{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:07:52Z","timestamp":1790899672280,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2021,8,21]],"date-time":"2021-08-21T00:00:00Z","timestamp":1629504000000},"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":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>A Phase 3 open\u2010label safety study (NCT02721069) evaluated long\u2010term safety of diazepam nasal spray (Valtoco) in patients with epilepsy and frequent seizure clusters.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients were 6\u201365\u00a0years old with diagnosed epilepsy and seizure clusters despite stable antiseizure medications. The treatment period was 12\u00a0months, with study visits at Day 30 and every 60\u00a0days thereafter, after which patients could elect to continue. Doses were based on age and weight. Seizure and treatment information was recorded in diaries. Treatment\u2010emergent adverse events (TEAEs), nasal irritation, and olfactory changes were recorded.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 163 patients in the safety population, 117 (71.8%) completed the study. Duration of exposure was \u226512\u00a0months 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\u00a0seizure clusters, with 485\u00a0clusters treated with a second dose within 24\u00a0h; 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                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a030) 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>In this large open\u2010label 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.17041","type":"journal-article","created":{"date-parts":[[2021,8,21]],"date-time":"2021-08-21T16:09:47Z","timestamp":1629562187000},"page":"2485-2495","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Final results from a Phase 3, long\u2010term, open\u2010label, repeat\u2010dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy"],"prefix":"10.1111","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4735-3431","authenticated-orcid":false,"given":"James W.","family":"Wheless","sequence":"first","affiliation":[{"name":"Le Bonheur Children's Hospital University of Tennessee Health Science Center Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0416-1015","authenticated-orcid":false,"given":"Ian","family":"Miller","sequence":"additional","affiliation":[{"name":"Formerly Nicklaus Children's Hospital Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2272-5005","authenticated-orcid":false,"given":"R. Edward","family":"Hogan","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Dlugos","sequence":"additional","affiliation":[{"name":"Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Biton","sequence":"additional","affiliation":[{"name":"Arkansas Epilepsy Program Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory D.","family":"Cascino","sequence":"additional","affiliation":[{"name":"Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kore","family":"Liow","sequence":"additional","affiliation":[{"name":"Hawaii Pacific Neuroscience Honolulu Hawaii USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Vazquez","sequence":"additional","affiliation":[{"name":"New York University, Comprehensive Epilepsy Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric B.","family":"Segal","sequence":"additional","affiliation":[{"name":"Hackensack University Medical Center and Northeast Regional Epilepsy Group Hackensack New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Tarquinio","sequence":"additional","affiliation":[{"name":"Center for Rare Neurological Diseases Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weldon","family":"Mauney","sequence":"additional","affiliation":[{"name":"Northwest Florida Clinical Research Group Gulf Breeze Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Desai","sequence":"additional","affiliation":[{"name":"Children's Hospital of Los Angeles Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian L.","family":"Rabinowicz","sequence":"additional","affiliation":[{"name":"Neurelis San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8788-0722","authenticated-orcid":false,"given":"Enrique","family":"Carrazana","sequence":"additional","affiliation":[{"name":"Neurelis San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the DIAZ.001.05 Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/NRL.0000000000000140"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1999.tb01607.x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2016.02.030"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1999.tb02047.x"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2018.05.013"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S105913110200170X"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2016.07.001"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2010.10.001"},{"key":"e_1_2_9_10_1","unstructured":"Shire Pharmaceuticals.Buccolam: summary of product characteristics. 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