Trasylol

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
Trasylol (aprotinin injection)Safety Update

• FDA Cardiovascular and Renal Drugs Advisory
  Committee
• September 21, 2006

3
Background

• Publications
• NEJM
• Transfusion
• FDA Public Health Advisory
• Sponsors review/FDA submissions
• Advisory Committee
• Completion of FDA review
• Actions

4
Purpose

• To obtain perspectives and advice for FDA to
  consider in
• completion of its review
• Published data
• Spontaneous post-marketing reports
• Sponsors cumulative clinical data submissions
• possible regulatory actions

5
Considerations

• 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
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
New England Journal of Medicine Publication

• In certain patients, increased risk for
• Renal failure requiring dialysis
• Myocardial infarction or heart failure
• Stroke or encephalopathy

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
Topics

• 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
• Sponsors database
• FDA Adverse Event Reporting System

10

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

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
Outline of Presentation

• Current Trasylol label
• Regulatory history highlights
• New developments

13
Trasylol Current Label

• 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
Trasylol Current Label
Dose and Administration
Regimen Test Dose Loading Dose Pump Prime Constant Infusion
A full dose 10,000 KIU 2 million KIU 2 million KIU 500,000 KIU/hr
B half dose 10,000 KIU 1 million KIU 1 million KIU 250,000 KIU/hr
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 of Patients Receiving Transfusions of Patients Receiving Transfusions
Patients PL Reg A Reg B
Repeat CABG 76 47 49
Primary CABG 54 37 37
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).

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
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
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
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
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
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
Presentation

• Overview of Adverse Event Reporting System (AERS)
• Hypersensitivity findings
• Sponsor
• FDA
• Risk management of Trasylol-associated
  hypersensitivity

24
FDA AERS Database

• Computerized database containing gt 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
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
U.S. Patient Exposure for Trasylol
Source Bayer Analysis of Aprotinin Spontaneous
Data 7/26/06
27
Reporting of Trasylol- associated Hypersensitivity

• Bayer Global Drug Safety Database

28
Overview of Hypersensitivity Sponsor Analysis

• 41 of Bayers worldwide postmarketing safety
  database consists of reports of hypersensitivity
  reactions (306/745)
• 85 reports were coded as anaphylactic
  reaction/anaphylactic shock
• Sponsors review determined 291 hypersensitivity
  cases possibly associated with Trasylol
• 52 of 291 cases were fatal

29
Re-exposure to TrasylolSponsor 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
Test Dose (N139) 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
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
Reporting of Trasylol- associated Anaphylaxis

• FDA Adverse Event Reporting System Database

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
Initial Review of AERS Reporting for Anaphylaxis

• Total reports 70
• Death outcome 23
• Demographics
• Gender (n65) Male (51), Female (41)
• Age (n55) 81 adult and 41 gt60 yrs
• Origin of report
• U.S. 58
• Foreign 12

35
Time to Onset (n49)

• Following test dose 23
• lt10 min 14
• 10-15 min 2
• Unspecified 7
• During Therapeutic dose 26
• During loading dose 15
• During infusion 9
• Unspecified 2

36
Test Dose Administration (n49)

• all fatal
• Reaction after test dose alone 23 10
• Test dose negative-reaction with
• therapeutic dose 20 1
• Test dose result not documented-
• reaction with therapeutic dose 6 1

37
Previous Exposure to Trasylol

• Previous exposure documented 34 (48)
• Timing of previous exposure (n29)
• lt2 mo 9
• 2-4 mo 9
• 4-6 mo 2
• gt6 mo-1 yr 2
• gt 1yr 7
• No previous exposure stated 7 (10)
• Exposure history unknown 29 (41)
• 18/29 cases mentioned previous surgery

38
Indication for Use (n64)

• 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
Clinical Features of Anaphylaxis

• Reported signs of anaphylaxis (n57)
• 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
  (n46)
• Vasopressors (32)
• Steroids (10)
• Antihistamines (7)

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
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 199967837-8

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
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
RiskMAP ToolsSponsors 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
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
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
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
Outline

• Guest Presentations
• Dennis Mangano, MD, PhD
• Keyvan Karkouti, MSc, MD
• Sponsor Presentation
• Public Hearing
• Discussion

49
Questions

• Discussions of
• Unlabeled safety findings from
• Observational studies
• Controlled studies
• Labeled hypersensitivity risks
• Efficacy, in light of current surgical,
  anesthesia and blood transfusion practices
• Overall safety and efficacy/Indication