Safety of Diazepam Nasal Spray in Children and Adolescents With Epilepsy: Results From a Long-Term Phase 3 Safety Study

Tarquinio, Daniel; Dlugos, Dennis J.; Wheless, James W.; Desai, Jay; Carrazana, Enrique; Rabinowicz, Adrián L.

doi:10.1016/j.pediatrneurol.2022.04.011

Cited by 13 publications

(23 citation statements)

References 25 publications

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“…The rates of treatment-emergent adverse events were generally similar between the patients in the broad pediatric developmental epileptic encephalopathy group (89.1%), the 3 specific syndrome groups (66.7%-100%), the previously published results of the a larger group of all pediatric patients in the study (87.2%), 10 and the overall study population (82.2%). 9 Rates of serious treatment-emergent adverse events were also similar between the broad pediatric developmental epileptic encephalopathy group (39.1%) and the entire pediatric study population (35.9%) and the overall study population (30.7%), even though these groups with severe disease might have been expected to report elevated rates.…”

Section: Discussionsupporting

confidence: 70%

“…8 Results of a long-term phase 3 safety study of diazepam nasal spray have been published for both the overall patient population, aged 6-65 years, 9 and the pediatric subpopulation, aged 6-17 years. 10 This post hoc analysis explored possible differences in longterm safety and effectiveness of diazepam nasal spray to treat seizure clusters in groups of patients with pediatric developmental epileptic encephalopathies: a broad group with pediatric developmental epileptic encephalopathies and 3 groups with specific diagnoses: Rett syndrome, Lennox-Gastaut syndrome, and Dravet syndrome.…”

mentioning

confidence: 99%

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Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study

Tarquinio¹,

Wheless

Segal

et al. 2023

J Child Neurol

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Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients (ClinicalTrials.gov NCT02721069).

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Section: Discussionsupporting

confidence: 70%

mentioning

confidence: 99%

Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study

Tarquinio¹,

Wheless

Segal

et al. 2023

J Child Neurol

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“…In addition, participants in the diazepam nasal spray appear to have had roughly twice as many seizure clusters per year, suggestive of a high degree of intractability in that population. Notably, the diazepam nasal spray study included children with developmental and epileptic encephalopathies (30 of 78 patients 6–17 years of age received concomitant clobazam 30 ), while a substantial majority of the intranasal midazolam population were adults with a focal form of seizures, 19 suggesting that the diazepam nasal spray population may have had a higher level of seizure intractability. Although people with allergic rhinitis were not excluded from the midazolam study, the impact of this condition was not formally evaluated.…”

Section: Discussionmentioning

confidence: 99%

Implications of Seizure-Cluster Treatment on Healthcare Utilization: Use of Approved Rescue Medications

Rabinowicz¹,

Faught²,

Cook³

et al. 2022

NDT

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People with epilepsy may experience seizure clusters despite a stable regimen of antiseizure medications. Such clusters have the potential to last ≥24 hours, typically occur in the community setting, and may progress to medical emergencies, such as status epilepticus, if untreated. Thus, long-acting rescue therapy for seizure clusters is needed that can be administered by nonmedical individuals outside a hospital. Benzodiazepines are the foundation of rescue therapy for seizure clusters. The approved outpatient treatments (ie, diazepam, midazolam) have differing profiles that may affect multiple aspects of health-care utilization. The current labeling of these medications allows for a second dose if needed to control the cluster. Although no head-to-head studies directly comparing rescue treatments have been conducted, differences between studies with generally similar designs may provide context for the potential importance of second doses of rescue therapy on health-care utilization. Methods: For this analysis, large, long-term, open-label studies of approved seizure-cluster treatments designed for use by nonmedical caregivers were reviewed, and the percentage of seizure clusters for which a second dose was used or that were not controlled at 6, 12, and 24 hours was examined. Available data on hospitalizations were also collected. Results:The 3 identified studies meeting the inclusion criteria were for use of diazepam rectal gel, intranasal midazolam, and diazepam nasal spray. Across these studies, the use of a second dose ranged from <40% at 6 hours to <13% at 24 hours. Hospitalizations and serious treatment-emergent adverse events were reported variably across these studies. Conclusion:These results demonstrate the importance of second doses of rescue therapy for seizure clusters for optimizing healthcare utilization. Need for second doses should be included as one component. In turn, when second doses are needed, they have the potential to curtail emergency department use and hospitalization and to prevent further seizure clusters.

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“…In a long-term safety analysis of repeated nasal diazepam in pediatric patients (6–17 years of age) with frequent seizures showed a safety profile consistent with that of all study populations (ages 6–65 years). ( Tarquinio et al, 2022 ). Hence, intra-nasal first aid is a good treatment option.…”

Section: Discussionmentioning

confidence: 99%

A bibliometric analysis of the recent advances in diazepam from 2012 to 2021

Zhang

Kou²,

Qin³

et al. 2022

Front. Pharmacol.

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Background: Diazepam is a classic benzodiazepine drug that has been widely used for disorders such as anxiety, sleep disorders, and epilepsy, over the past 59 years. The study of diazepam has always been an important research topic. However, there are few bibliometric analyses or systematic studies in this field. This study undertook bibliometric and visual analysis to ascertain the current status of diazepam research, and to identify research hotspots and trends in the past 10 years, to better understand future developments in basic and clinical research.Methods: Articles and reviews of diazepam were retrieved from the Web of Science core collection. Using CiteSpace, VOSviewer, and Scimago Graphica software, countries, institutions, authors, journals, references, and keywords in the field were visually analyzed.Results: A total of 3,870 publications were included. Diazepam-related literature had high volumes of publications and citations. The majority of publications were from the USA and China. The highest number of publications and co-citations, among the authors, was by James M Cook. Epilepsia and the Latin American Journal of Pharmacy were the journals with the most publications on diazepam and Epilepsia was the most frequently cited journal. Through a comprehensive analysis of keywords and references, we found that current research on diazepam has focused on its mechanism of action, application in disease, pharmacokinetics, risk, assessment, and management of use, status epilepticus, gamma-aminobutyric acid receptors (GABAR), intranasal formulation, gephyrin, and that ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is the current research hotspot.Conclusion: Research on diazepam is flourishing. We identified research hotspots and trends in diazepam research using bibliometric and visual analytic methods. The clinical applications, mechanisms of action, pharmacokinetics, and assessment and management of the use of diazepam are the focus of current research and the development trend of future research.

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Safety of Diazepam Nasal Spray in Children and Adolescents With Epilepsy: Results From a Long-Term Phase 3 Safety Study

Cited by 13 publications

References 25 publications

Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study

Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study

Implications of Seizure-Cluster Treatment on Healthcare Utilization: Use of Approved Rescue Medications

A bibliometric analysis of the recent advances in diazepam from 2012 to 2021

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