Adverse reactions : תופעות לוואי

4.8    Undesirable effects

The following undesirable effects have been reported in users of Progynova and other oral HRT preparations.

Neoplasms benign, malignant and unspecified
Breast cancer*, Endometrial cancer*

Immune system disorders
Hypersensitivity reaction, Exacerbation of hereditary angioedema
Metabolism and nutrition disorder
Porphyria aggravated, Increased or decreased weight, Increased appetite, Carbohydrate tolerance decreased

Psychiatric disorders
Anxiety/depressive symptoms, Decreased or increased libido

Nervous system disorders
Migraine, Headache, Dizziness, Fatigue, Chorea, Stroke*
Eye disorders
Visual disturbances, Intolerance to contact lenses

Cardiac disorders
Palpitations, Myocardial infarction*

Vascular disorders
Hypertension, Thrombophlebitis, Venous Thromboembolism*
Respiratory, thoracic and mediastinal disorders
Epistaxis
Gastrointestinal disorders
Dyspepsia, Abdominal pain, Vomiting, Nausea, Bloating, Flatulence

Hepatobiliary disorders
Gall bladder disease including Cholestasis

Skin and subcutaneous tissue disorders
Rashes, various Skin disorders (including Pruritus, Eczema, Urticaria, Acne, Hirsutism, Hair loss, Erythema nodosum, Erythema multiforme, Rash hemorrhagic, Chloasma (see section 4.4)

Musculoskeletal and connective tissue disorders
Muscle cramps, Leg pain

Renal and urinary disorders
Cystitis-like symptom
Reproductive system and breast disorders
Increased size of uterine fibroids, Vaginal candidosis, Uterine cervical erosions, Changes in vaginal bleeding pattern and abnormal bleeding or flow, Breakthrough bleeding, Spotting (bleeding irregularities usually subside during continued treatment), Dysmenorrhoea, Changes in vaginal secretion, Premenstrual-like syndrome, Breast secretion, Breast tenderness, enlargement or pain.

General disorders and administration site conditions
Oedema

* Please see further information below.
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.
•   Any increased risk in users of oestrogen-only therapy is substantially 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).
• Results of the largest randomised placebo-controlled trial (WHI study) and largest epidemiological study (MWS) are presented.
Million Women Study – estimated additional risk of breast cancer after 5 years of use Age        Additional cases per 1000        Risk ratio &     Additional cases per 1000 range       never-users of HRT over a         95% CI b                 HRT (years)           5 year period a                              users over 5 years (95% CI)
Oestrogen-only HRT
50 - 65      9 - 12                             1.2              1 - 2 (0 - 3) Combined oestrogen-progestogen
50 - 65      9 - 12                             1.7              6 (5 - 7) a Taken from baseline incidences in developed countries.
b Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use.
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.


US WHI studies - additional risk of breast cancer after 5 years of use Age      Incidence per 1000 women in          Risk ratio &        Additional cases per range       placebo arm over 5 years             95% CI                 1000 HRT (years)                                                              users over 5 years (95% CI)
CEE oestrogen-only
50 - 79    21                               0.8 (0.7 – 1.0)        -4 (-6 - 0) a 
CEE + MPA oestrogen & progestogen b
50 - 79    17                               1.2 (1.0 – 1.5)       +4 (0 - 9) a WHI study in women with no uterus, which did not show an increased in risk of breast cancer.
b 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 an 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 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 - additional risk of VTE over 5 years of use
Age range    Incidence per 1000 women        Risk ratio & 95%      Additional cases (years)        in placebo arm over 5               CI              per 1000 HRT years                                           users
Oral oestrogen-only a
50 - 59                  7                     1.2 (0.6 – 2.4)        1 (-3 - 10) 
Oral combined oestrogen & progestogen b
50 - 59                 4                     2.3 (1.2 – 4.3)        5 (1 - 13) a 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 strokea over 5 years of use Age range   Incidence per 1000 women           Risk ratio &        Additional cases per (years)      in placebo arm over 5              95% CI                1000 HRT years                                         Users over 5 years

50 - 59                  8                    1.3 (1.1 – 1.6)          3 (1 – 5) a No differentiation was made between ischaemic and haemorrhagic stroke.


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

-      Gall bladder disease.
-      Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura
-      Probable dementia over the age of 65 (see Section 4.4)

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 http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic @moh.gov.il