Trasylol® (aprotinin injection) Safety Update

11

TrasylolTrasylol® ® (aprotinin injection)(aprotinin injection)

Bayer Pharmaceuticals Corp. Bayer Pharmaceuticals Corp. NDA 20-304 NDA 20-304

Opening RemarksOpening Remarks

______________________Dwaine Rieves, M.D.Dwaine Rieves, M.D.

Deputy DirectorDeputy DirectorDivision of Medical Imaging and Hematology Division of Medical Imaging and Hematology

ProductsProducts

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

22

TrasylolTrasylol®® (aprotinin injection)(aprotinin injection)

Safety UpdateSafety Update

FDA Cardiovascular and FDA Cardiovascular and

Renal Drugs Advisory Renal Drugs Advisory

CommitteeCommittee

September 21, 2006September 21, 2006

33

BackgroundBackground

Publications:Publications:– NEJMNEJM– TransfusionTransfusion

FDA Public Health AdvisoryFDA Public Health Advisory

Sponsor’s review/FDA submissionsSponsor’s review/FDA submissions

Advisory CommitteeAdvisory Committee

Completion of FDA reviewCompletion of FDA review

ActionsActions

44

PurposePurpose

To obtain perspectives and advice for To obtain perspectives and advice for FDA to consider in:FDA to consider in:

– completion of its review completion of its review

Published dataPublished data

Spontaneous post-marketing reports Spontaneous post-marketing reports

Sponsor’s cumulative clinical data submissions Sponsor’s cumulative clinical data submissions

– possible regulatory actionspossible regulatory actions

55

ConsiderationsConsiderations

Published data:Published data:

– Important sourceImportant source

– LimitationsLimitations

– Data integrity/conclusions/opinionsData integrity/conclusions/opinions

Assumed by authors/publisherAssumed by authors/publisher

Not FDANot FDA

““Off-label” use of marketed drugs:Off-label” use of marketed drugs:

– Practice of medicinePractice of medicine

– Variable evidence of safety and efficacyVariable evidence of safety and efficacy

66

New England Journal of Medicine PublicationNew England Journal of Medicine Publication

““The risk associated with aprotinin in cardiac The risk associated with aprotinin in cardiac surgery” surgery”

NEJM 354(4): 353-365 (Jan 26, 2006)NEJM 354(4): 353-365 (Jan 26, 2006)

– Multi-center, observational study of Multi-center, observational study of patients undergoing CABG with CPB patients undergoing CABG with CPB

– Compared aprotinin, aminocaproic acid, Compared aprotinin, aminocaproic acid, tranexamic acid, no hemostatic drugtranexamic acid, no hemostatic drug

– Propensity adjustment methodologyPropensity adjustment methodology

77

New England Journal of Medicine PublicationNew England Journal of Medicine Publication

– In certain patients, increased risk for:In certain patients, increased risk for:

Renal failure requiring dialysisRenal failure requiring dialysis

Myocardial infarction or heart failureMyocardial infarction or heart failure

Stroke or encephalopathyStroke or encephalopathy

88

Transfusion PublicationTransfusion Publication

""A propensity score case-control comparison of A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery” risk cardiac surgery”

Transfusion 46(3): 327-338 (January 20, 2006; March 2006)Transfusion 46(3): 327-338 (January 20, 2006; March 2006)

– Single-center, obSingle-center, observational servational study in high study in high transfusion risk patients undergoing transfusion risk patients undergoing cardiac surgery with CPBcardiac surgery with CPB

– Propensity adjustment methodologyPropensity adjustment methodology

– Renal dysfunction increased Renal dysfunction increased

99

““Unlabeled” risks: e.g., renal, CVUnlabeled” risks: e.g., renal, CV– Safety concerns not described in product labelSafety concerns not described in product label– New findings from:New findings from:

Observational studiesObservational studies

Controlled clinical studiesControlled clinical studies

““Labeled” risks: HypersensitivityLabeled” risks: Hypersensitivity– Safety concerns described in product labelSafety concerns described in product label– New summary from:New summary from:

Sponsor’s databaseSponsor’s database

FDA Adverse Event Reporting SystemFDA Adverse Event Reporting System

Topics

1010

FDA Summary of “Labeled” RisksFDA Summary of “Labeled” Risks

– Office of New Drugs (OND)Office of New Drugs (OND)

Kathy Robie-Suh, MD, PhDKathy Robie-Suh, MD, PhD

– Office of Surveillance and Office of Surveillance and Epidemiology (OSE)Epidemiology (OSE)

Susan Lu, RPhSusan Lu, RPh

1111



Regulatory OverviewRegulatory Overview

______________________Kathy M. Robie-Suh, M.D., Ph.D. Kathy M. Robie-Suh, M.D., Ph.D.

Division of Medical Imaging and Hematology Division of Medical Imaging and Hematology ProductsProducts


1212

Outline of Presentation

Current Trasylol labelCurrent Trasylol label

Regulatory history highlightsRegulatory history highlights

New developmentsNew developments

1313

Trasylol – Current LabelTrasylol – Current Label

Trasylol is a bovine-sourced protease inhibitor approved Trasylol is a bovine-sourced protease inhibitor approved

for the following indication:for the following indication:

Indication:Indication:““For prophylactic use to reduce For prophylactic use to reduce perioperative blood loss and the need perioperative blood loss and the need for blood transfusion in patients for blood transfusion in patients undergoing cardiopulmonary bypass undergoing cardiopulmonary bypass (CPB) in the course of coronary artery (CPB) in the course of coronary artery bypass graft (CABG) surgery”bypass graft (CABG) surgery”

1414


RegimenRegimen Test Test DoseDose

Loading Loading DoseDose

““Pump Pump Prime”Prime”

Constant Constant InfusionInfusion

A A

““full dose”full dose”

10,000 10,000 KIUKIU

2 million 2 million KIUKIU


500,000 500,000 KIU/hrKIU/hr

B B

““half dose”half dose”

10,000 10,000 KIUKIU



250,000 250,000 KIU/hrKIU/hr

Dose and Administration:

1515


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):

PatientsPatients % of Patients Receiving % of Patients Receiving TransfusionsTransfusions

PLPL Reg AReg A Reg BReg B

Repeat CABGRepeat CABG 76%76% 47%47% 49%49%

Primary CABGPrimary CABG 54%54% 37%37% 37%37%

1616


““Black Box Warning”Black Box Warning”

____________________________________________________________________________________________

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

1717


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

1818


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

1919

Regulatory HistoryRegulatory History

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

2020

Regulatory HistoryRegulatory History

19981998 ““For prophylactic use to reduce For prophylactic use to reduce perioperative blood loss and the need for perioperative blood loss and the need for blood transfusion in patients undergoing blood transfusion in patients undergoing cardiopulmonary bypass (CPB) in the cardiopulmonary bypass (CPB) in the course of coronary artery bypass graft course of coronary artery bypass graft (CABG) surgery.”(CABG) surgery.”

Black box -- Black box -- re: anaphylaxis riskre: anaphylaxis risk

2121

New DevelopmentsNew Developments

Sponsor NDA submissions and proposals:Sponsor NDA submissions and proposals:

– Cumulative clinical study findings show Cumulative clinical study findings show increased risk for renal dysfunctionincreased risk for renal dysfunction

– Proposed modifications to the labelProposed modifications to the label

– Other plansOther plans

2222

Post-marketing review of Post-marketing review of Hypersensitivity Reactions Hypersensitivity Reactions associated with Trasylolassociated with Trasylol®®

(Aprotinin injection)(Aprotinin injection)

Susan Lu, R.Ph., Safety Evaluator Team Susan Lu, R.Ph., Safety Evaluator Team LeaderLeader

Division of Drug Risk EvaluationDivision of Drug Risk EvaluationOffice of Surveillance and EpidemiologyOffice of Surveillance and Epidemiology

CDER, FDACDER, FDA

2323

PresentationPresentation

Overview of Adverse Event Reporting Overview of Adverse Event Reporting System (AERS)System (AERS)

Hypersensitivity findings Hypersensitivity findings – SponsorSponsor– FDAFDA

Risk management of Trasylol-associated Risk management of Trasylol-associated hypersensitivityhypersensitivity

2424

FDA AERS Database FDA AERS Database

Computerized database containing Computerized database containing >> 3 3 million reportsmillion reportsSpontaneous reportingSpontaneous reporting– Not required of health care providersNot required of health care providers– Sponsors required to report any adverse Sponsors required to report any adverse

events of which they become awareevents of which they become awareStrengthsStrengths– Detection of rare but serious adverse Detection of rare but serious adverse

events (i.e., anaphylactic reactions)events (i.e., anaphylactic reactions)– Descriptive case seriesDescriptive case series

2525

FDA AERS Database FDA AERS Database

Limitations Limitations – Lower utility for expected events in an at-Lower utility for expected events in an at-

risk population (renal failure, MI, CHF)risk population (renal failure, MI, CHF)– UnderreportingUnderreporting– Biases in reportingBiases in reporting– Quality of reportsQuality of reportsOther considerationsOther considerations– No pre-1993 reports for TrasylolNo pre-1993 reports for Trasylol– Limited foreign reports Limited foreign reports

2626

U.S. Patient Exposure for TrasylolU.S. Patient Exposure for Trasylol

Domestic Patient Exposure by Year

27.941 46 56.8 68 78

101

131145

169189

246

0

50

100

150

200

250

300

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

Year

Nu

mb

er o

f p

atie

nts

(th

ou

san

ds)

Source: Bayer Analysis of Aprotinin Spontaneous Data 7/26/06

2727

Reporting of Trasylol- Reporting of Trasylol- associated Hypersensitivityassociated Hypersensitivity

Bayer Global Drug Safety Bayer Global Drug Safety DatabaseDatabase

2828

Overview of Hypersensitivity Overview of Hypersensitivity Sponsor AnalysisSponsor Analysis

41% of Bayer’s worldwide postmarketing 41% of Bayer’s worldwide postmarketing safety database consists of reports of safety database consists of reports of hypersensitivity reactions (306/745)hypersensitivity reactions (306/745)– 85% reports were coded as anaphylactic 85% reports were coded as anaphylactic

reaction/anaphylactic shockreaction/anaphylactic shock

Sponsor’s review determined 291 Sponsor’s review determined 291 hypersensitivity cases possibly associated hypersensitivity cases possibly associated with Trasylolwith Trasylol52 of 291 cases were fatal52 of 291 cases were fatal

2929

Re-exposure to TrasylolRe-exposure to TrasylolSponsor AnalysisSponsor Analysis

47% (138/291) patients had documented 47% (138/291) patients had documented previous exposure to Trasylolprevious exposure to Trasylol

67% (93/138) cases with reported re- 67% (93/138) cases with reported re- exposure to Trasylol were re-exposed exposure to Trasylol were re-exposed within 6 months within 6 months

3030

Test Dose Test Dose (N=139)(N=139)

Sponsor Analysis Sponsor Analysis

81 cases- reaction with test dose alone 81 cases- reaction with test dose alone – 19 fatal19 fatal– 62 non-fatal62 non-fatal

38 cases -negative test dose but hypersensitivity 38 cases -negative test dose but hypersensitivity reaction with therapeutic dosereaction with therapeutic dose– 9 fatal9 fatal– 29 non-fatal29 non-fatal

2 cases- positive test dose, infusion given2 cases- positive test dose, infusion given18 cases-test dose given but no result 18 cases-test dose given but no result documenteddocumented

Sponsor Assessment Report 5/17/06Sponsor Assessment Report 5/17/06

3131

Summary of Trasylol-associated Summary of Trasylol-associated HypersensitivityHypersensitivity

Sponsor Analysis Sponsor Analysis

Hypersensitivity reaction is the most frequently Hypersensitivity reaction is the most frequently reported spontaneous event associated with reported spontaneous event associated with Trasylol.Trasylol.291 reports of hypersensitivity 291 reports of hypersensitivity – 52 fatal52 fatal– 47% patients had history of previous exposure 47% patients had history of previous exposure

~2/3~2/3 patients with previous exposure had received patients with previous exposure had received aprotinin in previous 6 monthsaprotinin in previous 6 months

– Test dose associated with 19 fatalitiesTest dose associated with 19 fatalities– Despite a negative test dose result, 27% patients Despite a negative test dose result, 27% patients

experienced a hypersensitivity reaction experienced a hypersensitivity reaction – The majority of cases occurred in the setting of The majority of cases occurred in the setting of

surgical procedures other than CABG surgerysurgical procedures other than CABG surgery

3232

Reporting of Trasylol- Reporting of Trasylol- associated Anaphylaxisassociated Anaphylaxis

FDA Adverse Event Reporting FDA Adverse Event Reporting System DatabaseSystem Database

3333

MethodsMethods

AERS database searched for all reports of AERS database searched for all reports of anaphylactic/anaphylactoid and Type 1 anaphylactic/anaphylactoid and Type 1 hypersensitivity reactionshypersensitivity reactionsIndividual review of reports identified from Individual review of reports identified from AERS searchAERS searchAnalysis excluded reports in which:Analysis excluded reports in which:– reaction was most likely due to another causereaction was most likely due to another cause– inadequate information was provided for inadequate information was provided for

assessmentassessment

3434

Initial Review of AERS Reporting Initial Review of AERS Reporting for Anaphylaxis for Anaphylaxis

Total reportsTotal reports 7070

Death outcomeDeath outcome 2323

DemographicsDemographicsGender (n=65)Gender (n=65) Male (51%), Female (41%) Male (51%), Female (41%)

Age (n=55)Age (n=55) 81% adult and 41% >60 81% adult and 41% >60 yrsyrs

Origin of reportOrigin of reportU.S.U.S. 5858ForeignForeign 1212

3535

Time to Onset Time to Onset (n=49)(n=49)

Following test doseFollowing test dose 23 23 <10 min<10 min 14 1410-15 min10-15 min 2 2UnspecifiedUnspecified 7 7

During Therapeutic doseDuring Therapeutic dose 26 26 During loading doseDuring loading dose 15 15During infusionDuring infusion 9 9UnspecifiedUnspecified 2 2

3636

Test Dose Administration Test Dose Administration (n=49)(n=49)

allall fatalfatal

Reaction after Reaction after test dose alonetest dose alone 2323 10 10

Test dose Test dose negativenegative-reaction with-reaction with

therapeutic dosetherapeutic dose 2020 1 1

Test dose result not documented-Test dose result not documented-

reaction with therapeutic dosereaction with therapeutic dose 6 1 6 1

3737

Previous Exposure to TrasylolPrevious Exposure to Trasylol

Previous exposure documentedPrevious exposure documented 34 (48%)34 (48%)– Timing of previous exposure (n=29)Timing of previous exposure (n=29)

<2 mo<2 mo 99

2-4 mo2-4 mo 994-6 mo4-6 mo 22>6 mo-1 yr>6 mo-1 yr 22> 1yr> 1yr 77

No previous exposure statedNo previous exposure stated 7 (10%) 7 (10%)Exposure history unknownExposure history unknown 29 29 *(41%)*(41%)

*18/29 cases mentioned previous surgery*18/29 cases mentioned previous surgery

3838

Indication for Use Indication for Use (n=64)(n=64)

Where indication stated, 25% of patients Where indication stated, 25% of patients were receiving Trasylol for the approved were receiving Trasylol for the approved indication of CABG surgeryindication of CABG surgery

The most frequently reported use for valve The most frequently reported use for valve surgery (35%)surgery (35%)

3939

Clinical Features of Anaphylaxis Clinical Features of Anaphylaxis

Reported signs of anaphylaxis (n=57)Reported signs of anaphylaxis (n=57)Cardiovascular events (53)Cardiovascular events (53)– Hypotension (45)Hypotension (45)– Cardiac arrest/CV collapse (13)Cardiac arrest/CV collapse (13)

Respiratory events (11)Respiratory events (11)– Bronchospasm in 2 cases, changes in airway pressure/ventilator Bronchospasm in 2 cases, changes in airway pressure/ventilator

readings in several casesreadings in several casesDermatologic events (10)Dermatologic events (10)– Erythema (5)Erythema (5)– Rash (5)Rash (5)

Most commonly reported treatment for anaphylaxis (n=46)Most commonly reported treatment for anaphylaxis (n=46) Vasopressors (32)Vasopressors (32)Steroids (10)Steroids (10)Antihistamines (7)Antihistamines (7)

4040

Case #1 Case #1 (2004)(2004)

Anaphylactic reaction with negative test dose and unknown previous Anaphylactic reaction with negative test dose and unknown previous exposure to aprotininexposure to aprotinin

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

4141

Case #2Case #2Near fatal anaphylactic reaction to test dose in patient with no Near fatal anaphylactic reaction to test dose in patient with no

previous exposure to aprotininprevious exposure to aprotinin

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

Ann Thorac Surg 1999;67:837-8Ann Thorac Surg 1999;67:837-8

4242

Findings from AERS reports of Findings from AERS reports of Trasylol associated anaphylaxisTrasylol associated anaphylaxis

Test doseTest dose43% of fatal cases associated with test dose 43% of fatal cases associated with test dose 40% of patients who were documented to have received a 40% of patients who were documented to have received a test dose experienced an anaphylactic reaction despite test dose experienced an anaphylactic reaction despite negative test dose result negative test dose result

Previous ExposurePrevious Exposure48% of patients had previous exposure to aprotinin 48% of patients had previous exposure to aprotinin – 67% of patients had been re-exposed within 6 months67% of patients had been re-exposed within 6 months

10% patients had no previous exposure to aprotinin 10% patients had no previous exposure to aprotinin Severity of presentationSeverity of presentation

Cardiovascular events (hypotension, cardiac arrest) reported Cardiovascular events (hypotension, cardiac arrest) reported predominantlypredominantly

Indication for UseIndication for Use25% patients received Trasylol for approved indication25% patients received Trasylol for approved indication

4343

Sponsor Proposed Risk Sponsor Proposed Risk Minimization Action Plan Minimization Action Plan

(RiskMAP) for Hypersensitivity(RiskMAP) for HypersensitivityStated goal- Stated goal-

“The RiskMAP will identify those “The RiskMAP will identify those patients most at risk of a patients most at risk of a hypersensitivity reaction to Trasylol hypersensitivity reaction to Trasylol and provide information to reduce and provide information to reduce these patients from re-exposure to these patients from re-exposure to the drug within the period of the drug within the period of highest risk of hypersensitivity”highest risk of hypersensitivity”

4444

RiskMAP ToolsRiskMAP ToolsSponsor’s ProposalSponsor’s Proposal

Aprotinin IgG assayAprotinin IgG assay

Education targeted at physiciansEducation targeted at physiciansAppropriate indication for useAppropriate indication for use

Risk of hypersensitivity high with re-exposure Risk of hypersensitivity high with re-exposure within 6 months within 6 months

Complete medical history to uncover previous Complete medical history to uncover previous exposureexposure

Use of test doseUse of test dose

Readiness for handling hypersensitivity reactionsReadiness for handling hypersensitivity reactions

Information on cross-reacting productsInformation on cross-reacting products

4545

Comments on RiskMAPComments on RiskMAP

Clinical utility of Aprotinin IgG Assay Clinical utility of Aprotinin IgG Assay Educational message may not mitigate riskEducational message may not mitigate risk– Value of test dose Value of test dose

Test dose frequently not predictiveTest dose frequently not predictiveSerious reactions occur with test doseSerious reactions occur with test dose

– Medical history may not uncover previous exposureMedical history may not uncover previous exposurePatients not often aware of exposures to drugs during surgeryPatients not often aware of exposures to drugs during surgeryMay not be part of a medical recordMay not be part of a medical record

– Reactions may not be recognized in the surgical settingReactions may not be recognized in the surgical settingNon-cardiovascular symptoms (e.g., nausea, dyspnea, and skin Non-cardiovascular symptoms (e.g., nausea, dyspnea, and skin reactions) may not be detected. reactions) may not be detected. First recognizable sign may be circulatory failureFirst recognizable sign may be circulatory failure

4646

AcknowledgementsAcknowledgementsMark Avigan, MD, Director, Div Drug Risk Evaluation (DDRE)Mark Avigan, MD, Director, Div Drug Risk Evaluation (DDRE)Allen Brinker MD, DDRE Epidemiology Team LeaderAllen Brinker MD, DDRE Epidemiology Team LeaderTiffany Brown, DMIHP Project Manager Tiffany Brown, DMIHP Project Manager Yuan (Richard) Chen, PhD, Statistician, OB, OTSYuan (Richard) Chen, PhD, Statistician, OB, OTSGerald Dal Pan, MD, Director, OSEGerald Dal Pan, MD, Director, OSEMary Dempsey, Project Manager, OSEMary Dempsey, Project Manager, OSERosemary Johann-Liang, MD, DDRE Dep Division DirectorRosemary Johann-Liang, MD, DDRE Dep Division DirectorClaudia Karwoski PharmD, OSE Scientific CoordinatorClaudia Karwoski PharmD, OSE Scientific CoordinatorCindy Kortepeter PharmD, DDRE SE Team LeaderCindy Kortepeter PharmD, DDRE SE Team LeaderParivash Nourjah PhD, DDRE EpidemiologistParivash Nourjah PhD, DDRE EpidemiologistDwaine Rieves, MD, DMIHP, Dep DirectorDwaine Rieves, MD, DMIHP, Dep DirectorKathy Robie-Suh, MD, PhD, DMIHP Medical Team LeaderKathy Robie-Suh, MD, PhD, DMIHP Medical Team LeaderGeorge Rochester, PhD, Statistical Team Leader, OB, OTSGeorge Rochester, PhD, Statistical Team Leader, OB, OTSGeorge Shashaty, MD, DMIHP Medical OfficerGeorge Shashaty, MD, DMIHP Medical OfficerMary Ross Southworth PharmD, DDRE Safety EvaluatorMary Ross Southworth PharmD, DDRE Safety EvaluatorJoyce Weaver PharmD, OSE Drug Risk Management AnalystJoyce Weaver PharmD, OSE Drug Risk Management AnalystMike Welch, PhD, Associate Director, OB, OTSMike Welch, PhD, Associate Director, OB, OTSJyoti Zalkikar, PhD, Statistical Team Leader, OB, OTSJyoti Zalkikar, PhD, Statistical Team Leader, OB, OTS

4747



FDA Topics of DiscussionFDA Topics of Discussion

______________________

Dwaine Rieves, M.D.Dwaine Rieves, M.D.Deputy DirectorDeputy Director

Division of Medical Imaging and Hematology Division of Medical Imaging and Hematology ProductsProducts


4848

OutlineOutline

Guest PresentationsGuest Presentations

Dennis Mangano, MD, PhDDennis Mangano, MD, PhD

Keyvan Karkouti, MSc, MDKeyvan Karkouti, MSc, MD

Sponsor PresentationSponsor Presentation

Public HearingPublic Hearing

DiscussionDiscussion

4949

QuestionsQuestions

Discussions of:Discussions of:

– ““UnlabeledUnlabeled” safety findings from:” safety findings from:

Observational studiesObservational studies

Controlled studiesControlled studies

– ““LabeledLabeled” hypersensitivity risks” hypersensitivity risks

– Efficacy, in light of current surgical, Efficacy, in light of current surgical, anesthesia and blood transfusion anesthesia and blood transfusion practicespractices

– Overall safety and efficacy/Indication Overall safety and efficacy/Indication

Documents

Trasylol® (aprotinin injection) Safety Update