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

Lamotrigine is used in the treatment of epilepsy, for partial seizures and generalised seizures, including tonic-clonic seizures and the seizures associated with Lennox-Gastaut Syndrome as well as prevention of mood episodes in patients with bipolar disorder, predominantly by preventing depressive episodes.¹

Erythema multiforme (EM) is an acute, self-limiting disease of the skin and mucous membranes. It is characterised by symmetrically distributed skin lesions, located primarily on the extremities, sometimes accompanied by oral, genital, or ocular mucosal erosions or a combination of these. EM with mucosal involvement is called erythema multiforme major; in the absence of mucosal disease, EM is called erythema multiforme minor.² EM and Stevens-Johnson Syndrome (SJS) were once thought of as being on the same spectrum of disease. However, they are now considered separate entities and although their difference in presentation is subtle, the potential complications necessitate significant differences in management. Both EM and SJS may present with erythematous, targetoid lesions. The key difference with EM is that the lesions are typically raised or papular.³

Trigger of the Safety Signal ⁴

This signal was triggered from the WHO global database of adverse event reports for medicines and vaccines (VigiBase), that prompted a disproportionality analysis on local ADR reports.

Disproportionality Analysis ^4-5

Disproportionality analysis in spontaneous reporting databases of adverse drug reactions (ADRs) refers to validated quantitative methods used for signal detection in pharmacovigilance. 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. IC₀₂₅ is the lower end of a 95% credibility interval for the IC. An IC₀₂₅ value greater than zero indicates disproportionality.

The IC₀₂₅ result for this drug-ADR pair was 1.6, which required further assessment.  Based on the cut-off date of 5^th January 2023, there were 10 reports received for EM associated with the use of lamotrigine. Globally, there were approximately 639 cases, with an IC₀₂₅ value of 3.0.

A signal assessment into both local and global pharmacovigilance databases, scientific literature, information obtained from the product registration holder, and regulatory actions taken by other regulatory agencies showed the signal was validated and further risk minimisation measures were needed.⁶

Signal Assessment Outcome

The outcome of the review led to an NPRA directive [NPRA.600-1/9/13(63) Jld 1] issued for product registration holders of lamotrigine-containing products to update the local package inserts and consumer medication information leaflets (RiMUPs) to reflect the risk of erythema multiforme (EM).

Recommendations for Healthcare Professionals

• Be aware that skin reactions, such as erythema multiforme, have been reported rarely in association with the use of lamotrigine.
• Educate patients to inform their doctor immediately if they develop a skin rash or blisters following treatment with lamotrigine, specifically skin rashes or redness, which may develop into severe skin reactions including red spots or patches that may look like a target or "bulls-eye" with a dark red centre surrounded by paler red rings (Erythema multiforme).
• Report all suspected adverse events associated with lamotrigine -containing products to the NPRA.

 References:

1. National Pharmaceutical Regulatory Agency (NPRA). LAMICTAL TABLET 100mg (lamotrigine) [Package Insert]. QUEST3+ Product Search. 2025 Mar 18 [cited 2025 Jul 30]. Available from: http://www.npra.gov.my.
2. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol. 2012 Aug;51(8):889-902. Available from: https://doi.org/10.1111/j.1365-4632.2011.05348.x
3. ENS Russell E. Newkirk, Daren A Fomi, et al. Erythema Multiforme Versus Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis: Subtle Difference in Presentation, Major Difference in Management. Military Medicine (2020), 185, 9/10: e1847
4. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2023 [cited 2023 Jan 5]. Available from: https://www.vigilyze.who-umc.org (access restricted)
5. Information from the Uppsala Monitoring Centre (UMC). The UMC Measures of Disproportionate Reporting [Internet]. 2016 [cited 2023 Jan 5].  Available from: https://who-umc.org/media/164041/measures-of-disproportionate-reporting_2016.pdf
6. National Pharmaceutical Regulatory Agency (NPRA). 194 MADRAC meeting minutes. 2025 Jun 26 [cited 2025 Jul 30] (access restricted)

Written by: Dr Vidhya Hariraj
Reviewed/Edited by: Dr Rema Panickar, Nora Ashikin Mohd Ali, Norleen Mohamed Ali