AGGRENOXAGGRENOXTM TM SafetySafety

Head, Drug Surveillance and InformationHead, Drug Surveillance and InformationBoehringer Ingelheim Pharmaceuticals, Inc.Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, ConnecticutRidgefield, Connecticut

Kenneth Rakowski, MDKenneth Rakowski, MD

Are there any particular safety Are there any particular safety concerns with the use of concerns with the use of

AGGRENOXAGGRENOXTMTM??

Safety Profile of AGGRENOXSafety Profile of AGGRENOXTMTM

SummarySummary

No unexpected adverse effectsNo unexpected adverse effects

Expected adverse effects are establishedExpected adverse effects are establishedfor the two componentsfor the two components

Benefit/risk is favorableBenefit/risk is favorable

Central & Peripheral Nervous Central & Peripheral Nervous 49.8 49.8 53.9 53.9 50.650.6 55.155.1System DisordersSystem Disorders

HeadacheHeadache 32.932.9 38.3 38.3 33.833.8 39.239.2Gastro-Intestinal System DisordersGastro-Intestinal System Disorders 36.436.4 41.8 41.8 37.737.7 43.743.7

DyspepsiaDyspepsia 16.716.7 17.4 17.4 18.118.1 18.418.4Abdominal painAbdominal pain 14.514.5 15.4 15.4 15.915.9 17.517.5NauseaNausea 14.114.1 15.4 15.4 12.7 12.7 16.016.0DiarrheaDiarrhea 9.89.8 15.5 15.5 6.86.8 12.712.7VomitingVomiting 7.27.2 7.8 7.8 6.16.1 8.48.4MelenaMelena 0.80.8 0.6 0.6 1.21.2 1.91.9

Platelet, Bleeding & Clotting DisordersPlatelet, Bleeding & Clotting Disorders 5.35.3 4.4 4.4 7.77.7 7.97.9Hemorrhage NOSHemorrhage NOS 1.51.5 1.5 1.5 2.82.8 3.23.2PurpuraPurpura 0.40.4 0.5 0.5 0.50.5 1.41.4

Red Blood Cell DisordersRed Blood Cell Disorders 0.70.7 1.0 1.0 1.31.3 1.81.8AnemiaAnemia 0.50.5 1.0 1.0 1.21.2 1.61.6

Placebo Placebo DP AloneDP Alone ASA AloneASA Alone AGGRENOX™ AGGRENOX™ Body System/Preferred Term Body System/Preferred Term (%)(%) (%)(%) (%)(%) (%)(%)

On-Treatment Adverse Events With an Incidence in the AGGRENOXOn-Treatment Adverse Events With an Incidence in the AGGRENOXTMTM Group Group Exceeding That in the Placebo Group by 1% or MoreExceeding That in the Placebo Group by 1% or More

Individual Treatment GroupIndividual Treatment Group

Total No. of Patients Total No. of Patients 16491649 1654 1649 1654 1649 1650 1650

Total No. of Patients With Total No. of Patients With 1 AE1 AE 13041304 (79.1)(79.1) 1305 1305 (78.9)(78.9) 13231323 (80.2)(80.2) 13191319 (79.9) (79.9)

Incidence of Most Common Adverse Events Associated Incidence of Most Common Adverse Events Associated With Treatment CessationWith Treatment Cessation

Treatment GroupsTreatment Groups

Total Number of PatientsTotal Number of Patients 16491649 1650 1650 16491649 16541654

Patients With at Least One AEPatients With at Least One AEAssociated With TreatmentAssociated With Treatment 2121 25 25 1919 2525

Cessation Cessation HeadacheHeadache 44 10 10 33 1010DizzinessDizziness 44 6 6 44 55NauseaNausea 33 6 6 33 66Abdominal painAbdominal pain 33 4 4 33 44DyspepsiaDyspepsia 33 4 4 33 44VomitingVomiting 11 3 3 22 33DiarrheaDiarrhea <1<1 22 <1<1 22StrokeStroke 44 3 3 33 22Transient ischemic attackTransient ischemic attack 33 22 22 22Angina pectorisAngina pectoris 22 11 <1<1 11Myocardial infarctionMyocardial infarction 11 <1<1 <1<1 <1<1

PlaceboPlacebo DPDP ASAASA AGGRENOX™ AGGRENOX™ %% %% %% %%

Potential InteractionsPotential Interactions

Drug-DiseaseDrug-Disease

No clinically significant differencesNo clinically significant differences

Drug-DemographicsDrug-Demographics

No clinically significant differencesNo clinically significant differences

Laboratory AnalysesLaboratory Analyses

No clinically significant effects in any groupNo clinically significant effects in any group

Hematology, indices of kidney function, presenceHematology, indices of kidney function, presenceof abnormal or normal liver function, fasting glucose, of abnormal or normal liver function, fasting glucose, total cholesterol, LDL cholesterol assessedtotal cholesterol, LDL cholesterol assessed

HeadachesHeadaches <0.001<0.001

Gastro-Intestinal EventsGastro-Intestinal Events <0.001<0.001NauseaNausea 0.0090.009

DiarrheaDiarrhea <0.001<0.001 <0.001<0.001

VomitingVomiting 0.0270.027

Bleeding EventsBleeding Events <0.001<0.001

UlcersUlcers 0.0590.059

Common Adverse Events of DP and ASA Common Adverse Events of DP and ASA Confirmed by Factorial AnalysisConfirmed by Factorial Analysis

Body System/Body System/ DP MainDP Main ASA ASAPreferred TermPreferred Term EffectEffect EffectEffect

Factorial Factorial AnalysisAnalysis

SignificantSignificantPP-Values-Values

Incidence of On-Treatment Adverse Events (Incidence of On-Treatment Adverse Events (1%)1%)Bleeding Events and UlcersBleeding Events and Ulcers

Total No. of PatientsTotal No. of Patients 1649 1654 1649 1650 1649 1654 1649 1650

Total No. of PatientsTotal No. of Patients 13041304 (79.1)(79.1) 1305 1305 (78.9)(78.9) 13231323 (80.2)(80.2) 13191319 (79.9)(79.9)With With 1 Adverse Event 1 Adverse Event

Bleeding EventsBleeding Events 9292 (6)(6) 94 94 (6) (6) 160160 (10)(10) 171171 (10)(10)EpistaxisEpistaxis 25 25 (1.5)(1.5) 16 16 (1.0) (1.0) 4545 (2.7)(2.7) 3939 (2.4)(2.4)PurpuraPurpura 7 7 (0.4)(0.4) 8 8 (0.5)(0.5) 99 (0.5)(0.5) 2323 (1.4)(1.4)MelenaMelena 13 13 (0.8)(0.8) 10 10 (0.6)(0.6) 2020 (1.2)(1.2) 3131 (1.9)(1.9)GI hemorrhageGI hemorrhage 7 7 (0.4)(0.4) 5 5 (0.3)(0.3) 1515 (0.9)(0.9) 2020 (1.2)(1.2)Rectal hemorrhageRectal hemorrhage 13 13 (0.8)(0.8) 2222 (1.3)(1.3) 1616 (1.0)(1.0) 2626 (1.6)(1.6)Hemorrhage NOSHemorrhage NOS 24 24 (1.5)(1.5) 24 24 (1.5)(1.5) 4646 (2.8)(2.8) 5252 (3.2)(3.2)HematuriaHematuria 8 8 (0.5)(0.5) 13 13 (0.8)(0.8) 2626 (1.6)(1.6) 1111 (0.7)(0.7)

UlcersUlcers 1414 (0.8)(0.8) 10 10 (0.6)(0.6) 2020 (1.2)(1.2) 1919 (1)(1)

PlaceboPlacebo DPDP ASAASA AGGRENOXAGGRENOXTMTM

(%)(%) (%) (%) Alone (%)Alone (%) (%)(%)

Treatment GroupTreatment Group

Incidence of On-Treatment Serious Adverse EventsIncidence of On-Treatment Serious Adverse Events Bleeding Events and UlcersBleeding Events and Ulcers

Intracranial HemorrhageIntracranial Hemorrhage 55 44 44 44

Bleeding EventsBleeding Events 1111 66 1717 2525MelenaMelena 44 11 55 1111

Gastrointestinal hemorrhageGastrointestinal hemorrhage 11 11 22 77

Rectal hemorrhageRectal hemorrhage 11 11 11 33

Hemorrhage NOSHemorrhage NOS 00 11 22 33

HematuriaHematuria 00 22 33 33

HematemesisHematemesis 55 22 44 33

Gastro-Intestinal UlcerGastro-Intestinal Ulcer 22 33 55 77

PlaceboPlacebo DPDP ASAASA AGGRENOXAGGRENOXTMTM

(%)(%) (%)(%) Alone (%)Alone (%) Alone (%)Alone (%)

Treatment GroupTreatment Group

Total No. of PatientsTotal No. of Patients 16491649 16541654 16491649 16501650

Total No. of PatientsTotal No. of Patients 560 (34)560 (34) 467 (28)467 (28) 529 (32)529 (32) 454 (28)454 (28) With With 1 SAE 1 SAE

On-Treatment DeathsOn-Treatment DeathsBleeding Events and UlcersBleeding Events and Ulcers

PlaceboPlacebo DPDP ASAASA AGGRENOX™AGGRENOX™(%)(%) (%)(%) (%)(%) (%)(%)

Treatment GroupTreatment Group

Total No. of PatientsTotal No. of Patients 16491649 16541654 16491649 16501650

Total DeathsTotal Deaths 135 (8)135 (8) 124 (7)124 (7) 125 (8)125 (8) 107 (6)107 (6)

Ulcers or BleedsUlcers or Bleeds 22 11 00 55

Safety ConclusionsSafety Conclusions

ESPS-2 clinical data supports the safetyESPS-2 clinical data supports the safetyof AGGRENOX™ of AGGRENOX™

No unexpected adverse events observedNo unexpected adverse events observedwith combined use of DP and ASAwith combined use of DP and ASA

Safety ConclusionsSafety Conclusions

DP-related adverse events are primarily headache DP-related adverse events are primarily headache and gastrointestinal complaints, as expectedand gastrointestinal complaints, as expected

ASA-related adverse events are primarily bleeding ASA-related adverse events are primarily bleeding events, as expectedevents, as expected

Safety ConclusionsSafety Conclusions

Serious adverse events of potential clinical Serious adverse events of potential clinical significance other than stroke were uncommonsignificance other than stroke were uncommon

No demographic or disease-related factors identified No demographic or disease-related factors identified

Data demonstrate the safety of AGGRENOX™Data demonstrate the safety of AGGRENOX™when taken as directed when taken as directed

Benefit-risk of AGGRENOX™ is favorableBenefit-risk of AGGRENOX™ is favorable