Safety of a Second Dose of Diazepam Nasal Spray Within 4 Hours in Patients with Seizure Clusters: Final Results from a Long-Term, Phase 3, Open-Label, Repeat-Dose Safety Study
Abstract number :
3.275
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2021
Submission ID :
1825583
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:44 AM
Authors :
Gregory Cascino, MD - Mayo Clinic; Jay Desai, MD - Children’s Hospital of Los Angeles; Daniel Tarquinio, DO - Center for Rare Neurological Diseases; James Wheless, MD - Le Bonheur Children’s Hospital, University of Tennessee Health Science Center; R. Edward Hogan, MD - Washington University in St. Louis; Michael Sperling, MD - Thomas Jefferson University; Kore Liow, MD - Hawaii Pacific Neuroscience; Sunita Misra, MD, PhD - Neurelis, Inc.; Enrique Carrazana, MD - Neurelis, Inc.; Adrian Rabinowicz, MD - Neurelis, Inc.
Rationale: Second doses of diazepam rescue therapy for seizure clusters are typically given 4–12 hours after the initial dose, if needed, based on the clinical development program for the rectal gel formulation approved by the US Food and Drug Administration in 1997. This timing was intended to address potential safety issues and drug blood levels. Untreated, however, approximately one-third of second seizures in clusters take place within 3 hours of the first; thus, waiting to administer a second dose may be a limitation. Diazepam has been shown to be safe at a range of concentrations. In a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray, an exploratory analysis descriptively evaluated the safety profile of second doses within 4 hours of the first dose.
Methods: Enrolled patients were aged 6–65 years who experienced seizure clusters. Patients and care partners were trained to administer age- and weight-based doses of diazepam nasal spray of 5, 10, 15, or 20 mg; if needed, a second dose could have been administered 4–12 hours later. Per protocol, dosing could be adjusted as deemed appropriate by the investigator. This analysis assessed the safety of diazepam nasal spray in patients treated with ≥1 second dose within 4 hours and 4–24 hours after the first dose at any point during the study duration. Treatment emergent adverse events (TEAEs) were recorded.
Results: Of 175 enrolled patients, 163 received at least 1 dose (mean age, 23.1 years; 54.6% female). A total of 3853 seizure clusters were treated with 4390 total doses of diazepam nasal spray. Of these doses, 485 were second doses given to 79 (48.5%) patients; 38 (23.3%) patients received ≥1 second dose within 4 hours (< 4 hours group; 152 doses), and 41 (25.2%) patients received second doses within 4–24 hours (4–24 hours group; 333 doses) of the initial dose. Overall rates of TEAEs were generally similar between the groups (Table). The most common treatment-related TEAEs (≥2 patients) in the < 4 hours group were of mild or moderate severity. Most common treatment-related TEAEs in the 4–24 hours group were rated as mild. One discontinuation due to a TEAE and one death (neither treatment-related) were reported in the 4–24 hours group; neither was reported in the < 4 hours group. No serious treatment-related TEAEs were reported in either group.
Conclusions: These safety data from a long-term, phase 3, open-label, repeat-dose safety study found few treatment-related TEAEs in patients who received a second dose within 4 hours of the first dose or in patients who received second doses at 4–24 hours. These treatment-related TEAEs were typically mild or moderate. The results for both subgroups were consistent with an earlier interim analysis in the overall safety population and the established profile for rectal diazepam.
Funding: Please list any funding that was received in support of this abstract.: Neurelis, Inc.
Anti-seizure Medications