Tips on Starting and Titrating ESL in Partial Onset Seizures

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For most patients with partial onset seizures (POS), starting eslicarbazepine acetate (ESL) at 400 mg daily results in fewer adverse effects than a starting dose of 800 mg daily, even after titrating up to higher maintenance doses, according to a study in Epilepsy Research.¹

However, results also showed that 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.

The results are notable because they may help physicians know better how to balance adequate seizure control against potential adverse effects of ESL, a newer antiepileptic drug (AED) approved by the FDA in 2013 for the adjunctive management of POS.

“Understanding the influence of dose titration schedule on tolerability is important for newer AEDs; 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 AEDs 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 like dizzinesss, somnolence, blurred vision, and imbalance. Rash can also occur with AEDs, ranging from mild to rare, life-threatening Stevens-Johnson syndrome.

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

The analysis included 1447 patients with refractory POS randomized to placebo (n=426) or adjunctive ESL (n=1021). Patients were started on doses of 400 mg or 800 mg daily for 1 or 2 weeks, followed by up-titration in 400 mg increments to a target, fixed, maintenance dose of 400 mg, 800 mg, or 1200 mg per day for 12 weeks.

Key Results
• Starting dose:
o 400 mg: 35% had ≥1 TEAE
o 800 mg: 62% had ≥1 TEAE
o Placebo: 32% had ≥1 TEAE

• Maintenance period:
o Starting dose 400 mg: Similar overall TEAE incidence for maintenance dose of 400 mg (66%), 800 mg (59%-69%), and 1200 mg (66%)
o Starting dose 800 mg: Similar overall TEAE incidence for maintenance dose of 800 mg (85%) and 1200 mg (82%)
o Placebo: Overall TEAE incidence 57%
• TEAEs leading to discontinuation:
o Starting dose 400 mg: Overall incidence with maintenance dose of 800 mg (12%) and 1200 mg (21%)
o Starting dose 800 mg: Overall incidence with maintenance dose of 800 mg (20%) and 1200 mg (27%)
o Placebo: 6.6%

The starting dose seemed to have more of an impact on TEAEs than the maintenance dose. The overall incidence of TEAEs during the maintenance period was lower for those who started on ESL 400 mg daily compared to 800 mg daily. Results were similar for rates of TEAEs leading to treatment discontinuation.

Likewise, rates for common CNS adverse events were lower in patients started on 400 mg daily, suggesting that using a lower starting dose may minimize these types of TEAEs.

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

The authors mentioned several potential limitations. About 72% of patients in the ESL group were taking at least 2 other AEDs, 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 over age 65, and results may not generalize to older populations. 

Take Home Points• For most patients with partial onset epilepsy (POS), starting eslicarbazepine acetate (ESL) at 400 mg daily will result in lower adverse effects than starting at 800 mg daily, even after titrating up to higher maintenance doses.
• 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 E1, Gabbai AA, Hufnagel A, et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010 May;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.