Tibolone: benefit-risk balance
- Medicines and Healthcare products Regulatory Agency
- 1 September 2007
- Therapeutic area:
- Endocrinology, diabetology and metabolism and Obstetrics, gynaecology and fertility
Increased risk of stroke in older women should be taken into account in prescribing decisions.
Article date: September 2007
Tibolone (Livial) is a first-line treatment for menopausal symptoms and a second-line therapy for prevention of osteoporosis. The balance of benefits and risks for tibolone has been assessed after termination of a large randomised placebo-controlled trial (LIFT study) because of an increased risk of stroke in those assigned tibolone compared with those assigned placebo.1
Benefit-risk balance in licensed indications
In younger women, the risk profile of tibolone is broadly similar to that for conventional combined hormone-replacement therapy (HRT). For women older than about 60 years, the risks associated with tibolone start to outweigh the benefits because of the increased risk of stroke.
Healthcare professionals should weigh the increased risk of stroke with tibolone against the increased risk of breast cancer with combined HRT for women with a uterus.
The LIFT study identified a significantly (2·2-times) increased risk of stroke, mostly ischaemic, in tibolone users; risk increased from the first year of treatment. Baseline risk of stroke is strongly age-dependent, and so the absolute risk with tibolone increases with older age. Randomised controlled trials have identified an approximate 1·3-times increase in stroke risk for combined HRT.2
Most studies show an increased risk of having endometrial cancer diagnosed associated with use of tibolone. In the LIFT study, tibolone users (n=1746) were diagnosed with one additional case of endometrial hyperplasia and four additional cases of endometrial cancer compared with placebo users (n=1773) after 2·7 years of treatment. In observational studies, risk increased with longer duration of use. Break-through bleeding and spotting may occur during the first months of treatment with tibolone.
Healthcare professionals should refer women who bleed beyond 6 months of treatment, or after stopping treatment, for gynaecological investigation to exclude endometrial malignancy.
There are limited clinical trial data for breast-cancer risk in healthy women. However, the LIBERATE study in women with previous breast cancer was stopped recently because it was unable to establish non-inferiority of tibolone compared with placebo.
The Million Women Study identified a significantly increased risk of having breast cancer diagnosed in tibolone users (relative risk [RR] 1·5 [95% CI 1·3–1·7]), which is comparable with that for oestrogen-only HRT (1·3 [1·2–1·4]) and significantly lower than that for combined HRT (2·0 [1·9–2·1]).3 Risk increased with longer duration of use and returned to baseline within a few years of stopping treatment. A study using the General Practice Research Database found no significant increase in risk. Unlike conventional HRT, tibolone has a limited effect on mammographic density.
The few data available do not suggest an increased risk of venous thromboembolism compared with combined HRT users or with non-users.
Coronary heart disease
No conclusions can be drawn from the available data. In view of the increased risk of stroke associated with tibolone, an increase in coronary events is biologically plausible. In studies, tibolone caused a marked dose-dependent decrease in HDL cholesterol (–22·4% after 2 years); total triglycerides and lipoprotein (a) levels were also reduced. A decrease in total cholesterol and VLDL cholesterol was not dose-dependent; levels of LDL cholesterol did not change. The clinical implication of these findings is not yet known.
Tibolone may increase blood fibrinolytic activity and enhance the effect of anticoagulants such as warfarin. Limited data suggest that tibolone may interact with cytochrome P450 3A4 substrates such as midazolam.
Healthcare professionals should exercise caution in the simultaneous use of tibolone and anticoagulants such as warfarin, especially when starting or stopping tibolone.
Advice for healthcare professionals to consider before prescribing tibolone:
- Every woman’s overall risk of stroke, breast cancer, and, in those with an intact uterus, endometrial cancer should be assessed carefully, taking into consideration any baseline risk factors, the increased risk due to tibolone use, and her therapeutic preferences
Article citation: Drug Safety Update September 2007, vol 1 issue 2: 5.
Hormone replacement therapy (HRT)
Published: 1 September 2007