Zonisamide
1,2-benzisoxazole-3-methanesulfonamide
Also known as: Zonegran · Excegran · AD-810 · CI-912 · PD-110843 · Zonisamidum
Reviewed by the VetSheet Veterinary TeamUpdated Apr 5, 2026Evidence-based veterinary reference
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Dosing by species
🌎 NA — North America🌍 EU — Europe
Dogs
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| Refractory epilepsy (with phenobarbital) | 5-10 mg/kg PO q12h | PO | q12h | — | 🌎 NA |
| Monotherapy | Initially at 5 mg/kg PO twice daily (q12h) | PO | q12h | — | 🌎 NA |
| Add-on with phenobarbital | 10 mg/kg PO q12h | PO | q12h | — | 🌎 NA |
| Initial monotherapy | 3-5 mg/kg PO q12h | PO | q12h | — | 🌎 NA |
| Add-on agent | 10 mg/kg PO q12h | PO | q12h | — | 🌎 NA |
| Epilepsy | 5-10 mg/kg PO q12h | PO | q12h | — | 🌎 NA |
| Epilepsy (monotherapy or adjunctive) | 5-10 mg/kg | PO | q12h | Long-term | 🌍 EU |
- Refractory epilepsy (with phenobarbital): The high end of the dose range is needed when used in combination with phenobarbital due to microsomal enzyme induction.
- Epilepsy: Gradual adaptation in dosing is recommended. Reduce phenobarbital doses by 25% at the time of starting zonisamide.
- Epilepsy (monotherapy or adjunctive): Start at 5 mg/kg q12h. If the dog is concurrently receiving phenobarbital, start at 10 mg/kg q12h due to induced metabolism.
Cats
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| Epilepsy (anecdotal) | 5 mg/kg PO every 12-24 hours | PO | q12-24h | — | 🌎 NA |
| Refractory to phenobarbital | 5-10 mg/kg PO once daily | PO | q24h | — | 🌎 NA |
| Epilepsy | 10-20 mg/kg PO once daily | PO | q24h | — | 🌎 NA |
| Epilepsy | 5-10 mg/kg | PO | q24h | Long-term | 🌍 EU |
- Epilepsy (anecdotal): Most commonly utilized anecdotal dose.
- Refractory to phenobarbital: Long half-life makes once daily dosing likely appropriate.
- Epilepsy: Longer half-life in cats allows for once-daily dosing.
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Overview
Zonisamide is a benzisoxazole-derivative, sulfonamide-based anticonvulsant used primarily in veterinary medicine as an 'add-on' drug for refractory idiopathic epilepsy, or as a first-line monotherapy in dogs and cats.
- Clinical Pearl: Because it undergoes less hepatic metabolism than phenobarbital, it is often preferred in patients where avoiding hepatotoxicity is a priority.
- It has a favorable pharmacokinetic profile in small animals, with a half-life of approximately 15 hours in dogs (allowing twice-daily dosing) and 33 hours in cats (allowing once-daily dosing).
- Unlike humans, zonisamide exhibits linear pharmacokinetics in dogs at standard doses.
Mechanism of action
The exact mechanism of action is multifactorial and not completely elucidated:
- Blocks voltage-gated sodium channels and reduces transient inward currents → stabilizes neuronal membranes and suppresses neuronal hypersynchronization.
- Inhibits T-type voltage-gated calcium channels.
- Acts as a weak carbonic anhydrase inhibitor.
- Note: Unlike diazepam or phenobarbital, it does not appear to potentiate GABAergic activity.
Safety & warnings
Contraindications
- Hypersensitivity to zonisamide
- Hypersensitivity to sulfonamide drugs
- Pregnancy (known teratogen in dogs)
- Hypersensitivity to sulfonamides
- Severe hepatic impairment
Adverse effects
- Sedation (usually transient)
- Ataxia
- Inappetence / Anorexia
- Vomiting
- Diarrhea
- Somnolence
- Keratoconjunctivitis sicca (KCS) - theoretical risk due to sulfonamide structure
- Polyarthropathy or blood dyscrasias - theoretical risk due to sulfonamide structure
- Hepatotoxicity (rare)
- Metabolic acidosis
Precautions
Teratogenic Risk: Zonisamide is a known teratogen in dogs. Doses of 10-30 mg/kg/day have caused ventricular septal defects, cardiomegaly, and valvular/arterial anomalies (threshold plasma level for malformation is 25 mcg/mL). Use in pregnant dogs carries significant risks.
- Sulfonamide Sensitivity: Because it is a sulfonamide, monitor for idiosyncratic sulfonamide reactions (e.g., KCS, blood dyscrasias), though clinical reports in veterinary patients are currently rare.
- Use with caution in nursing animals as it is unknown if it enters maternal milk.
Drug interactions
Increases the clearance of zonisamide. Repeated phenobarbital dosing decreases the bioavailability, peak concentrations, half-life, and AUC of zonisamide. This effect can persist up to 10 weeks after phenobarbital discontinuation. Higher zonisamide doses are typically required.
May inhibit the hepatic metabolism of zonisamide, potentially increasing serum concentrations.
Monitoring
- Clinical efficacy (seizure frequency and severity)
- Serum zonisamide concentrations (suggested therapeutic range in dogs: 10-40 mcg/mL)
- Adverse effects (sedation, ataxia, GI upset)
- Schirmer tear test (monitor for KCS due to sulfonamide structure)
- Serum zonisamide concentrations (therapeutic target typically 10-40 µg/mL)
- Schirmer Tear Test (STT) periodically
- Liver enzymes and bilirubin
- Complete Blood Count (CBC)
Pharmacokinetics
Half-life
Absorption
Well absorbed after oral administration in dogs with a bioavailability of about 70%. Can also be absorbed rectally.
Distribution
Low protein binding.
Metabolism
About 20% is metabolized, primarily in the liver.
Elimination
Most of the drug is excreted via the kidneys into the urine.
Overdose
The LD50 of zonisamide in dogs is reportedly 1 gram/kg.
In human overdoses, reported effects include coma, bradycardia, hypotension, and respiratory depression.
Treatment:
- GI evacuation if ingestion was recent.
- Supportive and symptomatic therapy.
- Because of the drug's long half-life, supportive care may be required for several days.
Available products
Formulations
- Capsules: 25 mg, 50 mg, 100 mg
- 25 mg capsule
- 50 mg capsule
- 100 mg capsule
Human-labeled
- Zonisamide Capsules: 25 mg, 50 mg & 100 mg (Zonegran®, generic)
- Zonegran 25 mg capsules
- Zonegran 50 mg capsules
- Zonegran 100 mg capsules
Regulatory status
Human authorized product (Zonegran) used off-label under the cascade.
Human authorized product (Zonegran) used off-label under the cascade.
No regulatory data for: 🇺🇸 US · 🇭🇰 HK · 🇹🇼 TW · 🇯🇵 JP · 🇰🇷 KR · 🇦🇺 AU
Storage & stability
Store capsules at 25°C (76°F); excursions permitted to 15-30°C (59-86°F). Store in a dry place and protect from light.
Client information
- Strict Schedule: Give this medication exactly as prescribed. Missed doses can lead to breakthrough seizures.
- Do Not Stop Abruptly: Sudden discontinuation can cause severe "rebound" seizures. Always consult your veterinarian before changing the dose.
- Seizure Diary: Keep a detailed log of any seizure activity (date, time, duration, severity) to help your veterinarian adjust the dose accurately.
- Side Effects: Mild sleepiness or clumsiness may occur initially but usually improves as your pet adjusts to the medication. Contact your vet if your pet stops eating, vomits, or develops red/dry eyes.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturer’s current label.