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Executive Summary

CHOLESTYRAMINE ALTERNATE DOSAGE FORMULATIONS REQUIRE FULL NDA to demonstrate bioequivalence due to the "nonsystemic" action of the drug, Questran-mfr. Mead Johnson maintained in April 25 comments to FDA on a Parke-Davis ANDA-suitability petition. "The nonsystemic nature of the [lipid-lowering] drug prohibits a standard bioequivalence-by-blood-level study being used to demonstrate safety and efficacy in the usual manner," Mead Johnson said. "Efficacy for new formulations and new dosage forms of cholestyramine can be demonstrated only by in vivo clinical studies of the capacity of the new dosage form to lower cholesterol to the level achieved by an equal weight dose of the marketed powder," the Bristol-Myers subsidiary said. Mead Johnson added that "this has been the policy of" FDA's Metabolism & Endocrine Drugs Div. Parke-Davis submitted an ANDA-suitability petition on March 10 for a solid oral dosage formulation of Questran oral powder. The firm asserted that its formulation differs from Questran powder "only in its dosage form" which "is more palatable and more convenient to administer." Because "the drug is not absorbed by the body and since the proposed dosage form delivers the same drug to the same site as the 'listed' dosage form," Parke-Davis contended, the solid oral formulation "is safe and effective" and "is suitable for submission as an ANDA." Parke-Davis said Mead Johnson's product "must be mixed with a noncarbonated liquid to mask its unpleasant texture and flavor, to avoid esophageal irritation or blockage, to aid in its delivery to the intestines, and to avoid intestinal blockage." Mead Johnson argued that "the facts that [cholestyramine] is an insoluble resin and is delivered orally are far from sufficient to guarantee that the two formulations in question will provide identical clinical results." The product's mechanism of action "involves the sequestration of bile acids from intestinal fluids by the resin. This is a surface phenomenon and, for quantitatively equivalent clinical effects, requires unrestricted access to the face of the resin beadlets by the intestinal fluids containing the bile acids," Mead Johnson said. "The effect of the excipients present in the Parke-Davis formulation on both the physical release in the digestive tract of cholestyramine beadlets from the dosage form matrix, as well as on the pH and enzyme density of the surrounding fluid, needs to be determined before safety and efficacy can be claimed."

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