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JANSSEN’s SUFENTA FOR EPIDURAL OBSTETRIC USE CLEARS FDA ADVISORY CMTE. BUT DATA FOUND LACKING FOR POST-OP PAIN; ICI’s DIPRIVAN IN ICU PATIENTS REVIEWED

Executive Summary

Janssen Pharmaceutica's Sufenta (sufentanil) administered epidurally for labor and delivery pain with a local anesthetic is an indication that FDA's Anesthetic and Life Support Drugs Advisory Committee feels "comfortable" with, the group agreed Nov. 23. However, the committee felt data were insufficient to recommend that Sufenta be indicated for epidural use to treat post-operative pain. Summing up the committee's discussion of Sufenta, Chairman Edward Miller, MD, Columbia University, said: "So the consensus . . is that the low dose with a local anesthetic, we're comfortable with that. With the 30 or 60 [micrograms of sufentanil] alone, there's not sufficient data to recommend its use." The Sufenta supplemental NDA (19-050) for use in both epidural analgesia in labor and delivery and treating post-op pain has been pending at FDA since Sept. 30, 1991. Sufenta is currently indicated as an adjunct to the maintenance of anesthesia in intubated and ventilated patients and, in some cases, as a primary agent for the induction and maintenance of anesthesia in the operating room. FDA brought Sufenta before the advisory committee for suggestions on what areas in product labeling might need added detail, FDAer Dan Spyker, MD, Pilot Drug Evaluation Staff, said. Spyker reported that FDA's review of Sufenta labeling will be completed "hopefully within the calendar year." "The combination with the local anesthetic makes good sense," committee member James Eisenach, MD, Bowman Gray School of Medicine, said. "The two drugs are synergistic in animal models ...when they are injected spinally, and there are potential advantages to using them in that setting. I feel much less comfortable...with the 30 and 60 microgram [epidural] boluses even in the recovery room," he explained. The recommended dosage range proposed for the obstetric indication is 10-15 micrograms administered with 0.125% bupivacaine. The higher dosage levels were proposed by Janssen for control of post-op pain. The committee looked at three studies of the post-operative analgesic use, two studies of the obstetric use, five safety studies and a literature review. Safety concerns raised by the committee for the epidural indications, particularly at the higher dosage levels, were respiratory depression and inadvertent intravascular injection of the drug. * In an effort to provide more data, Janssen agreed to try to "pull together its safety profile" for the two dose ranges at the suggestion of Donald Stanski, MD, Stanford University School of Medicine. Stanski suggested that if this were done "with the detail of...not respiratory arrest but...clinically relevant respiratory depression...that would be a way to make a decision on what is available." The high dosage epidural indication for "Sufenta, where the dose administered epidurally is greater than that which you would [give] intravenously to achieve analgesia, raises the possibility of a catastrophe" in the form of accidental I.V. administration, committee member Lawrence Saidman, MD, University of Chicago Medical Center, commented. An intravenous bolus in this dosage range could result in truncal rigidity and respiratory depression, Eisenach noted. He suggested that a blinded, controlled, efficacy study comparing epidural and I.V. administration be undertaken to weigh the "benefit versus the risk." Janssen noted that of 1,100 patients in the firm's studies and in the literature who received sufentanil epidurally, one was reported as having immediate absorption and respiratory arrest. The patient was believed to have had an intravascular injection. The committee also discussed the use of ICI Pharmaceutical's Diprivan (propofol) to induce sedation in intensive care units. On Nov. 23, during the open session of the committee meeting, ICI presented responses to questions from the committee on hypotension incidence, risk of sepsis and pharmacokinetics. The advisory committee revisited the application in closed session on Nov. 24. The intravenous hypnotic is currently indicated for the induction and maintenance of anesthesia in inpatient and outpatient procedures. The supplemental NDA (19-627) for ICU sedation was submitted Sept. 27, 1990. ICI is seeking approval for Diprivan only in ICU patients who are intubated or mechanically ventilated. Of 159 and 137 patients receiving Diprivan and a "comparator" agent, respectively, the incidence of hypotension was 33% with Diprivan and 16.8% with the other drug, ICI said. From this experience, the firm has stopped initial dosing in its Diprivan ICU protocols and decreased the rate of sedation to 5 micrograms from 10 micrograms per kilogram per minute. ICI also told the committee that its studies of Diprivan show a similar frequency of sepsis between Diprivan and comparative agents. ICI has data from pharmacokinetic studies of Diprivan administrated for up to 15 days with post-infusion monitoring of up to five days. The company said that in all studies there was a "rapid fall" in plasma levels within 20-30 minutes of termination of the infusion, maintaining that the rapid decrease should support the case for longer durations of infusion. ICI said Nov. 25 that its discussions with FDA during the closed portion of the meeting focused on "fine tuning" Diprivan labeling "to help a wide variety of patients." * The firm will submit its draft labeling to the agency the week of Nov. 30 and said it anticipates approval of the supplemental NDA "before the end of the year." The ICU indication is "a combination of uses for a lot of conditions," Pilot Drug Evaluation Staff Director John Harter, MD, said. He asked specific committee members to look at data on the use of Diprivan for a number of conditions treated in the intensive care unit (e.g., asthma, pulmonary edema, head injury, etc.) to see if specific instructions should be included in labeling. ICI noted that pediatric ICU studies of Diprivan were submitted to FDA in May 1992. Harter said these could be reviewed at a future advisory committee meeting. Currently, labeling states specifically that the drug is not recommended for pediatric use because "safety and effectiveness have not been established." The committee determined at a Sept. 1 meeting that the drug has no direct link to pediatric deaths in ICUs ("The Pink Sheet" Sept. 7, p. 14).
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