LIVIAL

Hormone replacement therapy (HRT) for estrogen deficiency symptoms in menopausal women for more than 1 year.

Experience with treatment in women aged over 65 years is limited.

For all women, the decision to prescribe tibolone should be based on a complete assessment of the patient's individual risks and, particularly in those over 60 years of age, the risks of stroke (see sections 4.4 and 4.8).

LIVIAL is not known to have effects on concentration or alertness.

This section describes the adverse effects that were recorded in 21 placebo-controlled studies (including the LIFT study), including 4 079 women treated with tibolone at therapeutic doses (1,25 mg or 2,5 mg) and 3 476 with a placebo. The duration of treatment was between 2 months and 4,5 years. Adverse effects that occurred statistically more frequently with tibolone than with placebo are listed in the table below.

Table 1: Adverse effects of LIVIAL

*Most abnormalities are benign in nature. Cervical pathologies (cervical carcinoma) were not increased in the tibolone group compared to the placebo group.

** These adverse effects were identified through post-marketing surveillance. The frequency was estimated from clinical studies.

Since marketing, other adverse effects have been observed such as dizziness, headache, migraine, vision disorder, rash, seborrheic dermatitis, depression, effects on the musculoskeletal system such as arthralgia or myalgia, and abnormal liver function tests.

Risk of breast cancer

An increase of up to 2 times the risk of breast cancer has been reported in women who have taken an estrogen-progestogen combination for more than 5 years.

The increase in risk in users of estrogen-only therapy and tibolone is lower than that observed in users of estrogen-progestogen combinations.

The level of risk depends on the duration of treatment (see section 4.4).

The results of the largest epidemiological study (MWS) are presented below.

Table 2: "Million Women Study (MWS)". Estimation of the additional risk of breast cancer over 5 years of treatment

Endometrial cancer

The risk of endometrial cancer is about 5 per 1 000 women with a uterus not using HRT.

Two observational studies, the Million Women Study (MWS) and the General Practice Research Database (GRPD) have shown that women treated with tibolone in routine practice had an increased risk of a diagnosis of endometrial cancer (MWS: RR = 1.78; 95% CI 1.4 - 2.3 and GRPD: RR = 1.5; 95% CI 1.0 - 2.3). In these studies, the risk increased with the duration of use. Two randomized controlled studies (LIFT and THEBES) present contradictory results on this subject, with only the LIFT study showing an increased risk of endometrial cancer (no case of endometrial cancer was diagnosed in the placebo group (n = 1 773) versus 4 cases in the tibolone group (n = 1 746)). This corresponds to a diagnosis of 0.8 additional cases of endometrial cancer per 1 000 women using Livial per year in this study (see section 4.4).

Other adverse effects have been reported in association with the use of estrogen or estrogen-progestogen-based treatments:

Ovarian cancer

The use of HRT with estrogens alone or with a combination of estrogens and progestogens has been associated with a slight increase in the risk of diagnosed ovarian cancer (see section 4.4).

A meta-analysis covering 52 epidemiological studies reported an increased risk of ovarian cancer in women currently taking HRT compared to women who had never taken it (RR 1.43, 95% CI 1.31 – 1.56). In women aged 50 to 54 years, taking HRT for five years results in one additional case per 2000 users. In women aged between 50 to 54 years who do not take HRT, a diagnosis of ovarian cancer will be made in about 2 women per 2000 over a five-year period.

In the Million Women Study, taking tibolone for five years caused 1 additional case per 2500 users (see section 4.4).

Risk of venous thromboembolism

HRT is associated with a 1.3 to 3-fold increase in the relative risk of developing venous thromboembolism, i.e. deep vein thrombosis or pulmonary embolism. The probability of such an event occurring is higher during the first year of HRT use (see section 4.4). The results of the WHI study are presented:

Table 3 - WHI study - Additional risk of venous thromboembolism over 5 years of treatment

** Study in hysterectomized women

Risk of coronary heart disease

The risk of coronary heart disease is slightly increased in users of combined estrogen-progestogen HRT over 60 years of age (see section 4.4). There is no evidence suggesting that the risk of myocardial infarction associated with tibolone is different from the risk associated with other HRT.

Stroke

· A 2.9-year randomized controlled study estimated that the risk of stroke was increased 2.2-fold in women (mean age 68 years) in the tibolone 1.25 mg group (28/2 249) compared to women in the placebo group (13/2 257). The majority (80 %) of strokes were ischemic.

· The baseline risk of stroke is strongly age-dependent. Thus, the incidence over a 5-year period is estimated at 3 cases per 1 000 women aged 50 to 59 years and 11 cases per 1 000 women aged 60 to 69 years.

· In women using tibolone for 5 years, the number of additional cases would be approximately 4 cases per 1 000 women aged 50 to 59 years and 13 cases per 1 000 women aged 60 to 69 years.

· The following adverse effects have been reported with estrogen-only or combined estrogen-progestogen treatment:

· gallbladder disease;

· skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum; vascular purpura;

· probable dementia over the age of 65 (see section 4.4).

Reporting of suspected adverse effects

Reporting suspected adverse effects after authorization of the medicinal product is important. It allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals report any suspected adverse effect via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and network of Regional Pharmacovigilance Centres - Website: www.signalement-sante.gouv.fr.