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SCHERING's LORATADINE RECOMMENDED FOR ONCE-A-DAY USE BY FDA ADVISORY PANEL; ANTIHISTAMINE SHOWS DOSE-SEDATION RELATIONSHIP SIMILAR TO TERFENADINE

Executive Summary

Schering-Plough's loratadine 10 mg tablets should be approved as a once-a-day treatment for seasonal allergic rhinitis in patients over twelve years of age, FDA's Pulmonary-Allergy Drugs Advisory Committee unanimously agreed at its Oct. 23 meeting. Summarizing the committee consensus, Chairman Oscar Frick, MD, PhD, University of California Medical School at San Francisco, said, "the minimum clinically effective dose is 10 mg of loratadine." Frick noted that the drug "does cause some sedation, but it is very low and not significantly different from placebo." Loratadine's dosing combined with the low sedation profile could, when approved, give the product a convenience, dosing advantage over the only non-sedating antihistamine currently available, Merrell Dow's Seldane (terfenadine), which is recommended for twice-a-day dosing. The committee found the dose-sedation ratio of loratadine at 10 mg once daily to be "about the same" as terfenadine 60 mg b.i.d. For its NDA submission, Schering designated three clinical trials as demonstrating efficacy: one compared loratadine 10 mg once a day to clemastine 1 mg b.i.d. with a placebo control in 313 patients; a second compared loratadine 10 mg once daily, clemastine 1 mg b.i.d. and placebo in 309 patients; and, the third compared loratadine 10 mg once a day to terfenadine 60 mg b.i.d. in 321 patients, with a placebo control. The major parameter in all three cases was an improvement in mean total symptom scores. "When we look at loratadine versus the comparative agent in all three trials, the activity was comparable -- there were no [statistically] significant differences," Schering VP-Clinical Research Jonathan Spicehandler, MD, noted during the firm's presentation. "I would also like to emphasize that in all three trials, loratadine was more effective than placebo." Spicehandler also described three initial placebo-controlled, randomized dose-ranging studies of 5, 10, 20 and 40 mg, in which 40-100 patients at each dose were evaluated at three days, seven days and the 14-day end of trial. "At the end of the third study there were no differences between the treatment groups although at day three there was a suggestion of a dose effect between 10 mg and 40 mg," he reported. "Subsequent analysis revealed that these differences were accountable by statistically significant changes at the baseline between the 10 mg and 40 mg groups and were not due to incremental increases in efficacy with rising dose. We concluded that there were no gross differences observed among the doses tested." Schering based its low-drowsiness claim for loratadine on two criteria: animal data showing poor penetration of the antihistamine across the blood-brain barrier, and thus into the central nervous system; and a series of special human studies requested by FDA at the end-of-Phase II conference. The latter, conducted by Thomas Roth, PhD, director, Sleep Disorder Center, Henry Ford Hospital, Detroit, included subjective evaluations, lab performance data, driving performance and physiological measures of sleep tendency. "I think the data seems to indicate that loratadine 10 mg is devoid of any signs of sedation using a myriad of methods," Roth concluded. "In terms of ranging, 20 mg could produce levels of sedation comparable to 10 mg as well as placebo, [and] the 40 mg dose does show some signs of sedation but these effects are highly inconsistent. More importantly, 40 mg is not a significantly different dose from 10 mg and consistently less sedating than traditional sedating antihistamines."
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