Zonisamide

Overview

Zonisamide (Zonegran®) is a sulfonamide anticonvulsant used in dogs and cats for the management of seizure disorders. It is most commonly administered as adjunctive therapy in patients that remain poorly controlled despite standard anticonvulsant treatment, although some clinicians may also use it as part of primary seizure management protocols.

In dogs, zonisamide is generally well absorbed after oral administration and has an elimination half-life of approximately 15–17 hours, allowing convenient maintenance dosing. The drug undergoes hepatic metabolism with subsequent renal excretion of metabolites.

Mechanism of Action (MOA): The exact anticonvulsant mechanism of zonisamide is not fully understood. Zonisamide primarily exerts its anticonvulsant effects by blocking voltage-gated sodium channels and T-type calcium channels, thereby reducing neuronal hyperexcitability. Although earlier veterinary references suggested that zonisamide may enhance GABA-mediated neurotransmission, more recent evidence indicates that it does not appear to directly potentiate GABA activity.

 CA inhibition + free-radical scavenging: zonisamide additionally has carbonic anhydrase inhibitory activity and can scavenge for free radicals in the brain — two MOA components beyond ion-channel block. The CA-inhibitor activity is clinically relevant to the metabolic-acidosis + kidney-stone interaction with acetazolamide and other CAIs. zonisamide may potentiate serotoninergic and dopaminergic neurotransmission — these monoamine effects complement the primary ion-channel mechanism and may contribute to the behavioural changes documented in long-term use.

 Detailed dog PK: Oral bioavailability 68%; volume of distribution 0.8 L/kg; average protein binding 40%; Tmax 0.44 h after single oral dose; Cmax 14.4 µg/mL single dose rising to 58 µg/mL after 8 weeks of repeated administration. Plasma clearance 32 mL/h/kg. Plasma half-life 17.2 h single dose lengthens to 23 h with chronic dosing; whole blood / RBC concentrations exceed plasma (RBC t½ ~37 h).

Cat PK distinct from dog: Cat PK — onset of action 4 hours; half-life 33 hours (vs 15-17 h dog) allowing once-daily dosing; steady state reached within 7 days. whole-blood and RBC concentrations of zonisamide are higher than plasma in cats — coordinate sample type with the lab when ordering TDM.

Renal/hepatic split + linear PK: In dogs approximately 80% of zonisamide is excreted unchanged via the kidneys and 20% is metabolized primarily in the liver.

 Rectal route FAILS: Rectal administration of zonisamide (10-30 mg/kg) FAILS to reach therapeutic plasma concentrations and is NOT recommended. Use intranasal or IV midazolam / diazepam for emergency seizure abortion instead, and reserve oral zonisamide for maintenance.

Indications

Zonisamide is used in dogs and cats for the management of seizure disorders, particularly in patients requiring additional anticonvulsant support beyond standard therapy. It is most commonly administered as part of long-term seizure control protocols.

• Adjunctive anticonvulsant therapy: Commonly used in dogs with refractory or poorly controlled epilepsy despite treatment with conventional anticonvulsants such as phenobarbital, potassium bromide, or other antiseizure medications.
• Monotherapy in canine idiopathic epilepsy: Monotherapy use in canine idiopathic epilepsy is supported by 58–81% response rates in open-label studies. zonisamide is a first-line option when seizure frequency is <1 per week. Reasonable initial choice for newly-diagnosed dogs not requiring loading.
• Feline seizure use — 2024 evidence: Feline seizure control with zonisamide is supported by growing 2024 evidence — the drug was well tolerated and efficacious in controlling seizure activity in most cats. zonisamide is increasingly used as a first-choice ASM in dogs and cats.

Dosage (Reference)

Dog

In dogs, zonisamide is most commonly used as an adjunctive anticonvulsant for long-term seizure management. Dose adjustments may be necessary when administered concurrently with hepatic enzyme–inducing anticonvulsants such as phenobarbital.

Cat

Clinical experience with zonisamide in cats is more limited than in dogs. Conservative dosing and careful monitoring are recommended during long-term anticonvulsant therapy.

Warnings & Precautions

Zonisamide is generally well tolerated in dogs and cats, but careful monitoring is recommended during long-term anticonvulsant therapy due to potential neurologic, hepatic, and gastrointestinal adverse effects.

• Hepatic impairment: Use cautiously in animals with hepatic dysfunction, as zonisamide undergoes hepatic metabolism. Avoid use in patients with severe hepatic disease.
• Abrupt discontinuation: Do not discontinue therapy suddenly, as rapid withdrawal may precipitate breakthrough seizures or worsening seizure activity.
• Pregnancy: Avoid use in pregnant animals due to evidence of toxicity in experimental studies.
• Renal elimination: Because metabolites are primarily excreted by the kidneys, use cautiously in patients with significant renal dysfunction.
• Neurologic depression: Sedation, ataxia, and lethargy may occur, particularly during initiation of therapy or dose escalation.
• Appetite and gastrointestinal effects: Monitor for vomiting, anorexia, and weight loss, especially during the early stages of treatment.
• Long-term monitoring: Periodic hepatic and hematologic monitoring is recommended during prolonged therapy due to reports of mild laboratory abnormalities in experimental studies.
• Sulfonamide derivative: Zonisamide is a sulfonamide anticonvulsant; use cautiously in patients with previous sulfonamide hypersensitivity reactions.
• TERATOGEN in dogs at therapeutic doses: Pregnant dogs receiving zonisamide 10 or 30 mg/kg/day showed ventricular septal defects, cardiomegaly, and various valvular and arterial anomalies in offspring (higher dose). Plasma zonisamide concentration of 25 µg/mL is the threshold for malformation. Counsel owners of intact breeding bitches about this risk; AVOID in any pregnant patient.
• NIOSH hazardous — PPE on handling: NIOSH-classified HAZARDOUS DRUG — the National Institute for Occupational Safety and Health classifies zonisamide as a hazardous drug (nonantineoplastic agent representing an occupational hazard to healthcare workers). Use PPE (gloves at minimum) when handling capsules/oral solution, especially in pregnancy (drug is teratogenic) or when handling patient excreta. Counsel owners similarly.
• Rare AEs — hepatopathy/calculi/ATA/behavior: Rare-but-recognized AEs — idiosyncratic acute hepatic necrosis, pseudolymphoma, urinary calculi, hepatopathy, acute tubular acidosis (clinically ‘renal tubular acidosis’), febrile neutropenia, erythema multiforme, and SEVERE behavioural changes (sudden aggression, insomnia, restlessness, attention-seeking) similar to human reports — signs resolve on discontinuation. Type II reactions are idiosyncratic and non-dose-dependent.
• Cat hypersensitivity — lymphadenopathy + pancytopenia: Cat-specific hypersensitivity syndrome — presumptive hypersensitivity to zonisamide resulting in lymphadenopathy and pancytopenia has been reported, albeit rarely. Stop drug immediately on suspicion and pursue alternative anticonvulsant.

Drug Interactions

Clinically important drug interactions with zonisamide primarily involve alterations in hepatic metabolism or additive central nervous system depression when used with other anticonvulsant medications.

• Phenobarbital: increases clearance of zonisamide up to 10 weeks after phenobarbital discontinuation. If using as an adjunctive to phenobarbital consider using doses at the higher end of the dose range.
• Carbonic anhydrase inhibitors (acetazolamide): Concurrent use of zonisamide with carbonic anhydrase inhibitors (e.g. acetazolamide; topiramate has similar mechanism) may increase the risk for metabolic acidosis and kidney-stone formation, because zonisamide itself has carbonic anhydrase inhibitory activity. Monitor electrolytes / blood gas and urinary calculi.
• CYP3A inducers (dexamethasone, rifampin):
  concurrent CYP3A inducers (e.g. dexamethasone, rifampin) may shorten the half-life of zonisamide and require an upward dose adjustment to maintain therapeutic levels. Consider TDM after starting any concurrent CYP3A inducer.
• Additive CNS depression with other ASMs: Additive CNS depression — zonisamide is expected to potentiate other central nervous system depressants and anticonvulsants (other ASMs, opioids, benzodiazepines, α2-agonists). Adjust dosing and monitor for excessive sedation when combining.

Side Effects & Overdose

Side Effects

Zonisamide is generally well tolerated in dogs and cats, although adverse effects may occur during treatment initiation, dose escalation, or when used in combination with other anticonvulsant medications.

• Ataxia, sedation, vomiting and anorexia have been reported in a few dogs and, experimentally, in cats.
• Doses up to 75 mg/kg q24h or divided q12h have been used experimentally for up to 52 weeks in dogs; initially there was weight loss and, in the longer term, minor hepatic and hematological changes.
• Acute hepatopathy <1% first 3 weeks: Less than 1% of dogs experienced acute, potentially life-threatening hepatopathy associated with oral zonisamide therapy within the first 3 weeks of therapy — this is the highest-risk window for idiosyncratic hepatotoxicity. Subclinical ALT/ALP abnormalities occurred in less than 10% of dogs during long-term therapy without clinical liver disease.
• Thyroid effects — ↓ T4: Thyroid effects — zonisamide can decrease total T4 in dogs (one study showed reduction; free T4 slightly decreased but remained within reference range). Consider periodic T4 monitoring on long-term therapy; do NOT diagnose hypothyroidism on T4 alone in a zonisamide-treated dog without additional testing.

Overdose

Information regarding zonisamide overdose in veterinary patients is limited, but excessive dosing is expected to produce exaggerated neurologic and gastrointestinal effects.

• Marked CNS depression: Severe sedation, lethargy, weakness, or ataxia may develop following overdose.
• Gastrointestinal signs: Vomiting, anorexia, and gastrointestinal upset may occur.
• Supportive care: Treatment is primarily supportive and may include fluid therapy, monitoring of neurologic status, and symptomatic management.
• Monitoring: Hepatic and renal parameters should be monitored in significant overdoses due to hepatic metabolism and renal excretion of metabolites.
• Dog LD50 1 g/kg + human 7.5 g survival: The dog LD50 of zonisamide is approximately 1 g/kg, and human patients have survived overdoses of up to 7.5 g (total dose) without complications. Supportive care may be required for SEVERAL DAYS due to the drug’s long half-life. Call a 24-hour veterinary poison consultation centre for case-specific guidance.

Key Notes

Practical clinical considerations that may help optimize the safe and effective use of zonisamide in dogs and cats during long-term anticonvulsant therapy:

• Adjunctive role: Zonisamide is most commonly incorporated into multimodal anticonvulsant protocols when seizure control with standard therapy alone is inadequate.
• Dosing convenience: The relatively long elimination half-life allows practical maintenance dosing schedules in many patients.
• Therapeutic response: Clinical response may vary considerably between individuals, and some patients require gradual dose titration to achieve optimal seizure control.
• Monitoring seizure trends: Owners should be encouraged to maintain a seizure log to help assess long-term treatment efficacy and identify changes in seizure frequency or severity.
• Combination protocols: Patients receiving multiple anticonvulsants may require periodic reassessment to balance seizure control with quality of life and medication tolerance.
• Administration consistency: Oral doses should be administered consistently at regular intervals to help maintain stable anticonvulsant activity.
• TDM target 10-40 µg/mL: Therapeutic drug monitoring — target plasma trough 10–40 µg/mL. Sample 1–2 weeks after initiating therapy or after a dose change. Use trough levels (within 1 h before next scheduled dose). Consider peak levels (3–4 h post-dose) for patients on phenobarbital with poor seizure control. Whole blood samples yield higher concentrations than plasma — coordinate sample type with the lab.
• Possible tolerance after 2-3 mo chronic: With chronic treatment, some tolerance that reduces efficacy after 2–3 months may develop. If seizure frequency starts to climb after stable control, consider TDM and possible dose adjustment rather than assuming the drug has failed.