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ORGANON’s ZEMURON (ROCURONIUM) "NDA DAY" REVIEW

Executive Summary

ORGANON's ZEMURON (ROCURONIUM) "NDA DAY" REVIEW by a subcommittee of the Anesthetic & Life Support Drugs Advisory Committee finds the non-depolarizing neuromuscular blocker safe and effective to facilitate endotracheal intubation and provide skeletal muscle relaxation during surgery or mechanical ventilation. The subcommittee convened on Oct. 7 to review the NDA, just over three months after Organon submitted the NDA (20- 214) for Zemuron on June 29. "I think the sponsor has shown adequately that if the dose is greater than .6 mg/kg, sometimes reaching up to 1.2 mg/kg, that this drug is an effective drug for rapid sequence induction of intubation," committee member Robert Merin, NM, Medical College of Georgia, said. "When compared to [the standard] succinylcholine [Burroughs Wellcome's Anectine], the drug is at least as good at one minute after injection," he noted. The Zemuron advisory committee meeting was unusual in that there was no formal presentation of data by FDA or the sponsor. Instead, section summaries were presented by subcommittee members. FDA Pilot Drug Staff Consultant Medical Officer Daniel Spyker, MD, commented: "We have done something a bit different with this particular NDA Day in that we have done it as a subcommittee, and all of the committee members who are here present have actually been involved in the review process." The majority of the meeting was held in closed session to conduct a "line by line" discussion of the drug's labeling. Some suggestions about the label were discussed during the open portion of the meeting. For example, Merin maintained that "it needs to go into the label [that] this is an intermediate" acting drug as opposed to short acting like succinylcholine. "You are going to have at least twenty to thirty minutes of paralysis" with rocuronium, Merin asserted. A summary of the cardiovascular effects of rocuronium, presented by subcommittee Chairperson Carol Lake, MD, University of Virginia Health Sciences Center, found no significant effect of the drug on myocardial function. However, Lake added that "there is some question with respect to the effects on pulmonary vascular tone and that may require some additional Phase IV work." Lake noted that histamine release with rocuronium is "infrequent." Merin asserted that "there is reasonable evidence that the drug falls between vecuronium and pancuronium [Organon's Norcuron and Pavulon] in terms of vagal blocking and hence stimulatory cardiovascular effects." He observed that rocuronium "certainly does not produce the tachycardia we see with pancuronium, [but] in some circumstances it does result in tachycardia. I believe that should be reflected in labeling." The subcommittee agreed that there is insufficient evidence to support the use of rocuronium in the intensive care unit. "Labeling should state that the experience is not there," Merin noted. Responding to a concern by FDA Pilot Drug Staff Medical Officer Curtis Wright, MD, that physicians using a non- depolarizing agent in the operating room would have a tendency to continue with the same agent in the ICU, Merin said: "Today, in most circumstances the clinician who is taking care of the patient in the OR is not the same physician who is going to take care of the patient in the ICU." Merin added that "intensivists tend not to use new drugs. They tend to use old drugs. So I don't think this is a big concern for a new drug like this." Organon was commended during the meeting for having conducted studies in obstetric patients. "The sponsor should be complimented for examining the drug in this setting," subcommittee member James Eisenach, MD, Bowman Gray School of Medicine, said. He remarked that there were "minor, if any, safety concerns relating to the newborn" in a study looking at rocuronium use in elective Caesarean section. Eisenach noted, however, that the optimum dose of rocuronium may not have been achieved in the obstetric study. "Many of these women were ventilated by mask during the period after the rocuronium was given while waiting for adequate muscle blockade to occur," he noted. "The package insert should reflect that we don't have good information regarding dose for that particular indication and that is rapid sequence induction for pregnant patients," Eisenach said. FDA's Wright asked the subcommittee several questions relating to the development of non-depolarizing neuromuscular blockers in general. He wanted to know whether the committee felt that open- label, unblinded studies are adequate and whether sponsors should be required to collect comparative data. Subcommittee members indicated that they were satisfied with open-label, unblinded data. With regard to comparative data, Eisenach said: "It is important to know the relative efficacies of different drug for clinicians, but I am not sure that it is necessary for a decision about whether a drug is safe and effective for approval." Wright summarized: "What I am hearing from the committee is that you are relatively comfortable with the mechanism of action of this class of agents. You know what to expect from a non- depolarizing blocker and don't think there is much in the way of surprises in this class of drugs."
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