Can amitriptyline be combined with levetiracetam (Keppra) and valproic acid (Depakote)?

Amitriptyline Can Be Combined with Levetiracetam and Valproic Acid with Appropriate Monitoring

Yes, amitriptyline can be combined with levetiracetam and valproic acid, but careful monitoring is required due to potential interactions between amitriptyline and valproic acid that can significantly increase amitriptyline serum levels. 1

Pharmacological Considerations

Interaction Between Amitriptyline and Valproic Acid

• Valproic acid can significantly increase serum levels of amitriptyline and its active metabolite nortriptyline
• A retrospective analysis showed that patients receiving this combination had nearly double the total concentration of amitriptyline and nortriptyline compared to controls (237.1 ng/mL vs 126.4 ng/mL) 1
• This interaction increases the risk of anticholinergic side effects, including delirium, especially in elderly patients

Levetiracetam and Valproic Acid Combination

• No significant pharmacokinetic interactions have been documented between levetiracetam and valproic acid 2
• In vitro and clinical studies demonstrate that levetiracetam does not affect the steady-state pharmacokinetics of valproic acid and vice versa 2
• This makes levetiracetam a favorable anti-seizure medication to combine with valproic acid

Clinical Management Algorithm

1. Initial Dosing:

   • Start with lower doses of amitriptyline when combining with valproic acid
   • Standard dosing of levetiracetam can be maintained as it doesn't interact significantly with either medication

2. Therapeutic Drug Monitoring:

   • Mandatory monitoring of amitriptyline and nortriptyline serum levels when combined with valproic acid 1
   • Monitor valproic acid levels to ensure therapeutic range
   • No special monitoring needed for levetiracetam levels when combined with these medications

3. Side Effect Monitoring:

   • Watch for signs of amitriptyline toxicity: confusion, sedation, anticholinergic effects, cardiac arrhythmias
   • Monitor for common side effects of levetiracetam: behavioral changes, somnolence
   • Check for valproic acid side effects: hepatotoxicity, thrombocytopenia, tremor

4. Specific Populations:

   • In women of childbearing age, consider switching from valproic acid to levetiracetam due to valproic acid's high teratogenic risk 3
   • In elderly patients, use extra caution with this combination due to higher risk of anticholinergic delirium 1

Rationale for This Combination

Current guidelines support the use of levetiracetam and valproic acid as effective anti-seizure medications:

• Levetiracetam has become the drug of first choice at most neuro-oncology centers due to its favorable side effect profile and limited drug interactions 4
• Valproic acid still has a firm place in seizure management given its efficacy, though it requires careful monitoring 4
• When seizure control requires multiple medications, this combination can be effective, with amitriptyline potentially added for comorbid depression or neuropathic pain

Important Precautions

• Avoid this combination in pregnant women or women planning pregnancy due to valproic acid's teratogenicity 4
• Use caution in patients with hepatic impairment as both valproic acid and amitriptyline undergo hepatic metabolism
• Be aware that adding meropenem to this regimen can significantly decrease valproic acid levels 5
• Monitor for psychiatric side effects, as levetiracetam can cause behavioral changes and amitriptyline can worsen these effects

Conclusion for Clinical Practice

This three-drug combination can be used effectively with appropriate monitoring, but clinicians should:

• Start with lower doses of amitriptyline
• Perform regular therapeutic drug monitoring
• Be vigilant for signs of amitriptyline toxicity
• Consider alternatives to valproic acid in women of childbearing age