Abstract Objective During the development of cenobamate, an antiseizure medication (ASM) for focal seizures, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. To mitigate the rate of DRESS, a start‐low, go‐slow approach was studied in an ongoing, open‐label, multicenter study. Also examined were long‐term safety of cenobamate and a method for managing the pharmacokinetic interaction between cenobamate, a 2C19 inhibitor, and concomitant phenytoin or phenobarbital. Methods Patients 18‐70 years old with uncontrolled focal seizures taking stable doses of one to three ASMs were enrolled. Cenobamate 12.5 mg/d was initiated and increased at 2‐week intervals to 25, 50, 100, 150, and 200 mg/d. Additional biweekly 50 mg/d increases to 400 mg/d were allowed. During titration, patients taking phenytoin or phenobarbital could not have their cenobamate titration rate or other concomitant ASMs adjusted; phenytoin/phenobarbital doses could be decreased by 25%‐33%. Results At data cutoff (median treatment duration = 9 months), 1347 patients were enrolled, of whom 269 (20.0%) discontinued, most commonly due to adverse events (n = 137) and consent withdrawn for reason other than adverse event (n = 74); 1339 patients received ≥1 treatment dose (median modal dose = 200 mg). The most common treatment‐emergent adverse events (TEAEs) were somnolence (28.1%), dizziness (23.6%), and fatigue (16.6%). Serious TEAEs occurred in 108 patients (8.1%), most commonly seizure (n = 14), epilepsy (n = 5), and pneumonia, fall, and dizziness (n = 4 each). No cases of DRESS were identified. In the phenytoin/phenobarbital groups, 43.4% (36/114) and 29.7% (11/51) of patients, respectively, had their doses decreased. At the end of titration, mean plasma phenytoin/phenobarbital levels were generally comparable to baseline. Significance No cases of DRESS were identified in 1339 patients exposed to cenobamate using a start‐low (12.5 mg/d), go‐slow titration approach. Cenobamate was generally well tolerated in the long term, with no new safety issues found. Phenytoin/phenobarbital dose reductions (25%‐33%), when needed during cenobamate titration, maintained stable plasma levels.