Can IV Levetiracetam (Keppra) Be Given to a Patient on Valproate?
Yes, IV levetiracetam can be safely administered to patients already taking valproate (Depakote/valproic acid), as there are no clinically significant pharmacokinetic or pharmacodynamic interactions between these medications. 1
Safety Profile of the Combination
No Pharmacokinetic Interactions
The FDA label for levetiracetam explicitly states that levetiracetam (1500 mg twice daily) does not alter the pharmacokinetics of valproate in healthy volunteers. 1
Valproate (500 mg twice daily) does not modify the rate or extent of levetiracetam absorption, plasma clearance, or urinary excretion. 1
Levetiracetam does not affect the in vitro glucuronidation of valproic acid, meaning it won't interfere with valproate metabolism. 1
Levetiracetam had no effect on plasma concentrations of valproate in clinical studies evaluating drug interactions. 1
Enhanced Therapeutic Benefit
Preclinical evidence demonstrates that combining levetiracetam with valproate provides enhanced anticonvulsant protection without exacerbation of side effects. 2
The combination of levetiracetam with agents that enhance GABAergic inhibition (like valproate) shows particularly strong enhancement of protective activity. 2
This enhanced efficacy is attributed to levetiracetam's novel and distinct mechanism of action, which complements valproate's GABAergic effects. 2
Clinical Application in Acute Settings
Status Epilepticus Management
For refractory status epilepticus after benzodiazepine failure, both valproate and levetiracetam are appropriate second-line agents that can be used sequentially or in combination. 3
Valproate loading dose: 20-30 mg/kg IV at a maximum rate of 10 mg/kg/min (or up to 40 mg/min). 3
Levetiracetam loading dose: 30-50 mg/kg IV at 100 mg/min. 3
Adverse Effect Profile
Levetiracetam has minimal adverse effects (nausea, rash) and notably low incidence of hypotension and respiratory depression when given as an IV load. 3
Valproate adverse effects include dizziness, thrombocytopenia, liver toxicity, and hyperammonemia. 3
The combination does not result in pharmacokinetic interactions that would increase these risks. 1, 2
Important Clinical Considerations
When to Add Levetiracetam
Optimize valproate levels first before adding levetiracetam, as monotherapy optimization should precede polytherapy. 4
If seizures persist despite therapeutic valproate levels, adding levetiracetam is appropriate and safe. 4, 2
Dosing in Combination Therapy
No dose adjustment of either medication is required when used together. 1
Standard loading and maintenance doses can be used for both agents without modification. 3, 1
Monitoring
Continue routine monitoring for valproate (liver function, ammonia, platelets) as the combination does not eliminate these risks. 3
Monitor for seizure control rather than specific drug levels, as the combination may provide synergistic benefit. 2
Common Pitfalls to Avoid
Do not withhold levetiracetam due to concerns about drug interactions with valproate—these concerns are unfounded. 1
Avoid assuming that enzyme-inducing antiepileptic drugs (like carbamazepine or phenytoin) behave similarly to valproate; those medications do increase levetiracetam clearance by approximately 22%, but valproate does not. 1
Do not confuse valproate's interactions with other drugs (phenytoin, phenobarbital) with its lack of interaction with levetiracetam. 5, 6