Management approaches to exocrine pancreatic insufficiency (EPI) include the following: 
Lifestyle modifications (eg, avoidance of fatty foods, limitation of alcohol intake, cessation of smoking, and consumption of a well-balanced diet)
Vitamin supplementation (primarily the fat-soluble vitamins A, D, E, and K)
Pancreatic enzyme replacement therapy (PERT), which is the therapeutic mainstay
Long-term monitoring of patients with EPI should focus on the following 2 issues:
Correction of nutritional deficiencies
Treatment of causative diseases (when possible); such treatment will vary according to the specific disease present
Pancreatic Enzyme Replacement Therapy
PERT is the basis of treatment of EPI [24, 25] ; the endpoints of treatment are normalization of gut absorption and correction of nutritional deficiencies. The typical indications for initiating PERT are progressive weight loss and steatorrhea.
The pancreatic enzyme products (PEPs) used for PERT are extracts of porcine pancreas that contain all 3 pancreatic enzymes (ie, amylase, protease, and lipase) in varying proportions. However, it is lipase that plays the paramount role in therapy. The following 6 PEPs have been approved by the US Food and Drug Administration (FDA) for the treatment of maldigestion in patients whose bodies do not produce sufficient pancreatic enzymes:
Creon (Abbott Laboratories, North Chicago, IL)
Zenpep (Eurand Pharmaceuticals, Yardley, PA)
Pancreaze (Janssen Pharmaceuticals, Titusville, NJ)
Ultresa (Aptalis Pharma US, Birmingham, AL)
Viokace (Aptalis Pharma US, Birmingham, AL)
Pertzye (Digestive Care, Bethlehem, PA)
These PEPs are not interchangeable. For example, Viokace, unlike the other 5 products, lacks an enteric coating and must be taken with a proton pump inhibitor.
Because exogenous pancreatic enzymes should exert their action on the ingested meal and because gastric emptying of nutrients should occur in parallel with pancreatic enzymes reaching the duodenum, PEPs are administered together with meals and snacks. When a sufficient enzyme concentration is delivered into the duodenal lumen simultaneously with a meal, fat absorption is enhanced.
PEP dosing for PERT is based on the content of lipase units (see Table 1 below). The pancreatic lipase replacement dose should be adjusted on the basis of body weight, clinical symptoms, and stool fat content. Several days should be allowed between dose adjustments.
Table 1. Lipase Content of Currently Available Pancreatic Enzyme Products (Open Table in a new window)
|Pancreatic Enzyme Product||Lipase Content, units|
|Zenpep EURAND 3||3000|
|Zenpep EURAND 5||5000|
|Zenpep EURAND 10||10,000|
|Zenpep EURAND 15||15,000|
|Zenpep EURAND 20||20,000|
|Zenpep EURAND 25||25,000|
|Pancreaze MT 4||4200|
|Pancreaze MT 10||10,500|
|Pancreaze MT 16||16,800|
|Pancrease MT 24||21,000|
The total daily dose is based on the assumption that the patient will have about 3 meals/day and 2-3 snacks/day, with half the mealtime dose given with a snack. Lipase doses larger than 2500 units/kg/meal (or dosages exceeding 10,000 units/kg/day) should be used with caution and only when supported by documentation of 3-day fecal fat measures. Lipase doses larger than 6000 units/kg/meal are associated with colonic stricture and should be reduced.
Dosing for pancreatic insufficiency is as follows:
Initial oral lipase dose, 500 units/kg/meal
Lipase dose range, 500-2500 units/kg/meal
Maximum lipase dosage, 10,000 units/kg/day or 4000 units per gram of fat daily
Dosing for pancreatic insufficiency due to chronic pancreatitis or pancreatectomy is as follows:
Oral lipase dose, 72,000 units/meal with consumption of at least 100 g of fat daily
Alternatively, lower initial lipase doses (500 units/kg/meal) with individualized dose titration may be considered
In a double-blind, randomized, multicountry, placebo-controlled, parallel-group trial enrolling 54 patients aged 18 years or older with confirmed EPI due to chronic pancreatitis or pancreatic surgery, Whitcomb et al found that Creon delayed-release 12,000–lipase unit capsules were effective in treating fat and nitrogen maldigestion, with a treatment-emergent adverse event rate similar to that of placebo. 
In an open-label extension of this study, the investigators determined that pancrelipase was well tolerated over 6 months and resulted in statistically significant weight gain and reduced stool frequency in patients with EPI due to chronic pancreatitis or pancreatic surgery who were previously managed with standard PERT. 
Toskes et al carried out a randomized, double-blind, dose-response, crossover study in which the effect of Zenpep on the coefficient of fat absorption was investigated with a placebo run-in (7-9 days) and 2 treatment periods (9-11 days) consisting of a high dose (7 × 20,000 lipase units/day) and a low dose (7 × 5000 lipase units/day).  The results suggested that chronic pancreatitis patients with EPI benefit from a low dose, whereas a high dose might be needed for patients with more severe EPI.
In a randomized, placebo-controlled PERT withdrawal study evaluating the efficacy and safety of Pancreaze in cystic fibrosis patients with EPI, Trapnell et al found that the agent effectively improved fat absorption and protein absorption in these patients without giving rise to unexpected adverse events. 
A study examining the use of endoscopic therapy in patients with chronic pancreatitis determined that although this therapy is most useful in patients with pancreatic duct stones and dilation and should be used as first-line treatment for those patients, it cannot be recommended as the treatment of choice for all patients with chronic pancreatitis. 
Liprotamase is a biologically engineered nonporcine PERT agent that has been advocated for the treatment of EPI associated with cystic fibrosis and pancreatectomy. In January 2011, the FDA withheld approval of the drug, citing the need for further study.
In a subsequently published phase III 12-month open-label trial designed to assess the safety, tolerability, and long-term nutritional effects of liprotamase in 215 patients with cystic fibrosis and EPI aged 7 years and older, Borowitz et al reported that treatment with a mean of 5.5 capsules of liprotamase per day during meals and snacks for up to 12 months was safe and well tolerated and was associated with age-appropriate growth and weight gain or weight maintenance. 
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