FDA Responds, Continues Watch

Cynthia G. McCormick, MD

The FDA strengthened the warnings of droperidol’s label due to reports that reflected a risk that was greater than that which was identified in the product label. The source of information was the postmarketing database as well as risk benefit analyses generated by the innovator. It is well known that postmarketing passive reporting is imperfect in its ability to generate incidences of adverse events. However, it is capable of identifying signals, which can then be followed up and studied. Droperidol is such a case. The number of droperidol-associated cases of Torsades, QTc prolongation, and sudden death reported to FDA through passive reporting was small, although reporting of adverse events for a drug that has been on the market for 20 years is generally very low. Published studies have described the dose-response effect of droperidol and QTc prolongation, and there is one, now famous, report of challenge-rechallenge with a patient who developed Torsades following IV bolus of droperidol. This information was known, but what was new was the information that these effects could occur at the most commonly used anesthetic doses.

The cases received by the FDA were carefully screened for duplicates, and the unique cases that were identified were evaluated for temporal relationship to drug, dose of drug, and sufficient detail to be able to make an assessment of the nature of the adverse event. The cases in the lower dose ranges of 0.625 or 1.25 were of greatest concern. The dilemma of having Torsades appear in the lower ranges was that, while low doses are in current use in the anesthetic setting, these doses have never been shown to be effective in an application to the FDA. Further, there is no adequate predictor of effect.

The FDA is concerned about these findings and, while we are mindful of the fact that this is a valuable drug for postoperative nausea and vomiting, its benefits should be weighed against the potential for a life-threatening arrhythmia. This is a clinical judgment, and one that should be appropriately informed.

In addition to warning clinicians about this rare, but well-documented risk, the Agency has committed to conducting a definitive pharmacokinetic and pharmacodynamic study to evaluate the effect of dose on the QTc interval. This study is exploring doses from placebo to 0.625 mg, 2.5 mg, and 5.0 mg in a crossover design in healthy volunteers who are on no concomitant medications. This study is still ongoing. The FDA is continuing to monitor droperidol adverse events and is conducting a comparative assessment of adverse events of other drugs indicated for postoperative nausea and vomiting. Further deliberations involving the Aesthetics and Life Support Advisory Committee will take place once the results of the pharmacokinetics study are available.

Cynthia G. McCormick, MD
Director, Division of Anesthetic, Critical Care,
and Addiction Drug Products
FDA

FDA Website Highlights Drug Shortages

In light of recent shortages of succinylcholine, fentanyl, and dexamethasone, it is useful to note that The Center for Drug Evaluation and Research (CDER) of the FDA currently has a website that provides timely information regarding drug shortages. This site also has links to a listserve which can provide subscribing anesthesiologists and anesthetists with email alerts for drugs that may be added to the lists of current shortages, products experiencing limited distribution, and resolved drug shortages. The website is

www.fda.gov/cder/drug/shortages/.

Other useful information is referenced including procedures for reporting drug shortages and practical suggestions for those facing shortage situations.