Abstract
Eslicarbazepine acetate (Zebinix®), a voltage-gated sodium channel blocker, is a once-daily, orally administered anti-seizure medication available in the EU for use as monotherapy in adults with newly diagnosed focal-onset seizures and as adjunctive therapy in adults, adolescents and children aged > 6 years with focal-onset seizures. In adult patients, adjunctive eslicarbazepine acetate was generally associated with a significant decrease in seizure frequency and an increase in responder rate compared with placebo. The drug was also an effective monotherapy agent in adult patients, demonstrating noninferiority to controlled-release carbamazepine, in terms of seizure freedom rates. In paediatric patients, eslicarbazepine acetate provided seizure control when administered as adjunctive therapy, with the benefits appearing to be dependent on age and dose. The antiepileptic efficacy of eslicarbazepine acetate as adjunctive therapy or as monotherapy was maintained during longer-term extension studies, with each extension study period being up to 2 years. Oral eslicarbazepine acetate was generally well tolerated when administered as adjunctive therapy or monotherapy in adult patients and when administered as adjunctive therapy in paediatric patients, with most adverse events being of mild or moderate intensity. In conclusion, with the convenience of once-daily administration, eslicarbazepine acetate is an effective and generally well-tolerated treatment option for adults, adolescents and children aged > 6 years with focal-onset seizures.
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References
Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia. 2017;58(4):512–21.
Galiana GL, Gauthier AC, Mattson RH. Eslicarbazepine acetate: a new improvement on a classic drug family for the treatment of partial-onset seizures. Drugs R D. 2017;17(3):329–39.
Moshe SL, Perucca E, Ryvlin P, et al. Epilepsy: new advances. Lancet. 2015;385(9971):884–98.
Slater J, Chung S, Huynh L, et al. Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: meta-analysis of pivotal trials. Epilepsy Res. 2018;143:120–9.
European Medicines Agency. Zebinix: summary of product characteristics. 2020. https://www.ema.europa.eu/. Accessed 17 Jun 2020.
US FDA. APTIOM (eslicarbazepine acetate) tablets, for oral use: US prescribing information. 2019. https://www.accessdata.fda.gov/. Accessed 17 Jun 2020.
Keating GM. Eslicarbazepine acetate: a review of its use as adjunctive therapy in refractory partial-onset seizures. CNS Drugs. 2014;28(7):583–600.
Shirley M, Dhillon S. Eslicarbazepine acetate monotherapy: a review in partial-onset seizures. Drugs. 2016;76(6):707–17.
Elger C, Halasz P, Maia J, et al. 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(3):454–63.
Ben-Menachem E, Gabbai AA, Hufnagel A, et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89(2–3):278–85.
Gil-Nagel A, Lopes-Lima J, Almeida L, et al. Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurol Scand. 2009;120(5):281–7.
Sperling MR, Abou-Khalil B, Harvey J, et al. 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(2):244–53.
Cramer JA, Velez FF, Anastassopoulos KP, et al. Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate. Epilepsy Behav. 2015;53:149–53.
Elger C, Koepp M, Trinka E, et al. Pooled efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: data from four double-blind placebo-controlled pivotal phase III clinical studies. CNS Neurosci Ther. 2017;23(12):961–72.
Biton V, Rogin JB, Krauss G, et al. Adjunctive eslicarbazepine acetate: a pooled analysis of three phase III trials. Epilepsy Behav. 2017;72:127–34.
Gil-Nagel A, Elger C, Ben-Menachem E, et al. Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: integrated analysis of pooled data from double-blind phase III clinical studies. Epilepsia. 2013;54(1):98–107.
Halasz P, Cramer JA, Hodoba D, et al. Long-term efficacy and safety of eslicarbazepine acetate: results of a 1-year open-label extension study in partial-onset seizures in adults with epilepsy. Epilepsia. 2010;51(10):1963–9.
Hufnagel A, Ben-Menachem E, Gabbai AA, et al. Long-term safety and efficacy of eslicarbazepine acetate as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy: results of a 1-year open-label extension study. Epilepsy Res. 2013;103(2–3):262–9.
Velez FF, Bond TC, Anastassopoulos KP, et al. Impact of seizure frequency reduction on health-related quality of life among clinical trial subjects with refractory partial-onset seizures: a pooled analysis of phase III clinical trials of eslicarbazepine acetate. Epilepsy Behav. 2017;68:203–7.
Toledo M, Mazuela G, Mauri JA, et al. Levels of anger in epilepsy patients treated with eslicarbazepine acetate. Acta Neurol Scand. 2019;140(1):48–55.
Trinka E, Ben-Menachem E, Kowacs PA, et al. Efficacy and safety of eslicarbazepine acetate versus controlled-release carbamazepine monotherapy in newly diagnosed epilepsy: a phase III double-blind, randomized, parallel-group, multicenter study. Epilepsia. 2018;59(2):479–91.
Trinka E, Pereira A, Moreira J, et al. Long-term efficacy and safety of eslicarbazepine acetate (ESL) monotherapy: results from BIA-2093-311/EXT study –the 2-year open-label extension of the ESL study (BIA-2093-311) [abstract + poster]. In: American Epilepsy Society (AES) 73rd Annual Meeting. 2019.
Sperling MR, Harvey J, Grinnell T, et al. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America. Epilepsia. 2015;56(4):546–55.
Jacobson MP, Pazdera L, Bhatia P, et al. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study. BMC Neurol. 2015;15(46):1–13.
Jozwiak S, Veggiotti P, Moreira J, et al. Effects of adjunctive eslicarbazepine acetate on neurocognitive functioning in children with refractory focal-onset seizures. Epilepsy Behav. 2018;81:1–11.
Kirkham F, Auvin S, Moreira J, et al. Efficacy and safety of eslicarbazepine acetate as adjunctive therapy for refractory focal-onset seizures in children: a double-blind, randomized, placebo-controlled, parallel-group, multicenter, phase-III clinical trial. Epilepsy Behav. 2020;105:106962.
European Medicines Agency. Zebinix: assessment report for paediatric studies submitted in accordance with article 46 of regulation (EC) No 1901/2006. 2018. https://www.ema.europa.eu/. Accessed 17 Jun 2020.
Weissinger F, Losch F, Winter Y, et al. Effectiveness of eslicarbazepine acetate in dependency of baseline anticonvulsant therapy: results from a German prospective multicenter clinical practice study. Epilepsy Behav. 2019;101(Pt A):106574.
Villanueva V, Bermejo P, Montoya J, et al. EARLY-ESLI study: long-term experience with eslicarbazepine acetate after first monotherapy failure. Acta Neurol Scand. 2017;136(3):254–64.
Villanueva V, Serratosa JM, Guillamon E, et al. Long-term safety and efficacy of eslicarbazepine acetate in patients with focal seizures: results of the 1-year ESLIBASE retrospective study. Epilepsy Res. 2014;108(7):1243–52.
Lattanzi S, Cagnetti C, Foschi N, et al. Eslicarbazepine acetate as adjunctive treatment in partial-onset epilepsy. Acta Neurol Scand. 2018;137(1):29–32.
Holtkamp M, McMurray R, Bagul M, et al. Real-world data on eslicarbazepine acetate as add-on to antiepileptic monotherapy. Acta Neurol Scand. 2016;134(1):76–82.
Correia FD, Freitas J, Magalhaes R, et al. Two-year follow-up with eslicarbazepine acetate: a consecutive, retrospective, observational study. Epilepsy Res. 2014;108(8):1399–405.
Villanueva V, Holtkamp M, Delanty N, et al. Euro-Esli: a European audit of real-world use of eslicarbazepine acetate as a treatment for partial-onset seizures. J Neurol. 2017;264(11):2232–48.
Giraldez BG, Garamendi-Ruiz I, Zurita J, et al. Clinical outcomes of eslicarbazepine acetate monotherapy for focal-onset seizures: a multicenter audit. Acta Neurol Scand. 2019;140(6):422–8.
Villanueva V, Bermejo P, Montoya J, et al. MONOZEB: long-term observational study of eslicarbazepine acetate monotherapy. Epilepsy Behav. 2019;97:51–9.
Toledano R, Jovel CE, Jimenez-Huete A, et al. Efficacy and safety of eslicarbazepine acetate monotherapy for partial-onset seizures: experience from a multicenter, observational study. Epilepsy Behav. 2017;73:173–9.
Holtkamp M, Delanty N, Sales F, et al. Eslicarbazepine acetate as monotherapy in clinical practice: outcomes from Euro-Esli. Acta Neurol Scand. 2019;139(1):49–63.
Doherty CP, Rheims S, Assenza G, et al. Eslicarbazepine acetate in epilepsy patients with psychiatric comorbidities and intellectual disability: clinical practice findings from the Euro-Esli study. J Neurol Sci. 2019;402:88–99.
Sales F, McMurray R, Loureiro RA, et al. Clinical predictors of 12-month retention in patients treated with eslicarbazepine acetate: real-world evidence from the Euro-Esli study [poster presentation]. In: American Epilepsy Society (AES) 73rd Annual Meeting 2019.
Gama H, Vieira M, Costa R, et al. Safety profile of eslicarbazepine acetate as add-on therapy in adults with refractory focal-onset seizures: from clinical studies to 6 years of post-marketing experience. Drug Saf. 2017;40(12):1231–40.
Andermann E, Biton V, Benbadis SR, et al. Psychiatric and cognitive adverse events: a pooled analysis of three phase III trials of adjunctive eslicarbazepine acetate for partial-onset seizures. Epilepsy Behav. 2018;82:119–27.
Carreno M, Benbadis S, Rocha F, et al. Incidence of seizure exacerbation and seizures reported as adverse events during adjunctive treatment with eslicarbazepine acetate: a pooled analysis of three phase III controlled trials. Epilepsia Open. 2017;2(4):459–66.
Costa R, Steinhoff B, Gama H, et al. Safety, tolerability and efficacy of eslicarbazepine acetate as adjunctive therapy in patients aged >= 65 years with focal seizures. Drugs Aging. 2018;35(12):1109–17.
Wechsler RT, Radtke RA, Smith M, et al. Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy. Epilepsia. 2019;60(7):1341–52.
Vaisleib I, Duchowny M, Grinnell T, et al. Analysis of sodium levels and hyponatremia events in trials of eslicarbazepine acetate (ESL) in pediatric patients (aged 4-17 years) [abstract no. P5-268]. Neurology. 2018;90(15 Suppl).
National Institute for Health and Clinical Excellence. Epilepsies: diagnosis and management (clinical guideline 137). 2020. https://www.nice.org.nk/. Accessed 3 Jul 2020.
Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: efficacy and tolerability of the new antiepileptic drugs II: treatment-resistant epilepsy: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018;91(2):82–90.
Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: efficacy and tolerability of the new antiepileptic drugs I: treatment of new-onset epilepsy: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018;91(2):74–81.
Lawthom C, Peltola J, McMurray R, et al. Dibenzazepine agents in epilepsy: how does eslicarbazepine acetate differ? Neurol Ther. 2018;7(2):195–206.
Willems LM, Zollner JP, Paule E, et al. Eslicarbazepine acetate in epilepsies with focal and secondary generalised seizures: systematic review of current evidence. Expert Rev Clin Pharmacol. 2018;11(3):309–24.
Mehta D, Lee J, Simeone J, et al. Adherence to AED treatment for patients with focal seizure receiving monotherapy with eslicarbazepine acetate or prior generation generics: evidence from a large us commercial claims database [abstract no. P5.5-003]. Neurology. 2019;92(15 Suppl):5.
Intravooth T, Staack AM, Juerges K, et al. Antiepileptic drugs-induced hyponatremia: review and analysis of 560 hospitalized patients. Epilepsy Res. 2018;143:7–10.
Costa R, Magalhaes LM, Graca J, et al. Eslicarbazepine acetate exposure in pregnant women with epilepsy. Seizure. 2018;58:72–4.
Li-Na Z, Deng C, Hai-Jiao W, et al. Indirect comparison of third-generation antiepileptic drugs as adjunctive treatment for uncontrolled focal epilepsy. Epilepsy Res. 2018;139:60–72.
Hu Q, Zhang F, Teng W, et al. Efficacy and safety of antiepileptic drugs for refractory partial-onset epilepsy: a network meta-analysis. J Neurol. 2018;265(1):1–11.
Brigo F, Trinka E, Bragazzi NL, et al. A common reference-based indirect comparison meta-analysis of eslicarbazepine versus lacosamide as add on treatments for focal epilepsy. Epilepsy Res. 2016;127:12–8.
Brigo F, Bragazzi NL, Nardone R, et al. Efficacy and tolerability of brivaracetam compared to lacosamide, eslicarbazepine acetate, and perampanel as adjunctive treatments in uncontrolled focal epilepsy: results of an indirect comparison meta-analysis of RCTs. Seizure. 2016;42:29–37.
Lattanzi S, Zaccara G, Giovannelli F, et al. Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis. Acta Neurol Scand. 2019;139(1):33–41.
Holtkamp D, Opitz T, Hebeisen S, et al. Effects of eslicarbazepine on slow inactivation processes of sodium channels in dentate gyrus granule cells. Epilepsia. 2018;59(8):1492–506.
Hebeisen S, Pires N, Loureiro AI, et al. Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: a comparison with carbamazepine, oxcarbazepine and lacosamide. Neuropharmacology. 2015;89:122–35.
Pellegrino G, Mecarelli O, Pulitano P, et al. Eslicarbazepine acetate modulates EEG activity and connectivity in focal epilepsy. Front Neurol. 2018;9(1054):1–7.
Falcao A, Fuseau E, Nunes T, et al. Pharmacokinetics, drug interactions and exposure-response relationship of eslicarbazepine acetate in adult patients with partial-onset seizures: population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses. CNS Drugs. 2012;26(1):79–91.
Milovan D, Almeida L, Romach MK, et al. Effect of eslicarbazepine acetate and oxcarbazepine on cognition and psychomotor function in healthy volunteers. Epilepsy Behav. 2010;18(4):366–73.
Levy-Cooperman N, Schoedel KA, Chakraborty B, et al. Abuse liability assessment of eslicarbazepine acetate in healthy male and female recreational sedative users: a phase I randomized controlled trial. Epilepsy Behav. 2016;61:63–71.
Vaz-Da-Silva M, Nunes T, Almeida L, et al. Evaluation of eslicarbazepine acetate on cardiac repolarization in a thorough QT/QTc study. J Clin Pharmacol. 2012;52(2):222–33.
Sunkaraneni S, Ludwig E, Fiedler-Kelly J, et al. Modeling and simulations to support dose selection for eslicarbazepine acetate therapy in pediatric patients with partial-onset seizures. J Pharmacokinet Pharmacodyn. 2018;45(4):649–58.
Fontes-Ribeiro C, Nunes T, Falcao A, et al. Eslicarbazepine acetate (BIA 2-093): relative bioavailability and bioequivalence of 50 mg/mL oral suspension and 200mg and 800mg tablet formulations. Drugs R D. 2005;6(5):253–60.
Falcao A, Pinto R, Nunes T, et al. Effect of repeated administration of eslicarbazepine acetate on the pharmacokinetics of simvastatin in healthy subjects. Epilepsy Res. 2013;106(1–2):244–9.
Falcao A, Vaz-da-Silva M, Gama H, et al. Effect of eslicarbazepine acetate on the pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive in healthy women. Epilepsy Res. 2013;105(3):368–76.
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During the peer review process, the manufacturer of eslicarbazepine acetate was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
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The preparation of this review was not supported by any external funding.
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Young-A Heo is a salaried employee of Adis International Ltd/Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.
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The manuscript was reviewed by: D. Lindhout, Department of Genetics, University Medical Center Utrecht/Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands; E. Santamarina, Epilepsy Unit, Neurology Department, Hospital Vall d´Hebron, Barcelona, Spain; P.E. Smith, Welsh Epilepsy Centre, University Hospital of Wales, Cardiff, United Kingdom; A. Strzelczyk, Department of Neurology and Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frankfurt and University Hospital Frankfurt, Frankfurt, Germany.
Enhanced material for this Adis Drug Evaluation can be found at https://doi.org/10.6084/m9.figshare.12486323.
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Heo, YA. Eslicarbazepine Acetate: A Review in Focal-Onset Seizures. CNS Drugs 34, 989–1000 (2020). https://doi.org/10.1007/s40263-020-00751-3
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DOI: https://doi.org/10.1007/s40263-020-00751-3