# Zonisamide vs Keppra for Dogs: Which Seizure Drug Fits? Zonisamide for dogs vs Keppra (levetiracetam) is a common choice owners face when a dog starts or switches seizure medication. Both are used to reduce seizure frequency, but they differ in how often they are given, how the body clears them, cost, and monitoring needs. Neither drug is automatically "better," the right fit depends on your dog's seizure pattern, other medications, liver and kidney health, and your daily routine. This article is educational and is not a substitute for veterinary diagnosis or treatment. ## Quick Answer - Zonisamide is usually given twice daily and is cleared partly by the liver, so it can interact with phenobarbital and other liver-metabolized drugs [1]. - Levetiracetam (the generic name for Keppra) is often given two to three times daily because it is cleared mainly by the kidneys, which makes it a frequent add-on drug for dogs already on phenobarbital [2]. - Zonisamide monotherapy helped about 59% of dogs with non-structural epilepsy in one large cohort, with 29% becoming seizure free and 30% having a good reduction [3]. - Levetiracetam can be given intravenously in the hospital and has been studied as an intranasal option for emergency seizure control, though that route is still research-stage [4]. - Your veterinarian sets the dose and schedule based on your dog's weight, kidney and liver values, seizure type, and other medications. Never adjust or stop a seizure drug on your own. ## What Each Drug Is and What Veterinarians Use It For Zonisamide is an antiseizure medication (often shortened to ZNS) used for long-term maintenance treatment of epilepsy in dogs. It is typically prescribed as an oral capsule or tablet. In a study of 207 dogs with non-structural epilepsy, zonisamide monotherapy produced a response in 59% of dogs, and the authors proposed a reference range for blood levels to help guide dosing [3]. Levetiracetam is the generic name for the drug many owners know as Keppra. It is used both as a maintenance antiseizure drug and, in hospital settings, as part of emergency treatment for cluster seizures or status epilepticus. Status epilepticus means a seizure lasting more than 5 minutes, or two or more seizures with incomplete recovery of consciousness between them [5]. Levetiracetam is popular as an add-on because it has limited liver metabolism and a favorable pharmacokinetic profile, which matters when a dog is already taking phenobarbital [2]. Both drugs are considered maintenance anticonvulsants. They are used to decrease how often seizures happen and how severe they are, not to cure epilepsy [5]. ## How They Work in the Body Zonisamide works on sodium and calcium channels in brain cells and has some effect on certain neurotransmitters. It is metabolized mainly by liver enzymes in the CYP450 family [1]. That detail matters because it means zonisamide competes with other drugs processed the same way. Levetiracetam works differently. It binds to a synaptic vesicle protein (SV2A) and modulates how brain cells release signaling chemicals. It is eliminated mostly unchanged by the kidneys, so the liver is not the main route of clearance [2]. This is one reason veterinarians often reach for levetiracetam when a dog is already on phenobarbital or has liver concerns. Because the two drugs act through different mechanisms, some dogs end up on both. Combination therapy is common in veterinary epilepsy care when one drug alone does not control seizures well enough. ## Zonisamide for Dogs vs Keppra: Dosing Basics ### Who decides the dose Your veterinarian does. Doses are calculated from your dog's body weight, kidney and liver function, seizure history, and any other medications. Do not use a dose from the internet, from a friend's dog, or from an old bottle. In published research, zonisamide has been studied at roughly 8 mg/kg every 12 hours as an add-on to phenobarbital, but that is a study protocol, not a prescription for your dog [1]. Levetiracetam has been studied at 30 mg/kg intravenously and intranasally in healthy dogs for emergency use, again as a research dose [4]. ### How it is given Zonisamide is given by mouth, usually twice daily. Levetiracetam is given by mouth, often two to three times daily, and can also be given intravenously in a hospital for emergency seizure control [5]. A compounded intranasal levetiracetam product has been studied in healthy dogs, but this route is not yet standard practice [4]. ### Missed doses If you miss a dose, do not double up. Call your veterinarian or your veterinary pharmacy for guidance on that specific drug and how far behind you are. Missing doses of any antiseizure medication can trigger breakthrough seizures. If your dog vomits a dose or spits out a pill, tell your vet instead of guessing. ## Side Effects: Common and Serious | Side effect | How common or serious | What to do | |---|---|---| | Sleepiness, wobbliness, unsteadiness | Common when starting or increasing a dose, often mild | Note the timing and call your vet if it does not improve or your dog seems sedated | | Vomiting, poor appetite, stomach upset | Fairly common | Call your vet, especially if it lasts more than a day | | Increased drinking and urination | Can happen, more often linked to other seizure drugs | Mention it at your next visit, or sooner if it is marked | | Elevated liver enzymes on bloodwork | Common with antiseizure drugs and often adaptive in dogs [6] | Your vet will track trends over time, not a single number | | Immune-mediated polyarthritis and anterior uveitis (joint pain, stiffness, red or painful eyes) | Rare but serious, reported as an idiosyncratic reaction to zonisamide [7] | Stop and contact your vet right away, this needs prompt evaluation | | Kidney-related changes | Levetiracetam is cleared by the kidneys, and short-term studies in dogs on phenobarbital plus levetiracetam found no significant changes in SDMA, creatinine, BUN, phosphorus, or albumin over four weeks [2] | Routine bloodwork still matters, especially in older dogs or dogs with kidney disease | | Behavior changes, agitation, or increased anxiety | Reported with antiseizure drugs in general | Call your vet, dose adjustment may help | Any antiseizure drug can cause changes in routine lab work, and the most common changes involve liver enzymes [6]. Your veterinarian will interpret those results alongside your dog's exam and history. For a deeper look at what monitoring typically involves, see [Canine Epilepsy: Antiepileptic Drug Selection and Monitoring](/knowledge/veterinary-medicine/clinical-internal-medicine/canine-epilepsy-antiepileptic-drug-selection-monitoring). ## Who Should Not Take These Drugs and What Interacts With Them Zonisamide is not the best first choice for every dog. Dogs with certain liver conditions, or those already on multiple liver-metabolized drugs, may need a different plan. A case report described a dog that developed immune-mediated polyarthritis and anterior uveitis after zonisamide was added to its seizure regimen, and both conditions resolved within weeks of stopping the drug [7]. That is a rare reaction, but it is a reason to report new joint or eye symptoms immediately. The bigger practical issue with zonisamide is drug interaction. When zonisamide was added to phenobarbital in a small group of epileptic dogs, phenobarbital blood levels rose in 9 out of 10 dogs even though the phenobarbital dose was not changed, and in 5 dogs the levels climbed above the reported hepatotoxic threshold, requiring a phenobarbital dose reduction [1]. If your dog takes both drugs, expect your vet to check phenobarbital levels after starting zonisamide. Levetiracetam has fewer liver interactions because it is not heavily metabolized by the liver [2]. That makes it a common add-on for dogs on phenobarbital or other liver-processed drugs. Because it is cleared by the kidneys, dogs with kidney disease may need dose adjustments, and your vet will factor that in. For a broader look at how these interactions are managed, see [Drug Interactions with Antiepileptic Drugs in Veterinary Patients: Managing Polypharmacy](/knowledge/veterinary-medicine/clinical-pharmacology/drug-interactions-antiepileptic-veterinary). ## Overdose and When to Call for Help If your dog gets into the pill bottle or receives more than the prescribed dose, treat it as an emergency. Signs can include heavy sedation, severe wobbliness, vomiting, agitation, or difficulty standing. Call your veterinarian or an animal poison control hotline right away. Have the bottle with you so you can tell them the drug name, strength, and how many pills may be missing. Do not wait for symptoms to appear before calling. Antiseizure drugs have a narrow margin between a therapeutic dose and a toxic one, and early guidance matters. ## Limitations and When to Contact a Veterinarian Individual cases need a veterinarian. No article can tell you which drug fits your dog, because the answer depends on seizure type, frequency, cluster history, lab work, other medications, and how your dog responds over weeks to months. Call the same day if your dog has new joint swelling or stiffness, red or painful eyes, vomiting that will not stop, marked sleepiness, or a sudden change in behavior after starting or changing a seizure medication [7]. Go to an emergency clinic now if a seizure lasts more than 5 minutes, if seizures cluster with incomplete recovery between them, or if your dog has repeated seizures in a short window [5]. These are emergencies that need injectable treatment, and levetiracetam is one of the drugs that may be used in that setting [5]. Schedule a routine visit if seizures are becoming more frequent or severe, if you are struggling to give the medication on schedule, or if you notice subtle changes like increased drinking, appetite loss, or wobbliness that is not improving. ## Frequently Asked Questions ### Is zonisamide or Keppra better for dog seizures? Neither is universally better. Zonisamide is often chosen for maintenance because it is given twice daily and has good monotherapy response rates in some dogs [3]. Levetiracetam is often chosen as an add-on because it has fewer liver interactions and can also be used in the hospital for emergencies [5][2]. Your vet picks based on your dog's full picture. ### Can zonisamide and levetiracetam be given together? Yes, they are sometimes combined. Because they work through different mechanisms and levetiracetam is not heavily liver-metabolized, the pair can make sense for dogs that need more seizure control [2]. Your vet will still monitor bloodwork and watch for added sedation or wobbliness. ### Does zonisamide affect phenobarbital levels in dogs? Yes, and this is a real concern. In one case series, adding zonisamide raised phenobarbital blood levels in most dogs even without a phenobarbital dose change, and several dogs needed their phenobarbital dose lowered [1]. If your dog takes both, expect follow-up bloodwork. ### How often is Keppra given to dogs? Levetiracetam is usually given by mouth two to three times daily for maintenance, and it can be given intravenously in a hospital for emergency seizure control [5]. The exact schedule depends on your dog's response and your vet's plan. ### What monitoring do these drugs need? Your vet will typically check bloodwork to watch liver values, kidney values, and drug levels when relevant. Antiseizure drugs commonly cause liver enzyme changes on lab work, and those changes are often adaptive in dogs instead of a sign of true liver damage [6]. Monitoring schedules vary, so ask your vet what to expect for your dog. For more on zonisamide dosing and liver safety, see [Zonisamide Seizure Dogs: Modern Anti-Seizure Dose and Liver Safety](/knowledge/veterinary-medicine/calculators-clinical-tools/zonisamide-seizure-dogs-modern-anti-seizure-dose-and-liver-safety). ## Related Articles - [Zonisamide Seizure Dogs: Modern Anti-Seizure Dose and Liver Safety](/knowledge/veterinary-medicine/calculators-clinical-tools/zonisamide-seizure-dogs-modern-anti-seizure-dose-and-liver-safety) - [Canine Epilepsy: Antiepileptic Drug Selection and Monitoring](/knowledge/veterinary-medicine/clinical-internal-medicine/canine-epilepsy-antiepileptic-drug-selection-monitoring) - [Canine Epilepsy: Diagnosis and Antiepileptic Drug Management](/knowledge/veterinary-medicine/clinical-methods/canine-epilepsy-diagnosis-antiepileptic-management) - [What Are the Side Effects of Seizure Medication in Dogs?](/knowledge/veterinary-medicine/pet-medication-guide/seizure-medication-side-effects-dogs) - [Drug Interactions with Antiepileptic Drugs in Veterinary Patients: Managing Polypharmacy](/knowledge/veterinary-medicine/clinical-pharmacology/drug-interactions-antiepileptic-veterinary) - [Drug Interactions with Anticonvulsant Medications in Veterinary Patients: Phenobarbital, Potassium Bromide, and Levetiracetam](/knowledge/veterinary-medicine/clinical-pharmacology/drug-interactions-anticonvulsant-medications-veterinary) - [Phenobarbital vs Keppra for Dogs: Which Seizure Drug?](/knowledge/veterinary-medicine/pet-medication-guide/phenobarbital-vs-keppra-dogs) - [Keppra for Dogs With Seizures or Brain Tumors](/knowledge/veterinary-medicine/pet-medication-guide/keppra-dogs-seizures-brain-tumor) - [Keppra for Dogs: Side Effects and Effectiveness](/knowledge/veterinary-medicine/pet-medication-guide/keppra-dogs-side-effects-effectiveness) ## References 1. [The effect of oral zonisamide treatment on serum phenobarbital concentrations in epileptic dogs](https://pubmed.ncbi.nlm.nih.gov/38868500/). Frontiers in veterinary science, 2024. 2. [Short-Term Renal Effects of Add-On Levetiracetam in Client-Owned Dogs with Idiopathic Epilepsy Receiving Phenobarbital: A Four-Week Prospective Study](https://pubmed.ncbi.nlm.nih.gov/42797888/). Veterinary sciences, 2026. 3. [Efficacy of monotherapy with zonisamide and proposed reference interval in dogs with epilepsy: a cohort of 207 dogs (2011-2021)](https://pubmed.ncbi.nlm.nih.gov/41742507/). Journal of veterinary internal medicine, 2026. 4. [Single-Dose Pharmacokinetics of Intranasal Levetiracetam in Healthy Dogs](https://pubmed.ncbi.nlm.nih.gov/41557509/). Journal of veterinary pharmacology and therapeutics, 2026. 5. [Anticonvulsants for Treatment of Animals - Pharmacology](https://www.merckvetmanual.com/pharmacology/systemic-pharmacotherapeutics-of-the-nervous-system/anticonvulsants-for-treatment-of-animals). Merck Veterinary Manual. 6. [Antiepileptic drug therapy in companion animals: New perspectives on clinical pathology monitoring](https://pubmed.ncbi.nlm.nih.gov/42571377/). Veterinary and animal science, 2026. 7. [Immune-mediated polyarthritis and anterior uveitis secondary to zonisamide administration in a dog with refractory epilepsy](https://pubmed.ncbi.nlm.nih.gov/38403976/). Veterinary medicine and science, 2024. ## Further Reading - [Anticonvulsants for Emergency Treatment of Seizures in Dogs and Cats - Pharmacology (Merck Veterinary Manual)](https://www.merckvetmanual.com/pharmacology/systemic-pharmacotherapeutics-of-the-nervous-system/anticonvulsants-for-emergency-treatment-of-seizures-in-dogs-and-cats) - [American Veterinary Medical Association: First Aid Tips for Pet Owners](https://www.avma.org/resources-tools/pet-owners/emergencycare/first-aid-tips-pet-owners) - [Merck Veterinary Manual: Dog Owners](https://www.merckvetmanual.com/dog-owners)