Reassessing the adverse event profiles of levetiracetam and brivaracetam: a systematic review and meta-analysis

Objective: To synthesize adverse event (AE) data from randomized controlled trials (RCTs) of levetiracetam (LEV) and brivaracetam (BRV), compare their safety profiles, and identify moderators of AE risk. Methods: We conducted a systematic review and meta-analysis of RCTs of LEV or BRV, searching PubMed, Web of Science, and ClinicalTrials.gov to August 2025. AE frequencies were summarized qualitatively, and random-effects meta-analyses compared LEV and BRV with placebo. Additional analyses compared LEV and BRV and assessed moderators. PROSPERO: CRD42023491050, CRD420251003207. Results: Ninety-six RCTs including 7145 patients exposed to LEV and 2549 to BRV were analyzed. Qualitative synthesis identified headache, somnolence, dizziness, and fatigue as the most common AEs, with higher frequencies of some psychiatric AEs (e.g., irritability, aggression) reported for LEV. Meta-analyses showed increased somnolence with both LEV (OR 1.80, 95% CI [1.41–2.30]) and BRV (OR 1.86, 95% CI [1.33–2.61]). LEV was additionally associated with irritability (OR 2.55, 95% CI [1.41–4.63]) and asthenia (OR 1.71, 95% CI [1.15–2.54]), whereas BRV was associated with dizziness (OR 1.75, 95% CI [1.24–2.46]) and fatigue (OR 2.14, 95% CI [1.43–3.20]). Few moderators of AE risk were identified, and no significant differences emerged between LEV and BRV in indirect comparisons. Conclusion: LEV and BRV show favorable safety profiles that appear comparable based on meta-analytic findings, despite higher rates of some psychiatric AEs with LEV on a descriptive level. Both remain safe treatment options, though larger head-to-head trials are needed to provide definitive comparative evidence.