Droperidol Gets Second-Line, Narrowed Indication Due To Arrhythmia Risk

Updated labeling for Akorn's Inapsine and droperidol generics restricts the drug to second-line use for a narrowed indication due to the risk of fatal cardiac arrhythmias.

"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," a black box warning in revised labeling states.

The injectable anesthetic is now restricted for use in the reduction of nausea and vomiting associated with surgical and diagnostic procedures.

Three indications have been removed from labeling: tranquilization after surgical and diagnostic procedures; premedication, induction, and as an adjunct in the maintenance of general and regional anesthesia; and use in neuroleptanalgesia "concurrently with an opioid analgesic...to aid in producing tranquility and decreasing anxiety and pain."

The black box warning includes the bolded statement, "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."

Revised labeling reduces the recommended dose for droperidol. Adult dosing is changed to 2.5 mg intramuscular injection or slow I.V. as an initial dose, with 1.25 mg additional doses as needed.

"However," labeling adds, "additional doses should be administered with caution, and only if the potential benefit outweighs the potential risk." Previous labeling recommended doses ranging from 2.5 mg to 10 mg depending on the indication, and did not include a caution about additional dosing.

For children ages two to 12, the maximum recommended initial dose is .1 mg/kg. The previous recommended dose for children was "as low as 1.0 to 1.5 mg...per 20 to 25 pounds."

Akorn described the changes in a Dec. 4 "Dear Doctor" letter.

FDA required labeling changes for droperidol after it received reports of 100 unique spontaneous cardiovascular adverse events following droperidol administration, 20 of which involved torsades de pointes or prolongation of the QT interval. Eighteen of the cases resulted in death, six of which were attributable to torsade or QT prolongation. Five deaths "occurred at or below the labeled doses of 2.5 mg," FDA said.

The agency issued a "Talk Paper" on droperidol Dec. 5. "Droperidol currently carries a warning about cases of sudden death at high doses (greater than 25 mg) in patients at risk for cardiac arrhythmias," the Talk Paper notes. However, "recent research has shown QT prolongation...within minutes after injection of a dose of droperidol at the upper end of the labeled dose range."

"FDA will continue to monitor the postmarketing safety data for droperidol to determine if further action is needed," the agency said.

Revised labeling reports that "a dose-dependent prolongation of the QT interval was observed within 10 minutes of droperidol administration in a study of 40 patients without known cardiac disease who underwent extracranial head and neck surgery."

"Significant QT prolongation was observed at all three dose levels evaluated, with .1 mg/kg, .175 mg/kg, and .25 mg/kg associated with prolongation of median QTc by 37 msec, 44 msec, and 59 msec, respectively."

The boxed warning says that "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 and 450 msec for females) is present. If there is a prolonged QT interval, Inapsine should NOT be administered."

For those for whom the benefit of droperidol outweighs its risk, "ECG monitoring should be performed prior to injection and continued for 2-3 hours after completing treatment," the black box says.

The oral formulation of droperidol was discontinued in the U.K. in March following concerns about potential QT prolongation in chronic use ( (Also see "Akorn Inapsine" - Pink Sheet, 15 Jan, 2001.), p. 29). Droperidol was marketed in the U.K. by Janssen; Akorn acquired Janssen's line of injectable anesthesia/analgesia products in 1996.