Liow, Kore

Abstract Objective An exploratory analysis from a long‐term, phase 3, open‐label, repeat‐dose safety study of diazepam nasal spray for acute treatment of seizure clusters assessed the use of a second dose up to 24 hours after the initial dose and effectiveness in potentially reducing the number of seizures. Methods Seizures and doses were recorded in diaries. Results Of 175 patients enrolled, 163 received ≥1 dose of diazepam nasal spray and were included in the safety population; those patients received a total of 4390 doses for a total of 3853 seizure clusters. Less than half of these patients used a second dose a least once during the study (79 patients [48.5%]), with a total of 485 second doses for seizure clusters (12.6% of all seizure clusters). Among these 79 patients, 33 (41.8%) used only one second dose during the study (range: 1–82). The proportion of seizure clusters treated with a second dose over time was consistently low across 24 h: 0–4 h, 152 (3.9%); 4–6 h, 72 (1.9%); 6–8 h, 39 (1.0%); 8–12 h, 55 (1.4%); 12–16 h, 42 (1.1%); 16–20 h, 42 (1.1%); 20–24 h, 83 (2.2%). Rates of treatment‐emergent adverse events (TEAEs) and treatment‐related TEAEs occurring within 1 day of a second dose were low (15.2% and 5.1%, respectively). Significance Patients with epilepsy may experience seizure clusters lasting up to 24 hours, and little is known about the effectiveness of rescue therapies for that duration. The current labeling of the US Food and Drug Administration (FDA)–approved outpatient treatments for seizure clusters (rectal diazepam, intranasal midazolam, and diazepam nasal spray) allows for a second dose, if needed, for control. These findings support the safety profile of second doses, and the low use supports the effectiveness of diazepam nasal spray across 24 hours.

Abstract Objective A Phase 3 open‐label safety study (NCT02721069) evaluated long‐term safety of diazepam nasal spray (Valtoco) in patients with epilepsy and frequent seizure clusters. Methods Patients were 6–65 years old with diagnosed epilepsy and seizure clusters despite stable antiseizure medications. The treatment period was 12 months, with study visits at Day 30 and every 60 days thereafter, after which patients could elect to continue. Doses were based on age and weight. Seizure and treatment information was recorded in diaries. Treatment‐emergent adverse events (TEAEs), nasal irritation, and olfactory changes were recorded. Results Of 163 patients in the safety population, 117 (71.8%) completed the study. Duration of exposure was ≥12 months for 81.6% of patients. There was one death (sudden unexpected death in epilepsy) and one withdrawal owing to a TEAE (major depression), both considered unlikely to be related to treatment. Diazepam nasal spray was administered 4390 times for 3853 seizure clusters, with 485 clusters treated with a second dose within 24 h; 53.4% of patients had monthly average usage of one to two doses, 41.7% two to five doses, and 4.9% more than five doses. No serious TEAEs were considered to be treatment related. TEAEs possibly or probably related to treatment ( n = 30) were most commonly nasal discomfort (6.1%); headache (2.5%); and dysgeusia, epistaxis, and somnolence (1.8% each). Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly usage, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis. Significance In this large open‐label safety study, the safety profile of diazepam nasal spray was consistent with the established profile of rectal diazepam, and the high retention rate supports effectiveness in this population. A second dose was used in only 12.6% of seizure clusters.

AbstractObjectiveNeed for rescue therapy differs among patients with seizure clusters. Diazepam nasal spray is approved to treat seizure clusters in patients with epilepsy ≥6 years of age. This analysis used interim data from a phase 3 safety study to assess safety profile and effectiveness of diazepam nasal spray using average number of doses/month as a proxy measurement.MethodsThis phase 3, open‐label, repeat‐dose, safety study of diazepam nasal spray enrolled patients (6‐65 years) with epilepsy and need of benzodiazepine rescue. Patients were stratified by average number of doses/month (<2, moderate frequency; 2‐5, high frequency; >5, very‐high frequency). Safety was evaluated based on treatment‐emergent adverse events (TEAEs), assessed nasal irritation, and olfaction. The proportion of treatments given as a second dose was used as an exploratory proxy for effectiveness.ResultsOf 175 enrolled patients (data cutoff, October 31, 2019), 158 received ≥1 dose of diazepam nasal spray. Frequency of use was moderate in 43.7% of patients, high in 50.6% of patients, and very high in 5.7% of patients. Patients treated 3397 seizure episodes (moderate frequency, 14.2%; high frequency, 59.9%; very high frequency, 25.8%). Nasal discomfort was the most common treatment‐related TEAE in all groups. No notable changes in nasal irritation or olfaction were observed. Second doses represented only 2.5%, 7.5%, and 17.2% of all doses in the moderate‐, high‐, and very‐high‐frequency groups, respectively. Overall retention rate was 82.9%, without an observed relationship to frequency of use.SignificanceFrequency of dosing diazepam nasal spray had little impact on the safety/tolerability profile across a range of <2 to >5 doses/month. Effectiveness was suggested for all dosing frequencies by the high proportion of seizure clusters not treated with a second dose. These results support the utility, safety profile, and effectiveness of diazepam nasal spray across frequencies of seizure cluster burden.