Advertisement

CNS Drugs

, Volume 19, Issue 4, pp 347–367 | Cite as

Zonisamide

A Review of its Use in the Management of Partial Seizures in Epilepsy
  • James E. Frampton
  • Lesley J. Scott
Adis Drug Evaluation

Summary

Abstarct

Zonisamide (Zonegran®, Excegran®) is a new-generation, broad-spectrum antiepileptic drug (AED) currently approved as adjunctive therapy for the treatment of medically refractory partial seizures in adults in the US and as adjunctive therapy or monotherapy in the control of partial and generalised seizures in adults and children in Japan and Korea.

Either as adjunctive therapy or monotherapy, zonisamide effectively reduces the frequency of partial seizures, with or without secondary generalisation to tonic-clonic seizures, in adults and children with epilepsy. The drug is generally well tolerated and, additionally, has a favourable pharmacokinetic profile permitting once- or twice-daily administration. Direct head-to-head comparisons with other AEDs would be beneficial in fully defining the place of zonisamide in therapy. In the meantime, adjunctive therapy or monotherapy with zonisamide is a convenient, useful option for the management of partial seizures, including those refractory to other AEDs.

Pharmacological Properties

Zonisamide demonstrates anticonvulsant activity in animal models of epilepsy, as well as in patients with various types of epilepsy. The drug appears to block the spread of seizure discharges and to suppress the epileptic focus, although the precise mechanism(s) of antiseizure activity are unknown.

Peak plasma zonisamide concentrations are attained 2–5 hours after administration of single oral doses of 200–800mg in healthy volunteers in Japan and the US. The drug has a bioavailability of ≈100%; food affects the rate, but not extent, of absorption. Steady-state concentrations are achieved within 14 days. Linear pharmacokinetics have been observed in adults and children with epilepsy in Japan, but not in adult volunteers or patients with epilepsy in the US.

Zonisamide is metabolised in the liver and excreted primarily by the kidneys. It has a long plasma terminal elimination half-life: 50–68 hours after single oral 200–800mg doses in healthy volunteers in the US and Japan. The pharmacokinetics of the drug are unaffected by advanced age, although the plasma clearance of the drug appears to be moderately higher in children than in adults in Japan. Zonisamide should not be used in patients with renal failure (estimated glomerular filtration rate <50 mL/min [<3.0 L/h]). Zonisamide has no hepatic enzyme-inducing effects; while it is sensitive to induction by enzyme-inducing AEDs (e.g. carbamazepine and phenytoin), these drug interactions seem to be of minor clinical significance.

Therapeutic Efficacy

In four short-term (≤24 weeks), placebo-controlled trials conducted in the US or Europe (n = 138–351), once- or twice-daily administration of zonisamide at dosages of ≥300 mg/day was mostly effective in the treatment of patients with medically refractory partial seizures, with or without secondary generalisation to tonic-clonic seizures, based on significantly greater reductions in median seizure frequency for all partial seizures, for complex partial seizures only and for all seizure types. The corresponding responder rates (i.e. patients achieving a ≥50% reduction from baseline in seizure frequency) in zonisamide ≥400 mg/day recipients were generally significantly greater than with placebo. When assessed in two of the above-mentioned trials, twice-daily administration of zonisamide 100 or 200 mg/day was mostly effective in one study, whereas 100 mg/day was not effective in the other.

Longer term, the antiepileptic efficacy of zonisamide was maintained in patients who continued therapy for up to 2 years, with no evidence of tachyphylaxis or pharmacological tolerance.

The efficacy of zonisamide at mean dosages of 5.9–8.8 mg/kg/day was demonstrated in a total of 1008 adults or children in Japan with various types of epilepsy mainly refractory to treatment who were recruited to a series of predominantly noncomparative clinical trials. In the only active comparator-controlled study performed to date, zonisamide (mean dosage 330 mg/day) was judged to be as effective as carbamazepine (mean dosage 600 mg/day) in Japanese patients with predominantly partial epilepsies.

Pooled analyses of open-label studies specifically in young adults and/or children showed zonisamide to be effective as adjunctive therapy for refractory partial seizures (dosage of 2.0–18.6 mg/kg/day) and as monotherapy for newly diagnosed or refractory partial seizures (dosage of 1–12 mg/kg/day).

Tolerability

Zonisamide was generally well tolerated as adjunctive therapy in patients (n = 499) with refractory partial seizures enrolled in placebo-controlled trials conducted in the US and Europe, and as adjunctive therapy or monotherapy in adults or children in Japan (n = 1008) with various types of epilepsy recruited in predominantly noncomparative clinical trials. The most frequently occurring adverse events common to these studies were somnolence, anorexia, ataxia, gastrointestinal discomfort/abdominal pain, mental slowing, weight loss and skin rash/itch.

Adverse events usually occurred early during treatment (within 4 weeks), were generally of mild-to-moderate intensity, and decreased with time in the US and European studies. Patient tolerability of zonisamide was optimised during slow titration from low initial dosages to therapeutic dosages over 4–8 weeks.

The tolerability profile of zonisamide in a Japanese study was generally similar to that of carbamazepine, although anorexia occurred more frequently with zonisamide, and ataxia was noted more frequently with carbamazepine.

Patients mainly in the US and Europe appear to be at increased risk of developing kidney stones (incidence equivalent to 18 cases per 1000 patient-years of exposure), while paediatric patients, in particular, appear to be at increased risk of zonisamide-associated oligohidrosis/hyperthermia (estimated reporting rate ≈1–2 cases per 10 000 patient-years of exposure).

Keywords

Lamotrigine Adjunctive Therapy Partial Seizure Seizure Frequency Vigabatrin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Leppik IE. Zonisamide: chemistry, mechanism of action, and pharmacokinetics. Seizure 2004; 13S: S5–9CrossRefGoogle Scholar
  2. 2.
    Sobieszek G, Borowicz KK, Kimber-Trojnar Z, et al. Zonisamide: a new antiepileptic drug. Pol J Pharmacol 2003 Sep–Oct; 55(5): 683–9PubMedGoogle Scholar
  3. 3.
    Masuda Y, Ishizaki M, Shimizu M. Zonisamide: pharmacology and clinical efficacy in epilepsy. CNS Drug Rev 1998; 4(4): 341–60CrossRefGoogle Scholar
  4. 4.
    Yagi K. Overview of Japanese experience — controlled and uncontrolled trials. Seizure 2004; 13Suppl. 1: S11–5PubMedCrossRefGoogle Scholar
  5. 5.
    Eisai Pharmaceuticals Inc. Zonegran zonisamide capsules prescribing information, Teaneck, NJ, USA. Eisai Pharmaceuticals Inc., 2004 MayGoogle Scholar
  6. 6.
    Oommen KJ, Mathews S. Zonisamide: a new antiepileptic drug. Clin Neuropharmacol 1999; 22(4): 192–200PubMedGoogle Scholar
  7. 7.
    Peters DH, Sorkin EM. Zonisamide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs 1993 May; 45: 760–87PubMedCrossRefGoogle Scholar
  8. 8.
    Leppik IE. Zonisamide. Epilepsia 1999; 40 Suppl. 5: 23–9CrossRefGoogle Scholar
  9. 9.
    Glauser TA, Pellock JM. Zonisamide in pediatric epilepsy: review of the Japanese experience. J Child Neurol 2002; 17: 87–96PubMedCrossRefGoogle Scholar
  10. 10.
    Mimaki T. Clinical pharmacology and therapeutic drug monitoring of zonisamide. Ther Drug Monit 1998 Dec; 20: 593–7PubMedCrossRefGoogle Scholar
  11. 11.
    Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs: focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet 1996 Jul; 31: 29–46PubMedCrossRefGoogle Scholar
  12. 12.
    Rambeck B, Specht U, Wolf P. Pharmacokinetic interactions of the new antiepileptic drugs. Clin Pharmacokinet 1996 Oct; 31: 309–24PubMedCrossRefGoogle Scholar
  13. 13.
    Woolf TF, Clang T. Metabolism of 14C-zonisamide in healthy volunteers [abstract no. 241]. Pharm Res 1986; 3 Suppl.: 159SGoogle Scholar
  14. 14.
    Wallace J, Shellenberger K, Groves L. Pharmacokinetics of zonisamide in young and elderly subjects [abstract no. 6.049]. Epilepsia 1998; 39 Suppl. 6: 190–1Google Scholar
  15. 15.
    Smith D, Brodie M, Dunkley D, et al. Steady-state drug interaction study of zonisamide and sodium valproate in epileptic patients [abstract no. PO5.058]. Neurology 2001 Apr; 56Suppl. 3: A338Google Scholar
  16. 16.
    Brodie M, Wilson E, Smith D, et al. Steady-state drug interaction study of zonisamide and lamotrigine in epileptic patients [abstract no. P05.055]. Neurology 2001 Apr; 56Suppl. 3: A337Google Scholar
  17. 17.
    Ito T, Yamaguchi T, Miyazaki H. Pharmacokinetic studies of AD-810, a new antiepileptic compound: phase I trials. Arzneim-Forsch Drug Res 1982; 32: 1581–6Google Scholar
  18. 18.
    Matsumoto K, Miyazaki H, Fujii T, et al. Absorption, distribution and excretion of 3-(sulfamoyl[14C]methyl)-1,2-benzisoxazole (AD-810) in rats, dogs, monkeys and of AD-810 in men. Arzneim-Forsch Drug Res 1983; 33: 961–8Google Scholar
  19. 19.
    Taylor CP, McLean JR, Bockbrader HN. Zonisamide (AD-810, CI-912). Meldrum & Porter. New anticonvulsant drugs. London: John Libbey, 1986: 277–94Google Scholar
  20. 20.
    Data on file. Eisai Pharmaceuticals Inc, 2004Google Scholar
  21. 21.
    Yagi K, Seino M, Mihara T, et al. Open clinical trial of a new antiepileptic drug, zonisamide, on 49 patients with refractory epileptic seizures. Seishin Igaku 1987; 29: 111–9Google Scholar
  22. 22.
    Ono T, Yagi K, Seino M. Clinical efficacy and safety of a new antiepileptic drug, zonisamide — a multi-institutional phase III study. Seishin Igaku 1988; 30: 471–82Google Scholar
  23. 23.
    Faught E, Ayala R, Montouris GG, et al. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology 2001 Nov 27; 57: 1774–9PubMedCrossRefGoogle Scholar
  24. 24.
    Wagner JG, Sackellares JC, Donofrio PD, et al. Nonlinear pharmacokinetics of CI-912 in adult epileptic patients. Ther Drug Monit 1984; 6(3): 277–83PubMedCrossRefGoogle Scholar
  25. 25.
    Wilensky AJ, Friel PN, Ojemann LM, et al. Zonisamide in epilepsy: a pilot study. Epilepsia 1985; 26: 212–20PubMedCrossRefGoogle Scholar
  26. 26.
    Yagi K, Seino M. Methodological requirements for clinical trials in refractory epilepsies — our experience with zonisamide. Prog Neuropsychopharmacol Biol Psychiatry 1992 Jan; 16: 79–85PubMedCrossRefGoogle Scholar
  27. 27.
    Hachad H, Ragueneau-Majlessi I, Levy RH. New antiepileptic drugs: review on drug interactions. Ther Drug Monit 2002 Feb; 24(1): 91–103PubMedCrossRefGoogle Scholar
  28. 28.
    Perucca E. Marketed new antiepileptic drugs: are they better than old-generation agents? Ther Drug Monit 2002 Feb; 24(1): 74–80PubMedCrossRefGoogle Scholar
  29. 29.
    Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003 Jun; 2(6): 347–56PubMedCrossRefGoogle Scholar
  30. 30.
    Ojemann LM, Shastri RA, Wilensky AJ, et al. Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy. Ther Drug Monit 1986; 8(3): 293–6PubMedCrossRefGoogle Scholar
  31. 31.
    Levy RH, Ragueneau-Majlessi I, Garnett WR, et al. Lack of a clinically significant effect of zonisamide on phenytoin steady-state pharmacokinetics in patients with epilepsy. J Clin Pharmacol 2004; 244: 1230–4Google Scholar
  32. 32.
    Ragueneau-Majlessi I, Levy RH, Bergen D, et al. Carbamazepine pharmacokinetics are not affected by zonisamide: in vitro mechanistic study and in vivo clinical study in epileptic patients. Epilepsy Res 2004; 62(1): 1–11PubMedCrossRefGoogle Scholar
  33. 33.
    Miura H. Zonisamide monotherapy with once-daily dosing in children with cryptogenic localization-related epilepsies: clinical effects and pharmacokinetic studies. Seizure 2004; 13S: S17–23CrossRefGoogle Scholar
  34. 34.
    Tasaki K, Minami T, Ieiri I, et al. Drug interactions of zonisamide with phenytoin and sodium valproate: serum concentrations and protein binding. Brain Dev 1995 May; 17: 182–5PubMedCrossRefGoogle Scholar
  35. 35.
    Ikawa K, Eshima N, Morikawa N, et al. Influence of concomitant anticonvulsants on serum concentrations of clonazepam in epileptic subjects: an age- and dose-effect linear regression model analysis. Pharm Pharmacol Commun 1999 Apr; 5: 307–10CrossRefGoogle Scholar
  36. 36.
    Shinoda M, Akita M, Hasegawa M, et al. The necessity of adjusting the dosage of zonisamide when coadministered with other anti-epileptic drugs. Biol Pharm Bull 1996 Aug; 19: 1090–2PubMedCrossRefGoogle Scholar
  37. 37.
    Griffith SG, Shah J, Kovelesky Y, et al. No effect of steady-state dosing of zonisamide on pharmacokinetics and pharmacodynamics of an oral contraceptive in healthy females. Epilepsia 2004; 45(Suppl. 3): 156Google Scholar
  38. 38.
    Sackellares JC, Ramsay RE, Wilder BJ, et al. Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures. Epilepsia 2004 Jun; 45(6): 610–7PubMedCrossRefGoogle Scholar
  39. 39.
    Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res 1993 May; 15: 67–73PubMedCrossRefGoogle Scholar
  40. 40.
    Brodie MJ, Duncan R, Vespignani H, et al. Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures. Epilepsia 2005; 46: 31–41Google Scholar
  41. 41.
    Brodie MJ. Zonisamide clinical trials: European experience. Seizure 2004; 13 Suppl.: S66–70PubMedCrossRefGoogle Scholar
  42. 42.
    Faught E. Review of United States and European clinical trials of zonisamide in the treatment of refractory partial-onset seizures. Seizure 2004; 13 Suppl.: S59–65PubMedCrossRefGoogle Scholar
  43. 43.
    Brodie MA, French JA, Breitmeyer W, et al. Long-term seizure amelioration on zonisamide [abstract no. L.10]. Epilepsia 2000; 41 Suppl. 7: 255Google Scholar
  44. 44.
    Alapati A, Hall-Bell C, Faught ER. Safety and efficacy of zonisamide as adjunctive therapy for refractory complex partial seizures: an open label study [abstract no. 3.201]. Epilepsia 2000; 41 Suppl. 7: 225–6Google Scholar
  45. 45.
    Seino M, Ohkuma T, Miyasaka M, et al. Efficacy evaluation of AD-810 (zonisamide) — results of a double-blind comparison with carbamazepine (CBZ) (in Japanese]. J Clin Exp Med (Japan) 1988; 144(4): 275–91Google Scholar
  46. 46.
    Seki T, Kumagai N, Maezawa M. Effects of zonisamide monotherapy in children with epilepsy. Seizure 2004; 13S: S26–32CrossRefGoogle Scholar
  47. 47.
    Fukushima K, Seino M. A long-term follow up of zonisamide monotherapy [abstract no. 1.348]. Epilepsia 2004; 45 Suppl. 7: 133Google Scholar
  48. 48.
    Yamauchi T, Aikawa H. Efficacy of zonisamide: our experience. Seizure 2004; 13S: S41–8CrossRefGoogle Scholar
  49. 49.
    Bergen D. Incidence of adverse events is reduced with titrated dosing of Zonegran™ (zonisamide) for partial seizures in the United States [abstract no. 2.037]. Epilepsia 1999; 40 Suppl. 7: 94Google Scholar
  50. 50.
    Penovich P. Slow titration with zonisamide: beneficial effects in tolerability [abstract no. 033]. Epilepsia 2000; 41 Suppl. Florence: 106–7CrossRefGoogle Scholar
  51. 51.
    Morris G. The effect of zonisamide administration on patient weight. Epilepsia 2000; 41 Suppl. Florence: 39–40Google Scholar
  52. 52.
    Welty TE, Kuzniecky RI, Limdi N, et al. Weight loss associated with use of zonisamide in European and United States clinical trials [abstract no. 3.140]. Epilepsia 2001; 42 Suppl. 7: 262Google Scholar
  53. 53.
    Shellenberger K, Beck K, Oida T. Safety of zonisamide in Japanese children [abstract no. 2.036]. Epilepsia 1999; 40 Suppl. 7: 94Google Scholar
  54. 54.
    Bennett WM. Risk of kidney stones in patients treated with zonisamide [abstract no. P04.102]. Neurology 2002 Apr; 58Suppl. 3: A298Google Scholar
  55. 55.
    Leppik IE, Mathur VS, Young EW. Is there a link between zonisamide treatment and nephrolithiasis? [abstract no. P03.121]. Neurology 1999 Apr; 52Suppl. 2: A237Google Scholar
  56. 56.
    Penovich PE, Shear NH, Leyden JJ, et al. Incidence of rash in clinical trials: how many cases are attributable to zonisamide? [abstract no. 2.305]Epilepsia 2003; 44 Suppl. 9: 280Google Scholar
  57. 57.
    McJilton JS, Ramsay RE. Sulfa-drug allergies and zonisamide [abstract no. 3.163]. Epilepsia 2001; 42 Suppl. 7: 269Google Scholar
  58. 58.
    Ritter FJ, Gustafson MC, Karney V, et al. Do allergic reactions to sulfonamide antibiotics predict allergy to zonisamide? [abstract no. 2.234]. Epilepsia 2002; 43 Suppl. 7: 209Google Scholar
  59. 59.
    Leppik IE, Willmore LJ, Homan RW, et al. Efficacy and safety of zonisamide: results of a multicenter study. Epilepsy Res 1993 Feb; 14: 165–73PubMedCrossRefGoogle Scholar
  60. 60.
    Wong IC, Lhatoo SD. Adverse reactions to new anticonvulsant drugs. Drug Saf 2000 Jul; 23(1): 35–56PubMedCrossRefGoogle Scholar
  61. 61.
    Kubota M, Nishi-Nagase M, Sakakihara Y, et al. Zonisamide — induced urinary lithiasis in patients with intractable epilepsy. Brain Dev 2000 Jun; 22: 230–3PubMedCrossRefGoogle Scholar
  62. 62.
    Knudsen JF, Thambi LR, Kapcala LP, et al. Oligohydrosis and fever in pédiatrie patients treated with zonisamide. Pediatr Neurol 2003 Mar; 28(3): 184–9PubMedCrossRefGoogle Scholar
  63. 63.
    Low PA, James S, Peschel T, et al. Zonisamide and associated oligohidrosis and hyperthermia. Epilepsy Res 2004; 62: 27–34PubMedCrossRefGoogle Scholar
  64. 64.
    Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurol 2004 Oct; 3: 618–21PubMedCrossRefGoogle Scholar
  65. 65.
    McAuley JW, Biederman TS, Smith JC, et al. Newer therapies in the drug treatment of epilepsy. Ann Pharmacother 2002 Jan; 36(1): 119–29PubMedCrossRefGoogle Scholar
  66. 66.
    Seino M, Yeh EA. Patterns of epilepsy care in Japan. Neurology 1997; 48Suppl. 8: S8–15PubMedCrossRefGoogle Scholar
  67. 67.
    Shorvon SD. Epidemiology, classification, natural history and genetics of epilepsy. Lancet 1990; 336: 93–6PubMedCrossRefGoogle Scholar
  68. 68.
    Dichter MA, Brodie MJ. New antiepileptic drugs. New Engl J Med 1996; 334(24): 1583–90PubMedCrossRefGoogle Scholar
  69. 69.
    LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review. JAMA 2004 Feb 4; 291(5): 605–14PubMedCrossRefGoogle Scholar
  70. 70.
    French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004 Apr 27; 62(8): 1261–73PubMedCrossRefGoogle Scholar
  71. 71.
    National Institute for Clinical Excellence. Newer drugs for epilepsy in adults [online]. Available from URL: http://www.nice.org.uk/pdf/TA076fullguidance.pdf [Accessed 2004 Nov 22]
  72. 72.
    National Institute for Clinical Excellence. Newer drugs for epilepsy in children [online]. Available from URL: http://www.nice.org.uk/pdf/ta079fullguidance.pdf [Accessed 2004 Nov 22]
  73. 73.
    Eisai Co. Ltd. Eisai receives a positive opinion for Zonegran marketing authorization from European Committee for Medicinal Products for Human Use (CMPH) [media release]. Available from URL: http://www.eisai.co.jp [Accessed 2004 Dec 29]
  74. 74.
    French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004 Apr 27; 62(8): 1252–60PubMedCrossRefGoogle Scholar
  75. 75.
    Cramer JA, Ben Menachem E, French J. Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation. Epilepsy Res 2001 Nov; 47(1–2): 17–25PubMedCrossRefGoogle Scholar
  76. 76.
    Newmark ME, Dubinsky S. Zonisamide monotherapy in a multi-group clinic. Seizure 2004 Jun; 13(4): 223–5PubMedCrossRefGoogle Scholar
  77. 77.
    Wilfong AA. Zonisamide monotherapy for epilepsy in children and young adults. Pediatr Neurol 2005; 32(2): 77–80PubMedCrossRefGoogle Scholar
  78. 78.
    Bunch ME, Mandelbaum DE, Kugler SL, et al. Efficacy of zonisamide at 12 months in children classified by seizure type, cognitive status, and prior and concomitant anticonvulsant drug use [abstract no. 1.253]. Epilepsia 2003; 44 Suppl. 9: 90–1Google Scholar
  79. 79.
    Konkol RJ. Pediatric experience with zonisamide in managed care [abstract no. 1.295]. Epilepsia 2001; 42Suppl. 7: 93–4Google Scholar
  80. 80.
    Palmieri C, Canger R. Teratogenic potential of the newer antiepileptic drugs: what is known and how should this influence prescribing? CNS Drugs 2002; 16(11): 755–64PubMedCrossRefGoogle Scholar
  81. 81.
    Kondo T, Kaneko S, Amano Y, et al. Preliminary report on teratogenic effects of zonisamide in the offspring of treated women with epilepsy. Epilepsia 1996 Dec; 37: 1242–4PubMedCrossRefGoogle Scholar
  82. 82.
    Tomson T. Drug selection for the newly diagnosed patient: when is a new generation antiepileptic drug indicated? J Neurol 2004; 251: 1043–9PubMedCrossRefGoogle Scholar
  83. 83.
    Seino M. Review of zonisamide development in Japan. Seizure 2004; 13 Suppl.: S2–4PubMedCrossRefGoogle Scholar
  84. 84.
    Sirven JI. Antiepileptic drug therapy for adults: when to initiate and how to choose. Mayo Clin Proc 2002 Dec; 77(12): 1367–75PubMedCrossRefGoogle Scholar
  85. 85.
    LaRoche SM, Helmers SL. The new antiepileptic drugs: clinical applications. JAMA 2004 Feb; 291(5): 615–20PubMedCrossRefGoogle Scholar
  86. 86.
    Arroyo S, Kramer G. Treating epilepsy in the elderly: safety considerations. Drug Saf 2001; 24(13): 991–1015PubMedCrossRefGoogle Scholar
  87. 87.
    Chadwick D. Standard approach to antiepileptic drug treatment in the United Kingdom. Epilepsia 1994; 35Suppl. 4: S3–10PubMedCrossRefGoogle Scholar
  88. 88.
    Perucca E, Dulac O, Shorvon S, et al. Harnessing the clinical potential of antiepileptic drug therapy: dosage optimisation. CNS Drugs 2001; 15(8): 609–21PubMedCrossRefGoogle Scholar
  89. 89.
    Burdette DE. Overall effectiveness of zonisamide therapy on a slow, low-dose titration schedule [abstract no. 2.075]. Epilepsia 2000; 41 Suppl. 7: 108–9Google Scholar
  90. 90.
    Uthman BM, Miller GS, Montouris G, et al. Safety of 25- and 50-mg capsules in the initiation of zonisamide therapy in patients with epilepsy: an uncontrolled, open-label study. Curr Med Res Opin 2004 Jun; 20(6): 837–42PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, AucklandNew Zealand

Personalised recommendations