Continuing Education Activity

Pancrelipase refers to a class of medications designed to treat malabsorption and abdominal pain secondary to exocrine pancreatic insufficiency. These agents serve as exogenous versions of digestive hormones and enzymes required for normal digestion and are ingested with meals to improve digestion, absorption, and abdominal pain frequently seen in chronic pancreatitis and exocrine pancreatic insufficiency. Pancrelipase can be used in all age groups. FDA Indications include exocrine pancreatic insufficiency due to chronic pancreatitis, pancreatic surgery, or cystic fibrosis. There are also non-FDA-approved indications. 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 where pancrelipase is effective.

Objectives:

• Describe the mechanism of action of pancrelipase.
• Review the approved and off-label indications for using pancrelipase.
• Identify the contraindications and adverse effects associated with pancrelipase use.
• Describe interprofessional team strategies for improving care coordination and communication to properly use pancrelipase to improve patient outcomes in the varied scenarios where it can be effective.

Indications

Pancrelipase refers to a class of medications designed to treat malabsorption and abdominal pain secondary to exocrine pancreatic insufficiency. These agents serve as exogenous versions of digestive hormones and enzymes required for normal digestion. As discussed below, these enzymes are ingested with meals to improve digestion, absorption, and abdominal pain frequently seen in chronic pancreatitis and exocrine pancreatic insufficiency. Pancrelipase can be used in all age groups.

Indications for pancrelipase are as follows:

FDA Indications

Exocrine pancreatic insufficiency due to any of the following conditions:

• Chronic pancreatitis 
• Pancreatic surgery 
• Cystic fibrosis

Non-FDA Indications

• As a presumptive test for pancreatic insufficiency
• Steatorrhea of post-gastrectomy syndrome
• Pancreatic insufficiency due to pancreatic cancer[1]

Key Clinical Background Information

Exocrine pancreatic insufficiency (EPI) is a syndrome characterized by poor absorption of fats, proteins, and, to a lesser extent, carbohydrates. This condition occurs primarily in patients with cystic fibrosis (CF) or chronic pancreatitis (CP). Clinicians can diagnose EPI by one of three criteria: fecal elastase test, fecal fat test, or a direct pancreatic function test.

Patients with EPI in CP have worse nutritional status, vitamin levels, and quality of life when compared to patients with CP without EPI.[2] Pancreatic enzyme products (PEPs) have been the standard of care for treating EPI in patients with CP for the past three decades. Treating patients with PEP improves nutritional status, quality of life, symptoms, and life expectancy in patients with EPI.

Manufacturers developed most PEPs before current United States Food and Drug Administration (FDA) New Drug Approval (NDA) requirements were enacted. In 2005, the FDA requested that manufacturers of PEPs now submit an NDA to approve these products.[3] A new wave of research is being conducted to discern the pharmacokinetic and pharmacodynamic profiles of PEP. For instance, this includes research concerning the bioavailability of PEP, the onset of action, and the improvement of fat absorption for this class of drugs.

Practitioners use the coefficient of fat absorption (CFA) to discern the efficacy of these drugs. In exocrine pancreatic insufficiency, many of the poor outcomes stem from the poor absorption of fats and fat-soluble vitamins. The administration of PEP enhances the absorption of fats and fat-soluble vitamins (A, D, E, K) and provides better outcomes for patients on therapy. Often, readers may encounter the term CFA. A simple way to understand the CFA is to know that the higher the CFA of any PEP, the better the drug will improve fat and fat-soluble vitamin absorption.

Some clinicians empirically begin patients on pancrelipase therapy when patients present with vitamin deficiencies, malabsorption, and poor nutritional status with risk factors for chronic pancreatitis, for example, chronic alcohol use disorder. The reason for this stems from the actual difficulty that one may encounter to diagnose chronic pancreatitis or exocrine pancreatic insufficiency. As mentioned above, EPI requires stool fat testing or even direct pancreatic function testing. Some clinicians may prefer to treat empirically given the immediate or rapid benefit conferred with PEP therapy; others often defer testing as testing is invasive (direct pancreatic stimulation testing) or unavailable in certain areas.

Mechanism of Action

PEPs are porcine enzymes and contain mixtures of pancreatic lipase, amylase, and protease. Lipase is a digestive enzyme involved in the hydrolysis and degradation of fats. Impairments in lipase metabolism lead to the malabsorption of fats. Amylase is a digestive enzyme involved in the hydrolysis and digestion of starches. Impairments in amylase metabolism lead to complex carbohydrates malabsorption. Proteases are enzymes involved in the breakdown of proteins and amino acids. Imbalances or insufficiency of proteases can lead to poor absorption of amino acids and breakdown of essential proteins.

PEPs are exogenous versions of these enzymes derived from porcine pancreatic ducts; these enzymes then act locally to break down fats, proteins, and carbohydrates. The main site of action is the duodenum. The duodenum represents the initial part of the small intestine where nutrient absorption and macromolecule degradation co-occurs. The drug has minimal systemic absorption.

Manufacturers developed newer formulations known as enteric-coated microspheres to protect enzymes against breakdown by gastric acid and provide better dispersion of enzymes in the chyme and, therefore, observed to provide consistent symptoms relief in CP compared to the older formulation.[4] Oral pancreatic enzymes appear to inhibit pancreatic exocrine secretion through a negative feedback mechanism involving intraduodenal proteases and exocrine pancreas.[5]

Administration

Different products have differing lipase/protease/amylase ratios; pancrelipase products are not interchangeable; patients should not switch between products.[6]

Patients should take this medication with meals; a general rule of thumb is to take half a dose of pancrelipase with snacks. 

Adult dosing for exocrine pancreatic insufficiency:

• 500 to 2500 lipase units/kg/dose orally with each meal or snack. 

Pediatric dosing for exocrine pancreatic insufficiency:

• Ages 1 to 3: 1000 to 2500 lipase units/kg/dose orally with each meal or snack; start with 1000 lipase units/kg with each meal or snack. The maximum dose is 6000 lipase units/kg/meal.
• Ages 4 to 11: 500 to 2500 lipase units/kg/dose orally with each meal or snack; start with 500 lipase units/kg/ with each meal or snack. The maximum dose is 6000 lipase units/kg/meal.
• Ages 12 and over: 500 to 2500 lipase units/kg/dose orally with each meal or snack; start with 500 lipase units/kg/meal.

Caps may be opened and sprinkled on soft food with a pH of 4.5 or lower, but patients must not crush or chew the contents. Doses exceeding 2500 lipase units/kg/meal, over 4000 lipase units per gram of fat ingested daily, or more than 10,000 lipase units/kg/day require objective evidence of improved therapeutic efficacy.

Most manufacturers recommend that patients not exceed 10,000 units of lipase/kg per day.

Adverse Effects

The most common adverse effects are headache, oral irritation, abdominal pain, lymphadenopathy, nasal congestion, and neck pain.

Notably, a beta-hemolytic streptococcal infection has been seen with the use of pancrelipase.

Rare (less than 1%) but severe side effects include cancer recurrence, anaphylaxis, duodenitis, and distal intestinal obstruction syndrome.

Warnings include fibrosing colonopathy (especially when doses exceed 2500 lipase units/kg of body weight per meal or greater than 10,000 lipase units/kg of body weight per day) and hyperuricemia as porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.

Pancrelipase has a pregnancy risk factor C; it can be used during pregnancy and breastfeeding. There is inadequate human data, but fetal/infant harm is not expected due to minimal maternal systemic absorption.[7]

Since these are porcine-derived products, there is a theoretical risk of viral transmission with their use; this risk is minimized by adhering to proper dosing instructions. Long-term pancreatic enzyme replacement products (PERPs), some of which had been available for over 100 years, fell under a 2006  US FDA directive that porcine-derived PERP products required the pharmaceutical manufacturer to submit a new drug application s(NDA) for each of these products, the first of the commercial PERP products approved following the FDA requirement received approval in 2009.[8]

Contraindications

Contraindications to pancrelipase include hypersensitivity to the drug or components of the formulation or hypersensitivity to pork protein.[9]

Caution is indicated in some conditions, including hyperuricemia or gout, a history of recurrent GI obstruction, meconium ileus, a history of short bowel syndrome, Crohn disease, or hypoglycemia/hyperglycemia.[10][11][12]

Pancrelipase can interact with certain drugs such as acarbose and calcium or magnesium salts; clinicians should consider alternative therapeutic choices.

Monitoring

No therapeutic levels exist concerning monitoring. Monitoring of the drug effect and adverse effect profile will be based on clinical symptoms and data, including abdominal symptoms, nutritional intake, weight, growth (in children), stool character, fecal fat. Glucose monitoring is advised if the patient has hypoglycemia or hyperglycemia risk.

Toxicity

No known toxicity has been documented per a 2008 report from the Center for Drug Evaluation and Research.

Enhancing Healthcare Team Outcomes

One of the common topics when reviewing the literature concerns the use of proton pump inhibitors with pancrelipase. These enzymes are enteric-coated to avoid the harsh conditions and low pH of the stomach. The goal of PEP therapy focuses on maximal drug delivery into the duodenum, which is where absorption occurs.[13]

Given the known effect of low pH on enzyme delivery for PEP, previous groups have attempted to increase the efficacy of PEP. Previously, preparations of PEP included supplements such as sodium bicarbonate as a neutralizing agent.[14] Other groups have looked at the effects of antacids to improve the efficacy of PEP.[15] Other researchers have studied the effect of H2 receptor blockers as well.[16] Research concerning the effect of H2 receptor blockers showed no improvements in outcomes.[16] Data demonstrate that antacids such as aluminum hydroxide and sodium bicarbonate tend to lower the efficacy of PEP.[16]

Proesmans et al. have shown that concurrent omeprazole administration improved steatorrhea when used with PEP therapy in patients with cystic fibrosis.[17]

The above-referenced literature may provide good clinical evidence for providers to begin PPI therapy in patients who are known hyper-secretors (produce too much stomach acid) or in patients who show minimal improvement with pancrelipase therapy for exocrine pancreatic insufficiency.

When using pancrelipase therapy for indicated conditions, the interprofessional healthcare team strategy will yield the best results. This team, comprised of clinicians, specialists, mid-level practitioners, nurses, and pharmacists, can oversee the therapy, monitor for therapeutic results and adverse events, and provide patient counseling to optimize treatment. With open collaboration and communication, the interprofessional team can achieve the best patient outcomes with the lowest incidence of adverse events. [Level 5]