1. 1 Combined CRD and DSaRM Advisory Committee Meeting Trasylol (aprotinin) NDA 20-304 Overview George Shashaty, M.D. Division of Medical Imaging and Hematology September 12, 2007

2. 2 Current Indication For prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion

3. 3 Recent Regulatory History Cardiovascular and Renal Advisory Committee Meeting on September 21, 2006 to review: Observational studies by Mangano et al and Karkouti et al that suggested an excess of adverse reactions associated with the use of Trasylol. These studies employed propensity score adjustment in an attempt to “randomize” patients. Anaphylactic reactions associated with the use of Trasylol

4. 4 Conclusions/Recommendations of Cardiorenal Advisory Committee Trasylol is associated with an increased risk of renal dysfunction Benefits of Trasylol appear to be greatest for patients undergoing complex surgery or who have other risk factors for bleeding Benefit/risk equation favors Trasylol Treated population should be more restricted Methods should be devised to minimize frequency and consequences of anaphylaxis Totality of information supports the continued use of Trasylol for the indication (Yes, 18; No, 0; Abstain, 1)

5. 5 Regulatory Actions Label revisions made to: Enhance warnings for anaphylaxis (Black Box; contraindication to re-exposure within 1 year; need for immediately available cardiopulmonary bypass; uncertainty of “test” dose to predict anaphylaxis) Warning for renal dysfunction Indication restricted to patients with increased bleeding risk

6. 6 Subsequent Events FDA informed of Bayer-sponsored i3 Study Observational study (2003-2006) of 66,435 patients undergoing CABG with CPB and receiving antifibrinolytic therapy (Trasylol, aminocaproic acid or tranexamic acid) With or without propensity score adjustment, the administration of Trasylol as compared to aminocaproic acid or tranexamic acid during CABG with CPB was associated with significantly greater relative risks for renal failure, death, acute heart failure and stroke but not for myocardial infarction Rationale for non-disclosure prior to AC meeting included time restraints for sponsor review and limited knowledge of study within the sponsor company

7. 7 Indications for Aminocaproic Acid and Tranexamic Acid Aminocaproic Acid (Amicar): for use “in enhancing hemostasis when fibrinolysis contributes to bleeding. In life-threatening situations, transfusion of appropriate blood products and other emergency measures may be required. Fibrinolytic bleeding may frequently be associated with surgical complications following heart surgery (with or without cardiac bypass procedures) and portacaval shunt; hematological disorders, such as amegakaryocytic thrombocytopenia (accompanying aplastic anemia); acute and life-threatening abruptio placenta; hepatic cirrhosis; and neoplastic disease such as carcinoma of the prostate, lung, stomach and cervix.” Tranexamic acid (Cyclokapron): for use "in patients with hemophilia for short term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction."

8. 8 Mangano Mortality Study Analysis of a portion of the same database (IREF EPI- II) previously described Five year all-cause mortality rates Compared aprotinin, EACA and TXA to no antifibrinolytic agent Hazard ratio for death with aprotinin compared to no therapy was 1.48 (95% CI, 1.19-1.85). Little change after propensity adjustment No increase in death rate with either EACA or TXA

9. 9 Additional Information BART Study (RCT). Compares aprotinin, EACA and TXA in 3000 high risk cardiac surgery patients. Current enrollment 2400 patients. After latest interim analysis (approximately 2100 patients), trial continues without modification Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists Guideline. 2006. Use of aprotinin in CABG with CPB is Class I recommendation with A level of evidence Other retrospective and meta-analytical studies have shown either an increased frequency of renal dysfunction or no increase in adverse reactions with aprotinin compared to other or no anti-fibrinolytic therapy

10. 10 Trasylol - Benefits and Risks Benefits Decreased blood loss and need for transfusion No demonstrated survival benefit Risks Definite - Renal dysfunction - Anaphylaxis Possible – Increased rates of death, myocardial infarction, congestive heart failure, stroke

11. 11 Discussion/Recommendations Continued marketing of aprotinin Modifications to approved label Need for additional studies

12. 12 BART Trial (2006 Abstract) Triple-blind, triple-dummy, RCT 18 Canadian cardiovascular centers Enrollment goal of 2970 high-risk CV surgery patients. Powered to detect a difference of at least 3% between groups. Aprotinin, aminocaproic acid, tranexamic acid Primary EP – Massive post-op bleeding Secondary endpoints – Tx, MI, CVA, 30 day mortality, SAEs Interim analysis -1210 patients. Incidence of massive bleeding was 11.2%. Overall mortality was 5.0%.