1. 1 Trasylol ® (aprotinin injection) Bayer Pharmaceuticals Corp. NDA 20-304 Opening Remarks ___________ Dwaine Rieves, M.D. Deputy Director Division of Medical Imaging and Hematology Products Center for Drug Evaluation and Research

2. 2 Trasylol ® (aprotinin injection) Safety Update FDA Cardiovascular and Renal Drugs Advisory Committee September 21, 2006

3. 3BackgroundPublications: –NEJM –Transfusion FDA Public Health Advisory Sponsor’s review/FDA submissions Advisory Committee Completion of FDA review Actions

4. 4Purpose To obtain perspectives and advice for FDA to consider in: – completion of its review Published data Spontaneous post-marketing reports Sponsor’s cumulative clinical data submissions –possible regulatory actions

5. 5Considerations Published data: –Important source –Limitations –Data integrity/conclusions/opinions Assumed by authors/publisher Not FDA “Off-label” use of marketed drugs: –Practice of medicine –Variable evidence of safety and efficacy

6. 6 New England Journal of Medicine Publication “The risk associated with aprotinin in cardiac surgery” NEJM 354(4): 353-365 (Jan 26, 2006) –Multi-center, observational study of patients undergoing CABG with CPB –Compared aprotinin, aminocaproic acid, tranexamic acid, no hemostatic drug –Propensity adjustment methodology

7. 7 New England Journal of Medicine Publication –In certain patients, increased risk for: Renal failure requiring dialysis Renal failure requiring dialysis Myocardial infarction or heart failure Myocardial infarction or heart failure Stroke or encephalopathy Stroke or encephalopathy

8. 8 Transfusion Publication "A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion- risk cardiac surgery” Transfusion 46(3): 327-338 (January 20, 2006; March 2006) –Single-center, observational study in high transfusion risk patients undergoing cardiac surgery with CPB –Propensity adjustment methodology –Renal dysfunction increased

9. 9 “Unlabeled” risks: e.g., renal, CV –Safety concerns not described in product label –New findings from: Observational studies Controlled clinical studies “Labeled” risks: Hypersensitivity –Safety concerns described in product label –New summary from: Sponsor’s database FDA Adverse Event Reporting System Topics

10. 10 FDA Summary of “Labeled” Risks – Office of New Drugs (OND) Kathy Robie-Suh, MD, PhD Kathy Robie-Suh, MD, PhD – Office of Surveillance and Epidemiology (OSE) Susan Lu, RPh Susan Lu, RPh

11. 11 Trasylol ® (aprotinin injection) Bayer Pharmaceuticals Corp. NDA 20-304 Regulatory Overview ___________ Kathy M. Robie-Suh, M.D., Ph.D. Division of Medical Imaging and Hematology Products Center for Drug Evaluation and Research

12. 12 Outline of Presentation Current Trasylol label Regulatory history highlights New developments

13. 13 Trasylol – Current Label Trasylol is a bovine-sourced protease inhibitor approved for the following indication: Trasylol is a bovine-sourced protease inhibitor approved for the following indication:Indication: “For prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass (CPB) in the course of coronary artery bypass graft (CABG) surgery”

14. 14 Trasylol – Current Label Regimen Test Dose Loading Dose “Pump Prime” Constant Infusion A “full dose” 10,000 KIU 2 million KIU 500,000 KIU/hr B “half dose” 10,000 KIU 1 million KIU 250,000 KIU/hr Dose and Administration:

15. 15 Trasylol – Current Label Clinical Trials: Efficacy Results from R, DB, PC, U.S. studies showed that Trasylol Regimens A and B decreased percentage of patients requiring donor blood in both repeat CABG patients (4 studies, total 412 patients) and primary CABG patients (4 studies, total 1440 patients): Patients % of Patients Receiving Transfusions PL Reg A Reg B Repeat CABG 76%47%49% Primary CABG 54%37%37%

16. 16 Trasylol – Current Label “Black Box Warning” ______________________________________________ ______________________________________________ “Anaphylactic or anaphylactoid reactions are possible when Trasylol is administered. Hypersensitivity reactions are rare in patients with no prior exposure to aprotinin. The risk of anaphylaxis is increased in patients who are re- exposed to aprotinin-containing products. The benefit of Trasylol to patients undergoing primary CABG surgery should be weighed against the risk of anaphylaxis should a second exposure to aprotinin be required. (See WARNINGS and PRECAUTIONS).” “Anaphylactic or anaphylactoid reactions are possible when Trasylol is administered. Hypersensitivity reactions are rare in patients with no prior exposure to aprotinin. The risk of anaphylaxis is increased in patients who are re- exposed to aprotinin-containing products. The benefit of Trasylol to patients undergoing primary CABG surgery should be weighed against the risk of anaphylaxis should a second exposure to aprotinin be required. (See WARNINGS and PRECAUTIONS).”

17. 17 Trasylol – Current Label Warnings and Precautions Anaphylactic or anaphylactoid reactions Hypersensitivity reactions rare in patients with no prior exposure Risk greatest if re-exposure within six months Range from skin eruptions, itching, dyspnea, nausea and tachycardia to fatal shock Severe (fatal) reactions can occur with test dose

18. 18 Trasylol – Current Label Adverse Reactions Based on placebo controlled U.S. studies (2002 Trasylol- treated patients, 1084 placebo-treated patients) Myocardial infarction No difference in rates (6% in both groups) Renal: serum creatinine alterations No increase in renal dysfunction (3% in Trasylol and 2% in placebo groups, respectively) Graft Patency One study: higher graft closure rate

19. 19 Regulatory History 1993 “for the prophylactic use to reduce perioperative blood loss and the need for transfusion in patients undergoing cardiopulmonary bypass in the course of repeat CABG surgery. Trasylol is also indicated in selected cases of primary CABG surgery where the risk of bleeding is especially high (impaired hemostasis, e.g., presence of aspirin or other coagulopathy) or where transfusion is unavailable or unacceptable.”

20. 20 Regulatory History 1998 “For prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass (CPB) in the course of coronary artery bypass graft (CABG) surgery.” Black box -- re: anaphylaxis risk

21. 21 New Developments Sponsor NDA submissions and proposals: –Cumulative clinical study findings show increased risk for renal dysfunction –Proposed modifications to the label –Other plans

22. 22 Post-marketing review of Hypersensitivity Reactions associated with Trasylol® (Aprotinin injection) Susan Lu, R.Ph., Safety Evaluator Team Leader Division of Drug Risk Evaluation Office of Surveillance and Epidemiology CDER, FDA

23. 23 Presentation Overview of Adverse Event Reporting System (AERS) Hypersensitivity findings –Sponsor –FDA Risk management of Trasylol-associated hypersensitivity

24. 24 FDA AERS Database Computerized database containing > 3 million reports Spontaneous reporting –Not required of health care providers –Sponsors required to report any adverse events of which they become aware Strengths –Detection of rare but serious adverse events (i.e., anaphylactic reactions) –Descriptive case series

25. 25 FDA AERS Database Limitations –Lower utility for expected events in an at- risk population (renal failure, MI, CHF) –Underreporting –Biases in reporting –Quality of reports Other considerations –No pre-1993 reports for Trasylol –Limited foreign reports

26. 26 U.S. Patient Exposure for Trasylol Source: Bayer Analysis of Aprotinin Spontaneous Data 7/26/06

27. 27 Reporting of Trasylol- associated Hypersensitivity Bayer Global Drug Safety Database

28. 28 Overview of Hypersensitivity Sponsor Analysis 41% of Bayer’s worldwide postmarketing safety database consists of reports of hypersensitivity reactions (306/745) –85% reports were coded as anaphylactic reaction/anaphylactic shock Sponsor’s review determined 291 hypersensitivity cases possibly associated with Trasylol 52 of 291 cases were fatal

29. 29 Re-exposure to Trasylol Sponsor Analysis 47% (138/291) patients had documented previous exposure to Trasylol 67% (93/138) cases with reported re- exposure to Trasylol were re-exposed within 6 months

30. 30 Test Dose (N=139) Sponsor Analysis 81 cases- reaction with test dose alone –19 fatal –62 non-fatal 38 cases -negative test dose but hypersensitivity reaction with therapeutic dose –9 fatal –29 non-fatal 2 cases- positive test dose, infusion given 18 cases-test dose given but no result documented Sponsor Assessment Report 5/17/06

31. 31 Summary of Trasylol-associated Hypersensitivity Sponsor Analysis Hypersensitivity reaction is the most frequently reported spontaneous event associated with Trasylol. 291 reports of hypersensitivity –52 fatal –47% patients had history of previous exposure ~2/3 patients with previous exposure had received aprotinin in previous 6 months –Test dose associated with 19 fatalities –Despite a negative test dose result, 27% patients experienced a hypersensitivity reaction –The majority of cases occurred in the setting of surgical procedures other than CABG surgery

32. 32 Reporting of Trasylol- associated Anaphylaxis FDA Adverse Event Reporting System Database

33. 33 Methods AERS database searched for all reports of anaphylactic/anaphylactoid and Type 1 hypersensitivity reactions Individual review of reports identified from AERS search Analysis excluded reports in which: –reaction was most likely due to another cause –inadequate information was provided for assessment

34. 34 Initial Review of AERS Reporting for Anaphylaxis Total reports 70 Death outcome23 Demographics Gender (n=65)Male (51%), Female (41%) Age (n=55)81% adult and 41% >60 yrs Origin of report U.S. 58 Foreign12

35. 35 Time to Onset (n=49) Following test dose 23 <10 min 14 10-15 min 2 Unspecified 7 During Therapeutic dose 26 During loading dose 15 During infusion 9 Unspecified 2

36. 36 Test Dose Administration (n=49) all fatal Reaction after test dose alone2310 Test dose negative-reaction with therapeutic dose20 1 Test dose result not documented- reaction with therapeutic dose 6 1

37. 37 Previous Exposure to Trasylol Previous exposure documented34 (48%) –Timing of previous exposure (n=29) <2 mo9 2-4 mo9 4-6 mo2 >6 mo-1 yr2 > 1yr7 No previous exposure stated 7 (10%) Exposure history unknown29 *(41%) *18/29 cases mentioned previous surgery

38. 38 Indication for Use (n=64) Where indication stated, 25% of patients were receiving Trasylol for the approved indication of CABG surgery The most frequently reported use for valve surgery (35%)

39. 39 Clinical Features of Anaphylaxis Reported signs of anaphylaxis (n=57) Cardiovascular events (53) –Hypotension (45) –Cardiac arrest/CV collapse (13) Respiratory events (11) –Bronchospasm in 2 cases, changes in airway pressure/ventilator readings in several cases Dermatologic events (10) –Erythema (5) –Rash (5) Most commonly reported treatment for anaphylaxis (n=46) Vasopressors (32) Steroids (10) Antihistamines (7)

40. 40 Case #1 (2004) Anaphylactic reaction with negative test dose and unknown previous exposure to aprotinin 74 year-old female hx of MVR/CABG admitted for redo mitral valve replacement. Preoperative records of prior surgery (7 wks ago) from another hospital revealed no prior aprotinin exposure. After induction of general anesthesia, 2 cc test dose Trasylol (negative) given followed by loading dose. Progressive hypotension developed followed by bradycardia unresponsive to IV phenylephrine, epi, norepi and atropine. CPR started with return of BP/heart rate after 5 min. Surgery cancelled and pt sent to ICU mechanically ventilated. Other hospital again contacted due to high suspicion of aprotinin reaction and anesthetic record confirmed previous exposure to aprotinin.

41. 41 Case #2 Near fatal anaphylactic reaction to test dose in patient with no previous exposure to aprotinin 3.5 year old male with no previous exposure to aprotinin admitted for elective replacement of r. ventricular pulmonary artery conduit. After induction of anesthesia/ intubation, received 1 ml test dose of aprotinin. Immediately BP became undetectable with sudden increase in airway pressures/difficulty maintaining ventilation. CPR initiated with repeated boluses of epinephrine, sodium bicarbonate and Ca Chloride and also methylprednisolone, diphenhydramine and cimetidine. After 50 min. of CPR, no recovery of cardiac function. Cardio-pulmonary bypass instituted and patient recovered after 1 hour. Subsequent immuno assays showed highly elevated IgE levels in response to aprotinin. Ann Thorac Surg 1999;67:837-8 Ann Thorac Surg 1999;67:837-8

42. 42 Findings from AERS reports of Trasylol associated anaphylaxis Test dose 43% of fatal cases associated with test dose 40% of patients who were documented to have received a test dose experienced an anaphylactic reaction despite negative test dose result Previous Exposure 48% of patients had previous exposure to aprotinin –67% of patients had been re-exposed within 6 months 10% patients had no previous exposure to aprotinin Severity of presentation Cardiovascular events (hypotension, cardiac arrest) reported predominantly Indication for Use 25% patients received Trasylol for approved indication

43. 43 Sponsor Proposed Risk Minimization Action Plan (RiskMAP) for Hypersensitivity Stated goal- “The RiskMAP will identify those patients most at risk of a hypersensitivity reaction to Trasylol and provide information to reduce these patients from re-exposure to the drug within the period of highest risk of hypersensitivity”

44. 44 RiskMAP Tools Sponsor’s Proposal Aprotinin IgG assay Education targeted at physicians Appropriate indication for use Risk of hypersensitivity high with re-exposure within 6 months Complete medical history to uncover previous exposure Use of test dose Readiness for handling hypersensitivity reactions Information on cross-reacting products

45. 45 Comments on RiskMAP Clinical utility of Aprotinin IgG Assay Educational message may not mitigate risk –Value of test dose Test dose frequently not predictive Serious reactions occur with test dose –Medical history may not uncover previous exposure Patients not often aware of exposures to drugs during surgery May not be part of a medical record –Reactions may not be recognized in the surgical setting Non-cardiovascular symptoms (e.g., nausea, dyspnea, and skin reactions) may not be detected. First recognizable sign may be circulatory failure

46. 46 Acknowledgements Mark Avigan, MD, Director, Div Drug Risk Evaluation (DDRE) Allen Brinker MD, DDRE Epidemiology Team Leader Tiffany Brown, DMIHP Project Manager Yuan (Richard) Chen, PhD, Statistician, OB, OTS Gerald Dal Pan, MD, Director, OSE Mary Dempsey, Project Manager, OSE Rosemary Johann-Liang, MD, DDRE Dep Division Director Claudia Karwoski PharmD, OSE Scientific Coordinator Cindy Kortepeter PharmD, DDRE SE Team Leader Parivash Nourjah PhD, DDRE Epidemiologist Dwaine Rieves, MD, DMIHP, Dep Director Kathy Robie-Suh, MD, PhD, DMIHP Medical Team Leader George Rochester, PhD, Statistical Team Leader, OB, OTS George Shashaty, MD, DMIHP Medical Officer Mary Ross Southworth PharmD, DDRE Safety Evaluator Joyce Weaver PharmD, OSE Drug Risk Management Analyst Mike Welch, PhD, Associate Director, OB, OTS Jyoti Zalkikar, PhD, Statistical Team Leader, OB, OTS

47. 47 Trasylol ® (aprotinin injection) Bayer Pharmaceuticals Corp. NDA 20-304 FDA Topics of Discussion ___________ Dwaine Rieves, M.D. Deputy Director Division of Medical Imaging and Hematology Products Center for Drug Evaluation and Research

48. 48Outline Guest Presentations Dennis Mangano, MD, PhD Keyvan Karkouti, MSc, MD Sponsor Presentation Public Hearing Discussion

49. 49Questions Discussions of: –“Unlabeled” safety findings from: Observational studies Observational studies Controlled studies Controlled studies –“Labeled” hypersensitivity risks –Efficacy, in light of current surgical, anesthesia and blood transfusion practices –Overall safety and efficacy/Indication