1. Focus on Pharmacologic Approaches Michael D. Kraft, PharmD, BCNSP Clinical Associate Professor University of Michigan College of Pharmacy Clinical Coordinator University of Michigan Health System Department of Pharmacy Services Ann Arbor, Michigan

2. Faculty Disclosure It is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty, activity planners, content reviewers, and staff participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a person with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation has identified and resolved any and all conflicts of interest prior to the release of this activity. Michael D. Kraft, PharmD, BCNSP, is a member of the speakers bureau and has received honorarium from Cubist Pharmaceuticals.

3. Educational Learning Objectives Describe the importance of improving time to gastrointestinal recovery that occurs postsurgery and consider how this affects length of hospital stay and overall quality of patient care Evaluate the evidence for therapeutic options that may improve gastrointestinal recovery postsurgery and integrate these efforts toward supporting overall surgical quality measures

4. GI Recovery Patient Case 58-year-old female, past medical history of hypertension, constipation-predominant IBS, diverticulosis and diverticulitis; presented to the ED with worsening left lower quadrant abdominal pain x ~5 days, decreased PO intake She states she has had discomfort off and on for several days (similar to previous episode of diverticulitis) then with onset of nausea and vomiting x 24 hours, denies fevers Past medical history: hypertension, constipation- predominant IBS, diverticulosis and diverticulitis (managed with PO antibiotics) Past surgical history: colonoscopy with biopsy (2009, negative for Crohn’s disease or cancer)

5. GI Recovery Patient Case Family history: N/C; no hx/o IBD, IBS, colon cancer Social history –Drinks socially ~1 or 2 times per month –Does not smoke or use illicit drugs Medications –Aspirin 81 mg PO daily –Metoprolol 75 mg PO twice daily –Polyethylene glycol 17 gm PO BID prn constipation (states she uses it 4–5 days/week) Allergies and intolerances – NKDA

6. GI Recovery Patient Case Hospital day 1 –CT with contrast revealed possible diverticulitis –Started on empiric piperacillin/tazobactam 3.375g IV q 6 hours –NG tube was placed and she was made NPO –Abdomen tender on exam, slightly distended –WBC = 12.3 cells x 10 3 /µL –BUN/SCr = 14 mg/dL/0.9 mg/dL –Other labs WNL CT = computed tomography NG = nasogastric NPO = nothing by mouth WBC = white blood cell WNL = within normal limits

7. Hospital day 2 –Patient continued to have increased pain –WBC increased to 14.6 cells x 10 3 /µL –Decision made to take her to the OR for exploratory laparotomy, left hemicolectomy with primary anastomosis Postoperatively –D5 ½ NS + 20 mEq/L KCl at 100 mL/hr –Morphine 2–4 mg IV q 4–6 hours prn pain –Heparin 5000 units SQ q 8 hours –Piperacillin/tazobactam 3.375g IV q6h x 24 hours GI Recovery Patient Case WBC = white blood cell

8. GI Recovery Patient Case Hospital day 3, postoperative day 1 –Patient c/o severe pain not controlled with intermittent morphine  morphine PCA initiated (demand dose = 1mg, lockout = 8 min, 4 hour limit = 40 mg, no basal dose) –Patient c/o mild nausea w/ morphine  NG tube left in place (output ~150 mL q 8 hrs), NPO –Limited ambulation, IS Hospital day 4, postoperative day 2 –Nausea improved  NG tube removed, attempted sips of clear liquids –Encouraged ambulation (patient not very willing to ambulate due to pain) NG = nasogastric PCA = patient-controlled analgesia NPO = nothing by mouth IS = incentive spirometry

9. GI Recovery Patient Case What could have been done preoperatively and immediately postoperatively to improve GI recovery after bowel resection surgery? What preventative/pre-emptive measures could have been taken? Specifically, what pharmacologic treatment options are available for the prevention and treatment of postoperative ileus?

10. Definition of POI “Transient cessation of coordinated bowel motility after surgical intervention, which prevents effective transit of intestinal contents or tolerance of oral intake” Postoperative Ileus Management Council Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006. “The time from surgical intervention until passage of flatus or stool and until initiation of adequate oral intake that is tolerated and maintains hydration during 24 hours” Duration of POI

11. Intestinal Segment Recovery After Surgery Average time to resolution of POI after major abdominal surgery – Small intestine ~12–24 hours – Stomach ~24–48 hours –Colon ~48–120 hours Prolonged POI: > 5 days Luckey A, et al. Arch Surg. 2003;138:206-214. Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:121-132. Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.

12. Pathophysiology of POI: Multifactorial The major causes of POI –Surgical trauma and manipulation of the bowel –Physiologic/metabolic stress (inhibitory inflammatory and acute-phase mediators) –Stimulation of GI opioid receptors by endogenous opioid peptides and exogenous (pharmacologic) opioids –Has been reported after non-abdominal surgeries as well (eg, hysterectomy, knee, thoracic) Kehlet H, Holte K. Am J Surg. 2001;182(5A Suppl):3S-10S. Holte K, Kehlet H. Drugs. 2002;62:2603-2615. Luckey A, et al. Arch Surg. 2003;138:206-214. Behm B, et al. Clin Gastroenterol Hepatol. 2003;1:71-80

13. GI Recovery Patient Case Question This patient has been treated postoperatively with IV morphine for pain. Which of the following best characterizes the expected effect of this pain management strategy on gastrointestinal function? A.Acceleration of gastric emptying B.Stimulation of motility C.Inhibitory effect on motility; bowel dysfunction D.No effect on the GI tract

14. C.Inhibitory effect on motility; bowel dysfunction The gastrointestinal effects of opioids include inhibition of enteric nerve activity, inhibition of propulsive motor activity, and inhibition of secretory activity, all of which contribute to “bowel dysfunction” and POI

15. Opioid-Induced Adverse Effects Nausea Vomiting Sedation Hypotension Respiratory Depression Sweating Urinary retention Pruritus Gastrointestinal effects –Opioid-induced bowel dysfunction (OBD) –Ileus and constipation Kurz A, Sessler DI. Drugs. 2003;63:649-671. Schug SA, et al. J Pain Symptom Manage. 1992;7:259-266. Walsh TD. J Pain Symptom Manage. 1990;5:362-367. “Bowel dysfunction” considered the most common, and often the most debilitating by patients on chronic opioids For more information on opioid-induced bowel dysfunction click on the following link: http://www.ncbi.nlm.nih.gov/pubmed?term=%22Drugs%22%5BJour%5D+AND+63%5Bvolume%5D+AND+649%5Bpag e%5D+AND+2003%5Bpdat%5D&cmd=detailssearch http://www.ncbi.nlm.nih.gov/pubmed?term=%22Drugs%22%5BJour%5D+AND+63%5Bvolume%5D+AND+649%5Bpag e%5D+AND+2003%5Bpdat%5D&cmd=detailssearch

16. Symptoms of POI Abdominal distention/bloating Pain Nausea/vomiting Inability to pass stools Inability to tolerate a solid diet Kehlet H, Holte K. Am J Surg. 2001;182 (5A Suppl):3S-0S. Holte K, Kehlet H. Drugs. 2002;62:2603-2615.

17. There Is an Overall Healthcare Burden Associated with POI Prolonged hospitalization POI Beds occupied for more time Increased nursing time Increased resource utilization Schuster TG, Montie JE. Urology. 2002;59:465-471. Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493. Chang SS, et al. J Urol. 2002;167:208-211. Sarawate CA, et al. Gastroenterology. 2003;124:A-828.

18. Financial Impact of POI After Colectomy “Practical” Definition of POI Retrospective review, 186 colectomy patients Primary POI: > 3 emesis and return to NPO and/or reinsertion of NGT Secondary POI: POI associated with intraabdominal complication Asgeirsson T, et al. J Am Coll Surg. 2010;210:228-231. Outcomen = 186 Primary POI38 (20.4 %)* Secondary POI7 (3.8%) LOS (Primary POI vs. Secondary POI vs. non-POI) 8.9 d vs. 7 d vs. 4 d* Total mean cost for admission (Primary POI vs Secondary POI vs. w/out POI) $15,914 vs. $17,311 vs. $8.316* *P < 0.05, ANOVA For more information on the economic impact of POI, click on the following link: http://www.ncbi.nlm.nih.gov/pubmed?term=%22Journal+of+the+American+College+of+Surge ons%22%5BJour%5D+AND+210%5Bvolume%5D+AND+228%5Bpage%5D+AND+2010%5B pdat%5D&cmd=detailssearch http://www.ncbi.nlm.nih.gov/pubmed?term=%22Journal+of+the+American+College+of+Surge ons%22%5BJour%5D+AND+210%5Bvolume%5D+AND+228%5Bpage%5D+AND+2010%5B pdat%5D&cmd=detailssearch NGT = nasogastric tube

19. Preventive and Therapeutic Management Options for POI Preoperative –Counseling, psychological information/preparation –Glucose-containing fluids –Anxiolytics? Intraoperative –Laparoscopic/minimally-invasive surgical technique –Fluid management/avoiding fluid overload Postoperative –Early NG removal –Early postoperative feeding –Early ambulation –Fluid/sodium/potassium/ magnesium/phosphorus optimization –Gum chewing/sham feeding? –Avoid medications that reduce gastrointestinal (GI) motility Luckey A, et al. Arch Surg. 2003;138:206-214. Mattei P, et al. World J Surg. 2006;30:1382-1391. Person B, et al. Curr Probl Surg. 2006;43:12-65. “Multimodal clinical pathways” Pharmacologic Management −Epidural, NSAIDs/opioid-sparing −Laxatives? Prokinetics? −Peripherally-acting mu-opioid receptor antagonists

20. Epidural Anesthetics/Analgesics

21. Epidural anesthesia with local anesthetics-suppression of inhibitory neural responses Randomized trials demonstrate decreased POI duration compared with systemic opioids –Epidural local anesthetic (epi-LA) better than systemic or epidural opioid –epi-LA vs systemic opioid =  POI –epi-LA vs epi-opioid =  POI –epi-LA/opioid vs systemic opioid =  POI (less than epi-LA) Location of catheter important: thoracic application more effective than lumbar or low-thoracic Epidural Thoracic Anesthetics Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493. Jorgensen H, et al. Cochrane Database Syst Rev. 2001;CD001893.

22. Epidural Anesthetic vs Parenteral Opioids Meta-analysis of 16 trials (n = 806) of colorectal surgery patients –Reduced postop pain by 15-18/100 (95% CI, 10-26; P < 0.001) –Earlier bowel function by ~1.6 days (95% CI, 0.84-2.3; P < 0.001) –Also observed:  Increased hypotension (OR = 13.5, 95% CI: 4-57.7; P < 0.001)  Pruritus (OR = 4.8, 95% CI: 1.3-17; P = 0.02)  Urinary retention (OR = 4.3, 95% CI: 1.2-15.9; P = 0.03) Cochrane Review: Epidural anesthesia reduces time to GI recovery  By 37 hour (19-56) vs systemic opioids  By 24 hour (10-39) vs epidural opioids Marret E, et al. Br J Surg. 2007;94:665-673. Jorgensen H, et al. Cochrane Database Syst Rev. 2001;CD001893.

23. Opioid-Sparing Regimens

24. If a non-steroidal anti-inflammatory drug (NSAID) was incorporated into the postoperative pain management plan for this patient, could benefits be expected with regard to gastrointestinal function? A.Yes B.No C.I’m not sure GI Recovery Patient Case Question

25. A.Yes Use of NSAIDs (such as ketorolac) is an opioid- sparing strategy, which is associated with earlier return of bowel function compared with morphine- only analgesia

26. Opioid-Sparing Analgesia Nonsteroidal anti-inflammatory drugs (NSAIDs) –Randomized, double-blind study of morphine PCA ± ketorolac in 79 colorectal surgeries showed 29% less morphine use, earlier first bowel movement (1.5 [0.7-1.9] vs 1.7 [1-2.8] days, P < 0.05), and earlier ambulation (2.2 ± 1 vs. 2.8 ± 1.2 days, P < 0.05) with NSAID use –Similar results in other surgeries and epidural route –Concerns: platelet inhibition (bleeding), not adequate as sole agent to control moderate-severe postoperative pain Cyclooxygenase-2 (COX-2) Inhibitors –Similar results as NSAIDs –Safety? Person B, Wexner S. Curr Probl Surg. 2006;43:12-65. Chen JY. Acta Anaesthesiol Scand. 2005;49:546-551. For more information on the use of NSAIDs as an opioid sparing strategy, click on the following link: http://www.ncbi.nlm.nih.gov/pubmed?term=%22Acta+anaesthesiologica+Scandinavica%22%5BJour%5D+AND+49%5Bvolu me%5D+AND+546%5Bpage%5D+AND+2005%5Bpdat%5D&cmd=detailssearch http://www.ncbi.nlm.nih.gov/pubmed?term=%22Acta+anaesthesiologica+Scandinavica%22%5BJour%5D+AND+49%5Bvolu me%5D+AND+546%5Bpage%5D+AND+2005%5Bpdat%5D&cmd=detailssearch

27. GI Recovery Patient Case (continued) Hospital day 6, postoperative day 3 –Developed nausea  returned to NPO status –Continued morphine PCA for analgesia –Bowel sounds hypoactive/absent, mild abdominal distention, no flatus or BM, “await return of bowel function” Hospital day 8, postoperative day 5 –Worsening nausea, emesis x 2  diagnosed with ileus –NG tube replaced (~400 mL per 8-hr shift), PN initiated –Ambulation/activity encouraged PN = parenteral nutrition

28. What pharmacologic options would be effective for the treatment of postoperative ileus at this point? A.Metoclopramide B.Erythromycin C.A or B D.None of the above GI Recovery Patient Case Question

29. D.None of the above The evidence does not support a role for either metoclopramide or erythromycin for reduction of POI

30. Prokinetics and Laxatives

31. Metoclopramide for POI Jepsen S et al. Br J Surg. 1986;73:290-291. Cheape JD et al. Dis Colon Rectum. 1991;34:437-441. Tollesson PO et al. Eur J Surg. 1991;157:355-358. Seta ML et al. Pharmacotherapy. 2001;21:1181-1186. Chan DC et al. World J Gastroenterol. 2005;11:4776-4781. Bungard TJ, Kale-Pradham PB. Pharmacotherapy. 1999;19:416-423. Metoclopramide may improve nausea but…studies demonstrate no benefit for reduction of POI Off-label discussion – not FDA-approved for this indication

32. Erythromycin and POI Thought to act as motilin agonist –Stimulates MMC and postprandial activity –Highest quantity of motilin receptors found in gastric antrum and proximal duodenum Few studies have assessed efficacy for reduction of POI and recovery of bowel function after intestinal surgery No studies demonstrate difference between erythromycin and placebo for reduction of POI Bonacini M, et al. Am J Gastroenterol. 1993;88:208-211. Smith AJ, et al. Dis Colon Rectum. 2000;43:333-337. Lightfoor AJ, et al. Urology. 2007;69:611-615. Baig MK, Wexner SD. Dis Colon Rectum. 2004;47:516-526. Bungard TJ, Kale-Pradham PB. Pharmacotherapy. 1999;19:416-423. Off-label discussion – not FDA-approved for this indication

33. Laxatives Double-blind, RCT, 20 patients undergoing elective colectomy for cancer –NG removed at end of surgery, morphine for analgesia, early ambulation –No PO diet until POD #5 (per protocol, regardless of BM) –Bisacodyl vs. placebo suppositories, given on POD #3 if no spontaneous defecation, repeated in 12 hours if no response –POD #3: all 10 bisacodyl patients defecated vs. 2 placebo patients (P < 0.001)  Placebo patients: 5/10 defecated on POD #4, 3/10 on POD #5 –LOS: 8.5 ± 2.7 d vs. 10.4 ± 5.3 d (bisacodyl vs placebo, P = 0.325) –Patients in control received ~twice as much morphine, but no clear correlation between amount of morphine and time to defecation Wiriyakosol S, et al. Asian J Surg. 2007;30:167-171. POD = postoperative day Off-label discussion – not FDA-approved for this indication

34. Laxatives Double-blind, RCT, 169 patients undergoing elective colon resection (open or laparoscopic), multimodal care pathway –Randomized to bisacodyl 10 mg PO or placebo (same capsule) twice daily on day 1 prior to surgery until POD #3 –NGT removed at end of operation; all patients offered epidural for analgesia (x 5-days postop); systemic opioids used as second-line; PO intake started POD #1 –Mean time to composite endpoint (1 st flatus, 1 st defecation, 1 st solid food) ~0.6 d shorter in favor of bisacodyl (P = 0.007), primarily due to reduction in time to defecation (~1.2 d shorter, P = 0.001) –No difference in secondary endpoints including LOS Bisacodyl may have a role in reducing POI, further data needed to determine optimal timing and dose Zingg U, et al. Int J Colorectal Dis. 2008;23:1175-1183. Off-label discussion – not FDA-approved for this indication

35. Peripherally-Acting mu-Opioid Receptor Antagonists

36. Methylnaltrexone and alvimopan are peripherally acting mu-opioid receptor antagonists. Evidence from phase 3 studies has demonstrated enhanced gastrointestinal recovery following colorectal surgery for patients treated with: A.Methylnaltrexone B.Alvimopan C.Both methylnaltrexone and alvimopan GI Recovery Patient Case Question

37. B.Alvimopan Methylnaltrexone is FDA-approved for chronic opioid- induced constipation in patients receiving palliative care, but benefits for POI were not demonstrated in phase 3 clinical trials. Data from multiple phase 3 trials demonstrated that compared with placebo, patients undergoing bowel resection treated with alvimopan had accelerated return of bowel function and reduced length of stay. Alvimopan is FDA-approved for accelerating gastrointestinal recovery following partial large or small bowel resection surgery

38. Methylnaltrexone Peripherally-acting mu-opioid receptor antagonist, approved for treatment of chronic opioid-induced constipation in patients with advanced illness receiving palliative care when response to laxative therapy has not been sufficient FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021964s009lbl.pdf. Accessed September 2012.

39. Methylnaltrexone Evaluated for treatment/reduction of POI –Patients undergoing segmental colectomy and ventral hernia repair –Treatment: IV methylnaltrexone (12 or 24 mg) or placebo every 6 hours –Primary endpoint: reduction in time to recovery of GI function compared with placebo –Results: treatment did not achieve primary or secondary endpoints in any of the phase III trials http://www.clinicaltrials.gov/ct2/show/NCT00387309. Accessed September 2012. http://www.clinicaltrials.gov/ct2/show/NCT00401375. Accessed September 2012. http://www.clinicaltrials.gov/ct2/show/NCT00528970. Accessed September 2012. http://www.progenics.com/releasedetail.cfm?ReleaseID=370543. Accessed September 2012. Yu CS, et al. Dis Colon Rectum. 2011;54:570-578. For more information about methylnaltrexone and POI, click the following link: http://www.ncbi.nlm.nih.gov/pubmed?term=%22Diseases+of+the+colon+and+rectum%22%5BJour%5D+AND+54%5B volume%5D+AND+570%5Bpage%5D+AND+2011%5Bpdat%5D&cmd=detailssearch http://www.ncbi.nlm.nih.gov/pubmed?term=%22Diseases+of+the+colon+and+rectum%22%5BJour%5D+AND+54%5B volume%5D+AND+570%5Bpage%5D+AND+2011%5Bpdat%5D&cmd=detailssearch Off-label discussion – not FDA-approved for this indication

40. Alvimopan

41. Azodo IA, et al. Curr Opin Investig Drugs. 2002;3:1496-1501. Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S. Taguchi A, et al. N Engl J Med. 2001;345:935-940. Wolff BG, et al. Ann Surg. 2004;240:728-735. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. Viscusi E, et al. Surg Endosc. 2006;20:67-70. Ludwig K, et al. Arch Surg. 2008;143:1098-1105. Buchler M, et al. Aliment Pharmacol Ther. 2008;28:312-325. FDA approval available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed September 2012. Peripherally acting µ-opioid receptor antagonist, highly selective for µ-opioid receptor Does not readily cross the blood-brain barrier or block central opioid receptors Bioavailability ~6%, metabolized by intestinal flora, primarily biliary (~65%) and renal (35%) elimination, terminal half-life ~14 hours P-glycoprotein substrate –Not affected by mild-moderate P-gp inhibitors; strong inhibitors? –Not apparent inhibitor or inducer of P450 isoenzymes Phase I, phase II, and phase III trials completed FDA approval May 2008

42. Alvimopan for POI Phase 3 Clinical Trial Summary StudySurgeryN (MITT) Alvimopan Dose (mg) Primary Endpoint Secondary Endpoints 313 1 Bowel resection or radical hysterectomy 510 (469)6, 12GI-3GI-2, DOW 302 2 Partial colectomy or simple or radical hysterectomy 451 (424)6, 12GI-3GI-2, DOW 308 3 Bowel resection or simple or radical hysterectomy 666 (615)6, 12GI-3GI-2, DOW 314 4 Bowel resection654 (629)12GI-2GI-3, DOW 001 5 Bowel resection738 (705)6, 12GI-3GI-2, DOW GI-3: later time of first tolerated solid food and time for first flatus or bowel movement; GI-2: later time of first tolerated solid food and time for bowel movement; DOW: time to discharge order written All studies conducted in North America except 001, which was conducted in Europe and New Zealand Wolff BG, et al. Ann Surg. 2004;240:728-735. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. Viscusi E, et al. Surg Endosc. 2006;20:67-70. Ludwig K, et al. Arch Surg. 2008;143:1098-1105. Buchler M, et al. Aliment Pharmacol Ther. 2008;28:312-325.

43. Alvimopan POI Phase 3 Study Design Upper and Lower GI Recovery GI-3: later time of first tolerated solid food and time for first flatus or bowel movement; GI-2: later time of first tolerated solid food and time for bowel movement Surgery Randomization Placebo BID Alvimopan 6 mg BID Pre-op dose ≥ 30 min and < 5 hrs before surgery Endpoints: GI-2, GI-3, Time to discharge order written, safety Treatment until discharge or up to 7 days, maximum 15 doses Alvimopan 12 mg BID* *FDA-approved dose

44. Alvimopan for POI: Phase 3 Trials Men and women, ≥ 18 years old All patients received standardized postoperative care –Analgesia via opioid patient-controlled analgesia (PCA) –Nasogastric (NG) tube out at end of surgery or POD #1 –Liquids offered, ambulation encouraged on POD 1 –Solid food offered on POD 2 Exclusions: opioids > 3 doses within 1 week of surgery, epidural opioids, local anesthetics, nonsteroidal antiinflammatory drugs (NSAIDs), or severe concomitant disease(s) Wolff BG, et al. Ann Surg. 2004;240:728-735. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. Viscusi E, et al. Surg Endosc. 2006;20:67-70. Ludwig K, et al. Arch Surg. 2008;143:1098-1105. Buchler M, et al. Aliment Pharmacol Ther. 2008;28:312-325.

45. Alvimopan North American Phase 3 Studies: GI Recovery 140 Studies 313, 302, 308: bowel resection and hysterectomy; Study 314: bowel resection only MITT Populations Wolff BG, et al. Ann Surg. 2004;240:728-735. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. Viscusi E, et al. Surg Endosc. 2006;20:67-70. Ludwig K, et al. Arch Surg. 2008;143:1098-1105. 0 20 40 60 80 100 120 Study 308 Viscusi, et al Study 302 Delaney, et al Study 313 Wolff, et al Study 314 Ludwig, et al Time to GI-2 (hours) Placebo 12 mg Alvimopan * *P < 0.001; § P < 0.02 § *

46. Alvimopan North American Phase 3 Studies: Discharge Orders Written -25 -20 -15 -10 -5 0 Study 308 Viscusi, et al Study 302 Delaney, et al Study 313 Wolff, et al Study 314 Ludwig, et al Reduction in Time to Discharge Order Written Compared with Placebo (hours) 12 mg Alvimopan P = 0.003 P = 0.01 P < 0.001 Studies 313, 302, 308: bowel resection and hysterectomy; Study 314: bowel resection only MITT Populations Wolff BG, et al. Ann Surg. 2004;240:728-735. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. Viscusi E, et al. Surg Endosc. 2006;20:67-70. Ludwig K, et al. Arch Surg. 2008;143:1098-1105.

47. Alvimopan POI-Related Morbidity Bowel Resection Pooled Analysis ‡ Wolff B, et al. J Am Coll Surg. 2007;204:609-616. *P ≤ 0.001 ‡ Studies 302, 308, 313, 314 POM: postoperative morbidity; NGT: nasogastric tube; POI: postoperative ileus 0 2 4 6 8 10 12 14 16 18 Overall POMPost-op NGT Insertion Overall POI Complications POI Complications Resulting in Prolonged Stay POI Complications Resulting in Readmission Patients (%) Placebo N = 695 Alvimopan 12 mg N = 714 * * * * To read more about this study, click on the following link: http://www.ncbi.nlm.nih.gov/pubmed?term=%22Journal+of+the+American+College+of+Surgeons%22%5BJour%5D+AND+204%5Bvolume%5D+AND+609 %5Bpage%5D+AND+2007%5Bpdat%5D&cmd=detailssearch http://www.ncbi.nlm.nih.gov/pubmed?term=%22Journal+of+the+American+College+of+Surgeons%22%5BJour%5D+AND+204%5Bvolume%5D+AND+609 %5Bpage%5D+AND+2007%5Bpdat%5D&cmd=detailssearch

48. Alvimopan for POI: Pooled Analysis Pooled analysis of patients from 4 Phase III North American trials –Only bowel resection patients  –Only alvimopan 12 mg (n = 714) or placebo (n = 695)  AlvimopanPlacebo Mean time to GI-2102.0 hrs121.8 hrs Mean time to D/C order written124.9 hrs142.9 hrs Mean LOS*6.6 ± 3.8 d7.6 ± 4.2 d Pts w/ prolonged LOS134 (19%)239 (34%)  FDA-approved dose and indication *Calculated from calendar day of surgery to calendar day of D/C order written Bell TJ, et al. Am J Health-Syst Pharm. 2009;66:1362-1368. For more information on this analysis, click on the following link: http://www.ncbi.nlm.nih.gov/pubmed?term=%22American+journal+of+health- system+pharmacy+%3A+AJHP+%3A+official+journal+of+the+American+Society+of+Health- System+Pharmacists%22%5BJour%5D+AND+66%5Bvolume%5D+AND+1362%5Bpage%5D+AND+2009%5Bpdat%5D&cmd=detailssearchhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22American+journal+of+health- system+pharmacy+%3A+AJHP+%3A+official+journal+of+the+American+Society+of+Health- System+Pharmacists%22%5BJour%5D+AND+66%5Bvolume%5D+AND+1362%5Bpage%5D+AND+2009%5Bpdat%5D&cmd=detailssearch

49. Treatment- Emergent Adverse Reaction Bowel Resection PatientsAll Surgical Patients Placebo (N = 986) % Alvimopan (N = 999) % Placebo (N = 1365) % Alvimopan (N = 1650) % Anemia4.25.25.4 Constipation3.94.07.69.7 Dyspepsia4.67.04.85.9 Flatulence4.53.17.78.7 Hypokalemia8.59.57.56.9 Back pain1.73.32.63.4 Urinary retention2.13.22.33.5 Worldwide POI Safety Population Entereg. www.accessdata.fda.gov/drugsatfda_docs/label/2009/021775s004lbl.pdf. Accessed September 2012. *Bell TJ, et al. Am J Health-Syst Pharm. 2009;66:1362-1368. Alvimopan Safety Treatment-emergent Adverse Events Reported in ≥ 3% of Alvimopan Patients & Rate for Alvimopan ≥ 1% than Placebo *Nausea: alvimopan 12 mg = 56%, placebo = 65% (P < 0.001) *Vomiting: alvimopan 12 mg = 19%, placebo = 27% (P < 0.001)

50. Alvimopan for POI: Potential Cost Considerations Mean doses of alvimopan = 8.9 Total hospital costs estimated from Premier’s Perspective Comparative Database, and from US Census Bureau data (2004- adjusted to 2007 dollars) Alvimopan cost estimated at $62.50 per dose (First Data Bank as of June 2008) AlvimopanPlacebo Total hospital costs-Premier’s ^ $14,798$15,677 Total hospital costs-Census data ^ $11,329$12,306 Bell TJ, et al. Am J Health-Syst Pharm. 2009;66:1362-1368. ^P < 0.05

51. Alvimopan Study 014 Safety Concerns

52. Alvimopan Safety: Adverse CV Events in Opioid-induced Bowel Dysfunction (OBD) Study 12-month study of alvimopan 0.5 mg or placebo twice daily, patients taking chronic opioids for chronic non-cancer pain More reports of myocardial infarction (MI) in patients treated with alvimopan (7 [1.3%]) vs. placebo (0) –Serious CV adverse events in patients at high risk for CV disease –MI did not appear to be linked to duration of dosing –Not observed in other alvimopan studies, including POI studies in patients undergoing bowel resection (12 mg dose BID up to 15 total doses) –Causal relationship between alvimopan and MI has not been established –POI studies: majority of patients (~95%) evaluated only to ~2 weeks –Ongoing monitoring of patients receiving alvimopan essential –FDA required Risk Evaluation and Mitigation Strategy (REMS) http://www.gsk.com/media/pressreleases/2007/2007_04_09_GSK1012.htm. Accessed September 2012 http://www.fda.gov/ohrms/DOCKETS/ac/08/briefing/2008-4336b1-02-Adolor.pdf. Accessed September 2012.

53. Alvimopan REMS Program E.A.S.E.™ Program –Distribution Program for alvimopan –Alvimopan only available to hospitals that perform bowel resection surgery and that enroll in E.A.S.E. Program –Hospital must acknowledge:  Staff who prescribe, dispense, or administer alvimopan have been provided the educational materials  Hospital has systems, order sets, protocols, or other measures in place to limit the use of alvimopan to short-term, inpatient use, and patients will not receive more than 15 doses  Alvimopan will not be dispensed to patients after they have been discharged from the hospital and will not be transferred to hospitals that are not registered E.A.S.E.: Entereg Access Support and Education. http://www.entereg.com/content/e_a_s_e_program/. Accessed September 2012

54. Alvimopan for POI Summary Treatment of patients undergoing bowel resection with alvimopan compared with placebo –Accelerated return of bowel function –Reduced the time to discharge order written –Reduced postoperative ileus-related morbidity Alvimopan did not reverse postoperative analgesia Alvimopan was well tolerated; adverse events were similar between placebo and alvimopan treatment groups

55. Alvimopan for POI Summary Alvimopan must be started PREOPERATIVELY (1 dose), continued postoperatively for maximum of 15 total doses, patients receiving systemic opioids for analgesia Hospitals must enroll in REMS program, ongoing monitoring essential Potential overall cost benefit if length of stay reduced

56. GI Recovery Patient Case (continued) Hospital day 10, postoperative day 7 –Nausea and vomiting improved –NG output decreased, distention improved –Morphine PCA changed to intermittent morphine IV –Given bisacodyl 10 mg suppository x 1 (no response) Hospital day 11, postoperative day 8 –NG removed – + flatus –Initiated clear liquid diet –Initiate polyethylene glycol 17g PO twice a day –Repeat bisacodyl suppository (with small BM)

57. GI Recovery Patient Case (continued) Hospital day 12, postoperative day 9 –Advanced to full liquid diet in morning, then regular diet in afternoon, wean PN off Hospital day 13, postoperative day 10 –Good PO intake + bowel movement –Incision clean, no distention –Minimal pain –No nausea/vomiting –Labs WNL –D/C home D/C = discharge

58. Summary: Pharmacologic Therapies With Proven Benefit Epidural anesthesia/analgesia Minimization of opioid administration (opioid- sparing) Alvimopan (started preoperatively, continued postoperatively)

59. Summary: Pharmacologic Therapies With NO Proven Benefit Prokinetic agents (erythromycin, metoclopramide)

60. Summary: Pharmacologic Therapies That May Be Beneficial Laxatives (bisacodyl)

61. Best Option to Enhance GI Recovery After Bowel Resection Surgery: “Fast-Track Recovery” or “Multimodal Treatment” Approach Interdisciplinary, multimodal concept to accelerate postoperative recovery and reduce general morbidity (including POI) by simultaneously applying several interventions Mattei P. World J Surg. 2006;30:1382-1391. Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.

62. Multimodal Approach: Preoperative Components Education: health care team AND patients Stabilize coexisting diseases Optimize comfort (minimize anxiety) Ensure appropriate hydration, correct electrolyte abnormalities, normothermia Appropriate use of prophylactic therapy (antiemetics, analgesics, antibiotics, possibly alvimopan if appropriate) White PF, et al. Anesth Analg. 2007;104:1380-1396. Kehlet H, et al. Br J Surg. 1999;86:227-230. Delaney CP, et al. Br J Surg. 2001;88:1533-1538. Delaney C, et al. Dis Col Rect. 2003;46:851-859. Person B, et al. Curr Probl Surg. 2006;43:12-65.

63. Multimodal Components: Intraoperative Components Anesthesia to optimize surgery and recovery Local anesthesia/analgesia (or thoracic epidural) if possible Laparoscopic/minimally-invasive surgery if possible White PF, et al. Anesth Analg. 2007;104:1380-1396. Kehlet H, et al. Br J Surg. 1999;86:227-230. Delaney CP, et al. Br J Surg. 2001;88:1533-1538. Delaney C, et al. Dis Col Rect. 2003;46:851-859. Person B, et al. Curr Probl Surg. 2006;43:12-65.

64. Multimodal Approach: Postoperative Components Early NG tube removal Fluid and electrolyte management Laxative/bowel regimen, start oral feeding early Minimize opioids, possibly alvimopan if appropriate and started prior to surgery Ambulation Discharge criteria White PF, et al. Anesth Analg. 2007;104:1380-1396. Kehlet H, et al. Br J Surg. 1999;86:227-230. Delaney CP, et al. Br J Surg. 2001;88:1533-1538. Delaney C, et al. Dis Col Rect. 2003;46:851-859. Person B, et al. Curr Probl Surg. 2006;43:12-65.

65. Engage the Multidisciplinary Team Surgeons Anesthesiologists Physician assistants, nurse practitioners Med-surgical nurses Hospital pharmacists Rehabilitation personnel

66. Potential Future Pharmacologic Therapies for POI* *None of the following agents have been approved by the FDA for this indication, therefore all discussions are off-label

67. Potential Future Therapies for POI? Prokinetic agents: 5-HT 4 agonists Prucalopride*: High affinity and selectivity for 5-HT 4 receptor –Evaluated in randomized, placebo-controlled, multicenter phase 3 trial x 12 weeks –Total 620 patients with severe chronic constipation –Prucalopride 2 mg and 4 mg daily significantly improved frequency of BMs, as well as satisfaction with treatment, severity of symptoms, & QOL; no significant effect on QTc Mosapride*: 5-HT 4 agonist, available in Japan –Evaluated for POI in 40 patients after hand-assist laparoscopic colectomy –Mosapride 15 mg PO q8h vs placebo, all received multimodal care –Mosapride significantly reduced time to first BM (48.5 vs. 69.3 hours, P = 0.0149) and LOS (6.7 v. 8.4, P = 0.0398) –No QT prolongation reported Camilleri M, et al. N Engl J Med. 2008;358:2344-2354. Narita K, et al. Dis Colon Rectum. 2008;51:1692-1695. www.clinicaltrials.gov. Accessed September 2012. *No current or ongoing US studies for POI

68. Potential Future Therapies for POI? Ghrelin agonists: hormone involved in regulation of appetite and GI motility –Studies of ghrelin agonists in rat model of surgical and morphine- induced ileus  RC-1139 1  TZP-101 (ulimorelin) 2  Ipamorelin 3 –Effects may be more pronounced in stomach vs small intestine –Phase 2 trial of ipamorelin for POI completed, 4 another ongoing 5 –Phase 2 study of TZP-101 (ulimorelin) for POI completed 6 1.Poitras P, et al. Peptides. 2005;26:1598-601 2.Fraser GL, et al. Eur J Pharmacol. 2009;604:132-137 3.Venkova K, et al. J Pharmacol Exp Ther. 2009;329:1110-1116. 4.NCT00672074. http://www.clinicaltrials.gov. Accessed September 2012. 5.NCT01280344. http://www.clinicaltrials.gov. Accessed September 2012. 6.Popescu I, et al. Dis Colon Rectum. 2010;53:126-134.

69. Potential Future Therapies for POI? Prokinetic agents: Motilin agonists (atilmotin) –Peptide analogue (IV dosage form) –Accelerated gastric emptying at 30 min, no effect on colonic filling or colonic transit –No trials recruiting or completed currently found –Others may be in development: BM-591348 (synthetic), KOS-2187 (non-peptide) –SK-896 evaluated in dog model of POI Park MI, et al. Neurogastroenterol Motil. 2006;18:28-36. Furuta Y, et al. Biological Pharmaceutical Bulletin. 2002;25:1063-1071. www.clinicaltrials.gov. Accessed August 2012.

70. Summary and Final Thoughts Limited pharmacologic options for prevention/treatment of POI Alvimopan may be of overall benefit if : –Started preoperatively (30 min–5 hours) x 1 dose –Patient receiving systemic opioids for analgesia –Length of stay can be reduced Early ambulation and early PO intake may not reduce POI, but should be encouraged given other benefits Multimodal approach may be best overall Future potential treatment options must be evaluated