Pancreatic Exocrine Insufficiency (PEI)

Transcription

1 Pancreatic Exocrine Insufficiency (PEI) Definition: Condition in which quantity of enzymes secreted into the duodenum in response to a meal are insufficient for maintaining normal digestion 1 Main reasons for inadequate availability of pancreatic enzymes 1,2 Reduced production and secretion of enzymes by the pancreas (due to injury to parenchyma) Inadequate stimulation Obstruction of the pancreatic duct Main clinical consequence of PEI is fat maldigestion and malabsorption resulting in steatorrhoea 1 PEI, pancreatic exocrine insufficiency. s 1. Australasian treatment guidelines for the management of pancreatic exocrine insufficiency. 2010: Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Clinical update. Advances in the treatment of pancreatic insufficiency. Gastroenterol Hepatol. 2011;7(6): For healthcare professional use only

2 Pancreatic Exocrine Insufficiency: Causes 1,2 Pancreatic exocrine insufficiency due to (and not only): Cystic Fibrosis Pancreatic cancer Chronic pancreatitis Acute pancreatitis >80% patients % 63-94% 80-85% patients 1 patients 2 patients 1 Gastrointestinal surgery Diabetes (IDDM*) Diabetes (NIDDM**) Approx % 70-90% patients 1 patients % patients 1 s 1. Keller J. Layer P. Human Pancreatic Response to nutrients in health and disease. The Gut Dumasy V, Delhaye Mcotton F and Deviere J. Fat Malabsorption Screening in Chronic Pancreatitis. American Journal of Gastroenterology 2004;99: * Insulin dependant diabetes mellitus ** Non Insulin dependant diabetes mellitus For healthcare professional use only

3 PEI Symptoms 1 Abdominal pain/ discomfort Many patients with malabsorption may be asymptomatic 2 Diagnoses of PEI may be missed in the absence of clinical steatorrhea 3 Undetected or untreated malabsorption may have harmful effects on weight, even when clinical Flatulence Common symptoms of PEI 1 Weight loss in adults and lack of weight gain/failure to thrive in children steatorrhea is not present 2 early detection of pancreatic exocrine insufficiency is essential; if left undetected and untreated, malabsorption leads to significant weight loss 5 Diarrhea Bloating & Belching s 1. Touuli J, Biankin AV, Oliver MR, et al. Management of pancreatic exocrine insufficiency. Australasian Pancreatic Club recommendations. Med J Aust 2010; 193(8): Dumasy V, et al. Fat malabsorption screening in chronic pancreatitis, Am J Gastroenterol. 2004; 99(7): Forsmark CE. Chronic pancreatis and malabsorption. AM J Gastroenterol 2004; Gooden HM, White, KJ. Pancreatic cancer and supportive carepancreatic exocrine insufficiency negatively impacts on quality of life. Support Care Cancer 2013; 21(7): Imrie CW, Connett G, Hall RI, et al. Enzyme supplementation in cystic fi brosis, chronic pancreatitis, pancreatic and periampulary cancer. Ailkment Pharmacol Ther 2010; 32(1): For healthcare professional use only

4 Assessment of Symptoms: PEI May be Missed in Asymptomatic Patients Relying only on symptoms may lead to over or under diagnosis of PEI 1 PEI can be present in the absence of overt steatorrhea 1 Presence of Steatorrhoea and Malabsorption in CP Patients 2 Every patient with PEI and maldigestion, independent of the degree of steatorrhoea and presence or absence of associated symptoms, should receive PERT 1 s 1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42): doi: /wjg.v19.i Dumasy V, et al. Fat malabsorption screening in chronic pancreatitis, Am J Gastroenterol. 2004; 99(7): PERT, pancreatic enzyme replacement therapy

5 Impact of Untreated PEI* Untreated PEI leads to a number of symptoms, which greatly impact patients lives 1-10 Acute pancreatitis Chronic pancreatitis Cystic fibrosis Post surgery Pancreatic cancer Pancreatic exocrine insufficiency Maldigestion Malabsorption Weight loss Steatorrhoea Diarrhoea Abdominal pain Vitamin deficiencies (A,D,E,K) Malnutrition Reduced bone mineral density Cardiovascul ar events Reduced life expectancy Failure to thrive (Cystic fibrosis only) Reduced pulmonary function (Cystic fibrosis only) s 1. Sikkens ECM, Cahen DL, Kuipers KJ. Pancreatic enzyme replacement therapy in chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2010;(24): Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Clinical update. Advances in the treatment of pancreatic insufficiency. Gastroenterol Hepatol. 2011;7(6): Borowitz D, Robinson KA, Rosenfeld M, et al. Cystic fibrosis foundation evidence-based guidelines for management of infants with cystic fibriosi. J Pediatr 2009; 155: S73-S Layer P, Keller J, Lankisch PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol reports 2001; 3: Lohr JM, Hummel FM, Pirilis kt, et al. Properties of different pancreatin preparations used in pancreatic exocrine insufficiency. Eur J Gastroenterol Hepatol 2009; 21(9): Touuli J, Biankin AV, Oliver MR, et al. Management of pancreatic exocrine insufficiency. Australasian Pancreatic Club recommendations. Med J Aust 2010; 193(8): Littlewood JM, Connett GJ, Struckmeier SS et al. A 2-year post-authorisation safety study of high-strength pancreatic enzyme replacement therapy (pancreatin 40,000) in cystic fibrosis. Expert Opin Drug Saf. 2011;10(2): Colombo C, Fredella C, Russo MC, et al. Efficacy and tolerability of Pancreatin for children in infants and toddlers with pancreatic exocrine insufficiency caused by cystic fibrosis: an open-label, single-arm, multicenter study. Pancreas. 2009;38(6): ; 9. Munck A. Nutritional considerations in patients with cystic fibrosis. Expert Rev Resp Med 2010; 4(1): Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Clinical update. Advances in the treatment of pancreatic insufficiency. Gastroenterol Hepatol. 2011;7(6):

6 Early Detection and Treatment 1 Early detection and adequate treatment with PERT may decrease risks of malnutrition-related morbidity and mortality 1 PERT: pancreatic enzyme replacement therapy. s 1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42): doi: /wjg.v19.i

7 Diagnosis of PEI: Pancreatic Function Tests Co-efficient of fat absorption (CFA) 1 Carbon 13 ( 13 C)- mixed triglyceride ( 13 C-MTG) breath test 1 Faecal elastase tests (FE-1) 2 In certain conditions, where these tests are not widely available in clinical practice, some practical approaches may aid diagnosis such as Assessment of symptoms 2 Pancreatic morphology in patients with CP 2 Nutritional markers in patients with CP 2 Trials of PERT 2 s 1. Dominguez-Munoz JE, et al. Pancreatic exocrine insufficiency: Diagnosis and treatment. J Gastroenterol Hepatol. 2011;26(2): Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42): doi: /wjg.v19.i For healthcare professional use only

8 Two or More Nutritional Bio-Markers Can Predict the Probability of PEI in Chronic Pancreatitis 1 Objective: To investigate the use of serum nutritional markers as surrogate markers for PEI 1 Results Cohort study of 114 patients, 38 had PEI PEI was associated with the following nutritional deficits Haemoglobin, albumin, prealbumin and retinol-binding protein below lower limit of normal 1 Magnesium below 2.05 mg/dl 1 HbA1c above upper limit of normal 1 In the absence of pancreatic function testing, Serum nutritional markers can be used to predict the probability of PEI in CP and provide guidance in decisions for PERT 1 Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol 2013 November 14; 19(42): For healthcare professional use only

9 Australasian Treatment Guidelines for the Management of PEI in Acute Pancreatitis 1 PERT Recommendations No evidence to support the use of PERT in the initial stages of acute pancreatitis 1 Patients recovering from an episode of acute pancreatitis should be monitored for PEI for at least 6-18 months 1 Patients recovering from an acute necrotising attack should be supplemented with oral PERT 1 Australasian treatment guidelines for the management of pancreatic exocrine insufficiency. 2010:1-89. For healthcare professional use only

10 A trial of PERT based only on clinical presentation is recommended by several national societies when the clinical presentation is strongly suggestive of PEI 1 1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42): doi: /wjg.v19.i For healthcare professional use only

11 What should you look for in your choice of PERT? 1 Optimal particle size (<1.7mm) to pass the pylorus 1 Enteric-coated particles which pass through to the duodenum undigested 1 Large specific surface area for optimal mixing with chyme 1 Rapid enzyme release once in the small intestine 1 Well-characterized efficacy profile 1 Multiple unit dose supplements 1 1. Lohr JM, Hummel FM, Pirilis KT, et al. Properties of different pancreatin preparations used in pancreatic exocrine insufficiency. Eur J Gastroenterol and Hepatol 2009; 21:

12 Pancreatin Composition1 PERT Pancreatin* standardized to: Amylase Ph. Eur. Units 1 Proteases 1000 Ph. Eur. Units 1 Lipase Ph. Eur. Units 1 s 1. Pancreatin Approved Local Leaflet. Effective date: 23 May 2014 For healthcare professional use only

13 For healthcare professional use only Indications of Pancreatin 1,2,3,4 Pancreatin is indicated in paediatric and adult patients with pancreatic exocrine insufficiency (PEI) 1 PEI is often associated with, but not limited to: Cystic fibrosis (CF) 1 Chronic pancreatitis (CP) 1 Pancreatic surgery 1 Gastrectomy 2 Pancreatic cancer 2 Gastrointestinal bypass surgery (e.g., Billroth II gastroenterostomy) 3 Ductal obstruction of the pancreas or common bile duct (e.g., from neoplasm) 3,4 Shwachman-Diamond Syndrome 4 Status after an attack of acute pancreatitis and initiation of enteral or oral feeding

14 Patented Minimicrosphere Technology 1 Pancreatin's innovative minimicrospheres technology with gastroresistant pellets was designed to achieve simultaneous passage through the pylorus with chyme 1 Recommended by guidelines 1 Capsules dissolve rapidly in the stomach releasing enteric-coated Minimicrospheres Ô 1 Immediate mixing with chyme and simultaneous passage through the pylorus into the duodenum 1 Rapid release of enzymes at ph>6 Using Pancreatin means digestion takes place in the right environment 1 Good distribution with the chyme Physiologically dictated particle size for unobstructed passage through the pylorus simultaneously with the chyme 1 1. Lohr JM, Hummel FM, Pirilis KT, et al. Properties of different pancreatin preparations used in pancreatic exocrine insufficiency. Eur J Gastroenterol and Hepatol 2009; 21:

15 Pancreatin Minimicrospheres : Optimizing Efficacy Through Innovation PERT should deliver a high and consistent amount of active enzymes to the proximal duodenum; which can be achieved by ensuring it is unaffected by gastric acid and mixes well with the chyme 1 Characteristic Resistant to Gastric acid Rapid enzyme release In small intestine Particle size < 2 mm Pancreatin Minimicrospheres TM are resistant to gastric acid 1 More than 80% to the initial activity of Pancreatin was measured after 15 minutes at ph6 (in an in vitro study) 1 Pancreatin has a particle size of <1.7mm 1 Pancreatin Minimicrospheres fulfill key characteristics required for a pancreatic enzyme replacement therapy 1 Large specific Surface area Optimal mixing With chyme In a comparative study* Pancreatin had the greatest specific surface area 1 Optimum particle size and a large specific surface area facilitates optimal mixing with chyme 1 PERT, pancreatic enzyme replacement therapy. 1. Lohr JM, Hummel FM, Pirilis KT, et al. Properties of different pancreatin preparations used in pancreatic exocrine insufficiency. Eur J Gastroenterol and Hepatol 2009; 21:

16 Treatment Goals Goals of treatment with PERT for PEI are to: Reduce steatorrhoea 1 Reduce stool frequency 1 Improve stool consistency 1 Prevent weight loss or increase body weight 2 Restore/maintain good nutritional status 1,2 s 1. Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Clinical update. Advances in the treatment of pancreatic insufficiency. Gastroenterol Hepatol. 2011;7(6): Sikkens ECM, Cahen DL, Kuipers KJ. Pancreatic enzyme replacement therapy in chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2010;(24): For healthcare professional use only

17 Most patients develop PEI after gastrointestinal surgery 100% PERT controls nutritional status and prevents long-term malnutrition s 1. Pezzilli R, Andriulli A, Bassi C et al. Exocrine pancreatic insufficiency in adults: A shared position statement of the Italian association for the study of the pancreas. World J Gastroenterol 2013; 19(44): Dervenis C. Exocrine pancreatic insufficiency and malnutrition after gastrointestinal surgery. HPB 2009;11 (Suppl. 3): 1 2 For healthcare professional use only

18 Pancreatic Exocrine Function in Patients After GI and Pancreatic Surgery Physiological alterations following gastrointestinal and pancreatic surgery result in maldigestion caused by the anatomical changes. 1 Total or partial resections of stomach, with or without duodenal resection, and partial pancreatic resection are associated with the following events 1 Disturbance of fundus relaxation caused by the disappearance of antro-fundic and duodeno-fundic reflexes 1 Absence of neurally stimulated pancreatic secretion caused by the lack of fundus relaxation 1 Reduction in CCK-mediated stimulation of pancreatic secretion secondary to duodenal resection 1 Large and hard-to-digest nutrient particles reaching the jejunal lumen because of resection of the distal stomach 1 Reduction in exocrine pancreatic secretion in cases of pancreatic resection 1 Asynchrony between the gastric emptying of nutrients and bilio-pancreatic secretion as a result of anatomical reconstruction 1 Maldigestion is reported in up to 80% of patients who have undergone gastric or pancreatic surgeries 1 1.Dominguez-Munoz JE. Pancreatic enzyme replacement therapy: exocrine pancreatic insufficiency after gastrointestinal surgery. HPB. 2009;11 (Suppl.3):3-6. For healthcare professional use only

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20 Australian Treatment Recommendations for the Management of PEI in Patients with Gastrectomy Position Statement Gastrectomy is performed most commonly to treat cancer, bleeding gastric ulcers, polyps and perforations of the stomach wall 1 Patients can benefit from PERT after surgery (Level 2a) 1 Adequate and appropriate enzyme substitution may 1 Reduce maldigestion Contribute to improvement in post-gastrectomy nutritional status Most patients who have undergone partial or total gastrectomy develop PEI 1 1.Toouli J, et al. Management of pancreatic exocrine insufficiency: Australasian pancreatic club recommendations. MJA.2010;93(8): For healthcare professional use only

21 Trial of PERT Trial of PERT may help diagnose PEI and establish significant improvement in maldigestionrelated symptoms 1,2 s 1. Toouli J, et al. Management of pancreatic exocrine insufficiency: Australasian pancreatic club recommendations. MJA.2010;93(8): Sikkens ECM, Cahen DL, Kuipers KJ. Pancreatic enzyme replacement therapy in chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2010;(24): For healthcare professional use only

22 Post-operative PERT has a positive impact on long-term patient survival 1 Treatment with PERT after surgery is an independent risk factor for survival 1 1 In a study examining long-term survival in post-operative patients, those who did not receive PERT at hospital discharge had a significantly reduced survival 1 Retrospective, single center, observational study, n=147 1 PERT has a positive impact on long term survival post surgery 1 Pancreatic enzyme replacement should be standard treatment after surgery for chronic pancreatitis at the time of hospital discharge 1 1.Winny M et al. Insulin dependence and pancreatic enzyme replacement therapy are independent prognostic factors for long-term survival after operation for chronic pancreatitis. Surgery 2014; 155: For healthcare professional use only

23 Pancreatin is effective following pancreatic surgery1 Treatment with Pancreatin, 75,000 lipase units per main meal and 50,000 lipase units per snack, was both effective and well tolerated. 1 P<0.05 Pancreatin significantly improved coefficients of fat absorption (CFA) and coefficients of nitrogen absorption (CNA) and significantly improved body weight and body mass index (BMI) 1 After 1 year, Pancreatin improved mean CFA and CNA 1 P<0.05 CFA and CNA values were similar to those seen after 1 week of double-blind treatment 1 Pancreatin improved clinical symptoms, including stool consistency, flatulence and abdominal pain 1 Pancreatin is engineered to help your patients recover after a surgery 1.Seiler CM et al. Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin Ph. Eur. minimicrosp heres (Pancreatin MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension. Aliment Pharmacol Ther 37(7):

24 For healthcare professional use only CLINICAL STUDIES OF Pancreatin IN CHRONIC PANCREATITIS

25 Pancreatin: Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (1/4) Objective To evaluate the effect of Pancreatin in controlling steatorrhoea in 27 adult patients (mean age, 51 years) with Chronic Pancreatitis 1 Study Design Randomized, double-blind, placebo-controlled, 2-week trial, with a placebo run-in phase. Dose: lipase units per meal (Pancreatin x 4 caps) and lipase units per snack (Pancreatin x 2 caps) 1 End Point The primary endpoint was the change between baseline and post-treatment in CFA (%). Secondary endpoints included evaluation of stool parameters and global improvement of symptoms scales. 1 CFA, coefficient of fat absorption; CP, chronic pancreatitis 1.Safdi M, Bekal PK, Martin S et al. The effects of oral pancreatic enzymes (Pancreatin 10 capsule) on steatorrhoea: a multicenter, placebo-controlled, parallel group trial in subjects with chronic pancreatitis. Pancreas. 2006;33(2): Erratum in: Pancreas 2007;34(1):174.

26 Pancreatin : Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (2/4) The mean change in CFA from the single-blind placebo phase to the double-blind phase was significantly greater in the Pancreatin group (36.7%) compared with the placebo group (12.1%; P = ) 1 CFA values greater than 80 % were observed in three-fourth of the patients treated with Pancreatin Results 1 Pancreatin treated patients achieved a mean CFA of 86.6% at the end of the 2-week double-blind period 1 Safdi M, Bekal PK, Martin S et al. The effects of oral pancreatic enzymes (Pancreatin 10 capsule) on steatorrhoea: a multicenter, placebo-controlled, parallel group trial in subjects with chronic pancreatitis. Pancreas. 2006;33(2): Erratum in: Pancreas 2007;34(1):174

27 Pancreatin : Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (3/4) Results Significant improvement in stool consistency with Pancreatin group compared with the placebo group (P =.0102) 1 Significant reduction in stool frequency with Pancreatin(from 10.8 to 5.2 stools/day) compared with placebo (14.0 to 14.6 stools/day; P=.0015) 1 Significant reduction in daily mean fat excretion in stool with Pancreatin compared to placebo (reduction of 56.5 vs g/day, P=.0181) 1 Global disease symptoms scores reached statistical significance in physician score for Pancreatin(P=.0435) and a showed a trend towards Pancreatin in subject score (P=.0634) compared to placebo 1 There were no significant differences in adverse events between groups and no serious events were reported 1 1.Safdi M, Bekal PK, Martin S et al. The effects of oral pancreatic enzymes (Pancreatin 10 capsule) on steatorrhoea: a multicenter, placebo-controlled, parallel group trial in subjects with chronic pancreatitis. Pancreas. 2006;33(2): Erratum in: Pancreas 2007;34(1):174

28 Pancreatin : Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (4/4) Conclusion Daily dose of Pancreatin at 40,000 lipase units/meal (4 x Pancreatin capsules) and 20,000 (2 x Pancreatin capsules) lipase units/snack controlled steatorrhoea and was found to be safe and well tolerated. 1 1.Safdi M, Bekal PK, Martin S et al. The effects of oral pancreatic enzymes (Pancreatin 10 capsule) on steatorrhoea: a multicenter, placebo-controlled, parallel group trial in subjects with chronic pancreatitis. Pancreas. 2006;33(2): Erratum in: Pancreas 2007;34(1):174.

29 Pancreatin : Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (1/3) Objective To evaluate the efficacy and safety of Pancreatin in treating PEI due to CP in patients > 18 years of age 1 Study Design 1-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in India Dose: 6 to 9 capsules of Pancreatin were to be taken per day: 80,000 lipase units / 2 capsules per main meal (3 main meals per day) and 40,000 lipase units / 1 capsule per snack (2 to 3 snacks) 1 End Point Primary outcome measure was change in CFA from baseline to end of double-blind treatment. Secondary evaluations included effect of Pancreatin on CNA, stool fat, stool weight, and clinical symptomatology 1 1.Thorat V, Reddy N, Bhatia S, et al. Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Pancreatin MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis - a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2012; 36:

30 Pancreatin: Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (2/3) Objective: To assess the safety and efficacy of Pancreatin in the treatment of PEI due to chronic pancreatitis 1 Thorat V, Reddy N, Bhatia S, et al. Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Pancreatin MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis - a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2012; 36:

31 Pancreatin: Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (3/3) Results Patients receiving Pancreatin had a significantly greater reductions in stool frequency and stool weight compared to those receiving placebo % of patients on Pancreatin reported treatment-emergent adverse events compared to 25.0% of patients on placebo. None led to study discontinuation Conclusion 1 Pancreatin at a dose of 80,000 lipase units/meal and 40,000 lipase units/snack showed significantly greater improvement in fat and nitrogen absorption compared to placebo, and is well tolerated in CP patients with PEI 1 CP, chronic pancreatitis; PEI, pancreatic exocrine insufficiency. Thorat V, Reddy N, Bhatia S, et al. Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Pancreatin MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis - a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2012; 36:

32 For healthcare professional use only CLINICAL STUDIES OF PERT IN PANCREATIC CANCER

33 Efficacy of PERT in Patients With Pancreatic Cancer Objective To investigate the efficacy of enteric-coated pancreatin microsphere* treatment on weight loss in 21 patients with unresectable cancer of the pancreatic head region 1 Study Design Randomized, double-blind, placebo-controlled 8 week trial 1 Primary End Point Change in body weight at week 8 1 *PERT formulation in this study was not Pancreatin brand CFA, Coefficient of fat absorption 1.Bruno MJ, Haverkort EB, Tijssen GP, et al. Placebo controlled trial of enteric coated pancreatin microsphere treatment in patient with unresectable cancer of the pancreatic head region. Gut 1998; 42:92-96.

34 Efficacy of PERT in Patients With Pancreatic Cancer There was a 1.2% increase in body weight in patients on enzyme replacement therapy, whereas a 3.7% decrease in body weight was noted in the placebo group 1 No observed adverse events were considered related to treatment 1 Weight loss in patients with unresectable cancer of the pancreatic head region and occlusion of the pancreatic duct can be prevented by high dose enteric coated pancreatin enzyme supplementation in combination with dietary counseling 1 1.Bruno MJ, Haverkort EB, Tijssen GP, et al. Placebo controlled trial of enteric coated pancreatin microsphere treatment in patient with unresectable cancer of the pancreatic head region. Gut 1998; 42: *PERT formulation in this study was not Pancreatin brand

35 For healthcare professional use only CLINICAL STUDIES WITH PANCREATIN IN CYSTIC FIBROSIS

36 Pancreatin : Efficacy and Safety in Infants <24 Months With CF (1/4) Objective To evaluate the efficacy and safety of PERT Micro in infants younger than 24 months with CF 1 Study Design Multicenter, open-label, baseline-controlled, single-arm study in 12 CF patients with PEI 1 Primary End Point Primary end point was mean change from baseline in the CFA after 2 weeks of treatment, based on 72-hour fat balance assessments 1 CF, cystic fibrosis. 1.Colombo C, Fredella C, Russo MC, et al. Efficacy and tolerability of Pancreatin for children in infants and toddlers with PEI caused by cystic fibrosis: an open-label, single-arm, multicenter study. Pancreas. 2009;38(6):

37 Pancreatin : Efficacy and Safety in Infants <24 Months With CF (2/4) The average dose of lipase units and dose of the capsules are shown in the table 1 Treatment Duration and Dosing 1 Study Treatment Treatment duration, day Mean SD (range) Daily lipase units/kg body weight Mean SD (range) Daily lipase units/g fat intake Mean SD (range) Patients Treated (N = 12) (57-64) ( ,936) ( ) Daily dose, mg Mean SD (range) ( ) CF, cystic fibrosis. 1.Colombo C, Fredella C, Russo MC, et al. Efficacy and tolerability of Pancreatin for children in infants and toddlers with PEI caused by cystic fibrosis: an open-label, single-arm, multicenter study. Pancreas. 2009;38(6):

38 Pancreatin : Efficacy and Safety in Infants <24 Months With CF (3/4) Results The CFA significantly increased from a baseline mean of 58.0% to a mean of 84.7% after 2 weeks of treatment 1 Statistically significant reductions at 2 weeks in 1 Mean stool fat excretion (from 13.3 to 5.3 g/d; P =.0013) Mean faecal energy loss (from to kj/d; P =.018) Subject acceptance of therapy was good in the majority of patients 1 Patient weight and height increased over 8 weeks of treatment 1 No serious adverse event was reported 1 N=12 CF, cystic fibrosis. 1.Colombo C, Fredella C, Russo MC, et al. Efficacy and tolerability of Pancreatin for children in infants and toddlers with pancreatic exocrine insufficiency caused by cystic fibrosis: an open-label, singlearm, multicenter study. Pancreas. 2009;38(6):

39 Pancreatin : Efficacy and Safety in Infants <24 Months With CF (4/4) Conclusion Pancreatin Micro was well tolerated and resulted in significantly lower fat malabsorption in infants younger than 24 months with PEI due to CF 1 CF, cystic fibrosis; PEI, pancreatic exocrine insufficiency. Colombo C, Fredella C, Russo MC, et al. Efficacy and tolerability of Pancreatin for children in infants and toddlers with pancreatic exocrine insufficiency caused by cystic fibrosis: an open-label, single-arm, multicenter study. Pancreas. 2009;38(6):

40 Pancreatin : Efficacy and Safety in CF Children 12 Years of Age (1/3) 1 Objective To study the efficacy and tolerability of Pancreatin compared with the placebo in children aged 12 years with PEI due to CF 1 Study Design Multicenter, randomised, double-blind, placebo-controlled, 2- period crossover, superiority study 1 End Point Primary outcome measure was CFA. The secondary outcome measures were CNA and clinical symptoms 1 Trapnell BC, Maguiness K, Graff GR et al. Efficacy and safety of Pancreatin 24,000 in subjects with exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros. 2009;8(6):

41 Pancreatin : Efficacy and safety in CF Children 12 Years of Age (2/3) Results Stool fat, stool nitrogen, and stool weight were all significantly lower with Pancreatin treatment compared with placebo 1 Abdominal pain and flatulence were less severe and stool consistency was less watery with Pancreatin compared with placebo 1 Safety: 1 Adverse clinical symptoms of PEI and incidence of TEAEs were reported less when the patients were treated with Pancreatin compared with the placebo-treated group (TEAEs in 43.8% and 64.5% of patients, respectively)1 CF, cystic fibrosis; CFA, coefficient of fat absorption; CNA, coefficient of nitrogen absorption. Trapnell BC, Maguiness K, Graff GR et al. Efficacy and safety of Pancreatin 24,000 in subjects with exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros. 2009;8(6):

42 Pancreatin : Efficacy and Safety in CF Children 12 Years of Age (3/3) Conclusion This study demonstrated that Pancreatin was effective in treating PEI due to CF in patients 12 years of age and was safe and well tolerated 1 CF, cystic fibrosis, PEI, pancreatic exocrine insufficiency. 1.Trapnell BC, Maguiness K, Graff GR, Boyd D, Beckmann K, Caras S. Efficacy and safety of Pancreatin 24,000 in subjects with exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros. 2009;8(6):

43 Pancreatin : Efficacy and Safety in Children, Adolescents, and Adults With CF (1/2) Objective To compare the efficacy of Pancreatin with placebo in the treatment of steatorrhoea in 47 children or adolescents and 50 adults (aged 18 years or older) with PEI due to CF 1 Study Design Multicentre, randomised, double-blind, placebo-controlled, parallel-group study with an open-label run-in phase trial. A high fat diet was stabilized with Pancreatin during the open period. Patients with CFA>80 were then randomized to either continue Pancreatin or receive placebo for 5-7 days 1 Primary End Point Primary outcome measure was change from baseline (end of open-label run-in phase) CFA. The secondary outcome measures were change from baseline stool frequency, stool consistency and CGI 1 CF, cystic fibrosis; CFA, coefficient of fat absorption; CGI, clinical global improvement; PEI, pancreatic exocrine insufficiency. 1.Stern RC, Eisenberg JD, Wagener JS, et al. A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhoea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency. Am J Gastroenterol. 2000;95(8):

44 Pancreatin : Efficacy and safety in Children, Adolescents, and Adults With CF (2/2) Improvement in secondary efficacy parameters with Pancreatin Stool frequency (P<.001 in adults; P =.002 in children/adolescents) 1 Stool consistency (P =.001 in both studies) 1 Global clinical improvement (P<.001 in both studies) 1 No serious adverse events were reported in the children/adolescents. One adult patient experienced a serious adverse event (pulmonary exacerbation) during the open-label period 1 Conclusion Pancreatin is an effective treatment for steatorrhoea associated with pancreatic insufficiency in patients with CF 1 1.Stern RC, Eisenberg JD, Wagener JS, et al. A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhoea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency. Am J Gastroenterol. 2000;95(8):

45 For healthcare professional use only PANCREATIN SAFETY AND DOSING

46 Treatment: Nutritional Recommendations Current Dietary Recommendations Frequent low-volume meals 1 Avoid foods difficult to digest (e.g., legumes) 1 Addition of medium chain triglycerides 1 No fat restrictions 1 Dominguez-Munoz JE. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency: when is it indicated, what is the goal and how to do it? Adv Med Sci. 2011;56(1). doi: /v

47 Using Pancreatin in your patients 1,2 Dosing is approximate and dosing recommendations are best made on an individual basis and should be titrated according to the individual s response and experience, and tailored to factors such as: 1, 2 Dietary Intake Weight Disease severity Symptoms Degree of steatorrhea 1. Ramesh H, Reddy N, Bhatia S et al. A 51-week, open-label clinical trial in India to assess the efficacy and safety of pancreatin enteric-coated minimicrospheres in patients with pancreatic exocrine insufficiency due to chronic pancreatitis. Pancreatology xxx 2013; Pancreatin Product Information For healthcare professional use only

48 Pancreatin : Effect of Different Dosing Schedules (1/2) Objective: To evaluate the effect of different dosing schedules of Pancreatin capsules in 24 patients with CP in PEI 1 Study Design: 3 way crossover, randomized, open-label study 1 Primary endpoint: 6 hour recovery rate of 13 CO2 measured by 13 MTG breath test 1 1.Dominguez-Munoz JE, Garcia JI, Iglesias Rey M, et al. Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomised, three-way crossover study. Aliment Pharmacol Ther. 2005;21:

49 Pancreatin: Effect of Different Dosing Schedules (2/2) Efficacy of the formulation in improving fat digestion was higher when the capsules were taken during the meals or just after the meals compared with the administration of Pancreatin before the meals 1 A: 4 capsules before meals B: 4 capsules after meals C: 1 capsule before meals, 2 during, and 1 after 1 1.Dominguez-Munoz JE, Garcia JI, Iglesias Rey M, et al. Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomised, three-way crossover study. Aliment Pharmacol Ther. 2005;21: For healthcare professional use only

50 When and How to take Pancreatin When Pancreatin must always be taken with enough fluid, during or immediately after meals or snacks 1 How Capsules should be swallowed without crushing or chewing 1 When swallowing is difficult, the capsules can be opened and the Minimicrospheres can be added to soft food or liquid (ph<5.5) 1 Ensure adequate hydration of patients at all times while dosing Pancreatin 1 1.Australian Public Assessment Report for Pancreatic extract. Available at Accessed 18 December, For healthcare professional use only

51 Using Pancreatin in your adult PEI patients 1,2 Dosing should be individualized for patients according to the degree of maldigestion and the fat content of the meal Doses of Pancreatin 80,000 lipase units per main meal and 40,000 lipase units per snack have been shown to be effective and well tolerated in long term (upto 1 year) treatment As a general guide dose a lipase content per meal between 20,000 and 80,000 Ph. Eur. Units is recommended. s 1. Dominguez-Munoz JE. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency: when is it indicated, what is the goal and how to do it? Adv Med Sci. 2011;56(1). doi: /v Ramesh H, Reddy N, Bhatia S et al. A 51-week, open-label clinical trial in India to assess the efficacy and safety of pancreatin enteric-coated minimicrospheres in patients with pancreatic exocrine insufficiency due to chronic pancreatitis. Pancreatology xxx 2013; Pancreatin Summary of product characteristics August 2013.

52 Pancreatin is Well Tolerated1 Pancreatin is well tolerated in infants, children and adult patients with PEI 1 Organ system Very Common 1/10 Common 1/100 to <1/10 Uncommon 1/1000 to <1/100 Frequency Not Known Gastrointestinal disorders Skin and subcutaneous tissue disorders Immune system disorders Abdominal pain* Nausea, vomiting, constipation, abdominal distention, diarrhea* Rash Strictures of the ileocaecum and large bowel (fibrinosing colonopathy) Pruritis, urticaria Hypersensitivity (anaphylactic reactions *Gastrointestinal disorders are mainly associated with the underlying disease. Similar or lower incidences compared to placebo were reported for abdominal pain and diarrhoea No specific adverse reactions were identified in the pediatric population 1 Pancreatin Approved Local Leaflet. Effective date: 23 May 2014

53 Pregnancy and lactation There is inadequate evidence of safety in human pregnancy and lactation 1 Pancreatic enzymes should therefore be used during pregnancy and by nursing mothers only if the potential benefits outweigh the potential risks 1 Highlights of prescribing information, Pancreatin. Available at Accessed 18 December, For healthcare professional use only

54 Recommendation for treating PEI with PERT Every patient with PEI and maldigestion, regardless of steatorrhoea and associated symptoms should receive PERT 1 The main treatment goal of PERT is to maintain healthy nutritional status to prevent osteoporosis and life-threatening cardiovascular events. 1,2 Treatment failure occurs due to poor adherence and patients should be counselled to prevent missed doses and to enforce scheduled dosing with meals. 1 Dietary fat restriction is not recommended for patients with PEI. 1,2 1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42): doi: /wjg.v19.i ;

55 SUMMARY PEI can be present in the absence of overt steatorrhea 1 A trial of PERT based only on clinical presentation is recommended by several national societies when the clinical presentation is strongly suggestive of PEI 1 Pancreatin Minimicrospheres fulfil key characteristics required for a pancreatic enzyme replacement therapy 2 Pancreatic enzyme replacement should be standard treatment after surgery for chronic pancreatitis at the time of hospital discharge, as it has a positive impact on long term survival 3 Pancreatin is safe, well tolerated and effective in controlling steatorrhea in chronic pancreatitis 4 Pancreatin is effective in lowering fat malabsorption in infants younger than 24 months with PEI due to Cystic fibrosis 5 Pancreatin dosing is approximate and dosing recommendations are best made on an individual basis and should be titrated according to the individual s response and experience 6 Pancreatin must always be taken with enough fluids 7 1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42): doi: /wjg.v19.i ; 2. Eur J Gastroenterol and Hepatol et al Surgery Pancreas Pancreas Pancreas. Pancreatology For healthcare professional use only