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. 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 Angeliq, 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
• Liver disorders (e.g. liver adenoma)
• Diabetes mellitus with or without vascular involvement
• Migraine or (severe) headache
• Systemic lupus erythematosus
• A history of endometrial hyperplasia (see below)
Reasons for immediate withdrawal of therapy
Therapy 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
Endometrial hyperplasia and carcinoma
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 progestogen 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.
Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough 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 oestrogen-progestagen and possibly also 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 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). 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.
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).
Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, a personal history or family history 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 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).
As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilization 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 mobilized.
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 of 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).
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 and 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.
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).
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).
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 radioimmunoassay) 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).
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 progestin component in Angeliq is an aldosterone antagonist exhibiting weak potassium sparing properties. In most cases, no increase of serum potassium levels is to be expected. In a clinical study, however, in some patients with mild or moderate renal impairment and concomitant use of potassium-sparing medicinal products (such as ACE inhibitors, angiotensin II receptor antagonists or NSAIDs) serum potassium levels slightly, but not significantly increased during drospirenone intake. Therefore, it is recommended to check serum potassium during the first month of treatment in patients presenting with renal insufficiency and pretreatment serum potassium in the upper reference range, and particularly during concomitant use of potassium sparing medicinal products (see also section 4.5).
Women with elevated blood pressure may experience a decrease in blood pressure under treatment with Angeliq due to the aldosterone antagonist activity of drospirenone (see section 5.1). Angeliq should not be used to treat hypertension. Women with hypertension should be treated according to hypertension guidelines.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking HRT.
Each tablet of this medicinal product contains 46 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration.