The Surprising Re-emergence of Droperidol

In February 2019, the pharmaceutical manufacturer, American Regent, Inc (Shirley, NY) reintroduced droperidol to the US drug market. Droperidol is a butyrophenone, the same drug class as the typical antipsychotic agent haloperidol, and acts as a dopamine D2 receptor antagonist producing antiemetic and sedative-hypnotic effects. Not only has it been used along with fentanyl to produce a state of neuroleptic analgesia, previously marketed in combination as Innovar (Janssen Pharmaceutica, Beerse, Belgium) and since discontinued, but it also has a compelling history as an antiemetic agent. In fact, anesthesia providers who treated patients in the late 20th century likely remember it as an affordable and effective prophylactic antiemetic agent that carried minimal risks of QT prolongation or extrapyramidal side effects when administered in small doses. Despite its long track record of success, the drug has had a convoluted history since its discovery in the early 60s, and its reemergence into the current healthcare landscape only adds to its intriguing legacy.

Droperidol originally received US Food and Drug Administration (FDA) approval back in 1970 as an antiemetic and tranquilizing agent and was used for over 30 years to effectively prevent and treat postoperative nausea and vomiting (PONV). However, in the late 90s, reports arose indicating increased potential for cardiac complications with droperidol use, specifically risks of QT interval prolongation, ventricular arrhythmias, and torsades de pointes. Janssen Pharmaceutica, the manufacturer of the proprietary products Droleptan (oral droperidol) and Inapsine (parenteral droperidol), halted production of both formulations outside of the United States in March 2001 as a direct response to these concerns, prompting an emergency reassessment of the drug's safety and the reported adverse events data by the FDA. At that time Janssen Pharmaceutica was also the main source for bulk quantities of the raw materials needed to produce droperidol. As such, Akorn Pharmaceuticals (Buffalo Grove, IL), the main manufacturer of droperidol in the United States, was left searching for acceptable alternative sources. In December 2001, the FDA mandated the addition of a “black box” warning to the droperidol package insert due to concerns about the increased risk of cardiac complications. The warning label not only stipulated that patients should be given droperidol only after failing other treatment options but also stated that electrocardiography should be used prior to drug administration and continue for 2 to 3 hours afterwards to monitor for cardiac arrhythmias. The FDA's decision led to the substantial decline in routine droperidol use as hospital systems and practitioners looked elsewhere for alternatives devoid of the increased risk of cardiac issues and overly burdensome monitoring requirements. Droperidol seemingly disappeared from hospital pharmacies and drug formularies overnight.

Despite the withering demand for droperidol, the outcry from the medical community throughout the early 2000s was substantial, highlighting the apparent lack of sound scientific evidence in the FDA's decision. It was pointed out that the data used by the FDA consisted of a few hundred patients receiving varying doses of droperidol, with the vast majority of doses far exceeding the usual antiemetic dosing by 2 orders of magnitude. In fact, most of the patients who died received droperidol doses of 25 to 250 mg, which is remarkable when compared with the significantly lower standard antiemetic dosing of 0.625 to 1.25 mg intravenously (IV). It was also noted upon review that many of the patients who received droperidol doses of 1.25 mg or less and experienced cardiac complications had confounding factors present, which were not accounted for by the FDA. An independent review of the FDA's data performed in 2007 at Washington University School of Medicine in St. Louis and an extensive literature review from 2015 both arrived at similar conclusions regarding the safety and efficacy of droperidol.^1,2 However, the FDA refused to reverse its decision, standing firm on the necessity of the black box warning despite the uproar.

The FDA did provide some clarity on the droperidol warning label during a 2003 Advisory Committee meeting, explaining that it had requested Akorn Pharmaceuticals undertake additional safety studies or possibly submit an extensive literature review. This request was rebuffed by the drug manufacturer citing financial constraints. Interestingly, the FDA further explained the black box warning was only meant to apply to droperidol doses as specified by the package insert, which detailed an initial dose of 2.5 mg, not the reduced antiemetic dosing, considered to be off-label use. In short, the FDA only had data pertaining to dosing ≥2.5 mg; therefore, it could not assess the safety and efficacy of the lower dose droperidol use. Furthermore, the FDA repeatedly pointed out that it does not regulate off-label drug use as deemed appropriate by a clinician's professional judgement. It should be noted that the FDA's black box warning remains fully intact within the current American Regent package insert.

So, what does the reintroduction of droperidol mean for today's modern anesthesia providers? It seems logical after reviewing droperidol's history that it deserves a place as an antiemetic within current anesthesia practice. Low-dose droperidol combined with ondansetron has repeatedly outperformed either agent alone for PONV prevention, without any significant side effects.^3,4 Droperidol undeniably carries an inherent risk for QT prolongation or induction of torsades de points; however, the available evidence fails to clearly illustrate an association between off-label reduced antiemetic dosing and an increased incidence of significant cardiac complications. Furthermore, a review of drugs known to have similar cardiac risks reveals a long list replete with examples still commonly used today, such as erythromycin, fluoxetine, haloperidol, tizanidine, and most notably, ondansetron. In a similar fashion, droperidol appears to be a safe and effective antiemetic drug if used properly by a clinician with the requisite knowledge of the drug's particular risks, indications, and contraindications. From a financial aspect, droperidol is currently available at ∼$3.00 per 0.625-mg dose as compared with ondansetron and dexamethasone, which cost ∼$1.00 and ∼2.00 per 4-mg dose, respectively. Droperidol appears to be a cost-effective antiemetic alternative as drug prices and availability are always subject to alterations in supply and demand. Taking into consideration the increased frequency of drug shortages and manufacturing disruptions occurring these days, it would appear wise to have several antiemetic options readily available. As such, droperidol likely warrants re-inclusion into contemporary PONV management algorithms.

Shifting focus to the ambulatory or office-based dental environment, droperidol's role becomes somewhat murkier. Ensuring a clean, rapid emergence and recovery is paramount when providing sedation and general anesthesia in any environment lacking a dedicated, monitored postanesthesia recovery space. Sedating antiemetics carry the potential for prolonging recovery and slowing discharge, and this may render their routine use impractical from an office-efficiency and patient-safety standpoint. Even though droperidol is an excellent antiemetic, its potential to cause undue sedation is concerning, although the degree of sedation found with 0.625 to 1.25 mg may not prove problematic. For patients with low PONV risk, droperidol seems most practical as a secondary rescue agent, following early dexamethasone administration and ondansetron given either prophylactically or as the primary rescue agent in recovery. High-risk PONV patients would likely benefit from low-dose droperidol given early along with dexamethasone and ondansetron prior to emergence, optimizing the antiemetic potential and providing more time to monitor intraoperatively for cardiac complications. Like other dopamine antagonists, droperidol can cause extrapyramidal side effects, which may further reduce its appeal in the ambulatory dental environment, but the incidence is rare and likely dose dependent. Promethazine carries similar risks due to its weak dopamine receptor antagonism and is quite useful for PONV rescue with minimal side effects if administered in small divided doses of 6.25 to 12.5 mg IV. Ultimately time will tell if these concerns are unfounded and droperidol will reemerge as a safe and effective antiemetic that fits well within the current practice of anesthesia for dentistry.