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):

MedDRA                   Very   Common                   Uncommon               Rare system organ             common ≥1/100, <1/10            ≥1/1,000,              ≥1/10,000, class                    ≥1/10                           <1/100                 <1/1,000 Infections and                  Vaginal                  Cystitis-like infestations                    candidiasis              syndrome
Neoplasms                                                Increase in size of benign,                                                  leiomyoma malignant and unspecified
Immune system                                          Hypersensitivity disorders

Psychiatric                 Depression,                Influence on disorders                   Nervousness                libido
Nervous system     Headache Migraine,
disorders                   Dizziness

Cardiac                                                                    Myocardial disorders                                                                  infarction Vascular                                               Hypertension,
disorders                                              Peripheral vascular disease,
Varicose vein,
Venous thromboembolism


Gastrointestinal   Abdominal Nausea, Vomiting,         Dyspepsia disorders          pain      Flatulence
Hepatobiliary                                          Abnormal hepatic disorders                                              function,
occasionally with jaundice asthenia or malaise, and abdominal pain,
Gall bladder disorder

Skin and                       Allergic skin                               Angioedema, subcutaneous                   reactions (e.g. rash,                       Vascular purpura tissue disorders               urticaria, pruritus)


Musculoskeletal    Back pain and connective tissue disorders
Reproductive       Breast     Menstrual disorders      Breast system and         pain/      (including               enlargement,
breast disorders   tenderness postmenopausal           Premenstrual spotting,                syndrome metrorrhagia,
menorrhagia, oligo-
/amenorrhoea,
irregular menstruation,
dysmenorrhoea),
Pelvic pain, Cervical discharge
General disorders    Asthenic and administration   conditions site reactions       (asthenia,
fatigue,
malaise),
Peripheral oedema


Investigations       Increased    Decreased weight       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) Age at the start Incidence per 1000 never-users of Risk        Additional cases per of HRT           HRT over a 5 year period (50-54 ratio         1000 HRT users after 5 (years)          years)*                                       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             Risk ratio & Additional cases per 1000 (years)       women in placebo arm       95%CI            HRT users over 5 years over 5 years                                (95%CI)
CEE estrogen-only
50-79         21                         0.8 (0.7 –       -4 (-6 – 0)* 1.0)
CEE+MPA estrogen & progestogen‡
50-79         17                         1.2 (1.0 –       +4 (0 – 9) 1.5)
*
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
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 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 risk of endometrial cancer (R.R 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 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 - Additional risk of VTE over 5 years’ use
Age range     Incidence per 1000 women in Risk ratio             Additional cases per (years)       placebo arm over 5 years     and 95%CI             1000 HRT users Oral estrogen-only*1
50-59         7                            1.2 (0.6-2.4)         1 (-3 – 10) Oral combined estrogen-progestogen
50-59         4                            2.3 (1.2 –            5 (1 - 13) 4.3)
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 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*2 over 5 years’ use Age range       Incidence per 1000 women    Risk ratio     Additional cases per (years)         in placebo arm over 5 years and 95%CI      1000 HRT users 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 (including estradiol/dydrogesterone):

Neoplasms benign, malignant and unspecified:
Estrogen dependent neoplasms both benign and malignant, e.g. endometrial cancer, ovarian cancer. Increase in size of progestogen dependent neoplasms, e.g.
meningioma.

Blood and lymphatic system disorders:
Haemolytic anaemia

Immune system disorders:
Systemic lupus erythematosus
Metabolism and nutrition disorders:
Hypertriglyceridemia

Nervous system disorders:
Probable dementia over the age of 65 (see section 4.4), chorea, exacerbation of epilepsy

Eye disorders:
Steepening of corneal curvature, contact lenses intolerance

Vascular disorders:
Arterial thromboembolism
Gastrointestinal disorders:
Pancreatitis (in women with pre-existing hypertriglyceridemia)

Skin and subcutaneous tissue disorders:
Erythema multiforme, erythema nodosum, chloasma or melasma, which may persist when drug is discontinued.

Musculoskeletal and connective tissue disorders:
Leg cramps

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 /