Can lamotrigine be added to levetiracetam (Keppra) in a patient with focal seizures who is not adequately controlled on levetiracetam alone?

Adding Lamotrigine to Levetiracetam for Focal Seizures

Yes, lamotrigine can and should be added to levetiracetam in patients with focal seizures inadequately controlled on levetiracetam monotherapy, as this combination demonstrates complementary mechanisms of action and favorable clinical outcomes. 1

Rationale for Combination Therapy

The combination of lamotrigine and levetiracetam provides complementary antiseizure effects through distinct mechanisms:

• Lamotrigine acts primarily as a sodium channel modulator 1
• Levetiracetam binds to synaptic vesicle protein SV2A, offering a completely different mechanism 1
• This mechanistic diversity supports rational polytherapy when monotherapy fails 1

Evidence Supporting This Combination

Clinical effectiveness data strongly favor this combination:

• A retrospective study of 344 drug-resistant patients found that lamotrigine was used significantly more often in combination with levetiracetam in responders than non-responders (p = 0.003), suggesting a beneficial pharmacodynamic interaction 2
• In this cohort, 16.3% of previously drug-resistant patients became seizure-free with levetiracetam add-on therapy, with responders more likely to be on lamotrigine co-therapy 2
• Recent expert consensus identifies levetiracetam as favorably combinable with sodium channel blockers including lamotrigine 3

Pharmacokinetic Compatibility

This combination has excellent pharmacokinetic compatibility:

• Levetiracetam does not affect plasma concentrations of lamotrigine 4
• Lamotrigine does not influence levetiracetam pharmacokinetics 4
• Neither drug induces or inhibits hepatic enzymes, avoiding problematic drug-drug interactions 1, 4
• Both medications have favorable interaction profiles compared to older antiepileptics 1

Dosing Considerations

When adding lamotrigine to existing levetiracetam:

• Lamotrigine: Initiate with slow titration to minimize rash risk; effective range typically 50-300 mg/day 1
• Levetiracetam: Maintain current dose if tolerated; effective range 500-2000 mg/day 1
• Titrate lamotrigine slowly over several weeks according to standard protocols to reduce risk of serious cutaneous reactions 1

Safety Profile

Both medications have generally favorable tolerability:

• The adverse effect profile of this combination is superior to older antiepileptics like carbamazepine or phenytoin 1
• Monitor for levetiracetam-associated psychiatric effects including irritability, aggression, mood changes, and rarely psychotic symptoms 1, 4
• Monitor for lamotrigine-associated rash, particularly during titration phase 1
• Common levetiracetam adverse effects include somnolence and behavioral changes 4
• Lamotrigine adverse effects include ataxia, dizziness, diplopia, and nausea 5

Clinical Caveats

Important considerations when implementing this combination:

• While lamotrigine monotherapy remains superior to levetiracetam monotherapy for newly diagnosed focal epilepsy (based on SANAD II trial showing lamotrigine superiority for time to 12-month remission and treatment failure) 6, this does not preclude adding lamotrigine when levetiracetam monotherapy fails
• The evidence for beneficial interaction comes from add-on therapy studies in drug-resistant populations, which is the appropriate context for your patient 2
• Psychiatric monitoring is essential given levetiracetam's propensity for behavioral adverse effects 1, 4
• Slow lamotrigine titration is mandatory regardless of concomitant medications 1