Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Clinical experience
The most frequently reported adverse events in the clinical trials with Activelle were vaginal bleeding and breast pain/tenderness, reported in approximately 10% to 20% of patients. Vaginal bleeding usually occurred in the first months of treatment. Breast pain usually disappeared after a few months of therapy. All adverse events observed in the randomised clinical trials with a higher frequency in patients treated with Activelle as compared to placebo, and which on an overall judgement are possibly related to treatment, are presented in the table below.
System organ class      Very common      Common                 Uncommon                Rare ≥ 1/10           ≥ 1/100; < 1/10        ≥ 1/1,000; < 1/100      ≥ 1/10,000; < 1/1,000
Infections and                           Genital candidiasis infestations                             or vaginitis, see also ‘Reproductive system and breast disorders’
Immune system                                                   Hypersensitivity, disorders                                                       see also ‘Skin and subcutaneous tissue disorders’
Metabolism and                           Fluid retention, see nutrition disorders                      also ‘General disorders and administration site conditions’
Psychiatric disorders                    Depression or          Nervousness depression aggravated
Nervous system                           Headache,
disorders                                migraine or migraine aggravated
Vascular disorders                                              Thrombophlebitis        Deep venous superficial             thromboembolism
Pulmonary embolism
Nausea                 Abdominal pain,
Gastrointestinal                                                abdominal disorders                                                       distension or abdominal discomfort
Flatulence or bloating
Skin and                                                        Alopecia, hirsutism subcutaneous tissue                                             or acne disorders                                                       Pruritus or urticaria Musculoskeletal and                      Back pain              Leg cramps connective tissue disorders
Reproductive system     Breast pain or   Breast oedema or and breast disorders    breast           breast enlargement tenderness       Uterine fibroids
Vaginal          aggravated or haemorrhage      uterine fibroids reoccurrence or uterine fibroids
General disorders                        Oedema peripheral      Drug ineffective and administration site conditions
Investigations                           Weight increased
Post-marketing experience

In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported, and are by an overall judgement considered possibly related to Activelle treatment. The reporting rate of these spontaneous adverse drug reactions is very rare (< 1/10,000, not known (cannot be estimated from the available data)). Post-marketing experience is subject to underreporting especially with regard to trivial and well-known adverse drug reactions. The presented frequencies should be interpreted in that light: 
–      Neoplasms benign and malignant (including cysts and polyps): Endometrial cancer –      Immune system disorders: Generalised hypersensitivity reactions (e.g. anaphylactic reaction/shock) –      Psychiatric disorders: Insomnia, anxiety, libido decreased, libido increased –      Nervous system disorders: Dizziness, stroke
–      Eye disorders: Visual disturbances
–      Cardiac disorders: Myocardial infarction
–      Vascular disorders: Hypertension aggravated
–      Gastrointestinal disorders: Dyspepsia, vomiting
–      Hepatobiliary disorders: Gallbladder disease, cholelithiasis, cholelithiasis aggravated, cholelithiasis recurrence
–      Skin and subcutaneous tissue disorders: Seborrhoea, rash, angioneurotic oedema –      Reproductive system and breast disorders: Endometrial hyperplasia, vulvovaginal pruritus –      Investigations: Weight decreased, blood pressure increased.

Other adverse reactions have been reported in association with oestrogen/progestagen treatment: –     Skin and subcutaneous disorders: Alopecia, chloasma, erythema multiforme, erythema nodosum, vascular purpura
–     Probable dementia over the age of 65 (see section 4.4).

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 1,000     Risk ratio                              Additional cases per (years)                        never-users of HRT                                              1,000 HRT users after over a 5 year period                                            5 years (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 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               Incidence per 1,000             Risk ratio                      Additional cases per (years)                        never-users of HRT                                              1,000 HRT users after over a 10 year period                                           10 years (50-59 years)*
Oestrogen-only HRT
50                    26.6                                     1.3                             7.1 Combined oestrogen-progestagen
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 range (years)              Incidence per 1,000    Risk ratio and                           Additional cases per women in placebo       95% CI                                   1,000 HRT users over arm over 5 years                                                5 years’ use (95% CI) CEE oestrogen-only
50-79                          21                     0.8 (0.7-1.0)                            -4 (-6-0)* CEE+MPA oestrogen-progestagen**
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

The endometrial cancer risk is about 5 in every 1,000 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 epidemiological studies varied from between 5 and 55 extra cases diagnosed in every 1,000 women between the ages of 50 and 65.

Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk.
In the Million Women Study, the use of 5 years of combined (sequential or continuous) HRT did not increase the risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer risk

Use of oestrogen-only or combined oestrogen-progestagen 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.
Risk of venous thromboembolism

HRT is associated with a 1.3- to 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 below: 
WHI Studies – Additional risk of VTE over 5 years’ use

Age range (years)             Incidence per 1,000    Risk ratio and            Additional cases per women in placebo       95% CI                    1,000 HRT users over arm over 5 years                                 5 years’ use (95% CI) Oral oestrogen-only*
50-59                         7                      1.2 (0.6-2.4)             1 (-3-10) Oral combined oestrogen-progestagen
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-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 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 per 1,000           Risk ratio and     Additional cases per women in placebo              95% CI             1,000 HRT users over arm over 5 years                                 5 years’ use (95% CI) 50-59                         8                             1.3 (1.1-1.6)      3 (1-5) * No differentiation was made between ischaemic and haemorrhagic stroke.

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