Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Norgine Pharmaceuticals Limited, Norgine House, Widewater Place, Moorhall Road, Harefield, Uxbridge, UB9 6NS, UK
Estraderm MX should not be used by women with any of the following conditions:
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.
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.
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 Estraderm MX, in particular:
Therapy should be discontinued in case a contra-indication is discovered and in the following situations:
In 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.
For oral doses of estradiol >2mg, conjugated equine oestrogens >0.625 mg and patches >50 ug/day the endometrial safety of added progestagens 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 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.
The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen – progestagen or oestrogen-only HRT, that is dependent on the duration of taking HRT.
The randomised placebo-controlled trial, the 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 oestrogen-progestagen for HRT that becomes apparent after about 3 (1-4) years (see section 4.8).
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).
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 oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer is much rarer that 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).
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 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).
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.
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.
Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.
Combined 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).
Cases 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.
Oestrogens 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.
The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Oestradiol is predominantly metabolized by CYP3A4; concomitant administration of inhibitors of CYP3A4 such as ketoconazole, erythromycin or ritonavir may therefore result in an increase of approximately 50% in oestradiol exposure.
Caution should be used if the women is receiving protease inhibitors (e.g.ritonavir and nelfinavir) which are known as strong inhibitors of cytochrome P450 enzymes, and by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations containing St John’s wort (Hypericum perforatum) may induce the metabolism of oestrogens and progestagens.
At transdermal HRT administration, the first-pass effect in the liver is avoided and, thus transdermally applied oestrogens HRT may be less affected than oral hormones by enzyme inducers.
Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effects and changes in the uterine bleeding profile.
Some laboratory tests may be influenced by oestrogen therapy, such as tests for glucose tolerance or thyroid function.
Estraderm 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.
Estraderm MX is not indicated during lactation.
None known.
Adverse drug reactions from multiple sources including clinical trials and post-marketing experience (Table 1) are listed according to the system organ class in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, the most frequent first. Within each frequency grouping, adverse drug reactions are presented in the order of decreasing seriousness. In addition the corresponding frequency using the following convention (CIOMS III) is also provided for each adverse drug reaction: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), and not known (cannot be estimated from the available data).
Table 1:
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | |
|---|---|
| Uncommon: | Breast cancer. |
| Immune system disorders | |
| Very rare: | Anaphylactoid reaction. |
| Not known*: | Hypersensitivity (incl. anaphylactic reaction and angioedema). |
| Psychiatric disorders | |
| Not known*: | Depression, nervousness, affect lability, libido disorder. |
| Nervous system disorders | |
| Common: | Headache. |
| Rare: | Dizziness. |
| Not known*: | Migraine. |
| Vascular disorders | |
| Very rare: | Embolism, hypertension, varicose veins (including exacerbation). |
| Gastrointestinal disorders | |
| Common: | Nausea, abdominal pain, abdominal distension. |
| Not known*: | Vomiting, diarrhoea. |
| Hepatobiliary disorders | |
| 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. |
* Reported in post-marketing experience.
** Application site reactions includes localized bleeding, bruising, burning, discomfort, dryness, eczema, edema, erythema, inflammation, irritation, pain, papules, paraesthesia, pruritus, rash, skin discolouration, skin pigmentation, swelling, urticaria, and vesicles.
Largest meta-analysis of prospective epidemiological studies – Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m²):
| Age at start HRT (years) | Incidence per 1000 never-users of HRT over a 5 year period (50-54 years)* | Risk ratio | Additional cases per 1000 HRT users after 5 years |
|---|---|---|---|
| Oestrogen only HRT | |||
| 50 | 13.3 | 1.2 | 2.7 |
| Combined oestrogen-progestagen | |||
| 50 | 13.3 | 1.6 | 8.0 |
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 rates in England in 2015 in women with BMI 27 (kg/m²)
Estimated additional risk of breast cancer after 10 years' use in women with BMI 27 (kg/m²):
| Age at start HRT (years) | Incidence per 1000 never-users of HRT over a 10 year period (50-59 years)* | Risk ratio | Additional cases per 1000 HRT users after 10 years |
|---|---|---|---|
| Oestrogen only HRT | |||
| 50 | 26.6 | 1.3 | 7.1 |
| Combined oestrogen-progestagen | |||
| 50 | 26.6 | 1.8 | 20.8 |
* Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m²)
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 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) |
|---|---|---|---|
| CEE oestrogen-only | |||
| 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) |
‡ 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.
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)).
Use 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.
HRT 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 |
|---|---|---|---|
| Oral oestrogen-only* | |||
| 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.
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 | dditional 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
The following other adverse reactions have been reported in association with oestrogen alone and oestrogen-progestagen treatments:
None known.
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