Pancrelipase, which is 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 a 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 was effective in relieving the obstruction. The efficacy was further improved by the application of the solution closer to the clogged area using a catheter.[7]

The alkaline pH of the duodenum activates the components of pancrelipase, which then help with digestion.

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.

Oral Administration

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

Tablets 

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

Enteric-Coated Capsules

• Administered with a meal or immediately before it with sufficient fluids
• The enteric coating is not to be destroyed; to be consumed whole
• If the patient cannot swallow, the enteric-coated micro-spherules are to 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 to be destroyed by crushing and then administered after mixing with sodium bicarbonate.

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

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.

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 transmission of 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 for 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, as well as 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, who have taken more than 6000 lipase units/kg per meal for more than six months, who have a history of meconium ileus, intestinal obstruction, inflammatory bowel disease, 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 in cases 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.