Evaluating Bioequivalence of a New, Higher-Concentration Diazepam Nasal Spray for Seizure Clusters Compared with the Current Formulation in Healthy Adults

Diazepam nasal spray is an immediate-use seizure medication for seizure clusters in patients with epilepsy aged ≥ 2 years. Currently, administration of 5- and 10-mg age- and weight-based doses requires a single device, and two devices are needed for the 15- and 20-mg doses (1 spray/nostril). This phase 1, open-label, randomized, 2-sequence, 2-treatment, 3-period crossover study in healthy adults examined whether a single 20-mg diazepam nasal spray actuation of a new formulation with a higher diazepam concentration (test formulation) was bioequivalent to two 10-mg actuations of the current formulation (reference formulation). Participants were randomly assigned to receive the test formulation twice and the reference formulation once or the reference formulation twice and the test formulation once. Safety was assessed. Eighty-six participants were assigned 1:1 to each treatment sequence ( n = 43 each). The mean plasma diazepam concentration–time profiles following the administration of the test and reference formulations were largely overlapping. Bioequivalence criteria were met for area under the concentration–time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC 0– t ) and AUC from time 0 extrapolated to infinity (AUC 0–∞ ) but not met for maximum observed plasma concentration ( C max ). Two patients receiving the test formulation had mild coronavirus disease 2019 during the study; there were no treatment-related or serious treatment-emergent adverse events. A single 20-mg actuation of diazepam nasal spray was bioequivalent to two 10-mg actuations with respect to AUC 0– t and AUC 0–∞ but not C max . There were no new safety signals for either formulation. The single-actuation formulation may represent a valid and simpler alternative for treatment of seizure clusters.