Can Xcopri (cenobamate) and Lamictal (lamotrigine) be taken concurrently in a patient with a history of epilepsy or seizures?

Concurrent Use of Xcopri (Cenobamate) and Lamictal (Lamotrigine)

Yes, Xcopri and Lamictal can be taken concurrently, but lamotrigine dosage must be increased to maintain therapeutic efficacy because cenobamate significantly reduces lamotrigine plasma concentrations. 1

Drug Interaction Mechanism and Clinical Impact

• Cenobamate decreases lamotrigine plasma concentrations through enzyme induction, specifically by inducing CYP3A4 and CYP2B6 enzymes that metabolize lamotrigine. 1, 2

• The FDA label explicitly states that lamotrigine dosage should be increased as needed when used concomitantly with cenobamate to compensate for reduced efficacy from decreased plasma levels. 1

• This interaction is bidirectional in nature—cenobamate reduces lamotrigine levels, while lamotrigine does not significantly affect cenobamate pharmacokinetics. 2, 3

Dosage Adjustment Strategy

Proactive vs. Reactive Adjustment

• For patients taking lamotrigine at standard doses (≤500 mg/day), reactive dose adjustment is sufficient—meaning you should increase lamotrigine only if breakthrough seizures occur or therapeutic drug monitoring shows subtherapeutic levels. 4

• For patients taking high-dose lamotrigine (>500 mg/day), consider proactive dose increase when cenobamate reaches 200 mg/day to prevent potential loss of seizure control. 5, 4

• Expert consensus recommends tailored titration with close follow-up during the cenobamate titration period, monitoring for both breakthrough seizures (indicating need for lamotrigine increase) and adverse effects (indicating need for dose reduction of other concomitant medications). 5, 4

Monitoring Requirements

• Monitor seizure frequency closely during cenobamate titration, as the reduction in lamotrigine levels may manifest as increased seizure activity before plasma levels drop to clearly subtherapeutic ranges. 4

• Therapeutic drug monitoring of lamotrigine levels is advisable when adding cenobamate, particularly if seizure control deteriorates, to objectively assess whether lamotrigine dose escalation is needed. 4, 2

• The interaction develops gradually as cenobamate is titrated upward, so lamotrigine adjustments may be needed at multiple points during the cenobamate titration schedule. 5, 4

Additional Safety Considerations

• Cenobamate carries risk of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), which requires slow titration starting at 12.5 mg daily and gradual escalation to the target dose of 200 mg daily (maximum 400 mg daily). 1

• Both medications are non-enzyme-inducing antiepileptic drugs preferred for patients with brain tumors or those receiving chemotherapy to avoid interactions with cancer treatments, though cenobamate does have some enzyme-inducing properties affecting specific substrates. 6, 1

• CNS adverse effects (somnolence, dizziness, fatigue, diplopia) are common with cenobamate, occurring in >10% of patients, and may be additive with lamotrigine's CNS effects. 1

• Cenobamate is contraindicated in patients with familial short QT syndrome and should be used cautiously with other QT-shortening drugs, though lamotrigine does not shorten QT interval. 1

Practical Implementation Algorithm

1. Initiate cenobamate at 12.5 mg daily following the FDA-approved titration schedule while maintaining current lamotrigine dose. 1

2. Monitor seizure frequency weekly during cenobamate titration to detect early breakthrough seizures. 5, 4

3. If lamotrigine dose is ≤500 mg/day: Wait for clinical indication (breakthrough seizures or subtherapeutic levels) before increasing lamotrigine dose. 4

4. If lamotrigine dose is >500 mg/day: Consider proactive 10-25% lamotrigine dose increase when cenobamate reaches 200 mg/day. 5, 4

5. Obtain lamotrigine levels if seizure control deteriorates, comparing to baseline levels before cenobamate initiation. 4

6. Increase lamotrigine dose by 25-50 mg every 1-2 weeks as needed to restore seizure control, guided by clinical response and drug levels. 4

7. Once cenobamate reaches maintenance dose (200 mg/day), reassess overall antiseizure medication burden and consider whether other concomitant medications can be reduced or discontinued if seizure control improves markedly. 5, 4