Source: Health Products Regulatory Authority (IE) Revision Year: 2020 Publisher: Novo Nordisk A/S, Novo Alle, DK-2880, Bagsvaerd, Denmark
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.
As the experience in treating women with a premature menopause (due to ovarian failure or surgery) is limited, the evidence regarding the risks associated with HRT in the treatment of premature menopause is also 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 and 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 Estrofem, 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 for at least 12 days per cycle in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.
Breakthrough bleeding and spotting may occur during the first months of treatment in women with intact uterus. If breakthrough bleeding or spotting appears after some time during 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 Women’s Health Initiative study (WHI) 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 the risk of having breast cancer diagnosed that is 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 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 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- to 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).
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 (see section 4.3).
Generally recognised risk factors for VTE include use of oestrogens, 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 to 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.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a 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.
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).
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.
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).
Oestrogens 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 oestrogen replacement or hormone replacement therapy, since rare cases of large increases of 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 biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-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 oestrogen-only HRT after the age of 65.
Estrofem tablets contain lactose monohydrate. Patients with rare hereditary galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
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).
Ritonavir and nelfinavir, although known as strong inhibitors, 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.
Clinically, an increased metabolism of oestrogens may lead to decreased effect and changes in the uterine bleeding profile.
Estrofem is not indicated during pregnancy. If pregnancy occurs during medication with Estrofem treatment should be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.
Estrofem is not indicated during breast-feeding.
Estrofem has no known effect on the ability to drive and use machines.
In clinical trials less than 10% of the patients experienced adverse drug reactions. The most frequently reported adverse reactions are breast tenderness/breast pain, abdominal pain, oedema and headache.
The adverse reactions listed below may occur during Estrofem treatment:
| System organ class | Very common ≥1/10 | Common ≥1/100; <1/10 | Uncommon ≥1/1,000; <1/100 | Rare ≥1/10,000; <1/1,000 |
|---|---|---|---|---|
| Psychiatric disorders | Depression | Anxiety, Libido decreased or Libido increased | ||
| Nervous system disorders | Headache | Dizziness | Migraine | |
| Eye disorders | Vision abnormal | Contact lens intolerance | ||
| Cardiac disorders | Palpitations | |||
| Vascular disorders | Venous embolism | |||
| Gastrointestinal disorders | Abdominal pain, nausea | Dyspepsia, vomiting, flatulence or bloating | ||
| Hepatobiliary disorders | Cholelithiasis | |||
| Skin and subcutaneous tissue disorders | Rash or urticaria, Erythema nodosum | Hirsutism, Acne | ||
| Musculoskeletal and connective tissue disorders | Leg cramps | |||
| Reproductive system and breast disorders | Breast tenderness, breast enlargement or breast pain, Uterine/Vaginal bleeding including spotting | Dysmenorrhea, Vaginal discharge, Premenstrual-like syndrome | ||
| General disorders and administration site conditions | Oedema | Fatigue | ||
| Metabolism and nutrition disorders | Weight increase or weight decrease | |||
| Immune system disorders | Hypersensitivity reaction |
In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported, and are by an overall judgement considered possibly related to Estrofem treatment. The reporting rate of these spontaneous adverse drug reactions is very rare (<1/10,000, not known (cannot be estimated from the available data)). Post-marketing experience is subject to under-reporting especially with regard to trivial and well-known adverse drug reactions. The presented frequencies should be interpreted in that light:
The following adverse reactions have been reported in association with other oestrogen treatment:
* In non-hysterectomised women.
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.
The increased risk in users of oestrogen-only therapy is 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).
Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented below.
Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m²):
| Age at start HRT (years) | Incidence per 1,000 never-users of HRT over a 5-year period (50-54 years)* | Risk ratio | Additional cases per 1,000 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 |
* 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 proportionally.
Estimated additional risk of breast cancer after 10 years' use in women with BMI 27 (kg/m²):
| Age at start HRT (years) | Incidence per 1,000 never-users of HRT over a 10 year period (50-59 years)* | Risk ratio | Additional cases per 1,000 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 (years) | Incidence per 1,000 women in placebo arm over 5 years | Risk ratio and 95% CI | Additional cases per 1,000 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) |
* WHI study in women with no uterus which did not show an increase in risk 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.
The endometrial cancer risk is about 5 in every 1,000 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 epidemiological studies varied from between 5 and 55 extra cases diagnosed in every 1,000 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 5 years of combined (sequential or continuous) HRT did not increase the 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 2,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over a 5-year period.
HRT is associated with a 1.3* to 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 HRT (see section 4.4). Results of the WHI studies are presented below.
WHI Studies – Additional risk of VTE over 5 years' use:
| Age range (years) | Incidence per 1,000 women in placebo arm over 5 years | Risk ratio and 95% CI | Additional cases per 1,000 HRT users over 5 years (95% CI) |
|---|---|---|---|
| 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
The risk of coronary artery disease is slightly increased in users of combined oestrogen progestogen HRT over the age of 60 (see section 4.4).
The use of oestrogen-only and oestrogen-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 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 1,000 women in placebo arm over 5 years | Risk ratio and 95% CI | Additional cases per 1,000 HRT users over 5 years (95% CI) |
|---|---|---|---|
| 50-59 | 8 | 1.3 (1.1-1.6) | 3 (1-5) |
* No differentiation was made between ischaemic and haemorrhagic stroke.
Reporting 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: HPRA Pharmacovigilance, Website: www.hpra.ie.
Not applicable.
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