Evaluating Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Associated With Newer Antiseizure Medications Using...

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are rare but life-threatening cutaneous adverse reactions associated with certain antiseizure medications (ASMs). While risks for first- and second-generation ASMs are well-established, the safety profile of third-generation ASMs across different populations remains unclear. This study aimed to systematically evaluate SJS/TEN signals associated with four third-generation ASMs (lacosamide, clobazam, perampanel, and rufinamide) using the Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases, and to explore potential mechanisms through bioinformatics analysis.

Disproportionality analysis using reporting odds ratio (ROR) and proportional reporting ratio (PRR) was performed on FAERS and JADER. For mechanistic exploration, differentially expressed genes were identified from Gene Expression Omnibus (GEO) datasets, and core targets were obtained by intersecting drug targets with SJS/TEN disease-related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, followed by molecular docking to assess drug-target interactions.

FAERS analysis revealed positive signals for all 4 ASMs: clobazam (ROR = 4.12, 95% CI, 3.38-5.10), lacosamide (ROR = 2.30, 95% CI, 1.84-2.88), perampanel (ROR = 2.71, 95% CI, 1.53-4.77), and rufinamide (ROR = 2.57, 95% CI, 1.15-5.73). In JADER, clobazam (ROR = 1.95, 95% CI, 1.05-3.65) and lacosamide (ROR = 2.15, 95% CI, 1.19-3.89) showed consistent positive signals, while perampanel and rufinamide had no significant signals. Network pharmacology identified 6 core targets (ACE, ALB, CASP3, MAPK1, PPARG, and SYK) intersecting with SJS/TEN pathogenesis. Functional enrichment revealed significant involvement of T-cell receptor signaling, inflammatory response, and apoptosis pathways. Molecular docking confirmed strong binding affinities between all 4 ASMs and these core targets.

Clobazam and lacosamide showed consistent SJS/TEN signals in both FAERS and JADER, while perampanel and rufinamide showed signals only in FAERS. The limited case numbers in JADER preclude definitive conclusions about population differences; larger Asian cohort studies are needed to clarify these observations. Mechanistic insights implicate immune dysregulation through T-cell-mediated and apoptotic pathways. These findings highlight the importance of population-specific pharmacovigilance and provide a foundation for future research into predictive biomarkers and preventive strategies.