Zonisamide (Zonegran)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Partial-onset (focal) seizures with or without secondary generalization | Adults and patients ≥16 years | Adjunctive therapy | FDA Approved |
Zonisamide was first approved in the United States in 2000 as adjunctive therapy for partial-onset seizures in adults. The FDA-approved oral suspension formulation (Zonisade) was approved in 2022 for adults and pediatric patients aged 16 years and older. Efficacy was established across three pivotal multicenter, placebo-controlled trials in 499 patients with refractory partial-onset seizures, demonstrating median seizure frequency reductions of 27–41% in the zonisamide groups versus –3% to 9% in the placebo groups, with ≥50% responder rates of 28–42% versus 12–22%. Notably, there was no apparent difference between once-daily and twice-daily dosing regimens in these trials. Although only approved for adjunctive use, zonisamide is used as monotherapy in clinical practice, particularly in regions outside the US.
Monotherapy for focal epilepsy — The SANAD-II trial and other controlled data support zonisamide as first-line monotherapy for focal seizures, and it is licensed for monotherapy in Europe and Japan. Evidence quality: High (RCT data from SANAD-II).
Generalized epilepsy syndromes (including infantile spasms) — Japanese and international observational studies report efficacy in generalized tonic-clonic seizures and infantile spasms at 2–12 mg/kg/day. Evidence quality: Low (open-label data, no large RCTs).
Adjunctive therapy for Parkinson disease — Zonisamide 25–50 mg/day is approved in Japan for Parkinson disease wearing-off. Randomized trials show modest improvement in motor symptoms. Evidence quality: Moderate (RCTs in Japanese populations).
Weight management — Weight loss is a common pharmacological effect, and zonisamide has been studied in combination with bupropion for obesity. Evidence quality: Low.
Migraine prophylaxis — Small controlled trials suggest efficacy at 100–300 mg/day, though the drug is not FDA-approved for this indication. Evidence quality: Low.
Dosing
Adult Dosing (≥16 Years)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Focal epilepsy — adjunctive therapy, drug-resistant | 100 mg/day | 200–400 mg/day | 600 mg/day | Increase by 100 mg/day every 2 weeks; no clear added benefit above 400 mg/day in controlled trials QD or BID dosing; take with or without food |
| Focal epilepsy — monotherapy (off-label, supported by SANAD-II) | 100 mg/day | 300–500 mg/day | 600 mg/day | Titrate as per adjunctive regimen; SANAD-II used 300–500 mg/day target range Licensed as monotherapy in EU and Japan |
| Elderly patients (≥65 years) | 100 mg/day | 100–300 mg/day | 400 mg/day | Start low and titrate cautiously; greater frequency of hepatic, renal, or cardiac impairment Limited Phase 3 data in this population |
| Concurrent enzyme-inducing AEDs (phenytoin, carbamazepine, phenobarbital) | 100 mg/day | 300–500 mg/day | 600 mg/day | Half-life reduced to 27–38 h; higher maintenance doses may be needed Monitor serum levels if available (target 20–30 µg/mL) |
| Renal impairment (CrCl <50 mL/min) | Use not recommended | Insufficient data on dosing and toxicity in renal failure; AUC increases by ~35% with marked impairment (CrCl <20 mL/min) Low protein binding suggests dialysis may remove zonisamide | ||
Zonisamide has one of the longest plasma half-lives (~63 hours) of any antiseizure medication, reaching steady state in approximately 14 days. This supports once-daily dosing in many patients, improving adherence. However, it also means that dose adjustments should not be made more frequently than every two weeks, and adverse effects from a dose increase may take days to manifest. The extensive erythrocyte binding (8-fold higher than plasma) acts as a drug reservoir, contributing to the prolonged elimination and stable plasma concentrations.
Pharmacology
Mechanism of Action
Zonisamide is a 1,2-benzisoxazole derivative with a multi-modal mechanism of action that is not fully elucidated. It blocks voltage-gated sodium channels and reduces low-threshold T-type calcium currents, stabilising neuronal membranes and suppressing the hypersynchronised firing that underlies seizure propagation. Additionally, zonisamide allosterically binds to the GABA/benzodiazepine receptor complex without augmenting chloride flux, and facilitates both dopaminergic and serotonergic neurotransmission as demonstrated in microdialysis studies. It also acts as a weak carbonic anhydrase inhibitor, which does not appear to directly contribute to seizure control but accounts for several clinically relevant metabolic effects including metabolic acidosis and reduced sweating.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid; Tmax 2–6 h; dose-proportional 200–400 mg; food delays Tmax to 4–6 h without affecting extent | Can be taken with or without food; disproportionate increase at 800 mg due to saturable RBC binding |
| Distribution | Vd ~1.45 L/kg; 40% plasma protein binding; extensive RBC binding (8-fold higher concentration than plasma) | RBC reservoir contributes to prolonged elimination; protein binding is not displaced by PHT, PB, or CBZ |
| Metabolism | CYP3A4-mediated reduction to SMAP (50% of dose as glucuronide); N-acetyltransferase acetylation (15%); 35% excreted unchanged | CYP3A4 inducers (CBZ, PHT, PB) reduce half-life to 27–38 h; does not induce own metabolism; CYP3A4 inhibitors have no clinically significant effect |
| Elimination | t½ ~63 h (plasma), ~105 h (RBCs); 62% urinary (35% unchanged), 3% fecal; plasma clearance 0.30–0.35 mL/min/kg (non-induced); renal clearance ~3.5 mL/min | Steady state in ~14 days; supports QD dosing; clearance increases to 0.5 mL/min/kg with enzyme-inducing AEDs; dialysis may be effective given low protein binding |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Somnolence | 17% (vs 7% placebo) | Dose-related; most frequent at 300–500 mg/day; tends to occur within the first month and was a leading cause of discontinuation |
| Anorexia / decreased appetite | 13% (vs 6% placebo) | Often accompanied by weight loss (>5 lbs in 21.6% of zonisamide-treated patients vs 10.4% placebo); may be therapeutically advantageous in overweight patients |
| Dizziness | 13% (vs 7% placebo) | Usually mild-to-moderate; dose-related; contributes to falls in elderly patients on polytherapy |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Agitation / irritability | 9% (vs 4% placebo) | Part of the broader psychiatric adverse effect profile; monitor mood at each visit |
| Nausea | 9% (vs 6% placebo) | Usually transient; may improve if taken with food |
| Headache | 10% (vs 8% placebo) | Marginal difference from placebo; generally mild |
| Fatigue / asthenia | 7% (vs 5% placebo) | Overlaps with somnolence; occurs within first month; dose-related at 300–500 mg/day |
| Ataxia | 6% (vs 1% placebo) | Significant excess over placebo; dose-related; leading cause of discontinuation (combined with somnolence/fatigue: 6%) |
| Difficulty concentrating | 6% (vs 2% placebo) | Occurred in first month; associated with doses above 300 mg/day; part of the cognitive dysfunction profile |
| Difficulty with memory | 6% (vs 2% placebo) | May be dose-limiting at higher doses; distinguish from baseline cognitive effects of epilepsy |
| Depression | 6% (vs 3% placebo) | 2.2% discontinued or were hospitalised vs 0.4% placebo; 1.0% hospitalised for depression or suicide attempts |
| Insomnia | 6% (vs 3% placebo) | Evening dosing may exacerbate; consider switching to morning administration |
| Diplopia | 6% (vs 3% placebo) | More common in polytherapy; generally resolves with dose reduction |
| Abdominal pain | 6% (vs 3% placebo) | Consider metabolic acidosis or kidney stone as possible underlying causes |
| Speech abnormalities | 5% (vs 2% placebo) | Word-finding difficulty; tended to occur after 6–10 weeks at doses above 300 mg/day |
| Diarrhea | 5% (vs 2% placebo) | Usually mild and self-limiting |
| Mental slowing | 4% (vs 2% placebo) | Associated with doses above 300 mg/day; occurred in first month of treatment |
| Weight loss | 3% (vs 2% placebo) | Weight loss >5 lbs reported in 21.6% of zonisamide-treated patients (vs 10.4% placebo) in pivotal study |
| Rash | 3% (vs 2% placebo) | 2.2% discontinued due to rash in controlled trials (vs 0% placebo); 85% occur within 16 weeks; evaluate for SJS/TEN immediately |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Stevens-Johnson syndrome / toxic epidermal necrolysis | Rare (46 per million patient-years, Japan postmarketing; 7 fatalities) | 85% within 16 weeks (US/EU); 90% within 2 weeks (Japan) | Discontinue immediately at first sign of rash unless clearly not drug-related; do not rechallenge |
| Aplastic anemia | Very rare (2 confirmed cases, Japan postmarketing) | Variable | Obtain urgent CBC; discontinue zonisamide; haematology referral |
| Agranulocytosis | Very rare (3 confirmed cases across all programs) | Variable | Discontinue; monitor for infection; haematology consultation |
| DRESS / multi-organ hypersensitivity | Rare (postmarketing reports; some fatal) | Typically 2–8 weeks | Discontinue if no alternative aetiology; evaluate for hepatitis, nephritis, haematologic abnormalities |
| Metabolic acidosis | Common (21–43% adults; up to 90% pediatric at higher doses) | Early in treatment; can occur at any time; dose-dependent | Measure serum bicarbonate at baseline and periodically; consider dose reduction, alkali supplementation, or discontinuation if persistent |
| Kidney stones (nephrolithiasis) | 4% of adults; 8% pediatric (by ultrasound) | Most common between 6–12 months of use | Encourage adequate hydration; investigate flank/abdominal pain promptly; stones are calcium or urate composition |
| Oligohidrosis and hyperthermia | Uncommon (~12 per 10,000 patient-years, US postmarketing); primarily pediatric | Any time; worse in warm weather | Monitor for decreased sweating and fever, especially in pediatric patients and warm climates; may require hospitalisation for heat stroke |
| Acute myopia / secondary angle-closure glaucoma | Rare (postmarketing) | Typically within 1 month of initiation | Discontinue zonisamide rapidly; ophthalmology referral; untreated elevated IOP can cause permanent vision loss |
| Suicidal behaviour / ideation | 0.43% (AED class risk) | Within first week; persists during treatment | Monitor mood at every visit; balance risk against untreated epilepsy |
| Hyperammonemia / encephalopathy | Rare (postmarketing) | Variable | Check ammonia if encephalopathic symptoms develop; risk increased with concomitant valproate or other CAI drugs |
| Psychosis / psychotic symptoms | ~2% (2.2% discontinued or hospitalised vs 0% placebo) | Variable | Discontinue if psychotic symptoms emerge; psychiatric referral |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Somnolence / fatigue / ataxia | 6% | Combined CNS-depressant effects; dose-related; most common reason for stopping treatment |
| Anorexia | 3% | May be accompanied by clinically significant weight loss |
| Depression | 2.2% (vs 0.4% placebo) | Includes patients hospitalised for depression or suicide attempts (1.0%) |
| Psychosis / psychotic symptoms | 2.2% (vs 0% placebo) | 0.9% discontinued treatment; 1.4% hospitalised across all studies |
| Rash | 2.2% (vs 0% placebo) | Discontinuation rate of 1.4% (12.0 events per 1000 patient-years) across all US/EU trials |
Zonisamide causes hyperchloraemic, non-anion gap metabolic acidosis through inhibition of renal carbonic anhydrase. This is dose-dependent and can occur at doses as low as 25 mg/day. In adults, serum bicarbonate decreases by approximately 2 mEq/L at 100 mg/day and nearly 4 mEq/L at 300 mg/day. Pediatric patients are disproportionately affected, with up to 90% developing bicarbonate levels below 20 mEq/L at higher doses. Chronic untreated acidosis increases the risk for kidney stones, osteomalacia, and reduced growth in children. Measure baseline serum bicarbonate before starting therapy, recheck periodically, and consider alkali supplementation or dose reduction if persistent acidosis develops.
Drug Interactions
Zonisamide is metabolised primarily by CYP3A4 and N-acetyltransferase. It does not induce its own metabolism and shows negligible inhibition of major CYP isoenzymes. Its main interaction vulnerability is susceptibility to CYP3A4 inducers, which substantially reduce its plasma half-life. As a carbonic anhydrase inhibitor, concurrent use with other such agents carries additive metabolic risk.
Zonisamide does not meaningfully affect plasma levels of carbamazepine, lamotrigine, phenytoin, or valproic acid at steady state. It does not affect serum concentrations of ethinylestradiol or norethisterone in combined oral contraceptives. At therapeutic concentrations, zonisamide shows negligible (<25%) inhibition of CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4, 2B6, and 2C8.
Monitoring
-
Serum Bicarbonate
Baseline, then periodically
Routine Essential for detecting metabolic acidosis. Recheck at 1–3 months, then at least annually. More frequent monitoring in pediatric patients, patients on ketogenic diet, or those on concomitant carbonic anhydrase inhibitors. -
Renal Function
Baseline, then annually
Routine Serum creatinine and BUN. Zonisamide causes a persistent ~8% increase in creatinine (effect on GFR). Discontinue if clinically significant sustained increase or acute renal failure occurs. Avoid use if GFR <50 mL/min. -
Seizure Frequency
Every visit
Routine Seizure diary review. Remember steady state takes ~14 days; assess efficacy no sooner than 2 weeks after each dose change. -
Mood & Cognition
Every visit
Routine Screen for depression, suicidal ideation, psychomotor slowing, memory difficulty, and word-finding problems. Psychiatric discontinuation rate was 2.2% for both depression and psychosis. -
CBC
Baseline, then as clinically indicated
Trigger-based Obtain if fever, sore throat, oral ulcers, or easy bruising develop. Aplastic anaemia and agranulocytosis have been reported (rare, sulfonamide class effect). -
Body Temperature / Sweating
Ongoing (especially warm weather)
Trigger-based Particularly important in pediatric patients and those on concomitant anticholinergics or other carbonic anhydrase inhibitors. Decreased sweating may lead to heat stroke requiring hospitalisation. -
Eye Symptoms
First month, then as clinically indicated
Trigger-based Acute myopia and secondary angle-closure glaucoma typically occur within one month of starting. Advise patients to report sudden visual changes or eye pain immediately. -
Weight
Every visit
Routine Weight loss is common; >5 lbs in ~22% of treated patients. Monitor nutritional status, particularly in underweight patients and the elderly.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to sulfonamides or zonisamide — Cross-reactivity with sulfonamide antibiotics is possible, though the actual risk of cross-allergy between antibiotic and non-antibiotic sulfonamides is debated. Fatalities have occurred from sulfonamide-type reactions.
Relative Contraindications (Specialist Input Recommended)
- Renal failure (estimated GFR <50 mL/min) — Insufficient data regarding dosing and toxicity; AUC increases by 35% with CrCl <20 mL/min; increased risk of metabolic acidosis and nephrolithiasis.
- Severe metabolic acidosis — Existing acidosis may be worsened; zonisamide can decrease bicarbonate at doses as low as 25 mg/day.
- Active suicidal ideation — All AEDs carry a class-wide suicidality risk; 2.2% of zonisamide patients discontinued or were hospitalised for depression.
- Pregnancy or planned pregnancy — Teratogenic in animals at plasma levels similar to or lower than therapeutic human levels; cardiovascular defects and embryo-fetal deaths observed.
Use with Caution
- History of nephrolithiasis — Kidney stones developed in 4% of adults; maintain adequate hydration.
- History of psychiatric illness — Depression (6%), psychosis (2%), and cognitive dysfunction (6%) were common in controlled trials.
- Hepatic impairment — PK not formally studied in hepatic disease; zonisamide is extensively hepatically metabolised.
- Pediatric patients (<16 years) — Not FDA-approved in this population; increased risk for oligohidrosis, hyperthermia, metabolic acidosis, and reduced growth.
- Elderly patients — Start at low end of dosing range; greater frequency of decreased hepatic, renal, or cardiac function.
- Patients on ketogenic diet — Additive risk of metabolic acidosis.
Pooled analysis of 199 placebo-controlled trials of 11 different AEDs demonstrated approximately double the risk of suicidal thinking or behaviour compared with placebo (adjusted RR 1.8; 95% CI 1.2–2.7). The estimated incidence was 0.43% in AED-treated patients versus 0.24% in those receiving placebo. The increased risk was observed as early as one week after treatment initiation.
Fatalities have occurred from severe reactions to sulfonamides, including SJS/TEN, fulminant hepatic necrosis, agranulocytosis, and aplastic anaemia. In postmarketing experience from Japan, 7 deaths from SJS/TEN and 49 total cases were reported (rate ~46 per million patient-years). These reactions may occur when a sulfonamide is re-administered regardless of route. Discontinue zonisamide immediately if signs of hypersensitivity appear.
Patient Counselling
Purpose of Therapy
Zonisamide is a medicine that helps control seizures by reducing abnormal electrical activity in the brain through multiple mechanisms, including blocking sodium and calcium channels. It is used alongside other seizure medications to reduce the frequency of partial-onset seizures. It does not cure epilepsy but can help provide sustained seizure control.
How to Take
Zonisamide may be taken once or twice daily, with or without food. Swallow capsules whole with liquid. If using the oral liquid (Zonisade), shake well before each dose and measure carefully with the provided device — a household spoon is not accurate enough. Discard unused liquid 30 days after opening. Drink plenty of fluids throughout the day to reduce the risk of kidney stones. Do not stop zonisamide suddenly, as this can trigger more frequent or severe seizures — always taper gradually under medical guidance.
Sources
- ZONEGRAN (zonisamide) capsules [prescribing information]. Smyrna, GA: Advanz Pharma (US) Corp.; Revised 2020. FDA Label Primary source for all dosing, PK parameters, adverse reactions, drug interactions, and warnings for the capsule formulation (original NDA).
- ZONISADE (zonisamide oral suspension) [prescribing information]. Woburn, MA: Azurity Pharmaceuticals, Inc.; Revised May 2025. DailyMed Updated labelling for the oral suspension formulation approved in 2022; includes current warnings and indications for patients ≥16 years.
- Faught E, Ayala R, Montouris GG, Leppik IE. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology. 2001;57(10):1774–1779. doi:10.1212/WNL.57.10.1774 Pivotal US placebo-controlled Phase 3 trial establishing efficacy and safety of adjunctive zonisamide in refractory partial-onset seizures.
- Sackellares JC, Ramsay RE, Wilder BJ, Browne TR, Shelton DL. Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures. Epilepsia. 2004;45(6):610–617. doi:10.1111/j.0013-9580.2004.48503.x US dose-ranging study (n=203) demonstrating efficacy across 100–400 mg/day with a dose-response relationship in refractory partial seizures.
- Marson AG, Burnside G, Appleton R, et al. The SANAD II study of the effectiveness of zonisamide, or lamotrigine versus levetiracetam for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet. 2021;397(10282):1363–1374. doi:10.1016/S0140-6736(21)00247-6 SANAD-II focal epilepsy arm comparing zonisamide, lamotrigine, and levetiracetam as monotherapy; supports use of zonisamide as first-line treatment for focal seizures.
- Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy. Neurology. 2018;91(2):82–90. doi:10.1212/WNL.0000000000005756 AAN/AES guideline reviewing evidence for newer AEDs in treatment-resistant epilepsy; Level B recommendation for adjunctive zonisamide.
- Leppik IE. Zonisamide: chemistry, mechanism of action, and pharmacokinetics. Seizure. 2004;13(Suppl 1):S5–S9. doi:10.1016/j.seizure.2004.04.016 Comprehensive review of zonisamide pharmacology including sodium channel blockade, T-type calcium current reduction, and carbonic anhydrase inhibition.
- Biton V. Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol. 2007;30(4):230–240. doi:10.1097/wnf.0b013e3180413d7d Detailed review of the multiple mechanisms of action and their relationship to clinical efficacy and side effect profile.
- Sills GJ, Brodie MJ. Pharmacokinetics and drug interactions with zonisamide. Epilepsia. 2007;48(3):435–441. doi:10.1111/j.1528-1167.2007.00983.x Key PK review detailing CYP3A4-dependent metabolism, RBC binding kinetics, and drug interaction profile with concomitant AEDs.
- Kothare SV, Kaleyias J. Zonisamide: review of pharmacology, clinical efficacy, tolerability, and safety. Expert Opin Drug Metab Toxicol. 2008;4(4):493–506. doi:10.1517/17425255.4.4.493 Comprehensive review of PK in special populations including pediatric, elderly, and renal impairment.
- Gidal BE, Resnick T, Smith MC, Wheless JW. Zonisamide: a comprehensive, updated review for the clinician. Neurol Clin Pract. 2024;14(1):e200210. doi:10.1212/CPJ.0000000000200210 Most recent comprehensive clinical review covering contemporary prescribing practice, off-label uses, and safety updates.
- Janković SM. Evaluation of zonisamide for the treatment of focal epilepsy: a review of pharmacokinetics, clinical efficacy and adverse effects. Expert Opin Drug Metab Toxicol. 2020;16(3):169–177. doi:10.1080/17425255.2020.1729739 Recent focused review of zonisamide PK and tolerability profile in focal epilepsy populations.