Is there an interaction between Keppra (levetiracetam) and valproic acid?

Interaction Between Levetiracetam (Keppra) and Valproic Acid

Levetiracetam and valproic acid can be safely co-administered without significant pharmacokinetic interactions, as both are classified as non-enzyme-inducing antiepileptic drugs. 1

Pharmacokinetic Interactions

• Levetiracetam does not affect the pharmacokinetics of valproic acid, and valproic acid does not modify the rate or extent of levetiracetam absorption, plasma clearance, or urinary excretion 2
• According to FDA labeling, levetiracetam does not affect the in vitro glucuronidation of valproic acid 2
• Levetiracetam is primarily eliminated unchanged through renal excretion (66% of administered dose), making it less prone to drug interactions mediated by hepatic metabolism 2
• In vitro data indicates that levetiracetam and its major metabolite are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, which further reduces potential for interactions 2

Clinical Efficacy of Combination

• Preclinical studies have shown that the combination of levetiracetam with valproic acid may provide enhanced therapeutic benefit due to levetiracetam's novel mechanism of action 3
• The combination of levetiracetam with valproic acid has shown particularly strong enhancement of protective activity in seizure models 3
• Both medications are considered equally effective options for the treatment of status epilepticus in adults 4

Monitoring Considerations

• When co-administering these medications, patients should be monitored for:
  • Valproic acid-specific adverse effects, including thrombocytopenia and hepatotoxicity 1
  • Potential behavioral side effects of levetiracetam (e.g., aggression, agitation, anger, anxiety, depression) 2
• High doses of both medications may cause delayed awakening, prolonged need for mechanical ventilation, and increased critical care days in post-cardiac arrest patients 5

Special Considerations

• In patients with brain tumors receiving chemotherapy, levetiracetam is generally better tolerated than valproic acid due to lower risk of hematologic toxicities 1
• Valproic acid and levetiracetam are considered first-line drugs for post-cardiac arrest seizure treatment 5
• In a comparison study of valproate, levetiracetam, and fosphenytoin for convulsive status epilepticus, all three drugs were equally effective, but fosphenytoin caused more episodes of hypotension and need for tracheal intubation 5

Important Drug Interaction Warnings

• While levetiracetam and valproic acid don't have significant pharmacokinetic interactions with each other, be aware that:
  • Valproic acid levels can decrease significantly when co-administered with meropenem 6
  • Levetiracetam has shown reduced bioavailability (approximately 70.3%) when changing from intravenous to enteral liquid application 6

In conclusion, levetiracetam and valproic acid can be safely used together without significant pharmacokinetic interactions, and this combination may even provide enhanced therapeutic benefit in certain seizure disorders. Regular monitoring for medication-specific adverse effects is recommended.