• For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect the 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.
Conditions which need supervision
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 Premique, in particular:
- Leiomyoma (uterine fibroids) or endometriosis
- Risk factors for thromboembolic disorders (see below)
- Risk factors for estrogen dependent tumours (e.g. first degree heredity for breast cancer)
- Liver disorders (e.g. liver adenoma)
- Diabetes mellitus with or without vascular involvement
- Migraine or (severe) headaches
- Systemic lupus erythematosus (SLE)
- A history of endometrial hyperplasia (see below)
Reasons for immediate withdrawal of therapy
Therapy should be discontinued in case a contraindication is discovered and in the following situations:
- Jaundice or deterioration in liver function
- Significant increase in blood pressure
- New onset of migraine-type headache
Endometrial hyperplasia and carcinoma
• In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.
• The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-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.
The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.
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 estrogen-progestogen for HRT that becomes apparent after about 3 years (see section 4.8, Undesirable effects).
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 estrogen-progestogen 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 estrogen-only or combined estrogen-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).
• Hormone replacement therapy (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 use than later (see section 4.8).
• 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).
• Generally recognised risk factors for VTE include use of estrogens, older age, major surgery, prolonged immobilisation, obesity (Body Mass Index >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 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 young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophillic 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 doctor immediately when they are aware of potential thromboembolic symptoms (e.g. 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 estrogens-progesterone or estrogen-only HRT.
The relative risk of CAD during use of combined estrogen+progestogen 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 estrogen+progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.
Combined estrogen-progestogen and estrogen-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).
• Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
• The use of estrogens may influence the laboratory results of certain endocrine tests and liver enzymes.
Estrogens 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 usually unaltered. Patients dependent on thyroid hormone replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range.
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 usually unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).
• A two- to four-fold increase in the risk of gallbladder disease requiring surgery in women receiving HRT has been reported.
• A worsening of glucose tolerance may occur in some patients on estrogen/progestogen therapy and therefore diabetic patients should be carefully observed while receiving hormone replacement therapy.
• Patients with rare hereditary problems of galactose or fructose intolerance, the Lapp lactase deficiency, sucrase-isomaltase insufficiency or glucose-galactose malabsorption should not take this medicine, as the excipients in the tablet include lactose monohydrate and sucrose.
• Estrogens should be used with caution in patients with disease that can predispose to severe hypocalcaemia.
• Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.
• 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 estrogen-only HRT after the age of 65. It is unknown whether the findings apply to younger postmenopausal women or other HRT products.