Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy.

Authors

• Michael R Sperling
• Kevin F Haas
• Gregory Krauss
• Hussam Seif Eddeine
• Herbert R Henney
• Adrian L Rabinowicz
• Gary Bream
• David Squillacote
• Enrique J Carrazana

Publication/Presentation Date

10-1-2014

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.

SIGNIFICANCE: 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.

Volume

55

Issue

10

First Page

1544

Last Page

1550

ISSN

1528-1167

Published In/Presented At

Sperling, M. R., Haas, K. F., Krauss, G., Seif Eddeine, H., Henney, H. R., 3rd, Rabinowicz, A. L., Bream, G., Squillacote, D., & Carrazana, E. J. (2014). Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy. Epilepsia, 55(10), 1544–1550. https://doi.org/10.1111/epi.12755

Disciplines

Medicine and Health Sciences

PubMedID

25154625

Department(s)

Department of Medicine

Document Type

Article