Section 01 · Monograph

Zonisamide

Reviewed Nov 2026FDA label

ZonegranMulti-mechanism AED

Indications

Adjunctive therapy for partial-onset seizures in adults with epilepsyFDA-labeled

Sulfonamide-derivative antiseizure drug that blocks voltage-gated sodium channels and reduces T-type (low-threshold) calcium currents, stabilizing neuronal membranes and suppressing synchronized firing
Also has weak carbonic anhydrase inhibitory activity, contributing to metabolic acidosis and kidney stone risk (mechanistically similar to topiramate/acetazolamide)
Additional proposed effects include facilitation of GABAergic and dopaminergic/serotonergic neurotransmission; precise mechanism of antiseizure effect is not fully established

Adults: initiate 100mg once daily; after 2 weeks may increase to 200mg/day, with further increases of 100mg/day at intervals of ≥2 weeks (long half-life requires 2 weeks to reach new steady state)
Effective range generally 100-600mg/day; doses above 400mg/day have not shown added benefit in controlled trials and are associated with more adverse effects
Long elimination half-life (~63 hours in the absence of enzyme inducers) allows once-daily dosing but also slows response to dose changes and taper

Avoid use in patients with estimated GFR <50 mL/min given limited data; use with caution and closer monitoring in renal impairment

Known hypersensitivity to zonisamide or any component of the formulation
Hypersensitivity to sulfonamides — zonisamide is a sulfonamide derivative; cross-reactivity risk with sulfonamide antibiotics and other sulfonamide-class drugs

CYP3A4 enzyme-inducing antiseizure drugs (carbamazepine, phenytoin, phenobarbital) shorten zonisamide half-life substantially and may require dose adjustment
Concomitant use with other carbonic anhydrase inhibitors (topiramate, acetazolamide, dichlorphenamide) increases risk of metabolic acidosis and nephrolithiasis
Weak inhibitor of P-glycoprotein — caution with P-gp substrates such as digoxin
Zonisamide itself has minimal effect on the pharmacokinetics of other AEDs (lamotrigine, carbamazepine, phenytoin, valproate) or oral contraceptives

Common: somnolence, anorexia/weight loss, dizziness, ataxia, irritability/agitation, cognitive slowing and word-finding difficulty (more prominent at higher doses)
Oligohidrosis and hyperthermia, predominantly reported in pediatric patients — decreased sweating with risk of heat stroke, especially in hot weather; use caution with exercise/heat exposure and monitor closely in children
Nephrolithiasis (kidney stones) — encourage adequate hydration; risk related to metabolic acidosis and carbonic anhydrase inhibition
Metabolic (non-anion gap, hyperchloremic) acidosis due to renal bicarbonate wasting — can occur at any dose and may be associated with osteoporosis/osteomalacia and, in children, reduced growth
Serious cutaneous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (rare)
Psychiatric effects including depression and psychosis; increased risk of suicidal ideation/behavior (class effect across AEDs)
Acute myopia with secondary angle-closure glaucoma
Rare hematologic events (aplastic anemia, agranulocytosis) and hyperammonemia/encephalopathy

Baseline and periodic serum bicarbonate to detect metabolic acidosis
Renal function (BUN/creatinine); assess for signs/symptoms of nephrolithiasis and ensure adequate hydration
Body temperature and sweating, particularly in pediatric patients during exercise or hot weather
Mental status/mood for depression, psychosis, or suicidal ideation
Visual symptoms suggestive of acute angle-closure glaucoma

Teratogenic in multiple animal species at clinically relevant exposures, with cardiovascular and skeletal malformations reported; drug-associated metabolic acidosis may also impair fetal oxygenation
Encourage enrollment in the North American Antiepileptic Drug (NAAED) Pregnancy Registry (1-888-233-2334) for patients exposed during pregnancy
Zonisamide is excreted in human milk; monitor breastfed infants for adverse effects or discontinue nursing/drug based on maternal need