Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Two large-scale clinical trials (ESPS-2, PRoFESS) enrolling a total of 26,934 patients, of whom 11,831 were allocated to Aggrenox, were used to define the adverse event profile. Events from sp- ontaneous reports were also taken into account where sufficient data were available to warrant their classification as an adverse event.

Owing to the granularity of the coding system, bleeding events are distributed over several system org- an classes. A summary description of bleeding events is therefore given below.

Bleeding events categorised as any bleeding, major bleeding, intracranial bleeding and gastrointestinal bleeding:

In the ESPS-2 trial, 1650 patients were treated in the Aggrenox group (100%) and 1649 in the placebo group (100%). The mean duration of treatment was 1.4 years. The overall incidence of bleeding was 8.7% in the Aggrenox group and 4.5% in the placebo group. The incidence of major bleeding was 1.6% and 0.4% respectively. The incidence of intracranial bleeding was 0.6% and 0.4% respectively, whilst the incidence of gastrointestinal bleeding was 4.3% and 2.6% respectively.

In the PRoFESS trial, a total of 10,055 patients were treated in the Aggrenox group (100%). The me- an duration of treatment was 1.9 years. The overall incidence of bleeding was 5.3%. The incidence of major bleeding was 3.3%. The incidence of intracranial bleeding was 1.2% (including intraocular ble- eding (0.2%)), whilst the incidence of gastrointestinal bleeding was 1.9%.

The undesirable effects of Aggrenox are listed below according to system organ class and frequency.
The following frequency convention has been used for the classification of undesirable effects: 
Very common                    ≥ 1/10
Common                         ≥ 1/100 to < 1/10
Uncommon                       ≥ 1/1000 to < 1/100
Rare                           ≥ 1/10,000 to < 1/1000
Very rare                      < 1/10,000
Not known                      Frequency cannot be estimated from the available data 
Blood and lymphatic system disorders
Common:                                                   Anaemia
Rare:                                                     Thrombocytopenia, iron deficiency anaemia due to occult gastrointestinal bleeding

Immune system disorders
Common:                                                   Hypersensitivity reactions such as rash and urticaria, severe bronchospasm and angioe- dema

Nervous system disorders
Very common:                                              Headache*, dizziness* Common:                                                   Intracranial bleeding, migraine-like head- ache* (particularly at the start of treatment)

Eye disorders
Uncommon:                                                 Eye haemorrhage 

Cardiac disorders
Common:                                                   Worsening of symptoms of coronary heart disease (PRoFESS: 0.07%; ESPS-2: 7.6%
(Aggrenox) / 7.8% (placebo)), syncope
(PRoFESS: 1.5% within 7 days of the start of treatment, uncommon thereafter; ESPS-2:
1.0% (Aggrenox) / 0.5% (placebo))
Uncommon:                                                 Tachycardia 
Vascular disorders
Uncommon:                                                 Hot flushes, hypotension 
Respiratory, thoracic and mediastinal disorders
Common:                                                   Epistaxis

Gastrointestinal disorders
Very common:                                              Dyspepsia, abdominal pain, nausea*, diarrhoea*
Common                                                    Vomiting*, (severe) gastrointestinal bleeding
Uncommon:                                                 Gastric ulcers, duodenal ulcers Rare:                                                     Erosive gastritis 
Skin and subcutaneous tissue disorders
Frequency not known:                                      Skin haemorrhages such as haematomas or ecchymoses

Musculoskeletal, connective tissue and bone disorders
Common:                                                   Myalgia*

Investigations
Frequency not known:                                      Prolonged bleeding time 
Injury, poisoning and procedural complications
Frequency not known:                                      Increased postoperative or other postproce- dural bleeding, increased intraoperative bl- eeding

* Usually resolves with continued therapy

The individual components of Aggrenox are known to cause the following undesirable effects in add- ition to those listed above for the combination product:

Additional undesirable effects with dipyridamole alone were:

Incorporation of dipyridamole into gallstones (see section 4.4)
Additional undesirable effects with ASA alone were:

Blood and lymphatic system disorders
Disseminated intravascular coagulation, coagulopathy

Immune system disorders
Anaphylactic reactions (especially in patients with asthma)
Metabolism and nutrition disorders
Hypoglycaemia (especially in children), hyperglycaemia, thirst, dehydration, hyperkalaemia, metabolic acidosis, respiratory alkalosis

Psychiatric disorders
Confusion
Nervous system disorders
Agitation, cerebral oedema, lethargy, convulsion

Ear and labyrinth disorders
Tinnitus, deafness
Cardiac disorders
Arrhythmia

Respiratory, thoracic and mediastinal disorders
Dyspnoea, gingival bleeding, laryngeal oedema, hyperventilation, pulmonary oedema, tachypnoea 
Vascular disorders
Shock (mainly in patients with asthma)

Gastrointestinal disorders
Gastric ulcer perforation, duodenal ulcer perforation, melaena, haematemesis, pancreatitis, micro- haemorrhages

Hepatobiliary disorders
Hepatitis, Reye's syndrome

Skin and subcutaneous tissue disorders
Severe skin reactions, including erythema exsudativum multiforme
Musculoskeletal, connective tissue and bone disorders
Rhabdomyolysis

Renal and urinary disorders
Impaired renal function, renal failure, interstitial nephritis, renal papillary necrosis, proteinuria 
Pregnancy, puerperium and perinatal conditions
Prolonged pregnancy, prolonged labour, small-for-gestational age neonate, stillbirth, antepartum haemorrhage, postpartum haemorrhage

General disorders and administration site conditions
Pyrexia, hypothermia

Investigations
Abnormal liver function test, increased blood uric acid level (potentially leading to gout attacks), pro- longed prothrombin time

There have been rare to very rare reports of major bleeding events such as cerebral haemorrhage (esp- ecially in patients who had uncontrolled high blood pressure and/or who were receiving concomitant treatment with anticoagulants); in isolated cases, these events may be life-threatening