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Executive Summary

Neuromuscular blocking agents, including Organon's Norcuron and Burroughs Wellcome's Tracrium, should bear warnings about the risk of prolonged paralysis when used on a long-term basis in the hospital intensive care unit, committee member Robert Bedford, MD, University of Virginia School of Medicine, recommended at a Nov. 23 meeting of FDA's Anesthetic & Life Support Drugs Advisory Committee. Bedford said: "We have no alternative but to put very, very stern warnings for the clinician [who] uses muscle relaxants... so that they are well aware that there are real problems that occur." While the committee met in open and closed sessions to consider labeling changes specifically for Norcuron (vecuronium) with relation to its potential for prolonged paralysis in the ICU, the committee meeting also addressed the risks of Tracrium (atricurium) and pancuronium. Following the meeting, Organon disclosed that in the closed session the committee discussed the possibility of relocating certain language that already exists in Norcuron labeling about the potential for prolonged paralysis and the need for monitoring. The committee apparently agreed that labeling about monitoring should be similar for Tracrium and pancuronium. Reportedly, the committee did not discuss the need for additional studies in its closed session. During the open portion of the meeting, committee member Michael Roizen, MD, University of Chicago Medical Center, reported that neuromuscular blockade in the ICU has produced prolonged paralysis, including myopathy and disuse atrophy, lasting from several hours up to several months. Roizen pointed out, however, that the relative incidence of prolonged paralysis "differs importantly among muscle relaxants." In the medical literature, Roizen said, there have been 45 case reports of prolonged paralysis for vecuronium compared to 22 case reports for pancuronium and zero to one cases for atricurium. Since vecuronium is used one-tenth as frequently as pancuronium in the ICU and atricurium even less, Roizen maintained that the relative incidence of the adverse event would be 450 for vecuronium, 22 for pancuronium and 30 for atricurium. Roizen recommended that "warnings are to be issued, but I think they should be different for the different drugs." FDA consultant Ronald Miller, MD, University of California-San Francisco, took the most restrictive position on the issue. "I think that a warning should exist in the package insert for all muscle relaxants that clearly states that there are no data that the muscle relaxants improve patient welfare or outcome or that you could postulate that they may worsen outcome" of patients in the ICU, Miller said. Miller was one of the authors of an article that found that half of the 16 patients in a study had prolonged paralysis after vecuronium therapy was discontinued. Two patients died in the study, which was published in the Aug. 20 issue of the New England Journal of Medicine. "Neither company should be allowed to promote the use of muscle relaxants in the ICU in any way shape or form until they get data to justify their use," Miller asserted. FDA previously has warned Organon and Burroughs Wellcome against making comparative efficacy claims for their products ("The Pink Sheet" Aug. 12, 1991, T&G-4). Other presenters at the meeting pointed out that it would be impractical to conduct clinical studies in ICU patients. Instead, they recommended continued use of the neuromuscular blockers in the ICU with adequate monitoring. "It is our perception that if you do routine train-of-four [peripheral nerve stimulation] monitoring in the critically-ill patients, the problems with prolonged paralysis are either nonexistent or very very minimal," John Hoyt, MD, University of Pittsburgh, said during the public comment portion of the meeting. Noting that muscle relaxants are "an essential part of critical care medicine," Hoyt maintained that "they facilitate a new form of mechanical ventilation and allow us to minimize airway pressure, which we believe is destructive to the lung."

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