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Post Hoc Analysis Provides Insights on Low Need for Second Dose of Diazepam Nasal Spray in Pediatric Epilepsy
Key Takeaways
- Interim analysis shows low second-dose requirement for diazepam nasal spray in children aged 2-5, supporting its efficacy for seizure clusters.
- Study completion rate was 88.6%, with 264 doses administered; only 14% required a second dose within 24 hours.
A recent study presented at AES 2024 showed that fewer than 15% of doses of diazepam nasal spray administered to pediatric patients with epilepsy required a second dose in 24 hours.
James Wheless, MD, BScPharm, FAAP, FACP, FAAN, FAES
(Credit: LinkedIn)
A newly presented interim analysis from an ongoing phase 1/2a study (NCT05076838) revealed a low proportion of pediatric patients, aged between 2 years and 5 years, who required a second dose of diazepam nasal spray (Valtoco; Neurelis) on the same day as their initial dose. These findings support the efficacy of the age-based dosing regimen for diazepam nasal spray for treating seizure clusters.1
As of October 2023, 31 out of 35 patients completed the 180-day safety period, representing a completion rate of 88.6%. Presented at the 2024 American Epilepsy Society Annual Meeting, held December 6-10, in Los Angeles, California, the mean age of participants was 3.9 years, ranging from 2.0 to 5.8 years. During the safety period, a total of 264 doses of diazepam nasal spray were administered, including 8 doses of 5 mg given to 3 patients, 210 doses of 10 mg given to 28 patients, and 46 doses of 15 mg given to 4 patients. Of these doses, 37 (14.0%) were administered as second doses within 24 hours of the first, meaning that 86.0% of doses were given without the need for a second dose.
"This is great news for families and clinicians, it reaffirms the efficacy and use of Valtoco in infants, along with the safety. It allows clinicians to talk to families of infants about an easy to use, socially acceptable method to have an immediate use agent for their seizures that are not typical (clusters or prolonged). This gives parents more options to treat seizures in their child's seizures," lead author James Wheless, MD, BScPharm, FAAP, FACP, FAAN, FAES, told NeurologyLive® when sharing his initial reaction to the main findings from the analysis.
This analysis features data from pediatric patients with epilepsy and seizure clusters who participated in an ongoing phase 1/2a, open-label, pharmacokinetic (PK) and safety study that consisted of a single-day PK assessment period, 180-day open-label safety period, and at least 1-year optional extension period. Authors noted that caregivers of the participants were supplied with diazepam nasal spray (0.5 mg/kg) to administer as needed to treat seizure clusters. Researchers also noted that the doses were based on patients’ body weight and if needed, a second dose could be administered between 4 hours and 12 hours to patients after the first dose. In addition, the dosage could be modified by the investigator for efficacy or safety reasons. For this post-hoc analysis, authors used the nasal-spray usage and seizure diary data collected during the 180-day open-label safety period.
In the study, 10 of the enrolled patients (28.6%) received second doses within 24 hours of the initial dose, with 8 of them (80%) receiving a second dose in less than 4 hours at least once. Of the total doses administered, 162 (61.4%) were used to treat seizure clusters, defined as at least 2 seizures occurring within a 24-hour period. Notably, treatment-related adverse events were reported in 7 patients (20.0%), but none occurred in more than 1 patient, and none were reported as serious.
All told, the rates of second-dose usage in this current analysis were comparable to those observed in pediatric patients aged 6 years and older in a prior phase 3, long-term, open-label safety study (NCT0272109). In the previous phase 3 safety study, findings showed that 11.4% of seizure clusters required second doses, with rates of 11.5% in the 6–11 age group and 11.3% in the 12–17 age group.2 In the present study, 28.6% of patients received at least 1 second dose, compared with 52.6% of patients aged 6–17 years in the phase 3 study.
Wheless, professor and chief of pediatric neurology and the Le Bonheur Chair in Pediatric Neurology at the University of Tennessee Health Science Center, said, "Ease of use by the families when using this and acceptance of this product; safety of multiple doses when given in under 4 hours; effects of having this treatment on health care utilization, family quality of life; and day care acceptance," when asked about what should be further investigated with this treatment.
Diazepam nasal spray was officially approved in the US in January 2020 for acute treatment of seizure clusters in patients with epilepsy aged at least 6 years with age-based dosing of 0.2 and 0.3 mg/kg.3 The current labeling of the FDA approved outpatient treatments for seizure clusters, such as diazepam nasal spray, allows for a second dose at least 4 hours after the first if needed. Findings from a prior study published in Epilepsia supported the safety profile of second doses and also the efficacy of low use of diazepam nasal spray across 24 hours of the initial dose to treat a cluster among patients aged between 6 years and 65 years.4
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REFERENCES
1. Wheless J, Segal E, Shih E, et al. Second Dose Use as a Proxy for Effectiveness of Diazepam Nasal Spray in Patients with Epilepsy Aged 2-5 Years: Interim Results from a Phase 1/2a Study. Presented at: AES 2024; December 6-10; Los Angeles, CA.
2. Tarquinio D, Dlugos D, Wheless JW, Desai J, Carrazana E, Rabinowicz AL. Safety of Diazepam Nasal Spray in Children and Adolescents With Epilepsy: Results From a Long-Term Phase 3 Safety Study. Pediatr Neurol. 2022;132:50-55. doi:10.1016/j.pediatrneurol.2022.04.011
3. Neurelis Announces FDA Approval of Valtoco® (Diazepam Nasal Spray) for Seizure Rescue, Featuring Intravail® Technology for Reliable Absorption. News Release. Neurelis. Published January 13, 2020. Accessed December 5, 2024. https://www.neurelis.com/neurelis-news/neurelis-announces-fda-approval-seizure-rescue-treatment-valtocor-diazepam-nasal-spray-incorporates
4. Sperling MR, Wheless JW, Hogan RE, et al. Use of second doses of Valtoco® (diazepam nasal spray) across 24 hours after the initial dose for out-of-hospital seizure clusters: Results from a phase 3, open-label, repeat-dose safety study. Epilepsia. 2022;63(4):836-843. doi:10.1111/epi.17177
