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Inflammation and inflammatory bowel disease: R A J Ransford and M J S Langman Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines Gut 2002; 51: 536-539 [Abstract] [Full text] [PDF]

Electronic letters published:

Mesalazine is safe for the treatment of IBD

Geert R D'Haens, Ad van Bodegraven   (9 June 2003)

Mesalazine is safe for the treatment of IBD 9 June 2003
Geert R D'Haens, MD, PhD University of Leuven, Belgium, Ad van Bodegraven Send letter to journal: Re: Mesalazine is safe for the treatment of IBD geert.dhaens{at}imelda.be Geert R D'Haens, et al.	Dear Editor The article by Ransford and Langman [1] on suspected serious adverse drug reactions for sulphasalazine and mesalazine reported in the UK from 1991 to 1998 revealed significant differences between both drugs. Pancreatitis and interstitial nephritis were reported more frequently for mesalazine in comparison with sulphasalazine. The authors’ conclusion that mesalazine would not offer a safety benefit over sulphasalazine, however, appears unjustified for several reasons. Sulphasalazine is an older compound used for the treatment of both rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). For 30 years, the adverse event (AE) profile of sulphasalazine has been well known [2]. It often induces oligoteratozoöspermy in male patients and frequently causes nausea, vomiting, headache, and folic acid deficiency. Although not ‘serious’ AEs, these often lead to low compliance, incorrect use and early discontinuation. In addition, it is more than likely that the many adverse reactions, identified in the 1970s, were not reported again to the medical authorities in the nineties. The introduction of mesalazine in the 1980s enabled effective treatment (often at higher doses) without the numerous adverse effects attributed to the sulphapyridine moiety of sulphasalazine.[3] Focus on the risk of interstitial nephritis caused by mesalazine preparations in the mid nineties undoubtedly led to a low threshold for reporting. However, the incidence of renal insufficiency was recently studied in a large cohort of 1449 European IBD patients (more than 70 % on mesalazine/sulphasalazine) and did not exceed the expected incidence in the general population.[4] Furthermore, pooling the data of all pure mesalazine products (as done by Ransford and Langman, 2002)[5] does not seem appropriate, since the different release mechanisms of the various products could bring along different AE profiles. PENTASA® has less frequently been associated with interstitial nephritis than other 5-ASAs.[6] Unlike PENTASA®, Asacol®, Claversal® and Salofalk® indeed have a relative dose dumping effect with higher peak serum concentrations, allegedly contributing to potential nephrotoxicity.[7] In addition, reporting serious AEs in relation to the number of prescriptions is an unusual approach. Dosage and duration of therapy would have been more relevant, since the risk of side effects is dose-dependent with sulphasalazine but not with mesalazine. Physicians may prefer to prescribe mesalazine to patients who are susceptible to side effects caused by sulphasalazine. For an unclear reason, adverse events with fatal outcome were not mentioned separately in Ransford and Langman’s report.[1] Based on the British CSM database, 18 fatal events occurred in patients taking sulphasalazine, versus 12 in the pooled pure mesalazine group during the same observation period. Moreover, PENTASA® mortality rate was zero in an earlier French pharmacovigilance report revealing an incidence of reported adverse events with this product (the most commonly used mesalazine preparation in France with a market share > 70%) between 6 and 9 per million days of therapy.[8] In conclusion, based on all available data on mortality, serious irreversible adverse events and tolerability of both drugs, mesalazine should be preferred to sulphalsalzine in the treatment of IBD. Eighty per cent of the patients intolerant to sulphasalzine will tolerate mesalazine without problems. [9-11] References (1) Ransford RAJ, Langman MJS. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut 2002;51: 536-539. (2) Das KM, Eastwood MA, McManus JP, Sircus W. Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. New Engl J Med 1973:289:491-5. (3) Forbes, A. Clinicians' guide to inflammatory bowel disease. London: Chapman & Hall, 1997. (4) G D'Haens, M Elseviers, L Lemmens, C Plane, E Lerebours, JC Stolear, G Riegler, M Van Outryve, P Mishevska, S Djuranovica and M De Broe. Absence of renal impairment with longstanding use of aminosalicylates in chronic inflammatory bowel disease. 8th UEGW, Bruxelles. Gut Suppl 2000. (5) Ransford RAJ, Langman MJS. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut 2002;51:536-539. (6) World MJ, Stevens PE, Ashton MA, Rainford DJ. Mesalazine-associated interstitial nephritis. Nephrol Dial Transplant. 1996; 11:614-21. (7) Corrigan G, Stevens PE. Review article: interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease. Aliment Pharmacol Ther 2000; 14:1-6. (8) Marteau P, Nelet F, Le Lu M, Devaux C. Adverse events in patients treated with 5-aminosalicyclic acid: 1993-1994 pharmacovigilance report for Pentasa in France. Aliment Pharmacol Ther 1996;10:949-956. (9) Dew MJ, Harries AD, Evans BK, Rhodes J. Treatment of ulcerative colitis with oral 5-aminosalicyclic acid in patients unable to take sulphasalazine. Lancet 1983;2:801 (10) Turunen U, Elomaa I, Anttila VJ, Seppala K. Mesalazine tolerance in patients with inflammatory bowel disease and previous intolerance or allergy to sulphasalazine or sulphonamides. Scand J Gastroenterol 1987;22: 798-802. (11) Rao SS, Cann PA, Holdsworth CD. Clinical experience of the tolerance of mesalazine and olsalazine in patients intolerant of sulphasalazine. Scand J Gastroenterol 1987; 22:332-336.