Livial Adverse Reactions

This section describes undesirable effects, which were registered in 21 placebo-controlled studies (including the LIFT study), with 4,079 women receiving therapeutic doses (1.25 or 2.5 mg) of Livial and 3,476 women receiving placebo. The duration of treatment in these studies ranged from 2 months to 4.5 years. Table 2 shows the undesirable effects that occurred statistically significantly more frequently during treatment with Livial than with placebo. (See Table 2.)

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In market use, other undesirable effects that have been observed include: dizziness, rash, seborrheic dermatosis, headache, migraine, visual disturbances (including blurred vision), depression, effects on the musculoskeletal system such as arthralgia or myalgia and changes in liver function parameters.
Breast cancer: An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen therapy for more than 5 years. The increased risk in users of oestrogen-only and tibolone therapy is lower than seen in users of oestrogen-progestogen combinations.
The level of risk is dependent on the duration of use (see Precautions).
Results of the largest epidemiological study (MWS) are presented. (See Table 3.)

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Endometrial cancer risk: Postmenopausal women with a uterus: The endometrial cancer risk is about 5 in every 1,000 women with a uterus not using HRT or tibolone.
The randomised placebo controlled trial that included women who had not been screened for endometrial abnormalities at baseline, and therefore reflected in clinical practice, identified the highest risk of endometrial cancer, (LIFT study, mean age 68 years). In this study, no cases of endometrial cancer were diagnosed in the placebo group, (n=1,773) after 2.9 years compared with 4 cases of endometrial cancer in the Livial group (n=1,746). This corresponds to a diagnosis of 0.8 additional case of endometrial cancer in every 1,000 women who used Livial for one year in this study (see Precautions).
Risk of ischaemic stroke: The relative risk of ischaemic stroke is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of ischaemic stroke in women who use HRT or tibolone will increase with age, see Precautions.
A 2.9 year randomised controlled study has estimated a 2.2-fold increase in the risk of stroke in women (mean age 68 years) who used 1.25 mg Livial (28/2,249) compared with placebo (13/2,257). The majority (80%) of strokes were ischaemic.
The baseline risk of stroke is strongly age-dependent. Thus, the baseline incidence over a 5 year period is estimated to be 3 per 1,000 women aged 50-59 years and 11 per 1,000 women aged 60-69 years.
For women who use Livial for 5 years, the number of additional cases would be expected to be about 4 per 1,000 users aged 50-59 years and 13 per 1,000 users aged 60-69 years.
Other adverse reactions have been reported in association with oestrogen and oestrogen-progestogen treatment: Ovarian cancer: Use of oestrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Precautions).
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.
In the Million Women Study, taking 5 years of tibolone resulted in 1 extra case per 2,500 users (see Precautions).
HRT is associated with a 1.3-3-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 Precautions).
Results of the WHI studies are presented: (See Table 4.)

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The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestogen HRT over the age of 60 (see Precautions). There is no evidence to suggest that the risk of myocardial infarction with tibolone is different to the risk with other HRT. (See Table 5.)

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Gall bladder disease.
Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
Probable dementia over the age of 65 (see Precautions).