Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Aromasin was generally well tolerated across all clinical studies conducted with Aromasin at a standard dose of 25mg/day and undesirable effects were usually mild to moderate.
The withdrawal rate due to adverse events was 7.4% in patients with early breast cancer receiving adjuvant treatment with Aromasin following initial adjuvant tamoxifen therapy. The most commonly reported adverse reactions were hot flushes (22%), arthralgia (18%), and fatigue (16%).



The withdrawal rate due to adverse events was 2.8% in the overall patient population with advanced breast cancer. The most commonly reported adverse reactions were hot flushes (14%) and nausea (12%).
Most adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g., hot flushes).
The reported adverse reactions from clinical studies and post-marketing experience are listed below by system organ class and by frequency.
Frequencies are defined as: Very common (≥1/10); Common ( ≥1/100 to <1/10) ; Uncommon (≥1/1,000 to <1/100) ; Rare ( ≥1/10,000 to <1/1,000) ; Very rare (<1/10,000); Not known (cannot be estimated from the available data).


Blood and lymphatic system disorders:
Very common     Leucopenia(**)
Common          Thrombocytopenia(**)
Not known       Lymphocyte count decreased(**)
Immune system disorders:
Uncommon        Hypersensitivity

Metabolism and nutrition disorders:
Common          Anorexia

Psychiatric disorders:
Very common       Depression, insomnia

Nervous system disorders:
Very common      Headache, dizziness
Common           Carpal tunnel syndrome, paraesthesia
Rare             Somnolence

Vascular disorders:
Very common      Hot flushes
Gastrointestinal disorders:
Very common       Abdominal pain, nausea
Common            Vomiting, diarrhoea, constipation, dyspepsia

Hepatobiliary disorders:
Rare              Hepatitis (†), cholestatic hepatitis (†)

Skin and subcutaneous tissue disorders:
Very common     Hyperhidrosis
Common          Alopecia, rash, urticaria, pruritus
Rare            Acute generalised exanthematous pustulosis (†)


Musculoskeletal and connective tissue disorders:
Very common      Joint and musculoskeletal pain (*)
Common           Fracture, osteoporosis

General disorders and administration site conditions:
Very common      Pain, fatigue
Common           Oedema peripheral, asthenia

Investigations:
Hepatic enzyme increased, blood bilirubin
Very common      increased, blood alkaline phosphatase increased

(*) Includes: arthralgia, and less frequently pain in extremity, osteoarthritis, back pain, arthritis, myalgia and joint stiffness.
(
**) In patients with advanced breast cancer thrombocytopenia and leucopenia have been rarely reported. An occasional decrease in lymphocytes has been observed in approximately 20% of patients receiving Aromasin, particularly in patients with pre-existing lymphopenia;
however, mean lymphocyte values in these patients did not change significantly over time and no corresponding increase in viral infections was observed. These effects have not been observed in patients treated in early breast cancer studies.
(†)
Frequency calculated by rule of 3/X.


The table below presents the frequency of pre-specified adverse events and illnesses in the early breast cancer study Intergroup Exemestane Study (IES), irrespective of causality, reported in patients receiving trial therapy and up to 30 days after cessation of trial therapy.


Exemestane               Tamoxifen
Adverse events and illnesses
(N = 2249)               (N = 2279)
Hot flushes                          491 (21.8%)              457 (20.1%) Fatigue                              367 (16.3%)              344 (15.1%) Headache                             305 (13.6%)              255 (11.2%) Insomnia                             290 (12.9%)               204 (9.0%) Sweating increased                   270 (12.0%)              242 (10.6%) Gynaecological                       235 (10.5%)              340 (14.9%) Dizziness                            224 (10.0%)               200 (8.8%) Nausea                                200 (8.9%)               208 (9.1%) Osteoporosis                          116 (5.2%)                66 (2.9%) Vaginal haemorrhage                    90 (4.0%)               121 (5.3%) Other primary cancer                   84 (3.6%)               125 (5.3%) Vomiting                               50 (2.2%)                54 (2.4%) Visual disturbance                     45 (2.0%)                53 (2.3%) Thromboembolism                        16 (0.7%)                42 (1.8%) Osteoporotic fracture                  14 (0.6%)               12 (0.5%) Myocardial infarction                  13 (0.6%)                4 (0.2%) 

In the IES study, the frequency of ischemic cardiac events in the exemestane and tamoxifen treatment arms was 4.5% versus 4.2%, respectively. No significant difference was noted for any individual cardiovascular event including hypertension (9.9% versus 8.4%), myocardial infarction (0.6% versus 0.2%) and cardiac failure (1.1% versus 0.7%).
In the IES study, exemestane was associated with a greater incidence of hypercholesterolemia compared with tamoxifen (3.7% versus 2.1%).
In a separate double blinded, randomised study of postmenopausal women with early breast cancer at low risk treated with exemestane (N=73) or placebo (N=73) for 24 months, exemestane was associated with an average 7-9% mean reduction in plasma HDL- cholesterol, versus a 1% increase on placebo. There was also a 5-6% reduction in apolipoprotein A1 in the exemestane group versus 0-2% for placebo. The effect on the other lipid parameters analysed (total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-B and lipoprotein-a) was very similar in the two treatment groups. The clinical significance of these results is unclear.
In the IES study, gastric ulcer was observed at a higher frequency in the exemestane arm compared to tamoxifen (0.7% versus <0.1%). The majority of patients on exemestane with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.
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/