Amitiza® (lubiprostone), Linzess® () Prior Authorization Criteria Program Summary

OBJECTIVE The intent of the Prior Authorization (PA) program for Amitiza (lubiprostone) and Linzess (linaclotide) is to ensure appropriate selection of patients for treatment according to product labeling and/or clinical studies and/or guidelines. The PA defines appropriate use as use in patients with a Food and Drug Administration (FDA) approved indication of chronic idiopathic (in adults), with constipation (for Amitiza, in women >18 years of age; for Linzess, in adults >18 years of age), or -induced constipation in adults with chronic non-cancer pain (Amitiza only). The PA criteria require that the patient has had symptoms of chronic idiopathic constipation or irritable bowel syndrome with constipation > 3 months. The PA criteria also require that patients have tried at least two standard therapy classes for constipation, including osmotic (, , -based including milk of magnesia), fiber or bulking agents (, bran, methylcellulose), stool softeners (), or over-the-counter stimulant laxatives containing senna or . Criteria do not allow coverage for lubiprostone or linaclotide in patients who have FDA labeled contraindication(s) to the requested product. Requests for lubiprostone and linaclotide will be reviewed when patient- specific documentation has been provided.

TARGET DRUG  Amitiza (lubiprostone)  Linzess (linaclotide)

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL Amitiza or Linzess will be approved when BOTH of the following are met: 1. ONE of the following: a. The patient has a diagnosis of irritable bowel syndrome with constipation with documentation of symptoms for >3 months and ONE of the following: i. For Linzess, the patient is an adult >18 years of age OR ii. For Amitiza, the patient is a woman >18 years of age OR b. The patient is an adult >18 years of age with a diagnosis of chronic idiopathic constipation with documentation of symptoms for >3 months OR c. For Amitiza only, the patient is an adult >18 years of age with a diagnosis of opioid-induced constipation with chronic non-cancer pain and ALL of the following: i. The patient has chronic use of an opioid agent in the past 30 days AND ii. The patient is not receiving a diphenylheptane opioid (e.g. methadone) in the past 30 days AND 2. ONE of the following: a. The patient has tried at least 2 standard laxative therapy classes OR b. The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least 2 standard laxative therapy classes AND 3. The patient does NOT have any FDA labeled contraindication(s) to the requested agent

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© Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved Length of approval: 12 months

FDA Labeled Contraindication(s) Agent Contraindication(s) Amitiza (lubiprostone) Known or suspected mechanical gastrointestinal obstruction Linzess (linaclotide) Known or suspected mechanical gastrointestinal obstruction Pediatric patients up to 6 years of age

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© Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved FDA APPROVED INDICATIONS AND DOSAGE1,12 Product Indication(s) Dosage and Administration Amitiza Treatment of irritable bowel IBS- 8 mcg taken twice daily (lubiprostone) syndrome with constipation orally with food and water. (IBS-C) in women ≥ 18 years old. capsules (8 mcg, 24 mcg) Treatment of chronic idiopathic CIC, OIC - 24 mcg taken twice constipation (CIC) in adults daily orally with food and water.

Treatment of opioid-induced constipation (OIC) in adults with For patients with moderately chronic, non-cancer pain impaired hepatic function Limitation of Use: Effectiveness (Child-Pugh Class B), of Amitiza in the treatment of recommended starting dose is OIC in patients taking 16 mcg twice daily; for patients diphenylheptane with severely impaired hepatic (e.g. methadone) has not been function (Child-Pugh Class C), established. recommended starting dose is 8 mcg twice daily. If tolerated dose can be escalated if needed. Linzess Treatment of irritable bowel IBS- 290 mcg taken once daily (linaclotide) syndrome with constipation orally on an empty , at (IBS-C) in adults. least 30 minutes prior to the first capsules meal of the day. (145 mcg, 290 mcg) Treatment of chronic idiopathic constipation (CIC) in adults. CIC- 145 mcg taken once daily orally on an empty stomach, at least 30 minutes prior to the first meal of the day

Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating CIC-2 chloride channels, a normal constituent of the apical membrane of the human intestine. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, alleviating symptoms associated with constipation.1

Linaclotide is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, resulting in increased intestinal fluid and accelerated transit.12 CLINICAL RATIONALE Chronic Constipation: Chronic constipation is characterized by decreased frequency of bowel movements, persistent symptoms of straining, lumpy or hard stools, and feelings of blockade or incomplete bowel evacuation.2,11 In a position statement on the management of chronic constipation, the American College of Gastroenterology (ACG) Task Force advocates this definition: “Constipation is a symptom-based disorder and is characterized by infrequent defecation, difficult stool passage, or both,” with chronic constipation defined as the presence of these symptoms for at least three months.11 Chronic constipation is generally differentiated as primary or secondary in nature. Primary is classified as normal transit constipation (functional) or slow transit constipation. Secondary constipation may have several factors AL_PS_Amitiza_Linzess_PA_ProgSum_AR0715 Page 3 of 9

© Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved contributing to the condition.3,11 These include dietary causes, such as low fiber and fluid consumption, neurological disease, metabolic or endocrine disorders, psychological illness, or . Unknown causes of constipation are identified as chronic idiopathic constipation (CIC).3,11

The ACG Task Force review recommends the following for treatment of chronic constipation: bulking agents (psyllium), osmotic laxatives (polyethylene glycol [PEG], lactulose), and . The task force found data insufficient to make a recommendation regarding stool softeners, stimulant laxatives, or herbal supplements.11

The efficacy of lubiprostone for CIC was demonstrated in two double-blind, placebo-controlled dose ranging study, phase III trials, a withdrawal study, and several open-label studies. The dose-ranging study evaluated the efficacy and safety of lubiprostone in 120 patients with symptoms of chronic constipation for ≥ 6 months of duration.6 Patients received either lubiprostone (24, 48, or 72 micrograms/day) or placebo for 3 weeks. Patients in the treatment groups had a significant increase in the average number of weekly spontaneous bowel movements (SBMs) during the first (p=0.006) and second week of the study (p=0.014) and over the entire study period (p=0.046) compared with placebo. Adverse effects increased with increasing dosage, especially (occurring in up to 44% of patients on the 48 microgram dose). Data from the two other phase III trials reinforced the findings of the dose-ranging study.7-8 In the first study patients (N=242) with CIC were treated with lubiprostone (24 micrograms) or placebo twice daily for four weeks.8 Compared to placebo, the treatment group had more SBMs during week 1 (5.69 vs 3.46, p=0.0001), and the effect was sustained during each of the subsequent weeks of the study.8

The efficacy of linaclotide for the management of the signs and symptoms of CIC was assessed in two double-blind, placebo-controlled, randomized, multicenter studies in adult patients.13. A total of 642 patients in Trial 3 and 630 patients in Trial 4 received treatment with linaclotide 145 mcg or linaclotide 290 mcg or placebo. Patients with IBS were excluded from the studies. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of ≥ CSBMs from baseline during ≥ 9 of the 12 weeks. The proportion of patients who were CSBM responders was statistically significantly greater in each of the 2 trials with each dose of linaclotide (145 mcg and 290 mcg) compared to placebo. Secondary endpoints included stool frequency, stool consistency, severity of straining, abdominal discomfort, bloating, and constipation severity.13

The primary end point was reached by 21.2% and 16.0% of the patients who received 145 mcg of linaclotide and by 19.4% and 21.3% of the patients who received 290 mcg of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (P<0.01 for all comparisons of linaclotide with placebo). Improvements in all secondary end points were significantly greater in both linaclotide groups than in the placebo groups. The incidence of adverse events was similar among all study groups, with the exception of , which led to discontinuation of treatment in 4.2% of patients in both linaclotide groups (P <0.001 vs placebo for secondary endpoints).13

Irritable Bowel Syndrome with Constipation (IBS-C): According to the Rome III diagnostic criteria, IBS is defined as or discomfort recurring at least 3 days per month in the previous 3 months, and this pain or discomfort must be associated with 2 or more of the following: (1) defecation improves pain or discomfort, (2) a change in stool frequency is associated with the pain or discomfort, and/or (3) a change in stool form/appearance is associated with the onset of pain or discomfort. These criteria must be met in the last 3 months of the onset of symptoms and at least 6 months prior to diagnosis.3,4

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© Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved The American College of Gastroenterology monograph (2014) on the management of IBS and CIC states that although linaclotide and lubiprostone are effective in constipation- predominant IBS, these agents were evaluated vs. placebo rather than “standard therapy”. Their position in an IBS treatment algorithm (i.e., for those who have failed other treatments or as primary therapy) is difficult to define and complicated by lack of consensus on what “standard” therapy should be in IBS, given the limitations of data on other agents.20

The goal of treatment of IBS-C is to improve symptoms such as abdominal bloating, discomfort, and constipation. The American College of Gastroenterology states that in some patients, lifestyle modifications, high fiber diets, over-the-counter laxatives (including bulking agents such as psyllium and polyethylene glycol [PEG]), tricyclic antidepressants and SSRIs, or antispasmodics may be effective treatment. In more severe cases of IBS-C, lubiprostone may be effective.4 The guideline states that lubiprostone has not been studied in men and that more data is needed before lubiprostone can be recommended in men with IBS-C.4

The FDA approval of lubiprostone for the treatment of IBS-C was based on a clinical study program that included two Phase 3, multi-center, double-blinded, randomized, placebo- controlled trials involving 1,171 adults, followed by an open-label safety and efficacy extension trial involving 522 adults diagnosed with IBS-C.10 In the two Phase 3 trials, patients received lubiprostone 8 mcg twice daily or placebo twice daily over a 12-week period. Patients receiving lubiprostone were nearly twice as likely to achieve overall relief that was statistically significant compared to those receiving placebo (17.9% vs. 10.1%; P=0.001). Individually, each study showed lubiprostone's efficacy over placebo for overall relief (P=0.009 and P=0.031).

The efficacy of linaclotide for the management of IBS-C was assessed in two double- blind, placebo-controlled, randomized, multicenter studies in adult patients.14,15 A total of 800 patients in Trial 1 and 804 patients in Trial 2 received treatment with linaclotide 290 mcg or placebo once daily. Patients had a mean abdominal pain score of ≥ 3 on a 0-10 point numeric rating scale, < 3 complete spontaneous bowel movements (SBMs) [complete bowel movement {CSBM} is defined as a SBM that is associated with a sense of complete evacuation; a SBM is a bowel movement occurring in the absence of laxative use), and ≤ 5 SBMs per week during a 2 week baseline period.

In Trial 1 patients received linaclotide (n = 405) or placebo (n = 395) for 12 weeks. An additional 4 weeks after the initial 12-week treatment period were included to assess the effects of therapy withdrawal (randomized withdrawal period). During this time, patients previously randomized to placebo received linaclotide, and patients who originally received linaclotide were randomly assigned to either linaclotide or placebo. After 12 weeks, the percentage of patients meeting the composite endpoint was significantly greater with linaclotide compared with placebo (12.1 versus 5.1, respectively; P = 0.0004).14 All secondary endpoints (abdominal pain/discomfort, bloating, straining, stool consistency, and number of CSBMs and SBMs per week) demonstrated statistically significant improvements with drug compared with placebo. Abdominal pain, discomfort, and bloating had a mean change from baseline of approximately -2 (rated on a 10-point scale), compared with -1.1 with placebo (P < 0.0001), and straining -1.3 (rated on a five-point scale) compared with - 0.7 with placebo (P< 0.0001). The number of weekly CSBMs and SBMs increased to 2.3 and 3.9, respectively, compared with 0.7 and 1.1 with placebo (P < 0.0001). After the initial 12 weeks, patients originally given linaclotide and who remained on linaclotide showed continued improvements, but a return of symptoms was seen in those patients who were switched to placebo therapy. On the other hand, patients given placebo showed improvement in abdominal pain in just one week after being switched to linaclotide.14

In another double-blind Phase III trial-Trial 2, the long term use of linaclotide was assessed, in which patients were randomized to receive either linaclotide 290 mcg (n = 401) or placebo

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© Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved (n = 403) for a period of 26 weeks38. The primary endpoint of the trial was a composite endpoint identical to the previous study. In total, 12.7% of patients randomized to linaclotide demonstrated significant improvement in the primary endpoint compared with only 3% given placebo (P < 0.0001); these improvements were sustained throughout the 26 weeks of the trial.15  Approximately 39% of patients given linaclotide had a >30% reduction in abdominal pain as compared with 19% for placebo. A significant decrease in abdominal pain, discomfort, and bloating of −1.9 (rated on a 10-point scale) occurred with linaclotide versus −1.1 with placebo at 12 weeks (P < 0.0001 for all measures), and a further decrease of -2.2 in the linaclotide group compared with −1.2 with placebo was seen at 26 weeks.  At 12 and 26 weeks, the number of weekly CSBMs and SBMs increased to 2.2 and 4.0 for linaclotide treated patients, compared with 0.7 and 1.2 for placebo treated patients.15

Opioid-Induced Constipation (OIC): Opioids are commonly used analgesics for moderate to severe pain and are a mainstay of pain management for patients with advanced illness receiving palliative care. A common side effect of opioid treatment is OIC. The signs and symptoms of OIC include dry, hard stools; straining during evacuation; incomplete evacuation; bloating; and . Additional symptoms include cramping, nausea, and . OIC may continue for the duration of opioid therapy.16

There is no single definition of OIC. In clinical trials of lubiprostone, inclusion criteria for OIC were defined as ”the occurrence of either less than 3 spontaneous bowel movements per week, with at least 25% of SBMs associated with one or more of the following conditions: hard to very hard stool consistency; moderate to very severe straining; and/or having a sensation of incomplete evacuation.”1 Oral laxatives are the mainstay of the treatment of OIC, classified into two general categories, softening (i.e., docusate) and peristalsis-inducing agents (i.e., senna and bisacodyl). These agents are non-specific, as they do not affect the opioid receptor-mediated reason for constipation.16 Current National Comprehensive Cancer Network (NCCN) guidelines17,18 recommend the following for treatment of OIC: polyethylene glycol (PEG), lactulose, , magnesium hydroxide, , or bisacodyl. A prokinetic agent such as metoclopramide may also be useful. Other reviewers also mention the use of fiber bulking agents and stool softeners, noting that there are few clinical trials on which to base treatment guidelines.19

A treatment pathway for OIC (2014, U.K.) first recommends non-pharmacologic intervention (increased fluids, fiber, and physical activity), and then laxative intervention (e.g., stimulants, softeners, , etc) on starting opioid use and for the duration of treatment, followed by use of opioid antagonists as the last step in the pathway.21

A review on OIC (2013, U.S.) suggests stimulant laxatives, with or without stool softeners, as the first-line pharmacologic treatment used in most patients. Only 50 % of patients experience satisfactory relief using this strategy. For this reason, treatment with laxatives often requires frequent dose adjustments, combination therapy, and laxative switching before achieving satisfactory results. Unfortunately, these agents rarely provide complete relief from OIC. In resistant patients, opioid rotation, and agents such as lubiprostone, and should be considered.22

Efficacy of lubiprostone in the treatment of OIC in patients receiving opioid therapy for chronic, non-cancer-related pain was assessed in three randomized, double-blinded, placebo- controlled studies. Patients had been receiving stable opioid therapy for at least 30 days prior to screening, which was to continue throughout the 12-week treatment period. At baseline, mean oral morphine equivalent daily doses (MEDDs) were 99 mg and 130 mg for placebo-

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© Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved treated and lubiprostone-treated patients, respectively, in Study 1. Baseline mean MEDDs were 237 mg and 265 mg for placebo-treated and lubiprostone-treated patients, respectively, in Study 2. In Study 3, baseline mean MEDDs were 330 mg and 373 mg for placebo-treated and lubiprostone-treated patients, respectively.1

In Study 1, patients receiving non-diphenylheptane (e.g., non-methadone) opioids (n = 431) were randomized to receive placebo (n = 217) or lubiprostone 24 mcg twice daily (n = 214) for 12 weeks. The primary efficacy analysis was a comparison of the proportion of “overall responders” in each treatment arm. A patient was considered an “overall responder” if ≥1 spontaneous bowel movements (SBM) improvement over baseline were reported for all treatment weeks for which data were available and ≥3 SBMs/week were reported for at least 9 of 12 treatment weeks. The proportion of patients in Study 1 qualifying as an “overall responder” was 27.1% in the group receiving lubiprostone 24 mcg twice daily compared to 18.9% of patients receiving placebo twice daily (treatment difference = 8.2%; p-value = 0.03).1

Study 2 randomized 208 patients to placebo and 418 to lubiprostone. Study 2 did not exclude patients receiving diphenylheptane opioids. The primary efficacy endpoint was the mean change from baseline in SBM frequency at Week 8; 3.3 vs. 2.4 for lubiprostone and placebo- treated patients, respectively; treatment difference = 0.9; p-value = 0.004.1

In Study 3, patients receiving opioids (N = 451) were randomized to placebo (n = 216) or lubiprostone24 mcg twice daily (n = 235) for 12 weeks. Study 3 did not exclude patients receiving diphenylheptane opioids. The primary efficacy endpoint was the change from baseline in SBM frequency at Week 8. The study did not demonstrate a statistically significant improvement in SBM frequency rates at Week 8 (mean change from baseline of 2.7 vs. 2.5 for lubiprostone and placebo-treated patients, respectively; treatment difference = 0.2; p- value = 0.76).1

Safety Lubiprostone-The FDA Medical Review states that lubiprostone is a E1 metabolite analogue.5 have been shown to have effects on uterine myometrial tissues in women. (a synthetic analogue), because of its capacity to stimulate uterine contractility, is used with mifepristone as part of a medical regimen for termination of an early pregnancy. It is also used off label to induce cervical ripening in late pregnancy prior to induction of labor.

Since safety studies have not been conducted in pregnant women, the FDA mandated the labeling of lubiprostone to include the following:  A negative pregnancy test within two weeks prior to beginning therapy.  The use of effective contraceptive measures is required.  Women should receive adequate information about potential risks of lubiprostone in pregnancy.5  Lubiprostone is pregnancy category C. The most commonly observed adverse events in clinical studies included nausea (30.9%), diarrhea (13.2%), (13.0%), abdominal pain (6.8%), and distension (6.8%).5

Linaclotide product labeling contains a boxed warning stating that linaclotide is contraindicated in patients up to the age of 6 years old.12 Linaclotide should be avoided in patients 6-17 years of age. In non-clinical studies when linaclotide caused death in juvenile mice. Diarrhea occurred in 20% of patients treated with linaclotide 290 mcg in the IBS-C trials and 16% in the CIC trials on the 145 mcg dose; abdominal pain occurred in 7% of IBS- C patients (290 mcg) and in 7% of CIC patients on 145 mcg; headache occurred in 4% of patients in the IBS-C trials (290 mcg), and occurred in 4% of patients with IBS-C (290 mcg) and in 6% of those with CIC (145 mcg).13-15

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© Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved For additional clinical information see the Prime Therapeutics Formulary Chapters 7.1: Laxatives and 7.7E: Irritable Bowel Syndrome Agents and Formulary Monograph: Linaclotide.

REFERENCES 1. Amitiza Prescribing Information. Sucampo Pharmaceuticals,Inc. April 2013. 2. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006;130:1480–1491. 3. Velio P, Bassotti G. Chronic idiopathic constipation: Pathophysiology and treatment. J Clin Gastroenterol. 1996;22:190–196. 4. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. American College of Gastroenterology task force on irritable bowel syndrome 2009. Available at: http://www.acg.gi.org/media/releases/ajg2008122a.pdf. 5. FDA Medical Review # 21-908 (Amitiza). January 30, 2006. Available at: http://www.fda.gov/cder/foi/nda/2006/021908s000_Etreva_MEDR.pdf. 6. Johanson JF, Ueno R. Lubiprostone a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther. 2007;25:1351-1361. 7. Johanson JF, Gargano MA, Holland PC, et al. Initial and sustained effects of lubiprostone, a chloride channel-2 (ClC-2) activator for the treatment of constipation: data from a 4-week Phase III study. Am J Gastroenterol. 2005;100:A884. 8. Johanson JF, Morton D, Geenan J, et al. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol. 2008;103:170-177. 9. Johanson JF, Gargano MA, Holland PC, et al. Phase III, randomized withdrawal study of RU-0211, a novel chloride channel activator for the treatment of constipation. Gastroenterol. 2004;100:A884. 10. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome-results of two randomized, placebo- controlled studies. Aliment Pharmacol Ther. 2009;29:329-341. 11. Brandt LJ, Prather CM, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(suppl 1):S5- S21. 12. Linzess Prescribing Information. Forest Pharmaceuticals, Inc. July 2014. 13. Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation .N Engl J Med 2011;365;527-536. 14. Rao S, Jia XD, Shi K, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107:1714-1724. 15. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol. 2012;107:1702-1712. 16. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003;63:649–71. 17. National Comprehensive Cancer Network (NCCN) Clinical Practice guidelines in oncology. Adult Cancer Pain. Version. 2.2013. http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf. Accessed June 2013. 18. National Comprehensive Cancer Network (NCCN) Clinical Practice guidelines in oncology. Palliative Care. Version 2.2013. http://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf. Accessed June 2013. 19. Thomas J. Opioid-induced bowel dysfunction. J Pain Symptom Manage. 2008;35:103- 113. 20. Ford A, Moayyedi P, Lacy B, et al. Task Force on the Management of Functional Bowel Disorders. American College of Gastroenterology monograph on the management of AL_PS_Amitiza_Linzess_PA_ProgSum_AR0715 Page 8 of 9

© Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014; 109:S2-S26. 21. Kumar L, Barker C, Emmanuel A. Review Article- Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterology Research and Practice. 2014, Article ID 141737. Accessed at: http://dx.doi.org/10.1155/2014/141737 . 22. Ketwaroo G, Cheng V, Lembo A. Opioid-induced bowel dysfunction. Curr Gastroenterol Rep. 2013;15:344: DOI 10.1007/s11894-013-0344-2.

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© Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved