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1/16/2004

FDA Advisory Panel Discusses Droperidol Concerns

Donna Young

Two years after FDA approved the addition of a black-box warning to the antiemetic drug droperidol, a public advisory committee agreed that there is a need for additional data regarding whether the drug can be given safely and under what conditions.

The warning was added to droperidol’s labeling in November 2001 because of reports of fatal cardiac arrhythmias associated with use of the drug.

FDA called on its Anesthetic and Life Support Drugs Advisory Committee during a two-day meeting in November 2003 to assist the agency in determining the “best path forward” for risk analysis of cardiovascular toxicity associated with droperidol.

A recent review by FDA officials of the agency’s postmarketing spontaneous reports database from the “time of marketing to October 2003” found 89 cardiac arrhythmia-related events associated with droperidol use, 46 of which were fatal, according to Nancy Chang, lead medical officer for FDA’s division of anesthetic, critical care, and addiction drug products.

Chang noted that in 2001, FDA had reported different numbers. An agency spokeswoman told AJHP in 2002 that “approximately 100 cases of cardiovascular events, including torsades de pointes (TdP) and death,” had been reported to the agency (March 15, 2002, AJHP).

Of the 89 adverse events reported, Chang said, 22 cases involved QT-interval prolongation and TdP. At least 5 of those cases were fatal.

She noted that there were 10 deaths, 18 cardiac arrests, 6 cases of QT-interval prolongation, and 3 cases of TdP that occurred at dosages less than or equal to the recommended minimum dosage for adults of 2.5 mg.

After Janssen-Cilag suspended worldwide marketing of droperidol in March 2001—except for the United States, where an injectable form of the drug is marketed by Akorn Inc. of Buffalo Grove, Illinois, under the brand name Inapsine—FDA reviewed its own postmarketing safety database, Janssen’s analysis, and available literature about QT-interval prolongation and TdP associated with droperidol use, said Robert Rappaport, director of FDA’s division of anesthetics, critical care, and addiction drug products.

FDA held numerous teleconferences with Akorn in 2001, he noted, to find ways to establish an evidence-based data set that would allow the agency to ensure safe use of droperidol and avoid removing the product from the market.

But, Rappaport stated at the November meeting, “we were unable to fully achieve this goal.”

“Based on a clear demonstration of a significant QT prolongation and torsades, the absence of a clear safety margin or clear prevention and management strategies, and the existence of alternative treatments, we chose to take the relatively conservative approach of a labeling change,” he said.

Akorn issued a “Dear Health Care Professional” letter on December 4, 2001, that described the labeling changes and the added warning about reports of patient deaths associated with use of droperidol at or below the recommended minimum dosage of 2.5 mg.

Black box a shock. The addition of the black-box warning came as “quite a shock” to the anesthesiology community, declared Bruce Cullen, vice president for scientific affairs for the American Society of Anesthesiologists (ASA).

“It goes without saying that large numbers of anesthesiologists are quite disturbed by the action that the FDA took,” he testified before FDA’s advisory committee.

The dosage used by anesthesiologists for the treatment of postoperative nausea and vomiting (PONV) is usually “a milligram or less,” Cullen said.

“The evidence that droperidol is unsafe at these low doses, in terms of its potential for serious dysrhythmias, I think and many of my colleagues think, is nearly nonexistent,” he said.

FDA’s Chang stressed that droperidol is approved at dosages of 2.5 mg and above only.

“The agency has not reviewed data to demonstrate safety and effectiveness of less than 2.5 milligrams,” she said. “The use of droperidol at doses less than 2.5 milligrams is off-label.”

Akorn would need to submit additional data to FDA about the safety and efficacy of droperidol at dosages lower than 2.5 mg before the agency could consider approving a labeling change to reflect a lower dosage, Chang said.

But Abu Alam, vice president of research and development for Akorn, said “there is no financial incentive” for his company to conduct a prospective clinical trial.

When drug maker McNeil Laboratories submitted its new drug application for droperidol in June 1968, the studies the company used to support claims of safety and efficacy were acceptable by FDA’s standards in the 1960s, but left the agency without a pharmacologic profile for the drug’s use in humans and only scant information on its excretion in animals, said Art Simone, a medical officer in the division of anesthetic, critical care, and addiction drug products.

FDA recently funded a prospective controlled study that measured QT-interval prolongation after administration of droperidol to eight healthy adult volunteers, but the study was prematurely terminated because of neuropsychiatric adverse events, said Mehul Desai, a medical officer in FDA’s division of cardio-renal drug products.

The study was conducted at Indiana University School of Medicine, he noted.

The placebo-controlled trial involved droperidol dosages of 0.625, 2.5, and 5 mg.

Although the study was halted early, Desai said, “we feel there is a strong suggestion that relatively low doses of droperidol prolongs the QT interval, and although we can’t make any definitive conclusions, we feel that further studies that characterize this better may be warranted.”

Some committee members expressed concerns about the ethics involved in administering high doses of droperidol in a clinical study or making a determination of risk without using a surrogate, such as QT-interval prolongation.

As an alternative to a prospective trial, FDA’s Rappaport said, the agency might consider reviewing a “literature-based submission” as the basis to modify the current labeling.

But, he said, “we need to have the data submitted to us to review. The problem right now is we just don’t have any data. None has been submitted to us by anybody.”

Until FDA receives a literature-based submission or clinical data, Rappaport said, there is no way for the agency to consider a revision of droperidol’s labeling.

Anesthesiologists’ other concerns. Because of the addition of the black-box warning to droperidol’s labeling, “patients are denied an effective, cost-efficient drug for treatment and prophylaxis of postoperative nausea and vomiting,” said Tong Joo Gan, associate professor of anesthesiology for Duke University at Durham, North Carolina.

The warning’s requirement to use a 12-lead electrocardiograph (ECG) before administration of the drug, and continued monitoring for arrhythmias for two to three hours after completing treatment has “effectively removed droperidol for use as a treatment for postoperative nausea and vomiting,” ASA’s Cullen said.

“Yes, anesthesiologists typically monitor ECG intraoperatively, and yes, it’s monitored postoperatively in the recovery room, but it’s not typically monitored for two or three hours after administration of the drug,” he maintained.

Many anesthesiologists are vexed by concerns of facing malpractice suits if a patient experiences an adverse event associated with droperidol, Cullen asserted.

“Anesthesiologists now fear that if they give that drug and the patient has any complication, whether it’s related to droperidol or not, if it comes out in the courtroom or in the testimony . . . that you gave droperidol and didn’t monitor the patient appropriately, no matter what the complication is, you’re kind of hanging yourself out to dry,” he lamented.

Many hospitals, pharmacies, and physicians have removed droperidol from their formularies because of similar concerns, Cullen added.

“They just don’t want to take the risk associated with it,” he said.

The alternative drugs to droperidol for PONV, such as ondansetron, may pose a greater risk to patients, Cullen asserted.

But FDA’s Chang said droperidol should be used only after other drugs had been tried first. “In other words, [droperidol] was regulated to second-line status, and that again was a reflection of the very high level of concern that we had for the drug at the time,” she said.

The recommendation for a baseline ECG and ECG monitoring was “in accordance with the best advice and guidance that we have with respect to these drugs that can prolong QT,” Chang said.

The monitoring period was based on literature that reported that the elimination half-life for droperidol is about two to three hours, she said.

“The most conservative approach might have been to say . . . ECG monitoring should go on for two to three half-lives when we’re pretty sure that the drug is more or less gone,” Chang said. “But when we started looking at a possible monitoring time of six to nine hours, that seemed to be clinically impracticable, and the two to three hours was chosen as sort of a compromise between what might be clinically practicable and the pharmacokinetic considerations.”

Chang said that the black-box warning is “really just a tool to try to emphasize particular safety information.”

“We’re certainly aware that in practice and in the community a boxed warning can have a different significance,” she said.

Committee members agreed that regulators were justified in requiring the addition of the black box to droperidol’s labeling because of the lack of safety data available to FDA about the drug and reports the agency received about QT-interval prolongation and TdP associated with droperidol use.

Panel members also agreed that additional data were necessary for review before FDA could make any further decisions about droperidol’s labeling.

Akorn’s Alam acknowledged that his company has not manufactured droperidol “for the last two years” because Janssen stopped supplying the Illinois company with raw materials to make the drug.

Akorn has selected a “European vendor” from which to obtain the raw materials for droperidol, Alam told the advisory committee.

“We’re still working with FDA for the clearance of that alternate vendor,” he said.

Alam claimed that a company in Paris, France, called OTL Pharma is manufacturing droperidol, “and they sell to six countries without a black-box warning.”

“As of yesterday before I came [to the meeting], I contacted them again in France,” he said. “They said they do not have any torsades. They have no records of any QT prolongation.”

FDA’s Rappaport said that FDA does not have information supporting Alam’s claims that droperidol has been approved by French regulators for PONV use.

“We can certainly look into it,” he told the advisory committee.