Adverse reactions : תופעות לוואי

4.8 Undesirable effects

The safety of Evorel was evaluated in 2584 subjects who participated in 15 clinical trials and received at least one administration of Evorel. Subjects were also asked about application site signs and symptoms in 8 of the 15 clinical trials (N = 1739 subjects). Based on safety data from these clinical trials, the most commonly reported (≥5% incidence) adverse drug reactions (ADRs) were (with % incidence): application site rash (20.8%), application site pruritus (19.8%), application site erythema (8.5%), headache (7.8%), and breast pain (6.6%).

Including the above-mentioned ADRs, the following table displays ADRs that have been reported with the use of Evorel from either clinical trial or post-marketing experiences. The displayed frequency categories use the following convention: 
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data).
Adverse Drug Reactions



Rare



Hypersensitivity
Psychiatric disorders



Rare                       Epilepsy

Cerebrovascular accident


Palpitations
Rare                         Thrombosis


Gastrointestinal disorders


Uncommon                     Flatulence

Rare

Hepato-biliary disorders
Cholelithiasis


Common

Angioedema


Common                       Arthralgia

Uncommon                     Myalgia


Common
Uncommon



Common

Uncommon

Investigations



* Additional adverse drug reactions reported in clinical trials of Evorel (estradiol only) 
The table below reports additional undesirable effects that have been reported in users of other hormone replacement therapy (HRT) by MedDRA system organ classes (MedDRA SOCs).
Common

Psychiatric disorders



Rare
Gastrointestinal ‫מ‬disorders

Nausea

Uncommon                       Dyspepsia


Rare                       Vomiting


Uncommon

Rare


Rare


Uncommon

Rare


Rare                       Fatigue

Other adverse reactions have been reported in association with oestrogen/progestogen treatment:

•   Gall bladder disease.

•   Skin and subcutaneous disorders: chloasma, erythema multiforme, 
•   Vascular purpura.

•   Probable dementia over the age of 65 (see section 4.4).

Serious undesirable effects associated with the use of hormone replacement therapy are also mentioned in section 4.4 Special warnings and precautions for use

Breast Cancer risk

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years.

The increased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogen-progestagen combinations.

The level of risk is dependent on the duration of use (see section 4.4).

Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented below:



Largest meta-analysis of prospective epidemiological studies– Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m2) Age at start HRT    Incidence per 1000 never-users     Risk ratio                              Additional cases per 1000 HRT users (years)             of HRT over a 5 year period                                                after 5 years (95% CI) (50-54 years) *

Oestrogen only HRT

50                  13.3                               1.2                                     2.7 
Combined oestrogen-progestagen

50                  13.3                               1.6                                     8.0 
* Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2).

Note: since the background incidence of breast cancer differs by EU country; the number of additional cases of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

Estimated additional risk of breast cancer after 10 years’ use in women with BMI 27 (kg/m2) 
Age at start HRT       Additional cases           Risk ratio                         Additional cases per 1000 (years)                incidence per 1000                                            HRT users after 10 years never-users of HRT over a 10 year period (50-59 years) *
Oestrogen only HRT
50                                                                                   7.1 26.6                            1.3
Combined oestrogen-progestagen
50                                                                                   20.8 26.6                            1.8

*Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2) Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.
US WHI studies - additional risk of breast cancer after 5 year's use 
Age range (years)   Incidence per 1000 women in      Risk ratio & 95%CI                     Additional cases per 1000 HRT users placebo arm over 5 years                                                over 5 years (95% CI) 
CEE oestrogen only

50-79               21                               0.8 (0.7-1.0)                           -4 (-6 - 0) * CEE + MPA oestrogen & progestagens §

50-79               17                               1.2 (1.0-1.5)                           +4 (0 - 9) 
* WHI study in women with no uterus, which did not show an increase of breast cancer.
§ When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.


Endometrial Cancer risk
In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2- to 12-fold greater compared with non- users. Adding a progestogen to oestrogen-only therapy greatly reduces this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

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 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 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

Adverse events which have been reported in association with oestrogen/ progestogen treatment:

Venous thrombo-embolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone HRT users than among non-users. For further information see Section 4.3 Contra-indications and 4.4 Special warnings and precautions for use.
Risk of venous thromboembolism
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 HT (see section 4.4).
Results of the WHI studies are presented:
WHI Studies - Additional risk of VTE over 5 years’ use
Age range       Incidence per 1000           Risk ratio & 95%CI              Additional cases per 1000 HRT (years)         women in placebo arm                                         users over 5 years
Oral oestrogen-only*

50-79            7                           1.2 (0.6-2.4)                    1 (-3 - 10) Oral combined oestrogen-progestogen
50-79            4                           2.3 (1.2-4.3)                    5 (1 - 13) 
*Study in women with no uterus
Risk of coronary artery disease
• The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).
Risk of ischaemic stroke
• The use of oestrogen-only and oestrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.
• This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age- dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.
WHI studies combined - Additional risk of ischaemic stroke* over 5 years’ use Age range (years)       Incidence             Risk ratio and         Additional cases per 1000 women        95%CI                  per 1000 HRT in placebo arm                               users over 5 over 5 years                                 years
50-59                   8                     1.3 (1.1 1.6)          3 (1-5) 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 https://sideeffects.health.gov.il