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, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Background

Mefenamic acid is a pain reliever/analgesic classified as non-steroidal anti-inflammatory drugs (NSAIDs).^1,2 It is effective in relieving musculoskeletal and joint pain associated with conditions like gout, rheumatoid arthritis, and osteoarthritis. Additionally, it is used to alleviate post-surgical pain, menstrual cramps, toothaches, and to reduce fever.

Fixed drug eruption (FDE) is a common drug-induced skin allergy where lesions characteristically recur at the same sites upon re-exposure to the causative drug.^3-5 It is a delayed type IV hypersensitivity reaction mediated by memory CD8+ T-cells within the skin.⁴ A rare but severe form of widespread FDE, known as generalised bullous fixed drug eruption (GBFDE), is potentially life-threatening and resembles Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) in terms of the extent of skin detachment.^5-7

Trigger of the Safety Signal^8-10

This signal was triggered from the Central Drugs Standard Control Organization of India, as reported in the WHO Pharmaceuticals Newsletter No. 3, 2022, which approved the recommendation to revise the prescribing information for mefenamic acid to include FDE as an adverse drug reaction (ADR). This prompted a disproportionality analysis on local ADR reports.

Disproportionality Analysis

Disproportionality analysis in spontaneous reporting databases of adverse drug reactions (ADRs) refers to validated quantitative methods used for signal detection in pharmacovigilance.¹¹ At NPRA, potential signals are detected using the WHO Vigilyze platform and information component (IC), a tool developed by the WHO-UMC (Uppsala Monitoring Centre) to measure the disproportionality in reporting.¹² IC₀₂₅ is the lower end of a 95% credibility interval for the IC. An IC₀₂₅ value greater than zero indicates disproportionality.

The IC result for this drug-ADR pair was 3.6, which required further assessment.¹² Based on the cut-off date of 1^st April 2023, there were 131 reports received. Malaysia was also the top country reporting FDE associated with mefenamic acid, followed by Thailand and Tunisia. Therefore, it was a validated signal for further review.

A signal review into both local and global pharmacovigilance databases, scientific literature, information obtained from product registration holders, and regulatory actions taken by other regulatory agencies revealed the presence of a more severe form of FDE, specifically GBFDE, which is associated with the use of mefenamic acid, as a potential risk.

Signal Assessment Outcome

The outcome of the review led to an NPRA directive [NPRA.600-1/9/13(41) Jld 1] issued for product registration holders of mefenamic acid-containing products to update the local package inserts and consumer medication information leaflets (RiMUPs) to reflect the risk of generalised bullous fixed drug eruption (GBFDE).

Recommendations for Healthcare Professionals

• Be aware that serious skin reactions, such as generalised bullous fixed drug eruption (GBFDE), have been reported very rarely in association with the use of mefenamic acid.
• Educate patients to inform their doctor immediately if they develop a skin rash or blisters following treatment with mefenamic acid.
• Discontinue mefenamic acid at the first appearance of a skin rash, mucosal lesions, or any other signs of hypersensitivity.
• Report all suspected adverse events associated with mefenamic acid-containing products to the NPRA.

References:

1. Wo WK. Benefit and risk of painkiller [Internet]. Portal MyHEALTH. 2015 Jun 24 [cited 2024 Jan 30] Available from: http://myhealth.moh.gov.my/en/benefit-and-risk-of-painkiller/
2. National Pharmaceutical Regulatory Agency (NPRA). PONSTAN TABLET 500MG (mefenamic acid) [Package Insert]. QUEST3+ Product Search. 2022 Apr 25 [cited 2024 Jan 30]. Available from: http://www.npra.gov.my
3. Johar A. Fixed Drug Eruption [Internet]. Portal MyHEALTH. 2019 Aug 23 [cited 2024 Jan 30] Available from: http://www.myhealth.gov.my/fixed-drug-eruption/
4. Oakley A. Fixed Drug Eruption [Internet]. DermNet. 2021 Mar [cited 2024 Jan 30] Available from: https://dermnetnz.org/topics/fixed-drug-eruption
5. Shiohara T. Fixed Drug Eruption [Internet]. UpTpDate. 2022 May 23 [cited 2024 Jan 30] Available from: https://www.uptodate.com/contents/fixed-drug-eruption
6. Lipowicz S, Sekula P, Ingen-Housz-Oro S, Liss Y, Sassolas B, Dunant A, Roujeau J-C, Mockenhaupt M. Prognosis of generalized bullous fixed drug eruption: comparison with Stevens–Johnson syndrome and toxic epidermal necrolysis. British Journal of Dermatology. 2013 Apr;168(4):726-32. Available from: https://doi.org/10.1111/bjd.12133
7. Paulmann M, Reinkemeier F, Lehnhardt M, Mockenhaupt M. Case report: Generalized bullous fixed drug eruption mimicking epidermal necrolysis. Frontiers in Medicine. 2023: 10:1125754. Available from: https://doi.org/10.3389/fmed.2023.1125754
8. WHO Pharmaceuticals Newsletter No. 3, 2022 [Internet]. Geneva: World Health Organization; 2022 [cited 2024 Jan 30]. Licence: CC BY-NC-SA 3.0 IGO. Available from: https://www.who.int/publications/i/item/9789240057883
9. National Pharmaceutical Regulatory Agency (NPRA). 187 MADRAC meeting minutes. 2023 Sep 5 [cited 2024 Jan 30] (access restricted)
10. National Pharmaceutical Regulatory Agency (NPRA). Appendix H 187 MADRAC meeting minutes. 2023 Sep 5 [cited 2024 Jan 30] (access restricted)
11. Cutroneo PM, Sartori D, Tuccori M, Crisafulli S, Battini V, Carnovale C, Rafaniello C, Capuano A, Poluzzi E, Moretti U and Raschi E (2024), Conducting and interpreting disproportionality analyses derived from spontaneous reporting systems. Front. Drug. Saf. Regul. 3:1323057. Available from: https://doi.org/10.3389/fdsfr.2023.1323057
12. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2024 [cited 2024 Jun 20]. Available from: https://www.vigilyze.who-umc.org (access restricted)

Written by: Dr Vidhya Hariraj, Nafiza Mohd. Ismail

Reviewed/Edited by: Nora Ashikin Mohd Ali, Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali