Diazepam nasal spray safe to use with benzodiazepine

For patients with epilepsy, diazepam nasal spray is safe regardless of concomitant benzodiazepine use, according to the results of a phase III, open-label safety study.

“To our knowledge, this is the first analysis of a large, long-term study evaluating use of an intranasal benzodiazepine for seizure clusters in patients with epilepsy who received concomitant chronic or intermittent benzodiazepines, such as clobazam, which is an important part of the treatment algorithm for refractory childhood epilepsies,” the investigators said. [Pediatr Neurol 2017;68:18-34.e3]

“This is a relevant point, because some studies, including those for intranasal midazolam, have used concomitant benzodiazepine therapy for epilepsy as an exclusion criterion,” they added. [Epilepsia 2019;60:1797-1819]

The study included 158 patients treated with diazepam nasal spray (age 6–65 years, 53.8 percent female), among whom 119 (75.3 percent) received concomitant benzodiazepines (60, chronic; 59, intermittent).

Treatment-emergent adverse events (TEAEs) occurred more frequently among patients who did vs did not receive concomitant treatment (80.0 percent vs 61.5 percent). The most common events were primarily related to nasal discomfort, which was mild and transient. [Epilepsia 2021;doi:10.1111/epi.16901]

Nevertheless, benzodiazepines exerted no clinically relevant impact on the safety, including cardiorespiratory outcomes, of diazepam nasal spray. None of the patients developed cardiorespiratory depression or experienced serious TEAEs associated with treatment.

The results were consistent in a subanalysis of patients who were (n=44) or were not (n=75) taking clobazam.

Study retention was high at 83.3 percent in the chronic benzodiazepine group, 86.4 percent in the intermittent-use group, and 76.9 percent in the no-use group.

“Maintenance benzodiazepines are generally reserved for management of refractory or difficult-to-treat epilepsy, and, in this study, the group of patients receiving concomitant benzodiazepines had a substantially higher seizure burden, as expected,” the investigators said.

“Patients in the concomitant benzodiazepines groups therefore received more doses of diazepam nasal spray, and they were also more likely to have been exposed to diazepam nasal spray >12 months. Even so, rates of second-dose use were similar [<12 percent] … which suggests that diazepam nasal spray maintained effectiveness,” they added.

Diazepam nasal spray is developed to provide a rapid, noninvasive, and socially acceptable route of administration in patients aged ≥6 years for acute treatment of intermittent, stereotypic episodes of frequent seizure activity. This formulation has comparable bioavailability with less pharmacokinetic intrapatient variability compared with rectal diazepam. [Epilepsia 2020;61:455-464; Epilepsia 2020;61:935-943]

“The results [of the present study] support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use,” according to the investigators.