel Sequi at any time.
Switching from other HRTWomen on a continuous combined regimen wishing to switch from another oestrogen to Evorel Sequi 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 Sequi may do so at the end of a cycle of the current therapy or after a 7 day hormone free interval.Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.
Method of AdministrationA treatment cycle with Evorel Sequi is 28 days. During the first 14 days, one estradiol-only (Evorel 50) patch should be worn at all times, without interruption. During days 15-28, one estradiol + norethisterone (Evorel Conti) patch should be worn at all times, without interruption. A subsequent treatment cycle should follow immediately, without a treatment free interval. Patches should be applied to the trunk, below the waist. Patches should be changed twice a week, i.e. every three to four days. Application of a new patch should be to a site different from the previous application site. The patch 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.
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.Wearing a patch for more than 4 days by mistake or any period without a patch may increase the likelihood of breakthrough bleeding or spotting.
ChildrenEvorel Sequi is not indicated in children.
ElderlyData are insufficient in regard to the use of Evorel Sequi 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 contra-indications 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 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 Sequi, 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 erythematosusA 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 if 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 carcinomaIn 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 remains elevated for at least 10 years. The addition of a progestogen for 12-14 days per cycle or continuous combined oestrogen/progestogen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT. 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.
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. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-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 thrombo-embolismHRT is associated with a 1.3-3 fold risk of developing venous thrombo-embolism (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 a personal history or family history, use of oestrogens, older age, major surgery, prolonged immobilisation, severe 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.Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3).In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age or recurrent spontaneous abortion, 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. 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-progestogen 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. Ishaemic StrokeCombined 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. 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).
HypothyroidismPatients who require thyroid hormone replacement therapy should have their thyroid function monitored regularly while on HRT to ensure that thyroid hormone levels remain in an acceptable range.
AngioedemaOestrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.
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 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-l-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.Contact sensitisation is known to occur with all topical applications. Although it is extremely rare, women who develop contact sensitisation to any of the components of the patch should be warned that a severe hypersensitivity reaction may occur with continuing exposure to the causative agent.Evorel Sequi 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 Sequi is not indicated during pregnancy. If pregnancy occurs during use of Evorel Sequi, treatment should be withdrawn immediately.Data on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the foetus. At doses higher than normally used in oral contraceptives and HRT formulations, masculinisation of female foetuses was observed.The results of most epidemiological studies to date, relevant to inadvertent foetal exposure to combinations of oestrogens and progestogens indicate no teratogenic or foetotoxic effect.
Breast FeedingEvorel Sequi is not indicated during breast feeding.
|Infections and Infestations|
|Neoplasms benign, malignant and unspecified (including cysts and polyps)|
|Uncommon||Breast cancer, fibroadenoma of breast|
|Frequency not known||Endometrial cancer|
|Immune System Disorders|
|Common||Depression, Insomnia, Affect lability, Nervousness|
|Uncommon||Libido decreased, Libido increased|
|Frequency not known||Mood swings|
|Nervous system disorders|
|Uncommon||Dizziness, Paraesthesia, Disturbance in attention|
|Frequency not known||Cerebrovascular accident, Epilepsy*|
|Frequency not known||Deep vein thrombosis, Thrombosis*|
|Respiratory, Thoracic and Mediastinal Disorders|
|Frequency not known||Pulmonary embolism|
|Common||Abdominal pain, Gastrointestinal disorder, Diarrhoea*, Flatulence*, Nausea|
|Frequency not known||Abdominal distension|
|Frequency not known||Cholelithiasis|
|Skin and subcutaneous tissue disorders|
|Common||Pruritus, Rash erythematous|
|Frequency not known||Rash*, Stevens-Johnson syndrome|
|Musculoskeletal and Connective Tissue Disorders|
|Common||Arthralgia, Back pain, Myalgia*|
|Reproductive system and breast disorders|
|Common||Breast pain, Dysmenorrhoea, Menorrhagia, Menstrual disorder|
|Uncommon||Breast enlargement, Endometrial hyperplasia, Metrorrhagia|
|General disorders and administration site conditions|
|Very Common||Application site erythema, Application site pruritus, Application site rash, Application site reaction|
|Common||Pain*, Oedema, Malaise|
|Uncommon||Generalised oedema*, Fatigue|
|Frequency not known||Oedema peripheral*, Application site oedema*|
|Nervous system disorders|
|Very rare||Cholestatic jaundice|
|Skin and subcutaneous tissue disorders|
|Common||Acne, Dry skin|
|Frequency not known||Alopecia|
|Musculoskeletal and connective tissue disorders|
|Common||Pain in extremity|
|Reproductive system and breast disorders|
|Very common||Breast tenderness|
|Common||Genital discharge, Uterine spasms, Vaginal infection|
|Rare||Uterine leiomyoma, Fallopian tube cysts, Cervical polyps|
Breast Cancer RiskAn up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen therapy for more than 5 years.- Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestogen combinations.- The level of risk is dependent on the duration of use (see section 4.4).- Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.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*||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)|
|# 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 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)*|
|CEE + MPA oestrogen & progestogens |
|50-79||17||1.2 (1.0-1.5)||+4 (0 - 9)|
| 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. * WHI study in women with no uterus, which did not show an increase in risk of breast cancer.|
Endometrial Cancer Risk
Postmenopausal women with a uterusThe endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT. In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.Adding a progestogen to oestrogen-only therapy for at least 12 days per cycle can prevent 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)).
Ovarian cancerUse of oestrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4).A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.
Risk of venous thromboembolismHRT is associated with a 1.3-3-fold increased relative 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 using HT (see section 4.4). Results of the WHI studies are presented:
WHI Studies - Additional risk of VTE over 5 years' use
|Age range (years)||Incidence per 1000 women in placebo arm over 5 years||Risk ratio & 95%CI||Additional cases per 1000 HRT users|
|50-59||7||1.2 (0.6 - 2.4)||1 (-3 - 10)|
|Oral combined, oestrogen -progesterone|
|50-59||4||2.3 (1.2 - 4.3)||5 (1 - 13)|
|* Study in women with no uterus.|
Risk of coronary artery diseaseThe risk of coronary artery disease is slightly increased in users of combined oestrogen-progestogen HRT over the age of 60 (see section 4.4).
Risk of ischaemic stroke• The use of oestrogen-only and oestrogen + progestogen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT. • This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age- dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.4).
WHI studies combined - Additional risk of ischaemic stroke* over 5 years' 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|
|50-59||8||1. 3 (1.1 1.6)||3 (1 5)|
|* No differentiation was made between ischaemic and haemorrhagic stroke.|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Signs and symptomsDue to the mode of administration, overdose of oestradiol or norethisterone is unlikely to occur. Symptoms of overdose of oral oestrogen are breast tenderness, nausea, vomiting and /or metrorrhagia. Over dosage of progestogens may lead to a depressive mood, fatigue, acne and hirsutism.
TreatmentThere is no specific antidote and treatment should be symptomatic. These symptoms can be reversed by removing the Evorel Sequi patch.
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. Oestrogens prevent bone loss following menopause or ovariectomy. Norethisterone: As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Clinical trial information:Relief of oestrogen-deficiency symptoms and bleeding patterns: Relief of menopausal symptoms was achieved during the first few weeks of treatment with Evorel Sequi. Regular withdrawal bleeding occurs in over 95% of women using Evorel Sequi. Two thirds of treatment cycles have only one bleeding episode of a median duration of five days. Where secondary bleeding episodes occurred, they were shorter with a median duration of 1.5 days.
Prevention of osteoporosisOestrogen 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. 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. Evorel Sequi was not tested for effects on bone mineral density (BMD). However, information is available on the efficacy of the two constituents of Evorel Sequi (Evorel 50 and Evorel Conti).After two years of treatment with Evorel 50, the increase in lumbar spine bone mineral density (BMD) was 4.46 ± 4.04 % (mean±SD). The percentage of women who maintained or gained BMD in the lumbar zone during treatment was 84%.Evorel 50 also had an effect on hip BMD. The increase in BMD in the femoral neck was 1.26 ± 2.86 % and the percentage of women maintaining or gaining BMD in the femoral neck was 65%. In the total hip, the increase in BMD was 2.17 ± 2.33 % (mean±SD) with 93% women maintaining or gaining BMD.After one year of treatment with Evorel Conti, the increase in lumbar spine bone mineral density (BMD) was 2.94 ± 2.62 % (mean±SD). The percentage of women who maintained or gained BMD in the lumbar zone during treatment was 90%.Evorel Conti also had an effect on hip BMD. The increase in BMD in the femoral neck was 2.42 ± 3.04 % and the percentage of women maintaining or gaining BMD in the femoral neck was 82%. In the total hip, the increase in BMD was 1.73 ± 2.55 % (mean±SD) with 74% women maintaining or gaining in BMD.
Estradiol pharmacokineticsUpon use of an estradiol-only patch (Evorel 50), serum estradiol levels rise within 11 hours (Tmax, multiple application) from pre-treatment levels by an average of 316 pmol/L (86 pg/mL) (Cmax, multiple application). The 95% confidence interval ranges from 150 to 484 pmol/L (42-132 pg/mL). Levels decrease over 3.5 days to an average of 77 pmol/L (21 pg/mL). When patch use is discontinued, serum estradiol levels decrease with a half-life of 6.6 hours. 24 hours after patch removal, pre-treatment levels are again observed. On use of an estradiol+norethisterone patch (Evorel Conti), serum estradiol levels rise from pre-treatment levels within 21 hours from patch change (Tmax, multiple application) by an average of 121 pmol/L (33 pg/mL) (Cmax, multiple applications). The 95% confidence interval for Cmax ranges from 77 to 165 pmol/L (21 to 45 pg/mL). 24 hours after patch removal, baseline levels are again observed. Norethisterone pharmacokineticsOn first use of Evorel Conti by post-menopausal women, serum norethisterone levels rise over 37 hours (Tmax, single application) to 706 pmol/L (240 pg/mL)(Cmax, single application) and then decrease to 420 pmol/L (143 pg/mL) at day 3.5. On patch change, levels rise again over 22 hours (Tmax, multiple applications) to 756 pmol/L (257 pg/mL)(Cmax, multiple applications). When patch use is discontinued, norethisterone levels decrease with a half-life of ~15 hours.
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