Scientific Insights Into OPIOID- INDUCED CONSTIPATION. Presenter Disclosure Information. Presenter Disclosure Information. Anthony J.

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1 9:15 1:3 m Achieving Blnce: Prcticl Mngement Strtegies for Opioid-Induced Constiption SPEAKERS Anthony J. Lembo, MD Jmes W. Atchison, DO Drren M. Brenner, MD Presenter Disclosure Informtion The following reltionships exist relted to this presenttion: Anthony J. Lembo, MD: Consulting so the non-cme whtever lnguge for: AstrZenec; Ironwood Phrmceuticls, Inc.; Slix Phrmceuticls, Inc.; Vlent Phrmceuticls. Jmes W. Atchison, DO: Non-CME/CE services for Best Doctors Inc; The Interntionl School for Primry Eduction; PAREXEL Interntionl; nd Pfizer, Inc. Drren M. Brenner, MD: Spekers Bureu: Allergn, Inc.; AstrZenec; Actvis; Ironwood Phrmceuticls, Inc.; Procter & Gmble Co.; Slix Phrmceuticls, Inc.; Advisory Bord: Allergn, Inc.; AstrZenec; Actvis; Ironwood Phrmceuticls, Inc.; Procter & Gmble Co.; QOL Medicl LLC; Slix Phrmceuticls, Inc. Presenter Disclosure Informtion Off-Lbel/Investigtionl Discussion In ccordnce with pmicme policy, fculty hve been sked to disclose discussion of unlbeled or unpproved use(s) of drugs or devices during the course of their presenttions. Amitriptyline Axeloprn Biscodyl Denosumb Diltizem Docuste clcium Docuste sodium Gbpentin ER Lctulose Lisinopril Lortdine Lubiprostone Metformin Methylcellulose Methylnltrexone Nldemedine Nloxegol Nloxone Oxycodone Polyethylene glycol PR oxycodone nd PR nloxone Psyllium Rosuvsttin Senn Trnsderml fentnyl Drug List Elvil Investigtionl Dulcolx, Bisc-Evc, Correctol Proli Dilt-cd, Crdizem Kopectte Aqulx, Colce, Colce Micro-Enem Horiznt Constulose, Kristlose Zestril, Prinivil Clritin Amitiz Glumetz, Glucophge, Fortmet, Riomet Citrucel Relistor Investigtionl Movntik Nrcn Oxect, OxyCONTIN, Oxyfst, Roxicodone Mirlx Trgin, Trginiq, Trginct Metmucil Crestor Senokot Durgesic Eductionl Objectives Describe the effects of opioid receptor ctivtion in the gstrointestinl trct Evlute ptients on chronic opioid therpy for bowel function nd risk fctors for OIC development Implement prophylctic tretment pln to ddress OIC concurrent with the initition of opioid therpy Compre the mechnisms of ction nd clinicl profiles of current presciption medictions for OIC Construct evidence-bsed tretment regimens for ptients with OIC tht reflect bowel symptoms, prior tretment response, nd ptient preferences Communicte with opioid-treted ptients bout tretment-emergent dverse events through open, ptient-centered dilogue throughout the course of therpy Scientific Insights Into OPIOID- INDUCED CONSTIPATION Anthony J. Lembo, MD Associte Professor of Medicine Director, GI Motility Lbortory Hrvrd Medicl School Beth Isrel Deconess Medicl Center Boston, Msschusetts OIC, opioid-induced constiption.

Scientific Insights Into Opioid-Induced Constiption Key Points Opioid nlgesics bind to opioid receptors throughout the CNS nd PNS, including in the gstrointestinl trct Opioid receptor ctivtion in the

2 Scientific Insights Into Opioid-Induced Constiption Key Points Opioid nlgesics bind to opioid receptors throughout the CNS nd PNS, including in the gstrointestinl trct Opioid receptor ctivtion in the gstrointestinl trct modultes physiologic processes from the lower esophgel sphincter to rectum By ntgonizing μ-opioid receptor ctivity, opioid ntgonists reverse the effects of opioid nlgesics Peripherlly cting μ-opioid receptor ntgonists re intended to block opioid receptor ctivtion outside of the CNS eg, the GI trct CNS, centrl nervous system; PNS, peripherl nervous system. Brennn MJ, et l. J Multidiscip Helth. 213;6:265-28; Leppert W. Adv Ther. 21;27(1):714-73; De Schepper HU, et l. Neurogstroenterol Motil. 24;16(4): ; Holzer P. Eur Rev Med Phrmcol Sci. 28;12(suppl 1): Rising Rtes of Chronic Pin 1 million US dults currently ffected by chronic pin Prevlence predicted to increse with ging popultion Arthritis Prevlence (1x) 8, 7, 6, 5, 4, 3, 2, 1, 65+ yers old yers old yers old Yer Projected prevlence of doctor-dignosed rthritis in the US by ge. Institute of Medicine. Relieving Pin in Americ: A Blueprint for Trnsforming Prevention, Cre, Eduction, nd Reserch. Wshington, DC: The Ntionl Acdemies Press; 211; Hootmn JM, Helmick CG. Arthritis Rheum. 26;54(1): Opioid-Induced Constiption Constiption is most common dverse effect of prescription opioid nlgesics 1,2 Up to 1 in every 2 ptients on opioid therpy will experience constiption symptoms 3 Constipted Not Constipted Silently Suffering 1 in every 3 ptients on opioid therpy does not discuss constiption symptoms with his or her clinicin 4 Discusses Constiption Discusses Constiption Ptients my not discuss constiption symptoms becuse they re embrrssed or worried tht the opioid tretment will be reduced or discontinued Chou R, et l. J Pin. 29;1(2):113-13; 2. Moore RA, McQuy HJ. Arthritis Res Ther. 25;7(5):R146-R Cook SF, et l. Aliment Phrmcol Ther. 28;27(12): ; 4. Coyne KS, et l. Clinicoecon Outcomes Res. 214;6: Opioid-Induced Constiption Multidisciplinry Working Group Definition A chnge when inititing opioid therpy from bseline bowel hbits tht is chrcterized by ny of the following: Reduced bowel movement frequency Development or worsening of strining to pss bowel movements A sense of incomplete rectl evcution Hrder stool consistency Cmillieri M, et l. Neurogstroenterol Motil. 214;26(1): Constiption Wht Does It Men to Your Ptient? Development of OIC Risk Fctors Infrequent Stools Pin Strining Hrd Stools Incomplete Evcution Bloting Ptient Chrcteristics Femle gender Advnced ge Drug Regimen Opioid type/ strength Dietry Considertions Dehydrtion Nutritionl deficits Medicl Issues Reltive immobility Nuse/vomiting fter strting opioids Mechnicl obstruction Recent hospitliztions Lcy BE, et l. Ther Adv Gstroenterol. 212;5(4): ; Coyne KS, et l. Clinicoecon Outcomes Res. 214;6: Ahmedzi SH, Bolnd J. BMJ Clin Evid (Online). 21;pii:247; Clemens KE, Klschik EK. Ther Clin Risk Mng. 21;6:77-82; Wn Y CS, et l. Ls Vegs, Nevd; 213; Abstrct 132.

Effect of OIC on Ptient Functioning nd Qulity of Life (QoL) Ptients with OIC often Skip opioid doses to precipitte bowel movement Suffer from indequte pin control due to tretment nondherence

3 Effect of OIC on Ptient Functioning nd Qulity of Life (QoL) Ptients with OIC often Skip opioid doses to precipitte bowel movement Suffer from indequte pin control due to tretment nondherence Experience reductions in QoL nd ctivities of dily living Exmples From Our Prctices Utilize more heth cre resources; contributing to higher helth cre costs Bell TJ, et l. Pin Med. 29;1(1):35-42; Coyne KS, et l. Clinicoecon Outcomes Res. 214;6: ; Gupt S, et l. J Opioid Mng. 215;11(4): ; Hrris JD. Clin J Pin. 28;24(suppl 1):S8-S13; Wn Y, et l. Am Helth Drug Benefits. 215;8(2): Ptient Resources Evluting Bowel Hbits in Ptients on Chronic Opioid Therpy Ptient Eductionl Tool Ptient Converstion Guide Opening the Converstion About Ptient Bowel Ptterns Ask quntittive questions rther thn open-ended or yes-or-no-style questions Insted of these Ask these Are you hving ny problems moving your bowels? Do you hve ny difficulties pssing stool? Are there ny chnges in your bowel hbits tht you would like to discuss? How mny times do you hve bowel movement ech week? Cn you describe wht your stool most commonly looks like? How hve your bowel ptterns chnged since you strted tking opioids? Bowel Function Index Assessment of Bowel Hbits Tools for Stools Ptient Assessment of Constiption Rentz AM, et l. J Med Econ. 29;12(4): ; Frnk L, et l. Scnd J Gstroenterol. 1999;34(9):87-887; Lewis SJ, Heton KW. Scnd J Gstroenterol. 1997;32(9): Bristol Stool Form Scle

4 Type 1 Type 2 Type 3 Type 4 Type 5 Type 6 Type 7 Bristol Stool Form Scle Seprte hrd lumps, like nuts Susge-like but lumpy Like susge but with crcks in the surfce Like susge or snke, smooth nd soft Soft blobs with cler-cut edges Fluffy pieces with rgged edges, mushy stool Wtery, no solid pieces Bowel Function Index (BFI) Scored by numericl ssessment scle (-1, free from symptom to most severe symptom experienced) for prior 7 dys Ese of defection Feeling of incomplete evcution Personl judgment of constiption BFI score is the men of the 3 component scores Lewis SJ, Heton KW. Scnd J Gstroenterol. 1997;32(9): Rentz AM, et l. J Med Econ. 29;12(4): Ptient Assessment of Constiption (PAC-SYM) 12-item questionnire of ptient-reported symptoms over the 2 prior weeks, using 3 subscles Bowel movements Rectl symptoms Abdominl symptoms Scored from no problems (score ) to very severe symptoms (score 4) Which bowel ssessment tool do you find most useful in prctice? Frnk L, et l. Scnd J Gstroenterol. 1999;34(9): Ptient-Provider Prtnership Educte Discuss Coordinte On the risks of developing OIC ~5% of ptients on chronic opioid therpy Incresed likelihood if ptients hve risk fctors Prophylctic tretment pln Bowel hbits t every follow-up visit Results of bowel function evlution Importnce of dherence to opioid therpy nd OIC mngement pln With other members of the helth cre tem Prophylctic nd Initil Mngement Options

5 Implementtion of Prophylctic Tretment Guidelines on long-term opioid therpy recommend tht ll ptients be dvised on prophylctic bowel regimen 1,2 Adequte dietry fiber Adequte wter intke Regulr exercise Lxtives? Ptients who receive prophylctic lxtive therpy re less likely to experience constiption 3,4 Commonly Used Lxtives to Tret Constiption Type of Lxtive Specific Exmple Stool Softener Docuste sodium, docuste clcium Stimulnt Senn, biscodyl, cstor oil Osmotic Polyethylene glycol, lctulose Lubricnt Minerl oil Bulking Agent Psyllium, brn, methylcellulose 1. Chou R, et l. Pin. 29;1(2):113-13; 2. Deprtment of Veterns Affirs/Deprtment of Defense. Accessed September 1, Myotoku M, et l. J Pllit Med. 21;13(4):41-46; 4. Ishihr M, et l. Clin J Pin. 212;28(5): Ford AC, Sures NC. Gut. 211;6(2):29-218; Lee YY. Front Med (Lusnne). 214;1-5; Pre P, Fedork RN. Cn J Gstroenterol Heptol. 214;28(1): Prcticl Issues Relted to Lxtive Tretment Bulking gents nd medicinl fiber, such s psyllium, should be voided 1,2 Efficcy dt re lcking My further hrden the ptient s stool Lxtives my hve side effects 3,4 Nuse, vomiting, dirrhe, bdominl pin ll of which usully dissipte fter bowel movement My increse the chnce of poor dherence High dosges of lxtives nd stimulnts my be needed to improve bowel ptterns 4 My increse the chnce of poor dherence Wht prophylctic bowel regimen do you recommend for ptients strting longterm opioid therpy? 1. Pre P, Fedork RN. Cn J Gstroenterol Heptol. 214;28(1): ; 2. Yng J, et l. World J Gstroenterol. 212;18(48): ; 3. Mueller-Lissner SA, Wld A. BMJ Clin Evid. 21;21. pii: 413; 4. Sykes NP. J Pin Symptom Mnge. 1996;11(6): STEP 1 STEP 2 Guidelines on Opioid Rottion Clculte new opioid dose bsed on equinlgesic tble Identify dose reduction window 25% to 5% lower thn equinlgesic dose (not for methdone or fentnyl) Switching to methdone: identify window 75% to 9% lower thn equinlgesic dose Switching to trnsderml fentnyl: clculte dose conversions bsed on rtios included in the product informtion Choose smller (25% of dose) or lrger (5% of dose) reduction bsed on chrcteristics of regimen or ptient Lrger reductions for ptients on high current opioid doses, non-cucsins, nd older or mediclly fril individuls Ressess pin nd other biopsychosocil chrcteristics to determine whether n dditionl 15% to 3% dose increse or decrese is needed Repetedly ssess response nd titrte new opioid to optimize outcomes FDA-Approved Therpies for Opioid-Induced Constiption Fine PG, et l. J Pin Symptom Mnge. 29;38(3):

Currently Approved Therpies Agent Lubiprostone Methylnltrexone Nloxegol Mechnism of Action Mode of Administrtion Recommended Dose Dosing Frequency Clinicl Considertions Chloride chnnel ctivtor

5 mg Twice dily Once dily Once dily Tke with food nd wter My be used concomitntly for length of opioid tretment My be less effective in ptients tking methdone Discontinue lxtive therpy prior to use

Primry Endpoint, % 3 25 2 15 1 5 Lubiprostone Chloride Chnnel Activtor [VALUE] Lubiprostone 24 μg BID (n=214) Plcebo (n=217) 12-week, double-blind, rndomized, plcebo-controlled, phse 3 clinicl tril

6 Currently Approved Therpies Agent Lubiprostone Methylnltrexone Nloxegol Mechnism of Action Mode of Administrtion Recommended Dose Dosing Frequency Clinicl Considertions Chloride chnnel ctivtor Peripherlly cting μ-opioid receptor ntgonist (PAMORA) Orl Subcutneous Orl 24 µg 12 mg/.6 ml 25 mg/12.5 mg Twice dily Once dily Once dily Tke with food nd wter My be used concomitntly for length of opioid tretment My be less effective in ptients tking methdone Discontinue lxtive therpy prior to use Need close proximity to toilet once dministered My be used concomitntly for length of opioid tretment Monitor for signs of opioid withdrwl Accessed September 1, 215. Discontinue lxtive therpy prior to use Tke on n empty stomch nd void grpefruit consumption My be used concomitntly for length of opioid tretment Monitor for signs of opioid withdrwl Ptients Achieving Primry Endpoint, % Lubiprostone Chloride Chnnel Activtor [VALUE] Lubiprostone 24 μg BID (n=214) Plcebo (n=217) 12-week, double-blind, rndomized, plcebo-controlled, phse 3 clinicl tril 18.9 Primry Endpoint: Overll SBM response rte ( 1 SBM/week improvement over bseline for ll 12 weeks nd 3 SBM/week for 9 out of the 12 tretment weeks) BID, twice dily; SBM, spontneous bowel movement. SBM, defined s BM with no lxtive use within prior 24 hours. P=.3 vs plcebo. N=431 ptients with chronic noncncer pin who were treted with non-methdone opioids. Jml MM, et l. Am J Gstroenterol. 215;11(5): TEAE, No. (%) of Ptients Lubiprostone 12-Week Sfety Dt Plcebo BID (n=212) Lubiprostone 24 µg BID (n=212) P vlue 1 TEAE 15 (49.5) 117 (55.2).285 Gstrointestinl disorders 41 (19.3) 59 (27.8).51 Dirrhe 8 (3.8) 24 (11.3) Nuse 1 (4.7) 21 (9.9) Vomiting 11 (5.2) 9 (4.2) Abdominl pin 15 (7.1) 1 Tretment-relted AE b 32 (15.1) 62 (29.2) <.1 Gstrointestinl disorders 22 (1.4) 49 (23.1) <.1 Dirrhe 3 (1.4) 21 (9.9) Nuse 6 (2.8) 18 (8.5) Abdominl pin 12 (5.7) Fltulence 5 (2.4) 6 (2.8) Vomiting 3 (1.4) 6 (2.8) AE, dverse event; TEAE, tretment-emergent dverse event. TEAEs observed in 5% of ptients in either tretment group. b Tretment-relted AEs observed in 2% of either tretment group. Jml MM, et l. Am J Gstroenterol. 215;11(5): Ptients Achieving Primry Endpoint, % Methylnltrexone Peripherlly Acting μ-opioid Receptor Antgonist Response Rtes in the mitt Popultion 59 Methylnltrexone 12 mg QD (n=15) Plcebo (n=162) 4-week, double-blind, rndomized, plcebo-controlled, phse 3 clinicl tril Primry Endpoint: % ptients with 3 SBMs per week, during 4-week period P<.1 vs plcebo; QD, once dily. N=312 ptients with chronic noncncer pin. mitt, modified intent-to-tret popultion, included ll rndomized ptients who received 1 dose of double-blind study mediction. Drugs@FDA: Accessed September 1, Adverse Event Methylnltrexone 4-Week Sfety Dt Methylnltrexone 12 mg QD (n=15), % Plcebo (n=162), % Adverse events occurring in 1% of ptients receiving methylnltrexone nd t n incidence greter thn plcebo Abdominl pin 21% 6% Nuse 9% 6% Dirrhe 6% 4% Hyperhidrosis 6% 1% Hot flush 3% 2% Tremor 1% <1% Chills 1% % Adverse events leding to tretment discontinution Any dverse event 7% 3% Sfety dt from 48-week, open-lbel, uncontrolled study (N=134) were consistent with 4-week results. Drugs@FDA: Accessed September 1, 215. Ptients Achieving Primry Endpoint, % Nloxegol Peripherlly Acting μ-opioid Receptor Antgonist Response Rtes in the ITT Popultion Plcebo Nloxegol 12.5 mg QD Nloxegol 25 mg QD [VALUE] Two 12-week, double-blind, rndomized, plcebo-controlled, phse 3 clinicl trils Primry Endpoint: 12-week response rte ( 3 SBM/week nd increse over bseline of 1 SBM for 9 of 12 weeks nd 3 of the finl 4 weeks) SBM, defined s BM with no lxtive use within prior 24 hours. P<.5 vs plcebo in ech study; N=652 ptients with noncncer pin, Study 4; N=7 ptients with noncncer pin, Study 5. ITT, intent-to-tret. Chey WD, et l. N Engl J Med. 214;37(25): Study 4 Study n=214 n=213 n=214 n=232 n=232 n=232

7 Nloxegol 12-Week Sfety Dt Emerging μ-opioid Receptor Antgonists for Tretment of OIC Adverse event, n (%) 1 Nloxegol Nloxegol Nloxegol Nloxegol 25 mg 12.5 mg Plcebo 25 mg 12.5 mg Plcebo (n=213) (n=231) (n=214) (n=211) (n=232) (n=23) Study 4 Study 5 Any AE 131 (62.2) 14 (49.3) 1 (46.9) 16 (69.) 137 (59.6) 136 (58.9) AE leding to 22 (1.3) 9 (4.3) 12 (5.6) 24 (1.3) 12 (5.2) 12 (5.2) discontinution Serious AE 7 (3.3) 11 (5.2) 11 (5.2) 8 (3.4) 14 (6.1) 12 (5.2) AEs in 5% of ny tretment rm b Abdominl pin 27 (12.6) 18 (8.5) 7 (3.3) 44 (19.) 25 (1.9) 18 (7.8) Dirrhe 2 (9.3) 7 (3.3) 9 (4.2) 21 (9.1) 18 (7.8) 1 (4.3) Nuse 16 (7.5) 15 (7.1) 1 (4.7) 2 (8.6) 14 (6.1) 1 (4.3) Fltulence 12 (5.6) 9 (4.3) 4 (1.9) 14 (6.) 4 (1.7) 7 (3.) Upper bdominl pin 11 (5.1) 3 (1.4) 4 (1.9) 6 (2.6) 5 (2.2) 3 (1.3) Vomiting 6 (2.8) 3 (1.4) 7 (3.3) 14 (6.) 7 (3.) 6 (2.6) Agent 1 Nldemedine Axeloprn Mode of Administrtion Orl Orl Mechnism of Action Peripherlly selective μ-opioid receptor ntgonist Peripherlly selective μ-opioid receptor ntgonist Current Stge Phse 3 Phse 2, completed Sfety dt from 52-week, open-lbel, prllel-group phse 3 study (N=84) with ptients rndomized 2:1 to either nloxegol 25 mg/dy or usul cre were similr to 12-week results. 2 Occurring during either the tretment or posttretment follow-up period. b Occurring during the tretment period. 1. Chey WD, et l. N Engl J Med. 214;37(25): ; 2. Webster L, et l. Aliment Phrmcol Ther. 214;4(7): The opioid gonist/ntgonist combintion of prolonged-relese oxycodone nd nloxone ws shown to reduce OIC in 3-week, open-lbel phse 3b study Informtion updted s of September 1, vn Dongen VC, et l. Int J Clin Prct. 214;68(11): Conclusions How do you incorporte ptient preference into the selection of phrmcologic therpy for the tretment of OIC? OIC is common in ptients on long-term opioid therpy Prophylctic tretment regimens cn reduce risk of constiption Routine bowel function ssessment is impertive Multimodl lxtive therpy cn be effective in some ptients Approved phrmcologic therpies include Orl nd injectble peripherlly cting μ-opioid receptor ntgonists Chloride chnnel ctivtor

OIC. Drug List. Learning Objectives. Opioids. Presenter Disclosure Information. Outline prevalence, severity, and resulting

OIC. Drug List. Learning Objectives. Opioids. Presenter Disclosure Information. Outline prevalence, severity, and resulting 1:3 11:45 m Personlized Approch to OIC: Improving Communiction nd Mnging Tretment SPEAKER Jeffrey A. Gudin, MD Presenter Disclosure Informtion The following reltionships exist relted to this presenttion: