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EDITORIAL

Droperidol: A Cost-Effective Antiemetic for Over Thirty Years

Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas

Address correspondence to Paul F. White, PhD, MD, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390–9068. Address e-mail to paul.white{at}utsouthwestern.edu

Droperidol is a butyrophenone that was approved by the U.S. Food and Drug Administration (FDA) for clinical use as an antiemetic and as an adjuvant during general anesthesia (as part of a neuroleptic anesthetic technique) in 1970 (1). Yet, in December 2001, the FDA mandated that the manufacturer of the generic formulation of droperidol (Akorn Pharmaceuticals, Buffalo Grove, IL) place a "Black Box" warning regarding the risk of serious pro-arrhythmogenic effects (e.g., torsade de pointes [TdP]) and even death after small doses of droperidol. The FDA refused to meet with Akorn representatives or their consultants to discuss concerns regarding the proposed labeling change. During its more than 30 years of clinical use during the perioperative period, there is not even a single case report documenting that droperidol caused a cardiac arrhythmia. This is even more remarkable because droperidol is typically administered to surgical patients being continuously monitored with an electrocardiogram (ECG) and a pulse oximeter!

According to the director of the FDA’s Division of Anesthetic, Critical Care, and Addiction Drug Products (2), approximately 100 "unique" reports of cardiovascular events and 20 reports of TdP or QT/QTc interval prolongation have been submitted to the agency. Interestingly, 74% of the reported cases were from outside the United States ("foreign"), and there were confounding factors in many of the cases (3). The majority of the deaths involved droperidol doses ranging from 25 to 250 mg! In 11 cases of alleged droperidol-induced arrhythmias, the onset time was 30 min or less after the drug administration. Of the unique adverse cardiovascular events associated with droperidol, 12 reportedly occurred at doses of 2.5 mg or less. At doses less than 1 mg, there were five reports of serious outcomes possibly related to droperidol (i.e., TdP, cardiac arrest, and/or death). Three of these cases were considered life threatening and/or required prolonged hospitalization, with one reported death. Although the true incidence of cardiovascular events cannot be determined, it is worth noting that over 25 million unit doses of generic droperidol were sold in the year 2000 alone!

In a study by Lischke et al. (4) involving droperidol doses ranging from 0.1 to 0.25 mg/kg (approximately 5 to 20 mg), the authors reported the rapid onset of dose-related prolongation of the QTc interval. However, they failed to report any arrhythmias even after these large doses of droperidol. Guy et al. (5) also reported significant prolongation of the QT interval in 55 patients given a 0.25-mg/kg bolus dose of droperidol. The onset of the change in the QTc interval typically occurred within 1 min after the injection and was not associated with any cardiac arrhythmias.

As a result of the cardiovascular events reported with chronic oral administration of large-dose (>25 mg) droperidol in psychiatric patients, the manufacturer of the proprietary product (Janssen-Cilag Ltd, Beerse, Belgium) discontinued production of both the oral (Droleptan^®) and parenteral (Inapsine^®) formulations. Their decision to discontinue production of the injectable formulation (droperidol 2.5 mg/mL), which is used during the perioperative period for the prevention and/or treatment of postoperative nausea and vomiting (PONV), was strictly a business decision based on the fact that the small injectable market would not be profitable (6). Because the principal manufacturer of the bulk raw materials required to produce droperidol was also Janssen-Cilag, Ltd, the manufacturer of the generic drug (Akorn) will now be burdened with the additional requirement of finding an alternative vendor if they are to continue making the injectable formulation of droperidol for the North American market.

Because 0.625 to 1.25-mg IV doses of droperidol have been widely accepted as the first-line therapy for the prophylaxis and treatment of PONV (7,8), this decision has far reaching clinical and economic implications on the practice of anesthesia. In a recent market survey, droperidol accounted for more than 30% of the antiemetic market share! In several well-controlled, randomized, comparative clinical trials (9–11), droperidol has been demonstrated to be as safe and effective as the more costly 5-hydroxytryptamine-type-3 (5-HT₃) antagonists. Of interest, a large-scale study involving more than 2000 outpatients was conducted by the manufacturer of ondansetron (Zofran^®, Glaxo Smith Kline) and failed to find any safety or efficacy advantages of ondansetron (4 mg IV) over droperidol (0.625 or 1.25 mg IV) (10).

According to the FDA-approved package inserts for the 5-HT₃ antagonists, ondansetron, dolasetron (Anzemet^®), and granisetron (Kytril^®) all possess the ability to prolong the QT interval and have the potential to produce arrhythmias. In fact, cardiac dysrhythmias have been reported following the intravenous administration of ondansetron (12).Recently, Bosek et al. (13) also described the acute onset of myocardial ischemia in a patient after the IV administration of ondansetron! Yet, there are no "Black Box" warnings or recommendations for a pretreatment screening 12-lead ECG and extended ECG monitoring (for up to 3 h) after the administration of the 5-HT₃ antagonist. Interestingly, a study by Smith and O’Connell (14) comparing scopolamine and droperidol when administered for premedication found fewer arrhythmias with droperidol during halothane anesthesia.

Given the increasing pressure on physicians to make cost-effective choices in medicine (15), it is difficult to understand why the FDA would place these impractical restrictions on the use of the most cost-effective parenteral antiemetic on the market. The FDA is probably unaware of the fact that when droperidol is administered for prophylaxis, it is typically given immediately before or after induction of anesthesia with continuous ECG monitoring. As a result of the "Black Box" warning, many hospital pharmacy and therapeutics committees in the United States have decided to simply remove droperidol from their formularies! Replacing an inexpensive drug (US $1.28 for droperidol 2.5 mg) with a much more expensive 5-HT₃ antagonist (Zofran 4 mg is $20.87; Anzemet 12.5 mg is $15.25; and Kytril 1 mg is $36.75) will have profound cost implications for patients, health care providers, third-party payers, as well as the federal government itself. More importantly, the 5-HT₃ antagonists may actually possess a higher risk of cardiac arrhythmias than droperidol!

In conclusion, the FDA "Black Box" warning regarding the use of small-dose droperidol for PONV does not seem to be justified based on the available data in the peer-reviewed medical literature (3,16). Unfortunately, the practicing anesthesiologist is now faced with a real dilemma (17) should they choose to continue using a cost-effective antiemetic drug (droperidol), which has clearly withstood the test of time!

Acknowledgments

Supported, in part, by departmental clinical research funds and endowment funds from the Margaret McDermott Distinguished Chair in Anesthesiology.

References

1. Zsigmond EK. Neurolept and dissociative. In: White PF, ed. Textbook of intravenous anesthesia. London: Williams & Wilkins, 1997: 393–403.
2. McCormick CG. FDA alert: current FDA report on droperidol status and basis for "Black Box" warning. ASA Newsl 2002; 66: 19–20.
3. Bailey P, Norton R, Karan S. The FDA droperidol warning: Is it justified? Anesthesiology 2002; 97: 288–9.
4. Lischke V, Behne M, Doelken P, et al. Droperidol causes a dose-dependent prolongation of the QT interval. Anesth Analg 1994; 79: 983–6.[Abstract/Free Full Text]
5. Guy JM, Andre-Fouet X, Porte J, et al. Torsades de pointes and prolongation of the duration of QT interval after injection of droperidol. Ann Cardiol Angeiol (Paris) 1991;40:541–5.
6. Tramer MR, Reynolds DJM, Goodman NW. Whose drug is it anyway? Lancet 2001; 258: 1275.
7. White PF, Watcha MF. Postoperative nausea and vomiting: prophylaxis versus treatment (editorial). Anesth Analg 1999; 89: 1337–9.[Free Full Text]
8. Watcha MF. The cost-effective management of postoperative nausea and vomiting. Anesthesiology 2000; 92: 931–3.[ISI][Medline]
9. Tang J, Watcha MF, White PF. A comparison of cost and efficacy of ondansetron and droperidol as prophylactic antiemetic therapy for elective outpatient gynecologic procedures. Anesth Analg 1996; 83: 304–13.[Abstract]
10. Fortney JT, Gan TJ, Graczyk S, et al. A comparison of the efficacy, safety, and patient satisfaction of ondansetron versus droperidol as antiemetics for elective outpatient surgical procedures: S3A-409 and S3A-410 Study Groups. Anesth Analg 1998; 86: 731–8.[Abstract]
11. Hill RP, Lubarsky DA, Phillips-Bute B, et al. Cost-effectiveness of prophylactic antiemetic therapy with ondansetron, droperidol, or placebo. Anesthesiology 2000; 92: 958–67.[ISI][Medline]
12. Baguley WA, Hay WT, Mackie KP, et al. Cardiac dysrhythmias associated with the intravenous administration of ondansetron and metoclopramide. Anesth Analg 1997; 84: 1380-1[ISI][Medline]
13. Bosek V, Hu P, Robinson LA. Acute myocardial ischemia after administration of ondansetron hydrochloride. Anesthesiology 2000; 92: 885–7.[ISI][Medline]
14. Smith DC, O’Connell P. Cardiac dysrhythmias during oral surgery: comparison of hyoscine and droperidol premedication. Anaesthesia 1986; 41: 745–8.[Medline]
15. Watcha MF, White PF. Economics of anesthetic practice. Anesthesiology 1997; 86: 1170–96.[ISI][Medline]
16. Gan TJ, White PF, Scuderi PE, et al. FDA "Black Box" warning regarding use of droperidol for postoperative nausea and vomiting: is it justified? Anesthesiology 2002; 97: 287.[ISI][Medline]
17. White PF, Watcha MF. The practice of anesthesiology and the package insert: decision-making regarding drug use in anesthesiology. Anesth Analg 1993; 76: 928–30.[Free Full Text]

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999