What s New in IBS with Diarrhea. Dr. Geoffrey K. Turnbull, MD April 6, 2018.

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1 What s New in IBS with Diarrhea Dr. Geoffrey K. Turnbull, MD April 6, 2018.

2 Objectives To learn how to diagnose IBS with particular emphasis on patients who have diarrhea predominantly. Review management strategies that are effective for IBS-D Learn about new treatments available for the treatment of IBS-D

3 Rome III Criteria for IBS Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more of the following: 1. Improvement with defecation 2. Onset associated with change in frequency of stool 3. Onset associated with a change in form (appearance) of stool * Criteria fulfilled for the last 3 months with symptoms onset at least 6 months prior to diagnosis.

4 Bristol Stool Scale

5 Diagnosis: Exclude Red Flags check for Red Flags symptoms before confirming diagnosis age of onset > 50 years symptoms of recent onset symptoms steadily worsening family history of I.B.D., especially Crohn s rectal bleeding, nocturnal symptoms, weight loss, fever, night sweats, vomiting abnormal exam - mass in abdomen (RLQ)

6 Red Flags on Lab testing anemia leukocytosis or thrombocytosis elevated ESR or CRP low albumin or total protein stool test for pathogens (parasites) if chronic diarrhea (Giardia and Cryptosporidia) consider TTG testing +/- IgA level (to exclude Celiac Disease)

7 Conditions associated with IBS Other functional GI disorders: Dyspepsia, vomiting, heartburn Chronic pelvic pain Functional urinary symptoms Dysmenorrhea Back pain / headache Fibromyalgia / chronic fatigue syndrome Sexual dysfunction Whitehead et al, Gastroenterology 2002; 122: 1140

8 History points to consider in Diarrhea Previous cholecystectomy OTC medications: Magnesium-containing products (antacids, calcium supplements) High doses of vitamin C (>1000 mg daily) OTC NSAIDs Prescription medications: Antibiotics NSAIDs SSRI medications Proton-pump inhibitors Other drugs

9 Dietary manipulations These are common triggers to diarrhea in our diet 1. Coffee 2. Milk and other lactose-containing foods/liquids 3. High fat foods 4. Candy, gum, breath mints (especially low calorie) 5. Alcoholic beverages 6. FODMAP foods

10 Low FODMAP Diet

11 Examples of FODMAPS The actual FODMAPS Compounds in Category Foods with these compounds F = Fermentable O = Oligosaccharides Fructans, galacto-oligosccharides Wheat, barley, rye, onion, leek, garlic, shallots, artichokes, fennel, peas, chicory, pistachio, cashews, lentils, chickpeas. D = Disaccharides Lactose Milk, custard, ice cream, yogurt M = Monosaccharides Free fructose (in excess of glucose) Corn syrup, apples, pears, cherries, watermelon, asparagus, honey A = And P = Polyols Sorbitol, mannitol, maltitol, xylitol Artificial sweeteners, the above fruits + plums, nectarines, peaches, apricots, mushrooms, cauliflower.

12 Therapies for Diarrhea in IBS Loperamide 2 mg tablets best to take 45 to 60 minutes before triggers for diarrhea (meal-induced diarrhea, exercise) Maximum dose 16 mg daily Cholestyramine or Colestid Taken daily 4 grams (Colestid 5 g) and take other medications one hour before or 3 hours after. Maximum dose 16 grams daily Note: Fiber rarely works unless the patient has IBS-M diagnosis

Eluxadoline: Mechanism of Action Patients with IBS-D Eluxadoline:

Reduces Visceral visceral pain 3 + + Eluxadoline Eluxadoline agonizes

modulates receptors the receptors GI tract fibres agonism Lumen Mucosa

Biochem Pharmacol. 2014;92:448; Wade PR et al. Br J Pharmacol.

13 Eluxadoline: Mechanism of Action Patients with IBS-D Eluxadoline: experience: Increased Slows GI transit 1 Decreases Increased secretion 2 Reduces Visceral visceral pain Eluxadoline Eluxadoline agonizes binds opioid antagonizes and antagonism receptors opioid opioid in Pain modulates receptors the receptors GI tract fibres agonism Lumen Mucosa Submucosa Dove LS et al. Gastroenterology. 2013;145:329; Fujita W et al. Biochem Pharmacol. 2014;92:448; Wade PR et al. Br J Pharmacol. 2012;167:1111; 13 Viberzi (eluxadoline) [prescribing information]. Parsippany, NJ: Actavis Pharma, Inc., 2016.

14 Systemic Bioavailability Eluxadoline has very low oral bioavailability (based on limited absorption and first pass effects; absolute bioavailability has not been determined) Since bioavailability is limited, the pharmacodynamic activity of eluxadoline is based predominantly on local action within the GI tract In an oral abuse liability study in recreational opioid users, doses of up to 1,000 mg did not produce significant pupillary constriction or significant drug liking When used as directed at therapeutic doses patients will not experience significant central nervous system effects or adverse events consistent with a drug of abuse TRUBERZI (eluxadoline) [summary of product characteristics]. Courbevoie, France: Aptalis Pharma SAS, 2016; Viberzi (eluxadoline) [prescribing information]. Parsippany, NJ: Actavis Pharma, Inc.,

15 Phase 2, Dose-Ranging Trial Double-blind, placebo-controlled trial conducted with 807 patients at 263 primary and tertiary care centres in the US Patients were randomized to receive either placebo or eluxadoline 5 mg, 25 mg, 100 mg, or 200 mg BID for 12 weeks Primary efficacy demonstrated: At Week 4 for eluxadoline 25 mg and 200 mg* At Week 12 for the FDA primary endpoint (post-hoc) for 100 mg or 200 mg *Clinical response at week 4, defined by a mean reduction in daily pain score from baseline of 30% and of at least 2 points on 0 10 scale, as well as a stool consistency score of 3 or 4 on the Bristol Stool Scale (1 7) for at least 66% of daily diary entries during that week; On at least 50% of days during the 12 weeks of the study, reduction of daily WAP score from baseline by 30%, and either a daily Bristol Stool Scale score <5 or no bowel movement. BID, twice a day; WAP, worst abdominal pain in past 24 hours. Dove LS et al. Gastroenterology. 2013;145:

16 Pivotal, Double-Blind, Phase 3 Trials EFFICACY SAFETY CONTINUATION RANDOMIZATION 1:1:1 (day 1) EFFICACY 12 weeks (FDA) EFFICACY 26 weeks (EMA) END OF TREATMENT 52 weeks IBS-3001 Placebo (n=427) BID PTX (2 weeks) PRE-SCREEN ( 1 week) SCREENING (2 3 weeks) Eluxadoline (n=427) 75 mg BID PTX (2 weeks) Eluxadoline (n=426) 100 mg BID PTX (2 weeks) IBS-3002 Placebo (n=382) BID PBO (4 weeks) PRE-SCREEN ( 1 week) SCREENING (2 3 weeks) Eluxadoline (n=381) 75 mg BID PBO (4 weeks) Eluxadoline (n=382) 100 mg BID PBO (4 weeks) Time (weeks) BID, twice a day; EMA, European Medicines Agency; FDA, US Food and Drug Administration; PBO, placebo withdrawal period; PTX, post treatment. Lembo AJ et al. N Engl J Med. 2016;374:

17 Daily composite responder rate (%) PRIMARY ENDPOINT AND ADDITIONAL ANALYSIS Composite Response Placebo Eluxadoline 75 mg Eluxadoline 100 mg Pooled IBS-3001 and IBS-3002 data Week Lembo AJ et al. N Engl J Med. 2016;374:

18 Daily composite responder rate (%) SECONDARY ENDPOINT AND ADDITIONAL ANALYSIS Stool Consistency Placebo Eluxadoline 75 mg Eluxadoline 100 mg Pooled IBS-3001 and IBS-3002 data Week At baseline, patients reported a mean stool consistency score of 6. Lembo AJ et al. N Engl J Med. 2016;374:242; Data on file, Allergan. 18

19 Common Adverse Reactions Discontinuation due to (%) Placebo (n=975) Eluxadoline 75 mg (n=807) Eluxadoline 100 mg (n=1,032) Any Constipation <1 1 2 Abdominal pain <1 1 1 In phase 2 and 3 studies. Viberzi (eluxadoline) [prescribing information]. Parsippany, NJ: Actavis Pharma, Inc.,

20 Common Adverse Reactions Adverse reaction (%) Placebo (n=975) Eluxadoline 75 mg (n=807) Eluxadoline 100 mg (n=1,032) Constipation Nausea Abdominal pain* Most constipation events occurred within the first 3 months of therapy, with ~50% occurring within the first 2 weeks Upper respiratory tract infection Vomiting Rates of constipation were similar between active and placebo arms beyond 3 months of treatment Nasopharyngitits Abdominal distension Severe constipation occurred in <1% of eluxadoline patients Bronchitis Dizziness No serious complications from constipation were reported Flatulence Rash Increased ALT Eluxadoline should be discontinued in patients who develop severe constipation for more than 4 days. Fatigue Viral gastroenteritis The table shows ADE reported in phase 2 and 3 studies in >2% of eluxadoline-treated patients at either dose and at an incidence greater than in placebo-treated patients. During the 4 week single-blind withdrawal period in Study 2, no evidence of worsening of diarrhea or abdominal pain compared to baseline was demonstrated at either dose. *Includes abdominal pain, abdominal pain lower, and abdominal pain upper; Includes dermatitis, dermatitis allergic, rash, rash erythematous, rash generalized, rash maculopapular, rash papular, rash pruritic, urticaria, and idiopathic urticaria. Lembo AJ et al. N Engl J Med. 2016;374:242; Viberzi (eluxadoline) [prescribing information]. Parsippany, NJ: Actavis Pharma, Inc.,

21 Sphincter of Oddi Spasm and Pancreatitis Events in Clinical Trials Eluxadoline 75 mg (n=807) * Eluxadoline 100 mg (n=1,032) Sphincter of Oddi spasm (SOS) 2 (0.2%) 8 (0.8%) All events resolved upon treatment discontinuation, typically improving by the following day; 80% of cases occurred within 1 week of treatment, and the rest within 1 month. 1 patient had abdominal pain and elevated hepatic enzymes 1 patient had abdominal pain and lipase elevation <3x ULN 7 patients had abdominal pain and elevated hepatic enzymes 1 patient had pancreatitis, occurring within minutes of taking treatment Pancreatitis 2 (0.2%) 3 (0.3%) All pancreatic events resolved with lipase normalization upon treatment discontinuation; 80% of cases resolved within 1 week. 3 patients had excessive alcohol intake 1 patient had biliary sludge 1 patient discontinued treatment prior to symptom onset *Of whom 165 did not have a gallbladder; Of whom 184 did not have a gallbladder; Occurred only in patients without a gallbladder. ULN, upper limit of normal Viberzi (eluxadoline) [prescribing information]. Parsippany, NJ: Actavis Pharma, Inc.,

22 Rifaximin Rifaximin effective for bloating in IBS and diarrhea The Target 1 and Target 2 studies showed benefit. Concern is the response with re-treatment is often significantly less Dose recommended: Rifaximin 500 mg TID for 2 weeks Long-term effects on intestinal microbiome of potential concern Pimentel M, Lembo A, Chey WD, et al. N Engl J Med. 2011;364(1):22 22

23 Antidepressant therapies Tricyclic antidepressants appear to be most helpful Reduce diarrhea and abdominal pain Often induce sedation, response may take awhile during the gradual incremental dose increase Long-term effects in older patients of concern Interaction with other medications (prolonged QT interval)

24 Summary Diet history and screen for triggers of diarrhea Loperamide 2 to 16 mg dose as required Cholestyramine or other bile-acid sequestrants Eluxadoline (Viberzi) 100 mg BID (75 mg BID for over age 65) Rifaximin 500 mg TID for 2 weeks Tricyclic antidepressants (start at 10 to 25 mg at night; increase gradually every 1 to 2 weeks)

What Is the Low-FODMAP Diet?

LOW-FODMAP DIET What Is the Low-FODMAP Diet? FODMAP refers to a group of five sugars found in certain foods. These sugars are lactose, fructose (in excess), fructans, galactans and polyols. Specifically,