Bruce F. Cullen, M.D.

The issues of drug shortages and droperidol have occupied a significant portion of my time while I have been an ASA officer. This article reviews the present status of these issues.

Drug Shortages
About four years ago, anesthesiologists began to experience a phenomenon never seen before — a shortage of drugs. Typically these drugs, such as fentanyl, succinylcholine and naloxone, were older, generic and cheap. In response to ASA members’ concerns, a meeting was convened in April 2001 by ASA and included representatives from ASA, the Food and Drug Administration (FDA), the American Hospital Association, the American Society of Health-System Pharmacists (ASHP) and the Pharmaceutical Research and Manufacturers of America. There was a consensus that this was a widespread problem and that the causes were complex and multifactorial. Further meetings were in order involving more parties.

In July 2002, a meeting of “stakeholders” involved in the drug-shortage problem was convened and included representatives from ASA, the American Medical Association, FDA, ASHP, the Institute of Medicine and others. Once again it was agreed that the problem is widespread and multifactorial. Identified causes included an unexpected shortage of raw materials (often sole providers in third-world locations), production line problems (often due to old equipment), corporate mergers (fewer suppliers), manufacturing preference for profitable proprietary drugs, FDA regulatory issues (closing a major supplier), cost-containment, smaller “just in time” inventories (manufacturers, distributors, pharmacies), limited communications between parties and antiterrorism or military requirements. There also is no federal law requiring notification by a manufacturer of intent to discontinue manufacture of a drug unless it is the sole provider of that drug. A number of solutions were suggested, and the meeting proceedings were published.¹

In March 2004, a second “stakeholders” meeting was convened. At this time, it was evident that the problem still existed but that some progress had been achieved. For example FDA has established a new Drug Shortage Program and is experiencing improved communication from consumers (who experience shortages) and from manufacturers (who anticipate decreased production). Informative drug shortage Web sites are maintained by both FDA² and ASHP.³ Anesthesiologists experiencing a drug shortage should call FDA or send an e-mail to <drugshortages@cder.fda.gov>.

Asking manufacturers to voluntarily cooperate in reducing the incidence of drug shortages is commendable, but application of pressure from elsewhere is indicated. Accordingly ASA plans to sponsor a resolution at the American Medical Association House of Delegates that will hopefully lead to legislation dictating that pharmaceutical manufacturers give FDA adequate advance notification when they anticipate decreased production of critical drugs.

Droperidol ‘Black Box’ Warning
In 1970 the FDA approved droperidol for use as a tranquilizer in doses above 2.5 mg (use of <2.5 mg is an “off label” use!). In 2001 Jannsen Pharmaceutical (Belgium) quit producing the drug (allegedly for economic reasons), and FDA again examined the drug. In December 2001, FDA issued a “black box” warning that caused anesthesiologists, primarily due to concerns about litigation risk, to stop using the drug (see the April 2002 and December 2002 ASA NEWSLETTERs).

Droperidol, like many other drugs used perioperatively, can prolong the QT interval of the cardiac cycle. If the effect is marked, particularly in patients with a pre-existing long QT interval, refractory ventricular fibrillation can result (torsades de pointes).⁴ There are several cases in the FDA database and a few published reports describing severe cardiac complications associated with the use of droperidol. There are no cases clearly associated with droperidol at low doses used to treat nausea and vomiting, however.

The anesthesiology community was alarmed and irritated by the FDA warning. ASA asked FDA to reconsider the issue and to revise or remove the warning. In November 2003, the FDA convened a meeting of its Anesthetic and Life Support Drugs Advisory Committee. T. J. Gan, M.D., (representing the Society for Ambulatory Anesthesia), a cardiac electrophysiologist and CEO of Akorn, Inc. (U.S. manufacturer of droperidol) and I (representing ASA) provided testimony. After the meeting, FDA concluded that there are insufficient data to demonstrate the safety of droperidol at lower (“off label”) doses and that the “black box” warning thus cannot be removed. Additional clinical and experimental data must be provided that demonstrate lack of cardiotoxicity at low doses.⁵

Submission of data to FDA is normally instigated by the drug manufacturer. In the case of droperidol, the company is small, the drug’s profit margin is small, and there is no incentive to undertake studies. The impetus and funding for studies to verify the safety of droperidol at low doses must come from elsewhere.


References:

1. Provisional observations on drug product shortages: Efforts, causes and potential solutions. Am J Health Syst Pharm. 2002; 59:2173-2182.

2. U.S. Food and Drug Administration Center for Drug Evaluation and Research. Drug Shortages. Available at: <www.fda.gov/cder/drug/shortages>. Accessed on April 8, 2004.

3. American Society of Health-Systems Pharmacists. ASHP Drug Product Shortages Management Resource Center. Available at: <www.ashp.org/shortage>. Accessed on April 8, 2004.

4. Rodin DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004; 350:1013-1022.

5. Anesthetic and Life Support Drugs Advisory Committee of the Food and Drug Administration, Center for Drug Evaluation and Research Meeting, November 18, 2003. <www.fda.gov/ohrms/dockets/ac/03/minutes/3978M1.htm>. Accessed on April 8, 2004.



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