What is the next agent to add for a patient not controlled on Levetiracetam (Keppra)?

Next Agent to Add for Seizures Not Controlled on Levetiracetam

For seizures not controlled on levetiracetam monotherapy, add lacosamide as the preferred second agent, with lamotrigine as an alternative option based on seizure type.

Recommended Add-On Strategy

First-Line Add-On: Lacosamide

• Lacosamide is specifically recommended as an add-on treatment for patients whose seizure disorder is not controlled by monotherapy 1
• This recommendation comes from the EANO-ESMO guidelines for neurological complications, which specifically identify lacosamide's role in refractory cases 1
• Lacosamide works through a different mechanism (sodium channel blocker with slow inactivation enhancement) than levetiracetam (SV2A modulation), providing complementary action 2

Alternative Add-On: Lamotrigine

• Lamotrigine is particularly effective when combined with levetiracetam based on clinical combination studies 3
• Lamotrigine requires several weeks of titration to reach therapeutic levels, which is a key limitation 1
• The combination of levetiracetam with lamotrigine has favorable experimental and clinical data showing good efficacy and tolerability 3

Seizure Type Considerations

For Focal Seizures

• Add lacosamide or lamotrigine to levetiracetam 1, 3
• The SANAD II trial demonstrated that lamotrigine remains superior for focal epilepsy outcomes, making it a rational add-on choice 4
• Levetiracetam combined with sodium channel blockers (lacosamide, lamotrigine) shows favorable outcomes 3

For Generalized Seizures

• Consider adding valproate if not contraindicated (particularly effective but avoid in women of childbearing potential) 1, 4
• Lamotrigine can be added as an alternative, though it requires slow titration 1

Agents to Avoid

Do Not Use Enzyme-Inducing Anticonvulsants

• Avoid phenytoin, phenobarbital, and carbamazepine as add-on agents due to their side-effect profile and significant drug interactions 1
• These older agents interact with steroids and various other medications, making them poor choices for combination therapy 1

Dosing Considerations

Lacosamide Add-On

• Typical starting dose: 50 mg twice daily, titrated to 100-200 mg twice daily based on response 1

Lamotrigine Add-On

• Requires slow titration over several weeks to minimize rash risk 1
• When added to levetiracetam alone: start 25 mg daily for 2 weeks, then 50 mg daily for 2 weeks, then increase by 50-100 mg every 1-2 weeks
• Target maintenance: 200-400 mg daily in divided doses

Common Pitfalls to Avoid

• Do not switch levetiracetam to another monotherapy without first attempting combination therapy, as adjunctive therapy has equivalent efficacy to alternative monotherapy 3
• Monitor for behavioral side effects when continuing levetiracetam, as hostility and aggressive behavior are not uncommon, particularly in children 2, 5
• Do not combine levetiracetam with other drugs that have similar mechanisms (such as brivaracetam), as this provides no additional benefit 3
• Avoid rapid titration of lamotrigine if chosen, as this increases rash risk significantly 1

Reassessment Strategy

• Assess efficacy of the combination after reaching therapeutic doses (4-6 weeks for lacosamide, 8-12 weeks for lamotrigine) 1
• If the combination is effective, continue both agents 3
• If seizures persist despite adequate combination therapy, consider referral to epilepsy specialist for evaluation of surgical candidacy or third-line agents 1