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Improving Standards of Care in Irritable Bowel Syndrome

Improving Standards of Care in Irritable Bowel Syndrome. Definition of Irritable Bowel Syndrome (IBS). IBS is a chronic, episodic medical condition characterized by abdominal pain or discomfort associated with altered bowel function

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Improving Standards of Care in Irritable Bowel Syndrome

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  1. Improving Standards of Carein Irritable Bowel Syndrome

  2. Definition of Irritable Bowel Syndrome (IBS) • IBS is a chronic, episodic medical condition characterized by abdominal pain or discomfort associated with altered bowel function • IBS with constipation is abdominal pain/discomfort associated with at least 2 of the 3:- < 3 bowel movements per week- Hard or lumpy stools- Straining with a bowel movement Drossman et al, Gastroenterology 1997; 112: 2120

  3. Overall prevalence of IBS greater in females Prevalence (%) 13.5 Female 14 13.0 Male 9.4 0 15–34 35–44 >45 Ages (years) Drossman et al, Dig Dis Sci 1993; 38: 1569

  4. 6.7 5.6 5.6 5.5 5.3 5.2 5.2 4.7 3.5 IBS-constipation IBS-diarrhea IBS-alternating Prevalence by IBS subgroups Survey respondents (%) Overall 8 Females Males 3022 residents surveyed in Minnesota536 respondents 0 Adapted from Talley et al, Am J Epidemiol 1995; 142: 76

  5. IBS patients suffer • In a recent survey (n = 350) conducted bythe International Foundation for FunctionalGastrointestinal Disorders, it was found that: • 42% of respondents reported having symptomsfor 10 years or more • 43% reported symptoms as 'severe', 40% described them as 'moderate' • two-thirds of IBS sufferers describe their symptoms as extremely or very bothersome www.iffgd.org; in press

  6. IBS patients with constipation (abc-ibs) suffer from abdominal pain/discomfort, bloating, and constipation Gas / gas pain Constipation Straining with BM Abdominal pain / discomfort Hard / lumpy stool Incomplete evacuation after BM Bloating / distension Inability to have BM Heartburn / acid reflux IBS with constipation Sudden urges to have BM General US population Rectal pain 0 10 20 30 40 50 60 70 % IBS patients that suffer once a week or more Lieberman Research Inc. 2000, GI Sufferer Study

  7. Who treats IBS? IBS is a common diagnosis in primary care and gastroenterology practices IBS IBS 12% 28% All other diagnoses 88% All other diagnoses 72% Primary care Gastroenterology Mitchell et al, Gastroenterology, 1987; 92: 1282 Drossman, Gastroenterology 1997; 112: 2120

  8. Impact of IBS on work or school IBS patients 13.4 *** Non-IBS 4.9 patients 0 5 10 15 Days missed from work or school in past year ***p<0.0001 Adapted from Drossman et al, Dig Dis Sci 1993; 38: 1569

  9. Mechanisms in IBS Enhancedperception Vagal nuclei 5-HT Sympathetic Alteredmotility Visceralhypersensitivity Adapted from Camilleri and Choi, Aliment Pharmacol Ther 1997; 11:3

  10. Physiologic distribution of 5-HT CNS: 5% GI tract: 95% Kim and Camilleri, Am J Gastroenterol 2000; 95: 2698

  11. Summary of Hypotheses on the Pathophysiology of IBS • IBS is characterized by changes in motility in response to environmental or enteric stimuli1 • Visceral hypersensitivity is well documented in IBS patients2 • Serotonin, which has both motility and sensory modulating properties, could represent a common factor linking the symptoms of IBS3 1AGA Patient Care Committee Gastroenterology 1997;112:2120-2137 2 Adapted from Camilleri and Choi et al., Aliment Pharmacol Ther 1997; 11: 3 3Kim and Camilleri et al., Am J Gastroenterol 2000; 95(10): 2698

  12. Identify Red Flags • History - Unintentional Weight loss • Onset in older patient (>50 years) - Family history ofcancer or IBD • Physical - Abnormal exams - Rectal bleeding/obstruction - Positive FOBT/flex. sigmoidoscopy or colonoscopy (>50 years) • Initial Labs -  HGB -  WBC -  ESR - Abnormal chemistry -  TSH Red Flags Adapted from A technical review, Gastroenterology 1997; 112: 2120 Paterson et al., Can Med Assoc J 1999; 161: 154 Camilleri et al., Aliment Pharmacol Ther 1997; 11: 3

  13. IBS: An enduring diagnosis 112 consecutive Olmstead County residents first diagnosed with IBS during 1961–63. Median follow-up: 29 years (range 1–32 years) No change in diagnosis: 97% Most have no change in diagnosis after initial evaluation Owens et al, Ann Intern Med 1995; 122: 107

  14. Goals of Pharmacotherapy in IBS with Constipation • Overall Relief (including impact on patients’ overall well-being)4 • Multi-symptom relief4 • Abdominal pain • Bloating • Constipation 4Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead,WE eds. Rome II The Functional Gastrointestinal Disorders 2nd ed. McLean, Va 2000:355,360,594-596

  15. Dietary advice • Patients often relate their functional symptomsto certain foods • Dietary restrictions are common, but may be inappropriate • dairy products, sorbitol, caffeine, alcohol, citrus fruit,gas-forming vegetables, grains Jones et al, Gut 2000; 47(suppl. II): 1

  16. Traditional therapies focused on individual symptoms of IBS with constipation Abdominal pain / discomfort • Antispasmodics • Tricyclics • Analgesics Bloating and distention • Dietary modifications • Antispasmodics • Antiflatulants • Digestive enzymes • Antibiotics Abdominal pain /discomfort Bloating /distention Constipation Constipation • Fiber • Laxatives • None of these medications effectively treat the multiple symptoms of IBS. May exacerbate individual symptoms e.g., fiber and bloating; antispasmodics and constipation

  17. Tegaserod: Indication and Dosage • Zelnorm (tegaserod maleate) is indicated for the short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation • The safety and effectiveness in men have not been established • Recommended dosage: tegaserod (Zelnorm) 6 mg twice daily orally before meals for 4–6 weeks • For patients who respond to therapy at 4–6 weeks, an additional 4–6 weeks can be considered • Efficacy of tegaserod beyond 12 weeks has not beenestablished Novartis, data on file

  18. Tegaserod: A New Class of Compound OH NH O NH NH2 N NH NH NH Tegaserod Serotonin (5-HT) • Tegaserod is a 5-HT4 receptor agonist • new class of compound: aminoguanidine indoles • Structure similar to serotonin Camilleri, Aliment Pharmacol Ther 2001; 15: 277

  19. Tegaserod: Pharmacological Effects • Stimulates 5-HT4 receptors and improves GI function • Stimulates the peristaltic reflex • Alters the chloride secretion in the intestine • Reduces visceral sensitivity* * animal data Camilleri M. Review article: Tegaserod. Aliment Pharmacol Ther. 2001; 15: 277-89.

  20. Subject’s Global Assessment of relief % Responders B301 70 * * * * * * * * * 60 * * 50 40 Tegaserod 6 mg bid (n = 294) Placebo (n = 288) 30 0 1 2 3 4 5 6 7 8 9 10 11 12 0 Weeks *p<0.05 Responders are defined as at least “somewhat relieved” ITT population Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655

  21. Mean relief in abdominal pain / discomfort score Change from baseline (pain score) Baseline Week 0 1 2 3 4 5 6 7 8 9 10 11 12 0 B301 -0.2 * -0.4 * * -0.6 * * * * * * * -0.8 Placebo (n = 288) * Tegaserod 6 mg bid (n = 294) -1.0 * p<0.05 (6 mg bid vs placebo) ITT analysis.100mm Visual Analogue Scale with 6 descriptors: noneto very severe Baseline pain score: placebo = 2.77; tegaserod = 2.78 Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655

  22. Placebo (n = 288) Tegaserod 6 mg bid (n = 294) Change in number of bowel movements Change from baseline (number of weekly bowel movements) * 3 B301 * * 2 * * * * * * * * 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Baseline Week *p<0.05 (6 mg bid vs placebo) ITT analysis • Improvement seen on Day 1 Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655

  23. Mean change in bloating score Change from baseline (bloating score) Week Baseline 0 1 2 3 4 5 6 7 8 9 10 11 12 0 B301 -0.2 -0.4 * * -0.6 * * * * * * * -0.8 Placebo Tegaserod 6 mg bid -1.0 *p<0.05 (6 mg bid vs placebo) ITT analysis 6-point scale: 0 = none to 6 = very severe Baseline bloating score: placebo = 2.67; tegaserod = 2.72 Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655

  24. Summary of Tegaserod Efficacy • Significant improvement in Subject's GlobalAssessment of relief • Relief of individual IBS symptoms: - Abdominal pain / discomfort - Bloating - Constipation Müller-Lissner et al., Aliment Pharmacol Ther 2001; 15: 1655

  25. Zelnorm: Safety Data

  26. Adverse events occurring >1% System / adverse experience Zelnorm 6 mg bid (n = 1327) % Placebo (n = 1305) % Gastrointestinal system disorders Abdominal pain Diarrhea Nausea Flatulence 12 9 8 6 11 4 7 5 Central and peripheral nervous system Headache Dizziness Migraine 15 4 2 12 3 1 Body as a whole – general disorders Accidental trauma Leg pain 3 1 2 <1 Musculoskeletal disorders Back pain Arthropathy 5 2 4 1 Novartis, data on file

  27. Overall Safety and Tolerability of Tegaserod • Tegaserod was generally well tolerated. Side effects reported significantly more often with tegaserod than with placebo were headache (15% vs 12%) and diarrhea (9% vs 4%) Novartis, data on file

  28. Overall Safety and Tolerability of Tegaserod • Diarrhea: • tegaserod 9% vs placebo 4% • In most cases, diarrhea occurred within the first week of treatment • Typically, diarrhea resolved with continued therapy • Overall, the discontinuation rate from the studies due to diarrhea was 1.6% among the tegaserod-treated patients Novartis, data on file

  29. Summary of Drug–Drug Interactions • In vitro: no inhibition of CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 • No clinically relevant drug–drug interactions were observed in healthy volunteers with: • theophylline • dextromethorphan • Digoxin3 • Warfarin4 • oral contraceptives5 • Dose adjustment is not required for any of the above drugs co-administered with tegaserod 1Zhou, et al., Am J Gastroenterol 1999; 94: 2623: 184 2Kalbag, et al., Gastroenterology 2000; 118 (suppl. 2): A1179: 5422 3Zhou, et al., J Pharm Sci 1999; 1: A2077 4Ledford, et al., Gastroenterology 2000; 118 (suppl. 2): A1184: 5445 5Zhou, et al., Gastroenterology 2000; 118 (suppl. 2): A1207: 5539

  30. Tegaserod is the first treatment proven to provide multi-symptom IBS relief of:- Abdominal pain/discomfort- Bloating- Constipation Favorable tolerability demonstrated in well-controlled clinical trials with more than 2,600 IBS patients Conclusions

  31. Digestive Diseases Week Key Findings Orlando, FL May 17-22, 2003

  32. Tegaserod Improves Gastric Emptying in Patients with Gastroparesis and Dyspeptic Symptoms Tougas G et al. Oral Presentation, DDW 2003

  33. Objective • To evaluate whether 8 weeks of tegaserod can improve abnormally delayed gastric emptying in patients with dyspeptic symptoms and delayed gastric emptying Tougas G et al. Oral Presentation, DDW 2003

  34. Gastric retention (%) of meal at 2 hours post meal 60 50 40 30 20 10 0 *‘normal’ gastricretention rate at2 hours is 40% ** * Retention (%) at 2 hours post meal ↓ 24% ↓ 35% ↓ 15% ↓ 6% 24 18 12 Placebo Tegaserod dose *p=0.077 vs placebo; **p=0.003 vs placebo Tougas G et al. Oral Presentation, DDW 2003

  35. Results and Conclusions • Gastric retention was reduced consistently with tegaserod, especially at 2 and 4 hours after meal • Tegaserod 18mg/day and 24mg/day decreased food retention in late phase emptying by 2x over placebo • 80% of patients given 18mg/day developed normal gastric emptying vs. 50% of placebo patients • Tegaserod improves gastric emptying in patients with gastroparesis and dyspeptic symptoms Tougas G et al. Oral Presentation, DDW 2003

  36. Efficacy and Safety of Tegaserod in Patients with Chronic Constipation

  37. Conclusions • Significant improvement as compared to placebo: • Number of complete, spontaneous bowel movements • Time to first complete, spontaneous bowel movement • Straining • Distention and bloating • Abdominal discomfort/pain • Satisfaction with bowel habits • Bothersome constipation • Additional evidence for safety • Most frequent adverse effects leading to discontinuation included nausea, diarrhea, abdominal pain, headache • No serious adverse events were noted with the use of tegaserod for up to 12 weeks in pts with CC. Johanson J, et al. Oral presentation. DDW 2003.

  38. Tegaserod provides rapid, effective relief of abdominal pain/discomfort, bloating and constipation in Chinese patients with irritable bowel syndrome with constipation (IBS-C) Lin S, et al. Poster S1017.DDW 2003.

  39. Results and Conclusions • Adverse events were reported in 10% of patients on tegaserod and 6% on placebo. • The most common adverse events seen in tegaserod group were diarrhea, abdominal pain and dizziness (frequency <3%). They did not result in discontinuation. • Tegaserod provided rapid relief of IBS-C symptoms including abdominal pain, bloating and constipation and was well tolerated in Chinese patients with IBS-C. • Lin S, et al. Poster S1017. DDW 2003.

  40. Tegaserod is an effective and safe therapy for irritable bowel syndrome in a Nordic population Nyhlin H, et al. Poster M1645. DDW 2003. In press, Gastroenterology.

  41. Results and Conclusions • The overall frequency of adverse events (AE) was comparable between treatments. • The most frequently reported AE was diarrhea : 9.2% tegaserod vs. 1.3% placebo. • Discontinuations due to diarrhea were 2.8% for tegaserod vs. 0% for placebo . • Tegaserod 6mg bid is an effective, safe and well tolerated therapy in a Nordic population of IBS patients with non-D IBS. • Nyhlin H, et al. Poster M1645. DDW 2003. In press, Gastroenterology.

  42. Results • Tegaserod treated patients with less than 10 yrs duration of IBS symptoms had a gain in weekly therapeutic effect (range 10% to 26%) each week (p<0.05) over weeks 1-12. • Tegaserod significantly affected number of days with no bowel movements and days with >3 bowel movements for weeks 1-4 (p<0.0001). • Nyhlin H, et al. Poster M1645. DDW 2003. In press, Gastroenterology.

  43. Relapse of Symptoms Following Withdrawal of Tegaserod Treatment in Irritable Bowel Syndrome with Constipation (IBS-C) Munoz V, et al, Poster T1804. DDW 2003.

  44. Conclusions • IBS-C patients respond favorably to initial treatment with tegaserod for 1 month (82%) • IBS-C patients respond favorably to maintenance therapy with tegaserod for another 2 months (90%) • Upon discontinuation of tegaserod, 2/3 of patients will relapse within 3 weeks • 10% of maintenance treatment patients relapsed (p<0.0001) • Patients who continue treatment 18x less likely to relapse Munoz V, et al, Poster T1804. DDW 2003.

  45. Tegaserod Treatment for IBS: A Model of Indirect Costs Smith D, et al. Poster T1303. DDW 2003.

  46. Conclusions • IBS has substantial impact on worker productivity • Net annual savings of $1,497 for employer per employee treated for IBS • Model can be tailored to match individual employers’ needs • Treatment of IBS with tegaserod may be cost-effective in reducing indirect costs under a variety of scenarios, using a series of assumptions on wages, epidemiology, therapy, and costs • Further validation of this model is warranted • Smith D, et al. Poster T1303. DDW 2003.

  47. Impact of IBS on Worker Productivity in an Employed U.S. Population Dean B, et al. Poster T 1302, DDW 2003.

  48. Results and Conclusions • 1,776 of 11,806 employees participated in both surveys • 41% met Rome II criteria for IBS • Participants with IBS more likely to be female and Caucasian or Hispanic, otherwise similar to those without IBS • Participants with IBS had work productivity losses of 19.8% due to GI symptoms compared with 5.6% among those without IBS • This reduction is equivalent to working 4 days out of a 5-day work-week • Reduced productivity of this magnitude may have substantial impact on employers. Dean B, et al. Poster T 1302, DDW 2003.

  49. Conclusions • Employees with IBS • ~20% reduced work productivity due to GI Sx • ~14% reduced work productivity compared to non-IBS co-workers • Work less than 4 days out of total 5 day work week • May have substantial financial impact on employers Bonnie Dean, Daniel Aguilar, et al. Poster Presentation DDW 2003.

  50. Tegaserod is Effective in the Retreatment of Irritable Bowel Syndrome with Constipation (IBS-C) Mueller-Lissner S., et al. Poster T1821. DDW 2003.

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