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ICI’s DIPRIVAN (PROPOFOL) ANESTHETIC HAS NO DIRECT LINK TO PEDIATRIC DEATHS IN ICUs, FDA ADVISORY COMMITTEE FINDS; FDA ASKS ICI TO PURSUE PEDIATRIC INDICATION

Executive Summary

ICI's general anesthetic Diprivan has no direct link to pediatric deaths in hospital intensive care units, FDA's Anesthetic and Life Support Drugs Advisory Committee concluded at its Sept. 1 meeting. The committee also concluded that Diprivan (propofol) has no identifiable link to cardiac adverse events in children and adults. Based on its conclusions, the committee determined that no additional warnings should be added to labeling. The meeting was called to discuss possible follow-up actions to an Aug. 18 "Dear Doctor" letter from ICI warning physicians that "Diprivan not be used in the pediatric ICU until the risks, benefits, and proper dosing instructions have been defined." The injectable drug, indicated for induction and maintenance of general anesthesia in combination with other agents, is not currently indicated for children because "safety and effectiveness have not been established" for that use, labeling states. Diprivan was approved in the U.S. in October 1989. ICI sent the "Dear Doctor" letter in mid-August to the heads of ICUs at every hospital in the U.S. and to all members of the Society of Critical Care Medicine. The U.S. correspondence followed a similar European "Dear Doctor" letter sent by ICI in February and an April 29 worldwide "Dear Doctor" letter sent by the World Health Organization. The European and WHO letters were triggered by the deaths of two Norwegian pediatric ICU patients who had received Diprivan. According to the U.S. letter, there were 66 reports of adverse cardiac events "temporally associated with use of Diprivan," 42 of which occurred in children under three years old. There were a total of 19 deaths, 13 in children under three. The infusion rate in the 42 pediatric cases ranged from 2 to 25 mg/kg/hr, the letter states, noting that "the available data on continuous infusion suggest that many of these patients received an anesthetic rather than a sedative dose." The letter adds: "Studies have not been done to determine whether these adverse experiences are more or less frequent when Diprivan is added to the pediatric ICU drug regimen." Advisory Committee Chairman Edward Miller, MD, Columbia University, who reviewed the cardiac adverse event reports, said: "I was unable to discern any direct link, at least with this information." Invited expert Peter Rothstein, MD, Baby's Hospital, New York City, said that based on his analysis of the pediatric deaths: "I really can't make a case for or against this drug being involved." Noting that only "a couple" of the pediatric deaths occurred in the U.S., Rothstein said it is unclear how Diprivan is used in other countries and that "if every child admitted to the ICU is being put on a full infusion [of Diprivan] for sedation, there will be deaths in that group." The U.S. "Dear Doctor" letter states that all the serious events reported are "common in intensive care practice." FDA Pilot Drug Evaluation Staff Director John Harter, MD, recommended against adding warnings to Diprivan labeling. He said: "If we know some specific warning, then we should tell people about it, but I don't think we should load the practitioner down with a lot of skull and crossbones." Current Diprivan labeling currently cautions that patients receiving the drug "should be continuously monitored for early signs of significant hypotension and/or bradycardia." The committee reached consensus that, because a link to adverse events is unclear, Diprivan should be tested in pediatric populations. Harter pointed out that there are "few alternatives" for extended sedation of pediatric patients in an ICU setting and he encouraged ICI to submit an IND to FDA for the new indication. An ICI statement prepared for the advisory committee states that the company is "in the process of reviewing, on an international basis, the need for clinical studies" for the pediatric ICU indication. Miller said that ICI will come before the advisory committee again in November to present clinical data on the use of Diprivan in adult ICU patients. The company said it is also working on other indications for the anesthetic and filling in unspecified parts of the label "where not enough is known."
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