Assessment of the real-world safety profile of vedolizumab using the United States Food and Drug Administration adverse event reporting system

Autoři: Raymond K. Cross aff001;  Michael Chiorean aff002;  Francis Vekeman aff003;  Yongling Xiao aff003;  Eric Wu aff004;  Jingdong Chao aff005;  Anthony W. Wang aff005
Působiště autorů: University of Maryland School of Medicine, Baltimore, Maryland, United States of America aff001;  Virginia Mason Medical Center, Seattle, Washington, United States of America aff002;  Groupe d’analyse, Ltée, Montréal, Québec, Canada aff003;  Analysis Group, Inc., Boston, Massachusetts, United States of America aff004;  AbbVie Inc., North Chicago, Illinois, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


Vedolizumab is the first gut-selective integrin blocker indicated for patients with Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to examine the adverse events (AEs) profile of vedolizumab compared to anti-tumor necrosis factors (anti-TNFs) indicated for CD and UC using the FDA Adverse Event Reporting System (FAERS) database. AE reports with vedolizumab (5/20/2014–6/30/2015) and CD/UC-indicated anti-TNF drugs (adalimumab, infliximab, certolizumab pegol, and golimumab, during 8/1/1998–6/30/2015) as primary suspects were extracted from the FAERS database. AEs associated with vedolizumab were compared for signals of disproportionate reporting against anti-TNF drugs and all other drugs (1969–6/30/2015), using the proportional reporting ratio (PRR) and the empirical Bayesian geometric mean (EBGM) algorithms. The search retrieved 499 reports for vedolizumab and 119,620 reports for anti-TNFs, with 35.9% and 32.1% of these, respectively, being serious AEs. With the PRR approach, vedolizumab-associated reports had signals for 22 groups of AEs (9 were associated with serious outcomes) relative to anti-TNFs and had 34 signals relative to all other drugs. Signals detected included those reported as warnings in prescribing information and new AEs related to cardiovascular disease. Due to the voluntary nature of FAERS, this finding should be considered hypothesis generating (rather than hypothesis testing). Longer-term observational studies are required to evaluate the safety of vedolizumab.

Klíčová slova:

Adverse events – Drug discovery – Drug information – Drug therapy – Gastrointestinal infections – Immune receptor signaling – Ulcerative colitis – Upper respiratory tract infections


1. Stidham RW, Lee TC, Higgins PD, Deshpande AR, Sussman DA, Singal AG, et al. Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn's disease. Aliment Pharmacol Ther. 2014;39(12):1349–62. Epub 2014/04/23. doi: 10.1111/apt.12749 24749763.

2. Stidham RW, Lee TC, Higgins PD, Deshpande AR, Sussman DA, Singal AG, et al. Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis. Aliment Pharmacol Ther. 2014;39(7):660–71. Epub 2014/02/11. doi: 10.1111/apt.12644 24506179.

3. Cohen LB, Nanau RM, Delzor F, Neuman MG. Biologic therapies in inflammatory bowel disease. Translational research: the journal of laboratory and clinical medicine. 2014;163(6):533–56. Epub 2014/01/29. doi: 10.1016/j.trsl.2014.01.002 24467968.

4. Gomollon F, Dignass A, Annese V, Tilg H, Van Assche G, Lindsay JO, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management. J Crohns Colitis. 2017;11(1):3–25. Epub 2016/09/24. doi: 10.1093/ecco-jcc/jjw168 27660341.

5. Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn's disease in adults. Am J Gastroenterol. 2009;104(2):465–83; quiz 4, 84. Epub 2009/01/29. doi: 10.1038/ajg.2008.168 19174807.

6. Magro F, Portela F. Management of inflammatory bowel disease with infliximab and other anti-tumor necrosis factor alpha therapies. BioDrugs. 2010;24 Suppl 1:3–14. Epub 2010/12/24. doi: 10.2165/11586290-000000000-00000 21175228.

7. Janssen Biotech I. SIMPONI (golimumab) prescribing information 2013 [cited 2017 March 2]. 1–33]. Available from:

8. Sedger LM, McDermott MF. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants—past, present and future. Cytokine Growth Factor Rev. 2014;25(4):453–72. doi: 10.1016/j.cytogfr.2014.07.016 25169849.

9. de Mattos BR, Garcia MP, Nogueira JB, Paiatto LN, Albuquerque CG, Souza CL, et al. Inflammatory bowel disease: an overview of immune mechanisms and biological treatments. Mediators Inflamm. 2015;2015:493012. doi: 10.1155/2015/493012 26339135; PubMed Central PMCID: PMC4539174.

10. McLean LP, Shea-Donohue T, Cross RK. Vedolizumab for the treatment of ulcerative colitis and Crohn's disease. Immunotherapy. 2012;4(9):883–98. doi: 10.2217/imt.12.85 23046232; PubMed Central PMCID: PMC3557917.

11. Ala A, Dhillon AP, Hodgson HJ. Role of cell adhesion molecules in leukocyte recruitment in the liver and gut. Int J Exp Pathol. 2003;84(1):1–16. doi: 10.1046/j.1365-2613.2003.00235.x 12694483; PubMed Central PMCID: PMC2517541.

12. Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis. 2012;6(10):991–1030. doi: 10.1016/j.crohns.2012.09.002 23040451.

13. Dignass A, Van Assche G, Lindsay JO, Lemann M, Soderholm J, Colombel JF, et al. The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management. J Crohns Colitis. 2010;4(1):28–62. doi: 10.1016/j.crohns.2009.12.002 21122489.

14. Terdiman JP, Gruss CB, Heidelbaugh JJ, Sultan S, Falck-Ytter YT, Practice AGAIC, et al. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the induction and maintenance of remission in inflammatory Crohn's disease. Gastroenterology. 2013;145(6):1459–63. Epub 2013/11/26. doi: 10.1053/j.gastro.2013.10.047 24267474.

15. Huang X, Lv B, Jin HF, Zhang S. A meta-analysis of the therapeutic effects of tumor necrosis factor-alpha blockers on ulcerative colitis. Eur J Clin Pharmacol. 2011;67(8):759–66. Epub 2011/06/22. doi: 10.1007/s00228-011-1079-3 21691804.

16. Zhang D, Xiong B, Li X, Xu T, Yu M. Meta-analysis: serious adverse events in Crohn's disease patients treated with TNF-alpha inhibitors. Hepatogastroenterology. 2013;60(126):1333–42. Epub 2013/01/24. doi: 10.5754/hge121057 23340167.

17. Singh JA, Wells GA. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database of Syst Rev. 2012;3:1–82.

18. Freling E, Baumann C, Cuny JF, Bigard MA, Schmutz JL, Barbaud A, et al. Cumulative incidence of, risk factors for, and outcome of dermatological complications of anti-TNF therapy in inflammatory bowel disease: a 14-year experience. Am J Gastroenterol. 2015;110(8):1186–96. Epub 2015/07/22. doi: 10.1038/ajg.2015.205 26195181.

19. Lees CW, Ali AI, Thompson AI, Ho GT, Forsythe RO, Marquez L, et al. The safety profile of anti-tumour necrosis factor therapy in inflammatory bowel disease in clinical practice: analysis of 620 patient-years follow-up. Aliment Pharmacol Ther. 2009;29(3):286–97. Epub 2009/01/10. doi: 10.1111/j.1365-2036.2008.03882.x 19132970.

20. Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, et al. Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol. 2012;107(9):1409–22. Epub 2012/08/15. doi: 10.1038/ajg.2012.218 22890223; PubMed Central PMCID: PMC3438468.

21. Marehbian J, Arrighi HM, Hass S, Tian H, Sandborn WJ. Adverse events associated with common therapy regimens for moderate-to-severe Crohn's disease. Am J Gastroenterol. 2009;104(10):2524–33. Epub 2009/06/18. doi: 10.1038/ajg.2009.322 19532125.

22. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699–710. Epub 2013/08/24. doi: 10.1056/NEJMoa1215734 23964932.

23. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013;369(8):711–21. Epub 2013/08/24. doi: 10.1056/NEJMoa1215739 23964933.

24. Baumgart DC, Bokemeyer B, Drabik A, Stallmach A, Schreiber S, Vedolizumab Germany C. Vedolizumab induction therapy for inflammatory bowel disease in clinical practice—a nationwide consecutive German cohort study. Aliment Pharmacol Ther. 2016;43(10):1090–102. doi: 10.1111/apt.13594 27038247.

25. Amiot A, Grimaud JC, Peyrin-Biroulet L, Filippi J, Pariente B, Roblin X, et al. Effectiveness and safety of vedolizumab induction therapy for patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2016;14(11):1593–601 e2. doi: 10.1016/j.cgh.2016.02.016 26917043.

26. Vivio EE, Kanuri N, Gilbertsen JJ, Monroe K, Dey N, Chen CH, et al. Vedolizumab effectiveness and safety over the first year of use in an IBD clinical practice. J Crohns Colitis. 2016;10(4):402–9. doi: 10.1093/ecco-jcc/jjv226 26681763.

27. Shelton E, Allegretti JR, Stevens B, Lucci M, Khalili H, Nguyen DD, et al. Efficacy of vedolizumab as induction therapy in refractory IBD patients: a multicenter cohort. Inflamm Bowel Dis. 2015;21(12):2879–85. Epub 2015/08/20. doi: 10.1097/MIB.0000000000000561 26288002; PubMed Central PMCID: PMC4745906.

28. Dulai PS, Singh S, Jiang X, Peerani F, Narula N, Chaudrey K, et al. The real-world effectiveness and safety of vedolizumab for moderate-severe Crohn's disease: results from the US VICTORY Consortium. Am J Gastroenterol. 2016;111(8):1147–55. Epub 2016/06/15. doi: 10.1038/ajg.2016.236 27296941.

29. Booth CM, Tannock IF. Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence. Br J Cancer. 2014;110(3):551–5. doi: 10.1038/bjc.2013.725 24495873; PubMed Central PMCID: PMC3915111.

30. Concato J, Peduzzi P, Huang GD, O'Leary TJ, Kupersmith J. Comparative effectiveness research: what kind of studies do we need? J Investig Med. 2010;58(6):764–9. doi: 10.231/JIM.0b013e3181e3d2af 20479661.

31. Armstrong K. Methods in comparative effectiveness research. J Clin Oncol. 2012;30(34):4208–14. doi: 10.1200/JCO.2012.42.2659 23071240; PubMed Central PMCID: PMC3504326.

32. Rothman KJ, Greenland S, Lash TL. Modern Epidemiology. 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2008.

33. Meyer RM. Generalizing the results of cancer clinical trials. J Clin Oncol. 2010;28(2):187–9. doi: 10.1200/JCO.2009.25.8608 19933900.

34. Xu R, Wang Q. Large-scale combining signals from both biomedical literature and the FDA Adverse Event Reporting System (FAERS) to improve post-marketing drug safety signal detection. BMC bioinformatics. 2014;15(1):17. doi: 10.1186/1471-2105-15-17 24428898; PubMed Central PMCID: PMC3906761.

35. Bailey S, Singh A, Azadian R, Huber P, Blum M. Prospective data mining of six products in the US FDA Adverse Event Reporting System: disposition of events identified and impact on product safety profiles. Drug Saf. 2010;33(2):139–46. Epub 2010/01/20. doi: 10.2165/11319000-000000000-00000 20082540.

36. Weaver J, Willy M, Avigan M. Informatic tools and approaches in postmarketing pharmacovigilance used by FDA. The AAPS journal. 2008;10(1):35–41. Epub 2008/05/01. doi: 10.1208/s12248-007-9004-5 18446503; PubMed Central PMCID: PMC2751449.

37. Sakaeda T, Tamon A, Kadoyama K, Okuno Y. Data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci. 2013;10(7):796–803. doi: 10.7150/ijms.6048 23794943; PubMed Central PMCID: PMC3689877.

38. Almenoff JS, LaCroix KK, Yuen NA, Fram D, DuMouchel W. Comparative performance of two quantitative safety signalling methods: implications for use in a pharmacovigilance department. Drug safety. 2006;29(10):875–87. doi: 10.2165/00002018-200629100-00005 16970511

39. Bate A, Edwards IR. Data mining in spontaneous reports. Basic Clin Pharmacol Toxicol. 2006;98(3):324–30. doi: 10.1111/j.1742-7843.2006.pto_232.x 16611210.

40. Center for Drug Evaluation and Research, U. S. Food and Drug Administration. FDA Adverse Event Reporting System (FAERS) Silver Spring, MD: U.S. Food and Drug Administration; 2015 [cited 2016 February 19, 2016]. Available from:

41. Giese P. MedDRA–Beyond that basic AE report. How SMQs and MedDRA structure can enhance reporting. 2013.

42. Office of the Commissioner, U. S. Food and Drug Administration. Reporting serious problems to the FDA—What is a serious adverse event? Silver Spring, MD: U.S. Food and Drug Administration; 2016 [cited 2016 February 19, 2016]. Available from:

43. Weiss-Smith S, Deshpande G, Chung S, Gogolak V. The FDA drug safety surveillance program: adverse event reporting trends. Arch Intern Med. 2011;171(6):591–3. Epub 2011/03/30. doi: 10.1001/archinternmed.2011.89 21444854.

44. Chhabra P, Chen X, Weiss SR. Adverse event reporting patterns of newly approved drugs in the USA in 2006: an analysis of FDA Adverse Event Reporting System data. Drug safety. 2013;36(11):1117–23. Epub 2013/10/01. doi: 10.1007/s40264-013-0115-x 24078293.

45. Duh MS, Cremieux P, Audenrode MV, Vekeman F, Karner P, Zhang H, et al. Can social media data lead to earlier detection of drug-related adverse events? Pharmacoepidemiol Drug Saf. 2016;25(12):1425–33. Epub 2016/09/08. doi: 10.1002/pds.4090 27601271; PubMed Central PMCID: PMC5157765.

46. Duggirala HJ, Tonning JM, Smith E, Bright RA, Baker JD, Ball R, et al. Data Mining at FDA. Silver Spring, MD: U.S. Food and Drug Administration, 2015.

47. Deshpande G, Gogolak V, Smith SW. Data Mining in drug safety. Pharmaceutical Medicine. 2010;24(1):37–43.

48. R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2014.

49. Colombel JF, Sands BE, Rutgeerts P, Sandborn W, Danese S, D'Haens G, et al. The safety of vedolizumab for ulcerative colitis and Crohn's disease. Gut [Internet]. 2016 Feb 18. Available from:

50. Wang MC, Zhang LY, Han W, Shao Y, Chen M, Ni R, et al. PRISMA—efficacy and safety of vedolizumab for inflammatory bowel diseases: a systematic review and meta-analysis of randomized controlled trials. Medicine. 2014;93(28):e326. Epub 2014/12/20. doi: 10.1097/MD.0000000000000326 25526490; PubMed Central PMCID: PMC4603082.

51. Luthra P, Peyrin-Biroulet L, Ford AC. Systematic review and meta-analysis: opportunistic infections and malignancies during treatment with anti-integrin antibodies in inflammatory bowel disease. Aliment Pharmacol Ther. 2015;41(12):1227–36. Epub 2015/04/24. doi: 10.1111/apt.13215 25903741.

52. Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum. 2002;46(12):3151–8. doi: 10.1002/art.10679 12483718.

53. Diak P, Siegel J, La Grenade L, Choi L, Lemery S, McMahon A. Tumor necrosis factor alpha blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum. 2010;62(8):2517–24. Epub 2010/05/28. doi: 10.1002/art.27511 20506368.

54. Deepak P, Sifuentes H, Sherid M, Stobaugh D, Sadozai Y, Ehrenpreis ED. T-cell non-Hodgkin's lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-alpha) inhibitors: results of the REFURBISH study. Am J Gastroenterol. 2013;108(1):99–105. doi: 10.1038/ajg.2012.334 23032984.

55. Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol. 2009;36(3):635–41. Epub 2009/01/10. doi: 10.3899/jrheum.080545 19132789.

56. Filimon AM, Negreanu L, Doca M, Ciobanu A, Preda CM, Vinereanu D. Cardiovascular involvement in inflammatory bowel disease: dangerous liaisons. World J Gastroenterol. 2015;21(33):9688–92. Epub 2015/09/12. doi: 10.3748/wjg.v21.i33.9688 26361415; PubMed Central PMCID: PMC4562952.

57. Fumery M, Xiaocang C, Dauchet L, Gower-Rousseau C, Peyrin-Biroulet L, Colombel JF. Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: a meta-analysis of observational studies. J Crohns Colitis. 2014;8(6):469–79. Epub 2013/11/05. doi: 10.1016/j.crohns.2013.09.021 24183231.

58. Singh S, Singh H, Loftus EV Jr., Pardi DS. Risk of cerebrovascular accidents and ischemic heart disease in patients with inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12(3):382–93 e1: quiz e22. Epub 2013/08/28. doi: 10.1016/j.cgh.2013.08.023 23978350.

59. Vizzardi E, Sciatti E, Bonadei I, Bordonali T, Ricci C, Lanzarotto F, et al. Subclinical cardiac involvement in Crohn's disease and ulcerative colitis: an echocardiographic case-control study. Panminerva medica. 2016;58(2):115–20. Epub 2016/03/11. 26964076.

60. Steyers CM 3rd, Miller FJ Jr. Endothelial dysfunction in chronic inflammatory diseases. International journal of molecular sciences. 2014;15(7):11324–49. Epub 2014/06/27. doi: 10.3390/ijms150711324 24968272; PubMed Central PMCID: PMC4139785.

61. Papa A, Scaldaferri F, Danese S, Guglielmo S, Roberto I, Bonizzi M, et al. Vascular involvement in inflammatory bowel disease: pathogenesis and clinical aspects. Dig Dis. 2008;26(2):149–55. Epub 2008/04/24. doi: 10.1159/000116773 18431065.

62. Deepak P, Stobaugh DJ, Ehrenpreis ED. Infectious complications of TNF-alpha inhibitor monotherapy versus combination therapy with immunomodulators in inflammatory bowel disease: analysis of the Food and Drug Administration Adverse Event Reporting System. J Gastrointestin Liver Dis. 2013;22(3):269–76. Epub 2013/10/01. 24078983.

63. Kip KE, Swoger JM, Grandinetti LM, Barrie AM 3rd, Greer JB, Regueiro MD. Tumor necrosis factor alpha antagonist-associated psoriasis in inflammatory diseases: an analysis of the FDA adverse event reporting system. Inflamm Bowel Dis. 2013;19(6):1164–72. Epub 2013/03/23. doi: 10.1097/MIB.0b013e31828075bd 23518804.

64. McKenna MR, Stobaugh DJ, Deepak P. Melanoma and non-melanoma skin cancer in inflammatory bowel disease patients following tumor necrosis factor-alpha inhibitor monotherapy and in combination with thiopurines: analysis of the Food and Drug Administration Adverse Event Reporting System. J Gastrointestin Liver Dis. 2014;23(3):267–71. Epub 2014/10/01. doi: 10.15403/jgld.2014.1121.233.mrmk 25267954.

65. Deepak P, Stobaugh DJ, Sherid M, Sifuentes H, Ehrenpreis ED. Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System. Aliment Pharmacol Ther. 2013;38(4):388–96. Epub 2013/06/28. doi: 10.1111/apt.12385 23802849.

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