Anticonvulsant Agents: Levetiracetam and Brivaracetam

Living reference work entry


Levetiracetam (LEV) and brivaracetam (BRV) are pyrrolidone derivate compounds binding at the presynaptic SV2A receptor site and thus representing antiepileptic drugs (AEDs) with a unique mode of action. LEV was extensively investigated in randomized controlled trials and has a very favorable efficacy in both focal and generalized epilepsies. Its pharmacokinetic profile is favorable. LEV does not undergo clinically relevant interactions. Adverse reactions comprise mainly asthenia, somnolence, and behavioral symptoms. It is nowadays established as a first-line AED. BRV has been recently introduced as adjunct (AED) in focal epilepsy with a similarly promising pharmacokinetic profile and possibly better tolerability concerning psychiatric adverse events.


  1. Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia. 2000;41:1276–83.PubMedCrossRefGoogle Scholar
  2. Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U, Levetiracetam N01057 Study Group. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology. 2007;69:1751–60.PubMedCrossRefGoogle Scholar
  3. Betts T, Waegemans T, Crawford P. A multicenter, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure. 2000;9:80–7.PubMedCrossRefGoogle Scholar
  4. Biton V, Berkovic SF, Abou-Khalil B, Sperling MR, Johnson ME, Lu S. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia. 2014;55:57–66.PubMedCrossRefGoogle Scholar
  5. Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ, Levetiracteam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology. 2007;68:402–8.PubMedCrossRefGoogle Scholar
  6. Brodie MJ, Besag F, Ettinger AB, Mula M, Gobbi G, Comai S, Aldenkamp AP, Steinhoff BJ. Epilepsy, antiepileptic drugs, and aggression: an evidence-base review. Pharmacol Rev. 2016;68:563–602.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Brodie MJ, Fakhoury T, McDonough B, Colson AO, Stockis A, Elmoufti S, Whitesides J. Brivaracetam-induced elevation of carbamazepine epoxide levels: a post-hoc analysis from the clinical development program. Epilepsy Res. 2018;145:55–62.PubMedCrossRefGoogle Scholar
  8. Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology. 2000;55:236–42.PubMedCrossRefGoogle Scholar
  9. D’Souza J, Johnson M, Borghs S. Meta-analysis of non-psychotic behavioural treatment-emergent adverse events in brivaracetam and levetiracetam development programmes (Abstract P402). Epilepsia. 2012;53(Suppl 5):118.Google Scholar
  10. De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam: part II, the clinical profile of a novel anticonvulsant drug. CNS Drug Rev. 2007;13:57–78.PubMedPubMedCentralCrossRefGoogle Scholar
  11. French JA, Costantini C, Brodsky A, von Rosenstiel P, N01193 Study Group. Adjunctive brivaracetam for refractory partial-onset seizures: a randomized, controlled trial. Neurology. 2010;75:519–25.PubMedCrossRefGoogle Scholar
  12. Gillard M, Fuks B, Leclercq K, Matagne A. Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. Eur J Pharmacol. 2011;664:36–44.PubMedCrossRefGoogle Scholar
  13. Harden CL. Safety profile of levetiracetam. Epilepsia. 2001;42(Suppl 4):36–49.PubMedCrossRefGoogle Scholar
  14. Hirsch M, Hintz M, Specht A, Schulze-Bonhage A. Tolerability, efficacy and retention rate of brivaracetam in patients previously treated with levetiracetam: a monocenter retrospective analysis. Seizure. 2018;61:98–103.PubMedCrossRefGoogle Scholar
  15. Kasteleijn-Nolst Trenité DG, Marescaux C, Stodieck SRG, Edelbroek PM, Oosting J. Photosensitive epilepsy: a model to study the effects of antiepileptic drugs. Evaluation of the piracetam analogue, levetiracetam. Epilepsy Res. 1996;25:225–30.PubMedCrossRefGoogle Scholar
  16. Klein P, Schiemann J, Sperling MR, Whitesides J, Liang W, Stalvey T, Brandt C, Kwan P. A randomized, double-blind, placebo- controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia. 2015;56:1890–8.PubMedCrossRefGoogle Scholar
  17. Klein P, Diaz A, Gasalla T, Whitesides J. A review of the pharmacology and clinical efficacy of brivaracetam. Clin Pharmacol. 2018;10:1–22.PubMedPubMedCentralGoogle Scholar
  18. Klitgaard H, Matagne A, Nicolas J-M, Gillard M, Lamberty Y, De Ryk M, Kaminski RM, Leclercq K, Niespodziany I, Wolff C, Wood M, Hannestad J, Kervyn S, Kenda B. Biravaracetam: rationale for the discovery and preclinical profile of SV2A ligand for epilepsy treatment. Epilepsia. 2016;57:538–48.PubMedCrossRefGoogle Scholar
  19. Kwan P, Trinka E, Van Paesschen W, Rektor I, Johnson ME, Lu S. Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia. 2014;55:38–46.PubMedCrossRefGoogle Scholar
  20. May TW, Rambeck B, Juerges U. Serum concentrations of levetiracetam in epileptic patients: the influence of dose and co-medication. Ther Drug Monit. 2003;25:690–9.PubMedCrossRefGoogle Scholar
  21. Nicolas JM, Chanteux H, Rosa M, Watanabe S, Stockis A. Effect of gemfibrozil on the metabolism of brivaracetam in vitro and in human subjects. Drug Metabol Dispos. 2012;40:1466–72.CrossRefGoogle Scholar
  22. Noachtar S, Andermann E, Meyvisch P, Andermann F, Gough WB, Schiemann-Delgado J, for the N166 Levetiracetam Study Group. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology. 2008;70:607–16.PubMedCrossRefGoogle Scholar
  23. Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther. 2000;85:77–85.PubMedCrossRefGoogle Scholar
  24. Patsalos PN. The pharmacokinetic characteristics of levetiracetam. Methods Find Exp Clin Pharmacol. 2003;25:123–9.PubMedCrossRefGoogle Scholar
  25. Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet. 2004;43:707–24.PubMedCrossRefGoogle Scholar
  26. Patsalos PN. Drug interactions with the newer antiepileptic drugs (AEDs) – part 1: pharmacokinetic and pharmacodynamic interactions between AEDs. Clin Pharm. 2013;52:927–66.CrossRefGoogle Scholar
  27. Ryvlin P, Werhahn KJ, Blaszczyk B, Johnson ME, Lu S. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a doubleblind, randomized, placebo-controlled trial. Epilepsia. 2014;55:47–56.PubMedCrossRefGoogle Scholar
  28. Sargentini-Maier ML, Rolan P, Connell J, Connell J, Tytgat D, Jacobs T, Pigeolet E, Riethuisen JM, Stockis A. The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males. Br J Clin Pharmacol. 2007;63:680–8.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Sargentini-Maier ML, Sokalski A, Boulanger P, Jacobs T, Stockis A. Brivaracetam disposition in renal impairment. J Clin Pharmacol. 2012;52:1927–33.PubMedCrossRefGoogle Scholar
  30. Schoemaker R, Wade JR, Stockis A. Brivaracetam population pharmacokinetics in children with epilepsy aged 1 month to 16 years. Eur J Clin Pharmacol. 2017;73:727–33.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Schubert-Bast S, Willems LM, Kurlemann G, Knake S, Müller-Schlüter K, Rosenow F, Strzelczyk A. Postmarketing experience with brivaracetam in the treatment of focal epilepsy in children and adolescents. Epilepsy Behav. 2018;89:89–93.PubMedCrossRefGoogle Scholar
  32. Shorvon SD, Löwenthal A, Janz D, Bielen E, Loiseau P, for the European Levetiracetam Study Group. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia. 2000;41:1179–86.PubMedCrossRefGoogle Scholar
  33. Steinhoff BJ, Staack AM, Wisniewski I. Seizure control with antiepileptic drug therapy in 517 consecutive adult outpatients at the Kork Epilepsy Centre. Epileptic Disord. 2012;14:379–87.PubMedCrossRefGoogle Scholar
  34. Steinhoff BJ, Bacher M, Bucurenciu I, Hillenbrand B, Intravooth T, Kornmeier R, Kurth C, Stockinger J, Staack AM. Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy – a monocenter survey. Seizure. 2017;48:11–4.PubMedCrossRefGoogle Scholar
  35. Steinig I, von Podewils F, Möddel G, Bauer S, Klein KM, Paule E, Reif PS, Willems LM, Zöllner JP, Kunz R, Runge U, Kurlemann G, Schubert-Bast S, Rosenow F, Strzelczyk A. Postmarketing experience with brivaracetam in the treatment of epilepsies: a multicenter cohort study from Germany. Epilepsia. 2017;58:1208–16.PubMedCrossRefGoogle Scholar
  36. Stephen LJ, Brodie MJ. Brivaracetam: a novel antiepileptic drug for focal-onset seizures. Ther Adv Neurol Disord. 2018;11:1–10.CrossRefGoogle Scholar
  37. Stockis A, Watanabe S, Fauchoux N. Interaction between brivaracetam (100 mg/day) and a combination oral contraceptive: a randomized, double-blind, placebo-controlled study. Epilepsia. 2014;55:e27–31.PubMedCrossRefGoogle Scholar
  38. Stockis A, Watanabe S, Scheen AJ, Tytgat D, Gerin B, Rosa M, Chanteux H, Nicolas JM. Effect of rifampin on the disposition of brivaracetam in human subjects: further insights into brivaracetam hydrolysis. Drug Metab Dispos. 2016;44:792–9.PubMedCrossRefGoogle Scholar
  39. Theochari E, Cock H, Lozsadi D, Galtrey C, Arevalo J, Mula M. Brivaracetam in adults with drug-resistant epilepsy and psychiatric comorbidities. Epilepsy Behav. 2019;90:129–31.PubMedCrossRefGoogle Scholar
  40. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, Sabers A, Thomas SV, Vajda F, EURAP Study Group. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018;17:530–8.PubMedCrossRefGoogle Scholar
  41. Van Paesschen W, Hirsch E, Johnson M, Falter U, von Rosenstiel P. Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial-onset seizures: a phase IIb, randomized, controlled trial. Epilepsia. 2013;54:89–97.PubMedCrossRefGoogle Scholar
  42. Villanueva V, Lopez-González FJ, Mauri JA, Rodriguez-Uranga J, Olivé-Gadea M, Monotoya J, Ruiz-Giménez J, Zurita J, BRIVA-LIFE Study Group. BRIVA-LIFE – a multicenter retrospective study of the long-term use of brivaracetam in clinical practice. Acta Neurol Scand. 2019;139:360–8.PubMedCrossRefGoogle Scholar
  43. Werhahn KJ, Trinka E, Dobesberger J, Unterberger I, Baum P, Deckert-Schmitz M, Kniess T, Schmitz B, Bernedo V, Ruckes C, Ehrlich A, Krämer G. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia. 2015;56:450–9.PubMedCrossRefGoogle Scholar
  44. Yates SL, Fakhoury T, Liang W, Eckhardt K, Borghs S, D’Souza J. An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. Epilepsy Behav. 2015;52:165–8.PubMedPubMedCentralCrossRefGoogle Scholar

Authors and Affiliations

  1. 1.Kork Epilepsy CenterKehl-KorkGermany

Section editors and affiliations

  • Christian E. Elger
    • 1
  1. 1.Beta Neurology – Competence Center for EpilepsyBeta Klinik GmbHBonnGermany

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