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. 2007 Apr 24;13(1):57–78. doi: 10.1111/j.1527-3458.2007.00005.x

Levetiracetam: Part II, the Clinical Profile of a Novel Anticonvulsant Drug

Tim De Smedt 1, Robrecht Raedt 1, Kristl Vonck 1, Paul Boon 1
PMCID: PMC6494152  PMID: 17461890

ABSTRACT

The objective of this article was to review and summarize the available reports on the profile of the novel anticonvulsant drug levetiracetam (LEV) in a clinical setting. Therefore, a careful search was conducted in the MEDLINE database and combined with guidelines from regulatory agencies, proceedings of professional scientific meetings, and information provided by the manufacturers. This article is devoted to the clinical pharmacology and clinical trials of LEV investigating its efficacy and safety as add‐on therapy or monotherapy for various seizure types. Finally, results from postmarketing surveillance of LEV are briefly discussed. In general, LEV is shown to be a safe, broad‐spectrum anticonvulsant drug with highly beneficial pharmacokinetic properties, a favorable long‐term retention rate, and a high responder rate, indicating that LEV is an efficient therapeutic option for the treatment of several types of epilepsy.

Keywords: Anticonvulsants, Epilepsy, Levetiracetam

Full Text

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Acknowledgments

Aknowledgments We would like to thank Liesbeth Waterschoot, Annelies Van Dycke, and Tine Wyckhuys for reviewing the manuscript and providing corrections where needed. Tim De Smedt is supported by a grant from the Ghent University Research Fund (B.O.F.). Robrecht Raedt is supported by a grant from the Institute for the Promotion of Innovation by Science and Technology in Flanders. Kristl Vonck is supported by a junior researcher (“Aspirant”) grant from the Fund for Scientific Research‐Flanders.

Paul Boon is a Senior Clinical Investigator of the Fund for Scientific Research‐Flanders (F.W.O.‐Vlaanderen) and he is supported by grants from the Fund for Scientific Research‐Flanders (F.W.O.‐Vlaanderen), by grants from Ghent University Research Fund (B.O.F.), and by the Clinical Epilepsy Grant Ghent University Hospital.

Footnotes

1

Keppra Epilepsy Evaluation of the Patient timE to Response (KEEPER), conducted in the U.S.A.

2

Safety of Keppra as Adjunctive Therapy in Epilepsy (SKATE), conducted in Europe.

3

Official title: A Multi‐Center, Double‐Blind, Historical Control, Randomized Conversion to Monotherapy Study With Keppra XR for Treatment of Partial Onset Seizures.

4

Enrolling is possible for healthcare providers and patients by calling (888) 233‐2334.

5

Contact data per country are available at http://www.eurapinternational.org/

6

Enrolling is possible for healthcare providers and patients by calling (888) 537‐7734.

REFERENCES

  1. Alsaadi TM, Thieman C (2003) Levetiracetam monotherapy for newly diagnosed epilepsy patients. Seizure 12:154‐156. [DOI] [PubMed] [Google Scholar]
  2. Alsaadi TM, Shatzel A, Marquez AV, Jorgensen J, Farias S (2005) Clinical experience of levetiracetam monotherapy for adults with epilepsy: 1‐year follow‐up study. Seizure 14:139‐142. [DOI] [PubMed] [Google Scholar]
  3. Arroyo S, Crawford P (2003) Safety profile of levetiracetam. Epileptic Disord 5:57‐63. [PubMed] [Google Scholar]
  4. Arroyo S, Chadwick DW, French J, Mattson R, Perucca E (2004) Epilepsies and convulsive disorders, Chapter 16, in: The IUPHAR Compendium of Basic Principles For Pharmacological Research in Humans (Du Souich P, Orme M, Erill S. eds.) p. 165‐182, International Union of Basic and Clinical Pharmacology, Irvine , California . [Google Scholar]
  5. Bauer J, Ben‐Menachem E, Kramer G, Fryze W, Da Silva S, Kasteleijn‐Nolst TDG (2006) Levetiracetam: A long‐term follow‐up study of efficacy and safety. Acta Neurol Scand 114:169‐176. [DOI] [PubMed] [Google Scholar]
  6. Ben‐Menachem E (2003) Preliminary efficacy of levetiracetam in monotherapy. Epileptic Disord 5:51‐55. [PubMed] [Google Scholar]
  7. Ben‐Menachem E, Falter U (2000) Efficacy and tolerability of levetiracetam 3000 mg in patients with refractory partial seizures: A multicenter, double‐blind, responder‐selected study evaluating monotherapy. Epilepsia 41:1276‐1283. [DOI] [PubMed] [Google Scholar]
  8. Ben‐Menachem E, Edrich P, Van Vleymen B, Sander JW, Schmidt B (2003) Evidence for sustained efficacy of levetiracetam as add‐on epilepsy therapy. Epilepsy Res 53:57‐64. [DOI] [PubMed] [Google Scholar]
  9. Ben‐Menachem E, Brodie MJ and Perucca E on behalf of the N01061 Study Group (2006) Efficacy of levetiracetam monotherapy; randomized double‐blind head‐to‐head comparison with carbamazepine‐CR in newly diagnosed epilepsy patients with partial onset or generalized tonic‐clonic seizures. Presented at the American Academy of Neurology, April 2006 and discussed in EMEA procedure number EMEA/H/C/277/II/63.
  10. Bergey GK (2005) Evidence‐based treatment of idiopathic generalized epilepsies with new antiepileptic drugs. Epilepsia 46:161‐168. [DOI] [PubMed] [Google Scholar]
  11. Betts T, Waegemans T, Crawford P (2000) 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. Seizure 9:80‐87. [DOI] [PubMed] [Google Scholar]
  12. Boon P, Chauvel P, Pohlmann‐Eden B, Otoul C, Wroe S (2002) Dose‐response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy. Epilepsy Res 48:77‐89. [DOI] [PubMed] [Google Scholar]
  13. Buck ML (2002) Levetiracetam for the treatment of partial seizures. Pediatric Pharmacoth 8:1‐5. [Google Scholar]
  14. Cereghino JJ, Biton V, Abou‐Khalil B, Dreifuss F, Gauer LJ, Leppik I (2000) Levetiracetam for partial seizures: Results of a double‐blind, randomized clinical trial. Neurology 55:236‐242. [DOI] [PubMed] [Google Scholar]
  15. Cohen J (2003) Levetiracetam monotherapy for primary generalized epilepsy. Seizure 12:150‐153. [DOI] [PubMed] [Google Scholar]
  16. Covanis A, Katsalouli M (2003) Levetiracetam monotherapy in generalized epilepsy and photosensitivity. Epilepsia 44:80 [abstract. [Google Scholar]
  17. Depondt C, Yuen AWC, Bell GS, Mitchell T, Koepp MJ, Duncan JS, Sander JW (2006) The long‐term retention of levetiracetam in a large cohort of patients with epilepsy. JNNP 77:101‐103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Edwards KR, Glantz MJ, Bator T, Button J (2004) Levetiracetam levels in human cerebrospinal fluid: A controlled, dose ranging pharmacokinetic study. Neurology 62:118 [abstract. [Google Scholar]
  19. Ferrendelli JA, French J, Leppik I, Morrell MJ, Herbeuval A, Han J, Magnus L (2003) Use of levetiracetam in a population of patients aged 65 years and older: A subset analysis of the KEEPER trial. Epilepsy Behav 4:702‐709. [DOI] [PubMed] [Google Scholar]
  20. Freedman B (1987) Equipoise and the ethics of clinical research. N Engl J Med 317:141‐145. [DOI] [PubMed] [Google Scholar]
  21. French J (2001) Use of levetiracetam in special populations. Epilepsia 42:40‐43. [PubMed] [Google Scholar]
  22. French J, Edrich P, Cramer JA (2001) A systematic review of the safety profile of levetiracetam: A new antiepileptic drug. Epilepsy Res 47:1‐2. [DOI] [PubMed] [Google Scholar]
  23. Genton P, Sadzot B, Fejerman N, Peltola J, Despland PA, Steinhoff B, Rektor I, Wroe S, Maubrey MC, Vandervelden C, et al (2006) Levetiracetam in a broad population of patients with refractory epilepsy: Interim results of the international SKATE trial. Acta Neurol Scand 113:387‐394. [DOI] [PubMed] [Google Scholar]
  24. Glauser TA, Pellock JM, Bebin EM, Fountain NB, Ritter FJ, Jensen CM, Shields WD (2002) Efficacy and safety of levetiracetam in children with partial seizures: An open‐label trial. Epilepsia 43:518‐524. [DOI] [PubMed] [Google Scholar]
  25. Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, Lu Z; N159 Study Group (2006) Double‐blind placebo‐controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 66:1654‐1660. [DOI] [PubMed] [Google Scholar]
  26. Grant R, Shorvon SD (2000) Efficacy and tolerability of 1000–4000 mg per day of levetiracetam as add‐on therapy in patients with refractory epilepsy. Epilepsy Res (42):89‐95. [DOI] [PubMed] [Google Scholar]
  27. Grünewald R (2005) Levetiracetam in the treatment of idiopathic generalized epilepsies. Epilepsia 46:154‐160. [DOI] [PubMed] [Google Scholar]
  28. Harden CL (2001) Safety profile of levetiracetam. Epilepsia 42:36‐49. [PubMed] [Google Scholar]
  29. Harden CL, Leppik I (2006) Optimizing therapy of seizures in women who use oral contraceptives. Neurology 67:S56‐S58. [DOI] [PubMed] [Google Scholar]
  30. Hirsch E, Thibault‐Menard A, Valenti MP, Chassagnon S (2002) Open study on the efficacy of levetiracetam monotherapy in idiopathic generalized epilepsies. Epilepsia 43:62 [abstract. [Google Scholar]
  31. Hunt S, Craig J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, Irwin B, Morrison PJ, Morrow J. (2006) Levetiracetam in pregnancy: Preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 67:1876‐1879. [DOI] [PubMed] [Google Scholar]
  32. Johannessen SI, Helde G, Brodtkorb E (2005) Levetiracetam concentrations in serum and in breast milk at birth and during lactation. Epilepsia 46:775‐777. [DOI] [PubMed] [Google Scholar]
  33. Kasteleijn‐Nolst TDGA, Marescaux C, Stodieck S, Edelbroek PB, Oosting J (1996) Photosensitive epilepsy: A model to study the effects of antiepileptic drugs: Evaluation of the piracetam analogue, levetiracetam. Epilepsy Res 25:225‐230. [DOI] [PubMed] [Google Scholar]
  34. Kelly K, Stephen LJ, Brodie MJ (2004) Levetiracetam for people with mental retardation and refractory epilepsy. Epilepsy Behav 5: 878‐883. [DOI] [PubMed] [Google Scholar]
  35. Krakow K, Walker M, Otoul C, Sander JW (2001) Long‐term continuation of levetiracetam in patients with refractory epilepsy. Neurology 56:1772‐1774. [DOI] [PubMed] [Google Scholar]
  36. Labate A, Colosimo E, Gambardella A, Leggio U, Ambrosio R, Quattrone A (2006) Levetiracetam in patients with generalised epilepsy and myoclonic seizures: An open label study. Seizure 15:214‐218. [DOI] [PubMed] [Google Scholar]
  37. Leppik IE, Biton V, Sander JW, Wieser HG (2003) Levetiracetam and partial seizure subtypes: Pooled data from three randomized, placebo‐controlled trials. Epilepsia 44:1585‐1587. [DOI] [PubMed] [Google Scholar]
  38. Long L (2003) Levetiracetam monotherapy during pregnancy: A case series. Epilepsy Behav 4:447‐448. [DOI] [PubMed] [Google Scholar]
  39. May TW, Rambeck B, Jurgens U (2003) Serum concentrations of levetiracetam in epileptic patients: The influence of dose and co‐medication. Ther Drug Monit 25:690‐699. [DOI] [PubMed] [Google Scholar]
  40. McAuley JW, Anderson GD (2002) Treatment of epilepsy in women of reproductive age: Pharmacokinetic considerations. Clin Pharmacokinet 41:559‐579. [DOI] [PubMed] [Google Scholar]
  41. Meencke HJ, Buyle S (2006) Assessment of a dose‐response relationship of levetiracetam. Eur J Neurol 13:942‐946. [DOI] [PubMed] [Google Scholar]
  42. Morrell MJ, Leppik I, French J, Ferrendelli J, Han J, Magnus L (2003) The KEEPER trial: Levetiracetam adjunctive treatment of partial‐onset seizures in an open‐label community‐based study. Epilepsy Res 54:153‐161. [DOI] [PubMed] [Google Scholar]
  43. Mula M, Trimble MR, Yuen A, Liu RS, Sander JWAS (2003) Psychiatric adverse events during levetiracetam therapy. Neurology 61:704‐706. [DOI] [PubMed] [Google Scholar]
  44. Mula M, Trimble MR, Sander JWAS (2004) Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam. Seizure 13:55‐57. [DOI] [PubMed] [Google Scholar]
  45. Otoul C, Arrigo C, Van Rijckevorsel KJ, French JA (2005) Meta‐analysis and indirect comparisons of levetiracetam with other second‐generation antiepileptic drugs in partial epilepsy. Clin Neuropharmacol 28:72‐78. [DOI] [PubMed] [Google Scholar]
  46. Patsalos PN. (2000) Pharmacokinetic profile of levetiracetam: Toward ideal characteristics. Pharmacol Ther 85:77‐85. [DOI] [PubMed] [Google Scholar]
  47. Patsalos PN (2004) Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet 43:707‐724. [DOI] [PubMed] [Google Scholar]
  48. Pellock JM, Glauser TA, Bebin EM, Fountain NB, Ritter FJ, Coupez RM, Shields WD (2001) Pharmacokinetic study of levetiracetam in children. Epilepsia 42:1574‐1579. [DOI] [PubMed] [Google Scholar]
  49. Perucca E, Baltes E, Ledent E (2000) Levetiracetam: Absence of pharmacokinetic interactions with other antiepileptic drugs (AEDs). Epilepsia 41:150 [abstract. [Google Scholar]
  50. Perucca E (2001) The management of refractory idiopathic epilepsies. Epilepsia 42:31‐35. [DOI] [PubMed] [Google Scholar]
  51. Perucca E, Gidal BE, Baltes E (2003) Effects of antiepileptic comedication on levetiracetam pharmacokinetics: A pooled analysis of data from randomized adjunctive therapy trials. Epilepsy Res 53:47‐56. [DOI] [PubMed] [Google Scholar]
  52. Privitera M (2001) Efficacy of levetiracetam: A review of three pivotal clinical trials. Epilepsia 42:31‐35. [PubMed] [Google Scholar]
  53. Ramael S, Daoust A, Otoul C, Toublanc N, Troenaru M, Lu ZS, Stockis A (2006a) Levetiracetam intravenous infusion: A randomized, placebo‐controlled safety, and pharmacokinetic study. Epilepsia 47:1128‐1135. [DOI] [PubMed] [Google Scholar]
  54. Ramael S, De Smedt F, Toublanc N, Otoul C, Boulanger P, Riethuisen JM, Stockis A (2006b) Single‐dose bioavailability of levetiracetam intravenous infusion relative to oral tablets and multiple‐dose pharmacokinetics and tolerability of levetiracetam intravenous infusion compared with placebo in healthy subjects. Clin Ther 28:734‐744. [DOI] [PubMed] [Google Scholar]
  55. Ragueneau‐Majlessi I, Levy RH, Janik F (2002) Levetiracetam does not alter the pharmacokinetics of an oral contraceptive in healthy women. Epilepsia 43:697‐702. [DOI] [PubMed] [Google Scholar]
  56. Resor SR, Resor LD (2002) Levetiracetam monotherapy in the treatment of convulsive seizures in juvenile myoclonic epilepsy. Presented at the 54th Annual Meeting of the American Academy of Neurology In: Grünewald R (2005) Levetiracetam in the treatment of idiopathic generalized epilepsies. Epilepsia 46:154‐160. [DOI] [PubMed] [Google Scholar]
  57. Rocamora R, Wagner K, Schulze‐Bonhage A (2006) Levetiracetam reduces frequency and duration of epileptic activity in patients with refractory primary generalized epilepsy. Seizure 15:428‐433. [DOI] [PubMed] [Google Scholar]
  58. Rosenfeld WE, Berkovic S And Knowlton R on behalf of LEV N01057 PGTC Study Group (2006) Efficacy and safety of levetiracetam as adjunctive treatment in adult and pediatric subjects suffering from idiopathic generalized epilepsy with primary generalized tonic‐clonic seizures. Neurology 66:A40 [abstract. [Google Scholar]
  59. Shorvon SD, Lowenthal A, Janz D, Bielen E, Loiseau P for the European Levetiracetam Study Group (2000) Multicenter double‐blind, randomized, placebo‐controlled trial of levetiracetam as add‐on therapy in patients with refractory partial seizures. Epilepsia 41:1179‐1186. [DOI] [PubMed] [Google Scholar]
  60. Shorvon SD, Van Rijckevorsel KJ (2002) A new antiepileptic drug. JNNP 72:426‐429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Sisodiya SM, Sander JW, Patsalos PN (2002) Carbamazepine toxicity during combination therapy with levetiracetam: A pharmacodynamic interaction. Epilepsy Res 48:217‐219. [DOI] [PubMed] [Google Scholar]
  62. Sohn YH, Kaelin‐Lang A, Jung HY, Hallett M (2001) Effect of levetiracetam on human corticospinal excitability. Neurology 57:858‐863. [DOI] [PubMed] [Google Scholar]
  63. Taubøll E, Wójtowicz AK, Ropstad E, Gregoraszczuk EL (2002) Valproate irreversibly alters steroid secretion patterns from porcine follicular cells in vitro. Reprod Toxicol 16:319‐325. [DOI] [PubMed] [Google Scholar]
  64. Taubøll E, Gregoraszczuk EL, Kołodziej A, Kajta M, Ropstad E (2003) Valproate inhibits the conversion of testosterone to estradiol and acts as an apoptotic agent in growing porcine ovarian follicular cells. Epilepsia 44:1014‐1021. [DOI] [PubMed] [Google Scholar]
  65. Taubøll E, Gregoraszczuk EL, Tworzydo A, Wojtowicz AK, Ropstad E (2006) Comparison of reproductive effects of levetiracetam and valproate studied in prepubertal porcine ovarian follicular cells. Epilepsia 47:1580‐1583. [DOI] [PubMed] [Google Scholar]
  66. Ten Berg K, Samren EB, Van Oppen AC, Engelsman M, Lindhout D (2005) Levetiracetam use and pregnancy outcome. Reprod Toxicol 20:175‐178. [DOI] [PubMed] [Google Scholar]
  67. Ten Berg K, Van Oppen ACC, Van Donselaar CA, Wentges‐van Holthe JM, Koppe WM, Tamminga P, Lindhout D (2006) Outcomes of human pregnancies after levetiracetam exposure. Birth Defects Res Part A Clin Mol Teratol 76:318. [Google Scholar]
  68. Van Rijckevorsel K, Boon P (2001) The number needed to treat with levetiracetam (LEV): Comparison with the other new antiepileptic drugs (AEDs). Seizure 10:235‐236. [DOI] [PubMed] [Google Scholar]
  69. Verdru P, Wajgt A, Schiemann Delgado J, Noachtar S (2005) Efficacy and safety of levetiracetam 3000 mg/d as adjunctive treatment in adolescents and adults suffering from idiopathic generalized epilepsy with myoclonic seizures. Epilepsia 46:56 [abstract]; discussed fully in EMEA guideline EMEA/H/C/277/II/61. [Google Scholar]
  70. Weintraub D, Buchsbaum R, Resor SR Jr, Hirsch LJ (2006) Psychiatric and behavioral side effects of the newer antiepileptic drugs in adults with epilepsy. Epilepsy Behav Oct 30 [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
  71. Welty TE, Gidal BE, Ficker DM, Privitera MD (2002) Levetiracetam: A different approach to the pharmacotherapy of epilepsy. Ann Pharmacother 36:296‐304. [DOI] [PubMed] [Google Scholar]
  72. White JR, Walczak TS, Leppik IE, Rarick J, Tran T, Beniak TE, Matchinsky DJ, Gumnit RJ (2003) Discontinuation of levetiracetam because of behavioral side effects: A case‐control study. Neurology 61:1218‐1221. [DOI] [PubMed] [Google Scholar]

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