November 28, 2000

TO: CF Center Directors

FROM: Preston W. Campbell, M.D.

Executive Vice President for Medical Affairs, Cystic Fibrosis Foundation

RE: Illegal Generic Pancreatic Enzymes

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Current Problem

Several generic drug companies have begun manufacturing and distributing microencapsulated pancreatic enzyme products intended for pharmacist substitution for Creon, Pancrease MT and Ultrase. According to the FDA Office of Generic Drugs, none of these companies have received approval to sell them. FDA’s final rule, published on April 25, 1995, declared that exocrine pancreatic insufficiency drug products, whether marketed on an OTC or prescription basis, are new drugs for which approved applications are required for marketing.⁽¹⁾ Such applications require efficacy or bioequivalence studies.

Background

Because pancreatic enzymes were available before passage of the 1938 Pure Food and Drug Act, they were exempt from having to obtain FDA approval to market the drug product.⁽²⁾ Newer microencapsulated formulations were, therefore, legally marketed without FDA approval ⁽²⁾⁽³⁾ .

Because of reports of treatment failures in CF patients after pharmacists substituted generic products for Pancrease⁽⁴⁾ and the association of fibrosing colonopathy with high daily doses,⁽⁵⁾ the FDA initiated the process to require firms to obtain an approved application to market their products.

Since pancreatic enzymes are life sustaining for patients with CF, the FDA allowed all brands that were on the market on April 25, 1995 to continue to be sold while the NDA process was being completed. Implicit in such a regulatory action is that no new products can be marketed without FDA approval. Since the generic products were introduced after the FDA’s final rule on exocrine pancreatic insufficiency drug products, they violate the intent of the agency’s Federal Register notice and, as new drugs without an approved application, are subject to regulatory action.

The FDA’s Office of Compliance has been notified about the illegal products but it will take some time before they are removed from the market place.

Recommendations

1. Physicians should mark all prescriptions for pancreatic enzymes with “Do Not Substitute” or whatever convention is required in their states to prevent pharmacists from substituting a generic for the prescribed brand name product until such time as bioequivalent and therapeutic equivalent drug products become available.

2. Forward this memo to pharmacists and prescription benefit plans insisting on dispensing a generic product.

3. Report any cases of treatment failure or adverse effects to Dr. Preston Campbell at the CF Foundation. The Foundation will pass this information on to the various concerned divisions within FDA.

References

1. FDA. Exocrine pancreatic insufficiency drug products for over-the-counter human use: Final Rule. Federal Register 1995;60:20162-5.

2. Hendeles L, Hochhaus G, Kazerounian S. Generic and alternative brand-name pharmaceutical equivalents: select with caution. Am J Hosp Pharm 1993;50:323-9.

3. Kraisinger M, Hochhaus G, Stecenko A, Bowser E, Hendeles L. Clinical pharmacology of pancreatic enzymes in patients with cystic fibrosis and in vitro performance of microencapsulated formulations. J Clin Pharmacol 1994;34:158-66.

4. Hendeles L, Dorf A, Stecenko A, Weinberger M. Treatment failure after substitution of generic pancrelipase capsules. JAMA 1990;263:2459-2461.

5. FitzSimmons SC, Burkhart GA, Borowitz D, Grand RJ, Hammerstrom T, Durie PR, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. N Engl J Med 1997;336:1283-1289.