- 62 Downloads
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.
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.
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).
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).
KeywordsLamotrigine Adjunctive Therapy Partial Seizure Seizure Frequency Vigabatrin
- 5.Eisai Pharmaceuticals Inc. Zonegran zonisamide capsules prescribing information, Teaneck, NJ, USA. Eisai Pharmaceuticals Inc., 2004 MayGoogle Scholar
- 13.Woolf TF, Clang T. Metabolism of 14C-zonisamide in healthy volunteers [abstract no. 241]. Pharm Res 1986; 3 Suppl.: 159SGoogle Scholar
- 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.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.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.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.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.Taylor CP, McLean JR, Bockbrader HN. Zonisamide (AD-810, CI-912). Meldrum & Porter. New anticonvulsant drugs. London: John Libbey, 1986: 277–94Google Scholar
- 20.Data on file. Eisai Pharmaceuticals Inc, 2004Google Scholar
- 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.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
- 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
- 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
- 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
- 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.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.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
- 47.Fukushima K, Seino M. A long-term follow up of zonisamide monotherapy [abstract no. 1.348]. Epilepsia 2004; 45 Suppl. 7: 133Google Scholar
- 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
- 51.Morris G. The effect of zonisamide administration on patient weight. Epilepsia 2000; 41 Suppl. Florence: 39–40Google Scholar
- 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.Shellenberger K, Beck K, Oida T. Safety of zonisamide in Japanese children [abstract no. 2.036]. Epilepsia 1999; 40 Suppl. 7: 94Google Scholar
- 54.Bennett WM. Risk of kidney stones in patients treated with zonisamide [abstract no. P04.102]. Neurology 2002 Apr; 58Suppl. 3: A298Google Scholar
- 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.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.McJilton JS, Ramsay RE. Sulfa-drug allergies and zonisamide [abstract no. 3.163]. Epilepsia 2001; 42 Suppl. 7: 269Google Scholar
- 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
- 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.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.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.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.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
- 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.Konkol RJ. Pediatric experience with zonisamide in managed care [abstract no. 1.295]. Epilepsia 2001; 42Suppl. 7: 93–4Google Scholar
- 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