PANCRELIPASE (CREON)USE IN

PANCREATIC DISORDERSShiny Parsai

Froedtert General Medicine RotationUniversity of Iowa PharmD Candidate 2016

OUTLINE• Patient presentation • Pancreatic disorders • Pancrelipase (Creon)• Questions

PATIENT BACKGROUND

PATIENT PRESENTATION• PS, 66 year old, retired, white male• Height: 6’0” Weight: 67.7kg(149.2lbs)• BMI: 20kg/m2 (normal)• CrCl 78.2ml/min (normal renal function)• No known drug allergies • Social History

• Married • Current smoker with 75 year pack history • Drank 8 to 10 beers a day until he stopped drinking 3 weeks ago

• Family history non-contributory • Insured• Admitted to Froedtert Wednesday 8/19/2015

PATIENT PRESENTATION • Chief complaint

• Epigastric abdominal pain • Nausea and vomiting

• History of illness • Lost 26 pounds over the last month with decreased appetite • Hospitalized recently 8/3 - 8/18 at another hospital

• Abdominal pain and dehydration • MRI showed pancreatic cyst measuring 6 X 6 X 4 cm

• Physical Exam • HEENT: + bilaterial horizontal nystagmus

• Diagnosis • Alcoholic pancreatitis

PATIENT PRESENTATION Past medical history

• Pancreatitis and pancreas mass requiring Whipple procedure (2007)

• Barrett's esophagus• Depression• Diverticulosis• Hypertension • Hyperlipidemia• Appendectomy (1965)

Immunization history – up to date • Influenza (10/20/2014)

• Next immunization due Fall 2015• Pneumococcal PPSV23

(12/19/2014)• Next dose PCV13 due after

12/19/2015• Tetanus Td (11/23/2012)

• Next booster dose in 7 years

ABNORMAL LABS• BP 86/48 (hypotensive) • Glucose 205 (65 – 99 mg/dL) • HgB 11 (13.7-17.5g/dL) • Hct 33 (40-51%)• RBC 3.5 (4.6-6.1 10e6uL)• Lipase 9 (23-85 U/L)

PRIOR TO ADMISSION MEDICATIONS

Drug Dose Indication Aspirin 81 mg PO 1 tablet daily INDICATION: cardiovascular prevention B complex vitamin Unknown PO 1 tablet daily INDICATION: supplementationCitalopram 40 mg PO 1 tablet daily INDICATION: depressionInsulin glargine 10 units SQ Inject nightly INDICATION: diabetes type 2Lansoprazole 30 mg PO 1 capsule daily INDICATION: barrett’s esophagus Multivitamin Unknown PO 1 tablet daily INDICATION: supplementation Omega3 fatty acids 1000 mg PO 2 capsule twice a day INDICATION: supplementation Oxycodone IR 5 mg PO 1-2 tablets every 6 hours as needed INDICATION: painPancrelipase (Creon DR)

24,000 units PO

Take 2-3 capsules by mouth three times daily with meals/snacksINDICATION: pancreatic disorder

Zaleplon 5 mg PO 1 capsule nightly as needed INDICATION: insomnia

DISEASE BACKGROUND

PANCREAS1,2,3

•Digestion and absorption of nutrients •Key enzymes

• Amylase – hydrolyzes starch into sugars (ex:  rice, potatoes)• Lipase – hydrolyzes fats

• Fat soluble vitamins A, D, E, K • PS taking multivitamin and omega 3 fatty acids

• Trypsin – hydrolyzes proteins• Chymotrypsin – hydrolyzes proteins

• Cleavage of vitamin B12 from protein • PS taking vitamin B supplementation

•Disorders associated with pancreatic insufficiency • Cystic fibrosis• Pancreatitis

•Effects• Pancreatic insufficiency leads to malabsorption, weight loss, steatorrhea, gas,

diarrhea

WHIPPLE PROCEDURE – pancreatic mass4

• Removes head of pancreas, portion of common bile duct, gallbladder, duodenum of small intestine, pylorus of stomach, and surrounding lymph nodes

• Reconnect the remaining pancreas and digestive organs

• Surgery lasts between 5- 8 hours• Pancreatic insufficiency and

maldigestion occurs in up to 80% of patients following gastric, duodenal, or pancreatic surgery

ALCOHOLIC PANCREATITIS – background5

•Epidemiology • Between 4.8 and 24.2 cases per 100,000 in the U.S.• One-third of acute pancreatitis cases in the U.S. are alcohol induced

•Risk increases with amount and duration of alcohol consumption•Smoking may have an additive effect with alcohol in inducing pancreatitis•80% - 95% of people who abuse alcohol also smoke• Incidence of alcoholism is 10x more likely in smokers than nonsmokers

•Potentiates pancreatic microcirculatory impairment by ethanol • Induces leukocyte aggregation and adhesion

ALCOHOLIC PANCREATITIS – pathophysiology5

•Mechanism not entirely clear•Alcohol metabolism

•Oxidative •Non-oxidative

•Alcohol could impair blood flow to pancreas causing hypoxia and build up of free radicals

ALCOHOLIC PANCREATITIS – symptoms/diagnosis6 •Symptoms

• Epigastric or left upper quadrant pain• Radiation to the back, chest, or flanks (nonspecific)• Intensity of the pain severe (variable)

•Diagnosis • Presence of 2 of the 3 following criteria

• Abdominal pain consistent with the disease• Serum amylase and/or lipase greater than three times the upper limit of

normal• Characteristic findings from abdominal imaging

• Contrast-enhanced computed tomography (CECT) and / or MRI of pancreas• Reserved for patients in whom the diagnosis is unclear or who fail to

improve clinically within the first 48 – 72 h after hospital admission or to evaluate complications

PS TREATMENT GOALS•Treat acute alcoholic pancreatitis •Alleviate pancreatic inflammation and pain •Correct the underlying cause •Resolve hypotension •Prevent DVTs

•SCDs and starting enoxaparin after GI consult procedure•Resolve hypergylycemia

ACG GUIDELINES – management of acute pancreatitis6 •Hydration

•250 - 500 ml/hr isotonic crystalloid solution for all patients unless cardiovascular, renal, or other related comorbidities

•Early aggressive intravenous hydration is most beneficial during the first 12 - 24 hr and may have little benefit beyond this (strong recommendation, moderate evidence)

•PS - 0.9% NaCl infusion continuous 100ml/hr BP normalized to 100/58 HR 76

•Antibiotics •Treat extrapancreatic infection (ex: UTI, pneumonia)•Prophylactic antibiotics in severe acute pancreatitis is not recommended

•PS – no antibiotics given

ADDITIONAL TREATMENT – pharmacological

•Pancrelipase •Not for acute pancreatitis management •PS – appropriate based on chronic pancreatitis, prior Whipple procedure, and pancreatic insufficiency

•Pain management •Nonopioids (acetaminophen, ibuprofen)•Opiods•PS – taking oxycodone 5mg Q6hr PRN

ADDITIONAL TREATMENT – nonpharmacological6 • NPO

• Allows pancreas to rest• PS - Esophagogastroduodenoscopy scheduled for Thursday 8/20

• Supplementation • Patients with chronic pancreatitis are often malnourished• Malnutrition may be due to inadequate pancrelipase enzyme treatment

not alcoholism • Dominguez-Munoz et al. (2007) showed that treatment with higher

enzyme doses resulted in normal nutrition measures regardless of alcohol use

• PS – taking B complex: B12>2000(211-946pg/ml), multivitamin, and omega 3 fatty acids

• Avoid alcohol – PS stopped drinking 3 weeks ago• Smoking cessation – PS received NICODERM CQ 7mg/24 hour patch Q24

hrs• Small, low fat meals, with plenty of fluids

DRUG BACKGROUND

PANCRELIPASE – indications/contraindications9

•FDA approved indications•Conditions causing pancreatic insufficiency

• Cystic fibrosis • Chronic Pancreatitis • Pancreatectomy

•Contraindications• None

PANCRELIPASE – ingredients9

•Natural product harvested from the porcine pancreatic glands•Patients may be allergic to pork product (rare)•Patient may refuse treatment due to religious reasons (muslims, orthodox jews)

•Pigs used to produce pancrelipase because pigs are omnivores and produce all the enzymes needed

•No other sources of pancrelipase available •Contains amylase, lipase, and protease

PANCRELIPASE – formulation7,8,9

•Formulation •Delayed-release capsules because replacement enzymes are destroyed by stomach acid•Designed to release enzymes at pH ≥ 5.5

•Microspheres allows enzymes to mix with food and empty from the stomach into the duodenum at the same rate as the food

CREON WITH GASTRIC ACID SUPPRESSANTS10

•Retrospective Analysis to Investigate the Effect of Concomitant Use of Gastric Acid Suppressing Drugs on the Efficacy and Safety of Creon in Patients With Pancreatic Exocrine Insufficiency•34 trials, 1142 unique subjects•Concomitant use of PPI/H2RAs•Result

•Efficacy of Creon not affected by concomitant PPI/H2RA •Acid suppression is not routinely required with pancreatic enzyme replacement therapy

•PS – taking lansoprazole for Barrett’s esophagus

PANCRELIPASE – alternative treatment2 •Options

•Creon (Abbvie Pharmaceuticals)•Pancrelipase (Generic)•Pancreaze (Janssen Pharmaceuticals)•Pertzye (Digestive Care)•Ultresa (Aptalis)•Viokace (Aptalis)•Zenpep (Aptalis)

•No head-to-head tests comparing these products•Not AB rated for bioequivalence

PANCRELIPASE – FDA8

•Pancreatic enzymes predate the 1938 of the FDA approval act•FDA allowed these products to be grandfathered in

•2004 review found inconsistencies in formulation, composition, enzymatic activities, dosage, stability, bioavailability, and manufacturing processes of enzymes that could significantly compromise the safety and effectiveness •Announced new drug application approval requirement by 2008

•Limited oversight and variability among the preparations

CREON – dosing8

•Not interchangeable with any other pancrelipase product•Dosing based on age and available for infants and older •Adults with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy • Individualize based on symptoms, steatorrhea, and fat content of diet

•Dosed by lipase units•Approx 1000-2000 units lipase/kg/meal or 2000-4,000 units lipase/gram dietary fat

•PS – taking 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase 2-3 capsules by mouth three times daily with meals/snacks

•Dose should not exceed 2,500 units of lipase/kg/meal or 10,000 units lipase/kg/day•Fibrosing colonopathy –  abdominal pain, distension, vomiting, and constipation

CREON – administration8

• Do not split, chew, or crush capsules• Swallow whole with plenty of water to avoid oral mucosa irritation • If unable to swallow

• Open the capsules and mix with soft, acidic food such as applesauce • Swallow the mixture right after mixing without chewing or crushing• Drink a full glass of water or juice immediately

• Timing• Dominguez-Mumoz et al. (2004) found that efficacy of pancreatic enzyme

supplements for the treatment of exocrine pancreatic insufficiency may be optimized by administration during or after meals

• Missed dose • Skip the missed dose and take your usual dose with your next meal or snack• Do not take a double dose to make up for a missed one

CREON – adverse effects8

• Occurring in at least 1 chronic pancreatitis or pancreatectomy patient (greater than or equal to 4%) • Hyperglycemia/hypoglycemia• Abdominal pain• Abnormal feces, flatulence, frequent bowel movements• Nasopharyngitis

• Occurring in at least 2 cystic fibrosis patients (greater than or equal to 4%)• Vomiting• Dizziness• Cough

ADDITIONAL INFORMATION

PROGNOSIS11,12 •GI Consult

•Esophagogastroduodenoscopy performed • Possible infected fluid • Await final cytology results • Avoid aspirin and NSAIDS

• Possible drugs associated with acute pancreatitis • Probable mechanism of inhibition of prostaglandins that otherwise cause pancreatic duct constriction

• Start antibiotics for infected pseudocyst •Patient mistakenly discharged on Thursday 8/20•Error realized on Friday 8/21 and patient called to discuss readmission • Outpatient antibiotics prescribed• Augmentin 875-125mg 1 tablet BID for 14 days

•Follow up with PCP for iron deficiency anemia

CREON – financial support13

• CREON Co-Pay Assistance Program • Savings up to $50 per month on CREON prescriptions

REFERENCES1. Damerla V et al. Pancreatic Enzyme Supplementation in Pancreatic Cancer. J Support Oncol 2008;6:393–396 Volume 6, Number 8.2. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated 2005 Aug 12]. Pancrealipase; [updated 2005 Jul 19;

reviewed 2005 May 4; cited 2005 Aug 12]; [about 2 p.]. Available from: https://www.nlm.nih.gov/medlineplus/druginfo/meds/a604035.html. 3. Image available from: http://www.livescience.com/34789-pancreatic-cancer-radiation-chemotherapy-treatment.html4. Mayo clinic. Whipple procedure. Available from: http://www.mayoclinic.org/tests-procedures/whipple-procedure/basics/definition/prc-

20021393. 5. Chowdhury P et al. Pathophysiology of alcoholic pancreatitis: An overview. World J Gastroenterol 2006; 12(46): 7421-7427.6. Tenner S et al. American College of Gastroenterology Guideline: Management of Acute Pancreatitis. Am J Gastroenterology. 2013

Sep;108(9):1400-15; 1416. 7. Dominguez-Munoz JE et al. 13C-mixed triglyceride breath test to assess oral enzyme substitution therapy in patients with chronic

pancreatitis. Clin Gastroenterol Hepatol. 2007;5:484–488. 8. Ferrone M. Pancreatic Enzyme Pharmacotherapy. Pharmacotherapy. Volume 27, Number 6, 2007.9. Creon [package insert]. North Chicago, IL. AbbVie Inc; 2015.10. Whitcomb DC. Clinical update Advances in the treatment of pancreatic insufficiency. Gastroenterology & Hepatology Volume 7, Issue 4

April 2011.11. Sander-Struckmeier S et al. Retrospective Analysis to Investigate the Effect of Concomitant Use of Gastric Acid Suppressing Drugs on

the Efficacy and Safety of Pancrelipase/Pancreatin (CREON) in Patients With Pancreatic Exocrine Insufficiency. Pancreas & Volume 42, Number 6, August 2013.

12. Kaurich T. Drug-induced acute pancreatitis Tracie. Bayl Univ Med Cent. 2008;21(1):77–81.13. Tisdale JE. Drug-Induced Diseases: Prevention, Detection, and Management. ASHP; Second Edition (February 11, 2010).14. Image available from https://www.creon.com/CFPatients/ActivateCopayCard.

QUESTIONS?