Adverse reactions : תופעות לוואי

4.8     Undesirable effects
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 1 shows the undesirable effects that occurred statistically significantly more frequently during treatment with Livial than with placebo.
Table 1          Undesirable effects of Livial
System organ class                       Common                         Uncommon             Rare >1%,<10%                       >0.1%,<1%
>0.01%,<0.1%

Metabolism and nutrition disorders                                      Oedema** 
Gastrointestinal disorders               Lower abdominal pain           Abdominal discomfort**

Skin and subcutaneous tissue             Abnormal hair growth           Acne                 Pruritus** disorders

Reproductive system and breast           Vaginal discharge              Breast discomfort disorders
Endometrial wall thickening Fungal infection

Postmenopausal                 Vaginal mycosis haemorrhage
Nipple pain
Breast tenderness

Genital pruritus
Vaginal candidiasis

Vaginal haemorrhage

Pelvic pain
Cervical dysplasia

Genital discharge

Vulvovaginitis
Investigations                           Weight increase

Abnormal cervical smear*
* The majority consisted of benign changes. Cervix pathology (cervical carcinoma) was not increased with Livial compared to placebo.
** These adverse reactions were identified through post-marketing surveillance. The frequency category was estimated based on relevant clinical trials.


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 section 4.4).
•    Results of the largest epidemiological study (MWS) are presented.


Table 2 Million Women study – Estimated additional risk of breast cancer after 5 years’ use 
Additional cases per 1,000                         Additional cases per 1,000 Age range                                            Risk ratio & never-users of HRT over a                          HRT users over 5 years (years)                                              95%CI#
5 year period                                      (95%CI)
Estrogen only HRT
50-65           9-12                                 1.2               1-2 (0-3) Combined estrogen-progestagen
50-65           9-12                                 1.7               6 (5-7) Tibolone
50-65                9-12                            1.3                 3 (0-6) #Overall risk ratio. The risk ratio is not constant but will increase with increasing duration of use.


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 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 section 4.4).
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 section 4.4.
•      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 estrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see section 4.4).
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, 5 years of HRT resulted in 1 extra case per 2,500 users.
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 section 4.4).
Results of the WHI studies are presented:

Table 3       WHI Studies - Additional risk of VTE over 5 years’ use Incidence per 1000                      Additional cases
Age range                            Risk ratio and women in placebo arm                    per 1000 HRT
(years)                              95%CI over 5 years                            users
Oral estrogen-only*4
50-59        7                     1.2 (0.6-2.4)    1 (-3-10)
Oral combined estrogen-progestogen
50-59        4                     2.3 (1.2–4.3)    5 (1-13)
4 *Study in women with no uterus

-     The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestogen HRT over the age of 60 (see section 4.4). There is no evidence to suggest that the risk of myocardial infarction with tibolone is different to the risk with other HRT.

Table 4      WHI Studies combined - Additional risk of ischaemic stroke over 5 years' use Age range (years)    Incidence per 1000 women Risk ratio and 95%CI          Additional cases per 1000 HRT in placebo arm over 5 years                            users over 5 yers 50-59                8                           1.3 (1.1-1.6)              3 (1-5) - Gall bladder 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 reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: http://sideeffects.health.gov.il