Behavioral adverse events with brivaracetam, levetiracetam, perampanel, and topiramate: A systematic review

Abstract

To understand the currently available post-marketing real-world evidence of the incidences of and discontinuations due to the BAEs of irritability, anger, and aggression in people with epilepsy (PWE) treated with the anti-seizure medications (ASMs) brivaracetam (BRV), levetiracetam (LEV), perampanel (PER), and topiramate (TPM), as well as behavioral adverse events (BAEs) in PWE switching from LEV to BRV. Methods: A systematic review of published literature using the Cochrane Library, PubMed/MEDLINE, and Embase was performed to identify retrospective and prospective observational studies reporting the incidence of irritability, anger, or aggression with BRV, LEV, PER, or TPM in PWE. The incidences of these BAEs and the rates of discontinuation due to each were categorized by ASM, and where possible, weighted means were calculated but not statistically assessed. Behavioral and psychiatric adverse events in PWE switching from LEV to BRV were summarized descriptively. Results: A total of 1500 records were identified in the searches. Of these, 44 published articles reporting 42 studies met the study criteria and were included in the data synthesis, 7 studies were identified in the clinical trial database, and 5 studies included PWE switching from LEV to BRV. Studies included a variety of methods, study populations, and definitions of BAEs. While a wide range of results was reported across studies, weighted mean incidences were 5.6% for BRV, 9.9% for LEV, 12.3% for PER, and 3.1% for TPM for irritability; 3.3%* for BRV, 2.5% for LEV, 2.0% for PER, and 0.2%* for TPM for anger; and 2.5% for BRV, 2.6% for LEV, 4.4% for PER, and 0.5%* for TPM for aggression. Weighted mean discontinuation rates were 0.8%* for BRV, 3.4% for LEV, 3.0% for PER, and 2.2% for TPM for irritability and 0.8%* for BRV, 2.4% for LEV, 9.2% for PER, and 1.2%* for TPM for aggression. There were no discontinuations for anger. Switching from LEV to BRV led to improvement in BAEs in 33.3% to 83.0% of patients (weighted mean, 66.6%).*Denotes only 1 study.

A post-approval observational study to evaluate the safety and tolerability of perampanel as an add-on therapy in adolescent, adult, and elderly patients with epilepsy

“…The prevalence of patients reporting psychiatric TEAEs in this study was similar to the pooled analysis of the seven phase II and III interventional clinical studies of perampanel presented in this paper, but was higher than a pooled analysis of the three pivotal phase III perampanel clinical trials alone (24.4% vs 24.3% vs 15.3%, respectively) [31]. A recent systematic review of brivaracetam, levetiracetam, perampanel, and topiramate, reported higher mean rates of irritability, anger, and aggression in phase IV realworld studies compared with clinical development trials [32]. It was concluded that this observation was not surprising, given the confines of controlled trials and the fact that real-world studies may allow inclusion of more patients with epilepsy at risk of these events.…”

Third-Generation Antiseizure Medications for Adjunctive Treatment of Focal-Onset Seizures in Adults: A Systematic Review and Network Meta-analysis

“…Both PER and BRV are among the ASMs traditionally associated with the strongest risk of behavioural adverse events. Although the incidence of these side effects is higher with PER than with BRV [ 49 ], the lack of analyses by individual TEAEs did not allow us to state whether the difference in the tolerability profile was driven by the risk of behavioural adverse events.…”

Long‐term efficacy, tolerability, and retention of brivaracetam in epilepsy treatment: A longitudinal multicenter study with up to 5 years of follow‐up

“…18 Interestingly, the BRV efficacy is similar to those reported in long-term follow-up trials using other ASMs 33,34 and appears to be comparable to that described in a previous retrospective study of BRV. 35,36 Few studies investigating BRV efficacy in the real-world setting have reached 12 months of follow-up. A retrospective Spanish study, which included adult patients with focal epilepsy, reported an overall response in 40% of patients, with 17.2% reporting seizure freedom after 12 months.…”