No Clinically Significant Drug Interaction Between Lithium and Keppra (Levetiracetam)
There is no clinically significant pharmacokinetic or pharmacodynamic interaction between lithium and levetiracetam (Keppra), and the combination can be used safely with standard monitoring of lithium levels.
Evidence from FDA Drug Labeling
The FDA-approved prescribing information for Keppra explicitly addresses drug interactions and states that levetiracetam has minimal interaction potential 1. Key points include:
- Levetiracetam does not interact with cytochrome P450 enzymes, epoxide hydrolase, or UDP-glucuronidation pathways
- Levetiracetam is less than 10% protein-bound, making protein displacement interactions unlikely
- Formal drug interaction studies evaluated phenytoin, valproate, oral contraceptives, digoxin, warfarin, and probenecid—lithium was not studied but no mechanism for interaction exists
- The label notes levetiracetam has a "minimal risk of adverse drug interactions" 2
Pharmacokinetic Considerations
Lithium is eliminated almost exclusively by renal mechanisms and is not metabolized 3. Levetiracetam is also primarily renally excreted (66% unchanged) without hepatic metabolism 1. Since neither drug affects the other's elimination pathway, no pharmacokinetic interaction is expected.
Clinical Evidence
A 2002 review examining lithium-anticonvulsant combinations noted that lithium may be safely combined with newer anticonvulsants including levetiracetam, though controlled studies were limited at that time 4. More recent pharmacovigilance data from 2016 and 2026 reviews of lithium drug interactions do not identify levetiracetam as a problematic combination 5, 6, 7.
Practical Management Recommendations
When combining lithium and levetiracetam:
- Continue standard lithium monitoring (serum levels every 3-6 months during maintenance, more frequently after dose changes)
- Monitor renal function as both drugs are renally cleared
- No dose adjustment of either medication is required based on the combination
- Watch for additive CNS effects (somnolence, dizziness) as both can cause these independently, though this is not a true drug interaction
Important Caveat
While lithium has well-documented interactions with diuretics (especially thiazides, which can increase lithium levels 25-40%) 8, NSAIDs (variable effects on lithium clearance), and ACE inhibitors (may impair lithium elimination) 3, 5, levetiracetam does not share these interaction mechanisms.
The combination of lithium and levetiracetam has been used clinically without specific warnings in guidelines for seizure management 9, 10 and is considered safe based on the pharmacological profiles of both agents.