{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T17:52:44Z","timestamp":1767117164258,"version":"3.40.5"},"reference-count":30,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T00:00:00Z","timestamp":1650326400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Current diazepam nasal spray labeling requires waiting 4\u00a0h before administering a second dose. The objective of the current analyses was to examine safety and pharmacokinetic profiles of second doses of diazepam nasal spray given 0\u22124\u00a0h after the first dose.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two datasets were analyzed. The first, a long\u2010term, repeat\u2010dose safety study of diazepam nasal spray, compared rates of treatment\u2010emergent adverse events (TEAEs), serious TEAEs, and treatment\u2010related TEAEs for patients receiving \u22651\u00a0second dose \u22644\u00a0h versus all second doses &gt;4\u00a0h after the first. The second was a population pharmacokinetic analysis using data from three phase 1\u00a0studies to model drug exposure when a second dose of diazepam nasal spray was administered across multiple time points (1\u00a0min\u22124\u00a0h) following the first dose.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the repeat\u2010dose safety study, a second dose of diazepam nasal spray was administered \u226424\u00a0h after the first to treat 485\u00a0seizure clusters in 79 patients. Rates of TEAEs were similar between patients receiving \u22651\u00a0second dose in \u22644\u00a0h (89.5%, <jats:italic>n<\/jats:italic>\u00a0=\u00a038) compared with &gt;4\u201324\u00a0h only (80.5%, <jats:italic>n<\/jats:italic>\u00a0=\u00a041). The most common treatment\u2010related TEAEs were associated with nasal discomfort, which was mild or moderate and transient. There were no reports of respiratory or cardiac depression. The pharmacokinetic simulations of second doses predicted comparable elevations of plasma diazepam concentrations with administrations across a range of intervals after the first dose (1\u00a0min\u22124\u00a0h).<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>These data indicate that the safety and pharmacokinetic profiles of a second dose of diazepam nasal spray administered within 4\u00a0h of the first dose are consistent with those associated with current labeling. This is potentially important for patients with seizure clusters who have a recurrent seizure within 4\u00a0h of first treatment and might benefit from immediate retreatment to reduce the risk of progression to status epilepticus.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17249","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T14:30:46Z","timestamp":1649082646000},"page":"1714-1723","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Lack of clinically relevant differences in safety and pharmacokinetics after second\u2010dose administration of intranasal diazepam within 4\u00a0h for acute treatment of seizure clusters: A population analysis"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5380-2977","authenticated-orcid":false,"given":"Gregory D.","family":"Cascino","sequence":"first","affiliation":[{"name":"Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Tarquinio","sequence":"additional","affiliation":[{"name":"Center for Rare Neurological Diseases  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4735-3431","authenticated-orcid":false,"given":"James W.","family":"Wheless","sequence":"additional","affiliation":[{"name":"Le Bonheur Children\u2019s Hospital University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2272-5005","authenticated-orcid":false,"given":"Robert Edward","family":"Hogan","sequence":"additional","affiliation":[{"name":"Washington University in St Louis  St Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0708-6006","authenticated-orcid":false,"given":"Michael R.","family":"Sperling","sequence":"additional","affiliation":[{"name":"Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay","family":"Desai","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Los Angeles  California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blanca","family":"Vazquez","sequence":"additional","affiliation":[{"name":"Comprehensive Epilepsy Center New York University  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emil","family":"Samara","sequence":"additional","affiliation":[{"name":"PharmaPolaris International  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7624-8825","authenticated-orcid":false,"given":"Sunita N.","family":"Misra","sequence":"additional","affiliation":[{"name":"Neurelis  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8788-0722","authenticated-orcid":false,"given":"Enrique","family":"Carrazana","sequence":"additional","affiliation":[{"name":"Neurelis  San Diego California USA"},{"name":"John A. 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