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Executive Summary

PANCREATIC ENZYME PRODUCTS ARE NOT "TRUE" GENERICS, FDA Office of Drug Standards Director Rheinstein said in an editorial letter in the May 9 issue of the Journal of the American Medical Association. "Different formulations of pancreatic enzyme products are not true generics in the sense of multisource products listed in the FDA's 'Orange Book'...are not tested one against the other, and cannot be expected to behave identically," Rheinstein remarked. "Physicians and patients must realize that these products differ and are not generic equivalents," he stated. Rheinstein's comments responded to a study in the same issue of JAMA by Leslie Hendeles, PharmD, et al. of the University of Florida, which reported several cases of therapeutic failure when cystic fibrosis patients were switched from brandname (McNeil's Pancrease) to "generic" pancrelipases. The article outlines three cases in which patients experienced gastrointestinal symptoms and fat malabsorption after their prescriptions had been refilled with generic pancrelipases. The symptoms included stomach cramps, greasy stools, and increases in appetite. In each case, the patients had been switched from Pancrease to a pancrelipase manufactured by Irvine, California-based Anabolic, Inc. and distributed by either Econolab Generic Products (case #1), Rugby Labs (case #2), or Major Pharmaceutical (case #3). When Pancrease therapy was reinstituted or the patient received another brandname pancrelipase, Reid-Rowell's Creon, the symptoms rapidly resolved. On analysis of the lipase activity in cold water of 20 capsules of both the brandname and generic pancrelipase products from the prescription vials of the patients, Hendeles found that Pancrease "contained 87% [7,480 v. 4,000 USP U/capsule] more lipase activity than listed on the label, whereas the generic product substituted in case 1 had 24% [3,030 v. 4,000 U/cap] less lipase activity than declared on the label." For the other two generic products the lipase activity was only slightly higher than labeled, 5,340 v. 4,000 U/cap. in case #2 and 4,840 v. 4,000 U/cap. in case #3. Creon contained 73% more than the labeled amount (11,100 v. 8,000 U/cap.). When lipase activity was measured in simulated gastric fluid for one hour, Pancrease had a 9% decrease and Creon had a 2% decrease in activity, while "lipase activity was virtually absent in the three generic products under the same conditions." Pancrease lipase activity decreased from 7,480 to 6,820 U/cap. and Creon decreased from 11,100 to 10,900 U/cap. Lipase activity in the generics was reduced from several thousand units per capsule to under 100 or 200 U/cap. The nearly complete destruction of the lipase in the generic products, Hendeles asserted, "indicates that the coating on the microsperes of the generic product was defective." He commented that "the composition of the acid-resistant enteric coating and the method of microencapsulation is a trade secret of the manufacturing process and difficult for a generic manufacturer to duplicate." However, FDA's Rheinstein pointed out that the pancrelipase product manufactured by Anabolic was bioinequivalent, not because it was a generic but because of a manufacturing defect. An FDA inspection last spring "revealed that there was no validation for the enteric coating process," resulting in subpotent or superpotent lots, Rheinstein said. The defective lots were recalled by Anabolic to the wholesale level last June ("The Pink Sheet" Aug. 28, T&G-15), with the firm extending the recall to the retail level in August following further reports of adverse effects. Pancreatic enzyme products have been marketed since before 1938 and therefore do not require FDA approval, Rheinstein noted. However, pancreatic enzyme products formulated with enteric-coated spheres or beads were not on the market prior to 1938. "This fact could be used by the FDA to assert that the marketing of each such product does require an approved new drug application," Rheinstein maintained. Rheinstein signaled that FDA may undertake a review of its position on pancrelipase products if supplied with the appropriate data. "One factor in a decision to commit scarce FDA resources to such a project would be an assessment of the extent to which manufacturing defects of the type reported by Hendeles et al. could be prevented by premarket approval," he commented. Furthermore, "FDA is reconsidering whether pancreatic enzymes should be included in a final OTC mongraph," Rheinstein noted.

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