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In December 2001, the Food and Drug Administration
(FDA) placed a “black box” warning on
droperidol labels because of serious concerns about
its potential to cause life-threatening ventricular
dysrhythmias. Droperidol has been shown to cause QTc
prolongation, and in March 2001, worldwide marketing
of droperidol outside the United States was discontinued
following a risk-benefit analysis and examination
of reported cases of QTc prolongation.
These events led the FDA to review its own postmarketing
safety database, Janssen’s analysis and the
available literature on droperidol and QTc prolongation.
Dose-dependent QTc prolongation and association with
torsades de pointes (TdP) upon challenge and rechallenge
with droperidol was well documented in the literature.
In addition, the postmarketing safety database was
found to contain cases of QTc prolongation, TdP, cardiac
arrest and death associated with doses of droperidol
at and below the lowest labeled dose of 2.5 mg.
Anesthesiologists typically use very low doses of
droperidol for the treatment and prevention of nausea
and vomiting — well below the lowest labeled
dose of 2.5 mg. — and the potential for QTc
prolongation at these low doses has not been well
characterized. In order for the FDA to approve droperidol
at doses below 2.5 mg, the Administration must be
provided with data that satisfy regulatory requirements
for the demonstration of efficacy and safety at these
doses.
Droperidol has been a priority within the FDA as evidenced
by its willingness to devote significant human and
financial resources to continue the evaluation of
the pharmacology and safety profile of this drug.
A comprehensive evaluation of the postmarketing safety
databases of droperidol and its alternatives has been
undertaken, and the FDA sponsored a study recently
that measured QTc prolongation after administration
of droperidol to healthy volunteers.
The study utilized a crossover design with droperidol
doses of 0 mg, 0.625 mg, 2.5 mg and 5 mg. Although
the study was prematurely terminated because of significant
neuropsychiatric adverse effects, including dysphoria
and anxiety, there were several findings of note.
Impressive QTc prolongations (approximately 80 ms
from baseline) were found in individuals following
the 2.5 mg and the 5 mg doses, even though only seven
and three subjects, respectively, received these doses.
Compared to placebo, the 0.625 mg dose did not appear
to have a significant effect on QTc; however, this
cannot be considered a definitive finding as only
five individuals were studied at this dose. Additional
investigation will be required to further define the
relationship between QTc prolongation, potential for
dysrhythmia and various doses of droperidol.
The FDA is now exploring options to obtain data that
satisfy regulatory standards for the demonstration
of safety and efficacy at doses lower than 2.5 mg.
An advisory committee meeting to discuss droperidol
also is planned. We continue to closely follow the
adverse events database for droperidol, and we urge
practitioners to participate in the postmarketing
safety assessment process by reporting all potential
drug-related adverse events. For more information
on reporting adverse events, visit <www.fda.gov/medwatch>.
| Nancy Chang, M.D.,
is Medical Team Leader for Anesthesia and
Critical Care, Division of Anesthesia, Critical
Care and Addiction Drug Products, Center for
Drug Evaluation and Research, Food and Drug
Administration, Rockville, Maryland. |
| Bob Rappaport, M.D., is
Acting Division Director, Division of Anesthesia,
Critical Care and Addiction Drug Products,
Center for Drug Evaluation and Research, Food
and Drug Administration, Rockville, Maryland. |
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