Special Warning : אזהרת שימוש

4.4    Special warnings and precautions for use
For the treatment of postmenopausal symptoms, Livial 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 Livial should only be continued as long as the benefit outweighs the risk.
The risks of stroke, breast cancer and, in women with an intact uterus, endometrial cancer (see below and section 4.8) for each woman should be carefully assessed, in the light of her individual risk factors and bearing in mind the frequency and characteristics of both cancers and stroke, in terms of their response to treatment, morbidity and mortality.
Evidence regarding the risks associated with HRT or tibolone 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.
Medical examination/follow-up
Before initiating or reinstituting HRT or tibolone, 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 Livial, 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 erythematosis
-   A history of endometrial hyperplasia (see below)
-   Epilepsy
-   Asthma
-   Otosclerosis
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
•   The available data from randomised controlled trials are conflicting; however, observational studies have consistently shown that women who are prescribed Livial in normal clinical practice are at an increased risk of having endometrial cancer diagnosed (see also section 4.8). In these studies risk increased with increasing duration of use. Tibolone increases endometrial wall thickness, as measured by transvaginal ultrasound.
•   Break-through bleeding and spotting may occur during the first months of treatment (see section 5.1). Women should be advised to report any break-through bleeding or spotting if it is still present after 6 months of treatment, if it starts beyond that time or if it continues after treatment has been discontinued. The woman should be referred for gynaecological investigation, which is likely to include endometrial biopsy to exclude endometrial malignancy.
Breast cancer
A meta-analysis of epidemiological studies, including the Million Women Study (MWS), showed a significant increase in the risk of breast cancer in association with use of the 2.5 mg dose. This risk became apparent within 3 years of use and increased with duration of intake, see section 4.8. 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. No data for persistence of risk after stopping are available for tibolone, but a similar pattern cannot be ruled out.

Ovarian 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 Women’s Health Initiative (WHI) trial suggest that the use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8).
In the Million Women Study it was shown that the relative risk for ovarian cancer with use of tibolone was similar to the risk associated with use of other types of HRT.


Venous thromboembolism
•   Oestrogen or oestrogen-progestogen 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). In an epidemiological study using a UK database, the risk of VTE in association with tibolone was lower than the risk associated with conventional HRT, but only a small proportion of women were current users of tibolone and a small increase in risk compared with non-use cannot be excluded.
•   Patients with known thrombophilic states have an increased risk of VTE and HRT or tibolone 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 or tibolone 4 to 6 weeks earlier is recommended, if possible. 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 or tibolone is contraindicated.
•   Women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT or tibolone.
•   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, dyspnea).
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- progestogen or oestrogen-only HRT. In an epidemiological study using the GPRD no evidence was found of protection against myocardial infarction in postmenopausal women who received tibolone.
Ischaemic stroke
•   Tibolone increases the risk of ischaemic stroke from the first year of treatment (see section 4.8). The baseline risk of stroke is strongly age-dependent and so the effect of tibolone is greater with older age.


Other conditions
•   Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
•   Livial is not intended for contraceptive use.
•   Treatment with Livial results in a marked dose-dependent decrease in HDL cholesterol (from -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose after 2 years). Total triglycerides and lipoprotein(a) levels were also reduced. The decrease in total cholesterol and VLDL-C levels was not dose-dependent. Levels of LDL-C were unchanged. The clinical implication of these findings is not yet known.
•   Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
•   Women with pre-existing hypertriglyceridaemia 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.
•     Treatment with Livial results in a very minor decrease of thyroid binding globulin (TBG) and total T4. Levels of total T3 are unaltered. Livial decreases the level of sex- hormone-binding globulin (SHBG), whereas the levels of corticoid binding globulin (CBG) and circulating cortisol are unaffected.
•     HRT 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.

Effects on Driving

4.7         Effects on ability to drive and use machines
Livial is not known to have any effects on alertness and concentration.