Aggrenox (Page 2 of 7)
6.1 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 (14)]; 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, extended-release 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.
| Individual Treatment Group | ||||||||
| Body System/Preferred Term | AGGRENOX | ER-DP Alone | ASA Alone | Placebo | ||||
| * 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 BIDNOS = not otherwise specified. | ||||||||
| 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 & 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%) | ||||
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)
| Treatment Groups | ||||
| AGGRENOX | ER-DP | ASA | Placebo | |
| Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID | ||||
| Total Number of Patients | 1650 | 1654 | 1649 | 1649 |
| Patients with at least one Adverse Eventthat 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%) |
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 0.13×106 /mm3.
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