Continuing Education Activity

Pancrelipase, a combination of lipase, protease, and amylase, has benefited patients with exocrine pancreatic insufficiency. The FDA-approved conditions that are associated with pancreatic insufficiency that may require supplementation with pancrelipase include chronic pancreatitis, obstructive pancreatic tumors, post-procedure loss of pancreatic tissue or ductal occlusion, insufficient mixing of chyme with pancreatic enzymes because of rapid gastric emptying, small bowel resection with inadequate secretion of cholecystokinin-pancreozymin and secretin, and lymph node dissection leading to decreased pancreatic stimulation. Also approved are genetic disorders including cystic fibrosis, Schwachman Diamond syndrome, hereditary hemochromatosis, Zollinger-Ellison syndrome, celiac disease, and Crohn disease. There are also non-FDA-approved indications as well. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, monitoring, and toxicity of pancrelipase so providers can direct patient therapy to optimal outcomes in conditions where pancrelipase has benefit.

Objectives:

• Identify the mechanism of action of pancrelipase.
• Summarize the approved and off-label indications for pancrelipase.
• Review the adverse event profile of pancrelipase.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with pancrelipase.

Indications

Pancrelipase, a combination of lipase, protease, and amylase, has been shown to benefit patients with exocrine pancreatic insufficiency.[1]

The different conditions that are associated with pancreatic insufficiency that may require supplementation with pancrelipase are:

FDA-Approved

• Chronic pancreatitis: Structural damage involving the pancreatic ducts and acinar cells, which result from a prolonged inflammatory reaction in the pancreas, is the most common cause of insufficiency[2]
• Tumors: Obstruction of the pancreatic duct by a tumor in the pancreas/ampulla leads to atrophy, causing enzyme deficiency[3]
• Post-surgery:
  • Pancreatic resection: Loss of glandular tissue or duct occlusion post-procedure[4]
  • Gastric resection: Insufficient mixing of chyme with pancreatic enzymes because of rapid gastric emptying[5]
  • Small bowel resection: Inadequate secretion of cholecystokinin-pancreozymin and secretin
  • Lymph node dissection: Postcibal asynchrony and decreased pancreatic stimulation
• Genetic disorders:
  • Cystic fibrosis: An autosomal recessive disorder resulting from mutations in both copies of the gene for cystic fibrosis transmembrane conductance regulator (CTFR) on chromosome 7. The resultant protein regulates chloride and sodium transport across the endothelial cell membranes in exocrine glands. The major implication of this condition is the blockage of pancreatic ducts from the inspissated secretions resulting thereof[6]
  • Schwachman Diamond syndrome: An autosomal recessive disorder that presents in infancy. The usual presentation includes skeletal abnormalities, neutropenia, bone marrow dysfunction, and exocrine pancreatic insufficiency.
  • Hereditary hemochromatosis: An autosomal recessive disorder resulting from mutations in the HFE gene coding for hepcidin, transferrin, hemojuvelin, and ferroportin results in the increased absorption and deposition of iron in the body. Deposition of iron in the pancreas leads to reduced glandular function.
  • Zollinger-Ellison syndrome: A rare condition resulting from the development of gastrinomas or gastrin-secreting tumors in the stomach and duodenum. About 30% of cases occur as a part of MEN1 syndrome, which has an autosomal dominant inheritance pattern. Increased gastrin production leads to the suppression of pancreatic enzymes.
  • Celiac disease: An autoimmune condition inherited in either an autosomal dominant or recessive manner that may result in a decreased CCK secretion which secondarily results in reduced pancreatic secretion
  • Crohn's disease: An autoimmune condition that may cause the production of antibodies directed against the pancreas, which interferes which enzyme production
  • Autoimmune pancreatitis: IgG4-related disease that eventually progresses to exocrine pancreas insufficiency

Non-FDA Approved

• Enteral feeding tube occlusion: Administration of a pancreatic enzyme and sodium bicarbonate solution to blocked feeding tube effectively relieved the obstruction. The efficacy was further improved by applying the solution closer to the clogged area using a catheter.[7]

Mechanism of Action

The alkaline pH of the duodenum activates the components of pancrelipase, which then helps with digestion.[8][9]

Lipase

• Pancreatic lipase catalyzes the hydrolysis of triglycerides to monoglycerides, fatty acids, and glycerol. 
• Colipase anchors the lipase to the lipid-water membrane of the micelle producing a change in the structure of that surface. The hydrophobic active site is thus exposed to the binding of the triglycerides and the subsequent interaction with the catalytic triad. There is hydrolyzation of the esters of the fatty acids.

Amylase

• Pancreatic amylase hydrolyzes the alpha 1-4 linkages in the polysaccharides of three or more linked glucose units.
• Starch is only reduced to a lower compound as alpha 1-6 linkages are not hydrolyzed. Therefore, starch breaks down into dextrins and lower sugars.

Protease

• Pancreatic protease comprises trypsin and chymotrypsin, which belong to the family of serine proteases.
• Trypsin acts on the arginine and lysine residues which are hydrophilic.
• Chymotrypsin acts on the hydrophobic residues tryptophan, tyrosine, and phenylalanine.
• Both components present a catalytic site formed by the triad of serine, histidine, and aspartate.

It, therefore, acts as the digestive enzymes inherently secreted by the pancreas in the absence of insufficiency.

Various factors affect the efficacy of this supplementation, for example:

• Dose
• Gastrointestinal (GI) pH
• Size of the micro-spherules

Pharmacokinetics

• The enzymes are released only if the pH is greater than 5.5.
• Some preparations are enteric-coated, which inhibit gastric inactivation during gastric passage and deliver more to the duodenum where it is active.
• The GI tract does not absorb the contents in any amounts.
• The drug is excreted in the feces.

Administration

Oral Administration

The oral preparation should not be kept in the mouth for prolonged periods as it tends to cause mucosal irritation and stomatitis.

Various pancrelipase products are not interchangeable; clinicians should not switch between products without verifying dosing.

For exocrine pancreatic insufficiency, the typical dosing is 500 to 2,500 lipase units with each meal or snack. Different formulations are not dose-transferable, so the prescriber should consult the drug information for each formulation when starting or switching agents.

Tablets 

• Administered with a meal or immediately before it with sufficient fluids.
• The tablet is not to be crushed or chewed.
• It should be taken whole along with a proton pump inhibitor (if not enteric-coated).

Enteric-Coated Capsules

• The drug is administered with a meal or immediately before it with sufficient fluids.
• The enteric coating is not to be destroyed; it should be consumed whole.
• If the patient cannot swallow, the enteric-coated micro-spherules can be removed from the capsule and mixed with a small amount of acidic food and administered.

Other Routes of Administration

• Gastrostomy tube: Factors to be considered include the size of the tube, size of the micro-spherules, feeding schedules, and other concurrent medications to be administered.
• Jejunostomy or duodenostomy tube: The enteric coating is destroyed by crushing and then administered after mixing with sodium bicarbonate.

Adverse Effects

Mild Adverse Reactions

• Abdominal pain: Early 3% to 18%
• Headache: Early 3% to 15%
• Nasal congestion: Early 14%
• Otalgia: Early 11%
• Infection: Delayed 3% to 11%
• Diarrhea: Early 10%
• Dyspepsia: Early 10%
• Cough: Delayed 4% to 10%
• Flatulence: Early 3% to 9%
• Pruritus ani: Early 7%
• Epistaxis: Delayed 7%
• Vomiting: Early 6%
• Dizziness: Early 4%
• Pharyngitis: Delayed 4%
• Pruritus: Early 0% to 1%
• Urticaria: Early 0% to 1%
• Maculopapular rash: Early 0% to 1% 
• Nausea: Early incidence not known
• Muscle cramps: Delayed incidence not known
• Myalgia: Early incidence not known
• Lactose intolerance: Early incidence not known

 Moderate Adverse Reactions

• Lymphadenopathy: Delayed 11%
• Cholelithiasis: Delayed 7%
• Ascites: Delayed 7%
• Peripheral edema: Delayed 3%
• Anemia: Delayed 3%
• Hyperglycemia: Delayed 2%
• Hypoglycemia: Early 2%
• Constipation: Delayed incidence not known
• Stomatitis: Delayed incidence not known
• Oral ulceration: Delayed incidence not known
• Gastritis: Delayed incidence not known
• Esophagitis: Delayed incidence not known
• Elevated hepatic enzymes: Delayed incidence not known
• Blurred vision: Early incidence not known
• Hyperuricemia: Delayed incidence not known

Severe Adverse Reactions 

• Bronchospasm: Rapid 0% to 1%
• Anaphylactoid reactions: Rapid 0% to 1%
• Fibrosing colonopathy: Delayed incidence not known
• GI obstruction: Delayed incidence not known
• Cholecystitis: Delayed incidence not known

Contraindications

Although pancreatic enzyme replacement therapy does have any absolute contraindications per se, a careful analysis of the underlying risks is necessary for the following conditions.[10][11]

Diabetes Mellitus 

Pancrelipase affects glycemic control. Hence patients diagnosed with diabetes mellitus or patients at risk for abnormal blood sugar levels should have strict glucose monitoring while taking pancrelipase.

Immunocompromised States

Pancrelipase derives from the pancreatic tissue of swine. Although rigorous measures are in place to ensure no risk of transmitting viral infections to the patient, there is a theoretical risk from unknown viruses in the swine. Therefore, patients who are immunocompromised/immunodeficient are at an increased risk of contracting infections while on this medication.

Hyperuricemia and Renal Impairment

As this medication is porcine-derived, it contains certain nucleic acids that tend to increase blood uric acid levels. Patients with pre-existing hyperuricemia or gout and patients with decreased renal functions are to be closely monitored when on the drug.

Dysphagia

As mentioned earlier, patients with a tendency to retain the contents of the medications higher up in the gastrointestinal tract may develop mucosal irritation and mucositis. Care is necessary while administering the drug to patients with esophageal strictures and dysphagia.

Meconium Ileus, Intestinal Obstruction, Inflammatory Bowel Disease, and Surgery

Patients younger than 12 years of age, patients who have taken more than 6000 lipase units/kg per meal for more than six months, or patients with a history of meconium ileus, intestinal obstruction, inflammatory bowel disease, or abdominal surgery have the highest risk for developing fibrosing colonopathy. It is a rare but serious complication of enzyme replacement characterized by GI obstruction, bloody diarrhea, abdominal pain, and poor weight gain.

Therefore, it has been recommended by the Cystic Fibrosis Foundation Consensus Conference Guidelines that the efficacy of lipase supplementation more than 2500 units/kg per meal be confirmed by a 3-day fecal-fat measure that indicated an increased fat absorption coefficient. The dose is then to be adjusted accordingly.

Pregnancy

There are not adequate numbers of human and animal reproduction studies for this drug. Therefore, its use in pregnancy should be limited to those patients with exocrine pancreatic insufficiency who have inadequate maternal weight gain; this may adversely affect fetal growth, and hence supplementation is justified.

Breastfeeding

All breastfeeding mothers should contact their healthcare provider before taking pancrelipase. Some proteins present in the product may undergo systemic absorption along with the dietary protein. There is no data available about the uptake of these substances into breast milk; it is only recommended when it is necessary to support the mother's nutritional status.

Porcine Protein Sensitivity

There are reports of anaphylactic reactions, hives, asthma, urticaria, and pruritus in patients with prior hypersensitivity to porcine protein. Caution is necessary for all these patients.

Monitoring

The maximum dosage of pancrelipase is as follows:

Adults

The recommendation is a maximum of 10,000 lipase units per kg per day orally (PO) or less than 4,000 lipase units per gram of dietary fat per day.

Geriatric

The recommendation is a maximum of 10,000 lipase units per kg per day PO or less than 4,000 lipase units per gram of dietary fat per day.

Adolescents

The recommendation is a maximum of 10,000 lipase units per kg per day PO or less than 4,000 lipase units per gram of dietary fat per day.

But at no time should the maximum dosage exceed 2,500 lipase units per kg per meal.

Infant Dosage

Infant dosages are product-specific. But the maximum dosage is not to exceed 4,000 lipase units per gram of ingested fat per day or 10,000 lipase units/kg per day.

Neonates

Neonatal dosages are product-specific.

There are no dosage adjustments required for renal and hepatic impairment.

Drug Interactions That May Require Dosage Adjustments

• Antacids: The efficacy of gastrointestinal enzyme replacement therapy becomes reduced in the presence of antacids. Calcium and magnesium cations exert their effect by forming poorly soluble calcium and magnesium soaps and precipitation of glycine-conjugated bile salts based on in-vitro studies.
• Alpha-glucosidase inhibitors: Concurrent administration of gastrointestinal enzyme replacement therapy reduces the efficacy of alpha-glucosidase inhibitors. Ideally, the administration of each drug should be at different times. But this may not be possible, considering both drugs are to b administered around mealtime.

Toxicity

Chronic, high-dose pancreatic enzyme replacement can cause colonic strictures and fibrosing colonopathy.[12] Fibrosing colonopathy is a condition in which there is a narrowing of the lumen of a long segment of the colon. This condition occurs due to submucosal widening due to the deposition of mature collagen. Most commonly seen in children with cystic fibrosis as they require long-term high-dose pancreatic enzyme replacement.

Enhancing Healthcare Team Outcomes

The administration of pancreatic enzyme replacement therapy requires the efficient functioning of an interprofessional team to ensure the best benefit to the patient. The team usually comprises a clinician, nurse practitioner, pharmacist, nutritionist/dietician, physiotherapist, and nurses. The primary provider may additionally involve physicians from oncology, gastroenterology, surgery, pulmonology, or pediatrics, depending on the etiology of the enzyme insufficiency. The primary care provider is involved in the diagnosis of insufficiency. The PCP is then responsible for managing the symptoms, deciding the supplementation requirements of the patients, monitoring progress, and managing any side effects that might result thereof. Nurse practitioners are required to alternate with physicians to monitor patient progress with the medications. Pharmacists should provide patients and families with information on the drug, side effects, precautions, and contraindications. They are also responsible for dose alterations as the case demands. Dieticians and nutritionists should assess the patient's nutritional status and determine the calorie requirement. They are also required to determine the need for vitamin supplements, growth hormone, and appetite stimulants. Physiotherapists are required to help with the ambulation of patients with chronic illnesses like pancreatic cancer and chronic pancreatitis. They should also be on board when dealing with cases of cystic fibrosis. Nurses are an integral part of the team, especially in the inpatient setting, to ensure that all orders are executed. They are also an essential link in communication between physicians and patients. No evidence is available for the effectiveness of an interprofessional approach to pancreatic enzyme replacement therapy.

Various studies have shown the benefit of involving an interprofessional team for patients with cystic fibrosis.[13]