FDA Issues Black Box Warning for Droperidol:
Recommendations of the Drug Therapy Committee
Volume XII, Issue 1

 

On December 4, 2001, the FDA changed the labeling requirements for droperidol injection, now including a so-called Black Box Warning.1 Akorn Laboratories issued a "Dear Healthcare Professional" letter to physicians and pharmacists and others advising of the label change. The warnings and suggested prescribing limitations included in the Black Box Warning are based on an unknown number of case reports of ventricular arrhythmias (including Torsades) and patient deaths associated with the use of droperidol. The FDA action was made without the involvement of any advisory groups including the Anesthetic and Life Support Drug Advisory Committee.

Here is the Black Box warning:

WARNING
Cases of QT prolongation and/or torsades de pointes have been reported in patients receiving INAPSINE at doses at or below recommended doses. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.

Due to its potential for serious proarrhythmic effects and death, INAPSINE should be reserved for use in the treatment of patients who fail to show an acceptable response to other adequate treatments, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs (see Warnings, Adverse Reactions, Contraindications, and Precautions).
Cases of QT prolongation and serious arrhythmias (e.g., torsades de pointes) have been reported in patients treated with INAPSINE. Based on these reports, all patients should undergo a 12-lead ECG prior to administration of INAPSINE to determine if a prolonged QT interval (i.e., QTc greater than 440 msec for males or 450 msec for females) is present. If there is a prolonged QT interval, INAPSINE should NOT be administered. For patients in whom the potential benefit of INAPSINE treatment is felt to outweigh the risks of potentially serious arrhythmias, ECG monitoring should be performed prior to treatment and continued for 2-3 hours after completing treatment to monitor for arrhythmias.
INAPSINE is contraindicated in patients with known or suspected QT prolongation, including patients with congenital long QT syndrome.
INAPSINE should be administered with extreme caution to patients who may be at risk for development of prolonged QT syndrome (e.g., congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia, hypomagnesemia, or administration of other drugs known to increase the QT interval). Other risk factors may include age over 65 years, alcohol abuse, and use of agents such as benzodiazepines, volatile anesthetics, and IV opiates. Droperidol should be initiated at a low dose and adjusted upward, with caution, as needed to achieve the desired effect.

 

We are currently attempting to determine the basis for the FDA actions. At the moment we do not know how many cases of arrhythmias were detected or the number of deaths possibly related to the use of droperidol. The literature suggests that the effects of droperidol on the QT interval are dose-related.2 A recent review of the world's literature identified 18 cases of torsades de pointes associated with the use of droperidol or haloperidol from 1966 to 1996.3 In the majority of the cases reported the dose of haloperidol and droperidol exceeded 50mg in a 24 hour period. A study published in 1994 examined the degree of QT interval prolongation with IV droperidol at doses of 0.1mg/kg, 0.175mg/kg and 0.25mg/kg . QT interval prolongations of 37msec, 44msec and 59msec respectively were seen on single dose.

Last year, the MGH used almost 24,000 doses of droperidol. Droperidol is used as an anti-emetic for post-operative and post-procedural nausea and vomiting (PONV), in the treatment of severe migraine and a variety of psychiatric conditions. Several years ago, the Department of Anesthesia recommended an altered dosing regimen for droperidol in the treatment of PONV limiting dosing to 0.625mg IV x 2. The rationale for the recommendation was the recognition that higher doses (such as those recommended in the PDR) were not necessary and exposed the patient to the potential for extrapyramidal side effects. To date, despite widespread use of droperidol for many years, we are not aware of any cases of torsades de pointes at the MGH. The lack of identifiable events with the use of droperidol at the MGH, the paucity of events reported in the medical literature and the apparent dose-response relationship of the toxicity is in sharp contrast to the FDA decision. None the less, the Drug Therapy Committee recommends that the FDA admonitions concerning the use of droperidol be considered until such time as additional information is obtained. The Committee is working in cooperation with other institutions to obtain any and all information used by the FDA in deciding on the Black Box Warnings.

The Drug Therapy Committee urges all physicians to weigh the risks and benefits of droperidol use. While there are no published data to suggest that low-dose droperidol will increase the QT interval, the FDA black box warning does NOT acknowledge a dose-response relationship for this side effect. Droperidol will continue to be available but with a limited distribution. A pharmacist will consult with physicians prior to the dispensing and administration of droperidol at any dose.

 

 

References:

    1. http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01123.html
    2. Drolet B, Zhang S, Deschenes D, et al. Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current. J Cardiovasc Electrophysiol. 1999; 10(12):1597-604.
    3. Lawrence KR, Nasaraway SA. Conduction disturbances associated with administration of butyrophenone antipsychotics in the critically ill: a review of the literature. Pharmacotherapy. 1997; 17(3):531-7.
    4. Lischke V, Behne M, Doelken P, et al. Droperidol causes a dose-dependent prolongation of the QT interval. Anesth Analg. 1994; 79(5):983-6.