Adverse reactions : תופעות לוואי

4.8    Undesirable effects
 a.    Summary of the safety profile
The reporting rate of adverse drug reactions with Oestrogel was calculated as 5/10,000 patient year's corresponding to approximately five spontaneously reported cases in every 10,000 patients exposed to Oestrogel (Periodic Benefit Risk Evaluation Report 01 September 2016 to 30 November 2017).
b.    Tabulated list of adverse reactions Clinical trial data
The table below lists adverse experiences which were reported in > 10% of patients (regardless of relationship to treatment) who received percutaneous 17beta-estradiol gel 1.25 g (containing 0.75 mg of oestradiol) or 2.5 g (containing 1.5 mg of oestradiol) or placebo gel applied once daily for 12 weeks, in a multi-centre, randomised, double-blind, placebo-controlled clinical trial in 221 postmenopausal women.


Adverse experiences (>10%) reported in a 221 patient placebo-controlled trial in postmenopausal women over a 12- week period
Adverse experience      Placebo                  0.75 mg oestradiol         1.5 mg oestradiol (n=73)              (n=75)                     (n=73)
Headache                     13                      13                          14 Nausea                       3                       4                           9 Breast pain                  7                       8                           8 Infection                    5                       12                          5 Pain                         8                       5                           4 Vaginitis                    3                       8                           1 

Post-Marketing experience
The information given below is based on extensive post marketing experience from administration of Oestrogel.
Adverse effects have been ranked under headings of frequency using the following convention: very common (≥ 1/10); common (≥ 1/100; ≤ 1/10); uncommon (≥ 1/1,000; ≤ 1/100); rare (≥ 1/10,000; ≤ 1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

System organ class                       Frequency Not known (cannot be estimated from the available data)


Gastrointestinal disorders                                Nausea
Nervous system disorders                                  Dizziness
Headache
Skin and subcutaneous tissue disorders                    Alopecia
Pruritus



Undesirable effects observed with HRT products used in menopause are reported in the table below: 
Frequency of occurrence of adverse reactions
System Organ Class
Common                     Uncommon                   Rare
(≥1/100;                (≥1/1,000;               (≥1/10,000;
<1/10)                  <1/100)                  <1/1,000)

Metabolism and                                                                       Glucose intolerance nutrition disorders
Psychiatric disorders                                      Depression,               Change in libido Mood swings
Nervous system disorders          Headache                 Vertigo,                  Aggravation of epilepsy Migraine
Vascular disorders                                          Venous               Arterial hypertension thromboembolic disease

Gastrointestinal disorders       Nausea,                    Flatulence, Abdominal pain             Vomiting

Hepatobiliary disorders                                                          Liver function tests abnormalities

Skin and subcutaneous                                       Pruritus             Skin decolouration, tissue disorders                                                                 Acne Reproductive system and          Breast swelling/pain,      Benign breast        Galactorrhoea breast disorders                                            neoplasm, Breast enlargement,
Increased volume
Dysmenorrhoea,             of uterine,
Menorrhagia,               Leiomyoma,
Metrorrhagia,              Vaginitis/vagi nal
Leucorrhoea,
candidiasis
Endometrial hyperplasia

General disorders and            Weight change              Asthenia             Anaphylactic reaction administration site              (increase or decrease),                         (in women with past condition                                                                        history of allergic Water retention with peripheral                                 reaction) oedema

 c. Description   of selected adverse reactions
The following risks apply in relation to systemic oestrogen/progestagen treatment: Breast cancer risk
• 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.
• Theincreased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogen- progestogen 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.
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        Incidence per 1000 start         never-users of HRT      Risk ratio           Additional cases per 1000 HRT users after 5 HRT           over a 5 year period                         years
(years)       (50-54 years)*

Oestrogen only HRT
50            13.3                    1.2                  2.7
Combined oestrogen-progestogen
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 will also change proportionately.


Estimated additional risk of breast cancer after 10 years’ use in women with BMI 27 (kg/m2) 
Age at        Incidence per 1000 start         never-users of HRT    Risk ratio             Additional cases per 1000 HRT users over HRT           over a 10 year period                        10 years
(years)       (50-59 years)*

Oestrogen only HRT
50            26.6                    1.3                  7.1
Combined oestrogen-progestogen
50            26.6                    1.8                  20.8
*: 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 years' use
Age           Incidence per 1000 range         women in placebo        Risk ratio & 95%CI Additional cases per 1000 HRT users over 5 (years)       arm over 5 years                           years (95%CI) 
CEE oestrogen only
50-79         21                      0.8 (0.7-1.0)        -4 (-6 – 0)* CEE + MPA oestrogen-progestogen‡
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 in risk 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
Postmenopausal women with a uterus
The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.
In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).
Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.
Adding a progestogen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study (MWS) 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.
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 combined - Additional risk of VTE over 5 years' use

Age                   Incidence per 1000       Risk ratio & 95%CI   Additional cases per 1000 HRT users women in placebo range arm over 5 years
(years)

Oral oestrogen-only*
50-59                             7            1.2 (0.6-2.4)        1 (-3 – 10) Oral combined oestrogen-progestogen
50-59                             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- progestogen HRT over the age of 60 (see section 4.4).
Risk of ischaemic stroke
The use of oestrogen-only and oestrogen + progestogen 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*5 over 5 years' use 
Age              Incidence per 1000    Risk ratio & 95%CI range            women in placebo                            Additional cases per 1000 HRT users over 5 (years)          arm over 5 years                            years

50-59                      8           1.3 (1.1– 1.6)        3 (1 – 5) 

5*no differentiation was made between ischaemic and haemorrhagic stroke.
The following adverse reactions have also been reported in association with systemic oestrogen/ progestogen treatment:
• Rash

• Chloasma/    melasma
• Vomiting

• Abdominal    pain
• Breast   tenderness
• Breast   enlargement
• Fluid   retention/ oedema
• Weight    changes
• Changes    in libido
• Depression
• Gall   bladder disease
• Probable   dementia over the age of 65 (see section 4.4)
• Skin   and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura 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/