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April
2002
Volume 66 |
Number
4
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FDA
Alert:
Current FDA Report on Droperidol Status and Basis for 'Black
Box' Warning |
Cynthia G.
McCormick, M.D.
U.S. Food and Drug Administration
Anesthesiologists
have been using droperidol for years in doses of less than 1 mg
and have not been aware of significant complications, according
to Bruce F. Cullen, M.D., Vice-President for Scientific Affairs.
So recently when the U.S. Food and Drug Administration (FDA) placed
stricter warnings on this product due to reported adverse cardiovascular
events, Dr. Cullen contacted FDA officials for an explanation.
While FDA continues to review all available information on this
matter, including ongoing studies, Cynthia G. McCormick, M.D.,
of the FDA agreed that making information more available to the
anesthesiology community was in order and supplied the following
article exclusively for the ASA NEWSLETTER. Comments about droperidol
can be directed to FDA at www.fda.gov/cder
/audiences/acspage/anestheticroster1.htm.
This brief
report will summarize the factors leading to the Food and Drug
Administration's (FDA's) action to place additional warnings on
droperidol labels that highlight the risk of QT prolongation and
torsades de pointe (TdP), a serious and sometimes fatal arrhythmia.
Droperidol is a butyrophenone approved in 1970 as an injectable
formulation for the reduction of nausea and vomiting associated
with surgical and diagnostic procedures. It also has been widely
used off-label for the treatment of acute mania in the psychiatric
emergency setting. Droperidol is only available in the United
States as an injectable formulation in a concentration of 2.5
mg/mL. The current recommended initial dose for adults is 2.5
mg intramuscularly or intravenously (I.V.). In the current anesthetic
setting, doses of 0.625 mg and lower are in frequent use, but
these doses have never been shown to be safe and effective in
an application to the FDA.
While the
labeling for droperidol carried warnings about the potential for
cardiovascular adverse events at high doses and in the setting
of alcoholic withdrawal, these warnings did not reflect what had
been reported to FDA over the years since the product¹s initial
marketing or in the world literature. In January 2001, following
notification that droperidol was being discontinued from worldwide
markets,1,2 FDA began to re-examine its databases for evidence
of cardiovascular adverse events reported in the United States
and globally. In June 2001, FDA concluded that the available information
confirmed a greater cardiovascular risk than was previously appreciated.
Examination
of all available spontaneous adverse event reports revealed approximately
100 unique reports of cardiovascular events of which there were
approximately 20 unique reports of TdP and/or QT/QTc prolongation.
Tabulation of selected cases from the FDA database and the sponsor's
worldwide database revealed at least 38 cases of cardiovascular
events of which there were 25 cases of cardiac or sudden death
and nine cases of TdP with the remainder ventricular extrasystole
or syncope. This subset of 38 cases was selected for careful review
due to the completeness of the information, such as information
on concomitant drugs, time of onset and specificity of report.
Eleven cases reported an onset time of 30 minutes or less following
drug administration.
Of 28 out
of 38 cases in which dose was reported, 12 cardiovascular adverse
events occurred at doses at or below 2.5 mg. These included reports
of TdP (three cases), cardiac arrest (three cases) and death (four
cases). At doses below 1 mg, there were five reports, including
one death, one cardiac arrest and one TdP. The maximum QT interval
reported in this group was 600 msec in a patient receiving a single
dose of 0.625 mg of droperidol. This patient also experienced
nonfatal TdP.
Spontaneous
reports of adverse events associated with a drug that has been
marketed for more than 30 years can be expected to be very limited.
Therefore, the number of reports passively received does not necessarily
reflect the magnitude of the problem but reflects only a fraction
of the total number of events. Since the total extent of exposure
is also not known once a drug is marketed, calculation of true
incidence is not possible because neither the actual total number
of events nor the total extent of exposure is known. In the case
of droperidol, the finding of a dose-dependent prolongation of
the QTc of the magnitude described in the German literature, coupled
with actual reports documenting TdP at and below the labeled dose,
was considered a serious risk, one with no margin of safety.
Information
from clinical trials in the published medical literature supports
the long-held belief that droperidol prolongs the QTc interval
length in a dose-dependent fashion. Two of these beliefs bear
mentioning.
In a German
prospective study3 designed to explore the relationship between
dose of droperidol and QTc prolongation, 40 patients undergoing
head and neck surgery were randomized to one of three dose groups
receiving 0.1, 0.175 and 0.25 mg/kg, respectively. Significant
prolongation of the median QTc was found in all three I.V. droperidol
dosing groups compared to their baseline control. The medians
of the maximum increases in QTc intervals seen in a dose-dependent
manner were: 37 msec at 0.1 mg/kg (n=10); 44 msec at 0.175 mg/kg
(n=10); and 59 msec at 0.25 mg/kg (n=20). These findings were
measured to only 10 minutes, but the increases were seen after
one minute.
A French case
report4 exploring the association between TdP and droperidol described
a patient with no risk factors for cardiovascular disease and
no history of QT prolongation who developed TdP with loss of consciousness
following a 12.5-mg I.V. dose of droperidol. Upon rechallenge,
she had a similar episode lasting 10-45 seconds without loss of
consciousness. The episode was followed by a run of ventricular
tachycardia that responded to electrical cardioversion. Following
this report, a small study was undertaken. This study reports
electrocardiographic (ECG) changes in 55 patients (22 with cardiac
history). All received droperidol 0.25 mg/kg I.V. before surgery
and had ECGs at baseline and serially for 10 minutes following
droperidol. The authors report a significant increase in QT above
baseline for 70 percent of patients by the end of the first minute.
QT increased from 387±34 msec to 423±37 msec, and the QT/QTc ratio
increased from 1.06±0.08 to 1.28±0.1. QTc changes were not directly
reported.
While both
of these reports involved higher doses than are currently used
in the anesthetic setting, they point out two important features.
First, there is a dose-response relationship between droperidol
administration and QTc prolongation, and next, the QT prolongation
can recur upon rechallenge with droperidol. These reports implicate
droperidol in these cardiovascular adverse events.
The FDA held
many internal meetings involving senior management to discuss
these findings, particularly in the context of other drugs that
have shared this characteristic, comparing this signal with other
similar drugs. The FDA conveyed its cardiovascular safety concerns
with representatives of Taylor Pharmaceuticals of Akorn, Inc.,
the U.S. holder of the marketing application for droperidol injection.
In response to these concerns, the firm proposed revised labeling
for a maximum initial adult dose of 2.5 mg or less and inclusion
of a "black box" warning.
Because of
the serious nature of the reported cardiovascular adverse events
associated with droperidol use and the fact that they were associated
with doses below the labeled dose, the FDA sought a conservative
but definitive means to warn the prescribing public of this information.
The FDA has used the black box warning for other drugs posing
similar adverse cardiovascular risk with relatively few reported
cases and more widespread use. Factors that were taken into consideration
in implementing the black box warning included the fact that warnings
about cardiovascular toxicity had already been in the package
insert for many years. The existing warnings understated the risks
in that the described events were reported to occur even at doses
below those approved.
The outcome
of the FDA meetings was that the administration committed itself
to conducting a definitive pharmacokinetic/pharmacodynamic study
to evaluate the effect of dose on the QTc interval, exploring
doses from placebo to 0.625 mg, 2.5 mg and 5.0 mg in a crossover
design in healthy volunteers who would be on no concomitant medications.
This study is ongoing and is expected to be completed later this
year. Concurrently, examination of alternative medications and
their adverse effects is being conducted by the administration.
The FDA continues to monitor droperidol adverse event reports
very closely for any new or stronger signals of risk associated
with droperidol use.
At the point
at which the FDA has reviewed these materials and the results
of the cardiovascular study, it plans to convene a meeting of
the Anesthetics and Life Support Drugs Advisory Committee to consider
and weigh all of the available information and discuss possible
future actions. In the interim, we are working with the manufacturer
of droperidol to inform practitioners of the new findings and
facilitate careful management of patients to prevent untoward
events related to QT prolongation from occurring.
References:
- World Health
Organization Pharmaceuticals. 1997; (7 and 8):3-4.
- Medicines
Control Agency: www.mca.gov.uk./ourwork/monitorsafequalmed/safetymessages/droleptan.htm.
- Lischke
V, et al. Droperidol causes a dose-dependent prolongation of
the QT interval. Anesth Analg. 1994; 79:983-986.
- Guy JM,
et al. Torsades de pointes et allongement de la duree de l'intervalle
QT apres injection de droperidol. An de Cardiologie et d'Angeiolie.
1991; 40:541-545.
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Cynthia G. McCormick,
M.D., is Director of the Division of Anesthetic, Critical
Care and Addiction Drug Products, Center for Drug Evaluation
and Research, U.S. Food and Drug Administration, Rockville,
Maryland. |
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