Adverse reactions : תופעות לוואי

4.8    Undesirable effects

The following table presents adverse reactions from clinical trials, post-marketing studies or spontaneous reports. Unless specified, the frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women with operable breast cancer given adjuvant treatment for five years (the Arimidex, Tamoxifen, Alone or in Combination [ATAC] study).

Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency groupings are defined according to the following convention: 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), and very rare (<1/10,000). The most frequently reported adverse reactions were headache, hot flushes, nausea, rash, arthralgia, joint stiffness, arthritis, and asthenia.

Table 1 Adverse reactions by System Organ Class and frequency

Adverse reactions by SOC and frequency
Metabolism and nutrition disorders     Common                  Anorexia Hypercholesterolaemia
Uncommon                Hypercalcaemia (with or without an increase in parathyroid hormone)
Psychiatric disorders                  Very common             Depression 
Nervous system disorders               Very common             Headache Common                  Somnolence
Carpal Tunnel Syndrome*
Sensory disturbances
(including paraesthesia, taste loss and taste perversion)
Vascular disorders                     Very common             Hot flushes Gastrointestinal disorders             Very common             Nausea Common                  Diarrhoea
Vomiting
Hepatobiliary disorders                Common                  Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase
Uncommon                Increases in gamma-GT and bilirubin
Hepatitis
Skin and subcutaneous tissue            Very common             Rash disorders
Common                  Hair thinning (alopecia)
Allergic reactions

Uncommon                Urticaria

Rare                    Erythema multiforme
Anaphylactoid reaction
Cutaneous vasculitis (including some reports of Henoch- Schönlein purpura)**
Very rare               Stevens-Johnson syndrome
Angioedema
Musculoskeletal and                     Very common             Arthralgia/joint stiffness connective tissue disorders
Arthritis
Osteoporosis
Common                  Bone pain
Myalgia
Uncommon                Trigger finger

Reproductive system and                 Common                  Vaginal dryness breast disorders
Vaginal bleeding ***
General disorders and                   Very common             Asthenia administration site conditions

* Events of Carpal Tunnel Syndrome have been reported in patients receiving Arimidex treatment in clinical trials in greater numbers than those receiving treatment with tamoxifen.
However, the majority of these events occurred in patients with identifiable risk factors for the development of the condition.
**Since cutaneous vasculitis and Henoch-Schönlein purpura was not observed in ATAC, the frequency category for these events can be considered as 'Rare' (≥ 0.01% and < 0.1%) based on the worst value of the point estimate.
***Vaginal bleeding has been reported commonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with Arimidex. If bleeding persists, further evaluation should be considered.

The table below presents the frequency of pre-specified adverse events in the ATAC study, after a median follow-up of 68 months, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.
Table 2 ATAC study pre-specified adverse events

Adverse events                                            ARIMIDEX (N=3092)    Tamoxifen (N=3094) 
Hot flushes                                                   1104   (35.7%)    1264    (40.9%) Joint pain/stiffness                                          1100   (35.6%)     911    (29.4%) Mood disturbances                                              597   (19.3%)     554    (17.9%) Fatigue/asthenia                                               575   (18.6%)     544    (17.6%) Nausea and vomiting                                            393   (12.7%)     384    (12.4%) Fractures                                                     315    (10.2%)     209     (6.8%) Fractures of the spine, hip, or wrist/Colles                   133    (4.3%)      91     (2.9%) Wrist/Colles fractures                                          67    (2.2%)      50     (1.6%) Spine fractures                                                 43    (1.4%)      22     (0.7%) Hip fractures                                                   28    (0.9%)      26     (0.8%) Cataracts                                                      182    (5.9%)     213     (6.9%) Vaginal bleeding                                               167    (5.4%)     317    (10.2%) Ischaemic cardiovascular disease                               127    (4.1%)     104     (3.4%) Angina pectoris                                                 71    (2.3%)      51     (1.6%) Myocardial infarct                                              37    (1.2%)      34     (1.1%) Coronary artery disorder                                        25    (0.8%)      23     (0.7%) Myocardial ischaemia                                            22    (0.7%)      14     (0.5%) Vaginal discharge                                              109    (3.5%)     408    (13.2%) Any venous thromboembolic event                                 87    (2.8%)     140     (4.5%) Deep venous thromboembolic events including PE                  48    (1.6%)      74     (2.4%) (pulmonary embolism)
Ischaemic cerebrovascular events                                62    (2.0%)      88     (2.8%) Endometrial cancer                                               4    (0.2%)      13     (0.6%) 
Fracture rates of 22 per 1000 patient-years and 15 per 1000 patient-years were observed for the Arimidex and tamoxifen groups, respectively, after a median follow up of 68 months. The observed fracture rate for Arimidex is similar to the range reported in age-matched postmenopausal populations. The incidence of osteoporosis was 10.5% in patients treated with Arimidex and 7.3% in patients treated with tamoxifen.

It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on Arimidex treatment reflect a protective effect of tamoxifen, a specific effect of Arimidex, or both.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allow 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 an online form: https://sideeffects.health.gov.il