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Drug Profile

Levetiracetam: a comprehensive review

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Pages 159-171 | Published online: 09 Jan 2014

References

  • Jallon P, Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia46(Suppl.), 910–914 (2005).
  • Treiman LJ, Treiman DM. Genetic and chromosomal disorders in epilepsy. In: Advanced Therapy in Epilepsy. Wheless JW, Willmore LJ, Brumback RA (Eds). People’s Medical Publishing House, CT, USA 67–76 (2009).
  • Mulley JC, Scheffer IE, Petrou S, Berkovic SF. Channelopathies as a genetic cause of epilepsy. Curr. Opin. Neurol.16(2), 171–176 (2003).
  • Hauser WA. Seizure disorders: the changes with age. Epilepsia33(Suppl. 4), S6–S14 (1992).
  • Noachtar S, Andermann E, Meyvisch P et al. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology70(8), 607–616 (2008).
  • Verrotti A, Cerminara C, Domizio S et al. Levetiracetam in absence epilepsy. Dev. Med. Child Neurol.50(11), 850–853 (2008).
  • Smith M, Wilcox KS, White HS. Discovery of antiepileptic drugs. Neurotherapeutics4(1), 12–17 (2007).
  • Kwan P, Brodie MJ. Early identification of refractory epilepsy. N. Engl. J. Med.342(5), 314–319 (2000).
  • De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam: the profile of a novel anticonvulsant drug-part I: preclinical data. CNS Drug Rev.13(1), 43–56 (2007).
  • Klitgaard H, Verdru P. Levetiracetam: the first SV2A ligand for the treatment of epilepsy. Expert Opin. Drug Discov.2(11), 1537–1545 (2007).
  • Klitgaard H, Matagne A, Gobert J, Wulfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur. J. Pharmacol.353(2–3), 191–206 (1998).
  • De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam: part II, the clinical profile of a novel anticonvulsant drug. CNS Drug Rev.13(1), 57–78 (2007).
  • Lynch BA, Lambeng N, Nocka K et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc. Natl Acad. Sci. USA101(26), 9861–9866 (2004).
  • Noyer M, Gillard M, Matagne A, Henichart JP, Wulfert E. The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. Eur. J. Pharmacol.286(2), 137–146 (1995).
  • Crowder KM, Gunther JM, Jones TA et al. Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proc. Natl Acad. Sci. USA96(26), 15268–15273 (1999).
  • Janz R, Goda Y, Geppert M, Missler M, Sudhof TC. SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release. Neuron24(4), 1003–1016 (1999).
  • Kaminski RM, Gillard M, Leclercq K et al. Proepileptic phenotype of SV2A-deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam. Epilepsia (2009) (Epub ahead of print).
  • Niespodziany I, Klitgaard H, Margineanu DG. Levetiracetam inhibits the high-voltage-activated Ca(2+) current in pyramidal neurones of rat hippocampal slices. Neurosci. Lett.306(1–2), 5–8 (2001).
  • Lukyanetz EA, Shkryl VM, Kostyuk PG. Selective blockade of N-type calcium channels by levetiracetam. Epilepsia43(1), 9–18 (2002).
  • Angehagen M, Margineanu DG, Ben-Menachem E et al. Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials in hippocampal neurons. Neuroreport14(3), 471–475 (2003).
  • Cataldi M, Lariccia V, Secondo A, di Renzo G, Annunziato L. The antiepileptic drug levetiracetam decreases the inositol 1,4,5-trisphosphate-dependent Ca2+I increase induced by ATP and bradykinin in PC12 cells. J. Pharmacol. Exp. Ther.313(2), 720–730 (2005).
  • Rigo JM, Hans G, Nguyen L et al. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br. J. Pharmacol.136(5), 659–672 (2002).
  • van Vliet EA, van SR, Edelbroek PM et al. Development of tolerance to levetiracetam in rats with chronic epilepsy. Epilepsia49(7), 1151–1159 (2008).
  • van Vliet EA, Aronica E, Redeker S, Boer K, Gorter JA. Decreased expression of synaptic vesicle protein 2A, the binding site for levetiracetam, during epileptogenesis and chronic epilepsy. Epilepsia50(3), 422–433 (2009).
  • Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin. Pharmacokinet.43(11), 707–724 (2004).
  • Doheny HC, Ratnaraj N, Whittington MA, Jefferys JG, Patsalos PN. Blood and cerebrospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat. Epilepsy Res.34(2–3), 161–168 (1999).
  • Tong X, Patsalos PN. A microdialysis study of the novel antiepileptic drug levetiracetam: extracellular pharmacokinetics and effect on taurine in rat brain. Br. J. Pharmacol.133(6), 867–874 (2001).
  • Benedetti MS, Coupez R, Whomsley R et al. Comparative pharmacokinetics and metabolism of levetiracetam, a new anti-epileptic agent, in mouse, rat, rabbit and dog. Xenobiotica34(3), 281–300 (2004).
  • Treiman DM, Good L, Marsh ST, Bautista TP, Wang NC. Lack of efficacy of levetiracetam in a rat model of SE: possible reasons why. Epilepsia48(s6), 286 (2007).
  • Gillard M, Chatelain P, Fuks B. Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing the human recombinant protein. Eur. J. Pharmacol.536(1–2), 102–108 (2006).
  • Stefan H, Wang-Tilz Y, Pauli E et al. Onset of action of levetiracetam: a RCT trial using therapeutic intensive seizure analysis (TISA). Epilepsia47(3), 516–522 (2006).
  • Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol. Ther.85(2), 77–85 (2000).
  • Shorvon SD, van RK. A new antiepileptic drug. J. Neurol. Neurosurg. Psychiatry72(4), 426–429 (2002).
  • Nicolas JM, Collart P, Gerin B et al.In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent. Drug Metab. Dispos.27(2), 250–254 (1999).
  • Czuczwar SJ, Kaplanski J, Swiderska-Dziewit G et al. Pharmacodynamic interactions between antiepileptic drugs: preclinical data based on isobolography. Expert Opin. Drug Metab. Toxicol. (2009) (Epub ahead of print).
  • Luszczki JJ, Andres MM, Czuczwar P et al. Pharmacodynamic and pharmacokinetic characterization of interactions between levetiracetam and numerous antiepileptic drugs in the mouse maximal electroshock seizure model: an isobolographic analysis. Epilepsia47(1), 10–20 (2006).
  • Luszczki JJ, Andres-Mach MM, Ratnaraj N, Patsalos PN, Czuczwar SJ. Levetiracetam and felbamate interact both pharmacodynamically and pharmacokinetically: an isobolographic analysis in the mouse maximal electroshock model. Epilepsia48(4), 806–815 (2007).
  • Wojda E, Wlaz A, Patsalos PN, Luszczki JJ. Isobolographic characterization of interactions of levetiracetam with the various antiepileptic drugs in the mouse 6Hz psychomotor seizure model. Epilepsy Res.86(2-3), 163–174 (2009).
  • Dudra-Jastrzebska M, Andres-Mach MM, Sielski M et al. Pharmacodynamic and pharmacokinetic interaction profiles of levetiracetam in combination with gabapentin, tiagabine and vigabatrin in the mouse pentylenetetrazole-induced seizure model: an isobolographic analysis. Eur. J. Pharmacol.605(1–3), 87–94 (2009).
  • Kaminski RM, Matagne A, Patsalos PN, Klitgaard H. Benefit of combination therapy in epilepsy: a review of the preclinical evidence with levetiracetam. Epilepsia50(3), 387–397 (2009).
  • Shorvon SD, Lowenthal A, Janz D, Bielen E, Loiseau P. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia41(9), 1179–1186 (2000).
  • 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. Epilepsia41(10), 1276–1283 (2000).
  • Cereghino JJ, Biton V, bou-Khalil B et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology55(2), 236–242 (2000).
  • Glauser TA, Ayala R, Elterman RD et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology66(11), 1654–1660 (2006).
  • Piña-Garza JE, Nordli DR Jr, Rating D et al. Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures. Epilepsia50(5), 1141–1149 (2009).
  • Lawlor KM, Devlin AM. Levetiracetam in the treatment of infantile spasms. Eur. J. Paediatr. Neurol.9(1), 19–22 (2005).
  • Gumus H, Kumandas S, Per H. Levetiracetam monotherapy in newly diagnosed cryptogenic West syndrome. Pediatr. Neurol.37(5), 350–353 (2007).
  • Mikati MA, El BD, Sinno D, Mroueh S. Response of infantile spasms to levetiracetam. Neurology70(7), 574–575 (2008).
  • Betts T, Waegemans T, Crawford P. A multicentre, 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. Seizure9(2), 80–87 (2000).
  • Tsai JJ, Yen DJ, Hsih MS et al. Efficacy and safety of levetiracetam (up to 2000 mg/day) in Taiwanese patients with refractory partial seizures: a multicenter, randomized, double-blind, placebo-controlled study. Epilepsia47(1), 72–81 (2006).
  • Wu XY, Hong Z, Wu X et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in Chinese patients with refractory partial-onset seizures. Epilepsia50(3), 398–405 (2009).
  • Meencke HJ, Buyle S. Assessment of a dose-response relationship of levetiracetam. Eur. J. Neurol.13(9), 942–946 (2006).
  • Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology69(18), 1751–1760 (2007).
  • Rosenfeld WE, Benbadis S, Edrich P, Tassinari CA, Hirsch E. Levetiracetam as add-on therapy for idiopathic generalized epilepsy syndromes with onset during adolescence: analysis of two randomized, double-blind, placebo-controlled studies. Epilepsy Res.85(1), 72–80 (2009).
  • Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology68(6), 402–408 (2007).
  • Dinapoli L, Maschio M, Jandolo B et al. Quality of life and seizure control in patients with brain tumor-related epilepsy treated with levetiracetam monotherapy: preliminary data of an open-label study. Neurol. Sci. (2009) (Epub ahead of print).
  • Lim DA, Tarapore P, Chang E et al. Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study. J. Neurooncol.93(3), 349–354 (2009).
  • Rupprecht S, Franke K, Fitzek S, Witte OW, Hagemann G. Levetiracetam as a treatment option in non-convulsive status epilepticus. Epilepsy Res.73(3), 238–244 (2007).
  • Knake S, Gruener J, Hattemer K et al. Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. J. Neurol. Neurosurg. Psychiatry.79(5), 588–589 (2008).
  • Berning S, Boesebeck F, van Baalen A, Kellinghaus C. Intravenous levetiracetam as treatment for status epilepticus. J. Neurol.256(10), 1634–1642 (2009).
  • Eue S, Grumbt M, Muller M, Schulze A. Two years of experience in the treatment of status epilepticus with intravenous levetiracetam. Epilepsy Behav.15(4), 467–469 (2009).
  • Moddel G, Bunten S, Dobis C et al. Intravenous levetiracetam: a new treatment alternative for refractory status epilepticus. J. Neurol. Neurosurg. Psychiatry.80(6), 689–692 (2009).
  • Uges JW, van H, Engelsman J et al. Safety and pharmacokinetics of intravenous levetiracetam infusion as add-on in status epilepticus. Epilepsia50(3), 415–421 (2009).
  • Nau KM, Divertie GD, Valentino AK, Freeman WD. Safety and efficacy of levetiracetam for critically ill patients with seizures. Neurocrit. Care11(1), 34–37 (2009).
  • Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia42(4), 515–524 (2001).
  • Milligan TA, Hurwitz S, Bromfield EB. Efficacy and tolerability of levetiracetam versus phenytoin after supratentorial neurosurgery. Neurology71(9), 665–669 (2008).
  • Loscher W, Honack D, Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J. Pharmacol. Exp. Ther.284(2), 474–479 (1998).
  • Wang H, Gao J, Lassiter TF et al. Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit. Care5(1), 71–78 (2006).
  • Brandt C, Glien M, Gastens AM et al. Prophylactic treatment with levetiracetam after status epilepticus: lack of effect on epileptogenesis, neuronal damage, and behavioral alterations in rats. Neuropharmacology53(2), 207–221 (2007).
  • Zhou JL, Zhao Q, Holmes GL. Effect of levetiracetam on visual-spatial memory following status epilepticus. Epilepsy Res.73(1), 65–74 (2007).
  • Marsh ST, Good LB, Garvey KJ, Treiman DM. EEG stage predicts impairment of spatial memory and learning after experimental status epilepticus in the rat. Epilepsia47(Suppl. 4), 314–315 (2006).
  • Hanon E, Klitgaard H. Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusion model of focal cerebral ischemia. Seizure10(4), 287–293 (2001).
  • Woods SW, Saksa JR, Baker CB, Cohen SJ, Tek C. Effects of levetiracetam on tardive dyskinesia: a randomized, double-blind, placebo-controlled study. J. Clin. Psychiatry69(4), 546–554 (2008).
  • Awaad Y, Michon AM, Minarik S. Use of levetiracetam to treat tics in children and adolescents with Tourette syndrome. Mov. Disord.20(6), 714–718 (2005).
  • Smith-Hicks CL, Bridges DD, Paynter NP, Singer HS. A double blind randomized placebo control trial of levetiracetam in Tourette syndrome. Mov. Disord.22(12), 1764–1770 (2007).
  • Hedderick EF, Morris CM, Singer HS. Double-blind, crossover study of clonidine and levetiracetam in Tourette syndrome. Pediatr. Neurol.40(6), 420–425 (2009).
  • Zesiewicz TA, Sullivan KL, Hauser RA, Sanchez-Ramos J. Open-label pilot study of levetiracetam (Keppra) for the treatment of chorea in Huntington’s disease. Mov. Disord.21(11), 1998–2001 (2006).
  • Bezard E, Hill MP, Crossman AR et al. Levetiracetam improves choreic levodopa-induced dyskinesia in the MPTP-treated macaque. Eur. J. Pharmacol.485(1–3), 159–164 (2004).
  • Alemdar M, Iseri P, Selekler M, Komsuoglu SS. Levetiracetam-responding paroxysmal nonkinesigenic dyskinesia. Clin. Neuropharmacol.30(4), 241–244 (2007).
  • Hering S, Wenning GK, Seppi K, Poewe W, Mueller J. An open trial of levetiracetam for segmental and generalized dystonia. Mov. Disord.22(11), 1649–1651 (2007).
  • Cochran JW. Levetiracetam as migraine prophylaxis. Clin. J. Pain20(3), 198–199 (2004).
  • Brighina F, Palermo A, Aloisio A et al. Levetiracetam in the prophylaxis of migraine with aura: a 6-month open-label study. Clin. Neuropharmacol.29(6), 338–342 (2006).
  • Jorns TP, Johnston A, Zakrzewska JM. Pilot study to evaluate the efficacy and tolerability of levetiracetam (Keppra) in treatment of patients with trigeminal neuralgia. Eur. J. Neurol.16(6), 740–744 (2009).
  • Finnerup NB, Grydehoj J, Bing J et al. Levetiracetam in spinal cord injury pain: a randomized controlled trial. Spinal Cord47(12), 861–867 (2009).
  • Rossi S, Mataluni G, Codeca C et al. Effects of levetiracetam on chronic pain in multiple sclerosis: results of a pilot, randomized, placebo-controlled study. Eur. J. Neurol.16(3), 360–366 (2009).
  • Farooq MU, Bhatt A, Majid A et al. Levetiracetam for managing neurologic and psychiatric disorders. Am. J. Health Syst. Pharm.66(6), 541–561 (2009).
  • Phillips KA, Menard W. A prospective pilot study of levetiracetam for body dysmorphic disorder. CNS Spectr.14(5), 252–260 (2009).
  • Kimland E, Hojeberg B, von EM. Levetiracetam-induced thrombocytopenia. Epilepsia45(7), 877–878 (2004).
  • Elouni B, Ben Salem C, Biour M. Levetiracetam-induced pancytopenia. Ann. Pharmacother.43(5), 985 (2009).
  • Tan TC, de Boer BW, Mitchell A et al. Levetiracetam as a possible cause of fulminant liver failure. Neurology71(9), 685–686 (2008).
  • Zesiewicz TA, Sanchez-Ramos J, Sullivan KL, Hauser RA. Levetiracetam-induced parkinsonism in a Huntington disease patient. Clin. Neuropharmacol.28(4), 188–190 (2005).
  • Dinkelacker V, Dietl T, Widman G, Lengler U, Elger CE. Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases. Epilepsy Behav.4(5), 537–547 (2003).
  • Youroukos S, Lazopoulou D, Michelakou D, Karagianni J. Acute psychosis associated with levetiracetam. Epileptic. Disord.5(2), 117–119 (2003).
  • Mula M, Sander JW. Suicidal ideation in epilepsy and levetiracetam therapy. Epilepsy Behav.11(1), 130–132 (2007).
  • Major P, Greenberg E, Khan A, Thiele EA. Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: preliminary results. Epilepsy Behav.13(3), 557–559 (2008).
  • Kalinin VV. Suicidality and antiepileptic drugs: is there a link? Drug Saf.30(2), 123–142 (2007).
  • Johannessen SI, Helde G, Brodtkorb E. Levetiracetam concentrations in serum and in breast milk at birth and during lactation. Epilepsia46(5), 775–777 (2005).
  • Tomson T, Palm R, Kallen K et al. Pharmacokinetics of levetiracetam during pregnancy, delivery, in the neonatal period, and lactation. Epilepsia48(6), 1111–1116 (2007).
  • Hunt S, Irwin B, Waddell R et al. Levetiracetam therapy in human pregnancy. Updated experience from the UK Epilepsy and Pregnancy Register. Epilepsia50(Suppl. 4), 44 (2009).
  • Alekar S, Leppik I, Montouris G, Harden C. UCB Antiepileptic Drug Pregnancy Registry. Epilepsia50(Suppl. 11), 245 (2009).
  • Food and Drug Administration. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations. FDA, MD, USA (2003).
  • Peltola J, Coetzee C, Jimenez F et al. Once-daily extended-release levetiracetam as adjunctive treatment of partial-onset seizures in patients with epilepsy: a double-blind, randomized, placebo-controlled trial. Epilepsia50(3), 406–414 (2009).
  • Bialer M, Johannessen SI, Levy RH et al. Progress report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT IX). Epilepsy Res.83(1), 1–43 (2009).
  • Matagne A, Margineanu DG, Kenda B, Michel P, Klitgaard H. Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A. Br. J. Pharmacol.154(8), 1662–1671 (2008).
  • Matagne A, Margineanu DG, Potschka H et al. Profile of the new pyrrolidone derivative seletracetam (ucb 44212) in animal models of epilepsy. Eur. J. Pharmacol.614(1–3), 30–37 (2009).
  • Bennett B, Matagne A, Michel P et al. Seletracetam (UCB 44212). Neurotherapeutics4(1), 117–122 (2007).
  • Kaminski RM, Matagne A, Leclercq K et al. SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology54(4), 715–720 (2008).
  • Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia22(4), 489–501 (1981).

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