Adverse reactions : תופעות לוואי

4.8 Undesirable effects

The most commonly reported adverse drug reactions of patients treated with estradiol/dydrogesterone in clinical trials are headache, abdominal pain, breast pain/tenderness and back pain.
The following undesirable effects have been observed with the frequencies indicated below during clinical trials (n=4929) *Undesirable effects from spontaneous reporting not observed in clinical trials have been attributed to the frequency “rare”:
MedDRA system             Very common              Common                   Uncommon                        Rare organ class                   ≥1/10             ≥1/100 to <1/10          ≥1/1,000 to <1/100            ≥1/10,000 to <1/1,000

Infections and                              Vaginal candidiasis Cystitis-like symptoms infestations

Neoplasms benign,                                                 Increase in size of leiomyoma malignant and unspecified

Blood and the                                                                                       Haemolytic lymphatic system                                                                                    anaemia* disorders

Immune system                                                     Hypersensitivity disorders

Psychiatric disorders                       Depression,           Influence on libido nervousness

Nervous system          Headache            Migraine, dizziness                                     Meningioma* disorders

Eye disorders                                                                                       Steepening of corneal curvature,
contact lenses intolerance

Cardiac disorders                                                                               Myocardial infarction

Vascular disorders                                             Venous                           Stroke* thromboembolism*,hypertension,
peripheral vascular disease,
varicose vein

Gastrointestinal      Abdominal pain   Nausea, vomiting,       Dyspepsia disorders                              abdominal distension
(including flatulence)

Hepatobiliary                                                  Abnormal hepatic function, disorders                                                      occasionally with jaundice, asthenia or malaise, and abdominal pain, gall bladder disorders

Skin and                               Allergic skin                                            Angioedema, subcutaneous tissue                    reactions (e.g. rash,                                    vascular purpura, disorders                              urticaria, pruritus)                                     erythema nodosum*,
Chloasma or melasma, which may persist when drug is discontinued*

Musculoskeletal and Back pain                                                                   Leg cramps* connective tissue disorders

Reproductive system Breast             Menstrual disorders Breast enlargement, premenstrual and breast disorders pain/tenderness   (including              syndrome postmenopausal spotting, metrorrha-
gia, menorrhagia,
oligo-/ amenorrhoea,
irregular menstruation,
dysmenorrhoea),
pelvic pain,
cervical discharge

General disorders                           Asthenic conditions and administration                          (asthenia, fatigue,
site reactions                              malaise), peripheral oedema

Investigations                              Increased weight       Decreased weight Breast cancer risk
• An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestogen therapy for more than 5 years.
• The increased risk in users of estrogen-only therapy is lower than that seen in users of estrogen- 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)
Incidence per
Age at the 1000 never- start of    users of HRT                     Additional cases per 1000 HRT users after 5 Risk ratio
HRT         over a 5 year                    years
(years)     period (50-54 years)*
Estrogen only HRT
50          13.3              1.2            2.7
Combined estrogen-progestogen
50          13.3              1.6            8.0
*Taken from baseline incidence rates 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)
Incidence per 1000
Age at the       never-users of HRT                                 Additional cases per 1000 start of HRT     over a 10 year period     Risk ratio
HRT users after 10 years
(years)          (50-59 years)*
Estrogen only HRT
50               26.6                   1.3                  7.1
Combined estrogen-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 range        Incidence per 1000 women in                                  Additional cases per 1000 HRT users Risk ratio & 95%CI
(yrs)            placebo arm over 5 years                                     over 5 years (95%CI) 
CEE estrogen-only

50 - 79          21                               0.8 (0.7 – 1.0)             -4 (-6 – 0)* 
CEE+MPA estrogen & 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 estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of estrogen-only use and estrogen 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 estrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five 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
Use of estrogen-only or combined estrogen-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.
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: WHI Studies - Additional risk of VTE over 5 years' use
Age range (years)        Incidence per 1000 women in       Risk ratio and 95%CI        Additional cases per 1000 HRT placebo arm over 5 years                                      users

Oral estrogen-only1

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) 1
Study in women with no uterus


Risk of coronary artery disease
The risk of coronary artery disease is slightly increased in users of combined estrogen-progestogen HRT over the age of 60 (see section 4.4).
Risk of ischaemic stroke
The use of estrogen-only and estrogen+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 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 stroke2 over 5 years' use 
Incidence per 1000 women in                                    Additional cases per 1000 Age range (years)                                         Risk ratio and 95%CI placebo arm over 5 years                                       HRT users over 5 years 
50 - 59                  8                                1.3 (1.1 - 1.6)               3 (1 - 5) 2
No differentiation was made between ischaemic and haemorrhagic stroke 

Other adverse reactions have been reported in association with estrogen/progestogen treatment Neoplasms benign, malignant and unspecified:
Estrogen-dependent neoplasms both benign and malignant, e.g. endometrial cancer, ovarian cancer.
Increase in size of meningioma.
Immune system disorders:
Systemic lupus erythematosus
Metabolism and nutrition disorders:
Hypertriglyceridemia
Nervous system disorders:
Probable dementia, chorea, exacerbation of epilepsy
Vascular disorders:
Arterial thromboembolism
Gastrointestinal disorders:
Pancreatitis (in women with pre-existing hypertriglyceridemia)
Skin and subcutaneous tissue disorders:
Erythema multiforme
Renal and urinary disorders:
Urinary incontinence
Reproductive system and breast disorders:
Fibrocystic breast disease, uterine cervical erosion
Congenital, familial and genetic disorders:
Aggravated porphyria
Investigations:
Total thyroid hormones increased


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/