title: Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy.
abstract: OBJECTIVE
  To determine the feasibility of administering a diazepam nasal spray formulation (diazepam-NS) to adults with epilepsy during a generalized tonic-clonic seizure or in the postictal period following a tonic-clonic or other seizure type, to assess pharmacokinetics and to assess tolerability.
  
  
  METHODS
  An open-label study was conducted in patients admitted to the epilepsy monitoring unit. Eligible patients received a single dose of diazepam-NS approximating 0.2 mg/kg. Plasma diazepam concentrations were measured serially up to 12 h postdose, and maximum observed plasma concentration (Cmax ); time to maximum concentration (Tmax ); and the area under the plasma concentration-time curve for time zero to last sampling time (AUC0-12 ) were estimated and dose-normalized. Pharmacodynamic assessments included Kaplan-Meier analysis to determine the time-to-next seizure. Safety and tolerability were assessed.
  
  
  RESULTS
  Of the 78 patients who consented, 30 had treatment and pharmacokinetic data. Ten patients were treated during a convulsive tonic-clonic seizure, seven within 5 min following the last clonic jerk, and 13 in the postictal period ≥ 5 min after a tonic-clonic or following other seizure-types. Diazepam median Tmax was 45 min. Dose-normalized mean Cmax and AUC0-12 values of diazepam were comparable among patients regardless of the timing of diazepam-NS administration in relation to seizure. Of those treated, 65% were seizure-free during the 12-h observation period and 35% had post-dose seizures. Treatment was well tolerated, with no unexpected safety findings: 74% had mild and 25% had moderate adverse events. Nasopharyngeal signs were resolved by 12 h postdose.
  
  
  CONCLUSIONS
  Diazepam can be delivered in effective therapeutic concentrations by a nasal spray device during the convulsive phase of tonic-clonic seizures or in the postictal periods following tonic-clonic or other seizure types.
authors.affiliation: Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sperling
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Haas
authors.forename: Gregory
authors.initials: G
authors.lastname: Krauss
authors.forename: Hussam
authors.initials: H
authors.lastname: Seif Eddeine
authors.forename: Herbert R
authors.initials: HR
authors.lastname: Henney
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Rabinowicz
authors.forename: Gary
authors.initials: G
authors.lastname: Bream
authors.forename: David
authors.initials: D
authors.lastname: Squillacote
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Carrazana
mesh_terms: D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003975:Diazepam / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D003975:Diazepam
keywords: Adults; Diazepam; Intranasal; Pharmacokinetics; Seizures