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Executive Summary

GLAXO's ZOFRAN PLUS METOPIMAZINE REDUCES NAUSEA COMPARED TO ZOFRAN ALONE in patients receiving moderately emetogenic chemotherapy who previously had been treated for cancer, according to a 30-patient study published in the April 15 issue of The New England Journal of Medicine. The study, conducted by Jorn Herrstedt, MD, et al., University of Copenhagen, found that the combination of Zofran (ondansetron) and the dopamine D[2] antagonist metopimazine was "a highly effective and safe anti- emetic regimen that is markedly superior to treatment with ondansetron alone in patients receiving moderately emetogenic chemotherapy." The results suggest that the addition of metopimazine enhances the efficacy of the selective serotonin receptor antagonist, especially in patients who previously have received chemotherapy, who are more likely to experience nausea and vomiting. The study also shows that the combination of ondansetron and metopimazine is able to control delayed emesis, not readily controlled by ondansetron alone. Metopimazine therapy does not produce extrapyramidal symptoms like the dopamine D[2] antagonist metoclopramide, the authors noted. Herrstedt et al. said that ondansetron alone has been found to be very effective against acute emesis in patients receiving highly emetogenic chemotherapy. However, they noted that "the vast majority" of anti-emetic trials enroll patients receiving chemotherapy for the first time, which does "not always reflect the clinical situation, since patients who have previously received chemotherapy are more likely to have nausea and vomiting." Also, the authors pointed out that "serotonin receptors have a major role in acute emesis, but probably are of only minor importance in delayed emesis." The randomized double-blind, placebo-controlled trial enrolled 30 breast cancer patients who previously had undergone chemotherapy and had had at least one vomiting episode. Patients were receiving chemotherapy treatments every three weeks: cyclophosphamide, methotrexate and fluorouracil; cyclophosphamide, epirubicin and fluorouracil; or cyclophosphamide alone. For nausea, the patients received 8 mg ondansetron twice a day and metopimazine four times a day or 8 mg ondansetron twice a day and placebo four times a day. The patients were crossed over to the opposite regimen when they returned after three weeks for their next course of chemotherapy. The combination of ondansetron and metopimazine reduced the number of patients with severe nausea in the first 24 hours from five to zero and the number of patients with five or more emetic episodes from five to two. On days two through five of treatment, 22 patients had no emetic episodes on the combination therapy compared to 15 receiving ondansetron alone. In addition, the incidence of severe nausea was reduced from five patients in the ondansetron alone group to zero in the combination therapy group. Adverse events were similar between the combination and ondansetron therapies, except for mild constipation, which was higher in the ondansetron plus metopimazine group. In a second study published in the April 15 NEJM, dexamethasone and metoclopramide in combination was superior to ondansetron in controlling nausea, especially in the first 24 hours, in patients receiving moderately emetic chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) for breast cancer. The 165-patient study, conducted by Martin Levitt, MD, University of Manitoba, et al. and partially sponsored by Glaxo, found, however, that there was no difference in nausea between the therapies over a seven-day period or in the overall number of patients who did not vomit, in the first 24 hours or over seven days.

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