10:30 – 11:45 am Presenter Disclosure Information

Personalized Approach to OIC: The following relationships exist related to this presentation:

Improving Communication and ►Jeffrey A. Gudin, MD: Speakers Bureau for AstraZeneca and Managing Treatment Salix Pharmaceuticals, Inc. Advisory Board for Daiichi Sankyo, Inc.

SPEAKER Off-Label/Investigational Discussion 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 • • : Dulcolax®, Bisac‐EvacTM, Correctol® Outline prevalence, severity, and resulting • sodium: Aqualax®, Colace®, Colace® Micro‐ burden of OIC on patients • Husk: Fybogel®, Ispagel® • IR : Nucynta® • Compare and contrast the best OIC treatment • : KristaloseTM, Constulose • : Amitiza® options for patient‐specific situations • : Relistor® • • Methylcellulose: Citrucel® Demonstrate specific and targeted questions • : MovantikTM for patients that can improve patient‐clinician • : Investigational • : MiraLAX® communication about OIC • : Resolor® • PR /: Targin®, TarginiqTM, Targinact® • SP‐333: Investigational

IR=immediate release

Prevalence 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‐ • most common and most bothersome Therapies physiology OTC – Affects quality of life and function Treatment

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

Scores on Domains of Work Productivity and • Findings from a national What Tools Can Clinicians Use to Activity Impairment Questionnaire health and wellness OIC No OIC study demonstrated Measure and Monitor OIC? Worse * 68.1 70 that, when compared 56 with individuals without 60 * OIC, those individuals * 47.7 50 44.9 with OIC reported: 35.8

(%) ‒ Higher percentage of

40 33.1 * work time missed 30 22.6

Score ‒ Greater impairment 16.1 20 while working 10 ‒ Greater overall work impairment 0 ‒ Greater activity Better Work time Impairment Overall work Activity missed while impairment impairment impairment working *P<.05, OIC vs no OIC Bell TJ, et al. J Opioid Manag. 2009;5:137‐144. The Patient History: Summary: PRO Assessment Tool Asking the Right Questions Use in OIC Drug Development

• Previous bowel pattern prior to starting opioids Assessment Tool Drug Development Program(s) in OIC Patients1 • Current pattern while taking opioids PAC‐SYM1 • PR oxycodone/naloxone PO • Stool frequency, consistency, and size • Methylnaltrexone SC • Degree of straining during defecation • Prucalopride POa,2 • History of delayed defecation • PO –OIC program discontinuedb,3,4 Stool Symptom Screener5 • None identified • Fiber intake • Fluid intake PAC‐QOL1 • Methylnaltrexone SC • Fruit and vegetable intake • Prucalopride POa,2 • Exercise – levels physical activity • Alvimopan PO –OIC program discontinuedb,3,4 BFI1 • PR oxycodone/naloxone PO BF‐Diary6 • IR tapentadol PO • use (frequency and types) a Approved in several countries (but not in the United States). b OIC program discontinued due to cardiovascular • Other (anticholinergics, calcium channel safety concerns. antagonists, iron supplements, calcium supplements) 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 online September 18, 2014]. Patient. 6Camilleri M, et al. Am J Gastroenterol. 2011;106(3):497‐506.

Tools for Patients

• Bowel Function Index – Three‐item assessment – Assesses: . Ease of BM Current Therapeutic Approaches . BM completeness . Overall assessment – Score is mean of 3 items – Selected by AAPM consensus panel to be a good choice as a validated tool1

AAPM=American Academy of Pain Medicine 1Webster LR. Pain Med. 2015;16 Suppl 1:S16-21.

Non‐Pharmacologic OTC Options: Constipation Therapies Current Therapy Falls Short

• Hydration • Manual maneuvers OIC treatment is currently dominated by the use of , which are only – No real evidence1 – Enema partially effective and cause complications of their own1 • Dietary modification – Digital stim – Fruits, juices – Positional • Laxatives do not prevent or treat the cause of OIC – Bran, fiber, psyllium . “Squatty‐potty” • activation of mu‐opioid receptors in the gastrointestinal tract1,3‐5 – Caffeine • Laxatives are only partially effective for OIC, providing relief 2 – Fried foods for fewer than 50% of patients 50% of the time • Laxatives pose serious risks with prolonged, • Exercise frequent or excessive use • Bowel hygiene – “Obey the urge”

1Thomas J. N Engl J Med. 2008;358:322. 2Pappagallo M. Am J Surg. 2001;182:Suppl. S11‐S18. 3Miralax Product Label, 1Leung L, et al. J Am Board Fam Med. 2011;24(4):436‐451. Schering‐Plough Healthcare Products. 4Metamucil Product Label, Proctor and Gamble. Appropriate use of laxatives requires an understanding of how different agents work, their effectiveness, and associated risk

Type Mechanism of Action Examples Side effects/complications

Bulk ; causes water Psyllium, husk, Increased gas; risk for bowel New and Emerging Treatments laxatives retention in the colon and methylcellulose obstruction in patients with increases stool bulk strictures in OIC Osmotic Salt content retains fluid , lactulose, Electrolyte imbalances; laxatives retention and increases polyethylene glycol, increased gas, nausea, and intestinal secretions dehydration Stool Decrease surface tension Docusate sodium Require adequate fluid intake, softeners to lubricate and soften useless in patients with 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

Brenner D, et al. Pain Medicine News. September 2013.; Schafer DC, et al. Am Fam Physician. 1998;58(4):907‐914.; Benyamin R, et al. Pain Physician. 2008;11(2 suppl):S105‐120.

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

Agent Lubiprostone Agent Methylnaltrexone Mechanism of Action Chloride channel activator Mechanism of Action Peripheral mu antagonist (PAMORA) Mode of Oral Mode of Subcutaneous. Administration Administration When selecting an injection site, choose from the abdomen, thighs, or upper arms. 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 Twice daily Frequency of Dosing Once daily

Clinical Capsules should be swallowed whole and should not be broken apart or chewed. Clinical Discontinue maintenance laxative therapy prior to use. Recommendations Take with food and water. Recommendations Need close proximity to toilet once administered. May be used concomitantly for length of opioid treatment. Use of methylnaltrexone beyond four months has not been studied. Effectiveness of use in patients taking has not been established. Monitor for signs of opioid withdrawal. Discontinue if treatment with opioid pain medication is also discontinued. Adverse Event Profile In most common adverse events in clinical trials were: nausea (19.8%), diarrhea Adverse Event Profile In most common adverse events in clinical trials were: abdominal pain (28.5%), (9.7%), abdominal distention (6.9%), headache (6.9%), abdominal pain (5.2%). flatulence (13.3%), nausea (11.5%), dizziness (7.3%), diarrhea (5.5%).

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‐ Relistor® (methylnaltrexone bromide subcutaneous injection). Full Prescribing Information, Salix 351.; Cryer B, et al. Pain Med. 2014;15(11):1825‐1834. Pharmaceuticals, Inc., Raleigh, NC, 2014.; Michna E, et al. J Pain. 2011;12(5):554‐562.

Current Approved Therapeutic Options for Opioid‐Induced Constipation PAMORAs • Opioid antagonists that bind to mu opioid receptors in Agent Naloxegol Mechanism of Action Peripheral mu opioid receptor antagonist (PAMORA) the gut, displacing or preventing opioids from binding Mode of Oral • Methylnaltrexone: First approved in 2008 for opioid‐ Administration induced constipation in patients with advanced illness receiving palliative care; indication expanded in 2014 Frequency of Dosing Once daily to include OIC in noncancer patients. Currently Clinical Take on an empty stomach at least 1 hour prior to meal or 2 hours after the meal. administered as a subcutaneous injection Recommendations Swallow tablets whole. Do not crush or chew. Avoid consumption of grapefruit or grapefruit juice. • Naloxegol approved in 2014 for OIC in adult patients Discontinue if treatment with opioid pain medication is also discontinued. with noncancer pain. First PAMORA oral tablet Adverse Event Profile In most common adverse events in clinical trials were: abdominal pain (21%), approved for OIC diarrhea (9%), nausea (8%), flatulence (6%), vomiting (5%), headache (4%), and hyperhidrosis (3%). • Others in development

Movantik™ (naloxegol). Full Prescribing Information, AstraZeneca Pharmaceuticals LP, Wilmington, DE, 2015.; Chey WD, et al. N Engl J Med. 2014;370(25):2387‐2396. PAMORA=Peripherally Acting Mu‐Opioid Receptor Antagonists Methylnaltrexone: Naloxegol: Peripherally Acting mu‐Receptor Antagonist Peripherally Acting mu‐Receptor Antagonist

Placebo Response Rates in the ITT Population Response Rates in the mITT Population 50 Naloxegol, 12.5 mg a 70 44.4 a 45 a Naloxegol, 25 mg a 59 40.8 39.7 60 40 34.9 During 50 % 35

38 29.4 29.3 40 30 SBMs

Period, >3

30 25

with 20

week 20 ‐ 4 10 15

Patients 0 10 Methlynaltrexone 12 mg QD (n=150) Placebo (n=162) 5 4‐week, double‐blind, randomized, placebo‐controlled, phase 3 clinical trial 0 Two 12‐week, double‐blind, randomized, placebo‐controlled, phase 3 clinical trials Primary Endpoint: % patients with >3 in SBMs per week, during 4‐week period 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<.001 versus placebo; QD=once daily. N=312 patients with chronic noncancer pain.; mITT=modified intent‐to‐treat population, included all randomized patients SBM, defined as a BM with no laxative use within prior 24 hours; aP<0.05 vs placebo in each study; N=652, who received ≥1 dose of double‐blind study medication Study 04; N=700, Study 05.; ITT=intention‐to‐treat Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed April 6, 2015. Chey WD, et al. N Engl J Med. 2014;370(25):2387‐2396.

Chlorine Channel Activator: Lubiprostone Chloride Channel Activator Lubiprostone Placebo (N = 208) Lubiprostone (n = 210) 4 • Works as an agonist at the chloride channel P = .005 P = .091 3.3 3.4 • Approved for IBS‐c and OIC 3 2.6 P = .004 2.4

• Doses of 24 mcg twice daily for treatment of OIC Baseline 2.2

in adults from 2

Frequency 1.6

• Unlike many laxative products, lubiprostone does SBM

Change

not show signs of tolerance, dependency, or in 1 altered serum electrolyte concentration Mean 0 Week 8Week 12 Overall No. of 159 151 140 138 204 205 Observations Primary endpoint: change at 8 weeks from baseline weekly frequency SBMs (bowel movements without the use of a laxative or stool softeners with the last 2 hours) IBS‐c=irritable bowel syndrome and constipation Cryer B, et al. Pain Med. 2014;15(11):1825‐1834.

OIC Improvements Desired OIC Therapies in Development by Patients • Methylnaltrexone ‐ oral formulation • A single additional BM per week may serve as the minimal – Oral peripherally mu opioid receptor antagonist – Phase 3 studies met endpoints clinically important difference for patients with OIC • Naldemedine – Oral peripherally selective mu opioid receptor antagonist Patients (%) – Phase 3 trial underway Most Commonly Desired Improvements N=513 • Prucalopride* Have 1 more BM per week 96.0% – Full agonist of 5‐HT4receptors Be able to have a BM without pain 87.9% – Ongoing phase 2 studies. Currently approved for chronic constipation in Europe and Canada • Axelopran Be able to have soft stool that is not loose or watery 87.1% – Oral peripherally selective mu opioid receptor antagonist Not experience rectal straining due to constipation 83.4% – Phase 2 trial underway Feel less bloated 83.0% • SP‐333 – Oral second‐generation uroguanylin analog Be more comfortable using opioid medication without fear of being constipated 82.1% – Phase 2 trial underway Worry less about being able to have a BM 80.5% *Prucalopride is not approved by the FDA for use in the United States Have less pain in stomach area 80.3% 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‐ peripherally‐acting‐mu‐opioid‐receptor‐?page=full. Accessed November 12, 2015. Clinicaltrials.gov accessed November, 2015. Epstein RS, et al. Adv Ther. 2014;31(12):1263‐1271. Patients and HCPs Have Different Perceptions of Satisfaction with Constipation Treatment Keeping the Dialogue Open

Very satisfied A little satisfied A little dissatisfied Very dissatisfied • When discussing this topic, health care providers 2.7% need to be open and empathetic 100.0% 14.9% 100.0% 10.7% 90.0% 23.2% 90.0% • Offer reasonable options that will work with the 80.0% 80.0% 29.3% patient’s daily routine 70.0% 70.0% 25.7% 69.3% 60.0% 53.1% 60.0% • When the first options do not work, encourage the 50.0% 50.0% patients to continue to try other 40.0% 28.4% 40.0% 44.0% 30.0% 30.0% options until one is successful 20.0% 28.9% 20.0% 22.7% 26.7% 10.0% 10.0% 16.0% 3.1% 1.3% 0.0% 0.0% Patient (n = 194) HCP (n = 75) Patient (n = 194) HCP (n = 75) Baseline Week 24 Datto C, et al. Poster, American Academy of Pain Medicine 31st Annual Meeting, March 19 ‐22, 2015. National Harbor, MD.

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