Study: Crushing, but not splitting, changes how extended-release levetiracetam behaves in dogs

For veterinarians dosing extended-release levetiracetam in small dogs, new research suggests splitting tablets may be a practical option. Crushing the tablets is a different story.

The study was published online October 23, 2026, in the American Journal of Veterinary Research.¹ Researchers at North Carolina State University College of Veterinary Medicine compared intact, split, and crushed 500-mg extended-release levetiracetam tablets in 7 healthy beagles. The team included first author Alejandra Mondino, DVM, PhD, and corresponding author Karen R. Muñana, DVM, DACVIM.¹

Compared with intact tablets, crushed tablets produced a higher peak drug level and lower drug levels late in the 12-hour dosing window. Split tablets showed no statistically significant differences from intact tablets on any of the pharmacokinetic measures the researchers evaluated.¹

Why tablet form matters

According to the study authors, levetiracetam is among the most commonly used second-generation antiseizure medications in veterinary practice. No veterinary-specific formulation exists, so dogs receive the drug extralabel using products made for human patients.¹

The immediate-release form has a half-life of 3 to 4 hours in dogs and requires dosing every 8 hours. The extended-release form allows dosing every 12 hours. However, the smallest extended-release tablet available is 500 mg. The manufacturer also advises that the tablets be swallowed intact to preserve their extended-release properties. In small dogs, such as those weighing less than 10 kg, a whole 500-mg tablet would exceed the recommended starting dose of 30 mg/kg every 12 hours, the authors wrote.¹

The authors also pointed to dosing frequency as a factor in owner compliance. The authors cited a 2021 study in which only about one-third of dog owners achieved at least 80% adherence to prescribed antiseizure medications. In the same study, only 1 in 5 owners followed the regimen exactly as prescribed.² Because immediate-release levetiracetam has a short half-life, even a single missed dose can lead to a marked decline in drug concentrations, the authors noted.¹

Split tablets held steady; crushed tablets peaked early

Each dog received all 3 tablet forms in random order, with a washout period between treatments. Split tablets were cut into roughly equal halves with a commercial pill cutter, with both halves given. Crushed tablets were ground with a mortar and pestle, mixed with water, then given by syringe. Dogs were fasted before each treatment. Blood samples were collected over the 12 hours after dosing.¹

Every dog received a 500-mg tablet. The drug was well tolerated. Mild sedation in some dogs was the only immediate adverse effect observed.¹

The work builds on an earlier in vitro dissolution study by the same group. The dissolution study found that splitting the tablets slightly increased drug release, while crushing eliminated the extended-release properties.³

In the new study, crushed tablets produced a higher peak drug level than intact tablets. Crushed tablets also produced lower drug levels between 8 and 12 hours after dosing.¹

No validated therapeutic range has been established for levetiracetam in dogs. The researchers therefore used a target level drawn from the human therapeutic reference range. With crushed tablets, drug levels fell below the target at approximately 8.5 hours, compared with nearly 11 hours for intact and split tablets.¹

The authors noted that crushed tablets reached peak levels in a time similar to what has previously been reported in dogs for immediate-release levetiracetam. Differences in observed time to peak across tablet forms were not statistically significant. However, an exploratory model estimated an earlier time to peak for crushed tablets than for intact tablets.¹

Implications and limitations

The authors wrote that splitting extended-release tablets may provide a practical option for dose adjustment in smaller dogs while preserving every-12-hours dosing. The study was not designed to assess bioequivalence. Even so, the authors wrote that the lack of major differences between intact and split tablets suggests splitting may reduce the need for compounded extended-release formulations. The authors noted that such compounded formulations are not FDA approved and may introduce concerns about quality, stability, consistency of drug strength, and regulatory issues.¹

Dogs receiving extended-release levetiracetam are often prescribed the immediate-release form for cluster seizures, when rapid absorption is preferred. According to the authors, some veterinarians anecdotally recommend splitting extended-release tablets to achieve more rapid absorption. In the new study, split tablets did not peak earlier or higher than intact tablets. The authors concluded that splitting did not appear to produce a faster rise in drug levels and is unlikely to provide an advantage when rapid drug levels are needed, such as during cluster seizures.¹

Instead, the authors said crushed extended-release tablets warrant further evaluation as an adjunct option during cluster seizures when the immediate-release form is unavailable. The study did not evaluate clinical efficacy during cluster seizures.¹

The authors also noted several limitations:

• The study tested a single extended-release product. The authors wrote that the findings cannot be assumed to apply to all generic extended-release levetiracetam products without formulation-specific information or direct evaluation.
• Crushed tablets were given as a suspension in water, so the results reflect that administration method rather than crushing alone.
• The study did not include an immediate-release comparison group and was not blinded.
• Dogs were fasted, so the effect of feeding on the results is undetermined.¹

References

1. Mondino A, Nettifee JA, Simon KE, Papich MG, Muñana KR. Tablet crushing, but not splitting, alters the pharmacokinetics of extended-release levetiracetam in dogs. Am J Vet Res. Published online October 23, 2026. doi:10.2460/ajvr.26.08.0360
2. Booth S, Meller S, Packer RMA, Farquhar R, Maddison JE, Volk HA. Owner compliance in canine epilepsy. Vet Rec. 2021;188(4):262–269. doi:10.1002/vetr.16
3. Mondino A, Nettifee JA, Papich MG, Muñana KR. Dissolution characteristics of split and crushed levetiracetam extended-release tablets in comparison with immediate-release formulation. J Vet Pharmacol Ther. 2025;48(4):340–343. doi:10.1111/jvp.13517