Can levetiracetam (Keppra) and Depakote (valproate) be taken together in patients with a history of seizure disorders or epilepsy?

Can Levetiracetam and Depakote Be Taken Together?

Yes, levetiracetam (Keppra) and Depakote (valproate) can be safely taken together and represent a rational combination therapy for patients with epilepsy whose seizures are inadequately controlled on monotherapy. 1, 2

Evidence Supporting Combination Therapy

Both medications are established second-line agents for status epilepticus with similar efficacy (46-47% seizure control as monotherapy), and they can be safely combined without significant pharmacokinetic interactions. 1, 2 The combination is particularly advantageous because:

• Levetiracetam and valproate work through different mechanisms of action, providing complementary seizure control 3
• No significant drug-drug interactions exist between these two agents 1
• Preclinical evidence demonstrates that levetiracetam combinations with agents enhancing GABAergic neurotransmission (like valproate) show particularly strong enhancement of protective activity 3

Clinical Guidelines for Combined Use

When adding valproate to levetiracetam for inadequately controlled seizures, this represents appropriate therapeutic escalation. 1 The treatment algorithm should follow:

• First, optimize levetiracetam dosing (up to 30 mg/kg or maximum tolerated dose) before adding a second agent 1
• Verify medication compliance by checking serum drug levels 4
• Rule out precipitating factors (sleep deprivation, alcohol use, medication non-compliance, intercurrent illness) 1
• If seizures persist despite optimized monotherapy, adding valproate is a reasonable next step 1, 2

Safety Monitoring Requirements

Monitor liver function tests regularly due to valproate's hepatotoxicity risk. 1 Additional monitoring considerations include:

• Both medications require dose adjustments in renal dysfunction 1
• Valproate protein binding is reduced in elderly patients, increasing free drug fraction 1
• Question patients about seizure occurrences at each follow-up visit 4
• Obtain serum levels to assess compliance and explore failure to control epileptic activity 4

Critical Contraindications

Valproate must not be used in women of childbearing potential due to significantly increased risks of fetal malformations and neurodevelopmental delay. 4, 1 In such patients:

• Levetiracetam monotherapy is the preferred option 1
• If combination therapy is necessary, consider lamotrigine or lacosamide as add-on agents instead of valproate 4, 1

Comparative Safety Profile

The combination demonstrates favorable tolerability compared to other antiepileptic combinations. 2 Specific safety data:

• Life-threatening hypotension occurs in only 0.7% with levetiracetam versus 1.6% with valproate 2
• Arrhythmias observed in only 0.7% of levetiracetam-treated patients 2
• Most common serious adverse events (42% of subjects) include continuous seizures, altered consciousness, and respiratory difficulty 2

Advantages Over Alternative Combinations

This combination avoids enzyme-inducing anticonvulsants (phenytoin, carbamazepine, phenobarbital), which should be avoided due to significant drug interactions and side effects. 4, 1 The levetiracetam-valproate combination offers:

• No significant cytochrome P450 enzyme induction 5
• Lower risk of drug-drug interactions with steroids, cytotoxic agents, and targeted therapies 4
• Better overall tolerability profile compared to traditional agents 4

Practical Implementation

When initiating combination therapy, maintain current levetiracetam dose and add valproate at standard dosing (20-30 mg/kg/day divided twice daily). 1 Key implementation points:

• Do not reduce levetiracetam dose when adding valproate unless side effects emerge 1
• Titrate valproate gradually to minimize gastrointestinal side effects 1
• Ensure adequate time (several weeks) to assess efficacy before further adjustments 4
• Consider EEG monitoring if clinical presentation suggests possible non-convulsive status epilepticus 1