Archived – Cardiovascular Toxicity with Injectable Droperidol

Important Drug Safety Information

February 12, 2002

To: Hospital Chief of Medical Staff, Otolaryngologists and Pharmacists in Retail Pharmacies

Please distribute to health professionals within your institution.

Health Canada, following a review of current national and international safety information and the scientific and medical literature, is advising health care professionals of important safety concerns related to injectable droperidol, a neuroleptic and antiemetic.

Cardiovascular Toxicity with Injectable Droperidol

More than 60 reports of cases of QT prolongation, serious arrhythmia (e.g., torsades de pointes) and sudden death have been reported worldwide in patients receiving injectable droperidol. In Canada there have been 8 reports of cases with a fatal outcome in association with injectable droperidol and concomitant administration of anesthetics, anxiolytics, muscle relaxants and narcotic analgesics.

In order to minimize the cardiovascular risks associated with the use of injectable droperidol, the following measures are recommended:

• Injectable droperidol should only be used in the hospital setting, to allow for screening and monitoring of ECGs. Droperidol should be reserved for use in treatment of patients who fail to show acceptable response to other adequate treatments.
• Droperidol should NOT be administered concomitantly with other drugs known to prolong the QT interval
• Droperidol should be avoided in patients who may be at risk for development of a prolonged QTc interval (e.g. including but not limited to cardiac conduction disorders, congestive heart failure, bradycardia, cardiac hypertrophy, long QT Syndrome, use of a diuretic, history of alcohol abuse or recent high intake, family history of sudden death, electrolyte imbalances including hypokalemia and hypomagnesaemia, impaired liver function). Other risk factors may include age over 65 years, and use of agents such as benzodiazepines, volatile anesthetics and IV opiates.
• All patients should undergo a 12-lead ECG prior to administration of droperidol to determine if a prolonged QTc interval (i.e., QTc greater than 440 msec for males or 450 msec for females) is present. If there is a prolonged QT interval, droperidol should NOT be administered. ECG monitoring should be performed prior to treatment and continued after completion of treatment (the elimination half-life of droperidol following intravenous droperidol infusions ranges from 3.5-10 hours).^{Footnote 1} Although monitoring is essential, it is not clear that baseline and continuous ECG monitoring will detect patients at risk, or prevent the occurrence of QT prolongation, serious arrhythmias and sudden death after droperidol administration. There have been case reports of QT prolongation and arrhythmias occurring up to 24 hours after droperidol administration.

You are referred to the Product Monograph for Droperidol Injection USP- 2.5 mg/mL (Sabex Inc. and Novopharm Limited) for information regarding indications and use of droperidol.

Janssen-Cilag Ltd issued a notice of discontinuation of their droperidol containing products worldwide on March 31/ 2001, following a risk-benefit assessment conducted by Janssen-Cilag. Although the focus of the safety issue identified by Janssen-Cilag Ltd was the risk of QT prolongation leading to Torsades de Pointes (TdP), and fatal ventricular arrhythmias with chronic use of the oral formulation of droperidol, these adverse events have also been reported with injectable droperidol use in several short-term indications including anaesthesia and nausea and vomiting following anesthesia. More than 60 reports of cardiovascular adverse reactions including QT prolongation, ventricular arrhythmia, and death have been reported worldwide with the use of injectable droperidol from Janssen-Cilag. In Canada, there are no oral droperidol formulations. However two injectable formulations are currently marketed by Sabex Inc. and Novopharm.

It should be noted that on December 05, 2001, the US FDA strengthened the warnings and precautions sections in the labeling for droperidol ², and a Dear Doctor Letter was issued by Akorn Pharmaceuticals (manufacturer of droperidol in USA)^{Footnote 2}.

Health Canada is assessing the situation and will continue to monitor the postmarketing safety data for droperidol to determine further action. Further information will be available upon completion of our assessment of injectable droperidol. All adverse drug reactions related to injectable droperidol in Canada should be reported to:

Any suspected adverse drug reactions can also be reported to:

Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Bureau of Licensed Product Assessment
Therapeutic Products Directorate
Health Canada
Address Locator: 0201C2
Ottawa, Ontario, K1A 1B9
Tel: (613) 957-0337 or Fax: (613) 957-0335
Toll free for consumers and health professionals:
Tel: 866 234-2345, Fax: 866 678-6789
cadrmp@hc-sc.gc.ca

The ADR Reporting Form can be found in The Canadian Compendium of Pharmaceuticals and Specialties, or on the TPD web site, along with the ADR Guidelines.

Yours sincerely,
original signed by

Robert G. Peterson, MD, PhD, MPH
Director General
Therapeutic Products Directorate