Comparative Safety of Six First-Line Antiepileptic Monotherapies in Pediatric Epilepsy Using the United States FDA...

Background and objective Selecting an initial antiepileptic monotherapy in children requires careful consideration of safety, as adverse drug reactions may have long-term consequences for the developing brain. However, comparative safety information across commonly used first-line antiepileptic drugs (AEDs) and pediatric age groups remains limited, particularly under strictly defined monotherapy conditions. The objective of this study is to compare the safety patterns and adverse event (AE) reporting profiles of valproic acid, lamotrigine, levetiracetam, carbamazepine, zonisamide, and topiramate used as first-line monotherapy in children (0-14 years) with epilepsy and to assess potential age-related differences in AE reporting. Methods Pediatric epilepsy cases (0-14 years) reported to the United States FDA Adverse Event Reporting System (FAERS) between 2004Q1 and 2025Q4 were identified. Reports were included when one of the six target AEDs was recorded as the primary suspect drug and used as quasi-monotherapy; cases with concomitant use of predefined second-line AEDs or more than one first-line AED were excluded. AEs were grouped into nine predefined clinical categories. Reporting ORs (RORs) and adjusted RORs were estimated with valproic acid as the reference, adjusting for age, sex, and reporter country. A Bonferroni-adjusted two-sided significance level of 0.01 was applied. Age-stratified sensitivity analyses (0-1, 2-5, 6-11, and 12-14 years) were performed to explore possible age-dependent patterns. Results Among 3,581 pediatric epilepsy cases treated with first-line antiepileptic monotherapy, 431 received valproic acid, 436 carbamazepine, 1,025 lamotrigine, 1,365 levetiracetam, 262 topiramate, and 62 zonisamide. CNS disorders were the most frequently reported category across all drugs. Dermatologic disorders were more frequently reported with carbamazepine, lamotrigine, and zonisamide, compared with valproic acid. Hepatic disorders were relatively more frequently reported with carbamazepine and valproic acid and less frequently with levetiracetam and topiramate, whereas renal disorders were more frequently reported with zonisamide and topiramate. In age-stratified analyses, dermatologic and hepatic disorders tended to be reported less often among infants than among older children, while renal disorder signals with zonisamide were observed across all age groups; CNS and psychiatric disorders generally appeared to be reported more frequently with increasing age, although some overall signals were attenuated in subgroup analyses, likely reflecting reduced sample sizes. Conclusions This FAERS-based analysis suggests drug-specific and age-related differences in AE reporting patterns among six first-line AEDs used as monotherapy in pediatric epilepsy. The higher reported frequencies of dermatologic disorders with lamotrigine and carbamazepine, relatively higher hepatic disorder reporting with carbamazepine and valproic acid, and renal disorders with zonisamide and topiramate may raise risk awareness and support clinical monitoring, particularly in older children. Given the inherent limitations of spontaneous reporting data and the attenuation of several signals in age-stratified analyses, these findings should be considered hypothesis-generating safety signals that merit further evaluation and confirmation in well-designed prospective and population-based studies.