Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures.
OBJECTIVE
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.
Brodie
Martin J
MJ
Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow, United Kingdom. Martin.J.Brodie@clinmed.gla.ac.uk
Duncan
Roderick
R
Vespignani
Herve
H
Solyom
Andras
A
Bitenskyy
Valeriy
V
Lucas
Cherry
C
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004828:Epilepsies, Partial / Q000188:drug therapy*; D017029:Epilepsy, Complex Partial / Q000188:drug therapy; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010612:Pharyngitis / Q000139:chemically induced; D010919:Placebos; D012893:Sleep Wake Disorders / Q000139:chemically induced; D016896:Treatment Outcome; D000078305:Zonisamide
D000927:Anticonvulsants; D007555:Isoxazoles; D010919:Placebos; D000078305:Zonisamide