What is the risk of QT prolongation with droperidol?

Introduction

Droperidol is a butyrophenone derivative that is similar to the antipsychotic haloperidol in pharmacologic action.¹ Both drugs were introduced in the US in 1967 as treatments for psychosis, and their use has expanded to various off-label indications.^2,3 Today, they differ in that haloperidol is in common use in many clinical scenarios, while use of droperidol has been very infrequent over the last 2 decades. This is because in 2001, the US Food and Drug Administration (FDA) issued a boxed warning for droperidol because of the risk for QT interval prolongation and torsades de pointes.² Following this safety labeling change, use of droperidol significantly declined, and many hospitals removed it from their formularies.

Use of droperidol is once again reemerging after a generic manufacturer began producing the drug in early 2019, making it easier to obtain.^2,4 Droperidol is undergoing a reintegration into emergency use settings as an analgesic, antiemetic, and sedative. This has rekindled the debate regarding the benefits and risks of droperidol, which has continued since the introduction of the boxed warning. Because of these conflicting views and the surge in use of a potentially unfamiliar drug, pharmacists may have questions regarding the risk of QT interval prolongation with droperidol, which is discussed in this review.

Droperidol pharmacology and dosing

Like other butyrophenones, droperidol has antidopaminergic activity.^3,5 It is a potent antagonist at D₂ receptors, as well as serotonin, γ-aminobutyric acid, and H₁ histamine receptors. Droperidol rapidly crosses the blood-brain barrier and has a rapid onset of effect. Among other adverse effects that are common among antidopaminergic agents (eg, sedation, extrapyramidal symptoms), droperidol causes QT prolongation via blockade of potassium efflux from myocardial cells.⁶ This disrupts membrane repolarization, resulting in QT prolongation. QT intervals >440 ms in males or >450 ms in females are considered abnormal and may cause torsades de pointes, a potentially fatal arrhythmia.⁵

The labeled adult dose of droperidol is a maximum initial dose of 2.5 mg intramuscularly (IM) or intravenously (IV) by slow administration to reduce the incidence of nausea and vomiting associated with surgical and diagnostic procedures.^3,7 Additional doses of 1.25 mg may be administered if needed. As the effect of droperidol on the QT interval is dose-dependent, higher dosages may result in greater risk of torsades de pointes.⁸

Evidence supporting the droperidol boxed warning

The 2001 boxed warning for QT prolongation with droperidol was based on 2 published studies and postmarketing adverse event reports.^2,9 In 2007, Jackson and colleagues reviewed 277 cases of adverse effects associated with droperidol that were used by FDA to determine the need for the boxed warning and which were obtained via a Freedom of Information Act request.⁹ This reanalysis was one of many publications that presented a different perspective questioning the need for the boxed warning.^1,10,11

Case reports

Of the cases reviewed by Jackson and colleagues, 65 unique reports described at least 1 cardiac symptom; 35 resulted in death, 25 of which were attributable to cardiac arrest.⁹ Torsades de pointes was described in 11 cases. Five of these patients died, and 4 of these deaths occurred in patients who received droperidol IV for psychosis at a dose of 600 mg. Six cases involved patients with psychiatric conditions treated with high doses of droperidol; 4 cases reported doses of 2.5 to 25 mg. Only 1 case of torsades de pointes occurred in a patient treated with droperidol 0.625 mg, which occurred in a patient with a history of use of amiodarone, hydrochlorothiazide, and simvastatin.

Jackson and colleagues highlighted limitations of these reports, including the voluntary and incomplete nature of adverse event reporting to the FDA.⁹ Additionally, many of the reviewed cases occurred outside of the US, where droperidol is often used at higher doses. Therefore, the overall safety findings may not be generalizable to use of droperidol at lower doses typically used in the US.

A query of the FDA Adverse Event Reporting System (FAERS) in December 2020 revealed that a total of 169 adverse event reports had been filed for droperidol since its reintroduction in 2019.¹² Of these, 4 reported arrhythmia and 4 reported torsades de pointes; the most commonly reported adverse event was drug hypersensitivity (n=25).

Observational studies

Two observational studies informing the boxed warning were carried out in Europe.⁹ One study involved 40 patients undergoing surgery who were randomized to droperidol 0.1, 0.175, or 0.25 mg/kg IV (which equate to doses of 7, 12.25, and 17.5 mg in a 70-kg adult).¹³ The QT interval was significantly prolonged in all groups by 37, 44, and 50 ms, respectively, suggesting a dose-response relationship. These increases occurred after 1 minute and no dysrhythmias occurred. The second study included 495 patients with psychiatric illness treated with droperidol 2.5 to 50 mg who were compared with 101 healthy controls. An abnormal QT interval (>456 ms) occurred in 40 patients, and droperidol increased the odds of QT prolongation (odds ratio, 6.7; 95% confidence interval, 1.8 to 24.8).¹⁴ Notably, patients in this study were permitted to have received other psychotropic agents, which may have increased risk of QT prolongation.

The FDA has clarified that the boxed warning applies only to high-dose droperidol (≥2.5 mg), and that the agency has not reviewed the risk of QT prolongation with low doses.⁸ Use at doses less than 2.5 mg was noted by FDA to be off-label, and no statements were made regarding safety at these doses. Nonetheless, the lack of this clarification in the boxed warning may leave potential for confusion.

Controlled studies

Additional studies reporting the QT-prolonging effect of droperidol have been published since  introduction of the boxed warning, which are summarized in Table 1.^14-22 These have continued to identify QT prolongation with droperidol even at dosages typically used in the US. For example, various observational cohort studies have found rapid QT prolongation of approximately 20 to 25 ms.^{14,16,18-20,22} However, none of these identified occurrence of dysrhythmias, and like the aforementioned case reports, several studies reported use of droperidol doses that exceed those normally used in the US. Moreover, higher-quality interventional randomized controlled trials (RCTs) have not found significant differences in QT prolongation in comparisons of droperidol with placebo or ondansetron.^21,22 While these RCTs are limited in number, sample size, and generalizability, they form the highest quality evidence available regarding the comparative risk of QT prolongation with droperidol. Their findings underscore that droperidol does prolong the QT interval, but suggest the risk may be lower than once believed and support the need for further study.

Recommendations for safe droperidol use

Recommendations on the use of droperidol in emergency settings were provided by the American Academy of Emergency Medicine (AAEM) in 2015.⁸ In this position statement, the AAEM described a literature review of the safety and efficacy of droperidol in emergency department use. From a review of 34 publications, the AAEM recommended that droperidol is safe and efficacious as a treatment of agitation, headache, and nausea. Further, the review concluded that when used at doses <2.5 mg, there was insufficient evidence to support routine electrocardiogram and telemetry monitoring, and that IM doses of up to 10 mg appear as safe and effective as other medications used to treat agitated patients.

The AAEM stated that cases of unexpected cardiovascular death due to normal doses of droperidol are exceedingly rare, although these cases supported the FDA boxed warning.⁸ As with other QT-prolonging medications commonly used in emergency settings (eg, ondansetron, azithromycin), the AAEM suggested that clinicians continue to exercise judgment with use of droperidol when used in patients at risk of torsades de pointes. Selected risk factors that should be considered in patients treated with droperidol are listed in Table 2. Additionally, open access databases are available for healthcare providers to search updated, comprehensive lists of disease states and drugs that are associated with QT prolongation and torsades de pointes.²³

Conclusion

Various studies and literature reviews have concluded that droperidol is safe and effective as an analgesic and antiemetic when used at low doses.^6,8,9 While these conclusions are in contrast to the boxed warning regarding QT interval prolongation with droperidol, this warning was based on case reports and uncontrolled studies, and many of these cases of QT prolongation occurred with doses above those commonly used in the US. The AAEM position statement provides recommendations for safe use, which should be considered as droperidol continues its reintegration into clinical practice.⁸ Risk factors for QT prolongation should be considered for individual patients receiving droperidol, and systems-level safeguards such as updated order sets and formulary restrictions should be implemented as appropriate to ensure its safe use.

References

1. Habib AS, Gan TJ. Pro: The Food and Drug Administration black box warning on droperidol is not justified. Anesth Analg. 2008;106(5):1414-1417. doi:10.1213/ane.0b013e31816ba463
2. Mattson A, Friend K, Brown CS, Cabrera D. Reintegrating droperidol into emergency medicine practice. Am J Health Syst Pharm. 2020;77:1838-1845. doi:10.1093/ajhp/zxaa271
3. Clinical Pharmacology. Elsevier; 2020. Accessed December 13, 2020. clinicalpharmacology-ip.com
4. American Regent. American Regent re-introduces droperidol injection, USP; AP rated and therapeutically equivalent to Inapsine®. American Regent. Published February 15, 2019. Accessed December 11, 2020. https://www.americanregent.com/media/2276/pp-dp-us-0011_droperidol_pressrelease_14feb2019.pdf
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7. Droperidol. Package insert. American Regent; 2019.
8. Perkins J, Ho JD, Vilke GM, DeMers G. American Academy of Emergency Medicine Position Statement: safety of droperidol use in the emergency department. J Emerg Med. 2015;49(1):91-97. doi:10.1016/j.jemermed.2014.12.024
9. Jackson CW, Sheehan AH, Reddan JG. Evidence-based review of the black-box warning for droperidol. Am J Health Syst Pharm. 2007;64(11):1174-1186. doi:10.2146/ajhp060505
10. Faine B, Hogrefe C. News flash: Old Mother Hubbard reports the cupboard is bare…time for the FDA to let droperidol out of the (black) box. Ann Pharmacother. 2012;46(9):1259-1261. doi:10.1345/aph.1R156
11. Newman DH. Training the mind, and the Food and Drug Administration, on droperidol. Ann Emerg Med. 2015;66(3):243-245. doi:10.1016/j.annemergmed.2015.05.030
12. US Food and Drug Administration. FDA Adverse Event Reporting System (FAERS) Public Dashboard. US Food and Drug Administration. Updated October 29, 2020. Accessed December 11, 2020. https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard
13. Lischke V, Behne M, Doelken P, Schledt U, Probst S, Vettermann J. Droperidol causes a dose-dependent prolongation of the QT interval. Anesth Analg. 1994;79(5):983-986. doi:10.1213/00000539-199411000-00028
14. Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SH. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet. 2000;355(9209):1048-1052. doi:10.1016/s0140-6736(00)02035-3
15. Gaw CM, Cabrera D, Bellolio F, Mattson AE, Lohse CM, Jeffery MM. Effectiveness and safety of droperidol in a United States emergency department. Am J Emerg Med. 2020;38(7):1310-1314. doi:10.1016/j.ajem.2019.09.007
16. Calver L, Page CB, Downes MA, et al. The safety and effectiveness of droperidol for sedation of acute behavioral disturbance in the emergency department. Ann Emerg Med. 2015;66(3):230-238 e231. doi:10.1016/j.annemergmed.2015.03.016
17. Calver L, Isbister GK. High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings. Br J Clin Pharmacol. 2014;77(5):880-886. doi:10.1111/bcp.12272
18. Yimcharoen P, Fogel EL, Kovacs RJ, et al. Droperidol, when used for sedation during ERCP, may prolong the QT interval. Gastrointest Endosc. 2006;63(7):979-985. doi:10.1016/j.gie.2006.01.052
19. Charbit B, Albaladejo P, Funck-Brentano C, Legrand M, Samain E, Marty J. Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology. 2005;102(6):1094-1100. doi:10.1097/00000542-200506000-00006
20. Guy JM, André-Fouet X, Porte J, Bertrand M, Lamaud M, Verneyre H. Torsades de pointes and prolongation of the duration of QT interval after injection of droperidol. Ann Cardiol Angeiol (Paris). 1991;40(9):541-545.
21. Tracz K, Owczuk R. Small doses of droperidol do not present relevant torsadogenic actions: a double-blind, ondansetron-controlled study. Br J Clin Pharmacol. 2015;79(4):669-676. doi:10.1111/bcp.12527
22. White PF, Song D, Abrao J, Klein KW, Navarette B. Effect of low-dose droperidol on the QT interval during and after general anesthesia: a placebo-controlled study. Anesthesiology. 2005;102(6):1101-1105. doi:10.1097/00000542-200506000-00007
23. CredibleMeds. QTDrugs Lists. CredibleMeds. Accessed December 13, 2020. https://crediblemeds.org/healthcare-providers/

Prepared by:
Ryan Rodriguez, PharmD, BCPS
Clinical Associate Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

January 2021

The information presented is current as of December 17, 2020.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.