# Presentation: 501758

## AGGRENOXTM Safety

- Head, Drug Surveillance and Information
- Boehringer Ingelheim Pharmaceuticals, Inc.
- Ridgefield, Connecticut

**Kenneth Rakowski, MD**

## Are there any particular safety concerns with the use of AGGRENOXTM?

## Safety Profile of AGGRENOXTMSummary

- Safety Profile of AGGRENOXTM**Summary**

- No unexpected adverse effects
- Expected adverse effects are establishedfor the two components
- Benefit/risk is favorable

## On-Treatment Adverse Events With an Incidence in the AGGRENOXTM Group Exceeding That in the Placebo Group by 1% or More

**Central & Peripheral Nervous ****	** 49.8	 53.9	50.6	55.1	**System Disorders**
- Headache	32.9	 38.3	33.8	39.2
**Gastro-Intestinal System Disorders****	**36.4	 41.8	37.7	43.7
- Dyspepsia	16.7	 17.4	18.1	18.4
- Abdominal pain	14.5	 15.4	15.9	17.5
- Nausea	14.1	 15.4	12.7 	16.0
- Diarrhea	9.8	 15.5	6.8	12.7
- Vomiting	7.2	 7.8	6.1	8.4
- Melena	0.8	 0.6	1.2	1.9
**Platelet, Bleeding & Clotting Disorders**	5.3	 4.4	7.7	7.9
- Hemorrhage NOS	1.5	 1.5	2.8	3.2
- Purpura	0.4	 0.5	0.5	1.4
**Red Blood Cell Disorders****	**0.7	 1.0	1.3	1.8
- Anemia	0.5	 1.0	1.2	1.6

**	**** ****Placebo ****	****DP Alone****	****ASA Alone****	**** AGGRENOXTM ****Body System/Preferred Term ****	****(%)****	****(%)****	****(%)****	****(%)**

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

**Individual Treatment Group**

**Total No. of Patients                                     **1649	                  1654                1649              	   1650
**Total No. of Patients With ********1 AE****	**1304	(79.1)	 1305	(78.9)	1323	(80.2)	1319	(79.9)

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

**Treatment Groups**

**Total Number of Patients**	1649	 1650 	1649	1654
**Patients With at Least One AE****Associated With Treatment** 	21	 25	19	25
**Cessation **
- Headache	4	 10	3	10Dizziness	4	 6	4	5Nausea	3	 6	3	6Abdominal pain	3	 4	3	4Dyspepsia	3	 4	3	4Vomiting	1	 3	2	3
- Diarrhea	<1	2	<1	2Stroke	4	 3	3	2Transient ischemic attack	3	2	2	2Angina pectoris	2	1	<1	1Myocardial infarction	1	<1	<1	<1

**	**** ****Placebo****	****DP****	****ASA****	****AGGRENOXTM ****	****%****	****%****	****%****	****%**

## Potential Interactions

**Drug-Disease**
- No clinically significant differences
**Drug-Demographics**
- No clinically significant differences

## Laboratory Analyses

- No clinically significant effects in any group
- Hematology, indices of kidney function, presenceof abnormal or normal liver function, fasting glucose, total cholesterol, LDL cholesterol assessed

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

**Gastro-Intestinal Events**		<0.001
- Nausea		0.009
- Diarrhea		<0.001	<0.001
- Vomiting		0.027
**Bleeding Events****	****	****	**<0.001
**Ulcers**			0.059

**Body System/****	****	****DP Main****	**** ASA**
**Preferred Term****	****	****Effect****	****Effect**

**Factorial Analysis****Significant*****P*****-Values**

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

**Total No. of Patients**                     1649               1654             1649            1650
**Total No. of Patients****	**** **1304	(79.1)	 1305	(78.9)**	**1323	(80.2)	1319	(79.9)**With ********1 Adverse Event **
**Bleeding Events**	92	(6)	 94	(6) 	160	(10)	171	(10)
- Epistaxis	 25	(1.5)	 16	(1.0) 	45	(2.7)	39	(2.4)
- Purpura	 7	(0.4)	 8	(0.5)	9	(0.5)	23	(1.4)
- Melena	 13	(0.8)	 10	(0.6)	20	(1.2)	31	(1.9)
- GI hemorrhage	 7	(0.4)	 5	(0.3)	15	(0.9)	20	(1.2)
- Rectal hemorrhage	 13	(0.8)	22	(1.3)	16	(1.0)	26	(1.6)
- Hemorrhage NOS	 24	(1.5)	 24	(1.5)	46	(2.8)	52	(3.2)
- Hematuria	 8	(0.5)	 13	(0.8)	26	(1.6)	11	(0.7)
**Ulcers**	14	(0.8)	 10	(0.6)	20	(1.2)	19	(1)

**	****Placebo****	****DP****	****ASA****	****AGGRENOX****TM**
**	****(%)****	**** (%)****	****Alone (%)****	****(%)**

**Treatment Group**

## Incidence of On-Treatment Serious Adverse Events Bleeding Events and Ulcers

**Intracranial Hemorrhage****	**5	4	4	4
**Bleeding Events**	11	6	17	25
- Melena	4	1	5	11
- Gastrointestinal hemorrhage	1	1	2	7
- Rectal hemorrhage	1	1	1	3
- Hemorrhage NOS	0	1	2	3
- Hematuria	0	2	3	3
- Hematemesis	5	2	4	3
**Gastro-Intestinal Ulcer**	2	3	5	7

**	****Placebo****	****DP****	****ASA****	****AGGRENOX****TM**
**	****(%)****	****(%)****	****Alone (%)****	****Alone (%)**

**Treatment Group**

**Total No. of Patients****	**1649	1654	1649	1650
**Total No. of Patients****	**** **560 (34)	467 (28)	529 (32)	454 (28)** ****With ********1 SAE **

## On-Treatment DeathsBleeding Events and Ulcers

**	****Placebo****	****DP****	****ASA****	****AGGRENOXTM**
**	****(%)****	****(%)****	****(%)****	****(%)**

**Treatment Group**

**Total No. of Patients****	**1649	1654	1649	1650
**Total Deaths****	**135 (8)	124 (7)	125 (8)	107 (6)
**Ulcers or Bleeds****	**2	1	0	5

## Safety Conclusions

- ESPS-2 clinical data supports the safetyof AGGRENOXTM
- No unexpected adverse events observedwith combined use of DP and ASA

## Safety Conclusions

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

## Safety Conclusions

- Serious adverse events of potential clinical significance other than stroke were uncommon
- No demographic or disease-related factors identified
- Data demonstrate the safety of AGGRENOXTMwhen taken as directed
- Benefit-risk of AGGRENOXTM is favorable