Overview

Mesalazine and sulfasalazine are anti-inflammatory agents from the 5-aminosalicylic acid (5-ASA) group which are commonly used for the treatment of inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD). Sulfasalazine is also used to treat rheumatoid arthritis.^1-4

In Malaysia, there are currently 16 registered products containing mesalazine (as tablet, granules, suppositories and enema) and three (3) registered products containing sulfasalazine (as tablet).

Background of the safety issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) regarding the risk of nephrolithiasis associated with the use of mesalazine. EMA had initiated a review after receiving reports of nephrolithiasis (kidney stones) that occurred following treatment of mesalazine. The stones were found to be composed of 100% of mesalazine deposits. Based on the data from the review, EMA requested the product registration holders of mesalazine to update the product information.⁵

Based on a review by NPRA, the time to onset of nephrolithiasis occurred variably from one individual to another. Reported cases in literature showed that the time to onset is between several weeks to years after starting treatment.^4,6

As mesalazine is the active moiety of sulfasalazine, NPRA has extended the review to sulfasalazine products.⁷ There were significant reports on nephrolithiasis that were recorded in WHO database following sulfasalazine use and had also been discussed in the literature.^8-10

Advice for Healthcare Professionals:

• Be alert on the risk of nephrolithiasis associated with the use of mesalazine and sulfasalazine.
• Advise patients to
  • consume sufficient amounts of fluids when on therapy with mesalazine or sulfasalazine.
  • inform their doctor immediately if they experience symptoms of nephrolithiasis such as pain in the sides of abdomen and presence of blood in the urine.
• Please report all suspected adverse events associated with mesalazine and sulfasalazine-containing products to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (11)] has been issued for registration holders of mesalazine and sulfasalazine (all dosage forms) products to update the local package inserts and consumer medication information leaflet (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. Masuda H., Takahashi Y., Nishida Y. & Asai S. Comparison of the effect of mesalazine and sulfasalazine on laboratory parameters: a retrospective observational study. Eur J Clin Pharmacol [Internet]. 2012 May 1 [Cited 2020 November 10]. Available from http://www.doi.org/10.1007/s00228-012-1289-3

2. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). Mesalazine local package insert [Internet]. Last revision date: 2017 May 23 [Cited 2020 May 21]. Available from http://www.npra.gov.my
3. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). Sulfasalazine local package insert [Internet]. Last revision date: 2017 May 23 [Cited 2020 May 21]. Available from http://www.npra.gov.my
4. The Netherlands Pharmacovigilance Centre Lareb. Mesalazine treatment and urinary stones composed of mesalazine [Internet]. 2019 February 7 [Cited 2020 November 10]. Available from 
   https://databankws.lareb.nl/Downloads/Signals_2019_Mesalazine%20treatment%20and%20urinary%20stones%20composed%20of%20mesalazine.pdf 
5. European Medicines Agency. Pharmacovigilance Risk Assessment Committee (PRAC). PRAC recommendations on signals. 2019 August 5 [Cited on 2020 November 10]. EMA/PRAC/347675/2019. 
6. Jacobsson H., Eriksen J., Karlén P. Mesalazine-induced renal calculi. Am J Case Rep [Internet] 2013 [Cited 2020 November 10] 14: 551-553. Available from http://www.doi.org/10.12659/AJCR.889719 
7. Brogden Rex N. and Sorkin Eugene M. Mesalazine. A review of its pharmacodynamics and pharmacokinetic properties, and therapeutic potential in chronic inflammatory bowel disease. ADIS Drug Information Services, Auckland, New Zealand. 1989 [Cited on 2020 November 10] Drugs 38 (4): 500-523. 
8. VigiLyze, World Health Organisation Uppsala Monitoring Centre [Internet]. 2021 [Cited 2020 Aug 28]. Available from http://vigilyze.who-umc.org/ 
9. Durando M., Tiu H., Kim J.S. Sulfasalazine-Induced Crystalluria Causing Severe Acute Kidney Injury. Am J Kidney Dis [Internet]. 2017 [Cited 2020 November 10]. 70(6):869-873. Available from http://www.doi.org/10.1053/j.ajkd.2017.05.013 
10. Demichelle J., Rezaizadeh H., Goldstein J.I. Sulfasalazine Crystalluria-Induced Anuric Renal Failure [Internet] Clinical Gastroenterology and Hepatology. 2012 [Cited 2020 November 10]. Available from http://www.doi.org/10.1016/j.cgh.2011.09.027

DISCLAIMER:

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.