David Leff, DO. April 13, Disclosure. I have the following financial relationships to disclosure:

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1 David Leff, DO AOMA 94 th Annual Convention April 13, 2016 Disclosure I have the following financial relationships to disclosure: Speaker s Bureau: Allergan Labs, Takeda Pharmaceutical, Valeant Pharmaceutical I will not discuss off label use and/or investigational use in my presentations.

2 Objectives Recognize that IBS is a symptom based diagnosis and its prevalence, impact on society and impact on quality of life Discuss the pathophysiology Review treatment options Identify techniques to strengthen doctor/patient relationships

IBS History Earliest descriptions of symptoms defining IBS 1849 W Cumming 1 Other historical terms mucous colitis The bowels are at colonic spasm one time constipated, neurogenic mucous colitis

3 IBS History Earliest descriptions of symptoms defining IBS 1849 W Cumming 1 Other historical terms mucous colitis The bowels are at colonic spasm one time constipated, neurogenic mucous colitis irritable colon at another lax, in the unstable colon same person. nervous colon spastic colon How the disease has nervous colitis two such different spastic colitis symptoms I do not 1962 Chaudhary & Truelove 2 profess to explain.... Irritable colon syndrome 1966 CJ DeLor 3 Irritable bowel syndrome References: 1. Cumming. Lond Med Gazette. 1849;NS9; Chaudhary and Truelove. Q J Med. July 1962;31: DeLor. Am J Gastroenterol. May 1967;47:

A Symptom-Based Strategy Should Be Used to Diagnose IBS A confident diagnosis of IBS can be made using a symptombased strategy that includes 1,2 : Identification of typical symptoms present for 3

4 A Symptom-Based Strategy Should Be Used to Diagnose IBS A confident diagnosis of IBS can be made using a symptombased strategy that includes 1,2 : Identification of typical symptoms present for 3 months 1,2 Physical examination 2 Exclusion of alarm features 2 IBS does not have to be considered a diagnosis of exclusion American College of Gastroenterology Task Force on IBS. Am J Gastroenterol. 2009;104(Suppl 1):S Cash BD, Chey WD. Aliment Pharmacol Ther. 2004;19(12): Talley NJ. Rev Gastroenterol Disord. 2003;3(Suppl 3):S18-S24.

Symptom-Based Diagnosis of IBS Is Accurate and Reliable Symptom-based diagnosis of IBS is reliable 1,2 98% positive predictive value in distinguishing between IBS and organic disease has been

recommended or needed in patients who fulfill symptom-based criteria for IBS and have no alarm features 3 1. El-Serag et al. Aliment Pharmacol Ther. 2004;19(8):861-870. 2. Cash BD et al.

5 Symptom-Based Diagnosis of IBS Is Accurate and Reliable Symptom-based diagnosis of IBS is reliable 1,2 98% positive predictive value in distinguishing between IBS and organic disease has been reported 2 2%-5% of patients will receive a diagnosis of organic disease during long-term follow-up 1 Repeat diagnostic work-ups are not necessary or recommended 1 Diagnostic testing is not recommended or needed in patients who fulfill symptom-based criteria for IBS and have no alarm features 3 1. El-Serag et al. Aliment Pharmacol Ther. 2004;19(8): Cash BD et al. Am J Gastroenterol. 2002;97(11): American College of Gastroenterology Task Force on IBS. Am J Gastroenterol. 2009;104(Suppl 1):S1-S35. Stool Form Correlates to Intestinal Transit Time

6 IBS Epidemiology IBS consultation pattern Specialists 1 Primary care 1 ~25% Consulters 1 ~75% Nonconsulters 1 ~70% ~30% Female 2 Male 2 References: 1. Drossman and Thompson. Ann Intern Med. June 1992;116(pt 1): Sandler. Gastroenterology. August 1990;99: IBS Epidemiology IBS vs other important disease states US prevalence up to 20% 1 US prevalence rates for other common diseases 2 : diabetes 3% asthma 4% heart disease 8% hypertension 11% References: 1. Camilleri and Choi. Aliment Pharmacol Ther. 1997;11: Adams and Benson. Vital Health Stat 10. December 1991:83. DHHS publication no (PHS)

Economic Impact of IBS IBS presents substantial economic impact on patients: 1 Annual direct

billion Comparable to or greater than other chronic conditions In an HMO study, the total

may or may not reduce economic impact Clinician visits, outpatient care, diagnostic testing 1.

7 Economic Impact of IBS IBS presents substantial economic impact on patients: 1 Annual direct costs estimated at up to $10 billion Annual indirect costs estimated to be at least $20 billion Comparable to or greater than other chronic conditions In an HMO study, the total cost of care for IBS patients was found to be 49% higher than population controls 2 Therapy may or may not reduce economic impact Clinician visits, outpatient care, diagnostic testing 1. Hulisz D. J Managed Care Pharm. 2004;10: Levy RL, et al. Am J Gastroenterol. 2001;96:

8 IBS Burden of disease Impact on work due to IBS Patients with some missed workdays 30% Average number missed workdays 1.7 Patients who cut back some days 46% Average number days cut back 3 Over the previous 4 weeks. Adapted from Hahn et al. Digestion. 1999;60: IBS Burden of disease Impact of IBS on quality of life compared with other medical conditions Mean SF-36 score National norm Diabetes type II IBS Clinical depression Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:

of 5-HT CNS 5% GI tract 95% enterochromaffin cells neuronal

9 Serotonin: A Key Mediator of Motility and Visceral Sensitivity IBS Pathophysiology Physiological distribution of 5-HT CNS 5% GI tract 95% enterochromaffin cells neuronal Reference: Gershon. Aliment Pharmacol Ther. 1999;13(suppl 2):15-30.

IBS Physiology Comparison of pain thresholds of IBS patients and controls Pain produced by rectosigmoid balloon distension 60 IBS % Reporting Pain 40 20 Normal 0 20 60 100 140 180 Rectosigmoid

11 IBS Physiology Comparison of pain thresholds of IBS patients and controls Pain produced by rectosigmoid balloon distension 60 IBS % Reporting Pain Normal Rectosigmoid balloon volume (ml) Reference: From Whitehead et al. Dig Dis Sci. June 1980;25: With permission. IBS Physiology Comparison of pain thresholds IBS Normal Colonic Distension Ice Water Immersion Reference: Whitehead et al. Gastroenterology. May 1990;98:

12 Summary of hypotheses on the pathophysiology of IBS Alterations in brain gut interactions, visceral perception and motility may account for pain and altered bowel habits in IBS 1 Visceral hypersensitivity is well documented in IBS patients 1 Serotonin, which has both sensory and motility modulating properties could represent a common factor linking the symptoms of IBS 2 1 Camilleri and Choi et al, Aliment Pharmacol Ther 1997; 11: 3 2 Kim and Camilleri et al, Am J Gastroenterol 2000; 95(10): 2698 IBS Diagnosis Make a positive diagnosis 1,2 Identify abdominal pain as dominant symptom with altered bowel function Look for red flags Perform diagnostic tests/physical exam to rule out organic disease Make/confirm diagnosis Initiate treatment program as part of diagnostic approach Follow up in 3 to 6 weeks References: 1. Paterson et al. Can Med Assoc J. July 1999;161: American Gastroenterological Association. Gastroenterology. June 1997;112:

13 IBS Diagnosis Red flags may suggest an alternative or coexisting diagnosis Additional diagnostic screening needed for atypical presentations such as Anemia Fever Persistent diarrhea Rectal bleeding Severe constipation Weight loss Nocturnal symptoms of pain and abnormal bowel function Family history of GI cancer, inflammatory bowel disease, or celiac disease New onset of symptoms in patients 50+ years of age Reference: Paterson et al. Can Med Assoc J. July 1999;161: Which Tests are Necessary in Suspected IBS? Pretest Probability of Organic Disease ACG IBS Task Force Update, 2009 Organic GI Disease IBS Patients (Pretest Probability %) General Population (Prevalence %) Colitis / IBD Colorectal cancer Celiac disease Gastrointestinal infection Thyroid dysfunction Lactose malabsorption N/A

15 The Goals of Treatment for IBS 1. Normalize GI motility 2. Provide relief of multiple symptoms, including: Straining Hard or lumpy stools Infrequent bowel movements Abdominal bloating Abdominal discomfort or pain 3. Improve global satisfaction with symptoms

Treatments Used for IBS Symptoms Prescription Medications OTC Laxatives OTC Antidiarrheals Herbals Other OTC None No Answer Patients have tried a total of 281 remedies Fewer than one third reported

16 Treatments Used for IBS Symptoms Prescription Medications OTC Laxatives OTC Antidiarrheals Herbals Other OTC None No Answer Patients have tried a total of 281 remedies Fewer than one third reported satisfaction with their remedies Includes fiber supplements Percent Mentioning Base=350 Adapted with permission from International Foundation for Functional Gastrointestinal Disorders. IBS in the real world survey. August Accessed November 16, 2007.

Xifaxan (rifaximin) Is an FDA-Approved Nonsystemic Antibiotic Xifaxan is a nonsystemic, rifamycin antibacterial approved by the FDA in 2004 and has multiple indications 1 : 2015: Xifaxan is indicated

24 Xifaxan (rifaximin) Is an FDA-Approved Nonsystemic Antibiotic Xifaxan is a nonsystemic, rifamycin antibacterial approved by the FDA in 2004 and has multiple indications 1 : 2015: Xifaxan is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults Xifaxan is available in 550 mg tablets used for the treatment of IBS-D Xifaxan is a nonsystemic antibiotic There is an increased systemic exposure in patients with severe hepatic impairment 1. Xifaxan (rifaximin) Tablets Prescribing Information Raleigh, NC: Salix Pharmaceuticals 2. Koo HL, et al. Ther Clin Risk Manag. 2005;5: Composite Endpoint: Xifaxan 550 mg Tablets Improved Abdominal Pain and Stool Consistency 100 Xifaxan 550 mg TID (n=309) Placebo (n=314) % Responders Composite Endpoint 79 % 68% 47 % 51 % 39 % 42 % Trial 1, 12-week trial in patients with IBS-D (N=623). Composite endpoint: Proportion of patients experiencing improvement in both abdominal pain and stool consistency according to the study criteria 20 0 Abdominal Pain and Stool Consistency P= Abdominal Pain P= Stool Consistency P= Xifaxan (rifaximin) Tablets Prescribing Information. Raleigh, NC: Salix Pharmaceuticals

25 Clinical Guidelines Clinical guidelines support using Xifaxan 550 mg tablets in this population 2014 American College of Gastroenterology (ACG) Task Force American Gastroenterological Association (AGA) 2014 guidelines for the pharmacological treatment of IBS-D 1. Ford AC et al. Am J Gastroenterol. 2014;109(Suppl 1):S2-S Weinberg DS et al. Gastroenterology. 2014;147(5):

Rationale for LOTRONEX (alosetron HCl), Neuroenteric Modulator (NEM) Neuroenteric 5HT Effects 1-3 5HT 3 Modulation May 1-3 Transmit nociceptive Relieve pain and discomfort impulses Reduce urgency

29 Rationale for LOTRONEX (alosetron HCl), Neuroenteric Modulator (NEM) Neuroenteric 5HT Effects 1-3 5HT 3 Modulation May 1-3 Transmit nociceptive Relieve pain and discomfort impulses Reduce urgency Initiate GI peristalsis Decrease stool frequency Stimulate colonic function Improve stool firmness Increase GI secretions Mechanism and site of action of alosetron have not been fully established. References: 1. Gershon. Aliment Pharmacol Ther. 1999;13(suppl 2): Humphrey et al. Aliment Pharmacol Ther. 1999;13(suppl 2): Bearcroft et al. Gut. 1998;42: Please consult complete Prescribing Information.

Percent reporting adequate relief 70 60 50 40 30 20 10 0 Clinical Trials With LOTRONEX (alosetron HCl): Effect on IBS Pain and Discomfort in Diarrhea- Predominant Female Patients Study 1 0 1 2 3 4 5

30 Percent reporting adequate relief Clinical Trials With LOTRONEX (alosetron HCl): Effect on IBS Pain and Discomfort in Diarrhea- Predominant Female Patients Study Week P<0.05 S3BA3002 Reference: Data on file, Glaxo Wellcome Inc. Please consult complete Prescribing Information. Study 2 Treatment Follow-up Treatment Follow-up Placebo LOCF LOTRONEX Week P<0.05, P<0.001 S3BA3001 VIBERZI

Baseline Week 0 1 2 3 4 5 6 7 8 9 10 11 12 0-0.2 B301-0.4-0.6-0.8 Placebo -1.0 p<0.

32 Tegaserod Mimics Serotonin to Target An Underlying Cause to CNS Increases motility Increases intestinal secretion Inhibits visceral sensitivity Mean change in bloating score Change from baseline (bloating score) Baseline Week B Placebo -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 Tegaserod 6 mg bid

Change in number of bowel movements Change from baseline (number of weekly bowel movements) 3 Placebo (n = 288) Tegaserod 6 mg bid (n = 294) 2 1 B301 0 0 1 2 3

33 Change in number of bowel movements Change from baseline (number of weekly bowel movements) 3 Placebo (n = 288) Tegaserod 6 mg bid (n = 294) 2 1 B Baseline Week p<0.05 (6 mg bid vs placebo) Improvement seen on Day 1 ITT analysis Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655

35 Summary Up to 20% of the US population, predominantly female, report symptoms consistent with IBS. 1,2 IBS results in an estimated $8 billion in direct medical costs annually. 3 5-HT may play a key role in IBS and may affect the symptoms of abdominal pain and altered bowel function. 4 It is important to establish a positive diagnosis of IBS. Success of current treatment options in addressing multiple symptoms of IBS has been limited. 5 The optimal medical management approach should treat a complex of symptoms. References: 1. Camilleri and Choi. Aliment Pharmacol Ther. 1997;11: Sandler. Gastroenterology. August 1990;99: Talley et al. Gastroenterology. December 1995;109: Prior and Read. Aliment Pharmacol Ther. 1993;7: Klein. Gastroenterology. July 1988;95:

Xifaxan, Lotronex and Viberzi Prior Authorization and Quantity Limit Program Summary

Xifaxan, Lotronex and Viberzi Prior Authorization and Quantity Limit Program Summary FDA APPROVED INDICATIONS DOSAGE 1,2 Lotronex (alosetron) a Indication For women with severe diarrheapredominant irritable