Clinical Medicine Insights: Therapeutics

Purpose: To provide a review of randomized controlled trials (RCTs) on the efficacy and safety of zonisamide as an adjunctive treatment for partial-onset seizures in epilepsy patients ages 12 years and above. Methods: Medline literature search for published double-blind RCTs involving zonisamide as adjunctive treatment for simple partial, complex partial, and secondarily generalized tonic-clonic seizures. Results: Four RCTs comprising a total of 841 patients with medically-intractable simple partial, complex partial and secondarily generalized tonic-clonic seizures were published between the years 1993 and 2005. Zonisamide doses included 0, 100, 300, 400, 500 and 600 mg/day. Median change in frequency of all partial seizures compared to baseline was a 26.9%–51.3% decrease at zonisamide doses of 400–600 mg/day compared to a 4.7% increase to 18.1% decrease with placebo. Responder rates (50% reduction) for all partial seizures was 26.9%–52.5% for zonisamide at these doses versus 9.8%–22% reduction for placebo. A dose-response relationship was noted up to 500 mg/day. Seizure free rates during the double blind treatment phases were 5%–6.2% for full-dose zonisamide versus 2% for placebo in two of the RCTs. Side effects were mostly CNS in type: somnolence, fatigue, dizziness and ataxia. Mild weight loss and anorexia were reported. Symptomatic renal calculi and serious rashes were not reported, but a few cases of possible stones seen transiently on ultrasound occurred, in these 4 RCTs. Four deaths occurred: none were taking zonisamide, and two appeared to be related to suffocation during seizures. Suicidal ideation and behavior occurred equally in placeboand ZNS-treated subjects. Post-approval information suggests the rare occurrences of metabolic acidosis, oligohydrosis and hyperthermia, more commonly in children. Conclusion: Zonisamide at a daily dose up to 600 mg is effective and generally well tolerated as adjunctive therapy in adolescents and adults with refractory partial-onset seizures.