PANCREATIC EXOCRINE INSUFFICIENCY (PEI) AND CREON

Transcription

1 A GUIDE FOR HEALTHCARE PROFESSIONALS PANCREATIC EXOCRINE INSUFFICIENCY (PEI) AND CREON AHCRE Date of preparation: September 2015 Prescribing information can be found on the inside back cover.

2 Introduction This booklet discusses the impact of Pancreatic Exocrine Insufficiency (PEI) as a consequence of pancreatic cancer, chronic pancreatitis, diabetes and cystic fibrosis. It provides information on recent data supporting Creon, a type of Pancreatic Enzyme Replacement Therapy (PERT) and explains how to achieve effective dosing and administration. 1 You will also be advised about important considerations when discussing the prescription of Creon for the treatment of PEI with patients. 2 3

3 Pancreatic Exocrine Insufficiency (PEI) The healthy pancreas What is PEI? The healthy pancreas releases thousands of enzyme units in response to food entering the stomach. These enzyme units travel to the duodenum where they come into contact with the food substrate and start to break down fats, proteins and carbohydrates into smaller molecules for absorption. Around 720,000 lipase units are released in response to a kcal meal; approximately 10% of these are needed to maintain normal digestion. 2 Lipase secretion by a healthy pancreas in response to a stimulus of a kcal meal Percentage of Basal Secretion Test meal Postprandial Minutes PEI is the primary or secondary disturbance of pancreatic functions which leads to maldigestion. 3 It occurs when the amount of enzymes secreted from the pancreas in response to an ingested meal or snack is insufficient to maintain normal digestive processes in the duodenum. 3 The main reasons for inadequate availability of enzymes are: reduced production and secretion, inadequate stimulation of enzyme production due to asynchrony and impaired delivery of enzymes to the duodenum due to obstruction of the pancreatic duct. 3 The main clinical consequence of PEI is fat maldigestion which, if left untreated, may lead to low circulating micronutrients, fat-soluble vitamins and lipoproteins. 4 Long-term outcomes of untreated PEI include: cardiovascular events, reduced bone mineral density, peripheral neuropathy and reduced life expectancy. 5-8 PEI is a major consequence of other serious conditions, including: 2,9 n pancreatic cancer n chronic pancreatitis n diabetes mellitus n cystic fibrosis n pancreatic or gastric surgery. I found this very confronting, her not wanting to eat. Male carer of a pancreatic cancer patient 11 Adapted from Keller J et al. Gut

4 Pancreatic Exocrine Insufficiency (PEI) Effects of PEI Consequences of PEI The main effects of PEI are listed below. However, some patients may have adapted their diet to minimise symptoms and therefore PEI may be more difficult to detect: 2,4,6,8-11 A E D K A signs of malnutrition bloating or flatulence diarrhoea weight loss abdominal pain or discomfort fatty stools fatigue steatorrhoea Steatorrhoea is a late-stage symptom and occurs when over 90% of normal pancreatic function is lost. Hence, diagnosis should be made before the presence of steatorrhoea. 12 Poor clinical outcomes 9 Increased nutritional risk has been associated with poor clinical outcomes in hospitalised patients with PEI. 9 Poor survival 5 Extremely severe PEI and low faecal elastase-1 ( 20 μg/g) has been strongly associated with poor survival in patients with advanced pancreatic cancer. 5 Reduced quality of life 9,11 Malnutrition and gastrointestinal symptoms associated with PEI can have a negative impact on patient quality of life. 9 Fat-soluble vitamin deficiencies 6 Malabsorption related to PEI can cause nutritional deficiencies, especially of fat-soluble vitamins (A, D, E and K), leading potentially to serious health problems: 6 n vitamin A: decreased immune competence n vitamin D: osteopenia/osteoporosis n vitamin E: neurological disorders n vitamin K: blood coagulation disorders and osteopenia/osteoporosis. Reduced bone mineral density (BMD) resulting in a high risk of fractures 13 Low bone mineral density may result in a significantly higher risk of low trauma fractures, especially in the vertebrae, the hip and the wrist. 13 The level of risk is similar to that seen in coeliac disease or after gastrectomy, and much higher than in patients with inflammatory bowel disease. 13 Poor lung function (in patients with cystic fibrosis) 14,15 Malnutrition may adversely affect the course of cystic fibrosis because of its close relationship with lung function. 14 A longitudinal analysis from a large cohort of cystic fibrosis patients found an association between malnutrition and poor lung function where malnourished patients of all ages had significantly worse lung function than their normally nourished counterparts

5 Pancreatic Exocrine Insufficiency (PEI) PEI is potentially under-diagnosed and under-treated Diagnosing PEI PEI may be overlooked because the primary attention is directed towards the treatment of underlying disease, despite the large burden of steatorrhoea-related symptoms and weight loss for patients. 16 Healthcare professionals may also not be well informed about the need to treat PEI and there is a lack of official guidelines for effective dosing of PERTs, leading to under-dosing. 16,17 Due to the potentially serious consequences of PEI, early detection and treatment is critical. Every patient with PEI and fat maldigestion, regardless of associated symptoms, should be treated with PERT. 10 Chronic pancreatitis Around 80 90% of chronic pancreatitis patients suffer with PEI to some degree 2 And yet Only 30 40% currently report PEI in chronic pancreatitis 12 Pancreatic cancer 68 92% have PEI before surgery 16 80% have PEI after surgery 16 And yet 50 56% are actually treated for PEI 18 Diabetes 3,200,000 people have diabetes in the UK 45 and approximately 200,000 of these may have PEI 19 And yet Less than 25,000 patients with PEI and diabetes are treated 20 The clinical signs of PEI can be confirmed with pancreatic function tests. The British Society of Gastroenterology (BSG) guidelines for the investigation of chronic diarrhoea recommend: n at least one non-invasive pancreatic function test n preferably the faecal elastase test (FE-1). 21 Endoscopic ultrasonography (EUS) EUS is emerging as an important diagnostic test for indicating PEI and deciding the need to recommend PERT. It provides highly accurate images of pancreatic ducts and parenchyma enabling the probability of PEI to be predicted in patients with pancreatic disease, such as chronic pancreatitis. In a recent study, duct calcifications and main pancreatic duct dilatation detected by EUS were independently associated with PEI (probability of %). 22 EUS Criteria for Chronic Pancreatitis 1. Hyperechoic foci without shadowing 2. Strandings 3. Lobularity 4. Hyperechoic foci with shadowing 5. Pseudocysts 6. Irregular main pancreatic duct contour 7. Hyperechoic main pancreatic duct margin 8. Main pancreatic duct dilatation 9. Dilated side branches 10. Main pancreatic duct calculi Increasing numbers of EUS criteria have been shown to indicate PEI 8 9

6 Pancreatic Exocrine Insufficiency (PEI) Diagnosing PEI Diagnosing PEI The probability of PEI in chronic pancreatitis patients is based on the number of EUS criteria and/or presence of some specific EUS criteria; increasing EUS criteria means higher probability of PEI. 22 Please see previous page for EUS criteria. Correlation between the number of EUS criteria in patients with chronic pancreatitis and the probability of having PEI Patient with PEI (%) Number of EUS criteria of chronic pancreatitis* Computed tomography (CT) CT can also be used to diagnose PEI and potentially offers the highest accuracy when detecting pancreatic calcifications specific to advanced chronic pancreatitis. 22,23 Faecal elastase test (FE-1) non-invasive FE-1 test sensitivity is around 100% in severe PEI but results can be less reliable in mild to moderate disease. The specificity is around 93% in moderate disease, however there is a risk of false positive results in patients with diarrhoea and other intestinal disorders. 24 FE-1 values: n normal: >200 μg/g stool 24 n mild PEI: μg/g stool 19 n severe PEI: <100 μg/g stool. 3 I [crying] try to force feed her. She gets upset, it makes it worse. Male carer of a pancreatic cancer patient 11 * Rosemont EUS criteria for chronic pancreatitis. Adapted from Dominguez-Muñoz JE et al. Pancreas

7 Creon Creon: the world s number 1 prescribed PERT 25 Creon s mode of action Creon is a PERT indicated for the treatment of PEI in adults, children and infants. Creon s active ingredient pancreatin provides the extra enzymes required to maintain healthy digestion. 1 Unique minimicrosphere technology Creon s minimicrospheres ensure that the correct amount of enzymes are delivered to the duodenum intact, resulting in a mode of action that closely mimics the physiological conditions of a healthy pancreas for effective enzyme delivery. 2, million patient years experience Creon has approximately 6.3 million patient years experience in managing PEI and a solid foundation of successful clinical trials providing a wealth of data. 26 A wide dosing range to accommodate all patients Creon offers a range of strengths from Creon 25,000 to Creon Micro (5,000), designed to deliver effective dosing to all patients. 1,27-29 Particles <2mm pass through the pylorus efficiently. 3 Creon s minimicrospheres are optimally sized at mm to pass through the pylorus Stomach 1 2 Creon capsules or Creon Micro taken with each meal and snack. 3 Creon capsules dissolve in the stomach releasing enteric-coated minimicrospheres that mix with food. 3 As the ph rises in the duodenum, the enteric coating dissolves releasing the enzymes to help digest nutrients. 3 5 Duodenum 3 The enteric coating prevents digestion of the complexes in the stomach. 3 Pancreas Food 12 13

8 Creon in Chronic Pancreatitis (CP) Creon has been shown to improve outcomes in patients with chronic pancreatitis 31,32 Creon has been shown to improve symptoms associated with PEI 31,32 Creon improved the following symptoms at 1 week and at 52 weeks versus baseline: 31,32 * Number of formed/ normal stools Proportion of patients with formed/normal stool consistency increased Flatulence Proportion of patients with no flatulence improved Abdominal pain severity Proportion of patients with no abdominal pain improved Clinical global impression of symptoms Proportion of patients rating symptoms as absent improved There were also significant improvements at 52 weeks in the coefficient of fat absorption (CFA) and nitrogen absorption (CNA) versus baseline: % p<0.001 CFA mean change from baseline 6.5% p<0.001 CNA mean change from baseline Baseline: 59.0% Baseline: 23.0% Baseline: 49.2% Baseline: ~18% 1 week: ~65%** 1 week: ~24%** 1 week: ~56%** 1 week: ~6%** 52 weeks 52 weeks 52 weeks 52 weeks 77.1% 60.4% 81.3% ~60% *1 week double-blind, randomised, placebo-controlled, parallel-group, multicentre study in India. Patients 18 years with proven chronic pancreatitis and PEI (n=62) were randomised 1:1 to Creon 40,000 or placebo (two capsules orally per main meal, one with snacks). The primary outcome measure was change in the coefficient of fat absorption (CFA) from baseline to the end of double-blind treatment (analysis of covariance). 51-week open-label extension (OLE): patients received Creon 40,000 at a dose of 80,000 lipase units per main meal and 40,000 lipase units per snack. Clinical symptoms and CGI: reported by patients and assessed by investigators at baseline, the end of the double-blind phase and at weeks 5, 13, 26, 39 and 52. Quality of life: assessed with the SF-36 Health Survey questionnaire at baseline, end of double-blind phase, and at study end. The SF-36 comprises eight component scores and two summary scores, with higher scores indicating better quality of life. **Values are estimations taken from graphs within the published paper as exact values unpublished. Adapted from Ramesh H et al. Pancreatology 2013; Thorat V et al. Aliment Pharmacol Ther

9 Creon in Chronic Pancreatitis (CP) Creon has been shown to significantly improve patients nutritional status 31 * Creon has been shown to improve quality of life as measured by the SF-36 Health Survey questionnaire 31 * Several nutritional parameters significantly improved from baseline in patients with chronic pancreatitis. 31 Mean percentage change in nutritional parameters from baseline to 52 weeks Percentage % Triglycerides Total cholesterol LDL cholesterol HDL cholesterol Retinol binding protein Transferrin Prealbumin Vitamin E *** p=0.001 vs. baseline ** p<0.01 vs. baseline * p<0.05 vs. baseline At 52 weeks, patient quality of life had improved from baseline with statistically significant changes in: 31 n bodily pain n general health n vitality n emotional well-being n mental health n mental component summary. Quality of life according to the SF-36 questionnaire n= Mental component summary Physical component summary Mental health Emotional well-being Social functioning Vitality General health Bodily pain Role-physical Physical functioning SF-36 score End of CLE (52 weeks) Baseline *** p=0.001 vs. baseline ** p<0.01 vs. baseline * p<0.05 vs. baseline Adapted from Ramesh H et al. Pancreatology Dose of 80,000 lipase units/meal; 40,000 lipase units/snack; 6-9 capsules per day. * See footnote on page 15 for study details. * See footnote on page 15 for study details. Adapted from Ramesh H et al. Pancreatology OLE: Open-label extension 52 weeks

10 Creon in Pancreatic Cancer (PC) Creon has been shown to improve outcomes in patients with pancreatic cancer 33 Creon has been shown to improve symptoms of PEI that can negatively impact quality of life 11 ** Creon has been shown to offer longer survival in patients with unresectable pancreatic cancer. 33 Median survival of patients treated with palliative chemotherapy with and without Creon 33 Gut problems and their management can negatively impact quality of life in both patients with pancreatic cancer and their carers: 11 Survival was longer in patients treated with Creon (50,000 lipase units/meal and 25,000 lipase units/ snack) plus palliative chemotherapy than those treated with palliative chemotherapy alone (p=0.002). 33 * Median Survival (Days) * p= ** Patients treated with Creon + palliative chemotherapy Patients treated with palliative chemotherapy * 301 days, 95% CI ** 89 days, 95% CI Doses of 50,000/meal and 25,000/snack. n increasing sense of social isolation n contributing to carer distress. Properly supervised Creon treatment showed: 11 n stabilisation or increase in weight n resolution of pain n resolution of diarrhoea n resolution of abdominal discomfort. Well the pancreatic enzyme [Creon] made such a huge difference. If we d only known we could have got that earlier. That would have been great. Male carer of a pancreatic cancer patient (bereaved) 11 * Retrospective analysis of a prospective database of 66 patients (mean age 69.3) with unresectable pancreatic cancer confirmed by EUS-FNB (fine needle biopsy). Patients with survival <30 days were excluded. All patients were evaluated for palliative chemotherapy. Patients diagnosed in the Department of Gastroenterology (Group 1; 31.8%) were also evaluated for PEI by 13 C-MTG breath test and nutritional status; patients in Group 2 (68.2%) were not. Group 1 patients with PEI were treated with Creon 50,000 lipase units/ meal and 25,000 lipase units/snack. 0 Group 1 Group 2 Adapted from Domínguez-Muñoz JE. Pancreatology ** Results from a qualitative inquiry framework involving both surgical and non-surgical patients with pancreatic cancer and their carers (patients, n=12; carers/family, n=23; bereaved participants, n=14). A thematic content analysis was conducted to explore participants perspectives and experience. need image 18 19

11 Creon in Diabetes PEI and PERT in diabetes mellitus Why do patients with diabetes develop PEI? Several mechanisms have been considered for the link between PEI and diabetes. These include fibrosis and atrophy of the pancreas due to specific diabetic angiopathy. Pancreatic atrophy may also be enhanced by diminished insulin production and has been observed in several studies of patients with diabetes. 19,34 In patients with chronic pancreatitis, pancreatic inflammation can lead to the destruction of islet cells, resulting in limited incretin production and pancreatogenic diabetes (type 3c). 35 Why is PEI in patients with diabetes currently not routinely diagnosed and treated? GI disturbance (when identified) in patients with diabetes may be attributed to other causes and not PEI. 19 Furthermore, patients with diabetes secondary to disease of the exocrine pancreas may be misclassified as having type 1 and type 2 diabetes. 36 Diabetes and Chronic Pancreatitis n Patients with long-standing duration of chronic pancreatitis seem to be at higher risk for developing pancreatogenic diabetes (type 3c). 35 n Chronic pancreatitis accounts for nearly 80% of all pancreatogenic diabetes (type 3c) cases % of diabetes mellitus cases are expected to be the result of pancreatogenic diabetes (type 3c). 35 Pancreatin has been shown to reverse the impaired gastric inhibitory polypeptide (GIP) response 37 Pancreatin improves the incretin effect in patients with chronic pancreatitis and impaired glucose tolerance, reducing post-prandial blood glucose levels. 37 * Change in immunoreactive gastric inhibitory polypeptide (IR-GlP) over time IR-GIP (µg/l) Test meal Results with pancreatin Results without pancreatin Time (min) * 24 patients with chronic pancreatitis and 21 healthy volunteers. 3 fasting blood samples were withdrawn followed by further samples following nutrient ingestion every 15 minutes for 60 minutes and then every 30 minutes until 180 minutes. Dose of 9.0g pancreatin per meal: roughly equivalent to 56,000 lipase units according to the Fédération Internationale Pharmaceutique. Adapted from Ebert R et al. Diabetologia

12 Creon in Diabetes Pancreatin has been shown to restore the incretin effect of fat 37 * Pancreatin has been shown to improve glucose tolerance 37 * Change in immunoreactive-insulin over time Change in glucose levels over time Test meal Results with pancreatin Results without pancreatin Test meal Results with pancreatin Results without pancreatin IR-Insulin (mu/l) Glucose (mg/dl) Time (min) Time (min) Dose of 9.0g pancreatin per meal: roughly equivalent to 56,000 lipase units according to the Fédération Internationale Pharmaceutique. Adapted from Ebert R et al. Diabetologia * 24 patients with chronic pancreatitis and impaired glucose tolerance and 21 healthy volunteers. 3 fasting blood samples were withdrawn followed by further samples following nutrient ingestion every 15 minutes for 60 minutes and then every 30 minutes until 180 minutes. Dose of 9.0g pancreatin per meal: roughly equivalent to 56,000 lipase units according to the Fédération Internationale Pharmaceutique Adapted from Ebert R et al. Diabetologia * 24 patients with chronic pancreatitis and impaired glucose tolerance and 21 healthy volunteers. 3 fasting blood samples were withdrawn followed by further samples following nutrient ingestion every 15 minutes for 60 minutes and then every 30 minutes until 180 minutes

13 Creon in Diabetes Creon in Cystic Fibrosis Creon has been shown to reduce mild to moderate episodes of hypoglycaemia 38 * Creon has been shown to reduce the effects of PEI 39 ** PEI in cystic fibrosis In the Creon group, there was a reduction in mild to moderate hypoglycaemic episodes after 16 weeks of treatment. 38 At the beginning of the study, patients randomised to the Creon group experienced more mild to moderate hypoglycaemic episodes than those randomised to the placebo group. 38 Reduction in mild to moderate hypoglycaemic episodes in the Creon-treated group at study end Number of mild hypoglycemias Creon Week 0 Week 4 Week 16 Placebo Week 0 Week 4 Week 16 From baseline to 6 months, treatment with Creon offered improvement in the following: 39 Flatulence Abdominal pain Diarrhoea Steatorrhoea p<0.001 p<0.001 p=0.003 p<0.001 Adapted from Mohan V et al. Int J Pancreatol Recent studies have shown that PEI occurs in more than 85% of patients with cystic fibrosis. 40 Malnutrition and growth retardation are important prognostic factors in children with cystic fibrosis and both may adversely affect the course of the disease with declining lung function and poor outcomes. 14 Population-based studies in both adults and children with cystic fibrosis have shown a clear association between normal growth status and both pulmonary function and survival. 41 * 80 patients with diabetes mellitus requiring insulin with FEC <100 μg/g were randomized to receive Creon (n=39) or placebo (n=41) in a double-blind manner. Creon dosage: individualised depending on dietary fat intake; advised to take 2,000 lipase units per gram of fat intake; higher doses were administered in 2 patients who were taking higher doses before enrolment. Parameters of glucose metabolism, diabetes therapy and clinical symptoms were recorded in standardised protocols for 16 weeks. 0 N= Placebo Creon Adapted from Ewald N et al. Diabetes Metab Res Rev Creon also significantly increased patients sense of wellbeing from baseline (p<0.001). 39 ** A 6 month study of 40 patients with evidence of diabetes and chronic pancreatitis. Dosage of Creon was 8,000 lipase units 3 x daily. No change in diet or exercise was made and patients continued on any antidiabetic medications

14 Creon in Cystic Fibrosis PEI in adult cystic fibrosis Infant and child cystic fibrosis and PEI Adult cystic fibrosis and PEI Following an open-label run-in phase whereby all patients were stabilised on Creon, patients who were then randomised to Creon experienced positive improvement in the mean coefficient of fat absorption (CFA), unlike those randomised to placebo, whose mean CFA decreased significantly (p<0.001). 42 * Furthermore, over the open label phase, Creon was found to: n maintain stool frequency n maintain stool consistency. * In the open-label run-in phase, 50 patients with PEI were stabilised on Creon and a high-fat diet (target of 100g fat/day). They could adjust their Creon dose to optimise digestion. 36 eligible patients with >80% CFA who were on a controlled high fat diet for 6 days proceeded to the double-blind phase and were randomised (1:1) to continue with Creon or switched to placebo. During double-blind treatment, placebo patients received the number of capsules equivalent to the actual mean lipase dose of U/kg/day and Creon patients received mean lipase U/kg/day. CFA in adults with cystic fibrosis ( 18 years) Mean CFA (%) % (±1.2) Creon Open Label Baseline 50.9% (±7.3) Placebo Double Blind 89.2% (±1.1) Creon Open Label Baseline 87.2% (±1.7) Creon Double Blind Creon Open Label Baseline (n=50) Creon Double Blind (n=18) Placebo Double Blind (n=18) Dose of pancrelipase during double-blind treatment: mean lipase U/kg/day. Mean open-label treatment duration: pancrelipase 18.9 days; placebo 17.3 days; mean double-blind treatment duration: pancrelipase 7.1 days; placebo 6.7 days. Adapted from Stern RC et al. Am J Gastroenterol In infants with cystic fibrosis aged 1 to 24 months, Creon Micro produced a rapid improvement in mean coefficient of fat absorption (CFA) versus baseline. 43 ** Furthermore, treatment with Creon Micro was found to: 43 n increase length and weight over 8 weeks n decrease the proportion of patients with steatorrhoea from 100% to 58% at 2 weeks n increase the number of patients with normal stool characteristics at 2 weeks n reduce mean faecal energy loss at 2 weeks. ** 12 patients with cystic fibrosis (<24 months old) with PEI and CFA <70% treated with Creon for Children for 8 weeks. Primary endpoint was mean change from baseline in CFA after 2 weeks of treatment, based on 72 hour fat balance assessments. CFA in infant patients with cystic fibrosis (1-24 months) Mean CFA (%) % Baseline (n=12) Dosing regimens were individualised depending on dietary fat intake. Adapted from Colombo C et al. Pancreas % Creon Micro (n=12) p= vs. baseline volume 26 27

15 Creon dosing Recommended dosing procedure for Creon in adults Adult patients should be initiated on the recommended Creon starting doses, based on disease severity and diet. Recommended starting doses: 1 Main meal 2 x Creon 25,000 50,000 units lipase/meal Administering Creon Patients should be advised to take Creon with food. Proper timing can improve intragastic mixing of enzymes with chyme and, therefore, simultaneous gastric emptying into the duodenum. 24 Creon capsules can be: 1 Swallowed whole Evidence has shown that efficacy is optimised when: 24 n beginning of the meal: half the dose is swallowed n half way through the meal: the remainder of the dose is swallowed. Opened to mix the granules with acidic fluids or soft food Snacks 1 x Creon 25,000 25,000 units lipase/meal Patients must not crush or chew the capsules in order to protect the enteric coating 1,28-29 Suitable food and drinks include undiluted apple sauce, yoghurt or any fruit juice with a ph less than 5.5, e.g. apple, orange or pineapple juice Patients should eat or drink the food or fluid immediately, without crushing or chewing the granules, in order to prevent the enteric coating from dissolving 1 Ensure patients are aware that they must take Creon with food. Patients should be advised to stay adequately hydrated at all times whilst taking Creon to avoid aggravating constipation

16 Creon dosing Recommended dosing procedure for Creon in infants and children Creon 25,000 and 10,000 capsules are available for children, as well as Creon Micro (5,000 lipase units per 100 mg scoop) for babies. Recommended starting dose for children: 1,28 Recommended starting dose for babies: 29 Administering Creon capsules Administering Creon Micro 1 or 2 x Creon 10,000 or Creon 25,000 Main Meal 1 or 2 x Creon 10,000 or 1 x Creon 25,000 Snacks Dose increases, if required, should be added slowly, with careful monitoring of response and symptomatology. 1 x scoop (100mg) Meal or feed 5,000 units lipase/meal or feed Dose increases, if required, should be added slowly, with careful monitoring of response and symptomatology. The maximum daily dose should not exceed 10,000 units lipase/kg/day. Encourage young children to swallow the capsules whole as early as they can, or open the capsule and mix the minimicrospheres with undiluted apple sauce, yoghurt or any fruit juice with a ph less than 5.5, e.g. apple, orange or pineapple juice. 1,28 n If the minimicrospheres are mixed with fluid or food, ensure that parents understand their child should eat the food immediately and not crush or chew the granules in order to prevent the enteric coating from dissolving. 28,29 n As children grow, their lipase requirements may increase, so they may benefit from taking fewer higher-strength capsules (e.g. Creon 25,000) instead of many lower-strength capsules. When administering Creon Micro, parents should be advised to mix the granules with acidic liquids or soft foods (e.g. undiluted apple juice or apple puree) that do not require chewing. Granules can also be mixed with a small amount of milk and administered immediately (granules shouldn t be added to the baby s bottle). Once mixed, give directly from a spoon ensuring that the infant swallows all the granules immediately and none are left on their infant s face, around their mouth, or in their gums. 29 Parents need to take care to wipe them off as sometimes the enzymes can make their baby s skin and gums sore. Advise parents to also take care to wipe away granules from other skin (e.g. nipples if breast feeding)

17 Creon dosing Ensuring understanding of dosage Is the starting dose effective? Patient materials are available for people taking Creon and for the parents of young children prescribed Creon. Many contain this simple grid shown below, which has been designed to help healthcare professionals communicate how much Creon their patients should be taking with meals, with snacks and with takeaways or large meals (the fattier the meal, the higher the necessary dose of Creon): Meals Snacks Takeaways/ large meals Starting dose Creon 25,000 Creon 10,000 Creon Micro Titrated dose In a study of adult patients taking a median daily dose of 6 x 25,000 units of lipase: 17 n 70% reported steatorrhoea-related symptoms n 42% reported weight loss. Whereas, in a study where patients took Creon doses of 80,000 units of lipase/meal and 40,000 units of lipase/ snack they showed improvements in baseline in: n fat and nitrogen absorption 31,32 n nutritional laboratory parameters 31,32 n clinical symptoms 31 n quality of life. 31 Hence, patients may achieve further benefit by titrating their dose up. 27,30,44 For their health and to ensure that they stay on track, patients with PEI should be reminded to let all healthcare professionals they come into contact with know that they have been prescribed Creon. Patient materials are available from Mylan EPD, BGP Products Ltd. Please order directly via

18 Creon dosing Suggested Creon Dosing Algorithm Suggested follow-up timing Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Starting dose of Creon minimicrospheres 1 Instruct patients to increase dose and consider timing Titrated dose example Main meal ( kcal) Snacks 2 x 1 x Reconsider the diagnosis 4 x of pancreatic Recheck dietary insufficiency Main intake and ensure meal Ensure effective adequate acid Check compliance acid suppression Unsuccessful suppression by use of PPIs Unsuccessful Unsuccessful Unsuccessful Check coeliac status Unsuccessful Is biliary obstruction contributing? 2 x Increase dose again If unsuccessful, consider alternative formulation KEY Successful Unsuccessful Snacks Explain why patients need to take Creon with meals Adapted from Layer P et al. Curr Gastro Rep. 2001; Imrie CW et al. Aliment Pharmacol Ther. 2010; Lohr J-M et al. United European Gastroenterol J Treatment is successful 34 35

19 Questions for patients Questions to ask patients at consultations Patients who have been taking Creon for 6 months Symptoms Understanding Diet Dosage Are they experiencing any of the symptoms of PEI? Do they have any gastro symptoms? Patients at the point of first prescription Symptoms Understanding Diet Dosage What additional information do they need to know about PEI and Creon? Can they explain why they are taking Creon? Can they explain why they are taking Creon and how long they will need to take Creon for? Can they explain which foods they should be eating? Patients at first follow-up of Creon Symptoms Understanding Diet Dosage Are they experiencing any of the symptoms of PEI? Do they have any gastro symptoms? How many capsules do they take with certain types of food, e.g. fatty meals? How do they time their capsules when eating? When do they take Creon? With every meal and snack, or just at home, or with very fatty meals? When do they take Creon? With every meal or just at home or just with very fatty meals? Do they eat fat or exclude it from their diet? What dose do they take according to meal type, and how and when do they take Creon? How many capsules do they take with meals to relieve symptoms? Is it more or less than originally recommended? How many capsules do they need take to relieve symptoms? When do they take them? Is it more or less than they were originally recommended? During consultations with patients who have been prescribed Creon for PEI, consider asking them the following questions according to how often you have seen them. Patients who are attending consultation less regularly than they used to Symptoms Understanding Diet Dosage Are they experiencing any of the symptoms of PEI? Do they have any gastro symptoms? If they answer yes, they may need to speak to their healthcare professional for review of their treatment. This may result in increasing their dose of Creon or an additional treatment intervention. What difficulties have they faced when taking Creon? Can they explain PEI and the reasons why they are taking Creon? Consider providing further guidance on how to optimise their Creon treatment if the patient demonstrates low understanding. Do they take Creon when eating outside of the home? If they are a child/adolescent, are they managing to take Creon at school? Provide advice to help them take their PERT outside of the home and encourage them to eat a normal balanced diet. How many capsules do they need take to relieve symptoms? Are they taking the right dose at the right time? Consider providing further guidance on how to optimise their Creon treatment if the patient demonstrates low understanding of Creon dosing. It is important that your patients who are taking Creon are confident and comfortable about how to take their medicine. Your involvement, as outlined in this booklet, is a key factor in determining the quality of their care

20 References Prescribing information 1. Creon 25,000 Summary of Product Characteristics Keller J et al. Gut 2005; 54(6): vi Toouli J et al. Med J Aust. 2010; 193(8): Domínguez-Muñoz JE. Curr Gastroenterol Rep. 2007; 9: Partelli S et al. Dig Liver Dis. 2012; 44(11): Sikkens ECM et al. Pancreatology 2013; 13(3): el Newihi H et al. Dig Dis Sci. 1988; 33: Montalto G et al. Pancreas 1994; 9: Ockenga J. HPB (Oxford) 2009; 11(3): Domínguez-Muñoz JE. Adv Med Sci. 2011; 56(1): Gooden HM et al. Support Care Cancer 2013; 21(7): Fieker A et al. Clin Exp Gastroent. 2011; 4: Tignor AS et al. Am J Gastroenterol. 2010; 105: Kraemer R et al. Acta Paediatr Scand. 1978; 67(1): Steinkamp G et al. Thorax 2002; 57: Sikkens ECM et al. J Gastrointest Surg. 2012; 16(8): Sikkens ECM et al. Pancreatology 2012; 12: Data on file, RM27549: October Cummings MH et al. Practical Diabetes 2015; 32(2): Data on file, RM27558: July Thomas PD et al. Gut 2003; 52(5): v Domínguez-Muñoz JE et al. Pancreas 2012; 00: 00. Online publication. 23. Kahl S et al. Chapter 29: Clinical Pancreatology for Practising Gastroenterologists and Surgeons. Blackwell. ISBN: Sikkens ECM et al. Best Pract Res Clin Gastro. 2010; 24: Data on file, RM27550: October Data on file, RM27559: July Imrie CW et al. Aliment Pharmacol Ther. 2010; 32(1): Creon 10,000 Summary of Product Characteristics Creon Micro Summary of Product Characteristics Lohr J-M et al. United European Gastroenterol J. 2013; 1(2): Ramesh H. Pancreatology 2013; 13: Thorat V et al. Aliment Pharmacol Ther. 2012; 36(5): Domínguez-Muñoz JE. Pancreatology 2013; 13: e1 e Hardt P et al. Exp Diabetes Res. 2011; doi: /2011/ Ewald N et al. World J Gastroenterol. 2013; 19(42): Ewald N et al. Diabetes Metab Res Rev. 2012; 28: Ebert R et al. Diabetologia 1980; 19: Ewald N et al. Diabetes Metab Res Rev. 2007; 23(5): Mohan V et al. Int J Pancreatol. 1998; 24(1): Littlewood JM et al. Pediatr pulmonol. 2006; 41: Stallings VA et al. J Am Diet Assoc. 2008; 108: Stern RC et al. Am J Gastro. 2000; 95(8): Colombo C et al. Pancreas 2009; 38: Layer P et al. Curr Gastro Rep. 2001; 3: Diabetes UK prevalence statistics Statistics/Diabetes-prevalence-2013/. Last accessed 8th September Creon Micro Pancreatin mg Gastro-resistant Granules, Creon Capsules, Creon Capsules PRESCRIBING INFORMATION Presentation: Creon Micro: Gastro-resistant granules of pancreatin, containing in 100mg: 5,000 PhEur units of lipase; 3,600 PhEur units of amylase; 200 PhEur units of protease. Creon 10000: Each capsule contains pancreatin equivalent to: 10,000 PhEur units of lipase; 8,000 PhEur units of amylase; 600 PhEur units of protease. Creon 25000: Each capsule contains pancreatin equivalent to: 25,000 PhEur units of lipase; 18,000 PhEur units of amylase; 1,000 PhEur units of protease. Indication: Pancreatic exocrine insufficiency. Dosage and Administration: Creon Micro: Initially 100mg (5000 lipase units) taken with each feed or meal. The required quantity of granules should be dispensed using the measuring scoop provided which holds 100mg. In young infants, mix with a small amount of (undiluted) apple juice and give from a spoon directly before the feed. In weaned infants, mix with acidic liquids or soft foods (e.g. undiluted apple juice or apple puree) and take directly before the meal without chewing. Alternatively, mix the granules with a small amount of milk and administer to the infant immediately. The granules should not be added to the baby s bottle. Creon and 25000: Initially one or two capsules with meals, then adjust according to response. The capsules can be swallowed whole, or for ease of administration they may be opened and the granules taken with acidic fluid or soft food, but without chewing. This could be apple sauce or yoghurt or any fruit juice with a ph less than 5.5, e.g. apple, orange or pineapple juice. Creon Micro, and 25000: Dose increases, if required, should be added slowly with careful monitoring of response and symptomatology. Maximum daily dosage of Creon Micro should not exceed 10,000 units lipase/kg/day. Ensure adequate hydration. If the granules are mixed with fluid or food, it is important that they are taken immediately and the mixture not stored, otherwise dissolution of the enteric coating may result. In order to protect the enteric coating, it is important that the granules are not crushed or chewed. Crushing and chewing of the minimicrospheres or mixing with food or fluid with a ph greater than 5.5 can disrupt the protective enteric coating. This can result in early release of enzymes in the oral cavity and may lead to reduced efficacy and irritation of the mucous membranes. Care should be taken to ensure that no product is retained in the mouth. Colonic damage has been reported in patients with cystic fibrosis taking in excess of 10,000 units of lipase/kg/day (see below). Contraindications, Warnings etc: Hypersensitivity to pancreatin of porcine origin or any excipients. Fibrosing colonopathy has been reported in CF patients taking high dose pancreatin preparations. As a precaution, medically assess unusual or changes in abdominal symptoms, especially for doses above units of lipase/kg/day. Pregnancy and Lactation: There is inadequate evidence of safety in use during pregnancy. Pancreatic enzymes can be used during breast-feeding. Ability to Drive and Operate Machinery: No or negligible influence on ability. Side Effects: Most commonly, gastrointestinal disorders. Common: nausea, vomiting, constipation, diarrhoea and abdominal distension. Gastrointestinal disorders are mainly associated with the underlying disease. Similar or lower incidences compared to placebo were reported for abdominal pain (very common, 1/10). Uncommon: rash. Frequency unknown: Hypersensitivity (anaphylaxis), pruritus and urticaria, strictures of the ileo-caecum and large bowel (fibrosing colonopathy). See SPC for further information. Interactions: no studies performed. Name and Address of Marketing Authorisation Holder: BGP Products Ltd., Abbott House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire SL6 4XE PL No: Creon Micro: PL 43900/0033, Creon 10000: PL 43900/0030, Creon 25000: PL 43900/0031 Basic NHS price: Creon Micro (20g): 31.50, Creon (100 capsules): 12.93, Creon (100 capsules): Legal Category: Creon Micro and Creon 10000: P, Creon 25000: POM Further information is available in the UK from: BGP Products Ltd., Building Q1, Quantum House, 60 Norden Road, Maidenhead, SL6 4AY Date of Last Revision: 15/05/2015 Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to BGP Products Ltd by phone

21 For more information, contact the medical information department at Mylan EPD, BGP Products Ltd.