The following adverse reactions are discussed elsewhere in the labeling:
- Hypersensitivity [see CONTRAINDICATIONS].
- Allergy [see CONTRAINDICATIONS].
- Risk of Bleeding [see WARNINGS AND PRECAUTIONS].
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The efficacy and safety of AGGRENOX was established in the European Stroke Prevention Study-2 (ESPS2). ESPS2 was a double-blind, placebo controlled study that evaluated 6602 patients over the age of 18 years who had a previous ischemic stroke or transient ischemic attack within ninety days prior to entry. Patients were randomized to either AGGRENOX, aspirin, ER-DP, or placebo [see Clinical Studies]; primary endpoints included stroke (fatal or nonfatal) and death from all causes.
This 24-month, multicenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of AGGRENOX with placebo, extendedrelease dipyridamole alone and aspirin alone. The study was conducted in a total of 6602 male and female patients who had experienced a previous ischemic stroke or transient ischemia of the brain within three months prior to randomization.
Table 1 presents the incidence of adverse events that occurred in 1% or more of patients treated with AGGRENOX where the incidence was also greater than in those patients treated with placebo. There is no clear benefit of the dipyridamole/aspirin combination over aspirin with respect to safety.
Table 1 : Incidence of Adverse Events in ESPS2*
| Body System/Preferred Term | Individual Treatment Group | |||
| AGGRENOX | ER-DP Alone | ASA Alone | Placebo | |
| Total Number of Patients | 1650 | 1654 | 1649 | 1649 |
| Total Number (%) of Patients With at Least | ||||
| One On-Treatment Adverse Event | 1319 (80%) | 1305 (79%) | 1323 (80%) | 1304 (79%) |
| Central and Peripheral Nervous System Disorders | ||||
| Headache | 647 (39%) | 634 (38%) | 558 (34%) | 543 (33%) |
| Convulsions | 28 (2%) | 15 (1%) | 28 (2%) | 26 (2%) |
| Gastrointestinal System Disorders | ||||
| Dyspepsia | 303 (18%) | 288 (17%) | 299 (18%) | 275 (17%) |
| Abdominal Pain | 289 (18%) | 255 (15%) | 262 (16%) | 239 (14%) |
| Nausea | 264 (16%) | 254 (15%) | 210 (13%) | 232 (14%) |
| Diarrhea | 210 (13%) | 257 (16%) | 112 (7%) | 161 (10%) |
| Vomiting | 138 (8%) | 129 (8%) | 101 (6%) | 118 (7%) |
| Hemorrhage Rectum | 26 (2%) | 22 (1%) | 16 (1%) | 13 (1%) |
| Melena | 31 (2%) | 10 (1%) | 20 (1%) | 13 (1%) |
| Hemorrhoids | 16 (1%) | 13 (1%) | 10 (1%) | 10 (1%) |
| GI Hemorrhage | 20 (1%) | 5 (0%) | 15 (1%) | 7 (0%) |
| Body as a Whole - General Disorders | ||||
| Pain | 105 (6%) | 88 (5%) | 103 (6%) | 99 (6%) |
| Fatigue | 95 (6%) | 93 (6%) | 97 (6%) | 90 (5%) |
| Back Pain | 76 (5%) | 77 (5%) | 74 (4%) | 65 (4%) |
| Accidental Injury | 42 (3%) | 24 (1%) | 51 (3%) | 37 (2%) |
| Malaise | 27 (2%) | 23 (1%) | 26 (2%) | 22 (1%) |
| Asthenia | 29 (2%) | 19 (1%) | 17 (1%) | 18 (1%) |
| Syncope | 17 (1%) | 13 (1%) | 16 (1%) | 8 (0%) |
| Psychiatric Disorders | ||||
| Amnesia | 39 (2%) | 40 (2%) | 57 (3%) | 34 (2%) |
| Confusion | 18 (1%) | 9 (1%) | 22 (1%) | 15 (1%) |
| Anorexia | 19 (1%) | 17 (1%) | 10 (1%) | 15 (1%) |
| Somnolence | 20 (1%) | 13 (1%) | 18 (1%) | 9 (1%) |
| Musculoskeletal System Disorders | ||||
| Arthralgia | 91 (6%) | 75 (5%) | 91 (6%) | 76 (5%) |
| Arthritis | 34 (2%) | 25 (2%) | 17 (1%) | 19 (1%) |
| Arthrosis | 18 (1%) | 22 (1%) | 13 (1%) | 14 (1%) |
| Myalgia | 20 (1%) | 16 (1%) | 11 (1%) | 11 (1%) |
| Respiratory System Disorders | ||||
| Coughing | 25 (2%) | 18 (1%) | 32 (2%) | 21 (1%) |
| Upper Respiratory Tract Infection | 16 (1%) | 9 (1%) | 16 (1%) | 14 (1%) |
| Cardiovascular Disorders, General | ||||
| Cardiac Failure | 26 (2%) | 17 (1%) | 30 (2%) | 25 (2%) |
| Platelet, Bleeding and Clotting Disorders | ||||
| Hemorrhage NOS | 52 (3%) | 24 (1%) | 46 (3%) | 24 (1%) |
| Epistaxis | 39 (2%) | 16 (1%) | 45 (3%) | 25 (2%) |
| Purpura | 23 (1%) | 8 (0%) | 9 (1%) | 7 (0%) |
| Neoplasm | ||||
| Neoplasm NOS | 28 (2%) | 16 (1%) | 23 (1%) | 20 (1%) |
| Red Blood Cell Disorders | ||||
| Anemia | 27 (2%) | 16 (1%) | 19 (1%) | 9 (1%) |
| * Reported by ≥ 1% of patients during AGGRENOX treatment where the incidence was greater than in those treated with placebo. Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID NOS = not otherwise specified. |
||||
Discontinuation due to adverse events in ESPS2 was 25% for AGGRENOX, 25% for extended-release dipyridamole, 19% for aspirin, and 21% for placebo (refer to Table 2)
Table 2 : Incidence of Adverse Events that Led to the Discontinuation of Treatment: Adverse Events with an Incidence of ≥ 1% in the AGGRENOX Group
| Treatment Groups | ||||
| AGGRENOX | ER-DP | ASA | Placebo | |
| Total Number of Patients | 1650 | 1654 | 1649 | 1649 |
| Patients with at least one Adverse Event that led to treatment discontinuation | 417 (25%) | 419 (25%) | 318 (19%) | 352 (21%) |
| Headache | 165 (10%) | 166 (10%) | 57 (3%) | 69 (4%) |
| Dizziness | 85 (5%) | 97 (6%) | 69 (4%) | 68 (4%) |
| Nausea | 91 (6%) | 95 (6%) | 51 (3%) | 53 (3%) |
| Abdominal Pain | 74 (4%) | 64 (4%) | 56 (3%) | 52 (3%) |
| Dyspepsia | 59 (4%) | 61 (4%) | 49 (3%) | 46 (3%) |
| Vomiting | 53 (3%) | 52 (3%) | 28 (2%) | 24 (1%) |
| Diarrhea | 35 (2%) | 41 (2%) | 9 ( < 1%) | 16 ( < 1%) |
| Stroke | 39 (2%) | 48 (3%) | 57 (3%) | 73 (4%) |
| Transient Ischemic Attack | 35 (2%) | 40 (2%) | 26 (2%) | 48 (3%) |
| Angina Pectoris | 23 (1%) | 20 (1%) | 16 ( < 1%) | 26 (2%) |
| Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID | ||||
Headache was most notable in the first month of treatment.
Other Adverse Events
Adverse reactions that occurred in less than 1% of patients treated with AGGRENOX in the ESPS2 study and that were medically judged to be possibly related to either dipyridamole or aspirin are listed below.
Body as a Whole: Allergic reaction, fever
Cardiovascular: Hypotension
Central Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage
Gastrointestinal: Gastritis, ulceration and perforation
Hearing and Vestibular Disorders: Tinnitus, and deafness. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism
Heart Rate and Rhythm Disorders: Tachycardia, palpitation, arrhythmia, supraventricular tachycardia
Liver and Biliary System Disorders: Cholelithiasis, jaundice, hepatic function abnormal
Metabolic and Nutritional Disorders: Hyperglycemia, thirst
Platelet, Bleeding and Clotting Disorders: Hematoma, gingival bleeding
Psychiatric Disorders: Agitation
Reproductive: Uterine hemorrhage
Respiratory: Hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edema
Special Senses Other Disorders: Taste loss
Skin and Appendages Disorders: Pruritus, urticaria
Urogenital: Renal insufficiency and failure, hematuria
Vascular (Extracardiac) Disorders: Flushing
Laboratory Changes
Over the course of the 24-month study (ESPS2), patients treated with AGGRENOX showed a decline (mean change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13x106/mm³.
Post-Marketing Experience
The following is a list of additional adverse reactions that have been reported either in the literature or are from post-marketing spontaneous reports for either dipyridamole or aspirin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to AGGRENOX.
Body as a Whole: Hypothermia, chest pain
Cardiovascular: Angina pectoris
Central Nervous System: Cerebral edema
Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia
Gastrointestinal: Pancreatitis, Reye syndrome, hematemesis
Hearing and Vestibular Disorders: Hearing loss
Immune System Disorders: Hypersensitivity, acute anaphylaxis, laryngeal edema
Liver and Biliary System Disorders: Hepatitis, hepatic failure
Musculoskeletal: Rhabdomyolysis
Metabolic and Nutritional Disorders: Hypoglycemia, dehydration
Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia
Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding
Respiratory: Tachypnea, dyspnea
Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis, and hematoma
Urogenital: Interstitial nephritis, papillary necrosis, proteinuria
Vascular (Extracardiac Disorders): Allergic vasculitis
Other adverse events: anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis.