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Executive Summary

DEXIDE ULTRADEX (CHLOROXYLENOL HAND SCRUB) TRANSDERMAL ABSORPTION POTENTIAL in solutions with differing concentrations of active ingredient should be determined, FDA told the firm in a Feb. 3 OTC feedback letter. Discussing the firm's studies submitted in support of a Category I status for chloroxylenol, also called PCMX, FDA OTC Division Director William Gilbertson, PharmD, said: "Dexide should address/support that there is or is not transdermal absorption due to concentration differences in chloroxylenol solution applied to the skin." Gilbertson explained that possible differences in absorptionrates of differing chloroxylenol solutions need to be addressed because in one of Dexide's studies "volunteers were bathed in dilute chloroxylenol solution (about 12 mcg/ml)" while the "surgical hand scrub products will have higher chloroxylenol concentrations (about 30 mg/ml)." In addition, Gilbertson noted that "this concern should also be addressed as related to situations where surgeons may be using occluding surgical gloves for extended periods of time (i.e., hours.)" FDA's comments to Dexide refer specifically to data submitted at a June 19 meeting between FDA and the firm. At the meeting, Wallace Guess, MD, University of Mississippi, a consultant for Texas-based Dexide, told FDA that long term safety studies with chloroxylenol were not needed based on the results of subchronic accumulation studies and data from a computer simulation model ("The Pink Sheet" July 1, T&G-3). Prior to the submission, FDA's position had been that more data was needed, including a two-year rat study, to assess the safety of the product for long term use as a surgical hand scrub or health care personnel handwash. Gilbertson also requested that Dexide "comment on the amounts of chloroxylenol unaccounted for in the bathing study on day 1; that is, the differences in the amounts of chloroxylenol found in the bath water before and after bathing as related to the amount excreted in urine." As an example Gilbertson cited one particular subject for which "there was about 100 mg less chloroxylenol in the bath water after bathing as compared to that present before bathing but there was only 4.4 mg of total chloroxylenol excreted in urine. Clarification is needed as to the 95 mg of chloroxylenol not accounted for from the post-bath water/urine analyses." Regarding Dexide's computer simulation data, Gilbertson requested that the firm "support and validate its selection of the use of the one-component model" in calculating the half-life of chloroxylenol. Noting that the half-life was calculated to the about 2.5 hours, Gilbertson commented that "this estimate is based upon urinary excretion data of 'total' chloroxylenol and reflects the composite pharmacokinetics of the different assayable drug/metabolite urine components." Analysis of the same data, Gilbertson said, "could suggest a biphasic elimination curve which potentially reflects a longer half-life due to one or more excreted components." FDA commented that wile "computer pharmacokinetic (PK) simulations can be a useful tool for predicting drug blood levels . . . the true test of its predictability is the actual comparison of 'simulated values' with 'observed values.'" In the "absence of such actual use data for chloroxylenol surgical scrubs and handwashings," Gilbertson said, "Dexide should indicate, taking into account the issues raised in the other questions, the level of confidence in the company's simulated accumulation predictions for chloroxylenol."

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