Pancrelipase Therapy

Mechanism of Action

The duodenum's alkaline pH activates the components of pancrelipase, which then aids digestion.[20][21] Pancreatic enzyme replacement therapy (PERT) includes 3 primary enzymes: lipase, amylase, and protease, each responsible for distinct stages of digestion. Pancreatic lipase catalyzes the hydrolysis of triglycerides into monoglycerides, fatty acids, and glycerol. The enzyme's activity is enhanced by colipase, which anchors lipase to the lipid-water interface of micelles, thereby exposing the hydrophobic active site and facilitating the hydrolysis of triglycerides. Pancreatic amylase acts by hydrolyzing the α-1,4-glycosidic linkages in polysaccharides containing glucose units. However, it does not break down α-1,6-glycosidic linkages, resulting in partial digestion of starch into dextrins and smaller sugars. Pancreatic proteases, such as trypsin and chymotrypsin, are serine proteases involved in protein digestion. Trypsin cleaves peptide bonds at the carboxyl side of the amino acids arginine and lysine, while chymotrypsin targets hydrophobic amino acids such as tryptophan, tyrosine, and phenylalanine. Both enzymes operate through a catalytic triad consisting of serine, histidine, and aspartate, which is crucial for their proteolytic activity.

Pancreatic enzyme preparations (PEPs) are porcine-derived enzymes containing lipase, amylase, and protease. These enzymes help digest fats, starches, and proteins. They primarily act in the duodenum, with minimal systemic absorption. Newer enteric-coated microsphere formulations protect enzymes from gastric acid and improve dispersion, offering better symptom relief than previous formulations.[22]

Pharmacokinetics

Absorption: The gastrointestinal tract does not absorb pancrelipase.

Distribution: Pancrelipase acts locally in the GI tract, with the principal site of action being the duodenum. Pancrelipase is not absorbed in any significant amount, so the volume of distribution is minimal.

Metabolism: The enzymes are released only if the pH exceeds 5.5. Some preparations are enteric-coated, which inhibits gastric inactivation during gastric passage and delivers more to the duodenum, where they are active. No significant metabolism occurs.

Elimination: Pancrelipase is excreted in feces.

Administration

Available Dosage Forms and Strengths

Pancrelipase is administered orally. Other routes of administration include a gastrostomy tube. Factors to be considered include the size of the tube, the size of the micro-spherules, feeding schedules, and other concurrent medications. Pancrelipase can also be administered in a jejunostomy or duodenostomy tube.

Capsule formulations with delayed-release, bicarbonate-buffered enteric-coated microspheres typically contain lipase, protease, and amylase in varying concentrations. For example, one formulation includes 4,000 units of lipase, 14,375 units of protease, and 15,125 units of amylase, while another consists of 8,000 units of lipase, 28,750 units of protease, and 30,250 units of amylase. Capsule formulations with delayed-release, enteric-coated beads include different strengths, such as 3,000 units of lipase, 10,000 units of protease, and 14,000 units of amylase; alternatively, a combination of 5,000 units of lipase, 17,000 units of protease, and 24,000 units of amylase is also possible. Additionally, capsules with delayed-release, enteric-coated micro tablets may contain 2,600 units of lipase, 8,800 units of protease, 15,200 units of amylase, up to 37,000 units of lipase, 97,300 units of protease, and 149,900 units of amylase.

Non-enteric-coated formulations should be administered with proton pump inhibitors. The dose is 10,440 units of lipase, 39,150 units of protease, and 39,150 units of amylase, or higher concentrations of 20,880 units of lipase, 78,300 units of protease, and 78,300 units of amylase.

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.

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.
• This drug should be taken whole 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 should not be destroyed; it should be consumed whole.
• If the patient cannot swallow, the enteric-coated micro-spherules can be removed from the capsule, 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, the 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.

Dosage

According to the American Gastroenterological Association (AGA), Pancreatic Enzyme Replacement Therapy (PERT) should be administered during meals, with an initial dose of at least 40,000 units of lipase per meal for adults and half of that amount for snacks. The dosage can be adjusted based on the size of the meal and its fat content. While humans have other digestive mechanisms for proteins and carbohydrates, they lack an efficient system for fat digestion. Therefore, PERT focuses on the lipase dose and the meal's fat content. The primary goal of PERT is to ensure proper digestion of lipids to meet both macro- and micronutrient needs, while a secondary goal is to alleviate steatorrhea.

A healthy pancreas secretes approximately 900,000 units of lipase during an average meal. Even with high doses, PERT formulations are less efficient than normal pancreatic secretion and may not entirely resolve steatorrhea. Most patients retain some residual pancreatic function, so an initial dosage of 40,000 to 50,000 units of lipase per meal is appropriate, with half of that amount for snacks. 

The typical starting dose in children and adults with advanced chronic pancreatitis or cystic fibrosis is 500 units of lipase/kg body weight per meal and snack. This dose should be titrated to reduce steatorrhea or other gastrointestinal symptoms. For cystic fibrosis, the maximum dose is less than 10,000 units of lipase/kg of body weight per day or less than 4,000 units/g of dietary fat consumed daily. The maximum dosage for adults, older patients, and adolescents is 10,000 lipase units/kg/d PO or less than 4,000 lipase units/g of dietary fat daily. However, the dosage should never exceed 2,500 lipase units/kg for each meal. The dosage is product-specific for infants, but the maximum limit is 4,000 lipase units/g of ingested fat per day or 10,000 lipase units/kg daily. In case of unsatisfactory clinical response, PERT dosage can be increased cautiously, or a proton pump inhibitor should be added.[23]

Specific Patient Populations

Hepatic impairment: No dosage adjustments are provided in the manufacturer's labeling. Administer with caution.

Renal impairment: No dosage adjustments are provided in the manufacturer's labeling. Administer with caution.

Pregnancy considerations: No adequate human and animal reproduction studies for pancrelipase exist. 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. According to the literature review, pancreatic enzymes are probably safe during pregnancy and delivery; administer cautiously.[24]

Breastfeeding considerations: All breastfeeding mothers should consult their healthcare provider before taking pancrelipase. No data is available regarding the transfer of pancrelipase into breast milk; it is only recommended when necessary to support the mother's nutritional status. Since pancreatic enzymes are not significantly absorbed from the mother's gastrointestinal tract, they are unlikely to reach the infant. Therefore, administering pancrelipase during breastfeeding may be considered acceptable.[25] 

Pediatric patients: The Cystic Fibrosis Foundation recommends initiating pancreatic enzyme replacement therapy (PERT) for infants younger than age 2 with cystic fibrosis (CF) who have pancreatic insufficiency (PI). This includes infants with 2 cystic fibrosis transmembrane conductance regulator (CFTR) mutations associated with pancreatic insufficiency, fecal elastase levels less than 200 μg/g, coefficient of fat absorption less than 85%, or symptoms of malabsorption. Pancreatic enzyme replacement therapy should not be started in infants with 1 or 2 CFTR mutations associated with pancreatic sufficiency unless there is objective evidence of fat malabsorption or unequivocal malabsorption symptoms.[26]

Older patients: The recommendation is a maximum of 10,000 lipase units/kg/d PO or less than 4,000 lipase units/g of dietary fat daily.

Adverse Effects

The common adverse drug reactions to pancrelipase treatment include headache, abdominal cramping, nausea, diarrhea, bloating, and constipation.[3] Other common adverse drug reactions include vomiting, dizziness, cough, irritability, dysglycemia, and nasopharyngitis. Due to the porcine preparation, there is a theoretical risk of viral infection. Post-marketing studies have revealed adverse drug reactions such as blurred vision, distal intestinal obstruction syndrome, anaphylaxis, asthma, hives, pruritus, elevations in liver enzymes, myalgia, muscle spasms, urticaria, and rash. Crushing/chewing the pancrelipase formulation can cause it to release enzymes in the oral cavity, leading to mucosal irritation or stomatitis.[27] Pancrelipase is commonly administered to patients with chronic pancreatitis, and has rarely been associated with drug-induced neutropenia. While transient neutropenia was reported in a cystic fibrosis study, a case represents possible pancrelipase-induced neutropenia; however, additional research is required.[28]

Drug-Drug Interactions

• Antacids: The efficacy of gastrointestinal enzyme replacement therapy is reduced by 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 α-glucosidase inhibitors. Ideally, each drug should be administered at a different time. However, this may not be possible, considering both drugs will be administered around mealtime.

• Iron supplements: Pancrelipase may interfere with the absorption of iron supplements. Clinicians should monitor iron status for patients receiving pancrelipase therapy. However, iron deficiency is common in cystic fibrosis and may be related to underlying gastrointestinal pathology and chronic inflammation.[29]

Contraindications

Although pancreatic enzyme replacement therapy has no absolute contraindications per se, a careful analysis of the underlying risks is necessary for the following conditions.[30][31]

Warnings and Precautions

• Fibrosing colonoapathy: High doses of pancreatic enzyme replacement therapy are associated with the risk of fibrosing colonopathy.[32][33] Colonic strictures have been reported in pediatric patients with cystic fibrosis who received dosages greater than 6,000 lipase units/kg for every meal. This rare but serious complication of enzyme replacement is characterized by GI obstruction, bloody diarrhea, abdominal pain, and poor weight gain. Patients with a history of fibrosing colonopathy should be closely monitored during treatment, as they may be at risk of progressing to colonic stricture. The recommended maximum dose is 2,500 lipase units/kg/meal, 10,000 lipase units/kg/d, or 4,000 lipase units/g fat ingested daily in patients older than 12 months. Higher doses may be used if effective, but patients on doses exceeding 6,000 lipase units/kg/meal should be regularly monitored for symptoms and have doses adjusted accordingly.

• Mucosal irritation: Crushing, chewing, or mixing pancreatic enzyme capsule contents with foods with a pH above 4.5 can cause premature enzyme release in the oral cavity and irritation of the oral mucosa.[27] Patients should swallow the capsules whole. If this is not possible, the capsule contents may be sprinkled onto foods like applesauce, bananas, or Greek yogurt. After taking the medication, patients should drink enough liquids, such as juice, water, and breast milk, to ensure complete swallowing. Caregivers of pediatric patients under 12 months or those unable to swallow intact capsules should inspect their mouths to ensure no medication remains and that irritation has not occurred.

• Distal intestinal obstruction syndrome: Distal intestinal obstruction syndrome (DIOS) in cystic fibrosis is caused by thickened fecal material in the terminal ileum and colon, commonly in patients with pancreatic insufficiency and a history of meconium ileus or prior DIOS episodes. Symptoms include abdominal pain, distension, and vomiting, diagnosed by x-ray. Treatment involves rehydration, polyethylene glycol, and sometimes aggressive interventions. Pancreatic enzyme therapy (eg, pancrelipase) can manage fat malabsorption and prevent DIOS, though it can occur in patients who are pancreatic-sufficient. Preventive measures include optimizing enzyme therapy, hydration, and maintenance laxatives. In patients who are post-transplant, early enzyme use may help prevent recurrence.[34]

• 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 and risk of viral infection: 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.[35]

• Hyperuricemia: 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. While earlier reports suggested hyperuricemia in patients with cystic fibrosis treated with pancreatic enzyme products, recent studies have not found a significant link between pancrelipase use and hyperuricemia.[36]

• Dysphagia: As reported above, patients who tend to retain the medications' contents higher up in the gastrointestinal tract may develop mucosal irritation and mucositis. Therefore, care must be taken when administering the drug to patients with esophageal strictures and dysphagia.

• 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.[37][38]

• Medication error/interchangibility of products: A case report was described as due to medication errors in the American College of Medical Toxicology. A 7-year-old girl experienced a fatal outcome following a medication administering error involving pancrelipase. The clinical findings included hypotension, bradycardia, metabolic acidosis, cardiac arrest, coagulopathy, thrombocytopenia, and leukocytosis. Despite aggressive measures, case fatality was reported.[39] The error likely occurred due to the wrong medication route or improper dilution technique, underscoring the importance of administration. Various pancrelipase formulations are not interchangeable.

Monitoring

Fecal elastase can be used to diagnose exocrine pancreatic insufficiency (EPI). According to the American Gastroenterological Association, monitoring effective treatment with pancreatic enzyme replacement therapy can be assessed by decreased steatorrhea and adverse gastrointestinal effects, increased weight and muscle mass, and enhanced levels of fat-soluble vitamins.[3] AGA recommends that EPI be closely monitored and baseline measurements of nutritional status be obtained. These include assessing body mass index (BMI), quality-of-life indicators, and fat-soluble vitamin levels. Additionally, a baseline dual-energy x-ray absorptiometry (DEXA) scan should be performed and repeated every 1 to 2 years. Providers must supplement and monitor the levels of fat-soluble vitamins to manage EPI effectively. Dietary adjustments should include a low to moderate-fat diet with smaller, more frequent meals while avoiding very-low-fat diets to prevent deficiencies in essential fatty acids and fat-soluble vitamins A, D, E, and K. Additionally, regular screening for vitamin and mineral deficiencies, including vitamins A, D, E, K, B12, folate, magnesium, selenium, zinc, and iron, is crucial at diagnosis and annually thereafter based on the patient's clinical status.[3] Clinicians should monitor uric acid levels in patients with renal impairment and a history of gout, and for signs of hypersensitivity and fibrosing colonopathy.[22]

Toxicity

Signs and Symptoms of Overdose

Chronic, high-dose pancreatic enzyme replacement can cause colonic strictures and fibrosing colonopathy.[40] Fibrosing colonopathy is a condition in which the lumen of a long segment of the colon narrows. This condition occurs due to submucosal widening caused by the deposition of mature collagen, and is most commonly observed in patients with cystic fibrosis, which requires long-term high-dose pancreatic enzyme replacement.

Management of Overdose

There is no antidote for pancrelipase. According to the American Society for Parenteral and Enteral Nutrition guidelines, in the early stages of fibrosing colonopathy, a reduction in the dosage of pancreatic enzyme replacement therapy may lead to improvement. However, in more advanced stages, a surgical intervention may be necessary.[41] The treatment of structuring fibrosing colonopathy using the conservative approach in cystic fibrosis has been reported. Case reports suggest an anti-inflammatory approach using prednisolone pulse therapy, followed by topical budesonide to avoid the adverse effects of long-term systemic steroids. Despite this, the patient developed a second stenosis at the cecum. If symptoms worsen, balloon dilation or limited surgery may be considered. In conclusion, this case demonstrates a non-passable colonic stricture in cystic fibrosis, managed conservatively over 3 years, suggesting a therapeutic approach for fibrosing colonopathy. However, additional research is required.[42]

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 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 study found that pancreatic exocrine insufficiency (PEI) in chronic pancreatitis (CP) patients was associated with a significantly increased mortality risk (HR 2.59; 95% CI 1.42-4.71, P<0.003). The most common causes of death were cancer (40.4%) and infection (21.3%). Nutritional markers were significantly lower in patients with PEI compared to those without PEI (P<0.001) and in those who died versus survivors (P<0.001).[43] 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. Nurse practitioners must alternate with physicians to monitor patient progress with the medications. Pharmacists should inform patients and families about the drug, its adverse 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 fat-soluble vitamins and supplements. 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. Various studies have shown the benefit of involving an interprofessional team for patients with cystic fibrosis.[44] An interprofessional team approach and communication among clinicians, pharmacists, dietitians, and nurses are crucial to decreasing potential adverse effects and improving patient outcomes related to pancrelipase therapy.