Presenter Disclosure Information 10:30 – 11:45 am The following relationships exist related to this presentation: Personalized Approach to OIC: ►Jeffrey A. Gudin, MD: Speakers Bureau for AstraZeneca and Salix Improving Communication and Pharmaceuticals, Inc. Advisory Board for Daiichi Sankyo, Inc. Managing Treatment

Off-Label/Investigational Discussion SPEAKER Jeffrey A. Gudin, MD ►In accordance with pmiCME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

Drug List Learning Objectives

• Axelopran: Investigational • • Bisacodyl: Dulcolax®, Bisac‐EvacTM, Correctol® Outline prevalence, severity, and resulting • Docusate sodium: Aqualax®, Colace®, Colace® Micro‐Enema burden of OIC on patients • Husk: Fybogel®, Ispagel® • IR Tapentadol: Nucynta® • Compare and contrast the best OIC treatment • Lactulose: KristaloseTM, Constulose • Lubiprostone: Amitiza® options for patient‐specific situations • Methylnaltrexone: Relistor® • • Methylcellulose: Citrucel® Demonstrate specific and targeted questions • Naloxegol: MovantikTM for patients that can improve patient‐clinician • Naldemedine: Investigational • Polyethylene Glycol: MiraLAX® communication about OIC • Prucalopride: Resolor® • PR Oxycodone/Naloxone: Targin®, TarginiqTM, Targinact® • SP‐333: Investigational

IR=immediate release

Prevalence Opioids Treatment Burden Algorithm • Considered “broad spectrum” analgesics effective for multiple nociceptive and neuropathic pain types • Approximately 250 million Rx written annually for opioids in US Safety and HCEO $$$ Warnings OIC • Controversy exists surrounding total daily dosing recommendations • Many potential side effects – Somnolence, nausea, itching, respiratory depression Rx Patho‐ • Constipation most common and most bothersome Therapies physiology OTC – Affects quality of life and function Treatment

OIC=opioid‐induced constipation; Rx=prescription; OTC=over‐the‐counter; HCEO=health care economic outcomes Coyne KS, et al. Clinicoecon Outcomes Res. 2014;6:269‐281. Development of Constipation As a Result…OIC Is Increasing Risk Factors • With the increase in opioid use, more patients are It is important to note, not all constipation while on opioids is OIC presenting with opioid‐induced constipation (OIC)1 • Among patients taking opioids, 40‐90% have constipation and other gastrointestinal side effects which can

adversely affect adherence to pain medication regimens Patient Dietary Drug Regimen Medical Issues and quality of life2‐6 Characteristics Considerations • Opioids • Relative immobility • Female gender • Dehydration • Anticholinergics • Nausea/vomiting • Unlike other opioid‐related side effects, OIC is not dose‐ • Advanced age • Nutritional deficits • Magnesium • Mechanical obstruction 4 • Calcium • Recent hospitalizations dependent nor does is resolve over time • Antidepressants • Instead, OIC remains a significant burden on patients and • Antihistamines the health care system4

1Nevins PH, et al. Pain Week. 2013. 2Chey W, et al. N Engl J Med. 2014;370(25):2387‐2396. 3Holzer P. Therapy. 2008;5:531‐543. 4Bell TJ, et al. Pain Med. 2009;10:35‐42. 5Kalso E, et al. Pain. 2004;112:372‐380. 6Tuteja AK, et al. Kalso E, et al. Pain. 2004;112(3):372‐380.; Ahmedzai SH, Boland J. Clin Evid (Online). 2010;pii:2407.; Clemens KE, Neurogastroenterol Motil. 2010;22:424‐430, e96. Klaschik EK. Ther Clin Risk Manag. 2010;6:77‐82.; Wan Y CS, et al. Las Vegas, Nevada; 2013; Abstract 132.

Physiological Effects of Opioid‐Agonists in the GI Tract: More than “Constipation” Proposed Definitions of OIC • Delay gut transit time Proposed Definitions of OIC Camilleri, et al. (2014)1 Gaertner, et al. (2015)2 • Results in excessive water resorption Consensus statement: A A change, when initiating opioid therapy, • Stimulate mucosal sensory receptors change when initiating opioid from baseline bowel habits, defecation therapy from baseline bowel patterns, and what individuals would – May result in pain habits that is characterized by consider as abnormal that is characterized • Stimulate non‐propulsive motility any of the following1: by any of the following2: 1. Reduced BM frequency 1. Reduced frequency of SBMs (in • Reduce GI secretions contrast to induced BMs) • Tightens/constricts pylorus and ileocecal sphincters 2. Development or worsening of straining to pass BMs 3. A sense of incomplete rectal evacuation 4. Harder stool consistency

BM=bowel movement; SBM=spontaneous bowel movement GI=gastrointestinal 1Camilleri M, et al. Neurogastroenterol Motil. 2014;26(10):1386‐1395. 2Gaertner J, et al. J Clin Gastroenterol. Camilleri M, et al. Am J Gastroenterol. 2011;106(3):497‐506.; Panchal SJ, et al. Int J Clin Pract. 200761(7):1181‐1187. 2015;49(1):9‐16.

What Patients Experience When Severe Potential Consequences of OIC OIC Occurs

Fecal Impaction Hard Stools Incomplete Straining Evacuation Overflow Incontinence

Bowel Ischemia Bloating Pain Infrequent Perforation Stools

Camilleri M, et al. Am J Gastroenterol. 2011;106(3):497‐506.; Holzer P. Expert Opin Investig Drugs. 2007;16(2):181‐194. OIC –Often Underdiagnosed OIC Can Compromise Pain Management

• Patient complaints regarding constipation may vary from one Patients missed, decreased, or stopped opioids….. individual to the next

• Clinical measures of constipation, the number of bowel to get relief from opioid‐induced AEs 35% movements/week, do not often correlate with patients’

perception of what is regular 28% to avoid opioid‐induced AEs • Patients may deny yet meet clinical criteria for constipation

• Patients may neglect or be embarrassed to discuss their to make it easier to have a bowel 33% constipation issues movement

0% 5% 10% 15% 20% 25% 30% 35%

Assessing symptoms by talking to patients is the most efficient 92% of patients who decreased or stopped opioids experienced increased pain and cost‐effective way to determine the presence of OIC

AEs=adverse events Coffin B, et al. Expert Rev Gastroenterol Hepatol. 2011;5(5):601‐613. Bell TJ, et al. Pain Med. 2009;10:35‐42.

Burden and Cost of OIC Cost Burden With OIC Without OIC

$23,631 • OIC has been found to represent a significant $25,000 ±$67,209 $16,923 economic cost burden, including impact on $20,000 $16,000 $12,652 $14,437 patient’s QOL and productivity $15,000 ±$38,191 $11,117 ±$22,897 ±$25,690 ±$19,717 $10,000 ±$19,525

$5,000

$‐ Nonelderly Elderly Long‐term care

Recent study demonstrated patients with OIC had significantly more hospital admissions and longer inpatient stays than patients without OIC. The group with OIC had significantly higher costs per patient than those without.

Wan Y, et al. Accessed at http://www.researchgate.net/publication/277143982_Economic_burden_of_opioid‐ Wan Y, et al Am Health Drug Benefits. 2015; 8(2): 93‐102. induced_constipation_among_long‐term_Opioid_users_with_non_cancer_pain. Accessed November 9, 2015.

Work Productivity and Overall Patient The Patient History: Quality of Life Asking the Right Questions

Scores on Domains of Work Productivity and • Findings from a national Activity Impairment Questionnaire • Previous bowel pattern prior to starting opioids health and wellness • OIC No OIC Current pattern while taking opioids study demonstrated • Stool frequency, consistency, and size Worse * 68.1 • Degree of straining during defecation 70 that, when compared • History of delayed defecation 56 with individuals without 60 * OIC, those individuals * 47.7 50 44.9 with OIC reported: • Fiber intake 35.8

(%) ‒ Higher percentage of • Fluid intake

40 33.1 • Fruit and vegetable intake * work time missed 30 22.6 • Exercise – levels physical activity

Score ‒ Greater impairment 16.1 20 while working 10 ‒ Greater overall work impairment 0 ‒ Greater activity • Laxative use (frequency and types) Better Work time Impairment Overall work Activity impairment • Other medications (anticholinergics, calcium channel missed while impairment impairment antagonists, iron supplements, calcium supplements) working *P<.05, OIC vs no OIC Bell TJ, et al. J Opioid Manag. 2009;5:137‐144. Summary: PRO Assessment Tool Tools for Patients Use in OIC Drug Development

Assessment Tool Drug Development Program(s) in OIC Patients1 • Bowel Function Index PAC‐SYM1 • PR oxycodone/naloxone PO – Three‐item assessment • Methylnaltrexone SC • Prucalopride POa,2 – Assesses: • Alvimopan PO –OIC program discontinuedb,3,4 . Ease of BM Stool Symptom Screener5 • None identified . BM completeness PAC‐QOL1 • Methylnaltrexone SC . Overall assessment • Prucalopride POa,2 • Alvimopan PO –OIC program discontinuedb,3,4 – Score is mean of 3 items BFI1 • PR oxycodone/naloxone PO – Selected by AAPM BF‐Diary6 • IR tapentadol PO consensus panel to be a a Approved in several countries (but not in the United States). b OIC program discontinued due to cardiovascular good choice as a safety concerns. validated tool1 1Gaertner J, et al. J Clin Gastroenterol. 2015;49(1):9‐16. 2Shire. www.shire.com/shireplc/en/products/ gastrointestinal/resolor. Accessed March 6, 2015.; 3Irving G, et al. J Pain. 2011;12(2):175‐184.; 4Sprawls KS, et al. Drugs in Development for Opioid‐Induced Constipation. Published March 7, 2012. 5Coyne KS, et al. [Published AAPM=American Academy of Pain Medicine online September 18, 2014]. Patient. 6Camilleri M, et al. Am J Gastroenterol. 2011;106(3):497‐506. 1Webster LR. Pain Med. 2015;16 Suppl 1:S16-21.

Non‐Pharmacologic Constipation Therapies • Hydration • Manual maneuvers – No real evidence1 – Enema • Dietary modification – Digital stim Current Therapeutic Approaches – Fruits, juices – Positional – Bran, fiber, psyllium . “Squatty‐potty” – Caffeine – Fried foods • Exercise • Bowel hygiene – “Obey the urge”

1Leung L, et al. J Am Board Fam Med. 2011;24(4):436‐451.

OTC Options: Appropriate use of laxatives requires an Current Therapy Falls Short understanding of how different agents work, their effectiveness, and associated risk OIC treatment is currently dominated by the use of laxatives, which are only partially effective and cause complications of their own1 Type Mechanism of Action Examples Side effects/complications

Bulk Dietary fiber; causes water Psyllium, husk, Increased gas; risk for bowel laxatives retention in the colon and methylcellulose obstruction in patients with • Laxatives do not prevent or treat the cause of OIC increases stool bulk strictures 1,3‐5 • activation of mu‐opioid receptors in the gastrointestinal tract Osmotic Salt content retains fluid Sorbitol, lactulose, Electrolyte imbalances; • Laxatives are only partially effective for OIC, providing relief laxatives retention and increases polyethylene glycol, increased gas, nausea, and for fewer than 50% of patients 50% of the time2 intestinal secretions magnesium citrate dehydration Stool Decrease surface tension Docusate sodium Require adequate fluid intake, • Laxatives pose serious risks with prolonged, softeners to lubricate and soften useless in patients with frequent or excessive use fecal matter compromised bowel motility Stimulants Increase colonic motility Senna, cascara, Electrolyte imbalances; and electrolyte transport; bisacodyl abdominal pain, nausea, and stimulate fluid secretion colonic dysmotility

1Thomas J. N Engl J Med. 2008;358:322. 2Pappagallo M. Am J Surg. 2001;182:Suppl. S11‐S18. 3Miralax Product Label, Brenner D, et al. Pain Medicine News. September 2013.; Schafer DC, et al. Am Fam Physician. 1998;58(4):907‐914.; Schering‐Plough Healthcare Products. 4Metamucil Product Label, Proctor and Gamble. Benyamin R, et al. Pain Physician. 2008;11(2 suppl):S105‐120. Current Approved Therapeutic Options for Opioid‐Induced Constipation

Agent Lubiprostone Mechanism of Action Chloride channel activator New and Emerging Treatments Mode of Oral Administration in OIC Frequency of Dosing Twice daily

Clinical Capsules should be swallowed whole and should not be broken apart or chewed. Recommendations Take with food and water. May be used concomitantly for length of opioid treatment. Effectiveness of use in patients taking methadone has not been established.

Adverse Event Profile In most common adverse events in clinical trials were: nausea (19.8%), diarrhea (9.7%), abdominal distention (6.9%), headache (6.9%), abdominal pain (5.2%).

Amitiza® (lubiprostone capsules). Full Prescribing Information, Sucampo Pharma Americas, LLC, Bethesda, MD and Takeda Pharmaceuticals America, Inc., Deerfield, IL, 2013.; Lacy BE, Levy LC. J Clin Gastroenterol. 2007;41(4):345‐ 351.; Cryer B, et al. Pain Med. 2014;15(11):1825‐1834.

Current Approved Therapeutic Options for Current Approved Therapeutic Options for Opioid‐Induced Constipation Opioid‐Induced Constipation

Agent Methylnaltrexone Agent Naloxegol Mechanism of Action Peripheral mu opioid receptor antagonist (PAMORA) Mechanism of Action Peripheral mu opioid receptor antagonist (PAMORA) Mode of Subcutaneous. Mode of Oral Administration When selecting an injection site, choose from the abdomen, thighs, or upper arms. Administration Rotate injection sites. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid areas with scars or stretch marks. Frequency of Dosing Once daily Frequency of Dosing Once daily

Clinical Discontinue maintenance laxative therapy prior to use. Clinical Take on an empty stomach at least 1 hour prior to meal or 2 hours after the meal. Recommendations Need close proximity to toilet once administered. Recommendations Swallow tablets whole. Do not crush or chew. Use of methylnaltrexone beyond four months has not been studied. Avoid consumption of grapefruit or grapefruit juice. Monitor for signs of opioid withdrawal. Discontinue if treatment with opioid pain medication is also discontinued. Discontinue if treatment with opioid pain medication is also discontinued. Adverse Event Profile In most common adverse events in clinical trials were: abdominal pain (28.5%), Adverse Event Profile In most common adverse events in clinical trials were: abdominal pain (21%), flatulence (13.3%), nausea (11.5%), dizziness (7.3%), diarrhea (5.5%). diarrhea (9%), nausea (8%), flatulence (6%), vomiting (5%), headache (4%), and hyperhidrosis (3%).

Relistor® (methylnaltrexone bromide subcutaneous injection). Full Prescribing Information, Salix Movantik™ (naloxegol). Full Prescribing Information, AstraZeneca Pharmaceuticals LP, Wilmington, DE, 2015.; Pharmaceuticals, Inc., Raleigh, NC, 2014.; Michna E, et al. J Pain. 2011;12(5):554‐562. Chey WD, et al. N Engl J Med. 2014;370(25):2387‐2396.

PAMORAs Methylnaltrexone: Peripherally Acting mu‐Receptor Antagonist

• Opioid antagonists that bind to mu opioid receptors in Response Rates in the mITT Population the gut, displacing or preventing opioids from binding 70 a 59 • Methylnaltrexone: First approved in 2008 for opioid‐ 60 During 50 %

induced constipation in patients with advanced illness 40 38 SBMs

Period, >3

receiving palliative care; indication expanded in 2014 30

to include OIC in noncancer patients. Currently with

week 20 ‐ 4 administered as a subcutaneous injection 10

• Naloxegol approved in 2014 for OIC in adult patients Patients 0 with noncancer pain. First PAMORA oral tablet Methlynaltrexone 12 mg QD (n=150) Placebo (n=162) approved for OIC 4‐week, double‐blind, randomized, placebo‐controlled, phase 3 clinical trial Primary Endpoint: % patients with >3 in SBMs per week, during 4‐week period • Others in development SBM, defined as a BM with no laxative use within prior 24 hours.; aP<.001 versus placebo; QD=once daily. N=312 patients with chronic noncancer pain.; mITT=modified intent‐to‐treat population, included all randomized patients who received ≥1 dose of double‐blind study medication PAMORA=Peripherally Acting Mu‐Opioid Receptor Antagonists Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed April 6, 2015. Naloxegol: Chlorine Channel Activator: Peripherally Acting mu‐Receptor Antagonist Lubiprostone Placebo Response Rates in the ITT Population 50 Naloxegol, 12.5 mg a • Works as an agonist at the chloride channel 44.4 45 Naloxegol, 25 mg a a 40.8 39.7 40 • Approved for IBS‐c and OIC 34.9 35 29.4 29.3 • Doses of 24 mcg twice daily for treatment of OIC 30 25 in adults 20 15 • Unlike many laxative products, lubiprostone does 10 not show signs of tolerance, dependency, or 5 altered serum electrolyte concentration 0 Two 12‐week, double‐blind, randomized, placebo‐controlled, phase 3 clinical trials Primary Endpoint: 12‐week response rate ( ≥3 SBM/week and increase over baseline of ≥1 SBM for ≥9 of 12 weeks and ≥3 of the final 4 weeks)

SBM, defined as a BM with no laxative use within prior 24 hours; aP<0.05 vs placebo in each study; N=652, Study 04; N=700, Study 05.; ITT=intention‐to‐treat Chey WD, et al. N Engl J Med. 2014;370(25):2387‐2396. IBS‐c=irritable bowel syndrome and constipation

Lubiprostone Chloride Channel Activator OIC Therapies in Development

Placebo (N = 208) Lubiprostone (n = 210) • Methylnaltrexone ‐ oral formulation 4 P = .091 P = .005 – Oral peripherally mu opioid receptor antagonist 3.4 3.3 – Phase 3 studies met endpoints

3 • Naldemedine 2.6 P = .004 – Oral peripherally selective mu opioid receptor antagonist 2.4 Baseline – 2.2 Phase 3 trial underway • Prucalopride*

from 2 – Full agonist of 5‐HT4receptors

Frequency 1.6 – Ongoing phase 2 studies. Currently approved for chronic constipation in Europe and Canada SBM

• Axelopran Change

in 1 – Oral peripherally selective mu opioid receptor antagonist – Phase 2 trial underway Mean • SP‐333 0 – Oral second‐generation uroguanylin analog Week 8Week 12 Overall – Phase 2 trial underway No. of 159 151 140 138 204 205 Observations *Prucalopride is not approved by the FDA for use in the United States Primary endpoint: change at 8 weeks from baseline weekly frequency SBMs (bowel movements Wanami M, et al. A review of peripherally acting mu‐opioid receptor antagonists. February 1, 2011. http://formularyjournal.modernmedicine.com/formulary‐journal/news/clinical/clinical‐pharmacology/review‐ without the use of a laxative or stool softeners with the last 2 hours) peripherally‐acting‐mu‐opioid‐receptor‐?page=full. Accessed November 12, 2015. Clinicaltrials.gov accessed Cryer B, et al. Pain Med. 2014;15(11):1825‐1834. November, 2015.

OIC Improvements Desired Improving Patient‐Clinician Communication by Patients • A single additional BM per week may serve as the minimal clinically important difference for patients with OIC

Talking with Patients (%) your patients Most Commonly Desired Improvements N=513 about Have 1 more BM per week 96.0% opioid‐ Be able to have a BM without pain 87.9% induced Be able to have soft stool that is not loose or watery 87.1% Not experience rectal straining due to constipation 83.4% constipation Feel less bloated 83.0% Be more comfortable using opioid medication without fear of being constipated 82.1% Worry less about being able to have a BM 80.5% Have less pain in stomach area 80.3%

Epstein RS, et al. Adv Ther. 2014;31(12):1263‐1271. Strategies to Effectively Communicate PCP‐Pain Specialist Collaboration in With Patients about OIC Patient Centered Care • If patients are unable to communicate directly, the clinician should discuss the issue with the caregiver • The discussion prior to commencing opioid therapy should include a Pain Specialist Primary Care plan for follow‐up communication, whether in the office or over the telephone, to assess the response to the medication • During the discussion, listen for clues that may be more representative of OIC than frequency, including cramping, hard small stools, and significant straining • Evaluate any reports of diarrhea, which could result from stool leaking around a fecal impaction, rule out impaction and obstruction, Improved and treat any secondary contributors to the constipation Patient • Consider prophylactic bowel management Outcomes

Safety / Warnings

• Constipation can be associated with morbidity Remember to Ask About Bowel • Treatment of constipation can be associated Function in Every Patient with morbidity Prescribed Opioids • Always assess for possibility of bowel obstruction There is no tool that replaces or perforation communication with the patient! • Understand adverse effects and drug:drug interactions of laxative therapies

Proposed Treatment Summary Algorithm • Opioid analgesics are a mainstay treatment in pain management  • Constipation is one of the most common and troubling symptoms related to opioids; does not usually improve over time  • Assessment is important as patients may not convey the severity • Stool softeners, laxatives and dietary modifications are often  not effective at controlling opioid induced constipation • Newer prescriptive agents are available that promote motility and lubrication of stool to improve the symptoms associated with opioid induced constipation Brenner DM, Chey WD. Am J Gastroenterol Suppl. 2014;2:38‐46