ASPIRIN AND EXTENDED-RELEASE DIPYRIDAMOLE

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Hypersensitivity [ see Contraindications (4.1) ] Allergy [ see Contraindications (4.2) ] Risk of Bleeding [ see Warnings and Precautions (5.1) ] The most frequently reported adverse reactions (>10% and greater than placebo) were headache, dyspepsia, abdominal pain, nausea, and diarrhea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 aspirin and extended-release dipyridamole 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 aspirin and extended-release dipyridamole capsules, 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 aspirin and extended-release dipyridamole capsules 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 annualized event rate for adverse events that occurred in 1%/year or more of patients treated with aspirin and extended-release dipyridamole capsules where the incidence was also at least 1%/year 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 a Individual Treatment Group Body System/Preferred Term Aspirin And Extended-Release Dipyridamole n (%/year) b ER-DP Alone n (%/year) b ASA Alone n (%/year) b Placebo n (%/year) b Total Number of Patients 1650 1654 1649 1649 Central and Peripheral Nervous System Disorders Headache 647(28.25) 634 (27.91) 558 (22.10) 543 (22.29) Gastrointestinal System Disorders Dyspepsia 303 (13.23) 288 (12.68) 299 (11.84) 275 (11.29) Abdominal Pain 289 (12.62) 255 (11.22) 262 (10.38) 239 (9.81) Nausea 264 (11.53) 254 (11.18) 210 (8.32) 232 (9.53) Diarrhea 210 (9.17) 257 (11.31) 112 (4.44) 161 (6.61) Vomiting 138 (6.03) 129 (5.68) 101 (4.00) 118 (4.84) Platelet, Bleeding and Clotting Disorders Hemorrhage NOS 52 (2.27) 24 (1.06) 46 (1.82) 24 (0.99) a Reported by ≥1%/year of patients during aspirin and extended-release dipyridamole capsules treatment where the incidence was at least 1%/year greater than in those treated with placebo. b Annual event rate per 100 pt-years = 100* number of subjects with event/subject-years. Subject-years is defined as cumulative number of days on treatment divided by 365.25. 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 aspirin and extended-release dipyridamole, 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 a Treatment Groups Aspirin And Extended-Release Dipyridamole n (%/year) b ER-DP n (%/year) b ASA n (%/year) b Placebo n (%/year) b Total Number of Patients 1650 1654 1649 1649 Patients with at least one Adverse Event that led to treatment discontinuation 417 (18.21) 419 (18.44) 318 (12.59) 352 (14.45) Headache 165 (7.20) 166 (7.31) 57 (2.26) 69 (2.83) Nausea 91 (3.97) 95 (4.18) 51 (2.02) 53 (2.18) Abdominal Pain 74 (3.23) 64 (2.82) 56 (2.22) 52 (2.13) Vomiting 53 (2.31) 52 (2.29) 28 (1.11) 24 (0.99) a Reported by ≥1%/year of patients during aspirin and extended-release dipyridamole capsules treatment where the incidence was at least 1%/year greater than in those treated with placebo. b Annual event rate per 100 pt-years = 100* number of subjects with event/subject-years. Subject-years is defined as cumulative number of days on treatment divided by 365.25. 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. 6.2 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 aspirin and extended-release dipyridamole. Body as a Whole: Hypothermia, chest pain, allergic reaction, syncope Cardiovascular: Angina pectoris, hypotension Central Nervous System: Cerebral edema, dizziness, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia Gastrointestinal: Pancreatitis, Reye syndrome, hematemesis, gastritis, ulceration and perforation, hemorrhage rectum, melena, GI hemorrhage Hearing and Vestibular Disorders: Hearing loss Heart Rate and Rhythm Disorders: Tachycardia, palpitation Immune System Disorders: Hypersensitivity, acute anaphylaxis, laryngeal edema Liver and Biliary System Disorders: Hepatitis, hepatic failure, cholelithiasis, jaundice, hepatic function abnormal Musculoskeletal: Rhabdomyolysis, myalgia Metabolic and Nutritional Disorders: Hypoglycemia, dehydration Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia, hematoma, gingival bleeding, epistaxis, purpura Psychiatric Disorders: Confusion, agitation Respiratory: Tachypnea, dyspnea, hemoptysis Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis, and hematoma, pruritus, urticaria, and drug reaction with eosinophilia and systemic symptoms (DRESS) Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, hematuria Vascular (Extracardiac) Disorders: Allergic vasculitis, flushing Other Adverse Events: Anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis.