Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures

Epilepsia. 2005 Jan;46(1):31-41. doi: 10.1111/j.0013-9580.2005.14704.x.


Purpose: To evaluate the safety and efficacy of zonisamide (ZNS) as adjunctive treatment in patients with refractory localization-related epilepsy.

Methods: This was a double-blind, placebo-controlled study of adjunctive ZNS in 351 patients with refractory partial seizures receiving a stable regimen of one to three antiepileptic drugs (AEDs). Patients were randomized to placebo or ZNS, 100 mg, 300 mg, or 500 mg/day (2:1:1:2) after a 12-week baseline. Dose titration was undertaken over a 6-week titration phase, which was followed by an 18-week fixed-dose assessment phase. Primary efficacy parameters were the differences between ZNS, 500 mg/day, and placebo in the change from baseline in frequency of complex partial (CP) seizures during the fixed-dose assessment phase and in the proportion of CP responders (> or =50% decrease from baseline in seizure frequency). Safety and tolerability also were assessed.

Results: Compared with placebo, the highest dose of ZNS (500 mg/day) resulted in a significantly greater decrease in CP seizure frequency from baseline (51.2% vs. 16.3%; p < 0.0001) and a significantly higher proportion of CP responders (52.3% vs. 21.3%; p < 0.001). Both ZNS, 500 mg/day, and 300 mg/day were statistically superior to placebo in reducing the frequency of "all seizures" and simple partial (SP) + CP seizures. For all seizures, a significant dose-response relation was observed (p < 0.0001). The most common adverse events were somnolence, headache, dizziness, and nausea during the titration phase and headache and pharyngitis during the fixed-dose assessment phase.

Conclusions: ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Anticonvulsants / adverse effects
  • Anticonvulsants / therapeutic use*
  • Child
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Epilepsies, Partial / drug therapy*
  • Epilepsy, Complex Partial / drug therapy
  • Female
  • Headache / chemically induced
  • Humans
  • Isoxazoles / adverse effects
  • Isoxazoles / therapeutic use*
  • Male
  • Middle Aged
  • Pharyngitis / chemically induced
  • Placebos
  • Sleep Wake Disorders / chemically induced
  • Treatment Outcome
  • Zonisamide


  • Anticonvulsants
  • Isoxazoles
  • Placebos
  • Zonisamide