Flumazenil: US clinical pharmacology studies.
Flumazenil, a benzodiazepine antagonist, blocks the central effects of benzodiazepines by competitive interaction at the receptor site. Two double-blind, placebo-controlled, randomized studies in healthy volunteers (110/study) were performed to determine the minimal effective dose of flumazenil required to reverse the sedative, psychomotor and amnesic effects of benzodiazepines used to produce conscious sedation. Conscious sedation was produced by i.v. diazepam (12-30 mg) in one study and i.v. lorazepam (0.045 mg kg-1) in the other. Intravenous flumazenil (0.001, 0.003, 0.007 or 0.014 mg kg-1) or placebo was administered after diazepam or lorazepam. Assessment of sedation, psychomotor performance and recall/recognition were made both before and after the benzodiazepine as well as serially after flumazenil or placebo. Doses as low as 0.007 and 0.014 mg kg-1 flumazenil consistently reversed diazepam- and lorazepam-induced effects, respectively. The duration of reversal produced by varying doses of flumazenil (0.2, 0.6, 1.0 or 3 mg) was evaluated in 50 volunteers in a double-blind, placebo-controlled, parallel group study. A constant level of conscious sedation was produced by a continuous infusion of midazolam. Assessments of sedation and psychomotor performance were assessed both before and at varying times after the administration of flumazenil or placebo. Preliminary results indicate that the duration of reversal produced by 3.0 mg flumazenil was longer than that produced by any of the lower doses. While the mean duration of reversal produced by the lower doses was comparable, the 0.2 mg dose resulted in the greatest between subject variability and only partial rather than complete reversal. Two further double-blind, placebo-controlled studies were done in healthy volunteers (45/study) to evaluate the safety of flumazenil 1.0 mg or placebo given i.v. to reverse midazolam-induced sedation in subjects who had been treated for up to 14 days with either oral diazepam or triazolam. No clinically significant changes were noted in laboratory test values, electrocardiograms or vital signs monitored for up to 36 h after flumazenil or placebo in any pre-treatment group.
Dunton
A W
AW
Hoffmann-La Roche Clinical Pharmacology Unit--D-11, Newark Beth Israel Medical Center, New Jersey 07112.
Schwam
E
E
Pitman
V
V
McGrath
J
J
Hendler
J
J
Siegel
J
J
D000328:Adult; D003975:Diazepam / Q000494:pharmacology; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D005442:Flumazenil / Q000494:pharmacology*; D006801:Humans; D008140:Lorazepam / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects; D011963:Receptors, GABA-A / Q000378:metabolism*; D014229:Triazolam / Q000494:pharmacology
D011963:Receptors, GABA-A; D014229:Triazolam; D005442:Flumazenil; D008140:Lorazepam; D003975:Diazepam