FDA “Black Box” Warning Regarding Use of Droperidol for Postoperative Nausea and Vomiting: Is It Justified?
Gan, Tong J. M.D.; White, Paul F. Ph.D., M.D.†; Scuderi, Philip E. M.D.; Watcha, Mehernoor F. M.D.; Kovac, Anthony M.D.
To the Editor:—
On December 5, 2001, the US Food and Drug Administration (FDA) issued a new “black box” warning on droperidol (Akorn Pharmaceuticals, Buffalo Grove, IL), a popular antiemetic for the treatment and/or prevention of postoperative nausea and vomiting (PONV). *
Droperidol previously carried a warning regarding the potential for sudden cardiac death at high doses (> 25 mg) in psychiatric patients. The revised warning suggests that even low doses of droperidol should only be used when other “first-line” drugs fail. Unfortunately, this situation places the practicing anesthesiologist in a real dilemma 1
as there is now a significant difference between standard clinical practice and the package insert recommendation for this commonly used antiemetic drug.
Droperidol has been used for the management of PONV for over 30 yr. Intravenous doses of 0.625–1.25 mg have been widely accepted as a first-line therapy for the prophylaxis and treatment of PONV. 2,3
In a recent market survey, droperidol constituted over 30% of the antiemetic market share in the US, with over 25 million units sold in 2000. Of the 30 million surgical procedures performed each year in the US, approximately 30% of these patients will develop PONV. Patients would rather experience pain than emesis, 4
and they are willing to pay out of pocket for an effective antiemetic. 5,6
Several large randomized controlled trials have demonstrated that droperidol is as safe and effective as ondansetron in adults. 6,7
The so-called number-to-treat for prevention of PONV is 5 to 6 for both drugs. 8,9
In a large, prospective, placebo-controlled study sponsored by the manufacturer of ondansetron (Zofran®; Glaxo Smith Kline, Research Triangle Park, NC), 2000 patients were randomized to receive 0.625 or 1.25 mg droperidol or 4 mg ondansetron intravenously for antiemetic prophylaxis. 7
There were no differences in the incidences of PONV (although droperidol was more efficacious in preventing nausea). More importantly, there were no significant differences in their side effect profiles. These findings have been confirmed in a meta-analysis of 76 trials, which included 5,351 patients receiving 24 different droperidol regimens. 8
In cost-effectiveness analyses, 6,10
0.625–1.25 mg droperidol was found to be more cost effective than 4 mg ondansetron for the prevention of PONV (due to droperidol's lower acquisition cost). The costs to gain an additional PONV-free patient were $149, $3.4, and $2.3 for 4 mg ondansetron, 0.625 mg droperidol, and 1.25 mg droperidol, respectively. 10
The revised black box warning was apparently based on nine case reports in which cardiac arrest was alleged to be caused by low-dose droperidol administration during the perioperative period. However, the details of these cases were not available for us to determine whether there was a direct cause-and-effect relationship. Based on these anecdotal reports, the FDA has recommended that all elective surgery patients should undergo 12-lead electrocardiographic monitoring prior to administration of droperidol to determine whether a prolonged QTc interval is present, and to continue electrocardiographic monitoring for 2 to 3 h after its administration. Since low-dose droperidol is most commonly used in outpatients undergoing ambulatory surgery, these recommendations are totally impractical and unnecessarily costly to the patients and the healthcare system.
Of note, there has not been a single case report in a peer-reviewed medical journal in which droperidol in doses used for the management of PONV has been associated with QTc prolongation, arrhythmias, or cardiac arrest. In fact, a study comparing hyoscine (scopolamine) and droperidol when administered under halothane general anesthesia found that significantly fewer patients in the droperidol group developed arrhythmias. 11
Following a safety concern raised by the UK Medicines Control Agency (London, United Kingdom) regarding the chronic use of high-dose oral droperidol (Inapsine®; Janssen-Cilag Ltd., Beerse, Belgium) in psychiatric patients, the manufacturer decided to withdraw all
formulations of droperidol. 12
The manufacturer predicted that intravenous droperidol use would decline to such a low level following the agency's new warning that it would not be economically viable to continue production of the parenteral formulation.
Given the extensive use of droperidol for antiemetic prophylaxis where it is routinely administered under anesthesia with continuous electrocardiographic monitoring, we believe that the recent black box warning by the FDA is totally unjustified. In light of the enormous economic impact of utilizing the more costly serotonin type 3 antagonist drugs (e.g., ondansetron, dolasetron [Anzemet®; Abbott Laboratories, Chicago, IL], granisetron [Kytril®; Roche Laboratories, Nutley, NJ]) as replacements for droperidol, we strongly urge the FDA to lift the black box warning regarding low doses of droperidol for the management of PONV. Furthermore, the agency should establish an expert advisory panel to examine these clinical case reports and the recommendations regarding the use of droperidol in the future.
Tong J. Gan, M.D.
Paul F. White, Ph.D., M.D.†
Philip E. Scuderi, M.D.
Mehernoor F. Watcha, M.D.
Anthony Kovac, M.D.
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