Starting and Titrating Eslicarbazepine Acetate in Partial Onset Seizures

According to a report in Epilepsy Research, for most patients with partial onset seizures, starting eslicarbazepine acetate (ESL) at 400 mg daily results in fewer adverse effects than a starting dosage of 800 mg daily, even after titrating to higher maintenance doses.¹ However, results also show that more rapid titration with a starting dose of 800 mg daily is feasible in patients for whom rapid seizure control outweighs concerns over adverse events. The results are notable because they may help physicians to balance adequate seizure control against the potential adverse effects of ESL (a newer antiepileptic drug approved by the FDA in 2013 for the adjunctive management of partial onset seizures).

“Understanding the influence of dose titration schedule on tolerability is important for newer antiepileptic drugs; without this information, substantial clinical experience with these drugs may be needed before clinicians understand how best to initiate treatment, minimize tolerability issues, and optimize outcomes,” wrote first author Gregory Krauss, MD, of Johns Hopkins University, and colleagues.

Adverse effects related to antiepileptic drugs can limit the range of doses used, and lead to inadequate seizure control, or treatment discontinuation. The most common treatment-limiting adverse effects include CNS-related issues such as dizzinesss, somnolence, blurred vision, and imbalance. Rash can also occur with antiepileptic drugs, ranging from mild to rare, life-threatening Stevens-Johnson syndrome.

Findings from phase 3 studies suggest that most adverse effects related to ESL occur within the first weeks of starting treatment. To further explore the issue, the researchers pooled data on treatment-emergent adverse events from 3 randomized, double-blind, placebo-controlled trials.^2-4

The analysis included 1447 patients with refractory partial onset seizures randomized to placebo (n = 426) or adjunctive ESL (n = 1021). Patients were started on dosages of 400 mg or 800 mg daily for 1 or 2 weeks, followed by increasing 400-mg increments to a target, fixed, maintenance dosage of 400 mg, 800 mg, or 1200 mg daily for 12 weeks.

The results show that with a starting dose of 400 mg, 35% had ≥ 1 treatment-emergent adverse events; with 800 mg, 62% had ≥ 1 treatment-emergent adverse events; and with placebo, 32% had ≥ 1 treatment-emergent adverse events. During the maintenance period, for those who were started at 400 mg, the incidence of overall treatment-emergent adverse events was similar at 400 mg (66%), 800 mg (59%-69%), and 1200 mg (66%); for those who started at 800 mg the incidence of overall treatment-emergent adverse events was also similar at 800 mg (85%) and 1200 mg (82%); the incidence of treatment-emergent adverse events with placebo was 57%. The overall incidence of treatment-emergent adverse events that led to discontinuation for those who started at 400 mg was 12% (800 mg) and 21% (1200 mg); for those who started at 800 mg it was 20% (800 mg), and 27% (1200 mg); the incidence was 6.6% with placebo.

The starting dose seemed to have more of an impact on treatment-emergent adverse events than the maintenance dose. The overall incidence of treatment-emergent adverse events during the maintenance period was lower for those who started on ESL 400 mg daily compared with 800 mg daily. Results were similar for rates of treatment-emergent adverse events that led to treatment discontinuation. Likewise, rates for common CNS adverse events were lower in patients started on 400 mg daily, which suggests that using a lower starting dose may minimize these types of treatment-emergent adverse events.

The authors also noted that a more rapid dose titration was nevertheless tolerated in most patients. About 80% to 89% who started on 800 mg daily completed the treatment period. These findings suggest that patients for whom rapid seizure control outweighs concerns over adverse events may feasibly start on 800 mg daily.

The study had several potential limitations. About 72% of patients in the ESL group were taking at least 2 other newer antiepileptic drugs, some of which may have had similar mechanisms. Combining them may have exceeded the threshold of tolerability, which could have affected the results. Also, the study contained few patients aged older than 65 years, thus results may not generalize to older populations.

Take Home Points
1. For most patients with partial onset epilepsy, starting eslicarbazepine acetate (ESL) at 400 mg daily will result in lower adverse effects than starting at 800 mg daily, even after titrating to higher maintenance doses.
2. A more rapid dose titration with a starting dose of 800 mg daily is feasible in patients for whom rapid seizure control outweighs concerns over adverse events.

References:

1. Krauss G, Biton V, Harvey JH, et al. Influence of titration schedule and maintenance dose on the tolerability of adjunctive eslicarbazepine acetate: an integrated analysis of three randomized placebo-controlled trials. Epilepsy Res. 2017;139:1-8.
2. Elger C, Halász P, Maia J, Almeida L, et al for the BIA Investigators Study Group. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia. 2009;50:454-463.
3. Ben-Menachem E, Gabbai AA, Hufnagel A, et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89:278-285.
4. Sperling MR, Abou-Khalil B, Harvey J, et al, for the 304 Study Team. Eslicarbazepine acetate as adjunctive therapy in patients with uncontrolled partial-onset seizures: results of a phase III, double-blind, randomized, placebo-controlled trial. Epilepsia. 2015;56:244-253.