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 digestion1

�Main reasons for inadequate availability of pancreatic enzymes1,2

� 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 steatorrhoea1

PEI, pancreatic exocrine insufficiency.

References

1. Australasian treatment guidelines for the management of pancreatic exocrine insufficiency. 2010:1-89.

2. Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Clinical update. Advances in the treatment of pancreatic insufficiency. Gastroenterol Hepatol. 2011;7(6):401-403. For healthcare professional use only

Pancreatic Exocrine Insufficiency: Causes1,2

* Insulin dependant diabetes mellitus

** Non Insulin dependant diabetes mellitus

>80% patients1

Cystic Fibrosis Pancreatic cancer Chronic pancreatitis

Diabetes (IDDM*)Gastrointestinal surgery

Acute pancreatitis

80-90% patients1

63-94% patients2

80-85% patients1

Approx.70-90% patients1

40-80% patients1

Pancreatic exocrine insufficiency due to (and not only):

Diabetes (NIDDM**)

15-73% patients1

References1. Keller J. Layer P. Human Pancreatic Response to nutrients in health and disease. The Gut 20052. Dumasy V, Delhaye Mcotton F and Deviere J. Fat Malabsorption Screening in Chronic Pancreatitis. American Journal of Gastroenterology 2004;99: 1350–1354

For healthcare professional use only

PEI Symptoms1

• Many patients with malabsorption may be

asymptomatic2

• Diagnoses of PEI may be missed in the absence of

clinical steatorrhea3

• Undetected or untreated malabsorption may have

harmful effects on weight, even when clinical

steatorrhea is not present2

References 1. Touuli J, Biankin AV, Oliver MR, et al. Management of pancreatic exocrine insufficiency. Australasian Pancreatic Club recommendations. Med J Aust 2010; 193(8): 461-467. 2. Dumasy V, et al. Fat malabsorption screening in chronic pancreatitis, Am J Gastroenterol. 2004; 99(7): 1350-1354. 3. Forsmark CE. Chronic pancreatis and malabsorption. AM J Gastroenterol 2004; 99. 1355-1357. 4. Gooden HM, White, KJ. Pancreatic cancer and supportive care-pancreatic exocrine insufficiency negatively impacts on quality of life. Support Care Cancer 2013; 21(7): 1835-1841. 5. 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): 1-25.

Common symptoms

of PEI1

Abdominal pain/

discomfort

Weight loss in adults and

lack of weight gain/failure to

thrive in children

Bloating &

BelchingDiarrhea

Flatulence

For healthcare professional use only

”…early detection of pancreatic exocrine insufficiency is

essential; if left undetected and untreated, malabsorption leads to significant weight loss…”5

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

“Every patient with PEI and maldigestion, independent of the degree of steatorrhoea and presence or absence of associated symptoms, should receive PERT” 1

Presence of Steatorrhoea and Malabsorption in CP Patients 2

References1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42):7258-7266. doi:10.3748/wjg.v19.i42.72582. Dumasy V, et al. Fat malabsorption screening in chronic pancreatitis, Am J Gastroenterol. 2004; 99(7): 1350-1354.

PERT, pancreatic enzyme replacement therapy

Impact of Untreated PEI*

References 1. Sikkens ECM, Cahen DL, Kuipers KJ. Pancreatic enzyme replacement therapy in chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2010;(24):337-347. 2. Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Clinical update. Advances in the treatment of pancreatic insufficiency. Gastroenterol Hepatol. 2011;7(6):401-403. 3. 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-S93. 4. Layer P, Keller J, Lankisch PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol reports 2001; 3: 101-108. 5. 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): 104-1031. 6. Touuli J, Biankin AV, Oliver MR, et al. Management of pancreatic exocrine insufficiency. Australasian Pancreatic Club recommendations. Med J Aust 2010; 193(8): 461-467. 7. 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):197-203. 8. 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):693-699.; 9. Munck A. Nutritional considerations in patients with cystic fibrosis. Expert Rev Resp Med 2010; 4(1): 47-56. 10. Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Clinical update. Advances in the treatment of pancreatic insufficiency. Gastroenterol Hepatol. 2011;7(6):401-403.

Untreated PEI leads to a number of symptoms, which greatly impact patients’ lives1-10

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

Cardiovascular events

Reduced life expectancy

Failure to thrive(Cystic fibrosis

only)

Reduced pulmonary function

(Cystic fibrosis only)

Early detection and adequate treatment with PERT may decrease risks of malnutrition-related morbidity and mortality1

PERT: pancreatic enzyme replacement therapy.

Early Detection and Treatment1

References

1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42):7258-7266. doi:10.3748/wjg.v19.i42.7258.

Diagnosis of PEI: Pancreatic Function Tests

Co-efficient of fat absorption (CFA)1

Carbon 13 (13C)- mixed triglyceride (13C-MTG) breath test1

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 symptoms2

� Pancreatic morphology in patients with CP2

� Nutritional markers in patients with CP2

� Trials of PERT2

References 1. Dominguez-Munoz JE, et al. Pancreatic exocrine insufficiency: Diagnosis and treatment. J Gastroenterol Hepatol. 2011;26(2):12-16.2. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42):7258-7266. doi:10.3748/wjg.v19.i42.7258. For healthcare professional use only

Two or More Nutritional Bio-Markers Can Predict the Probability of PEI in Chronic Pancreatitis1

ResultsPEI 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

Objective: To investigate the use of serum nutritional markers as surrogate markers for PEI 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

ReferenceLindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol 2013 November 14; 19(42): 7258-7266.

Cohort study of 114 patients, 38 had PEI

For healthcare professional use only

Australasian Treatment Guidelines for the Management of PEI in Acute Pancreatitis1

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

PERT Recommendations

ReferenceAustralasian treatment guidelines for the management of pancreatic exocrine insufficiency. 2010:1-89.

For healthcare professional use only

Reference1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42):7258-7266. doi:10.3748/wjg.v19.i42.7258

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

For healthcare professional use only

What should you look for in your choice of PERT?1

Reference1. Lohr JM, Hummel FM, Pirilis KT, et al. Properties of different pancreatin preparations used in pancreatic exocrine insufficiency. Eur J Gastroenterol and Hepatol 2009; 21:1024-1031.

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

Multiple unit dose supplements 1Well-characterized efficacy profile 1

coated particles which pass through

PERT 25000 - Pancreatin* standardized to:

Amylase 18000 Ph. Eur. Units 1

Proteases 1000 Ph. Eur. Units 1

Lipase 25000 Ph. Eur. Units 1

Pancreatin Composition1

References1. Pancreatin 25000 Approved Local Leaflet. Effective date: 23 May 2014

For healthcare professional use only

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 1Gastrectomy 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

Indications of Pancreatin 1,2,3,4

For healthcare professional use only

Patented Minimicrosphere Technology1

Pancreatin's innovative minimicrospheres technology with gastroresistant pellets was designed to achieve simultaneous passage through the pylorus with chyme1

Recommended by guidelines1

Capsules dissolve rapidly in the stomach releasing enteric-coated Minimicrospheres Ô 1Immediate mixing with chyme and simultaneous passage through the pylorus into the duodenum 1

Rapid release of enzymes at pH>6Using Pancreatin means digestion takes place in the right environment 1

Good distribution with the chymePhysiologically dictated particle size for unobstructed passage through the pylorus simultaneously with the chyme 1

Reference

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; 21:1024-1031.

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 chyme1

PERT, pancreatic enzyme replacement therapy.

Characteristic Pancreatin

Resistant to Gastric acid

Rapid enzyme release In small intestine

Particle size < 2 mm

Large specific Surface area

Optimal mixing With chyme

MinimicrospheresTM are resistant to gastric acid 1

Pancreatin has a particle size of <1.7mm 1

In a comparative study* Pancreatin had the greatest specific surface area 1

Pancreatin Minimicrospheresfulfill key characteristics required for a pancreatic enzyme replacement therapy1

More than 80% to the initial activity of Pancreatin was measured after 15 minutes at pH6 (in an in vitro study) 1

Optimum particle size and a large specific surface area facilitates optimal mixing with chyme 1

Reference

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; 21:1024-1031.

Treatment Goals

Goals of treatment with PERT for PEI are to:

Reduce steatorrhoea1

Reduce stool frequency1

Improve stool consistency1

Prevent weight loss or increase body weight2

Restore/maintain good nutritional status 1,2

References1. Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Clinical update. Advances in the treatment of pancreatic insufficiency. Gastroenterol Hepatol. 2011;7(6):401-403.2. Sikkens ECM, Cahen DL, Kuipers KJ. Pancreatic enzyme replacement therapy in chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2010;(24):337-347. For healthcare professional use only

�

Most patients develop PEI after gastrointestinal surgery

References1. 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): 7930-79462. Dervenis C. Exocrine pancreatic insufficiency and malnutrition after gastrointestinal surgery. HPB 2009;11 (Suppl. 3): 1–2

100%

PERT controls nutritional status and prevents long-term malnutrition�

For healthcare professional use only

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 events1

Disturbance of fundus relaxation caused by the disappearance of antro-fundic and duodeno-fundic reflexes1

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 stomach1

Reduction in exocrine pancreatic secretion in cases of pancreatic resection1

Asynchrony between the gastric emptying of nutrients and bilio-pancreatic secretion as a result of anatomical reconstruction1

Maldigestion is reported in up to 80% of patients who have undergone gastric or pancreatic surgeries 1

Reference1.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

Australian Treatment Recommendations for the Management of PEI in Patients with Gastrectomy

Position StatementGastrectomy 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 PEI1

Reference 1.Toouli J, et al. Management of pancreatic exocrine insufficiency: Australasian pancreatic club recommendations. MJA.2010;93(8):461-467.

For healthcare professional use only

Trial of PERT

Trial of PERT may help diagnose PEI and establish significant improvement in maldigestion-related symptoms1,2

References1. Toouli J, et al. Management of pancreatic exocrine insufficiency: Australasian pancreatic club recommendations. MJA.2010;93(8):461-467.2. Sikkens ECM, Cahen DL, Kuipers KJ. Pancreatic enzyme replacement therapy in chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2010;(24):337-347. For healthcare professional use only

�

Post-operative PERT has a positive impact on long-term patient survival1

Treatment with PERT after surgery is an independent risk factor for survival 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

1

Reference1.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: 271–279.

Pancreatic enzyme replacement should be standard treatment after surgery for chronic pancreatitis at the time of hospital discharge 1

For healthcare professional use only

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

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

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

Reference1.Seiler CM et al. Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrosp heres (Pancreatin 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension. Aliment Pharmacol Ther 37(7): 691–702.

��������������������������������������������������������������������������������������

P<0.05

P<0.05

CLINICAL STUDIES OF PancreatinIN CHRONIC PANCREATITIS

For healthcare professional use only

Pancreatin: Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (1/4)

CFA, coefficient of fat absorption; CP, chronic pancreatitis

To evaluate the effect of Pancreatin in controlling steatorrhoea in 27 adult patients (mean age, 51 years) with Chronic Pancreatitis 1

Objective

Randomized, double-blind, placebo-controlled, 2-week trial, with a placebo run-in phase. Dose: 40000 lipase units per meal (Pancreatin 10000 x 4 caps) and 20000 lipase units per snack (Pancreatin 10000 x 2 caps) 1

Study Design

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

End Point

Reference1.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):156-162. Erratum in: Pancreas 2007;34(1):174.

Results 1

Pancreatin : Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (2/4)

���������������������������������

Pancreatin treated patients achieved a mean CFA of 86.6% at the end of the 2-week double-blind period 1

ReferenceSafdi 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):156-162. Erratum in: Pancreas 2007;34(1):174

The mean change in CFA from the single-blind placebo phase to the double-blind phase was significantly greater in the Pancreatin 10000 group (36.7%) compared with the placebo group (12.1%; P = 0.0185)1

CFA values greater than 80 % were observed in three-fourth of the patients treated with Pancreatin 100001

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. 11.4 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 1There were no significant differences in adverse events between groups and no serious events were reported 1

Pancreatin : Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (3/4)

Reference1.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):156-162. Erratum in: Pancreas 2007;34(1):174

ConclusionDaily dose of Pancreatin at 40,000 lipase units/meal (4 x Pancreatin10000 capsules) and 20,000 (2 x Pancreatin® 10000 capsules) lipase units/snack controlled steatorrhoea and was found to be safe and well tolerated. 1

Pancreatin : Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (4/4)

Reference1.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):156-162. Erratum in: Pancreas 2007;34(1):174.

Pancreatin : Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (1/3)

To evaluate the efficacy and safety of Pancreatin 40000 in treating PEI due to CP in patients > 18 years of age 1

1-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in India Dose: 6 to 9 capsules of Pancreatin 40000 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

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

Objective

Study Design

End Point

Reference1.Thorat V, Reddy N, Bhatia S, et al. Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Pancreatin 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis - a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2012; 36: 426-436.

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

ReferenceThorat V, Reddy N, Bhatia S, et al. Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Pancreatin 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis - a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2012; 36: 426-436.

ResultsPatients receiving Pancreatin had a significantly greater reductions in stool frequency and stool weight compared to those receiving placebo 1

35.3% of patients on Pancreatin reported treatment-emergent adverse events compared to 25.0% of patients on placebo. None led to study discontinuation 1

Pancreatin: Efficacy and Safety in Treating PEI in Patients With Chronic Pancreatitis (3/3)

CP, chronic pancreatitis; PEI, pancreatic exocrine insufficiency.

ConclusionPancreatin 40000 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

ReferenceThorat V, Reddy N, Bhatia S, et al. Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Pancreatin 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis - a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2012; 36: 426-436.

CLINICAL STUDIES OF PERT IN PANCREATIC CANCER

For healthcare professional use only

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

Objective

Randomized, double-blind, placebo-controlled 8 week trial 1Study Design

Change in body weight at week 8 1PrimaryEnd Point

Efficacy of PERT in Patients With Pancreatic Cancer

*PERT formulation in this study was not Pancreatin brand

CFA, Coefficient of fat absorption

Reference1.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.

Efficacy of PERT in Patients With Pancreatic Cancer

*PERT formulation in this study was not Pancreatin brand

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

Reference1.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.

CLINICAL STUDIES WITH PANCREATIN IN CYSTIC

FIBROSIS

For healthcare professional use only

To evaluate the efficacy and safety of PERT® Micro in infants younger than 24 months with CF 1Objective

Multicenter, open-label, baseline-controlled, single-arm study in 12 CF patients with PEI 1Study Design

Primary end point was mean change from baseline in the CFA after 2 weeks of treatment, based on 72-hour fat balance assessments 1

PrimaryEnd Point

CF, cystic fibrosis.

Pancreatin : Efficacy and Safety in Infants <24 Months With CF (1/4)

Reference1.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):693-699.

CF, cystic fibrosis.

Pancreatin : Efficacy and Safety in Infants <24 Months With CF (2/4)

Treatment Duration and Dosing 1

Study Treatment

Treatment duration, dayMean SD (range)

Daily lipase units/kg body weightMean SD (range)

Daily lipase units/g fat intakeMean SD (range)

Daily dose, mgMean SD (range)

Patients Treated (N = 12)

58.8 2.5 (57-64)

8272 1773 (6875-12,936)

2326 1274 (1159-5148)

856 434 (336-1846)

The average dose of lipase units and dose of the capsules are shown in the table 1

Reference1.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):693-699.

CF, cystic fibrosis.

Pancreatin : Efficacy and Safety in Infants <24 Months With CF (3/4)

ResultsThe 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 238.5 to 137.9 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

Reference1.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):693-699.

N=12

CF, cystic fibrosis; PEI, pancreatic exocrine insufficiency.

Pancreatin : Efficacy and Safety in Infants <24 Months With CF (4/4)

ConclusionPancreatin Micro was well tolerated and resulted in significantly lower fat malabsorption in infants younger than 24 months with PEI due to CF 1

ReferenceColombo 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):693-699.

Pancreatin : Efficacy and Safety in CF Children ≥12 Years of Age (1/3)

����������������������������������������������

To study the efficacy and tolerability of Pancreatin compared with the placebo in children aged ≥12 years with PEI due to CF 1

Multicenter, randomised, double-blind, placebo-controlled, 2-period crossover, superiority study 1

Primary outcome measure was CFA. The secondary outcome measures were CNA and clinical symptoms 1

Objective

Study Design

End Point

1

ReferenceTrapnell 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):370-377.

CF, cystic fibrosis; CFA, coefficient of fat absorption; CNA, coefficient of nitrogen absorption.

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: 1Adverse 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

ReferenceTrapnell 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):370-377.

CF, cystic fibrosis, PEI, pancreatic exocrine insufficiency.

Pancreatin : Efficacy and Safety in CF Children ≥12 Years of Age (3/3)

ConclusionThis 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

Reference1.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):370-377.

Pancreatin : Efficacy and Safety in Children, Adolescents, and Adults With CF (1/2)

CF, cystic fibrosis; CFA, coefficient of fat absorption; CGI, clinical global improvement; PEI, pancreatic exocrine insufficiency.

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

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

Study Design

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

PrimaryEnd Point

Objective

Reference1.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):1932-1938.

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

��������������

ConclusionPancreatin is an effective treatment for steatorrhoea associated with pancreatic insufficiency in patients with CF 1

Reference1.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):1932-1938.

PANCREATIN SAFETY AND DOSING

For healthcare professional use only

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

ReferenceDominguez-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:10.2478/v10039-011-0005-3.

Using Pancreatin in your patients1,2

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 IntakeWeightDisease severitySymptomsDegree of steatorrhea

Reference1. 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 40000 enteric-coated minimicrospheres in patients with pancreatic exocrine

insufficiency due to chronic pancreatitis. Pancreatology xxx 2013; 1-72. Pancreatin Product Information For healthcare professional use only

Pancreatin : Effect of Different Dosing Schedules (1/2)

���������������������������������������������������

Study Design: 3 way crossover, randomized, open-label study 1

Primary endpoint: 6 hour recovery rate of 13CO2 measured by 13MTG breath test 1

Objective: To evaluate the effect of different dosing schedules of Pancreatin 10000 capsules in 24 patients with CP in PEI 1

Reference 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;21:993-1000.

Pancreatin: Effect of Different Dosing Schedules (2/2)

A: 4 capsules before mealsB: 4 capsules after mealsC: 1 capsule before meals,

2 during, and 1 after 1

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

Reference 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;21:993-1000.

For healthcare professional use only

When and How to take Pancreatin

HowCapsules 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

Pancreatin must always be taken with enough fluid, during or immediately after meals or snacks 1

Reference 1.Australian Public Assessment Report for Pancreatic extract. Available at https://www.tga.gov.au/sites/default/files/auspar-Pancreatin.pdf. Accessed 18 December, 2017.

When

For healthcare professional use only

Using Pancreatin in your adult PEI patients1,2

References1. 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:10.2478/v10039-011-0005-3.2. 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 40000 enteric-coated minimicrospheres in patients with pancreatic exocrine insufficiency

due to chronic pancreatitis. Pancreatology xxx 2013; 1-73. Pancreatin Summary of product characteristics August 2013.

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) treatmentAs a general guide dose a lipase content per meal between 20,000 and 80,000 Ph. Eur. Units is recommended.

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

Abdominal pain* Nausea, vomiting, constipation, abdominal distention, diarrhea*

Strictures of the ileo-caecum and large bowel (fibrinosing colonopathy)

Skin and subcutaneoustissue disorders

Rash Pruritis, urticaria

Immune system disorders

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

Reference Pancreatin 25000 Approved Local Leaflet. Effective date: 23 May 2014

No specific adverse reactions were identified in the pediatric population 1

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

ReferenceHighlights of prescribing information, Pancreatin. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020725s016lbl.pdf. Accessed 18 December, 2017.

For healthcare professional use only

Recommendation for treating PEI with PERT

Every patient with PEI and maldigestion, regardless of steatorrhoea and associated symptoms should receive PERT1

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

Reference1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42):7258-7266. doi:10.3748/wjg.v19.i42.7258.;

SUMMARY

Reference1. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World Journal of Gastroenterology : WJG. 2013;19(42):7258-7266. doi:10.3748/wjg.v19.i42.7258.; 2. �� � ����������������������������������������������������������������������������������Eur J Gastroenterol and Hepatol ����������������������et al�����������������������������������������������������������������������������������������������������������������������Surgery ����������������������������������������������������������������������������������������������������������������������������������������������������������������������Pancreas���������������������������Pancreas ������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������Pancreas. �������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������Pancreatology ���������������������������������������������������������������������������������������������������������������������������������������

� 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

For healthcare professional use only