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Droperidol: A Cost-Effective Antiemetic for Over Thirty Years

2002; Lippincott Williams & Wilkins; Volume: 95; Issue: 4 Linguagem: Inglês

10.1213/00000539-200210000-00001

1526-7598

Paul F. White,

Anesthesia and Pain Management

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!