Abstract
Exocrine pancreatic insufficiency (EPI) is associated with conditions including cystic fibrosis (CF), chronic pancreatitis (CP), and pancreatic surgery (PS). The symptoms include maldigestion, malnutrition, weight loss, flatulence, and steatorrhea. Pancreatic enzyme replacement therapy (PERT) is the standard treatment for EPI; it is regulated in many countries and most recently in the USA following a US FDA mandate for all PERT manufacturers to submit new drug applications. Pancrelipase delayed-release capsules (CREON®, Abbott, Marietta, GA, USA) have been available in Europe since 1984 and in the USA since 1987; a new formulation was the first PERT to gain approval in the USA in 2009. The efficacy and safety of CREON have been demonstrated in double-blind, randomized, placebo-controlled trials in patients with CF aged ≥7 years and in patients with CP or post-PS. The data consistently demonstrate significantly better fat and nitrogen absorption with CREON versus placebo, and improvements in clinical symptoms, stool frequency, and body weight. Additionally, efficacy and safety of CREON have been shown in open-label studies in young children with CF (aged 1 month to 6 years), with control of fat malabsorption and control of clinical symptoms. The most commonly reported adverse events (AEs) with PERT are gastrointestinal disorders and allergic skin reactions. In clinical studies, CREON was well tolerated with very few withdrawals due to AEs and a low frequency of AEs judged treatment related, regardless of patient age. To further support the known safety profile of PERT, all manufacturers are required to investigate risk factors for fibrosing colonopathy, a rare gastrointestinal complication of CF, and the theoretical risk of viral transmission from porcine-derived PERT products. Together, the clinical study data and wealth of clinical experience suggest that CREON is effective and safe in patients with EPI regardless of etiology, with a very favorable risk-benefit profile.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Layer P, Keller J. Pancreatic enzymes: secretion and luminal nutrient digestion in health and disease. J Clin Gastroenterol. 1999;28:3–10.
Konstan MW, Butler SM, Wohl ME, et al. Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. J Pediatr. 2003;142:624–630.
Steinkamp G, Wiedemann B. Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project. Thorax. 2002;57:596–601.
Beker LT, Russek-Cohen E, Fink RJ. Stature as a prognostic factor in cystic fibrosis survival. J Am Diet Assoc. 2001;101:438–442.
Lai HC, Corey M, FitzSimmons S, Kosorok MR, Farrell PM. Comparison of growth status of patients with cystic fibrosis between the United States and Canada. Am J Clin Nutr. 1999;69:531–538.
United States Pharmacopoeial Convention. The United States Pharmacopeia 33. National Formulary 28 (USP 33-NF 28). Rockville, MD. United States Pharmacopoeial Convention. 2010.
DiMagno EP, Malagelada JR, Go VL, Moertel CG. Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N Engl J Med. 1977;296:1318–1322.
Hendeles L, Dorf A, Stecenko A, Weinberger M. Treatment failure after substitution of generic pancrelipase capsules. Correlation with in vitro lipase activity. JAMA. 1990;263:2459–2461.
DeYoung JL. Development of pancreatic enzyme microsphere technology and US findings with Pancrease in the treatment of chronic pancreatitis. Int J Pancreatol. 1989;5(suppl.):31–36.
Littlewood JM, Kelleher J, Walters MP, Johnson AW. In vivo and in vitro studies of microsphere pancreatic supplements. J Pediatr Gastroenterol Nutr. 1988;7(suppl 1.):S22–S29.
Walters MP, Littlewood JM. Pancreatin preparations used in the treatment of cystic fibrosis-lipase content and in vitro release. Aliment Pharmacol Ther. 1996;10:433–440.
Kuhn RJ, Eyting S, Henniges F, Potthoff A. In vitro comparison of physical parameters, enzyme activity, acid resistance, and pH dissolution characteristics of enteric-coated pancreatic enzyme preparations: implications for clinical variability and pharmacy substitution. J Pediatr Pharmacol Ther. 2007;12:115–128.
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;34:158–166.
Brady MS, Rickard K, Yu PL, Eigen H. Effectiveness and safety of small vs. large doses of enteric coated pancreatic enzymes in reducing steatorrhea in children with cystic fibrosis: a prospective randomized study. Pediatr Pulmonol. 1991;10:79–85.
Halm U, Löser C, Löhr M, Katschinski M, Mössner J. A double-blind, randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency. Aliment Pharmacol Ther. 1999;13:951–957.
Santini B, Antonelli M, Battistini A, et al. Comparison of two enteric coated microsphere preparations in the treatment of pancreatic exocrine insufficiency caused by cystic fibrosis. Dig Liver Dis. 2000;32:406–411.
Stern RC, Eisenberg JD, Wagener JS, et al. A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency. Am J Gastroenterol. 2000;95:1932–1938.
Löhr JM, Hummel FM, Pirilis KT, Steinkamp G, Körner A, Henniges F. Properties of different pancreatin preparations used in pancreatic exocrine insufficiency. Eur J Gastroenterol Hepatol. 2009;21:1024–1031.
U.S. Food and Drug Administration. FDA news release; FDA requires pancreatic extract manufacturers to submit marketing applications. April 27, 2004. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm108289.htm. Accessed July 14, 2010.
Abbott Laboratories. CREON® (pancrelipase) delayed-release capsules. Prescribing information. August, 2010. Available at: http://www.creon-us.com/default.htm. Accessed November 4, 2010.
Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002;35:246–259.
Borowitz DS, Grand RJ, Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995;127:681–684.
Sinaasappel M, Stern M, Littlewood J, et al. Nutrition in patients with cystic fibrosis: a European Consensus. J Cyst Fibros. 2002;1:51–75.
Borowitz D, Robinson KA, Rosenfeld M, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009;155:S73–S93.
Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H. 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;108:832–839.
Layer P, Keller J, Lankisch PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol Rep. 2001;3:101–108.
Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of intestinal malabsorption in cystic fibrosis. Pediatr Pulmonol. 2006;41:35–49.
Kerem E, Corey M, Kerem BS, et al. The relation between genotype and phenotype in cystic fibrosis-analysis of the most common mutation (delta F508). N Engl J Med. 1990;323:1517–1522.
Walkowiak J, Sands D, Nowakowska A, et al. Early decline of pancreatic function in cystic fibrosis patients with class 1 or 2 CFTR mutations. J Pediatr Gastroenterol Nutr. 2005;40:199–201.
Bronstein MN, Sokol RJ, Abman SH, et al. Pancreatic insufficiency, growth, and nutrition in infants identified by newborn screening as having cystic fibrosis. J Pediatr. 1992;120:533–540.
Southern KW, Munck A, Pollitt R, et al. A survey of newborn screening for cystic fibrosis in Europe. J Cyst Fibros. 2007;6:57–65.
Munck A, Dhondt JL, Sahler C, Roussey M. Implementation of the French nationwide cystic fibrosis newborn screening program. J Pediatr. 2008;153:228–233, 233 e221.
Davis PB. Cystic fibrosis since 1938. Am J Respir Crit Care Med. 2006;173:475–482.
Löser C, Möllgaard A, Fölsch UR. Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut. 1996;39:580–586.
Schneider A, Funk B, Caspary W, Stein J. Monoclonal versus polyclonal ELISA for assessment of fecal elastase concentration: pitfalls of a new assay. Clin Chem. 2005;51:1052–1054.
Wagner MH, Bowser EK, Sherman JM, Francisco MP, Theriaque D, Novak DA. Comparison of steatocrit and fat absorption in persons with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002;35:202–205.
Van De Kamer JH, Ten Bokkel Huinink H, Weyers HA. Rapid method for the determination of fat in feces. J Biol Chem. 1949;177:347–355.
Farrell PM, Kosorok MR, Laxova A, et al. Nutritional benefits of neonatal screening for cystic fibrosis. Wisconsin Cystic Fibrosis Neonatal Screening Study Group. N Engl J Med. 1997;337:963–969.
Assael BM, Casazza G, Iansa P, Volpi S, Milani S. Growth and long-term lung function in cystic fibrosis: a longitudinal study of patients diagnosed by neonatal screening. Pediatr Pulmonol. 2009;44:209–215.
FitzSimmons SC, Burkhart GA, Borowitz D, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. N Engl J Med. 1997;336:1283–1289.
Smyth RL, Ashby D, O’Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a casecontrol study. Lancet. 1995;346:1247–1251.
Trapnell BC, Maguiness K, Graff GR, Boyd D, Beckmann K, Caras S. Efficacy and safety of Creon® 24,000 in subjects with exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros. 2009;8:370–377.
Graff GR, Maguiness K, McNamara J, et al. Efficacy and tolerability of a new formulation of pancrelipase delayed-release capsules in children aged 7 to 11 years with exocrine pancreatic insufficiency and cystic fibrosis: a multicenter, randomized, double-blind, placebo-controlled, two-period crossover, superiority study. Clin Ther. 2010;32:89–103.
Graff GR, McNamara J, Royall J, Caras S, Forssmann K. Safety and tolerability of a new formulation of pancrelipase delayed-release capsules (CREON®) in children under seven years of age with exocrine pancreatic insufficiency due to cystic fibrosis: an open-label, multicentre, single-treatment-arm study. Clin Drug Investig. 2010;30:351–364.
Colombo C, Fredella C, Russo MC, et al. Efficacy and tolerability of Creon for Children in infants and toddlers with pancreatic exocrine insufficiency caused by cystic fibrosis: an open-label, single-arm, multicenter study. Pancreas. 2009;38:693–699.
Munck A, Duhamel JF, Lamireau T, et al. Pancreatic enzyme replacement therapy for young cystic fibrosis patients. J Cyst Fibros. 2009;8:14–18.
Patchell CJ, Desai M, Weller PH, et al. Creon® 10,000 MinimicrospheresT vs. Creon® 8,000 microspheres-an open randomised crossover preference study. J Cyst Fibros. 2002;1:287–291.
Borowitz D, Konstan MW, O’Rourke MS, Cohen M, Hendeles L, Murray FT. Coefficients of fat and nitrogen absorption in healthy subjects and individuals with cystic fibrosis. J Pediatr Pharmacol Ther. 2007;12:47–52.
Solvay Pharmaceuticals. CREON® (pancrelipase delayed-release capsules). FDA Antiviral Drugs Advisory Committee. 2008. Available at: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4402b1-03-SOLVAY.pdf. Accessed July 14, 2010.
Marks IN, Banks S. Chronic pancreatitis. Etiology, clinical aspects, and medical management. In: Berk JE, Haubrich WS, Kalser MH, Roth JLA, Schaffner F, eds. Bockus Gastroenterology. Vol. 6. Philadelphia: W.B. Saunders;1985:4020–4040.
Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med. 2009;169:1035–1045.
Whitcomb DC. Genetic predisposition to alcoholic chronic pancreatitis. Pancreas. 2003;27:321–326
Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology. 2001;120:682–707.
Van Hoozen CM, Peeke PG, Taubeneck M, Frey CF, Halsted CH. Efficacy of enzyme supplementation after surgery for chronic pancreatitis. Pancreas. 1997;14:174–180.
Domínguez-Muñoz JE, Iglesias-García J. Oral pancreatic enzyme substitution therapy in chronic pancreatitis: is clinical response an appropriate marker for evaluation of therapeutic efficacy? J Pancreas (Online). 2010;11:158–162.
DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med. 1973;288:813–815.
Lankisch PG, Lembcke B, Wemken G, Creutzfeldt W. Functional reserve capacity of the exocrine pancreas. Digestion. 1986;35:175–181.
Carrière F, Grandval P, Gregory PC, et al. Does the pancreas really produce much more lipase than required for fat digestion? J Pancreas (Online). 2005;6:206–215.
Dutta SK, Bustin MP, Russell RM, Costa BS. Deficiency of fat-soluble vitamins in treated patients with pancreatic insufficiency. Ann Intern Med. 1982;97:549–552.
Marotta F, Labadarios D, Frazer L, Girdwood A, Marks IN. Fat-soluble vitamin concentration in chronic alcohol-induced pancreatitis. Relationship with steatorrhea. Dig Dis Sci. 1994;39:993–998.
Nakamura T, Takebe K, Imamura K, et al. Fat-soluble vitamins in patients with chronic pancreatitis (pancreatic insufficiency). Acta Gastroenterol Belg. 1996;59:10–14.
Bang Jorgensen B, Thorsgaard Pedersen N, Worning H. Short report: lipid and vitamin B12 malassimilation in pancreatic insufficiency. Aliment Pharmacol Ther. 1991;5:207–210.
Haaber AB, Rosenfalck AM, Hansen B, Hilsted J, Larsen S. Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency. Int J Pancreatol. 2000;27:21–27.
Mann ST, Stracke H, Lange U, Klör HU, Teichmann J. Alterations of bone mineral density and bone metabolism in patients with various grades of chronic pancreatitis. Metabolism. 2003;52:579–585.
Morán CE, Sosa EG, Martinez SM, et al. Bone mineral density in patients with pancreatic insufficiency and steatorrhea. Am J Gastroenterol. 1997;92:867–871.
Domínguez-Muñoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr Gastroenterol Rep. 2007;9:116–122.
Domínguez-Muñoz JE, Iglesias-García J, Iglesias-Rey M, Figueiras A, Vilariño-Insua M. Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005;21:993–1000.
Guarner L, Rodríguez R, Guarner F, Malagelada JR. Fate of oral enzymes in pancreatic insufficiency. Gut. 1993;34:708–712.
O’Keefe SJ, Cariem AK, Levy M. The exacerbation of pancreatic endocrine dysfunction by potent pancreatic exocrine supplements in patients with chronic pancreatitis. J Clin Gastroenterol. 2001;32:319–323.
Safdi M, Bekal PK, Martin S, Saeed ZA, Burton F, Toskes PP. The effects of oral pancreatic enzymes (Creon 10 capsule) on steatorrhea: a multicenter, placebo-controlled, parallel group trial in subjects with chronic pancreatitis. Pancreas. 2006;33:156–162.
Whitcomb DC, Lehman GA, Vasileva G, et al. Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: a double-blind randomized trial. Am J Gastroenterol. 2010;105:2276–2286.
Czakó L, Takács T, Hegyi P, et al. Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis. Can J Gastroenterol. 2003;17:597–603.
Borowitz D, Durie PR, Clarke LL, et al. Gastrointestinal outcomes and confounders in cystic fibrosis. J Pediatr Gastroenterol Nutr. 2005;41:273–285.
Dutta SK, Hlasko J. Dietary fiber in pancreatic disease: effect of high fiber diet on fat malabsorption in pancreatic insufficiency and in vitro study of the interaction of dietary fiber with pancreatic enzymes. Am J Clin Nutr. 1985;41:517–525.
Graham DY, Sackman JW. Mechanism of increase in steatorrhea with calcium and magnesium in exocrine pancreatic insufficiency: an animal model. Gastroenterology. 1982;83:638–644.
Proesmans M, De Boeck K. Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes. Eur J Pediatr. 2003;162:760–763.
Domínguez-Muñoz JE, Iglesias-García J, Iglesias-Rey M, Vilariño-Insua M. Optimising the therapy of exocrine pancreatic insufficiency by the association of a proton pump inhibitor to enteric coated pancreatic extracts. Gut. 2006;55:1056–1057.
Bruno MJ, Rauws EA, Hoek FJ, Tytgat GN. Comparative effects of adjuvant cimetidine and omeprazole during pancreatic enzyme replacement therapy. Dig Dis Sci. 1994;39:988–992.
Reichard KW, Vinocur CD, Franco M, et al. Fibrosing colonopathy in children with cystic fibrosis. J Pediatr Surg. 1997;32:237–241.
Littlewood JM. Update on intestinal strictures. J R Soc Med. 1999;92 Suppl 37:41–49.
Bakowski MT, Prescott P. Patterns of use of pancreatic enzyme supplements in fibrosing colonopathy: implications for pathogenesis. Pharmacoepidemiol Drug Saf. 1997;6:347–358.
Smyth RL, van Velzen D, Smyth AR, Lloyd DA, Heaf DP. Strictures of ascending colon in cystic fibrosis and high-strength pancreatic enzymes. Lancet. 1994;343:85–86.
Lloyd-Still JD, Beno DW, Kimura RM. Cystic fibrosis colonopathy. Curr Gastroenterol Rep. 1999;1:231–237.
Stevens J, Davis M, Pawel B, et al. Fibrosing colonopathy (FC)-a retrospective analysis of U.S. cases 1995–1999. Pediatr Pulmonol. 2001;32(S22):344.
Prieto G, Pérez-Moneo B, Molina M, et al. Fibrosing colonopathy associated with treatment with enteric-coated mesalazine pills. Inflamm Bowel Dis. 2009;15:1452–1453.
Schibli S, Durie PR, Tullis ED. Proper usage of pancreatic enzymes. Curr Opin Pulm Med. 2002;8:542–546.
Bansi DS, Price A, Russell C, Sarner M. Fibrosing colonopathy in an adult owing to over use of pancreatic enzyme supplements. Gut. 2000;46:283–285.
Brett AS, Mack EH. Fibrosing colonopathy in adults with cystic fibrosis. AJR Am J Roentgenol. 2008;190:W73.
Häusler M, Meilicke R, Biesterfeld S, Heimann G. First adult patient with fibrosing colonopathy. Am J Gastroenterol. 1998;93:1171–1172.
Mack EH, Brett AS, Brown D. Fibrosing colonopathy in an adult cystic fibrosis patient after discontinuing pancreatic enzyme therapy. South Med J. 2004;97:901–904.
Franzen D, Went P, Buhlmann U. Fibrosing colonopathy in absence of pancreatic enzyme supplementation in one adult patient with cystic fibrosis. Indian J Gastroenterol. 2008;27:133–134.
Waters BL. Cystic fibrosis with fibrosing colonopathy in the absence of pancreatic enzymes. Pediatr Dev Pathol. 1998;1:74–78.
Robertson MB, Choe KA, Joseph PM. Review of the abdominal manifestations of cystic fibrosis in the adult patient. Radiographics. 2006;26:679–690.
Agrons GA, Corse WR, Markowitz RI, Suarez ES, Perry DR. Gastrointestinal manifestations of cystic fibrosis: radiologic-pathologic correlation. Radiographics. 1996;16:871–893.
Sheth S, Shea JC, Bishop MD, et al. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet. 2003;113:286–292.
Dialer I, Hundt C, Bertele-Harms RM, Harms HK. Sonographic evaluation of bowel wall thickness in patients with cystic fibrosis. J Clin Gastroenterol. 2003;37:55–60.
Center for Drug Evaluation and Research, U.S. Department of Health and Human Services Food and Drug Administration. Guidance for industry. Exocrine pancreatic insufficiency drug products-submitting NDAs. April 2006. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071651.pdf. Accessed July 14, 2010.
Committee for Proprietary Medicinal Products (CPMP). Note for guidance on virus validation studies: the design, contribution and interpretation of studies validating the inactivation and removal of viruses (CPMP/BWP/268/95). February 14, 1996. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000351.jsp&mid=WC0b01ac058002956c&murl=menus/regulations/regulations.jsp&jsenabled=true. Accessed July 14, 2010.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin Q5A (R1). 1999. Available at: http://www.ich.org/cache/compo/363-272-1.html#Q5A. Accessed July 14, 2010.
Meng XJ. Recent advances in hepatitis E virus. J Viral Hepat. 2010;17:153–161.
Pavio N, Renou C, Di Liberto G, Boutrouille A, Eloit M. Hepatitis E: a curious zoonosis. Front Biosci. 2008;13:7172–7183.
Mushahwar IK. Hepatitis E virus: molecular virology, clinical features, diagnosis, transmission, epidemiology, and prevention. J Med Virol. 2008;80:646–658.
Meng XJ. Hepatitis E virus: animal reservoirs and zoonotic risk. Vet Microbiol. 2010;140:256–265.
Williams TP, Kasorndorkbua C, Halbur PG, et al. Evidence of extrahepatic sites of replication of the hepatitis E virus in a swine model. J Clin Microbiol. 2001;39:3040–3046.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published with open access at Springerlink.com
An erratum to this article can be found at http://dx.doi.org/10.1007/S12325-011-0034-0
Rights and permissions
This article is published under an open access license. Please check the 'Copyright Information' section either on this page or in the PDF for details of this license and what re-use is permitted. If your intended use exceeds what is permitted by the license or if you are unable to locate the licence and re-use information, please contact the Rights and Permissions team.
About this article
Cite this article
Kuhn, R.J., Gelrud, A., Munck, A. et al. CREON (Pancrelipase Delayed-Release Capsules) for the treatment of exocrine pancreatic insufficiency. Adv Therapy 27, 895–916 (2010). https://doi.org/10.1007/s12325-010-0085-7
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12325-010-0085-7