- estradiol hemihydrate
POM: Prescription only medicine
This information is intended for use by health professionals
|DOSAGE STRENGTHS||ESTRADERM MX 25|
|Nominal rate of estradiol release||25 micrograms /day|
|Drug-releasing area||11 cm2|
|Imprint (on backing film)||Product logo CG GRG|
Adults and ElderlyMenopausal symptoms: For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used (see also section 4.4). Depending on the clinical response the dose can then be adjusted to the patient's individual needs. If, after three months, there is insufficient response in the form of alleviated symptoms, the dose can be increased. A maximum dose of 100 micrograms per day should not be exceeded. Effects usually of estrogenic origin e.g. breast discomfort, water retention or bloating are often observed at the start of treatment, especially in patients receiving hormone replacement therapy for the first time. However, if symptoms persist for more than six weeks the dose should be reduced. General instructions: Estraderm MX is administered as a continuous treatment (uninterrupted application twice weekly). For most postmenopausal women not taking HRT Estraderm MX therapy may be started at any convenient time. However, for women with an intact uterus who are still menstruating regularly, commencement within 5 days of the onset of bleeding is recommended. In women with an intact uterus transferring from a continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen. In women transferring from a continuous-combined HRT regimen, or hysterectomised women transferring from other oestrogen-only HRT treatment, treatment may be started on any convenient day.Administration: Estraderm MX should be applied immediately after removal of the protective liner (see Figs.), to an area of clean, dry, and intact skin on the trunk below the waistline. The site chosen should be one at which little wrinkling of skin occurs during movement of the body, e.g. buttock. Estraderm MX should never be applied to, or near the breasts.Estraderm MX should be applied twice weekly on a continuous basis, each used patch being removed after 3-4 days and a fresh system applied to a slightly different site. If a woman has forgotten to apply a patch, she should apply a new patch as soon as possible. The subsequent patch should be applied according to the original treatment schedule. The interruption of treatment might increase the likelihood of recurrence of symptoms and include breakthrough spotting and bleeding.In the event that a patch should fall off a new patch may be applied. The original treatment schedule should be continued.The patch should not be exposed to sunlight. Special populations Patients with renal and /or hepatic impairment. No studies were performed in patients with renal and hepatic impairment. All oestrogen preparations are contraindicated in patients with severe hepatic impairment (see section 4.3 contra-indications).
ChildrenEstraderm MX is not indicated for use in children.
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 Estraderm MX, in particular:• Leiomyoma (uterine fibroids) or endometriosis• Risk factors for thromboembolic disorders (see below)• Risk factors for oestrogen 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 therapyTherapy 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 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 risk may remain elevated for at least 10 years.The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT. Withdrawal bleeding usually occurs following the 12 days or more of progestagen administration. 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 progestagens 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 - progestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT. Combined oestrogen-progestagen 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-progestagen 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 substantially lower than that found in users of oestrogen-progestagen 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-progestagen 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-progestagen 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 thromboembolismHRT 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 oestrogens, older age, major surgery, prolonged immobilisation, obesity (Body Mass Index > 30kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the role of varicose veins in VTE.Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3). Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.As in all post-operative patients prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery, temporarily stopping HRT four to six weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.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.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). Coronary artery disease (CAD) HRT should not be used to prevent cardiovascular disease.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. Combined oestrogen-progestagen therapy The relative risk of CAD during use of combined oestrogen and progestagen 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 oestrogen and progestagen use is very low in healthy women close to menopause, but will rise with more advanced age. Oestrogen-only Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.
Ischaemic strokeCombined oestrogen-progestagen 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).
Severe anaphylactic/anaphylactoid reactions and angioedemaCases of anaphylactic/anaphylactoid reactions, which developed anytime during the course of Estraderm treatment and required emergency medical management, have been reported in the post marketing setting. Involvement of skin (urticaria, pruritus, swelling of the face, throat, lips, tongue, skin and periorbital edema) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) has been noted. Angioedema requiring medical intervention involving the eye/eyelid, face, larynx, pharynx, tongue and extremities (hands, legs, ankles and fingers) with or without urticaria has occurred in the post marketing experience of using Estraderm. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop angioedema after treatment with Estraderm should not receive Estraderm again.Oestrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.
Other conditionsOestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Women with pre-existing hypertriglyceridemia should be monitored closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases in plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.Oestrogens 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). These effects may be less common with transdermal oestradiol than with oral oestrogens.Contact sensitisation is known to occur with all topical applications. Although it is extremely rare, patients who develop contact sensitisation to any of the components of the patch should be warned that a severe hypersensitivity reaction may occur with continuous exposure to the causative agent.Although observations to date suggest that oestrogens, including transdermal oestradiol, do not impair carbohydrate metabolism, diabetic women should be monitored during initiation of therapy until further information is available.Thyroid function should be monitored regularly in patients who require thyroid hormone replacement therapy and who are also taking oestrogen in order to ensure that thyroid hormone levels remain within an acceptable range.Women should be advised that Estraderm MX is not a contraceptive, nor will it restore fertility. Women requiring contraception should be advised to use non-hormonal contraception.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 oestrogen-only HRT after the age of 65.
PregnancyEstraderm MX is not indicated during pregnancy. If pregnancy occurs during medication with Estraderm MX treatment should be withdrawn immediately.The results of most epidemiological studies to date relevant to inadvertant foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.
LactationEstraderm MX is not indicated during lactation.
|Neoplasms benign, malignant and unspecified (including cysts and polyps)|
|Immune system disorders|
|Very rare:||Anaphylactoid reaction.|
|Not known*:||Hypersensitivity (incl. anaphylactic reaction and angioedema).|
|Not known*:||Depression, nervousness, affect lability, libido disorder.|
|Nervous system disorders|
|Very rare:||Embolism, hypertension, varicose veins (including exacerbation).|
|Common:||Nausea, abdominal pain, abdominal distension.|
|Not known*:||Vomiting, diarrhoea.|
|Very rare:||Liver function tests abnormal, jaundice cholestatic.|
|Not known*:||Cholelithiasis, gallbladder disorder.|
|Skin and subcutaneous tissue disorders|
|Very rare:||Contact dermatitis, pigmentation disorders, generalised pruritus, generalised exanthema.|
|Not known*:||Alopecia, chloasma, urticaria.|
|Musculoskeletal and connective tissue disorders|
|Rare:||Pain in extremity (leg pain).|
|Not known*:||Back pain.|
|Reproductive system and breast disorders|
|Very common:||Breast discomfort, breakthrough bleeding.|
|Not known*:||Endometrial hyperplasia, uterine leiomyoma, breast pain, breast tenderness, dysmenorrhoea, fibrocystic breast disease, breast enlargement, breast discharge.|
|General disorders and administration site conditions|
|Very common:||Application site reactions**.|
|Rare:||Oedema, weight increased or decreased.|
Breast cancer risk• 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.• Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen 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 & 95%CI#||Additional cases per 1000 HRT users over 5 years (95%CI)|
|Oestrogen only HRT|
|#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. * Taken from baseline incidence rate in developed countries|
US WHI studies - additional risk of breast cancer after 5 years' use
|Age range (yrs)||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)|
|50-79||21||0.8 (0.7 1.0)||-4 (-6 0)*|
|CEE+MPA oestrogen & progestagen|
|50-79||17||1.2 (1.0 1.5)||+4 (0 9)|
Endometrial cancer riskPostmenopausal women with a uterus The 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 progestagen 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-progestagen 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 and 95%CI||Additional cases per 1000 HRT users|
|50-59||7||1.2 (0.6-2.4)||1 (-3 10)|
|Oral combined oestrogen-progestagen|
|50-59||4||2.3 (1.2 4.3)||5 (1 - 13)|
* Study in women with no uterus.
Risk of coronary artery disease• The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).
Risk of ischaemic stroke• The use of oestrogen-only and oestrogen and progestagen 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 and 95%CI||Additional cases per 1000 HRT users over 5 years|
|50-59||8||1.3 (1.1 1.6)||3 (1-5)|