Abstracts

Rationale: Benzodiazepines are used as first-line rescue therapy in seizure emergencies, including seizure clusters and prolonged seizures, and can be used promptly when indicated. Diazepam nasal spray is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 y. Treatment of seizure clusters within 5 min with diazepam nasal spray has been associated with seizure termination within 2 min after administration. It is of interest to characterize temporal patterns of prolonged seizures within seizure clusters that are treated with diazepam nasal spray. This post hoc analysis describes and assesses timing and dosing with diazepam nasal spray (Valtoco^®) in the subset of prolonged seizures in a cluster within a dataset of all seizure clusters treated during a long-term, open-label, repeat-dose safety study of diazepam nasal spray.

Methods: This post hoc sensitivity analysis used timing data from seizure diaries and focused on prolonged seizures within seizure clusters treated 5–15 min after seizure start, analyzing age (< 18 y, ≥18 y), epilepsy type (generalized, focal, unclassified), and high seizure frequency (patients with ≥20 seizure clusters). Measures included time from treatment administration to seizure termination and second dose usage as a proxy for effectiveness.

Results: In this group of seizure clusters treated 5–15 min after seizure start (n=727 events among 103 patients [range 1–46 events per patient]), median time from seizure start to drug administration was 6 min and median time from drug administration to seizure termination was 7 min (Misra et al, Neurol Ther 2024;13(1):221). Generally similar times were observed for sensitivity analyses, ranging from 5 min to seizure termination in the pediatric and focal epilepsy groups to 15 min in the group with unclassified epilepsy type (Figure). Use of a second dose occurred in 9.3% of prolonged events and was generally consistent across subgroups. Second doses were administered ≤4 h (54%), 4–12 h (27%), and 12–24 h after the first dose. Safety results from the overall study (Wheless et al, Epilepsia 2021;62(10):2485) showed 82.2% of patients had ≥1 treatment-emergent adverse event (TEAE) irrespective of relationship to treatment, during a mean participation of 1.5 y. In addition, 30.7% patients had a serious TEAE, and 18.4% had TEAEs deemed at least possibly related to the study drug (none of which were serious). No events of cardiorespiratory depression were reported.

Conclusions: While immediate use of diazepam nasal spray (within 5 min) resulted in the fastest seizure termination, if treatment is delayed (as in a prolonged seizure within a cluster), diazepam nasal spray still resulted in rapid termination of the seizure cluster with high first-dose effectiveness and a well-characterized safety profile. These findings suggest that diazepam nasal spray controls seizure clusters that are treated promptly and those with seizures that have become prolonged.

Funding: Neurelis, Inc.