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Risk of Pancreatitis Following Treatment of Irritable Bowel Syndrome With Eluxadoline

  • Andrew J. Gawron
    Affiliations
    Gastroenterology Section, George E. Wahlen VA Medical Center, Salt Lake City, Utah

    Division of Gastroenterology, Hepatology, and Nutrition, University of Utah, Salt Lake City, Utah

    Salt Lake City Specialty Care Center of Innovation, Salt Lake City, Utah
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  • Klaus Bielefeldt
    Correspondence
    Reprint requests Address requests for reprints to: Klaus Bielefeldt, MD, PhD, Gastroenterology Section, George E. Wahlen VA Medical Center, 500 Foothill Drive, Salt Lake City, Utah 84148. fax: (801) 584-5640.
    Affiliations
    Gastroenterology Section, George E. Wahlen VA Medical Center, Salt Lake City, Utah
    Search for articles by this author
Published:August 10, 2017DOI:https://doi.org/10.1016/j.cgh.2017.08.006

      Background & Aims

      The Food and Drug Administration approved eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome despite cases of pancreatitis in early stage trials. We investigated the frequency of pancreatitis attributed to eluxadoline in postmarketing surveillance.

      Methods

      We extracted reports on eluxadoline submitted to the Federal Adverse Event Reporting System from January through September 2016. We collected data on patient age and sex, event date, reporting entity (consumer, physician, pharmacist, legal worker, or other), medications, dosages, presumed role in the event (coinciding, primary, or secondary suspect), treatment indication, and outcome (death, life threatening, hospitalization, disability, or other).We compared data for eluxadoline with data from antidiarrheals, oxycodone, and rifaximin using the κ2 test, Kruskal–Wallis rank test, and analysis of variance; findings with P < .05 were considered statistically significant.

      Results

      Pancreatitis accounted for 16.4% of the 597 reports of adverse events linked to eluxadoline; 53 cases required hospitalization. Pancreatitis was listed as treatment complication of other agents in significantly lower proportions of cases (loperamide, 0.3%; diphenoxylate, 0.4%; oxycodone, 0.2%; rifaximin, 0.5%), with 75% of these submissions not considering the agent as causal.

      Conclusions

      In an analysis of reports on eluxadoline submitted to the Federal Adverse Event Reporting System, we confirmed a previously reported risk of pancreatitis associated with eluxadoline. The need for hospitalization in at least half of these instances and a recent report of 2 fatalities should prompt reassessments of the agent’s risk-benefit ratio.

      Keywords

      Abbreviations used in this paper:

      FAERS (Federal Adverse Event Reporting System), FDA (Food and Drug Administration), IBS-D (diarrhea-predominant irritable bowel syndrome), SOD (sphincter of Oddi dysfunction)
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      References

      1. [email protected]: FDA Approved Drug Products; 2015. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=206940). Accessed April 17, 2017.

        • Dove L.S.
        • Lembo A.
        • Randall C.W.
        • et al.
        Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study.
        Gastroenterology. 2013; 145: 329-338.e1
        • Lembo A.J.
        • Lacy B.E.
        • Zuckerman M.J.
        • et al.
        Eluxadoline for irritable bowel syndrome with diarrhea.
        N Engl J Med. 2016; 374: 242-253
        • Cash B.D.
        • Lacy B.E.
        • Schoenfeld P.S.
        • et al.
        Safety of eluxadoline in patients with irritable bowel syndrome with diarrhea.
        Am J Gastroenterol. 2017; 112: 365-374
        • Talukdar R.
        • Vege S.S.
        Acute pancreatitis.
        Curr Opin Gastroenterol. 2015; 31: 374-379
        • Hoffman K.B.
        • Demakas A.R.
        • Dimbil M.
        • et al.
        Stimulated reporting: the impact of US food and drug administration-issued alerts on the adverse event reporting system (FAERS).
        Drug Saf. 2014; 37: 971-980
        • Swank K.A.
        • Wu E.
        • Kortepeter C.
        • et al.
        Adverse event detection using the FDA post-marketing drug safety surveillance system: cardiotoxicity associated with loperamide abuse and misuse.
        J Am Pharm Assoc (2003). 2017; 57: S63-S67
        • Wald A.
        Irritable bowel syndrome–diarrhoea.
        Best Pract Res Clin Gastroenterol. 2012; 26: 573-580
        • Camilleri M.
        Management of the irritable bowel syndrome.
        Gastroenterology. 2001; 120: 652-668
      2. FDA Drug Safety Communication. FDA warns about increased risk of serious pancreatitis with irritable bowel drug Viberzi (eluxadoline) in patients without a gallbladder, 2017. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm546154.htm. Accessed April 17, 2017.

        • Muddana V.
        • Whitcomb D.C.
        • Papachristou G.I.
        Current management and novel insights in acute pancreatitis.
        Expert Rev Gastroenterol Hepatol. 2009; 3: 435-444
        • Hoffman K.B.
        • Dimbil M.
        • Erdman C.B.
        • et al.
        The Weber effect and the United States Food and Drug Administration's Adverse Event Reporting System (FAERS): analysis of sixty-two drugs approved from 2006 to 2010.
        Drug Saf. 2014; 37: 283-294
        • Behar J.
        • Biancani P.
        Neural control of the sphincter of Oddi. Physiologic role of enkephalins on the regulation of basal sphincter of Oddi motor activity in the cat.
        Gastroenterology. 1984; 86: 134-141
        • Yokohata K.
        • Kimura H.
        • Ogawa Y.
        • et al.
        Biliary motility. Changes in detailed characteristics correlated to duodenal migrating motor complex and effects of morphine and motilin in dogs.
        Dig Dis Sci. 1994; 39: 1294-1301
        • Wu S.D.
        • Zhang Z.H.
        • Jin J.Z.
        • et al.
        Effects of narcotic analgesic drugs on human Oddi's sphincter motility.
        World J Gastroenterol. 2004; 10: 2901-2904
        • Labgaa I.
        • Uldry E.
        • Doerig C.
        • et al.
        Loperamide-induced recurrent acute pancreatitis.
        Clin Res Hepatol Gastroenterol. 2016; 40: e13-e14
        • Vidarsdottir H.
        • Vidarsdottir H.
        • Moller P.H.
        • et al.
        Loperamide-induced acute pancreatitis.
        Case Rep Gastrointest Med. 2013; 2013: 517414
        • Epelde F.
        • Boada L.
        • Tost J.
        Pancreatitis caused by loperamide overdose.
        Ann Pharmacother. 1996; 30: 1339
        • McCormick P.A.
        • O'Donoghue D.
        • Brennan N.
        Diphenoxylate and pancreatitis.
        Lancet. 1985; 1: 752
        • Thompson D.R.
        Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis.
        Am J Gastroenterol. 2001; 96: 1266-1272
        • Peiro A.M.
        • Martinez J.
        • Martinez E.
        • et al.
        Efficacy and tolerance of metamizole versus morphine for acute pancreatitis pain.
        Pancreatology. 2008; 8: 25-29
        • Sharma V.
        • Rana S.S.
        • Chaudhary V.
        • et al.
        Opium-related sphincter of Oddi dysfunction causing double duct sign.
        Endosc Ultrasound. 2016; 5: 269-271
        • Torres D.
        • Parrinello G.
        • Trapanese C.
        • et al.
        Sudden severe abdominal pain after a single low dose of paracetamol/codeine in a cholecystectomized patient: learning from a case report.
        Am J Ther. 2010; 17: e133-e134
        • Hastier P.
        • Buckley M.J.
        • Peten E.P.
        • et al.
        A new source of drug-induced acute pancreatitis: codeine.
        Am J Gastroenterol. 2000; 95: 3295-3298
        • Zahoor A.
        • Mateger M.
        • Ahmad N.
        Is previous cholecystectomy a contraindication to paracetamol/codeine premedication?.
        Eur J Anaesthesiol. 2013; 30: 131-132
        • Levy-Cooperman N.
        • McIntyre G.
        • Bonifacio L.
        • et al.
        Abuse potential and pharmacodynamic characteristics of oral and intranasal eluxadoline, a mixed μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist.
        J Pharmacol Exp Ther. 2016; 359: 471-481
        • Fant R.V.
        • Henningfield J.E.
        • Cash B.D.
        • et al.
        Eluxadoline demonstrates a lack of abuse potential in phase 2 and 3 studies of patients with irritable bowel syndrome with diarrhea.
        Clin Gastroenterol Hepatol. 2017; 15: 1021-1029.e6
        • Palmer K.R.
        • Corbett C.L.
        • Holdsworth C.D.
        Double-blind cross-over study comparing loperamide, codeine and diphenoxylate in the treatment of chronic diarrhea.
        Gastroenterology. 1980; 79: 1272-1275
        • Bergman L.
        • Djarv L.
        A comparative study of loperamide and diphenoxylate in the treatment of chronic diarrhoea caused by intestinal resection.
        Ann Clin Res. 1981; 13: 402-405
        • Mainguet P.
        • Fiasse R.
        • Turine J.B.
        Long-term survey of the treatment of diarrhoea with loperamide.
        Digestion. 1977; 16: 69-76
        • Jaffe J.H.
        • Kanzler M.
        • Green J.
        Abuse potential of loperamide.
        Clin Pharmacol Ther. 1980; 28: 812-819
        • McCarron M.M.
        • Challoner K.R.
        • Thompson G.A.
        Diphenoxylate-atropine (Lomotil) overdose in children: an update (report of eight cases and review of the literature).
        Pediatrics. 1991; 87: 694-700
        • Mehra A.
        • Sarkar S.
        • Basu D.
        Lomotil (diphenoxylate) dependence in India.
        Indian J Psychol Med. 2013; 35: 248-250
        • Drossman D.A.
        • Morris C.B.
        • Schneck S.
        • et al.
        International survey of patients with IBS: symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit.
        J Clin Gastroenterol. 2009; 43: 541-550
        • Halmos E.P.
        • Power V.A.
        • Shepherd S.J.
        • et al.
        A diet low in FODMAPs reduces symptoms of irritable bowel syndrome.
        Gastroenterology. 2014; 146: 67-75.e5
        • Zia J.K.
        • Barney P.
        • Cain K.C.
        • et al.
        A comprehensive self-management irritable bowel syndrome program produces sustainable changes in behavior after 1 year.
        Clin Gastroenterol Hepatol. 2016; 14 (e1–e2): 212-219
        • Ljótsson B.
        • Falk L.
        • Vesterlund A.W.
        • et al.
        Internet-delivered exposure and mindfulness based therapy for irritable bowel syndrome - a randomized controlled trial.
        Behav Res Ther. 2010; 48: 531-539
        • Labus J.
        • Gupta A.
        • Gill H.K.
        • et al.
        Randomised clinical trial: symptoms of the irritable bowel syndrome are improved by a psycho-education group intervention.
        Aliment Pharmacol Ther. 2013; 37: 304-315