Severe Cutaneous Adverse Reactions Associated With Newer-Generation Antiseizure Medications: A Real-World...

Severe cutaneous adverse reactions (SCARs) are rare but potentially fatal immune-mediated toxicities associated with antiseizure medications (ASMs). Phenotype-resolved post-marketing safety profiles for newer-generation ASMs have not been comprehensively characterized across pharmacovigilance systems.

A cross-database disproportionality analysis was conducted using FAERS and JADER (January 2004-September 2025). Twenty-two newer-generation ASMs coded as primary-suspect drugs were included; outcomes were the four SCAR phenotypes (Stevens-Johnson syndrome, SJS; toxic epidermal necrolysis, TEN; drug reaction with eosinophilia and systemic symptoms, DRESS; acute generalized exanthematous pustulosis, AGEP) defined using MedDRA preferred terms. Signals were evaluated using reporting odds ratios (RORs) and Bayesian information component metrics. Time-to-onset (TTO) was characterized by Weibull modeling with confidence-interval-based failure-pattern classification and Kaplan-Meier analysis. Pre-specified sensitivity analyses excluded reports with concomitant valproic acid or other SCAR-inducing co-medications, applied multivariate logistic regression, and restricted FAERS reports to healthcare professionals.

In total, 10,073 SCAR reports were included (SJS, 3776; TEN, 1762; DRESS, 4298; AGEP, 237). Lamotrigine and zonisamide showed the strongest, most reproducible associations across SJS/TEN/DRESS (FAERS RORs for lamotrigine, 35.60/22.35/27.30; zonisamide, 28.08/25.05/40.78), with concordant directions in JADER. Sensitivity analyses attenuated but did not abolish the principal lamotrigine, zonisamide, levetiracetam, and eslicarbazepine signals, whereas the gabapentin-TEN signal in JADER lost statistical significance after exclusion of high-risk co-medications. Median TTO was 22 days overall; SJS/TEN occurred earlier, while DRESS showed delayed and more dispersed onset (median, 28 days), with eslicarbazepine-DRESS uniquely exhibiting a wear-out pattern. TEN carried the highest reported fatality proportion (FAERS, 17.7%; JADER, 17.5%). Key signals remained robust under healthcare-professional restriction, with eslicarbazepine-DRESS further enhanced.

Across FAERS and JADER, reporting associations between newer-generation ASMs and SCARs were highly concentrated in a limited set of agents and exhibited phenotype-specific latency patterns. After accounting for polytherapy confounding, levetiracetam and eslicarbazepine emerged as the most consistent under-recognized signals, warranting heightened vigilance during initiation-particularly when co-administered with aromatic ASMs. Drug-phenotype combinations with both high disproportionality and a high reported fatality proportion (notably lamotrigine-TEN and zonisamide-TEN) warrant intensified early monitoring for SJS/TEN and sustained vigilance into maintenance therapy for DRESS, although population-level absolute risk cannot be inferred from spontaneous-report data.