AbstractRationaleData on weight changes associated with Cenobamate (CNB) in patients with epilepsy is scarce. We performed a case‐control study because of concern for clinically significant weight loss.MethodsAll patients exposed to CNB between its May in February 2020 until October 2023 with at least 180 days of exposure were evaluated. Baseline weight was assessed as the closest within 90 days prior to initiation of CNB. Trough and peak weights during CNB exposure and concomitant antiseizure medications (ASMs) were obtained.ResultsA total of 332 patients obtained at least one dose of CNB during the study period, of whom 118 with accurate weight measurements were included in the analysis. A total of 33 patients (27.8%) were recorded as having experienced at least a 10% weight loss during CNB exposure; 16 patients (13.6%) had 10%–14.9% weight loss, 11 patients (9.3%) had 15%–19.9%, and 6 patients (5.1%) had ≥20%. A total of 9 (7.6%) patients had at least 10% weight gain and 1 patient had >20% weight gain. Median dose was 200 mg/d (IQR 50–400 mg/d); 27 of 33 patients had doses of ≥200 mg/d and experienced greater weight loss. There was a trend for male sex and duration to be associated with >10% weight loss. In four patients who underwent dose reduction or discontinuation due to weight loss, weight stabilized or increased without seizure exacerbation. Patients with greater initial weight were more likely to move into a lower BMI category (p < .01).ConclusionsA larger than expected number of patients in two centers had significant unintentional weight loss associated with CNB use. In a subset, the effect appeared to be reversible with minor dose reduction, even with severe weight loss. Systematic weight assessment should be considered in all patients on CNB, especially with telehealth. Clinicians should rule out contributing etiologies and consider CNB dose reduction if excessive weight loss occurs.