Eslicarbazepine Combinations Compared for Focal Seizures

Eslicarbazepine acetate (Aptiom, Sunovion Pharmaceuticals) in combination with lamotrigine was found to be better tolerated than when combined with carbamazepine, in an analysis of 3 phase 3 trials of its use as an adjunct in treating focal (partial-onset) seizures.

"When antiepileptic drugs are used as adjunctive therapy, potential drug interactions are a concern," wrote study lead author Bassel Abou-Khalil, MD, department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues.

The investigators noted that specific combinations of antiepileptic drugs have been found to increase the frequency of some adverse events. They suggest that combinations exerting similar mechanisms of action are more likely to provoke an adverse reaction to the additive effects, and pointed out that carbamazepine, phenytoin, oxcarbazepine, lamotrigine, and lacosamide all act predominately on voltage-gated sodium channels (VGSCs).

"Eslicarbazepine, the primary metabolite of eslicarbazepine acetate, is also known to inhibit VGSCs, which may contribute to its anticonvulsant effect," Abou-Khalil and colleagues wrote. "A pharmacodynamic interaction between eslicarbazepine acetate and carbamazepine leading to higher incidences of dizziness and diplopia has been previously suggested."

To ascertain whether the eslicarbazepine combinations used for focal seizures in adults differed in adverse effects, the investigators conducted a post-hoc analysis of data pooled from 3 phase 3 studies of the addition of 3 different doses of eslicarbazepine to a stable, but only partially effective antiepileptic-drug regimen. There were sufficient numbers of patients receiving lamotrigine (91 with placebo, 167 with eslicarbazepine) or carbamazepine (172 with placebo, 441 with eslicarbazepine) to distinguish between these groups, but too few patients receiving phenytoin to include in the analysis.

Abou-Khalil and colleagues reported finding a numerically, but not statistically, higher incidence of treatment-emergent adverse events (TEAEs) with the combination of carbamazepine + eslicarbazepine (of any dose; 77%) than for lamotrigine combinations (73%) or with any of the 3 active agents combined with placebo (68%). Among the adverse events occurring with carbamazepine + eslicarbazepine, the most frequent were dizziness (30%), diplopia (14%) and vomiting (10%). In comparison, the incidences of these events with lamotrigine were 16%, 8%, and 5%, respectively.

The overall incidences of TEAEs leading to discontinuation was also higher with eslicarbazepine in combination with carbamazepine (21%) than with lamotrigine (13%) or with placebo (15%). Dizziness was specifically implicated for 9% of those discontinuing eslicarbazepine + carbamazepine, 3% of those discontinuing eslicarbazepine + lamotrigine, and 3% discontinuing eslicarbazepine +placebo. The overall incidences of serious adverse events were similar across groups.

Given that differences between the carbamazepine and lamotrigine combination were numerically, but not statistically significantly different, the investigators speculate that there might have been even fewer differences between the combinations with higher doses or higher serum concentrations of lamotrigine. Although they did not have these data to evaluate, they suggest that the shared mechanisms of action could contribute to similar risks of adverse effects.

"Clinicians should be aware of the potential risk for an increased incidence of TEAEs typically associated with VGSC inhibitors," the investigators advised. "One option for management of such events (with eslicarbazepine combinations) could be to reduce the dose of either lamotrigine or carbamazepine."

The study, “Tolerability of adjunctive eslicarbazepine acetate according to concomitant lamotrigine or carbamazepine use: A subgroup analysis of three phase III trials in adults with focal (partial-onset) seizures,” was published in Epilepsy Research.