1. CM-1 Chronic Constipation: An Unresolved Problem for Many Patients Charlene Prather, MD Division of Gastroenterology and Hepatology Saint Louis University School of Medicine Charlene Prather, MD Division of Gastroenterology and Hepatology Saint Louis University School of Medicine

2. CM-2 Presentation Objectives Definition of chronic constipation Epidemiology and resource utilization Review of available therapies and limitations Unmet medical need Definition of chronic constipation Epidemiology and resource utilization Review of available therapies and limitations Unmet medical need C

3. CM-3 Definition: Causes of Chronic Constipation Secondary –Drug induced –Metabolic factors –Comorbid conditions Primary –Impaired colonic transit/motility Altered neuroenteric function and reflexes Failure of muscular apparatus –Ineffective defecation (functional outlet obstruction) Pelvic dyssynergia and anismus –Normal transit constipation Secondary –Drug induced –Metabolic factors –Comorbid conditions Primary –Impaired colonic transit/motility Altered neuroenteric function and reflexes Failure of muscular apparatus –Ineffective defecation (functional outlet obstruction) Pelvic dyssynergia and anismus –Normal transit constipation C

4. CM-4 Constipation Is a Constellation of Symptoms Most commonly reported symptoms –Hard, lumpy stools –Increased straining –Infrequent bowel movements –Sensation of incomplete evacuation –Bloating/fullness Chronic constipation –More persistent than intermittent or episodic –Several months duration Most commonly reported symptoms –Hard, lumpy stools –Increased straining –Infrequent bowel movements –Sensation of incomplete evacuation –Bloating/fullness Chronic constipation –More persistent than intermittent or episodic –Several months duration C

5. CM-5 Sandler RS, et al. Dig Dis Sci. 1987;32:841-845. n = 1128 Constipation Is More Than Just Infrequent Passage of Stool 53 Constipation symptoms reported most often

6. CM-6 Reduced Stool Frequency Is Not the Most Commonly Reported Symptom in Constipation EPOC = Epidemiology of constipation; BM = Bowel movement. 1. Stewart WF, et al. Am J Gastroenterol. 1999;94:3530-3540. 2. Paré P, et al. Am J Gastroenterol. 2001;96:3130-3137. Stewart (EPOC) 1999 1 Paré 2001 2 n = 1476n = 1149 Constipation symptoms reported most often C

7. CM-7 Rome II Defines Functional Constipation Based on Multiple Symptoms Rome II diagnostic criteria for functional constipation At least 12 wk, which need not be consecutive, over the past 12 months of 2 or more of –Straining* –Lumpy or hard stools* –Sensation of incomplete evacuation* –Sensation of anorectal obstruction/blockage* –Manual maneuvers to facilitate defecation* –< 3 defecations/wk Loose stools not present Insufficient criteria for IBS Rome II diagnostic criteria for functional constipation At least 12 wk, which need not be consecutive, over the past 12 months of 2 or more of –Straining* –Lumpy or hard stools* –Sensation of incomplete evacuation* –Sensation of anorectal obstruction/blockage* –Manual maneuvers to facilitate defecation* –< 3 defecations/wk Loose stools not present Insufficient criteria for IBS * > 1/4 of defecations. Drossman DA, et al. In: Rome II: The Functional Gastrointestinal Disorders. 2000:382-391. C

8. CM-8 Prevalence in the General Population 1. Stewart WF, et al. Am J Gastroenterol. 1999;94:3530-3540. 2. Drossman DA, et al. Dig Dis Sci. 1993;38:1569-1580. 3. Harris Interactive Study, Wave 2. Data on file. 4. Paré P, et al. Am J Gastroenterol. 2001;96:3130-3137. 53 PopulationnCriteria Prevalence, n (%) US 1 10,018Rome I 461 (4.6) US 2 5430Rome I 195 (3.6) US 3 15,183Rome II2429 (16) Canada 4 1149Rome II 171 (14.9)

9. CM-9 Approximately 25% of Sufferers Seek Care 1. Stewart WF, et al. Am J Gastroenterol. 1999;94:3530-3540. 2. Drossman DA, et al. Dig Dis Sci. 1993;38:1569-1580. 3. Harris Interactive Study, Wave 2. Data on file. 4. Paré P, et al. Am J Gastroenterol. 2001;96:3130-3137. 53 PopulationnCriteria Prevalence, n (%) Sought care, % US 1 10,018Rome I 461 (4.6)NA US 2 5430Rome I 195 (3.6)22 US 3 15,183Rome II2429 (16)24 Canada 4 1149Rome II 171 (14.9)26

10. CM-10 Constipation Affects All Age Groups 53 Canadian population. Paré P, et al. Am J Gastroenterol. 2001;96:3130-3137. N = 1149 n = 378n = 367n = 217n = 187

11. CM-11 Epidemiology Chronic constipation is common Slightly more common in women –F/M ratio = range 1.3 to 2.5 Affects all age groups Chronic constipation is common Slightly more common in women –F/M ratio = range 1.3 to 2.5 Affects all age groups Stewart WF, et al. Am J Gastroenterol. 1999;94:3530-3540. Paré P, et al. Am J Gastroenterol. 2001;96:3130-3137. Sandler RS, et al. Dig Dis Sci. 1987;32:841-845. C

12. CM-12 Profile of a Typical Chronic Constipation Patient in My Practice Generally female Symptomatic for > 10 yr Majority have tried lifestyle changes, fiber, and OTC laxatives prior to seeking care Manages condition with multiple therapies Most often referred by a primary care physician Copes with condition, but is not completely satisfied Generally female Symptomatic for > 10 yr Majority have tried lifestyle changes, fiber, and OTC laxatives prior to seeking care Manages condition with multiple therapies Most often referred by a primary care physician Copes with condition, but is not completely satisfied C

13. CM-13 Constipation Can Have a Negative Impact on Quality of Life In Olmstead County, Minnesota, people with CC reported significant impairment in QoL on SF-36 scale (n = 126) 1 In Canada, people with self-reported or Rome II constipation had significantly worse SF-36 scores than the normal population (n = 472) 2 In Australia, people with constipation had significantly worse SF-12 scores on both mental and physical scales (n = 227) 3 In Olmstead County, Minnesota, people with CC reported significant impairment in QoL on SF-36 scale (n = 126) 1 In Canada, people with self-reported or Rome II constipation had significantly worse SF-36 scores than the normal population (n = 472) 2 In Australia, people with constipation had significantly worse SF-12 scores on both mental and physical scales (n = 227) 3 1. O’Keefe EA, et al. J Gerontol A Biol Sci Med Sci. 1995;50:M184-M189. 2. Irvine EJ, et al. Am J Gastroenterol. 2002;97:1986-1993. 3. Koloski NA, et al. Am J Gastroenterol. 2000;95:67-71. C

14. CM-14 Constipation Significantly Impacts Healthcare Utilization 5.7 million constipation-related outpatient visits annually 1,2 –4.1 million physician office-based visits –991,000 emergency room visits –587,000 hospital outpatient visits $2752/patient for tertiary care evaluation 3 5.7 million constipation-related outpatient visits annually 1,2 –4.1 million physician office-based visits –991,000 emergency room visits –587,000 hospital outpatient visits $2752/patient for tertiary care evaluation 3 1. National Ambulatory Medical Care Survey, 2001. www.cdc.gov 2. National Hospital Ambulatory Care Survey, 2001. www.cdc.gov 3. Rantis PC Jr, et al. Dis Colon Rectum. 1997;40:280-286. C

15. CM-15 Goal of Therapy in Chronic Constipation The goal of therapy is to improve GI function in order to provide relief of key symptoms: – Straining – Hard/lumpy stools – Feeling of incomplete evacuation – Infrequent bowel movements – Bloating/fullness The goal of therapy is to improve GI function in order to provide relief of key symptoms: – Straining – Hard/lumpy stools – Feeling of incomplete evacuation – Infrequent bowel movements – Bloating/fullness 53

16. CM-16 Medications Commonly Used for Constipation Fiber Laxatives –Osmotic laxatives –Stimulant laxatives Enemas or suppositories Miscellaneous Fiber Laxatives –Osmotic laxatives –Stimulant laxatives Enemas or suppositories Miscellaneous 53 Adapted from Lembo A, et al. N Engl J Med. 2003;349:1360-1368.

17. CM-17 Efficacy of Current Treatments for Chronic Constipation Variable treatment responses For the constellation of constipation symptoms, efficacy not evaluated or demonstrated with most agents Most agents indicated for ≤ 2 wk of treatment Variable treatment responses For the constellation of constipation symptoms, efficacy not evaluated or demonstrated with most agents Most agents indicated for ≤ 2 wk of treatment 53 Petticrew M, et al. Qual Health Care. 2001;10:268-273. Jones MP, et al. Dig Dis Sci. 2002;47:2222-2230. Rao SS. Gastroenterol Clin North Am. 2003;32:659-683.

18. CM-18 Limitations of Current Treatments for Constipation Worsening of some constipation symptoms –Bloating and gas –Cramping, abdominal pain/colic Development of complications –Diarrhea, hypovolemia –Metabolic disturbances Other adverse effects –Interference with concomitant drug absorption –Structural changes in gut mucosa –Abuse potential (dependency) Diminished therapeutic effect over time Worsening of some constipation symptoms –Bloating and gas –Cramping, abdominal pain/colic Development of complications –Diarrhea, hypovolemia –Metabolic disturbances Other adverse effects –Interference with concomitant drug absorption –Structural changes in gut mucosa –Abuse potential (dependency) Diminished therapeutic effect over time C Xing JH, et al. Dis Colon Rectum. 2001 Aug;44:1201-1209. Garcia MC, et al. Tenn Med. 2002 Aug;95:334-336. Chaussade S, et al. Aliment Pharmacol Ther. 2003 Jan;17:165-172. Riley SA, et al. Br J Clin Pharmacol. 1992 Jul;34:40-46. Gattuso JM, et al. Drug Saf. 1994 Jan;10:47-65. Wald A. J Clin Gastroenterol. 2003;36:386-89. Duncan A, et al. Eur J Gastroenterol Hepatol. 2001;13:599-601.

19. CM-19 Physicians Believe Patient Satisfaction With Current Therapies Is Low Yes 18% Are your patients completely satisfied? No 82% Schiller LR, et al. Am Coll Gastroenterol. 2004, abstract submitted. C n = 311 60% of physicians agreed that they do not have adequate products 90% of physicians wanted better treatment options Physicians cited “frustration with current treatments” one of the top 3 reasons patients state for seeking care Reasons for dissatisfaction* Efficacy93% Safety/side effects57% Other (ie, taste, compliance) 27% *Not mutually exclusive.

20. CM-20 Many Constipation Patients Are Not Satisfied With Available Treatments Reasons for dissatisfaction* 1 Efficacy82% Safety/side effects16% Other (ie, taste, compliance) 17% C 1. Schiller LR, et al. Am Coll of Gastroenterol. 2004, abstract submitted. 2. Irvine EJ, et al. Am J Gastroenterol. 2002;97:1986-1993. 3. Ferrazzi S, et al. Can J Gastroenterol. 2002;16:159-164. *Not mutually exclusive. Yes 53% Are you completely satisfied? 1 No 47% n = 557

21. CM-21 Chronic Constipation: A Condition in Need of a Better Approach Characterized by a constellation of symptoms High resource utilization and significant negative impact on patients’ lives Current pharmacologic agents have limitations Many patients are not satisfied with available therapies Better treatment options are needed Characterized by a constellation of symptoms High resource utilization and significant negative impact on patients’ lives Current pharmacologic agents have limitations Many patients are not satisfied with available therapies Better treatment options are needed C