11
TrasylolTrasylol®®
(aprotinin injection)(aprotinin injection)
Bayer Pharmaceuticals Corp.Bayer Pharmaceuticals Corp.
ND...
22
TrasylolTrasylol®®
(aprotinin injection)(aprotinin injection)
Safety UpdateSafety Update
FDA Cardiovascular andFDA Card...
3
BackgroundBackground
Publications:Publications:
– NEJMNEJM
– TransfusionTransfusion
FDA Public Health AdvisoryFDA Public...
4
PurposePurpose
To obtain perspectives and advice forTo obtain perspectives and advice for
FDA to consider in:FDA to cons...
5
ConsiderationsConsiderations
Published data:Published data:
– Important sourceImportant source
– LimitationsLimitations
...
6
New England Journal of Medicine PublicationNew England Journal of Medicine Publication
““The risk associated with aproti...
7
New England Journal of Medicine PublicationNew England Journal of Medicine Publication
– In certain patients, increased ...
8
Transfusion PublicationTransfusion Publication
""A propensity score case-control comparison ofA propensity score case-co...
9
““Unlabeled” risks: e.g., renal, CVUnlabeled” risks: e.g., renal, CV
– Safety concerns not described in product labelSaf...
10
FDA Summary of “Labeled” RisksFDA Summary of “Labeled” Risks
– Office of New Drugs (OND)Office of New Drugs (OND)
Kathy...
1111
TrasylolTrasylol®®
(aprotinin injection)(aprotinin injection)
Bayer Pharmaceuticals Corp.Bayer Pharmaceuticals Corp.
...
12
Outline of Presentation
Current Trasylol labelCurrent Trasylol label
Regulatory history highlightsRegulatory history hi...
13
Trasylol – Current LabelTrasylol – Current Label
Trasylol is a bovine-sourced protease inhibitor approvedTrasylol is a ...
14
Trasylol – Current LabelTrasylol – Current Label
RegimenRegimen TestTest
DoseDose
LoadingLoading
DoseDose
““PumpPump
Pr...
15
Trasylol – Current LabelTrasylol – Current Label
Clinical Trials: Efficacy
Results from R, DB, PC, U.S. studies showed ...
16
Trasylol – Current LabelTrasylol – Current Label
““Black Box Warning”Black Box Warning”
_______________________________...
17
Trasylol – Current LabelTrasylol – Current Label
Warnings and Precautions
Anaphylactic or anaphylactoid reactions
• Hyp...
18
Trasylol – Current LabelTrasylol – Current Label
Adverse Reactions
Based on placebo controlled U.S. studies (2002 Trasy...
19
Regulatory HistoryRegulatory History
19931993 “for the prophylactic use to reduce“for the prophylactic use to reduce
pe...
20
Regulatory HistoryRegulatory History
19981998 ““For prophylactic use to reduceFor prophylactic use to reduce
perioperat...
21
New DevelopmentsNew Developments
Sponsor NDA submissions and proposals:Sponsor NDA submissions and proposals:
– Cumulat...
22
Post-marketing review ofPost-marketing review of
Hypersensitivity ReactionsHypersensitivity Reactions
associated with T...
23
PresentationPresentation
Overview of Adverse Event ReportingOverview of Adverse Event Reporting
System (AERS)System (AE...
24
FDA AERS DatabaseFDA AERS Database
Computerized database containingComputerized database containing >> 33
million repor...
25
FDA AERS DatabaseFDA AERS Database
LimitationsLimitations
– Lower utility for expected events in an at-Lower utility fo...
26
U.S. Patient Exposure for TrasylolU.S. Patient Exposure for Trasylol
Domestic Patient Exposure by Year
27.9
41 46
56.8
...
2727
Reporting of Trasylol-Reporting of Trasylol-
associated Hypersensitivityassociated Hypersensitivity
Bayer Global Drug...
28
Overview of HypersensitivityOverview of Hypersensitivity
Sponsor AnalysisSponsor Analysis
41% of Bayer’s worldwide post...
29
Re-exposure to TrasylolRe-exposure to Trasylol
Sponsor AnalysisSponsor Analysis
47% (138/291) patients had documented47...
30
Test DoseTest Dose (N=139)(N=139)
Sponsor AnalysisSponsor Analysis
81 cases- reaction with test dose alone81 cases- rea...
31
Summary of Trasylol-associatedSummary of Trasylol-associated
HypersensitivityHypersensitivity
Sponsor AnalysisSponsor A...
3232
Reporting of Trasylol-Reporting of Trasylol-
associated Anaphylaxisassociated Anaphylaxis
FDA Adverse Event Reporting...
33
MethodsMethods
AERS database searched for all reports ofAERS database searched for all reports of
anaphylactic/anaphyla...
34
Initial Review of AERS ReportingInitial Review of AERS Reporting
for Anaphylaxisfor Anaphylaxis
Total reportsTotal repo...
35
Time to OnsetTime to Onset (n=49)(n=49)
Following test doseFollowing test dose 2323
<10 min<10 min 1414
10-15 min10-15 ...
36
Test Dose AdministrationTest Dose Administration (n=49)(n=49)
allall fatalfatal
Reaction afterReaction after test dose ...
37
Previous Exposure to TrasylolPrevious Exposure to Trasylol
Previous exposure documentedPrevious exposure documented 34 ...
38
Indication for UseIndication for Use (n=64)(n=64)
Where indication stated, 25% of patientsWhere indication stated, 25% ...
39
Clinical Features of AnaphylaxisClinical Features of Anaphylaxis
Reported signs of anaphylaxis (n=57)Reported signs of ...
40
Case #1Case #1
(2004)(2004)
Anaphylactic reaction with negative test dose and unknown previousAnaphylactic reaction wit...
41
Case #2Case #2
Near fatal anaphylactic reaction to test dose in patient withNear fatal anaphylactic reaction to test do...
42
Findings from AERS reports ofFindings from AERS reports of
Trasylol associated anaphylaxisTrasylol associated anaphylax...
4343
Sponsor Proposed RiskSponsor Proposed Risk
Minimization Action PlanMinimization Action Plan
(RiskMAP) for Hypersensit...
44
RiskMAP ToolsRiskMAP Tools
Sponsor’s ProposalSponsor’s Proposal
Aprotinin IgG assayAprotinin IgG assay
Education target...
45
Comments on RiskMAPComments on RiskMAP
Clinical utility of Aprotinin IgG AssayClinical utility of Aprotinin IgG Assay
E...
46
AcknowledgementsAcknowledgements
Mark Avigan, MD, Director, Div Drug Risk Evaluation (DDRE)Mark Avigan, MD, Director, D...
4747
TrasylolTrasylol®®
(aprotinin injection)(aprotinin injection)
Bayer Pharmaceuticals Corp.Bayer Pharmaceuticals Corp.
...
48
OutlineOutline
Guest PresentationsGuest Presentations
Dennis Mangano, MD, PhDDennis Mangano, MD, PhD
Keyvan Karkouti, M...
49
QuestionsQuestions
Discussions of:Discussions of:
– ““UnlabeledUnlabeled” safety findings from:” safety findings from:
...
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Trasylol® (aprotinin injection) Safety Update

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  • Trasylol® (aprotinin injection) Safety Update

    1. 1. 11 TrasylolTrasylol®® (aprotinin injection)(aprotinin injection) Bayer Pharmaceuticals Corp.Bayer Pharmaceuticals Corp. NDA 20-304NDA 20-304 Opening RemarksOpening Remarks ______________________ Dwaine Rieves, M.D.Dwaine Rieves, M.D. Deputy DirectorDeputy Director Division of Medical Imaging and HematologyDivision of Medical Imaging and Hematology ProductsProducts Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
    2. 2. 22 TrasylolTrasylol®® (aprotinin injection)(aprotinin injection) Safety UpdateSafety Update FDA Cardiovascular andFDA Cardiovascular and Renal Drugs AdvisoryRenal Drugs Advisory CommitteeCommittee September 21, 2006September 21, 2006
    3. 3. 3 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
    4. 4. 4 PurposePurpose To obtain perspectives and advice forTo obtain perspectives and advice for FDA to consider in:FDA to consider in: – completion of its reviewcompletion of its review Published dataPublished data Spontaneous post-marketing reportsSpontaneous post-marketing reports Sponsor’s cumulative clinical data submissionsSponsor’s cumulative clinical data submissions – possible regulatory actionspossible regulatory actions
    5. 5. 5 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
    6. 6. 6 New England Journal of Medicine PublicationNew England Journal of Medicine Publication ““The risk associated with aprotinin in cardiacThe 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 ofMulti-center, observational study of patients undergoing CABG with CPBpatients 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
    7. 7. 7 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
    8. 8. 8 Transfusion PublicationTransfusion Publication ""A propensity score case-control comparison ofA 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, observationalservational study in highstudy in high transfusion risk patients undergoingtransfusion risk patients undergoing cardiac surgery with CPBcardiac surgery with CPB – Propensity adjustment methodologyPropensity adjustment methodology – Renal dysfunction increasedRenal dysfunction increased
    9. 9. 9 ““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
    10. 10. 10 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 andOffice of Surveillance and Epidemiology (OSE)Epidemiology (OSE) Susan Lu, RPhSusan Lu, RPh
    11. 11. 1111 TrasylolTrasylol®® (aprotinin injection)(aprotinin injection) Bayer Pharmaceuticals Corp.Bayer Pharmaceuticals Corp. NDA 20-304NDA 20-304 Regulatory OverviewRegulatory Overview ______________________ Kathy M. Robie-Suh, M.D., Ph.D.Kathy M. Robie-Suh, M.D., Ph.D. Division of Medical Imaging and HematologyDivision of Medical Imaging and Hematology ProductsProducts Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
    12. 12. 12 Outline of Presentation Current Trasylol labelCurrent Trasylol label Regulatory history highlightsRegulatory history highlights New developmentsNew developments
    13. 13. 13 Trasylol – Current LabelTrasylol – Current Label Trasylol is a bovine-sourced protease inhibitor approvedTrasylol is a bovine-sourced protease inhibitor approved for the following indication:for the following indication: Indication:Indication: ““For prophylactic use to reduceFor prophylactic use to reduce perioperative blood loss and the needperioperative blood loss and the need for blood transfusion in patientsfor blood transfusion in patients undergoing cardiopulmonary bypassundergoing cardiopulmonary bypass (CPB) in the course of coronary artery(CPB) in the course of coronary artery bypass graft (CABG) surgery”bypass graft (CABG) surgery”
    14. 14. 14 Trasylol – Current LabelTrasylol – Current Label RegimenRegimen TestTest DoseDose LoadingLoading DoseDose ““PumpPump Prime”Prime” ConstantConstant InfusionInfusion AA ““full dose”full dose” 10,00010,000 KIUKIU 2 million2 million KIUKIU 2 million2 million KIUKIU 500,000500,000 KIU/hrKIU/hr BB ““half dose”half dose” 10,00010,000 KIUKIU 1 million1 million KIUKIU 1 million1 million KIUKIU 250,000250,000 KIU/hrKIU/hr Dose and Administration:
    15. 15. 15 Trasylol – Current LabelTrasylol – 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): 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%
    16. 16. 16 Trasylol – Current LabelTrasylol – Current Label ““Black Box Warning”Black Box Warning” ____________________________________________________________________________________________ ““Anaphylactic or anaphylactoid reactions areAnaphylactic or anaphylactoid reactions are possible when Trasylol is administered.possible when Trasylol is administered. Hypersensitivity reactions are rare in patients withHypersensitivity reactions are rare in patients with no prior exposure to aprotinin. The risk ofno 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. Theexposed to aprotinin-containing products. The benefit of Trasylol to patients undergoing primarybenefit of Trasylol to patients undergoing primary CABG surgery should be weighed against the risk ofCABG surgery should be weighed against the risk of anaphylaxis should a second exposure to aprotininanaphylaxis should a second exposure to aprotinin be required. (See WARNINGS and PRECAUTIONS).”be required. (See WARNINGS and PRECAUTIONS).”
    17. 17. 17 Trasylol – Current LabelTrasylol – 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. 18 Trasylol – Current LabelTrasylol – 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. 19 Regulatory HistoryRegulatory History 19931993 “for the prophylactic use to reduce“for the prophylactic use to reduce perioperative blood loss and the need forperioperative blood loss and the need for transfusion in patients undergoingtransfusion in patients undergoing cardiopulmonary bypass in the course ofcardiopulmonary bypass in the course of repeatrepeat CABG surgery. Trasylol is also indicated inCABG surgery. Trasylol is also indicated in selected cases of primary CABG surgery whereselected 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 otherhemostasis, e.g., presence of aspirin or other coagulopathy) or where transfusion iscoagulopathy) or where transfusion is unavailable or unacceptable.”unavailable or unacceptable.”
    20. 20. 20 Regulatory HistoryRegulatory History 19981998 ““For prophylactic use to reduceFor prophylactic use to reduce perioperative blood loss and the need forperioperative blood loss and the need for blood transfusion in patients undergoingblood transfusion in patients undergoing cardiopulmonary bypass (CPB) in thecardiopulmonary bypass (CPB) in the course of coronary artery bypass graftcourse of coronary artery bypass graft (CABG) surgery.”(CABG) surgery.” Black box --Black box -- re: anaphylaxis riskre: anaphylaxis risk
    21. 21. 21 New DevelopmentsNew Developments Sponsor NDA submissions and proposals:Sponsor NDA submissions and proposals: – Cumulative clinical study findings showCumulative 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
    22. 22. 22 Post-marketing review ofPost-marketing review of Hypersensitivity ReactionsHypersensitivity Reactions associated with Trasylolassociated with Trasylol®® (Aprotinin injection)(Aprotinin injection) Susan Lu, R.Ph., Safety Evaluator TeamSusan Lu, R.Ph., Safety Evaluator Team LeaderLeader Division of Drug Risk EvaluationDivision of Drug Risk Evaluation Office of Surveillance and EpidemiologyOffice of Surveillance and Epidemiology CDER, FDACDER, FDA
    23. 23. 23 PresentationPresentation Overview of Adverse Event ReportingOverview of Adverse Event Reporting System (AERS)System (AERS) Hypersensitivity findingsHypersensitivity findings – SponsorSponsor – FDAFDA Risk management of Trasylol-associatedRisk management of Trasylol-associated hypersensitivityhypersensitivity
    24. 24. 24 FDA AERS DatabaseFDA AERS Database Computerized database containingComputerized database containing >> 33 million reportsmillion reports Spontaneous reportingSpontaneous reporting – Not required of health care providersNot required of health care providers – Sponsors required to report any adverseSponsors required to report any adverse events of which they become awareevents of which they become aware StrengthsStrengths – Detection of rare but serious adverseDetection of rare but serious adverse events (i.e., anaphylactic reactions)events (i.e., anaphylactic reactions) – Descriptive case seriesDescriptive case series
    25. 25. 25 FDA AERS DatabaseFDA AERS Database LimitationsLimitations – 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 reports Other considerationsOther considerations – No pre-1993 reports for TrasylolNo pre-1993 reports for Trasylol – Limited foreign reportsLimited foreign reports
    26. 26. 26 U.S. Patient Exposure for TrasylolU.S. Patient Exposure for Trasylol Domestic Patient Exposure by Year 27.9 41 46 56.8 68 78 101 131 145 169 189 246 0 50 100 150 200 250 300 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Year Numberofpatients(thousands) Source: Bayer Analysis of Aprotinin Spontaneous Data 7/26/06
    27. 27. 2727 Reporting of Trasylol-Reporting of Trasylol- associated Hypersensitivityassociated Hypersensitivity Bayer Global Drug SafetyBayer Global Drug Safety DatabaseDatabase
    28. 28. 28 Overview of HypersensitivityOverview of Hypersensitivity Sponsor AnalysisSponsor Analysis 41% of Bayer’s worldwide postmarketing41% of Bayer’s worldwide postmarketing safety database consists of reports ofsafety database consists of reports of hypersensitivity reactions (306/745)hypersensitivity reactions (306/745) – 85% reports were coded as anaphylactic85% reports were coded as anaphylactic reaction/anaphylactic shockreaction/anaphylactic shock Sponsor’s review determined 291Sponsor’s review determined 291 hypersensitivity cases possibly associatedhypersensitivity cases possibly associated with Trasylolwith Trasylol 52 of 291 cases were fatal52 of 291 cases were fatal
    29. 29. 29 Re-exposure to TrasylolRe-exposure to Trasylol Sponsor AnalysisSponsor Analysis 47% (138/291) patients had documented47% (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-exposedexposure to Trasylol were re-exposed within 6 monthswithin 6 months
    30. 30. 30 Test DoseTest Dose (N=139)(N=139) Sponsor AnalysisSponsor Analysis 81 cases- reaction with test dose alone81 cases- reaction with test dose alone – 19 fatal19 fatal – 62 non-fatal62 non-fatal 38 cases -negative test dose but hypersensitivity38 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 given 18 cases-test dose given but no result18 cases-test dose given but no result documenteddocumented Sponsor Assessment Report 5/17/06Sponsor Assessment Report 5/17/06
    31. 31. 31 Summary of Trasylol-associatedSummary of Trasylol-associated HypersensitivityHypersensitivity Sponsor AnalysisSponsor Analysis Hypersensitivity reaction is the most frequentlyHypersensitivity reaction is the most frequently reported spontaneous event associated withreported spontaneous event associated with Trasylol.Trasylol. 291 reports of hypersensitivity291 reports of hypersensitivity – 52 fatal52 fatal – 47% patients had history of previous exposure47% patients had history of previous exposure ~2/3~2/3 patients with previous exposure had receivedpatients 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% patientsDespite a negative test dose result, 27% patients experienced a hypersensitivity reactionexperienced a hypersensitivity reaction – The majority of cases occurred in the setting ofThe majority of cases occurred in the setting of surgical procedures other than CABG surgerysurgical procedures other than CABG surgery
    32. 32. 3232 Reporting of Trasylol-Reporting of Trasylol- associated Anaphylaxisassociated Anaphylaxis FDA Adverse Event ReportingFDA Adverse Event Reporting System DatabaseSystem Database
    33. 33. 33 MethodsMethods AERS database searched for all reports ofAERS database searched for all reports of anaphylactic/anaphylactoid and Type 1anaphylactic/anaphylactoid and Type 1 hypersensitivity reactionshypersensitivity reactions Individual review of reports identified fromIndividual review of reports identified from AERS searchAERS search Analysis 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 forinadequate information was provided for assessmentassessment
    34. 34. 34 Initial Review of AERS ReportingInitial Review of AERS Reporting for Anaphylaxisfor Anaphylaxis Total reportsTotal reports 7070 Death outcomeDeath outcome 2323 DemographicsDemographics Gender (n=65)Gender (n=65) Male (51%), Female (41%)Male (51%), Female (41%) Age (n=55)Age (n=55) 81% adult and 41% >60 yrs81% adult and 41% >60 yrs Origin of reportOrigin of report U.S.U.S. 5858 ForeignForeign 1212
    35. 35. 35 Time to OnsetTime to Onset (n=49)(n=49) Following test doseFollowing test dose 2323 <10 min<10 min 1414 10-15 min10-15 min 22 UnspecifiedUnspecified 77 During Therapeutic doseDuring Therapeutic dose 2626 During loading doseDuring loading dose 1515 During infusionDuring infusion 99 UnspecifiedUnspecified 22
    36. 36. 36 Test Dose AdministrationTest Dose Administration (n=49)(n=49) allall fatalfatal Reaction afterReaction after test dose alonetest dose alone 2323 1010 Test doseTest dose negativenegative-reaction with-reaction with therapeutic dosetherapeutic dose 2020 11 Test dose result not documented-Test dose result not documented- reaction with therapeutic dosereaction with therapeutic dose 6 16 1
    37. 37. 37 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 99 4-6 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 *(41%)29 *(41%) *18/29 cases mentioned previous surgery*18/29 cases mentioned previous surgery
    38. 38. 38 Indication for UseIndication for Use (n=64)(n=64) Where indication stated, 25% of patientsWhere indication stated, 25% of patients were receiving Trasylol for the approvedwere receiving Trasylol for the approved indication of CABG surgeryindication of CABG surgery The most frequently reported use for valveThe most frequently reported use for valve surgery (35%)surgery (35%)
    39. 39. 39 Clinical Features of AnaphylaxisClinical 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/ventilatorBronchospasm in 2 cases, changes in airway pressure/ventilator readings in several casesreadings in several cases Dermatologic 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)
    40. 40. 40 Case #1Case #1 (2004)(2004) Anaphylactic reaction with negative test dose and unknown previousAnaphylactic reaction with negative test dose and unknown previous exposure to aprotininexposure to aprotinin 74 year-old female hx of MVR/CABG admitted for redo74 year-old female hx of MVR/CABG admitted for redo mitral valve replacement. Preoperative records of priormitral valve replacement. Preoperative records of prior surgery (7 wks ago) from another hospital revealed nosurgery (7 wks ago) from another hospital revealed no prior aprotinin exposure. After induction of generalprior aprotinin exposure. After induction of general anesthesia, 2 cc test dose Trasylol (negative) givenanesthesia, 2 cc test dose Trasylol (negative) given followed by loading dose. Progressive hypotensionfollowed by loading dose. Progressive hypotension developed followed by bradycardia unresponsive to IVdeveloped followed by bradycardia unresponsive to IV phenylephrine, epi, norepi and atropine. CPR startedphenylephrine, epi, norepi and atropine. CPR started with return of BP/heart rate after 5 min. Surgerywith 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 ofOther hospital again contacted due to high suspicion of aprotinin reaction and anesthetic record confirmedaprotinin reaction and anesthetic record confirmed previous exposure to aprotinin.previous exposure to aprotinin.
    41. 41. 41 Case #2Case #2 Near fatal anaphylactic reaction to test dose in patient withNear fatal anaphylactic reaction to test dose in patient with no previous exposure to aprotininno previous exposure to aprotinin 3.5 year old male with no previous exposure to aprotinin3.5 year old male with no previous exposure to aprotinin admitted for elective replacement of r. ventricularadmitted for elective replacement of r. ventricular pulmonary artery conduit. After induction of anesthesia/pulmonary artery conduit. After induction of anesthesia/ intubation, received 1 ml test dose of aprotinin.intubation, received 1 ml test dose of aprotinin. Immediately BP became undetectable with suddenImmediately BP became undetectable with sudden increase in airway pressures/difficulty maintainingincrease in airway pressures/difficulty maintaining ventilation. CPR initiated with repeated boluses ofventilation. CPR initiated with repeated boluses of epinephrine, sodium bicarbonate and Ca Chloride andepinephrine, sodium bicarbonate and Ca Chloride and also methylprednisolone, diphenhydramine andalso methylprednisolone, diphenhydramine and cimetidine. After 50 min. of CPR, no recovery of cardiaccimetidine. After 50 min. of CPR, no recovery of cardiac function. Cardio-pulmonary bypass instituted and patientfunction. Cardio-pulmonary bypass instituted and patient recovered after 1 hour. Subsequent immuno assaysrecovered after 1 hour. Subsequent immuno assays showed highly elevated IgE levels in response toshowed highly elevated IgE levels in response to aprotinin.aprotinin. Ann Thorac Surg 1999;67:837-8Ann Thorac Surg 1999;67:837-8
    42. 42. 42 Findings from AERS reports ofFindings from AERS reports of Trasylol associated anaphylaxisTrasylol associated anaphylaxis Test doseTest dose 43% of fatal cases associated with test dose43% of fatal cases associated with test dose 40% of patients who were documented to have received40% of patients who were documented to have received a test dose experienced an anaphylactic reaction despitea test dose experienced an anaphylactic reaction despite negative test dose resultnegative test dose result Previous ExposurePrevious Exposure 48% of patients had previous exposure to aprotinin48% 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 aprotinin10% patients had no previous exposure to aprotinin Severity of presentationSeverity of presentation Cardiovascular events (hypotension, cardiac arrest)Cardiovascular events (hypotension, cardiac arrest) reported predominantlyreported predominantly Indication for UseIndication for Use 25% patients received Trasylol for approved indication25% patients received Trasylol for approved indication
    43. 43. 4343 Sponsor Proposed RiskSponsor Proposed Risk Minimization Action PlanMinimization Action Plan (RiskMAP) for Hypersensitivity(RiskMAP) for Hypersensitivity Stated goal-Stated goal- “The RiskMAP will identify those“The RiskMAP will identify those patients most at risk of apatients most at risk of a hypersensitivity reaction to Trasylolhypersensitivity reaction to Trasylol and provide information to reduceand provide information to reduce these patients from re-exposure tothese patients from re-exposure to the drug within the period ofthe drug within the period of highest risk of hypersensitivity”highest risk of hypersensitivity”
    44. 44. 44 RiskMAP ToolsRiskMAP Tools Sponsor’s ProposalSponsor’s Proposal Aprotinin IgG assayAprotinin IgG assay Education targeted at physiciansEducation targeted at physicians Appropriate indication for useAppropriate indication for use Risk of hypersensitivity high with re-exposureRisk of hypersensitivity high with re-exposure within 6 monthswithin 6 months Complete medical history to uncover previousComplete 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
    45. 45. 45 Comments on RiskMAPComments on RiskMAP Clinical utility of Aprotinin IgG AssayClinical utility of Aprotinin IgG Assay Educational message may not mitigate riskEducational message may not mitigate risk – Value of test doseValue of test dose Test dose frequently not predictiveTest dose frequently not predictive Serious reactions occur with test doseSerious reactions occur with test dose – Medical history may not uncover previous exposureMedical history may not uncover previous exposure Patients not often aware of exposures to drugs during surgeryPatients not often aware of exposures to drugs during surgery May 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 setting Non-cardiovascular symptoms (e.g., nausea, dyspnea, and skinNon-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
    46. 46. 46 AcknowledgementsAcknowledgements Mark 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 Leader Tiffany Brown, DMIHP Project ManagerTiffany Brown, DMIHP Project Manager Yuan (Richard) Chen, PhD, Statistician, OB, OTSYuan (Richard) Chen, PhD, Statistician, OB, OTS Gerald Dal Pan, MD, Director, OSEGerald Dal Pan, MD, Director, OSE Mary Dempsey, Project Manager, OSEMary Dempsey, Project Manager, OSE Rosemary Johann-Liang, MD, DDRE Dep Division DirectorRosemary Johann-Liang, MD, DDRE Dep Division Director Claudia Karwoski PharmD, OSE Scientific CoordinatorClaudia Karwoski PharmD, OSE Scientific Coordinator Cindy Kortepeter PharmD, DDRE SE Team LeaderCindy Kortepeter PharmD, DDRE SE Team Leader Parivash Nourjah PhD, DDRE EpidemiologistParivash Nourjah PhD, DDRE Epidemiologist Dwaine Rieves, MD, DMIHP, Dep DirectorDwaine Rieves, MD, DMIHP, Dep Director Kathy Robie-Suh, MD, PhD, DMIHP Medical Team LeaderKathy Robie-Suh, MD, PhD, DMIHP Medical Team Leader George Rochester, PhD, Statistical Team Leader, OB, OTSGeorge Rochester, PhD, Statistical Team Leader, OB, OTS George Shashaty, MD, DMIHP Medical OfficerGeorge Shashaty, MD, DMIHP Medical Officer Mary Ross Southworth PharmD, DDRE Safety EvaluatorMary Ross Southworth PharmD, DDRE Safety Evaluator Joyce Weaver PharmD, OSE Drug Risk Management AnalystJoyce Weaver PharmD, OSE Drug Risk Management Analyst Mike Welch, PhD, Associate Director, OB, OTSMike Welch, PhD, Associate Director, OB, OTS Jyoti Zalkikar, PhD, Statistical Team Leader, OB, OTSJyoti Zalkikar, PhD, Statistical Team Leader, OB, OTS
    47. 47. 4747 TrasylolTrasylol®® (aprotinin injection)(aprotinin injection) Bayer Pharmaceuticals Corp.Bayer Pharmaceuticals Corp. NDA 20-304NDA 20-304 FDA Topics of DiscussionFDA Topics of Discussion ______________________ Dwaine Rieves, M.D.Dwaine Rieves, M.D. Deputy DirectorDeputy Director Division of Medical Imaging and HematologyDivision of Medical Imaging and Hematology ProductsProducts Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
    48. 48. 48 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
    49. 49. 49 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 transfusionanesthesia and blood transfusion practicespractices – Overall safety and efficacy/IndicationOverall safety and efficacy/Indication
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