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LILLY's AXID IS EFFECTIVE AS ONCE-A-DAY TREATMENT FOR DUODENAL ULCER, FDA ADVISORY CMTE. AGREES; CMTE. ALSO ENDORSES DUODENAL MAINTENANCE INDICATION

Executive Summary

Lilly's Axid (nizatidine) is effective in the treatment of acute duodenal ulcer, in either a once-a-day, 300 mg dose or a twice-daily, 150 mg dose, and as maintenance therapy for duodenal ulcer in a 150 mg once-a-day dose, FDA's Gastrointestinal Drugs Advisory Committee concluded at its Sept. 10 meeting. The committee unanimously agreed to recommend approval of the H[2] antagonist for the treatment and maintenance claims. For the duodenal ulcer treatment indication, the committee based its decision on the results of three double-blind, placebo-controlled multicenter trials involving a total of 139 centers and 1,257 patients. Duodenal ulcer healing rates for nizatidine 150 mg b.i.d. and 300 mg h.s. (one dose at night) were, on average, between 60-75% at 4 weeks, and were twice that of the placebo controls. Summarizing the committee's views on the treatment data, Chairman David Ransohoff, MD, Yale University School of Medicine, said: "I think you have a pretty strong consensus that the committee feels that the data are sufficient to establish efficacy and that either 300 mg h.s. or 150 mg b.i.d. would seem to be reasonable." The committee voted to approve the maintenance indication on the basis of a one-year, double-blind trial of 150 mg nizatidine vs. placebo in approximately 1,000 patients. FDA considered the 79-investigator trial, which was analyzed by the firm as five separate studies, to be one large, multicenter trial. While the committee acknowledged that two well controlled, multicenter trials are generally necessary for approval, it agreed that the efficacy results and the large patient population warranted an approval recommendation. Committee member Leon Burmeister, PhD, University of Iowa, for example, commented: "In reviewing this [trial] and hearing the description, I really thought of this as essentially being one study. I realize that there is concern [about approving a drug based on only one trial], but it was a large study, and based on its results, I would support the recommendation that it be approved as a maintenance treatment." The maintenance trial, which included patients with a healed ulcer in the three months prior to the beginning of the study, evaluated ulcer presence by endoscopy at three, six, and twelve months. Lilly Research Scientist and Statistician Walter Offen, Phd, reported that at the evaluation timepoints "roughly twice as many patients recurred on placebo than those that recurred on nizatidine." The twelve month recurrance rate was 22% for nizatidine and 44% for placebo. For both the duodenal treatment and maintenance indications, Lilly is recommending reduced dosing levels for patients with impaired renal function due to increased accumulation levels of nizatidine found in that patient population. Richard Bergstrom, PhD, a research scientist at Lilly, said that based on results of pharmacokinetic studies, the company "feels that individuals with moderate to severe renal function -- that is, creatinine clearances of 20-50 ml/minute -- should receive only 50% of the recommended dose. For individuals who have severe renal dysfunction -- that is, creatinine clearnace less than 20 ml/minute -- they should receive only 25% of the recommended dose." The committee's primary safety concern was evidence that nizatidine may cause liver toxicity in some patients. An independent analysis of patients with elevated liver enzyme levels presented by Hyman Zimmerman, MD, George Washington University School of Medicine, showed nizatidine elevated enzyme levels were not statistically different from other H[2] antagonists on the market. However, the committee was concerned that very high levels seen in patient might be indicative of a hepatotoxicity problem. Noting that the one instance of high liver enzyme levels was seen in a population base of approximately 5,000, FDA Office of New Drug Evaluation and Review Director Robert Temple, MD, commented that this "one case that is noticeable sort of hangs over [the safety of nizatidine]. If that is a true bill, and really represents a rate of one in 5,000, we're all going to be upset. If it is just a spurious association, and there isn't any way to tell for sure, then it won't amount to anything." The committee agreed that Axid appears to be relatively safe, but that labeling should note the occurrence of liver enzyme level elevations. Echoing the comments of several other panel members, Burmeister summarized, "I thought Dr. Zimmerman's presentation was effective, and at least from a statistical point of view, I think it does seem as if the data indicate that safety is not that much of a problem, particularly if precautionary wording about the possibilities of liver abnormalities is made available." With the exception of one committee member, the group agreed that formal post marketing studies would not be necessary to evaluate the potential hepatotoxicity. Responding to the suggestion that a formal study should be conducted, Temple commented: "I can't think of any reason why that should not be detected with ordinary spontaneous reporting. That system has picked up completely unexpected events with suprofen [Suprol] -- the flank pain syndrome -- and ticrynafen [Selacryn] was picked up in a couple of months when . . . there was no hint that [liver toxicity] was going to be a problem." Alternatively, Temple suggested that the company could tell physicians, in its launch announcements, that it would like to hear about liver toxicity problems. "I think one of the things we'd like to explore with the company afterwards," Temple said, "is the possibility of providing balanced information about the state of the information here, which includes two components: One, is that if you take the overall rate of liver injury, it looks about the same as the comparative drugs and placebo, but that there has been . . . one case of relatively severe injury which may or may not be related to the drug; and [two] that you are interested in hearing about any more cases if they occur." If approved as recommended by the committee, Axid would be the fourth H[2] antagonist in the U.S. market indicated for once-a-day treatment and maintenance of duodenal ulcers. The other H[2] antagoinists -- SmithKline's Tagamet (cimetidine), Glaxo's Zantac (ranitidine), and Merck's Pepcid (famotidine) -- are approved for the additional indication of treatment of pathological hypersecretory conditions. Zantac and Tagamet are also indicated for gastric ulcers. Lilly Associate Clinical Investigator Michelle Cloud, MD, noted that the firm has "conducted a study on gastric ulcer which has recently been completed." Data from the study, she said, "have not been analyzed yet, but we should be able to show you that in the next several months." Cloud also noted that the firm is currently conducting trials with an intravenous formulation in seriously ill patients. Zantac, Tagamet, and Pepcid are approved in I.V. as well as oral formulations.
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