Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials

P Schoenfeld, M Pimentel, L Chang, A Lembo, W D Chey, J Yu, C Paterson, E Bortey, W P Forbes, P Schoenfeld, M Pimentel, L Chang, A Lembo, W D Chey, J Yu, C Paterson, E Bortey, W P Forbes

Abstract

Background: The efficacy of rifaximin, a nonsystemic, gut-targeted antibiotic for reducing non-constipation-predominant irritable bowel syndrome (non-C IBS) symptoms, has been demonstrated in one phase 2b and two phase 3 randomised, double-blind, placebo-controlled trials, but detailed data about rifaximin safety and tolerability during treatment and subsequent follow-up periods are lacking.

Aim: To assess and determine the frequency of rifaximin and placebo adverse events (AEs) in phase 2b and phase 3 non-C IBS trials.

Methods: A post hoc pooled safety analysis of the phase 2b (rifaximin 275, 550, and 1100 mg twice daily for 2 weeks; 550 mg twice daily for 4 weeks) and phase 3 (rifaximin 550 mg three times daily for 2 weeks) studies was performed. Data on treatment and post-treatment AEs were collected. Patients were followed up for 12 weeks and 10 weeks post-treatment in the phase 2b and phase 3 trials, respectively.

Results: Patients receiving rifaximin (n = 1103) and placebo (n = 829) had a similar incidence of drug-related AEs (12.1% vs. 10.7%), serious AEs (1.5% vs. 2.2%), drug-related AEs resulting in study discontinuation (0.8% vs. 0.8%), gastrointestinal-associated AEs (12.2% vs. 12.2%) and infection-associated AEs (8.5% vs. 9.5%). There were no cases of Clostridium difficile colitis or deaths.

Conclusions: The safety and tolerability profile of rifaximin during treatment and post-treatment was comparable to placebo. Future research should define the safety and tolerability profile, including risk of C. difficile colitis and microbial antibiotic resistance, with repeated courses of rifaximin in patients with non-constipation-predominant irritable bowel syndrome (ClinicalTrials.gov: NCT00269412, NCT00731679, and NCT00724126).

© 2014 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

References

    1. Brandt LJ, Chey WD, Foxx‐Orenstein AE, et al An evidence‐based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104(Suppl. 1): S1–35
    1. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006; 130: 1480–91
    1. Shah E, Kim S, Chong K, Lembo A, Pimentel M. Evaluation of harm in the pharmacotherapy of irritable bowel syndrome. Am J Med 2012; 125: 381–93
    1. Tack J. Antibiotic therapy for the irritable bowel syndrome. N Engl J Med 2011; 364: 81–2
    1. Menees SB, Maneerattannaporn M, Kim HM, Chey WD. The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta‐analysis. Am J Gastroenterol 2012; 107: 28–35
    1. Adachi JA, DuPont HL. Rifaximin: a novel nonabsorbed rifamycin for gastrointestinal disorders. Clin Infect Dis 2006; 42: 541–7
    1. Basseri RJ, Weitsman S, Barlow GM, Pimentel M. Antibiotics for the treatment of irritable bowel syndrome. Gastroenterol Hepatol (NY) 2011; 7: 455–93
    1. Xifaxan (rifaximin) tablets [package insert]. Raleigh, NC: Salix Pharmaceuticals, Inc., 2012
    1. Pimentel M, Lembo A, Chey WD, et al Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011; 364: 22–32
    1. Lembo A, Zakko SF, Ferreira NL, et al Rifaximin for the treatment of diarrhea‐associated irritable bowel syndrome: short term treatment leading to long term sustained response. Gastroenterology 2008; 134: A–545
    1. . Study to assess the efficacy and safety of rifaximin administered BID in the treatment of patients with diarrhea‐associated irritable bowel syndrome. . December 21, 2009. Available at: Accessed January 15, 2013.
    1. Meyrat P, Safroneeva E, Schoepfer AM. Rifaximin treatment for the irritable bowel syndrome with a positive lactulose hydrogen breath test improves symptoms for at least 3 months. Aliment Pharmacol Ther 2012; 36: 1084–93
    1. Peralta S, Cottone C, Doveri T, Almasio PL, Craxi A. Small intestine bacterial overgrowth and irritable bowel syndrome‐related symptoms: experience with rifaximin. World J Gastroenterol 2009; 15: 2628–31
    1. Esposito I, de Leon A, Di Gregorio G, et al Breath test for differential diagnosis between small intestinal bacterial overgrowth and irritable bowel disease: an observation on non‐absorbable antibiotics. World J Gastroenterol 2007; 13: 6016–21
    1. Majewski M, McCallum RW. Results of small intestinal bacterial overgrowth testing in irritable bowel syndrome patients: clinical profiles and effects of antibiotic trial. Adv Med Sci 2007; 52: 139–42
    1. Lessa FC, Gould CV, McDonald LC. Current status of Clostridium difficile infection epidemiology. Clin Infect Dis 2012; 55(Suppl. 2): S65–70
    1. Prantera C, Lochs H, Grimaldi M, Danese S, Scribano ML, Gionchetti P. Rifaximin‐extended intestinal release induces remission in patients with moderately active Crohn's disease. Gastroenterology 2012; 142: 473–81
    1. Bass NM, Mullen KD, Sanyal A, et al Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362: 1071–81
    1. Gastrointestinal Drugs Advisory Committee . XIFAXAN® (Rifaximin) Tablets, 550 Mg, NDA 21‐361: Briefing Document for Gastrointestinal Drugs Advisory Committee Meeting, 16 November 2011. Silver Springs, MD: U.S. Department of Health & Human Services; U.S. Food and Drug Administration, 2011. Available at: Accessed January 14, 2013.
    1. Sanyal A, Mullen KD, Bass NM, et al Rates of commonly occurring infections in cirrhosis patients remain stable during long‐term rifaximin treatment. J Hepatol 2012; 56: S255–6
    1. Shah D, Dang MD, Hasbun R, et al Clostridium difficile infection: update on emerging antibiotic treatment options and antibiotic resistance. Expert Rev Anti Infect Ther 2010; 8: 555–64
    1. Venugopal AA, Johnson S. Current state of Clostridium difficile treatment options. Clin Infect Dis 2012; 55: S71–6
    1. Mattila E, Arkkila P, Mattila PS, Tarkka E, Tissari P, Anttila VJ. Rifaximin in the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2013; 37: 122–8
    1. Garey KW, Ghantoji SS, Shah DN, et al A randomized, double‐blind, placebo‐controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with Clostridium difficile infection. J Antimicrob Chemother 2011; 66: 2850–5
    1. Rubin DT, Sohi S, Glathar M, Thomas T, Yadron N, Surma BL. Rifaximin is effective for the treatment of Clostridium difficile‐associated diarrhea: results of an open‐label pilot study. Gastroenterol Res Pract 2011; 2011: 106978.
    1. Basu PP, Dinani A, Rayapudi K, et al Rifaximin therapy for metronidazole‐unresponsive Clostridium difficile infection: a prospective pilot trial. Therap Adv Gastroenterol 2010; 3: 221–5
    1. Scarpignato C, Pelosini I. Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential. Chemotherapy 2005; 51(Suppl. 1): 36–66
    1. De Leo C, Eftimiadi C, Schito GC. Rapid disappearance from the intestinal tract of bacteria resistant to rifaximin. Drugs Exp Clin Res 1986; 12: 979–81
    1. DuPont HL, Jiang ZD. Influence of rifaximin treatment on the susceptibility of intestinal Gram‐negative flora and enterococci. Clin Microbiol Infect 2004; 10: 1009–11
    1. Kothary V, Scherl EJ, Bosworth B, et al Rifaximin resistance in Escherichia coli associated with inflammatory bowel disease correlates with prior rifaximin use, mutations in rpoB, and activity of PAbN‐inhibitable efflux pumps. Antimicrob Agents Chemother 2013; 57: 811–7
    1. Carman RJ, Boone JH, Grover H, Wickham KN, Chen L. In vivo selection of rifamycin‐resistant Clostridium difficile during rifaximin therapy. Antimicrob Agents Chemother 2012; 56: 6019–20

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