6 ADVERSE REACTIONS Bleeding is the most commonly reported adverse reaction. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Medicure at 1-800-509-0544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 clinical practice. In the PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management), PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management — Patients Limited by Unstable Signs and Symptoms) and RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) trials, 1946 patients received AGGRASTAT in combination with heparin and 2002 patients received AGGRASTAT alone for about 3 days. Forty-three percent of the population was >65 years of age and approximately 30% of patients were female. In clinical studies with the recommended regimen (25 mcg/kg bolus followed by a 0.15 mcg/kg/min maintenance infusion), AGGRASTAT was administered in combination with aspirin, clopidogrel and heparin or bivalirudin to over 8000 patients for typically ≤24 hours. Approximately 30% of the population was >65 years of age and approximately 25% were female. Bleeding PRISM-PLUS Regimen The incidences of major and minor bleeding using the TIMI criteria in the PRISM-PLUS study are shown below. Table 2 TIMI Major and Minor Bleeding in PRISM-PLUS PRISM-PLUS (NSTE-ACS) Bleeding (TIMI Criteria)Major = Hemoglobin drop of >5.0 g/dL with or without an identified site, intracranial hemorrhage, or cardiac tamponade. Minor = Hemoglobin drop of >3.0 g/dL with bleeding from a known site, spontaneous gross hematuria, hematemesis or hemoptysis. AGGRASTAT0.4 mcg/kg/min initial infusion; 0.10 mcg/kg/min maintenance infusion.+ Heparin (n=773) Heparin alone (n=797) Major Bleeding 1.4% 0.8% Minor Bleeding 10.5% 8.0% Transfusions 4.0% 2.8% The incidence rates of TIMI major bleeding in patients undergoing percutaneous procedures in PRISM-PLUS are shown below. Table 3 TIMI Major Bleeding Associated with Percutaneous Procedures in PRISM-PLUS AGGRASTAT + Heparin Heparin alone N % N % Prior to Procedures 773 0.3 797 0.1 Following Angiography 697 1.3 708 0.7 Following PTCA 239 2.5 236 2.2 The incidence rates of TIMI major bleeding in patients undergoing coronary artery bypass graft surgery (CABG) in PRISM-PLUS within one day of discontinuation of AGGRASTAT were 17% on AGGRASTAT plus heparin (N=29) and 35% on heparin alone (N=31). Recommended (“High-Dose Bolus”) Regimen Rates of major bleeds (including any intracranial, intraocular or retroperitoneal hemorrhage, clinically overt signs of hemorrhage associated with a drop in hemoglobin of >3 g/dL or any drop in hemoglobin by 4g/dL, bleeding requiring transfusion of ≥2U blood products, bleeding directly resulting in death within 7 days or hemodynamic compromise requiring intervention) were consistent with the rates observed in subjects administered the PRISM-PLUS regimen of AGGRASTAT. There was a trend toward greater bleeding in ST segment elevation myocardial infarction (STEMI) patients treated with fibrinolytics prior to administration of AGGRASTAT using the recommended regimen during rescue PCI. Non-Bleeding The incidences of non-bleeding adverse events that occurred at an incidence of >1% and numerically higher than control, regardless of drug relationship, are shown below: Table 4 Non-bleeding Adverse Reactions in PRISM-PLUS AGGRASTAT + Heparin (N=1953) % Heparin alone (N=1887) % Body as a Whole Edema/swelling 2 1 Pain, pelvic 6 5 Reaction, vasovagal 2 1 Cardiovascular System Bradycardia 4 3 Dissection, coronary artery 5 4 Musculoskeletal System Pain, leg 3 2 Nervous System/Psychiatric Dizziness 3 2 Skin and Skin Appendage Sweating 2 1 Thrombocytopenia Patients treated with AGGRASTAT plus heparin, were more likely to experience decreases in platelet counts than were those on heparin alone. These decreases were reversible upon discontinuation of AGGRASTAT. The percentage of patients with a decrease of platelets to <90,000/mm3 was 1.5%, compared with 0.6% in the patients who received heparin alone. The percentage of patients with a decrease of platelets to <50,000/mm3 was 0.3%, compared with 0.1% of the patients who received heparin alone. 6.2 Post-Marketing Experience The following additional adverse reactions have been identified during post-approval use of AGGRASTAT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. Hypersensitivity: Severe allergic reactions including anaphylactic reactions have occurred during the first day of AGGRASTAT infusion, during initial treatment, and during readministration of AGGRASTAT. Some cases have been associated with severe thrombocytopenia (platelet counts <10,000/mm3). No information is available on the formation of antibodies to tirofiban.