Pancreatic Enzymes Clinical Care Guidelines

Pancreatic insufficiency (PI) remains a significant issue for the majority of individuals with cystic fibrosis. Recommendations include target doses of pancreatic enzyme replacement therapy (PERT) in infants, children, and adolescents.

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Summary
  • Pancreatic insufficiency (PI) remains a significant issue for the majority of individuals with cystic fibrosis.
  • The majority of individuals with CF are pancreatic insufficient.
  • The provision of safe and effective pancreatic enzyme replacement is a key therapy in CF.

Pancreatic Enzymes Clinical Care Guidelines: Executive Summary

Borowitz DS, Grant RJ Durie PR, the Consensus Committee. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. J Pediatr. 1995; 127:681-84.

Pancreatic insufficiency (PI) remains a significant issue for the majority of individuals with cystic fibrosis. Left untreated, it could lead to growth failure, weight loss, abdominal bloating, foul-smelling stools, or diarrhea. The use of pancreatic enzyme replacement therapy (PERT) has helped to alleviate these symptoms. 

However, the Cystic Fibrosis Foundation received reports of 35 cases of colonic stricture between January 1990 and December 1994, which were considered to be related to high doses of PERT. Guidelines for dosing of PERT and avoidance of fibrosing colonopathy were published in 1995 based on a consensus conference organized by the CF Foundation in conjunction with the U.S. Food and Drug Administration (FDA). Recommendations included target doses of PERT in infants, children, and adolescents, and a warning to use caution when PERT doses exceeded 2,500 lipase units/kg/meal. Since the publication of the original guideline in 1995, there have been a number of new publications relevant to the use of PERT in CF, some of which are mentioned below.

Recommendations 

The majority of individuals with CF are pancreatic insufficient. Thus, provision of safe and effective pancreatic enzyme replacement is a key therapy in CF.

Pancreatic Enzyme Replacement Therapy Recommendations

Recommendations Evaluation of the Evidence
1. Pancreatic insufficient patients should consume a high-calorie diet with unrestricted fat that is appropriate to age and clinical status. Such diets have been shown superior to low-fat diets in promoting growth and lung function. Consensus
2. A nutritional assessment should be performed regularly as a component of routine care in patients with CF. Additional assessment should occur when dosing of PERT is altered. Consensus
3. Enzyme dosing may be done either by grams of fat ingested or by weight. Dosing by grams of fat is more likely to mimic the normal pancreatic response to a meal, although weight-based dosing may be simpler and more convenient, particularly in older children and adults. Consensus
4. Infants generally require 450-900 lipase units/g of fat, OR 2,000–4,000 lipase units per 120 ml of formula or when breastfeeding. Infants generally ingest a higher amount of fat/kg of body weight than do adults. Consensus
5. Older children and adults generally require 500–4,000 lipase units per gram of fat ingested (mean, 1,800 lipase units/g of fat), OR 500-2,500 lipase units/kg/meal, 250-1,250 lipase units/kg/snack, with three meals and two to three snacks per day. It is suggested that initial dosing be in the lower range and titrated up as needed to treat malabsorption. Consensus
6. Doses of enzyme exceeding 2,500 lipase units/kg/meal, or 4,000 lipase units/g of fat warrant further investigation. Doses of enzyme >6,000 lipase units/kg/meal have been associated with fibrosing colonopathy. It is not clear if doses >2,500 lipase units/kg/meal or >4,000 lipase units/g of fat are safe. It is also unlikely that higher enzyme doses will improve clinical condition in patients with CF and poor growth or gastrointestinal symptoms, thus it is recommended not to exceed these doses and that patients on higher doses be titrated down to a lower dosing range. Consensus
7. Patients should receive only the product brands prescribed by their CF care center. Enteric-coated microencapsulated enzymes are the most effective treatment for PI in CF. Patients should not use health food store enzymes or enzymes without an enteric coating unless directed to do so by their CF physician. Consensus
8. Enzyme capsules may be opened and the contents mixed with a small quantity of applesauce or another non-alkaline food, but they should not be crushed or allowed to sit in food. Enzymes may be inactivated by exposure to alkaline environments or prolonged contact with a moist environment. Consensus
9. Enzymes should be stored in a cool, dry place and checked regularly for expiration dates. Consensus
10. Signs and symptoms of poor response to enzyme therapy include abdominal complaints (bloating, flatus, abdominal pain, and loose, frequent stools or overt diarrhea) along with symptomatic steatorrhea (bulky, oily, foul stools) and/or poor growth. These symptoms may also be seen with other conditions. Before increasing enzymes as a result of symptoms, consider dietary factors, adherence issues, intestinal hyperacidity, abnormal intestinal motility, and liver disease with low intestinal bile salt content, as well as non-CF gastrointestinal disease. Consensus
11. Fibrosing colonopathy should be considered in patients with CF who have evidence of obstruction, bloody diarrhea, or chylous ascites, or who have a combination of abdominal pain, ongoing diarrhea, and/or poor weight gain. Fibrosing colonopathy is characterized by colonic strictures. Its cause is unclear, but it has been associated with high doses of pancreatic enzyme supplements. Patients at highest risk include children younger than 12 years, patients taking >6,000 lipase units/kg/meal for more than 6 months, history of meconium ileus in infancy or distal intestinal obstruction syndrome, and history of previous intestinal surgery. Diagnosis is generally made by imaging or histopathology. Fibrosing colonopathy may respond to reduction of enzyme dose, particularly in the early stages, but in later stages colectomy may be required.     Consensus

New Issues

  1. The most commonly used test to screen/diagnose PI in individuals with CF is the fecal pancreatic elastase-1. When a value of <100 µg/g is used, the specificity and sensitivity of fecal pancreatic elastase-1 in a pediatric CF cohort is 100 percent. Every individual with CF should be screened for PI at diagnosis. Pancreatic sufficient patients should be screened annually for PI, especially those who carry two CFTR mutations potentially associated with PI (e.g., Class I, II or III) (Lahiri 2016, Turck D 2016).
  2. In 2004, the FDA determined that PERT products did not meet requirements for over-the-counter preparations and, therefore, would have to complete a new drug application. This meant that all companies would need to conduct clinical trials to demonstrate efficacy and safety of their PERT products and obtain FDA approval. Since 2009, FDA approval has been secured by five oral pancreatic enzyme products for PERT due to CF or other conditions: Creon®, Pancreaze®, Pertzye®, UltresaTM, and Zenpep® (Food and Drug Administration).
  3. Providers should be aware of factors affecting adherence to PERT in their patients (Barker 2016). 

Unanswered Questions

  1. It remains unclear if including an acid suppression medication in a PERT regimen does or does not aid in absorption. The CF Foundation preschool guidelines suggest adding a histamine-2-blocker or a proton pump inhibitor if PERT is maximized and malabsorption is still present (Lahiri 2016, Sander-Struckmeier 2013).
  2. To date there is no FDA-approved non-porcine product. Sollpura (LiprotamaseTM) has completed its Phase 3 trial and may represent an alternative to the current porcine-based available PERT products, if the FDA approves it. A non-porcine product, sollpura (LiprotamaseTM) contains highly purified biotechnology-derived enzymes (lipase, protease, and amylase) (Borowitz D 2012).
  3. There is no clear evidence on the best way to administer PERT with continuous overnight gastrostomy tube (g-tube) feedings (Borowitz 2012, Erskine 2007). The FDA has approved RELiZORB®, a cartridge with immobilized lipase, for use with tube feedings in adults. RELiZORB does not digest proteins or carbohydrates. 
  4. Ivacaftor, a CFTR potentiator, demonstrated improvement in fecal elastase-1 concentration (to 200 μg/g or greater) in seven (23 percent) pediatric participants at week 24. This may suggest that individuals with CF may avoid the need for PERT or require a decreased dosage of PERT, if given early in the course of the disease (Davies 2016).
  5. Providers monitoring PERT would appreciate a noninvasive test to help monitor how well patients are absorbing fats on their current PERT schedule. Presence or absence of symptoms is not a reliable indicator of PERT adequacy, and PERT adjustments are often empirical (Mascarenhas 2015).
  6. Head-to-head studies between different PERT products are needed to determine if the various PERT products are equivalent. A single such study has been done in the U.K. (Taylor CF 2016).

Further Reading

  1. More recent guidelines have discussed PERT:
    The preschool guidelines (Lahiri 2016) and nutritional guidelines (Borowitz 2002, Stallings 2008) extend the discussion from the publication discussed here in only a limited fashion.
    The infant guidelines (Borowitz 2009) contain detailed information on dosing and administering PERT in this age group.
    Dosing for adults is reviewed in the adult guidelines (Yankasksas 2004), however, some of the detail in the discussion of PERT in this document is now incorrect given the new FDA approval guidelines for PERT.
  2. Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, Spear SL, Michel SH, Parad RB, White TB, Farrell PM, Marshall BC, Accurso FJ. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009 Dec;155(6 Suppl):S73-93. PMID: 19914445
  3. Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Cystic fibrosis adult care: Consensus conference report. Chest. 2004 Jan;125(1 Suppl):1S-39S. PMID: 14734689
  4. Lahiri T, Hempstead SE, Brady C, Cannon CL, Clark K, Condren ME, Guill MF, Guillerman RP, Leone CG, Maguiness K, Monchil L, Powers SW, Rosenfeld M, Schwarzenberg SJ, Tompkins CL, Zemanick ET, Davis SD. Clinical practice guidelines from the Cystic Fibrosis Foundation for preschoolers with cystic fibrosis. Pediatrics. 2016 Apr;137(4). PMID: 27009033
  5. Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002 Sep;35(3):246-59. PMID: 12352509
  6. Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H; Clinical Practice Guidelines on Growth and Nutrition Subcommittee; Ad Hoc Working Group. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108(5):832-39. PMID: 18442507
  7. Borowitz D, Stevens C, Brettman LR, Campion M, Wilschanski M, Thompson H; Liprotamase 767 Study Group. Liprotamase long-term safety and support of nutritional status in pancreatic-insufficient cystic fibrosis. J Pediatr Gastroenterol Nutr. 2012 Feb;54(2):248-57. PMID: 22266487
  8. Erskine JM, Lingard C, Sontag M. Update on enteral nutrition support for cystic fibrosis. Nutr Clin Pract. 2007 Apr;22(2):223-32. PMID: 17374796
  9. Davies JC, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, Southern KW, Robertson S, Green Y, Cooke J, Rosenfeld M; KIWI Study Group. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med. 2016;4:107-15. Epub 2016 Jan 21. PMID: 26803277
  10. Mascarenhas MR, Mondick J, Barrett JS, Wilson M, Stallings VA, Schall JI. Malabsorption blood test: Assessing fat absorption in patients with cystic fibrosis and pancreatic insufficiency. J Clin Pharmacol. 2015;55:854-65. Epub 2015 Mar 23. PMID: 25689042
  11. Taylor CJ, Thieroff-Ekerdt R, Shiff S, Magnus L, Fleming R, Gommoll C. Comparison of two pancreatic enzyme products for exocrine insufficiency in patients with cystic fibrosis. J Cyst Fibros. 2016 Sep;15(5):675-80. Epub 2016 Mar 21. PMID: 27013382
  12. Turck D, Braegger CP, Colombo C, Declercq D, Morton A, Pancheva R, Robberecht E, Stern M, Strandvik B, Wolfe S, Schneider SM, Wilschanski M. ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clin Nutr. 2016 Jun;35(3):557-77. Epub 2016 Mar 15. PMID: 27068495
  13. Barker DH, Quittner AL. Parental depression and pancreatic enzymes adherence in children with cystic fibrosis. Pediatrics. 2016;137(2):2015-2296. Epub 2016 Jan 5. PMID: 26738883
  14. Sander-Struckmeier S, Beckmann K, Janssen-van Solingen G, Pollack P. Retrospective analysis to investigate the effect of concomitant use of gastric acid-suppressing drugs on the efficacy and safety of pancrelipase/pancreatin (CREON®) in patients with pancreatic exocrine insufficiency. Pancreas. 2013; 42(6);983-89. PMID: 27068495

This executive summary was prepared by:

Sarah Jane Schwarzenberg, MD (University of Minnesota Health) and Jill Dorsey, MD, MS (Nemours Children's Specialty Care)

The guidelines were published in November 1995, they were reviewed in April 2019 and it was determined that no update is needed at this time.

***

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Information contained on this site does not cover all possible uses, actions, precautions, side effects, or interactions. This site is not intended as a substitute for treatment advice from a medical professional. Consult your doctor before making any changes to your treatment.

Approved drug information is available at www.dailymed.nlm.nih.gov/dailymed.

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