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Executive Summary

SMITHKLINE BEECHAM's KYTRIL IS "APPROVABLE" at FDA as of Dec. 10. The NDA for the 5-HT[3] receptor antagonist granisetron in an I.V. formulation was submitted for the indication of prevention of nausea and vomiting associated with initial and repeated courses of emetogenic cancer therapy, including high-dose cisplatin. SB filed the NDA in late December 1991. The dosing regimen is 3 mg in a bolus injection. An FDA advisory committee reviewed Kytril on March 11 and concluded that the drug should not be approved until questions about potential carcinogenicity and cardiovascular effects were answered ("The Pink Sheet" March 15, p. 10). The committee agreed that granisetron is effective, based on studies in more than 1,500 patients and recommended that Kytril could be approved for second- line prevention of emesis in chemotherapy patients with label warnings if FDA and SmithKline resolved the genotoxicity questions. The carcinogenicity questions arose from animal studies that showed liver tumor formation in rats and mice that received granisetron. SB representatives told the advisory committee that, although tumor growth in animals was seen, no evidence of genotoxicity was found. They maintained that granisetron is a "promoter" that may cause tumor cell proliferation, but that the drug is not an "initiator" because it does not contribute to chromosomal damage or gene mutations in vitro. At the November European Conference on Clinical Oncology and Cancer Nursing (ECCO-7) in Jerusalem, John Bourke, University of Newcastle-upon-Tyne, presented a study, "Does Granisetron Share the Cardiac Arrhythmogenic Potential of Other 5-HT[3] Receptor Antagonists?" His study concluded that "detailed studies to date have not shown any clinically relevant arrhythmogenic effects" of the drug. Bourke reported that only one patient of 3,453 receiving granisetron in clinical trials suffered cardiac arrest within seven days of therapy, an event not considered related to therapy, and only one other patient required treatment for an arrhythmia. That patient had a known paroxysmal atrial fibrillation. The overall incidence of arrhythmias in the clinical trials, 39 of 3,269, were "within the expected range for this population," Bourke reported. The 1.2% overall incidence is "comparable to studies of other antiemetic agents," his report said. Granisetron is approved in more than 20 countries and has been administered to more than 300,000 patients. SmithKline Beecham also has an oral formulation of Kytril. The drug was developed in Japan by Beecham Yakuhin. As SmithKline prepares for Kytril's approval, the company's pricing strategy becomes more important to the product's acceptance by hospitals. Efforts by hospital pharmacies to reduce the costs of treating patients with Glaxo's anti-emetic Zofran (ondansetron) means SmithKline has less maneuvering room on the price of Kytril: the baseline has changed. At the recent mid-year meeting of the American Society of Hospital Pharmacists in Atlanta, a number of poster sessions and other presentations were focused on cutting the cost of Zofran. For example, at Brigham & Women's Hospital, chemotherapy patients are being given Zofran doses lower than those approved in labeling, and the hospital estimates it will save $323,000 this year as a result ("The Pink Sheet" Dec. 13, p. 5). Additionally, should Kytril be approved by FDA as a second-line therapy, SmithKline's pricing flexibility will be more constrained.

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