Can Keppra (Levetiracetam) be added to Depakote (Valproate)?

Adding Keppra (Levetiracetam) to Depakote (Valproate)

Yes, Keppra (levetiracetam) can be safely and effectively added to Depakote (valproate) for seizure management, with evidence showing this combination may provide enhanced seizure control without significant pharmacokinetic interactions or increased toxicity. 1, 2

Evidence for Combination Therapy

The 2024 clinical policy from the American College of Emergency Physicians supports using multiple antiepileptic medications when necessary, noting that levetiracetam and valproate are both effective second-line agents for seizure management 1. This guideline specifically states that either medication can be used with similar efficacy for seizures refractory to benzodiazepines.

The FDA label for levetiracetam explicitly addresses this combination, stating: "Levetiracetam (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion." 3

Pharmacological Advantages

The combination of levetiracetam and valproate is particularly beneficial because:

• They have different mechanisms of action:

  • Levetiracetam binds to synaptic vesicle protein SV2A
  • Valproate works through multiple mechanisms including sodium channel blockade and enhancement of GABA

• Preclinical evidence shows that levetiracetam particularly enhances the protective activity of valproate compared to other antiepileptic drug combinations 2

• No significant pharmacokinetic interactions exist between these medications 3

Efficacy of the Combination

Research demonstrates that the levetiracetam-valproate combination can be more effective than monotherapy:

• A 2022 meta-analysis showed that valproate combined with levetiracetam significantly improved overall therapeutic effect compared to valproate alone (RR=1.24,95% CI: 1.16 to 1.33) 4

• The same meta-analysis found reduced adverse drug reactions with the combination compared to valproate monotherapy or valproate with topiramate (RR=0.54,95% CI: 0.37 to 0.79) 4

Monitoring and Safety Considerations

When adding levetiracetam to valproate therapy:

• Monitor for common levetiracetam side effects including:

  • Somnolence
  • Dizziness
  • Behavioral changes (irritability, aggression, mood changes)
  • Potential suicidal thoughts (rare but important to monitor) 3

• No dosage adjustments are typically needed when combining these medications 3

• Laboratory monitoring should continue as normally recommended for valproate therapy

• The combination does not require additional monitoring beyond what is standard for each individual medication 5

Implementation Strategy

1. Start with a low dose of levetiracetam (typically 500 mg twice daily)
2. Titrate up to an effective dose (usually 1000-3000 mg daily in divided doses) based on seizure control and tolerability
3. Maintain the current valproate dosing during levetiracetam initiation
4. Monitor for seizure frequency and adverse effects
5. Consider therapeutic drug monitoring if needed, though routine monitoring of levetiracetam levels is not typically required

This combination therapy approach is supported by both clinical guidelines and research evidence, making it an appropriate option for patients with inadequate seizure control on valproate monotherapy.