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LETTERS TO THE EDITOR

"Black Box" Warning on Droperidol: Report of the FDA Convened Expert Panel

Director, CARE, Department of Anesthesiology, Duke University Medical Center, Durham, NC

To the Editor:

On November 18, 2003, the FDA convened an expert panel of the Anesthetic and Life Support Drugs Advisory Committee. The committee consisted of anesthesiologists, cardiologists, pharmacologists, and patient representatives. The purpose of the meeting was for the committee to provide advice and recommendations regarding the assessments and management of risk related to QTc prolongation by droperidol. On December 5, 2001, the FDA issued a "black box" warning on droperidol, a popular antiemetic for the treatment and/or prevention of postoperative nausea and vomiting (PONV) (1,2). Droperidol previously carried a warning regarding the potential for sudden cardiac death at high doses (>25 mg) in psychiatric patients. The revised warning cautioned the use of even small doses of droperidol.

I represented the Society of Ambulatory Anesthesia (SAMBA) membership and presented during the open public hearing session, to express the view that FDA’s "black box" warning is unwarranted for the antiemetic doses of droperidol, and that the warning has effectively removed one of the most efficacious drugs for the management of PONV for our patients. I presented evidence that droperidol is a cost-effective antiemetic and its safety profile when used in antiemetic doses is excellent. We have previously reported the 10 cases in the FDA database in which serious cardiovascular events were possibly related to the administration of droperidol at doses of 1.25 mg or less. Review of these case reports shows that there are many confounding factors that make it impossible to establish the precise cause of the adverse cardiac events. Many concomitant drugs with the potential of causing QTc prolongation were administered around the time of droperidol (3). Of note, since droperidol was approved in 1970, there has not been a single case report in a peer-reviewed journal where droperidol in doses used for the management of PONV has been associated with QTc prolongation, arrhythmias, or cardiac arrest (1).

The meeting opened with the representatives from the FDA presenting the background information of the droperidol approval process and the impact of the "black box" warning. Close to 10 million vials of droperidol were sold in 2001 before the "black box" warning, and it was estimated that its use was reduced by 90% following the warning. It was recognized that there is a significant lack of data for the small doses of droperidol causing QT prolongation. Recently, the FDA conducted a healthy human volunteer study (8 patients) investigating the effect of 0.625, 2.5 and 5 mg bolus doses of IV droperidol on QT interval. The study was prematurely terminated due to adverse events (restlessness, anxiety, and difficulty concentrating) seen in the larger doses. In addition the study was underpowered to detect the primary outcome. The option for further studies to address this issue was explored. However, it was concluded that a large-scale randomized study will be difficult to perform in view of the relatively low event rate and the enormous cost involved.

The panel heard evidence from an expert cardiologist on the frequency of drug-related QT prolongation and the complexity of measurement of the QT interval. The following preoperative drugs have been reported to cause QTc prolongation: inhaled anesthetics (4,5), serotonin antagonists (6), thiopental (7), propofol (8), neuromuscular reversal drugs (9), metoclopramide (6), succinylcholine (7,10), terfenadine (11), macrolide antibiotics (11), among others.

Measurement of QT interval is not an exact science. The relationship between the duration of cellular action potentials and the QT interval recorded at the body surface is complex. As Result, the QT interval is difficult to measure with precision. First, there is inherent imprecision in identifying the end of the T wave because of incomplete understanding of the recovery process and its projection on the body surface. Second, significant variation both in the onset of the QRS complex and the end of the T wave among some ECG leads provides different QT values depending on the leads selected for measurement. Third, technical factors such as paper speed and sensitivity influence QT measurements with higher paper speed leading to shorter interval values and higher sensitivity resulting in QT prolongation (12,13). The above problems do not appear to be solved by automatic QT measurement techniques, which have been found to be less accurate in cardiac patients than in healthy controls. Calculation of QT interval corrected for heart rate is again ambiguous; as there are numerous different formulae, each produces different results. The mathematical form of the different formulae is arbitrary and is not based on any physical or biological basis (14–16). In addition, QT interval is only a surrogate measure for Torsade de Pointe, which is what concerns clinicians.

At the end of the day, I did not get a sense that the FDA is closer to reversing the "black box" warning on droperidol. The FDA claimed that the approved minimum dose of droperidol is 2.5 mg and the use of smaller doses is outside the label and hence beyond the jurisdiction of the FDA. The panel was unanimous in recommending that more information is needed in order to make an intelligent decision, although it is not clear the nature of the evidence that would convince the FDA to reverse the "black box" warning. For more information about the meeting, you may visit the FDA Web site at http://www.fda.gov/oc/advisory/acdrugs.html.

References

1. 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.[Web of Science][Medline]
2. FDA strengthens warnings for droperidol. http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01123.html.
3. Habib AS, Gan TJ. Pharmacotherapy of postoperative nausea and vomiting: expert opinion on pharmacotherapy. 2003; 4: 457–73.
4. Kleinsasser A, Kuenszberg E, Loeckinger A, et al. Sevoflurane, but not propofol, significantly prolongs the Q-T interval. Anesth Analg 2000; 90: 25–7.[Abstract/Free Full Text]
5. Michaloudis D, Fraidakis O, Lefaki T, et al. Anaesthesia and the QT interval in humans: the effects of isoflurane and halothane. Anaesthesia 1996; 51: 219–24.[Web of Science][Medline]
6. 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.[Web of Science][Medline]
7. Saarnivaara L, Lindgren L. Prolongation of QT interval during induction of anaesthesia. Acta Anaesthesiol Scand 1983; 27: 126–30.[Web of Science][Medline]
8. Saarnivaara L, Hiller A, Oikkonen M. QT interval, heart rate and arterial pressures using propofol, thiopentone or methohexitone for induction of anaesthesia in children. Acta Anaesthesiol Scand 1993; 37: 419–23.[Web of Science][Medline]
9. Pleym H, Bathen J, Spigset O, Gisvold SE. Ventricular fibrillation related to reversal of the neuromuscular blockade in a patient with long QT syndrome. Acta Anaesthesiol Scand 1999; 43: 352–5.[Web of Science][Medline]
10. Lindgren L, Rautiainen P, Klemola UM, Saarnivaara L. Haemodynamic responses and prolongation of QT interval of ECG after suxamethonium-facilitated intubation during anaesthetic induction in children: a dose-related attenuation by alfentanil. Acta Anaesthesiol Scand 1991; 35: 355–8.[Medline]
11. www.Torsades.org. Drugs causing QT prologation.
12. Sylven JC, Horacek BM, Spencer CA, et al. QT interval variability on the body surface. J Electrocardiol 1984; 17: 179–88.[Web of Science][Medline]
13. Kautzner J. QT interval measurements. Cardiac Electrophysiology Review 2002; 6: 273–7.[Medline]
14. Cowan JC, Yusoff K, Moore M, et al. Importance of lead selection in QT interval measurement. Am J Cardiol 1988; 61: 83–7.[Web of Science][Medline]
15. Murray A, McLaughlin NB, Bourke JP, et al. Errors in manual measurement of QT intervals. Br Heart J 1994; 71: 386–90.[Abstract/Free Full Text]
16. Murray A, McLaughlin NB. Variation in the identification of Q wave initiation and its contribution to QT measurement. Physiol Meas 1995; 16: 39–42.[Medline]

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