Ms. Terrie is a clinical pharmacy writer based in Haymarket, Virginia.
This article is brought to you by Solvay Pharmaceuticals.
Pancreatic exocrine insufficiency is the inability of the exocrine pancreas to produce or secrete the enzymes necessary for digestion, which results in the malabsorption of nutrients and malnutrition.1 Pancreatic exocrine insufficiency is prevalent in conditions such as cystic fibrosis, chronic pancreatitis, pancreatic resection/ removal, and pancreatic tumors. Proper digestion of food relies on the effective secretion of pancreatic enzymes; thus, pancreatic exocrine insufficiency can cause nutritional deficiencies and symptoms such as diarrhea and steatorrhea.1,2
What Are PEPs?
Pancreatic exocrine insufficiency is treated with pancreatic enzyme products (PEPs), which are extracted mainly from the pancreas of the hog. PEPs contain lipase (which breaks down fat), amylase (which breaks down starches), and protease (which breaks down proteins). Because pancreatic enzymes are necessary for survival in individuals with exocrine pancreatic insufficiency, these individuals require the use of pancreatic enzyme supplements. 2,3 For example, 85% to 90% of individuals with cystic fibrosis require regular use of PEPs.2,3 PEPs are also indicated for use in individuals with chronic pancreatitis.3-6
Older PEP formulations contain pancreatin, whereas newer formulations contain pancrelipase, a more potent extract, also from the pancreas of the hog.7-9 Most modern PEPs are formulated as enteric-coated microencapsulated enzymes and are acid resistant—the enteric coating prevents inactivation of the enzymes in the acidic gastric environment.8,9 According to the FDA, as of April 2004, 23 manufacturers and 26 repackagers marketed 38 PEP formulations. The dosage prescribed is based on clinical symptoms, age, and weight and is then modified according to the patient’s clinical response.10 Examples of PEPs on the market include Creon Minimicrosphere capsules (Solvay Pharmaceuticals Inc), Pancrecarb Microsphere capsules (Digestive Care Inc), Pancrease MT capsules (Ortho-McNeil), and Ultrase/ Ultrase MT capsules (Axcan Pharma).
PEPs have been on the market for decades and are sometimes referred to as “grandfathered” products, because many predate the federal 1938 Food, Drug, and Cosmetic Act.3,7,8 Prior to enactment of this legislation, manufacturers of brand and generic products were allowed to formulate, manufacture, and market their products without submitting safety, efficacy, or bioequivalence testing data to the FDA for approval.7,8
Initially, PEPs were available as both prescription and nonprescription products. In 1995, concerns arose regarding significant differences in bioavailability among various PEPs, in addition to therapeutic failures and adverse events associated with underdosing and overdosing of products. After reviewing all available data, the FDA determined that PEPs could no longer be marketed on an OTC basis.7,8,11 The FDA made known its intent to require new drug applications (NDAs) for all prescription pancreatic exocrine insufficiency products.8 The FDA also concluded that the safe and effective use of PEPs requires that the products be approved through the new drug approval process to ensure standardized enzyme activity.3,12
Are PEPs Interchangeable?
Because each brand of PEP has a unique active pharmaceutical ingredient source and formulation, these products should not be substituted with products marketed as “generic” versions of the products.3,7 Generic PEPs have not gone through any FDA approval process to demonstrate bioequivalence to the branded products they imitate, and no AB-rated generics are available for branded PEPs. PEPs are often interchanged, however, without physician knowledge or clinical monitoring.7,8,11
In February 2001, the FDA received a correspondence from the Cystic Fibrosis Foundation reporting apparent therapeutic failures associated with the practice of substituting brand name PEPs with generic PEPs.3,8 Some adverse effects reported included abdominal pain, intestinal obstruction, and increased incidence of steatorrhea and rectal prolapse.3,8
Various published case studies have documented the clinical ineffectiveness after substituting brand name with generic PEPs, and researchers have explored the variances among different PEPs.11 Hendeles et al reported adverse events in 3 patients with cystic fibrosis after pharmacists substituted generic pancrelipase capsules for the brand name product, Pancrease.7 After these patients were restarted on the brand name products, the gastrointestinal symptoms and fat malabsorption effects were resolved. The researchers found in vitro evidence that the generic capsules had significantly lower levels of the active ingredients when compared with the brand name product. Thus, the generic product was not bioequivalent to the brand name product.7
On April 28, 2004, the FDA issued a Federal Register Notice stating that all manufacturers of PEPs will be required to obtain approval of their products through the NDA process within a 4-year period for the products to remain available on the market.3 The FDA stipulated that because PEPs are medically necessary for many patients, the manufacturers could continue to market currently available products without an approved application for 4 years while preparing the application to the FDA.3,8,12,13
In October 2007, the FDA announced that the period during which the FDA intends to exercise its enforcement discretion against unapproved PEPs was to be extended to April 2010, if the manufacturer had an active investigational NDA on or before April 28, 2008, and has submitted an NDA on or before April 28, 2009— to ensure the availability of exocrine PEPs during the time needed by manufacturers to obtain marketing approval.12 Prompted by reports of adverse reactions, the FDA stated that the substitution of PEPs made by different manufacturers is not recommended.12,13
Variances among PEPs
Kuhn et al evaluated in vitro variability of key performance parameters of 3 brand name PEPs and 3 generic PEPs.8 The researchers found that all of the PEPs studied varied considerably in actual versus labeled lipase activity. The actual lipase activity exceeded 165% of the label claim in 4 batches of one of the generic PEPs and in 1 batch of another generic PEP. The study substantiated the concerns of pharmacy substitution of PEPs and further validated the need for the FDA to standardize these products.8
A study by Case et al evaluated the enzyme contents and dissolution characteristics of 9 PEPs using current USP methods.14 The study concluded that, whereas the assay of PEPs showed that they were equal to their USP claims with regard to enzyme content, not all the PEPs were equal in their lipase activity following dissolution according to USP requirements; the findings may be clinically seen with therapeutic failures of PEPs.14
Pancreatic enzymes are sensitive proteins and liable to inactivation during storage. To compensate for enzyme degradation, many manufacturers may overfill the capsules.2,8,15 Kuhn et al reported that several studies have suggested that PEPs may vary with regard to actual enzyme content and in vitro response to both simulated gastric and duodenal environments.8 The April 2006 FDA guidance states that, due to the potential for adverse effects associated with high doses of pancreatic enzymes, the finished product should be formulated to 100% of the labelclaimed lipase enzyme activity.13
On May 1, 2007, the USP standard that became official stated that pancrelipase capsules should not contain less than 90% nor more than 150% of the labeled lipase activity, and delayedrelease or enteric-coated capsules should not contain less than 90% nor more than 165% of the labeled lipase activity.8,16 Furthermore, for both amylase and protease activity, the USP set a lower limit of 90% of labeled activity. 8,16 Standardization of the enzyme bioactivity is necessary to avoid serious safety problems resulting from too little or too much supplementation.12,15 The FDA’s attempt to standardize the formulation and manufacturing processes of PEPs through the NDA process will improve the safety and effectiveness of these drugs, thus positively affecting therapeutic outcomes.12,15
Various manufacturers have responded to the FDA’s request. On August 20, 2007, Solvay Pharmaceuticals received an approvable letter from the FDA with regard to their NDA for CREON, and in August 2007, Axcan Pharma announced it submitted its NDA application for Ultrase.17,18 On June 18, 2008, Eurand received an approvable letter for their product, EUR-1008.19 Finally, in October 2008, Digestive Care Inc announced that it completed submission of an NDA for Pancrecarb.20 To date, few marketers of generic drugs are on target to meet the guidelines of the 2004 Federal Register Notice. In June 2008, X-Gen Pharmaceuticals Inc announced that it had entered into an exclusive distribution agreement with Eurand Pharmaceuticals Inc for its PEP product, Pancrelipase.21 In August 2008, Altus Pharmaceuticals Inc announced that its product Trizytek (formerly known as ALTU-135) was in phase 3 efficacy trials. If approved by the FDA, this product has the potential to be the first porcine-free enzyme replacement therapy for malabsorption due to pancreatic insufficency.22
Clearly there is a need for standardization of PEPs to avoid substitution with “generic” enzymes that are most likely to lead to treatment failures; therefore, pharmacists can expect to see changes in the supply of pancreatic enzyme products between now and April 2010. Such standardization will ensure consistent dosing, better product quality, potency, and stability. Guaranteeing the overall quality of these products will greatly benefit the various patient populations who require these supplements and in turn will result in improved patient adherence and therapeutic outcomes.