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

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1 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: Jeffrey A. Gudin, MD: Spekers Bureu for AstrZenec nd Slix Phrmceuticls, Inc. Advisory Bord for Diichi Snkyo, Inc. 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. Drug List Axeloprn: Investigtionl Biscodyl: Dulcolx, Bisc Evc TM, Correctol Docuste sodium: Aqulx, Colce, Colce Micro Enem Husk: Fybogel, Ispgel IR Tpentdol: Nucynt Lctulose: Kristlose TM, Constulose Lubiprostone: Amitiz Methylnltrexone: Relistor Methylcellulose: Citrucel Nloxegol: Movntik TM Nldemedine: Investigtionl Polyethylene Glycol: MirLAX Pruclopride: Resolor PR Oxycodone/Nloxone: Trgin, Trginiq TM, Trginct SP 333: Investigtionl Lerning Objectives Outline prevlence, severity, nd resulting burden of OIC on ptients Compre nd contrst the best OIC tretment options for ptient specific situtions Demonstrte specific nd trgeted questions for ptients tht cn improve ptient clinicin communiction bout OIC IR=immedite relese Prevlence Opioids Sfety nd Wrnings Tretment Algorithm Rx Therpies OIC OTC Tretment Burden Pthophysiology HCEO $$$ Considered brod spectrum nlgesics effective for multiple nociceptive nd neuropthic pin types Approximtely 25 million Rx written nnully for opioids in US Controversy exists surrounding totl dily dosing recommendtions Mny potentil side effects Somnolence, nuse, itching, respirtory depression Constiption most common nd most bothersome Affects qulity of life nd function OIC=opioid induced constiption; Rx=prescription; OTC=over the counter; HCEO=helth cre economic outcomes Coyne KS, et l. Clinicoecon Outcomes Res. 214;6:

2 As Result OIC Is Incresing With the increse in opioid use, more ptients re presenting with opioid induced constiption (OIC) 1 Among ptients tking opioids, 4 9% hve constiption nd other gstrointestinl side effects which cn dversely ffect dherence to pin mediction regimens nd qulity of life 2 6 Unlike other opioid relted side effects, OIC is not dosedependent nor does is resolve over time 4 Insted, OIC remins significnt burden on ptients nd the helth cre system 4 Ptient Chrcteristics Femle gender Advnced ge Development of Constiption Risk Fctors It is importnt to note, not ll constiption while on opioids is OIC Dietry Considertions Dehydrtion Nutritionl deficits Drug Regimen Opioids Anticholinergics Mgnesium Clcium Antidepressnts Antihistmines Medicl Issues Reltive immobility Nuse/vomiting Mechnicl obstruction Recent hospitliztions 1 Nevins PH, et l. Pin Week Chey W, et l. N Engl J Med. 214;37(25): Holzer P. Therpy. 28;5: Bell TJ, et l. Pin Med. 29;1: Klso E, et l. Pin. 24;112: Tutej AK, et l. Neurogstroenterol Motil. 21;22:424 43, e96. Klso E, et l. Pin. 24;112(3): ; Ahmedzi SH, Bolnd J. 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. Physiologicl Effects of Opioid Agonists in the GI Trct: More thn Constiption Dely gut trnsit time Results in excessive wter resorption Stimulte mucosl sensory receptors My result in pin Stimulte non propulsive motility Reduce GI secretions Tightens/constricts pylorus nd ileocecl sphincters Proposed Definitions of OIC Proposed Definitions of OIC Cmilleri, et l. (214) 1 Gertner, et l. (215) 2 Consensus sttement: A chnge when inititing opioid therpy from bseline bowel hbits tht is chrcterized by ny of the following 1 : A chnge, when inititing opioid therpy, from bseline bowel hbits, defection ptterns, nd wht individuls would consider s bnorml tht is chrcterized by ny of the following 2 : 1. Reduced BM frequency 1. Reduced frequency of SBMs (in contrst to induced BMs) 2. Development or worsening of strining to pss BMs 3. A sense of incomplete rectl evcution 4. Hrder stool consistency GI=gstrointestinl Cmilleri M, et l. Am J Gstroenterol. 211;16(3): ; Pnchl SJ, et l. Int J Clin Prct. 2761(7): BM=bowel movement; SBM=spontneous bowel movement 1 Cmilleri M, et l. Neurogstroenterol Motil. 214;26(1): Gertner J, et l. J Clin Gstroenterol. 215;49(1):9 16. Wht Ptients Experience When OIC Occurs Severe Potentil Consequences of OIC Strining Hrd Stools Incomplete Evcution Fecl Impction Overflow Incontinence Bloting Infrequent Stools Pin Bowel Ischemi Perfortion Cmilleri M, et l. Am J Gstroenterol. 211;16(3): ; Holzer P. Expert Opin Investig Drugs. 27;16(2):

3 OIC Often Underdignosed Ptient complints regrding constiption my vry from one individul to the next Clinicl mesures of constiption, the number of bowel movements/week, do not often correlte with ptients perception of wht is regulr Ptients my deny yet meet clinicl criteri for constiption Ptients my neglect or be embrrssed to discuss their constiption issues OIC Cn Compromise Pin Mngement Ptients missed, decresed, or stopped opioids.. to get relief from opioid induced AEs to void opioid induced AEs to mke it esier to hve bowel movement 28% 35% 33% % 5% 1% 15% 2% 25% 3% 35% Assessing symptoms by tlking to ptients is the most efficient nd cost effective wy to determine the presence of OIC Coffin B, et l. Expert Rev Gstroenterol Heptol. 211;5(5): % of ptients who decresed or stopped opioids experienced incresed pin AEs=dverse events Bell TJ, et l. Pin Med. 29;1: Burden nd Cost of OIC Cost Burden With OIC Without OIC OIC hs been found to represent significnt economic cost burden, including impct on ptient s QOL nd productivity $25, $2, $15, $1, $23,631 ±$67,29 $12,652 ±$19,717 $16,923 $16, $14,437 ±$38,191 $11,117 ±$22,897 ±$25,69 ±$19,525 $5, $ Nonelderly Elderly Long term cre Recent study demonstrted ptients with OIC hd significntly more hospitl dmissions nd longer inptient stys thn ptients without OIC. The group with OIC hd significntly higher costs per ptient thn those without. Wn Y, et l Am Helth Drug Benefits. 215; 8(2): Wn Y, et l. Accessed t term_opioid_users_with_non_cncer_pin. Accessed November 9, 215. Work Productivity nd Overll Ptient Qulity of Life Worse 7 Score (%) Better Scores on Domins of Work Productivity nd Activity Impirment Questionnire OIC No OIC Work time missed P<.5, OIC vs no OIC Impirment while working 47.7 Overll work Bell TJ, et l. J Opioid Mng. 29;5: Activity Findings from ntionl helth nd wellness study demonstrted tht, when compred with individuls without OIC, those individuls with OIC reported: Higher percentge of work time missed Greter while working Greter overll work Greter ctivity The Ptient History: Asking the Right Questions Previous bowel pttern prior to strting opioids Current pttern while tking opioids Stool frequency, consistency, nd size Degree of strining during defection History of delyed defection Fiber intke Fluid intke Fruit nd vegetble intke Exercise levels physicl ctivity Lxtive use (frequency nd types) Other medictions (nticholinergics, clcium chnnel ntgonists, iron supplements, clcium supplements)

4 Summry: PRO Assessment Tool Use in OIC Drug Development Assessment Tool Drug Development Progrm(s) in OIC Ptients 1 PAC SYM 1 PR oxycodone/nloxone PO Methylnltrexone SC Pruclopride PO,2 Alvimopn PO OIC progrm discontinued b,3,4 Stool Symptom Screener 5 None identified PAC QOL 1 Methylnltrexone SC Pruclopride PO,2 Alvimopn PO OIC progrm discontinued b,3,4 BFI 1 PR oxycodone/nloxone PO BF Diry 6 IR tpentdol PO Approved in severl countries (but not in the United Sttes). b OIC progrm discontinued due to crdiovsculr sfety concerns. 1 Gertner J, et l. J Clin Gstroenterol. 215;49(1): Shire. gstrointestinl/resolor. Accessed Mrch 6, 215.; 3 Irving G, et l. J Pin. 211;12(2): ; 4 Sprwls KS, et l. Drugs in Development for Opioid Induced Constiption. Published Mrch 7, Coyne KS, et l. [Published online September 18, 214]. Ptient. 6 Cmilleri M, et l. Am J Gstroenterol. 211;16(3): Bowel Function Index Three item ssessment Assesses: Ese of BM BM completeness Overll ssessment Score is men of 3 items Selected by AAPM consensus pnel to be good choice s vlidted tool 1 Tools for Ptients AAPM=Americn Acdemy of Pin Medicine 1 Webster LR. Pin Med. 215;16 Suppl 1:S Current Therpeutic Approches Non Phrmcologic Constiption Therpies Hydrtion No rel evidence 1 Dietry modifiction Fruits, juices Brn, fiber, psyllium Cffeine Fried foods Exercise Bowel hygiene Obey the urge Mnul mneuvers Enem Digitl stim Positionl Squtty potty 1 Leung L, et l. J Am Bord Fm Med. 211;24(4): OTC Options: Current Therpy Flls Short OIC tretment is currently dominted by the use of lxtives, which re only prtilly effective nd cuse complictions of their own 1 Approprite use of lxtives requires n understnding of how different gents work, their effectiveness, nd ssocited risk Type Mechnism of Action Exmples Side effects/complictions Lxtives do not prevent or tret the cuse of OIC ctivtion of mu opioid receptors in the gstrointestinl trct 1,3 5 Lxtives re only prtilly effective for OIC, providing relief for fewer thn 5% of ptients 5% of the time 2 Lxtives pose serious risks with prolonged, frequent or excessive use Bulk lxtives Osmotic lxtives Stool softeners Stimulnts Dietry fiber; cuses wter retention in the colon nd increses stool bulk Slt content retins fluid retention nd increses intestinl secretions Decrese surfce tension to lubricte nd soften fecl mtter Increse colonic motility nd electrolyte trnsport; stimulte fluid secretion Psyllium, husk, methylcellulose Sorbitol, lctulose, polyethylene glycol, mgnesium citrte Docuste sodium Senn, cscr, biscodyl Incresed gs; risk for bowel obstruction in ptients with strictures Electrolyte imblnces; incresed gs, nuse, nd dehydrtion Require dequte fluid intke, useless in ptients with compromised bowel motility Electrolyte imblnces; bdominl pin, nuse, nd colonic dysmotility 1 Thoms J. N Engl J Med. 28;358: Pppgllo M. Am J Surg. 21;182:Suppl. S11 S18. 3 Mirlx Product Lbel, Schering Plough Helthcre Products. 4 Metmucil Product Lbel, Proctor nd Gmble. Brenner D, et l. Pin Medicine News. September 213.; Schfer DC, et l. Am Fm Physicin. 1998;58(4): ; Benymin R, et l. Pin Physicin. 28;11(2 suppl):s15 12.

5 Current Approved Therpeutic Options for Opioid Induced Constiption New nd Emerging Tretments in OIC Agent Mechnism of Action Mode of Administrtion Frequency of Dosing Lubiprostone Chloride chnnel ctivtor Orl Twice dily Clinicl Recommendtions Adverse Event Profile Cpsules should be swllowed whole nd should not be broken prt or chewed. Tke with food nd wter. My be used concomitntly for length of opioid tretment. Effectiveness of use in ptients tking methdone hs not been estblished. In most common dverse events in clinicl trils were: nuse (19.8%), dirrhe (9.7%), bdominl distention (6.9%), hedche (6.9%), bdominl pin (5.2%). Amitiz (lubiprostone cpsules). Full Prescribing Informtion, Sucmpo Phrm Americs, LLC, Bethesd, MD nd Tked Phrmceuticls Americ, Inc., Deerfield, IL, 213.; Lcy BE, Levy LC. J Clin Gstroenterol. 27;41(4): ; Cryer B, et l. Pin Med. 214;15(11): Current Approved Therpeutic Options for Opioid Induced Constiption Current Approved Therpeutic Options for Opioid Induced Constiption Agent Methylnltrexone Agent Nloxegol Mechnism of Action Peripherl mu opioid receptor ntgonist (PAMORA) Mechnism of Action Peripherl mu opioid receptor ntgonist (PAMORA) Mode of Administrtion Frequency of Dosing Subcutneous. When selecting n injection site, choose from the bdomen, thighs, or upper rms. Rotte injection sites. Do not inject into res where the skin is tender, bruised, red, or hrd. Avoid res with scrs or stretch mrks. Once dily Mode of Administrtion Frequency of Dosing Orl Once dily Clinicl Recommendtions Discontinue mintennce lxtive therpy prior to use. Need close proximity to toilet once dministered. Use of methylnltrexone beyond four months hs not been studied. Monitor for signs of opioid withdrwl. Discontinue if tretment with opioid pin mediction is lso discontinued. Adverse Event Profile In most common dverse events in clinicl trils were: bdominl pin (28.5%), fltulence (13.3%), nuse (11.5%), dizziness (7.3%), dirrhe (5.5%). Clinicl Recommendtions Tke on n empty stomch t lest 1 hour prior to mel or 2 hours fter the mel. Swllow tblets whole. Do not crush or chew. Avoid consumption of grpefruit or grpefruit juice. Discontinue if tretment with opioid pin mediction is lso discontinued. Adverse Event Profile In most common dverse events in clinicl trils were: bdominl pin (21%), dirrhe (9%), nuse (8%), fltulence (6%), vomiting (5%), hedche (4%), nd hyperhidrosis (3%). Relistor (methylnltrexone bromide subcutneous injection). Full Prescribing Informtion, Slix Phrmceuticls, Inc., Rleigh, NC, 214.; Michn E, et l. J Pin. 211;12(5): Movntik (nloxegol). Full Prescribing Informtion, AstrZenec Phrmceuticls LP, Wilmington, DE, 215.; Chey WD, et l. N Engl J Med. 214;37(25): PAMORAs Opioid ntgonists tht bind to mu opioid receptors in the gut, displcing or preventing opioids from binding Methylnltrexone: First pproved in 28 for opioidinduced constiption in ptients with dvnced illness receiving pllitive cre; indiction expnded in 214 to include OIC in noncncer ptients. Currently dministered s subcutneous injection Nloxegol pproved in 214 for OIC in dult ptients with noncncer pin. First PAMORA orl tblet pproved for OIC Others in development PAMORA=Peripherlly Acting Mu Opioid Receptor Antgonists Ptients with >3 SBMs During 4 week Period, % Methylnltrexone: Peripherlly Acting mu Receptor Antgonist Response Rtes in the mitt Popultion 59 Methlynltrexone 12 mg QD (n=15) 38 Plcebo (n=162) 4 week, double blind, rndomized, plcebo controlled, phse 3 clinicl tril Primry Endpoint: % ptients with >3 in SBMs per week, during 4 week period SBM, defined s BM with no lxtive use within prior 24 hours.; P<.1 versus 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 April 6, 215.

6 Nloxegol: Peripherlly Acting mu Receptor Antgonist Plcebo Nloxegol, 12.5 mg Nloxegol, 25 mg 4.8 Response Rtes in the ITT Popultion 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, Study 4; N=7, Study 5.; ITT=intention to tret Chey WD, et l. N Engl J Med. 214;37(25): Chlorine Chnnel Activtor: Lubiprostone Works s n gonist t the chloride chnnel Approved for IBS c nd OIC Doses of 24 mcg twice dily for tretment of OIC in dults Unlike mny lxtive products, lubiprostone does not show signs of tolernce, dependency, or ltered serum electrolyte concentrtion IBS c=irritble bowel syndrome nd constiption Lubiprostone Chloride Chnnel Activtor OIC Therpies in Development Men Chnge from Bseline in SBM Frequency P = Plcebo (N = 28) Lubiprostone (n = 21) P = Week 8 Week 12 Overll No. of Observtions 2.6 P =.4 Primry endpoint: chnge t 8 weeks from bseline weekly frequency SBMs (bowel movements without the use of lxtive or stool softeners with the lst 2 hours) Cryer B, et l. Pin Med. 214;15(11): Methylnltrexone orl formultion Orl peripherlly mu opioid receptor ntgonist Phse 3 studies met endpoints Nldemedine Orl peripherlly selective mu opioid receptor ntgonist Phse 3 tril underwy Pruclopride Full gonist of 5 HT4receptors Ongoing phse 2 studies. Currently pproved for chronic constiption in Europe nd Cnd Axeloprn Orl peripherlly selective mu opioid receptor ntgonist Phse 2 tril underwy SP 333 Orl second genertion urogunylin nlog Phse 2 tril underwy Pruclopride is not pproved by the FDA for use in the United Sttes Wnmi M, et l. A review of peripherlly cting mu opioid receptor ntgonists. Februry 1, journl/news/clinicl/clinicl phrmcology/reviewperipherlly cting mu opioid receptor?pge=full. Accessed November 12, 215. Clinicltrils.gov ccessed November, 215. Improving Ptient Clinicin Communiction Tlking with your ptients bout opioidinduced constiption OIC Improvements Desired by Ptients A single dditionl BM per week my serve s the miniml cliniclly importnt difference for ptients with OIC Ptients (%) Most Commonly Desired Improvements N=513 Hve 1 more BM per week 96.% Be ble to hve BM without pin 87.9% Be ble to hve soft stool tht is not loose or wtery 87.1% Not experience rectl strining due to constiption 83.4% Feel less bloted 83.% Be more comfortble using opioid mediction without fer of being constipted 82.1% Worry less bout being ble to hve BM 8.5% Hve less pin in stomch re 8.3% Epstein RS, et l. Adv Ther. 214;31(12):

7 Strtegies to Effectively Communicte With Ptients bout OIC If ptients re unble to communicte directly, the clinicin should discuss the issue with the cregiver The discussion prior to commencing opioid therpy should include pln for follow up communiction, whether in the office or over the telephone, to ssess the response to the mediction During the discussion, listen for clues tht my be more representtive of OIC thn frequency, including crmping, hrd smll stools, nd significnt strining Evlute ny reports of dirrhe, which could result from stool leking round fecl impction, rule out impction nd obstruction, nd tret ny secondry contributors to the constiption Consider prophylctic bowel mngement PCP Pin Specilist Collbortion in Ptient Centered Cre Pin Specilist Improved Ptient Outcomes Primry Cre Sfety / Wrnings Remember to Ask About Bowel Function in Every Ptient Prescribed Opioids There is no tool tht replces communiction with the ptient! Constiption cn be ssocited with morbidity Tretment of constiption cn be ssocited with morbidity Alwys ssess for possibility of bowel obstruction or perfortion Understnd dverse effects nd drug:drug interctions of lxtive therpies Proposed Tretment Algorithm Brenner DM, Chey WD. Am J Gstroenterol Suppl. 214;2:38 46 Summry Opioid nlgesics re minsty tretment in pin mngement Constiption is one of the most common nd troubling symptoms relted to opioids; does not usully improve over time Assessment is importnt s ptients my not convey the severity Stool softeners, lxtives nd dietry modifictions re often not effective t controlling opioid induced constiption Newer prescriptive gents re vilble tht promote motility nd lubriction of stool to improve the symptoms ssocited with opioid induced constiption