Lamotrigine versus Levetiracetam and Zonisamide for First-Line Therapy of Focal Epilepsy

July 2022

Focal epilepsy accounts for approximately two-thirds of epilepsy diagnoses. Lamotrigine is a first-line therapy for focal epilepsy regardless of subtype. Levetiracetam and zonisamide are also approved for focal epilepsy but have not been tested head-to-head with lamotrigine. Their relative clinical effectiveness and cost-effectiveness are therefore unknown.

In this report, the SANAD II investigators compared lamotrigine with levetiracetam and zonisamide in patients with newly diagnosed focal epilepsy. SANAD II was designed for both noninferiority and superiority. The study included 990 participants aged ≥5 years with a mean age of 39.3 years. All had ≥2 focal seizures.

Participants were randomly assigned to open-label levetiracetam, zonisamide, or lamotrigine. The primary outcome was time to 12-month remission beginning with the date of randomization. The investigators used both intention-to-treat analysis, which included all participants, and per-protocol analysis, which excluded participants who were misdiagnosed for epilepsy or who had major deviations from the protocol.

In the intention-to-treat analysis, the investigators found that levetiracetam did not meet the criteria for noninferiority for time to 12-month remission compared with lamotrigine but zonisamide did meet the criteria for noninferiority. Results differed in the per-protocol analysis, however, and 31 patients were excluded because of protocol deviations or misdiagnoses. By this analysis, lamotrigine was superior to both levetiracetam and zonisamide in terms of 12-month remission.

Investigators studied several secondary outcomes measures, including time to 24-month remission and time to first seizure, which were similar among the 3 treatment groups. Time to treatment failure and annual failure rates, however, were superior with lamotrigine treatment. In addition, more adverse reactions, including psychiatric adverse reactions, were seen with levetiracetam and zonisamide than with lamotrigine. Lamotrigine was also associated with better self-reported quality-of-life measures and cost-effectiveness.

One limitation that the SANAD II investigators pointed out was that only 17.9% of participants were children. In addition, other newer drugs were not considered in this study.

Overall, the study showed that lamotrigine should remain the first-line treatment for focal epilepsy. “This finding is most relevant to levetiracetam, which has become a commonly prescribed first-line anti-seizure medication because of its ease of titration and assumed efficacy and tolerability,” the investigators noted. They also suggested that other more recently approved drugs should be evaluated in head-to-head cost-effectiveness trials, perhaps using the SANAD II data as historic controls.


Marson A, Burnside G, Appleton R, et al. The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet. 2021;397(10282):1363-1374.

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