Pancrelipase (Systemic)


VA CLASSIFICATION
Primary: HS451
Secondary: GA500

Commonly used brand name(s): Cotazym; Cotazym E.C.S. 20; Cotazym E.C.S. 8; Cotazym-65 B; Cotazym-S; Creon 10; Creon 20; Creon 5; Enzymase-16; Ilozyme; Ku-Zyme HP; Pancoate; Pancrease; Pancrease MT 10; Pancrease MT 16; Pancrease MT 20; Pancrease MT 4; Panokase; Protilase; Ultrase MT 12; Ultrase MT 20; Viokase; Zymase.

Another commonly used name is
lipancreatin .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Enzyme (pancreatic) replenisher—

digestant—

diagnostic aid (pancreatic function)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Pancreatic insufficiency (treatment)—Pancrelipase is indicated as a pancreatic enzyme supplement and replacement therapy in conditions where pancreatic enzymes are either absent or deficient, resulting in inadequate fat and carbohydrate digestion. {01} Such conditions are usually due to chronic pancreatitis, pancreatectomy, cystic fibrosis, gastrointestinal bypass surgery (Billroth II and total), and ductal obstruction from neoplasm (of the pancreas or common bile duct). {01} {08}

Steatorrhea (treatment){01}—Indicated for treating steatorrhea associated with the postgastrectomy syndrome and bowel resection, and for decreasing malabsorption in these patients.

[Pancreatic insufficiency (diagnosis)]1—Pancrelipase is used as a presumptive test for pancreatic function, especially in pancreatic insufficiency due to chronic pancreatitis. {13}

Unaccepted
Pancrelipase is not effective in the treatment of gastrointestinal disorders unrelated to pancreatic enzyme insufficiency. {05}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Mechanism of action/Effect:

Proteolytic, amylolytic, and lipolytic enzymes in pancrelipase enhance the digestion of proteins, starches, and fats in the gastrointestinal tract, {01} primarily in the duodenum and upper jejunum. The activity of pancrelipase is greater in neutral or faintly alkaline media. Pancrelipase has about 12 times the lipolytic activity, 4 times the proteolytic activity, and 4 times the amylolytic activity of pancreatin. {05}

The efficacy of pancrelipase activity is dependent on how much of the enzyme reaches the small intestine. This can be influenced by the enzyme dose, the prevention of release of pancrelipase in the stomach, the microsphere size of the delayed-release product, and the pH at which the microsphere dissolves and releases the enzyme, with activity being greater at a neutral or alkaline pH. {18} {19} {23}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to pancreatin or pork protein may be sensitive to this medication also. {01}

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans.

Studies have not been done in animals.

FDA Pregnancy Category C. {06}

Breast-feeding

It is not known whether pancrelipase is distributed into breast milk. However, problems in humans have not been documented. {07}

Pediatrics

Appropriate studies on the relationship of age to the effects of pancrelipase have not been performed in children up to 6 months of age. {06}


Geriatrics


Appropriate studies on the relationship of age to the effects of pancrelipase have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Antacids, calcium carbonate– and/or magnesium hydroxide–containing    (concurrent administration of antacids may be required to prevent inactivation of pancrelipase [except the enteric-coated dosage forms] by gastric pepsin and acid pH; however, calcium carbonate– and/or magnesium hydroxide–containing antacids are not recommended since they may decrease the effectiveness of pancrelipase {03} {09})


Iron, supplements or preparations    (iron absorption may be decreased when used concurrently with pancrelipase {10})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Uric acid{01}{09}    (blood and urine concentrations may be increased; ribonuclease present in pancreatic extracts catalyzes the formation of purine precursors of uric acid, thus increasing the risk of hyperuricosuria, especially with large doses of the purine-rich older formulations {18} {21} of pancrelipase)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used if the following medical problems exist:
» Pancreatitis, acute{08}
» Sensitivity to pork protein, pancrelipase, or pancreatin{01}

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Allergic reaction {01}(skin rash or hives)
    
irritation of the mouth —induced by enzymatic digestion of mucous membranes when tablet dosage form is retained in mouth
    
sensitization (shortness of breath; stuffy nose; troubled breathing; wheezing; tightness in chest)—induced by repeated inadvertent inhalation of powder dosage form or the powder from opened capsules

With high doses {18} {19}
    
Gastrointestinal effects, specifically{01} diarrhea
intestinal obstruction{19}
nausea
stomach cramps or pain
hyperuricemia or{22} hyperuricosuria{21} (blood in urine; joint pain; swelling of feet or lower legs)—more frequent with extremely high doses{01} of the purine-rich older formulations of pancrelipase{18}{21}
Note: There have been reports of gastrointestinal stricture requiring surgery in cystic fibrosis patients receiving high potency pancrelipase for 12 months or longer. The pathogenesis is unknown at this time. The U. S. Food and Drug Administration has issued a voluntary recall of pancrelipase products that contain greater than 20,000 Units of lipase. {25} {26}







Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Pancrelipase (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to pork protein, pancrelipase, or pancreatin
Other medical problems, especially acute pancreatitis

Proper use of this medication
Taking dose before or with meals for maximum effectiveness

» Importance of following diet ordered by physician

» Not chewing tablets; swallowing them quickly with liquid to lessen potential for mouth irritation

Not chewing or crushing capsules containing enteric-coated spheres

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Possible concurrent use with antacids that contain calcium carbonate and/or magnesium hydroxide

Not changing brands or dosage forms of pancrelipase without checking with physician

Possible sensitization resulting from repeated inhalation of powder, either from opened capsules or from powder dosage form


Side/adverse effects
Signs of potential side effects, especially allergic reaction, hyperuricemia or hyperuricosuria (with extremely high doses); gastrointestinal effects; irritation of mucous membranes; and respiratory problems (with inhalation of powder)


General Dosing Information
The destruction of pancrelipase's enzymes by gastric pepsin or their inactivation by acid pH may be prevented by the use of enteric-coated dosage forms, particularly the enteric-coated spheres. Or, if dosage forms of pancrelipase which are not enteric-coated are used, the gastric and duodenal pH may be raised instead by the concurrent administration of sodium bicarbonate, aluminum hydroxide, histamine H 2-receptor antagonists, {09} {13} misoprostol, {20} or omeprazole {13} {16} (also, antacid, H 2-receptor antagonist, misoprostol, {20} or omeprazole {16} administration may be necessary in patients with deficient pancreatic bicarbonate secretion for the control of steatorrhea). An H 2-receptor antagonist administered with meals may be preferred instead of antacids, especially in patients with high rates of acid secretion. {09}

Dosage should be individualized and determined by the degree of maldigestion and malabsorption, the fat content of the diet, and the enzyme activity of each preparation rather than by the weight of the extract. Ideally, a starting dose of 8,000 {24} to 10,000 Units of lipase should be given with each meal. {18}

To avoid irritation of the mouth, lips, and tongue, the tablets should not be chewed. Instead, the tablets should be swallowed quickly, preferably with some liquid, since proteolytic enzymes (trypsin and chymotrypsin) present in pancrelipase, when retained in the mouth may begin to digest the mucous membranes and cause ulcerations. {01} {02}

Retention of the tablet dosage form in the esophagus may occur in some patients with esophageal abnormalities or in patients taking the tablet in a recumbent position. To decrease the likelihood of mucous membrane digestion, 1 or 2 mouthfuls of solid food should be swallowed after each dose.

Diet/Nutrition
Pancrelipase should preferably be taken before or with meals for maximum effectiveness. {09}

In pancreatic insufficiency, a high-calorie diet which is high in protein and low in fat is recommended. In severe cases, higher doses of pancrelipase and dietary adjustment may be necessary. {09} Some clinicians recommend that cystic fibrosis patients consume a liberal {24} fat diet along with an increase in pancelipase dosage to ensure adequate energy intake. {17} {18}Adequate hydration should be ensured at all times for patients taking pancreatic enzymes.{30}{31}{32}

Capsule dosage forms may be opened and sprinkled on food for administration to young children. However, capsules containing the enteric-coated spheres should be taken with liquids or small amounts of soft foods (e.g., applesauce, gelatin)that have a pH less than 5.5 and that do not require chewing.The soft food should be swallowed immediately and followed with a glass of water or juice.{30}{31}{32}

Bioequivalence information
The microsphere size of the delayed-release product, among other factors, determines how much of the enzyme reaches the small intestine. It has been found that some delayed-release pancrelipase products provide higher levels of enzyme activity than labeled. {15} {19} Since substitution of one manufacturer's delayed-release product for another may sometimes be accompanied by therapeutic failure, caution should be exercised in substituting. {14} {15} {19}


Oral Dosage Forms

PANCRELIPASE CAPSULES USP

Usual adult and adolescent dose
Enzyme (pancreatic) replenisher and
Digestant
Oral, 1 to 3 capsules before or with meals and snacks, the dosage being adjusted as needed and tolerated. {01}


Usual pediatric dose
Enzyme (pancreatic) replenisher and
Digestant
Oral, contents of 1 to 3 capsules with meals, the dosage being adjusted as needed and tolerated. {01}


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


8000 USP Units of lipase, 30,000 USP Units of protease, and 30,000 USP Units of amylase, per capsule (Rx) [Cotazym (calcium carbonate 25 mg)] [Ku-Zyme HP]

Canada—


8000 USP Units of lipase, 30,000 USP Units of protease, and 30,000 USP Units of amylase, per capsule (Rx) [Cotazym] [Cotazym-65 B (bile salts 65 mg) ( cellulase 2 mg)]

Packaging and storage:
Store below 25 °C (77 °F), in a tight container, unless otherwise specified by manufacturer. Store with a desiccant.

Auxiliary labeling:
   • Take before or with meals.
   • If capsules are opened, do not inhale powder. {02}


PANCRELIPASE DELAYED-RELEASE CAPSULES USP

Note: Substitution of one manufacturer's delayed-release product for another has resulted in therapeutic failure. {14} {15}


Usual adult and adolescent dose
Enzyme (pancreatic) replenisher and
Digestant
Oral, 1 to 4 capsules before or with meals and snacks (for capsules containing the enteric-coated spheres), the dosage being adjusted as needed and tolerated. Initial starting dose should be determined by clinical experience.{30}{31}{32}{01}


Usual pediatric dose
Enzyme (pancreatic) replenisher and
Digestant
Children up to 6 years of age—Oral, contents of 1 or 2 capsules with meals, the dosage being adjusted as needed and tolerated.{01}{30}{31}{32} Initial starting dose should be determined by clinical experience.{30}{31}{32}
Children 6 years of age and over—See Usual adult and adolescent dose.

Note: Contents of capsules containing the enteric-coated spheres should be taken with liquids or a small amount of soft foods with a pH less than 5.5 that do not require chewing. The soft food should be swallowed immediatly without chewing and followed with a glass of water or juice to insure swallowing.



Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


4000 USP Units of lipase, 12,000 USP Units of protease, and 12,000 USP Units of amylase, per capsule (Rx) [Pancrease MT 4]


4000 USP Units of lipase, 25,000 USP Units of protease, and 20,000 USP Units of amylase, per capsule (Rx) [Pancoate] [Pancrease] [Protilase][Generic]{28}


5000 USP Units of lipase, 20,000 USP Units of protease, and 20,000 USP Units of amylase, per capsule (Rx) [Cotazym-S]


5000 USP Units of lipase, 18,750 USP Units of protease, and 16,600 USP Units of amylase, per capsule (Rx) [Creon 5]


10,000 USP Units of lipase, 30,000 USP Units of protease, and 30,000 USP Units of amylase, per capsule (Rx) [Pancrease MT 10]


10,000 USP Units of lipase, 37,500 USP Units of protease, and 33,200 USP Units of amylase, per capsule (Rx) [Creon 10]


12,000 USP Units of lipase, 24,000 USP Units of protease, and 24,000 USP Units of amylase, per capsule (Rx) [Zymase]


12,000 USP Units of lipase; 39,000 USP Units of protease, and 39,000 USP Units of amylase, per capsule (Rx) [Ultrase MT 12]


16,000 USP Units of lipase, 48,000 USP Units of protease, and 48,000 USP Units of amylase, per capsule (Rx) [Enzymase-16] [Pancrease MT 16][Generic]


20,000 USP Units of lipase, 44,000 USP Units of protease, and 56,000 USP Units of amylase, per capsule (Rx) [Pancrease MT 20{29}]


20,000 USP Units of lipase, 65,000 USP Units of protease, and 65,000 USP Units of amylase, per capsule (Rx) [Ultrase MT 20]


20,000 USP Units of lipase, 75,000 USP Units of protease, and 66,400 USP Units of amylase, per capsule (Rx) [Creon 20]

Canada—


4000 USP Units of lipase, 12,000 USP Units of protease, and 12,000 USP Units of amylase, per capsule (Rx) [Pancrease MT 4]


4000 USP Units of lipase, 25,000 USP Units of protease, and 20,000 USP Units of amylase, per capsule (Rx) [Pancrease]


8000 USP Units of lipase, 30,000 USP Units of protease, and 30,000 USP Units of amylase, per capsule (Rx) [Cotazym E.C.S. 8]


10,000 USP Units of lipase, 30,000 USP Units of protease, and 30,000 USP Units of amylase, per capsule (Rx) [Pancrease MT 10]


16,000 USP Units of lipase, 48,000 USP Units of protease, and 48,000 USP Units of amylase, per capsule (Rx) [Pancrease MT 16]


20,000 USP Units of lipase, 55,000 USP Units of protease, and 55,000 USP Units of amylase, per capsule (Rx) [Cotazym E.C.S. 20]

Packaging and storage:
Store below 25 °C (77 °F), in a tight, light-resistant container, unless otherwise specified by manufacturer. Store with a desiccant.

Auxiliary labeling:
   • Take before or with meals (for capsules containing the enteric-coated spheres).
   • Do not chew or crush (for capsules containing the enteric-coated spheres only).


PANCRELIPASE POWDER

Usual adult and adolescent dose
Enzyme (pancreatic) replenisher and
Digestant
Oral, 0.7 gram with meals and snacks, the dosage being adjusted as needed and tolerated. {12}


Usual pediatric dose
Enzyme (pancreatic) replenisher and
Digestant
Oral, 0.7 gram with meals, the dosage being adjusted as needed and tolerated. {12}


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


16,800 USP Units of lipase, 70,000 USP Units of protease, and 70,000 USP Units of amylase, per 0.7 gram (Rx) [Viokase]

Canada—
Not commercially available.

Packaging and storage:
Store below 25 °C (77 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Take with meals.
   • Do not inhale. {02}


PANCRELIPASE TABLETS USP

Usual adult and adolescent dose
Enzyme (pancreatic) replenisher and
Digestant
Oral, 1 to 3 tablets before or with meals and snacks, the dosage being adjusted as needed and tolerated. {12}


Usual pediatric dose
Enzyme (pancreatic) replenisher and
Digestant
Oral, 1 or 2 tablets with meals.


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


8000 USP Units of lipase, 30,000 USP Units of protease, and 30,000 USP Units of amylase, per tablet (Rx) [Panokase] [Viokase{27}]


11,000 USP Units of lipase, 30,000 USP Units of protease, and 30,000 USP Units of amylase, per tablet (Rx) [Ilozyme]

Canada—
Not commercially available.

Packaging and storage:
Store below 25 °C (77 °F), in a tight container, unless otherwise specified by manufacturer. Store with a desiccant.

Auxiliary labeling:
   • Take before or with meals.
   • Do not chew.



Revised: 03/28/2001



References
  1. Cotazym S label information, rec 10/89, rev 3/88, U.S.
  1. Federal Register Vol. 50 No. 217 11/8/85 p. 46600.
  1. AMA-DE 6th ed Ch. 55, p. 997.
  1. CPS 1988.
  1. AHFS, 1990.
  1. AMA-DE, 7th Edition.
  1. Ku-zyme product information, Schwarz, rec 1/89, rev 8/88, U.S.
  1. Pancrease MT, McNeil, rec 11/88, rev 1988, U.S.
  1. Perry R and J Gallagher, Management of maldigestion associated with pancreatic insufficiency, Clin Pharm, 1985, 4: 161-169.
  1. Hansten"s Drug Interactions, 6th Edition, p. 404.
  1. Cotazym product information, rec 10/88, rev 1/87.
  1. Facts and Comparisons, 1990.
  1. Manufacturer comment, 1990 revision cycle.
  1. Panel consensus, 1990 revision cycle.
  1. Hendeles L, Dorf A, Stecenko A, Weinberger M, Treatment failure after substitution of generic pancrelipase capsules, J Am Med Assoc, 1990, 263[18]: 2459-2461.
  1. Heijerman H, Lamers C, Bakker W, Omeprazole enhances the efficacy of pancreatin (pancrease) in cystic fibrosis, Annals of Int Med, 1991, 114[3]: 200-201.
  1. Luder E, Kattan M, Thornton J, Koehler K, Bonforte R, Efficacy of a nonrestricted fat diet in patients with cystic fibrosis, Am J Dis Child, 1989, 143: 458-464.
  1. Reviewer comment, 1991 revision.
  1. Federal Register, 1991, 56[135]: 32282-32290.
  1. Robinson P, Sly P, Smith A, Effect of misoprostil on fat malabsorption in cystic fibrosis, Arch Dis Child, 1988, 63: 1081-1082.
  1. Nousia-Arvanitakis S, Stapleton F, Linshaw M, Kennedy J, Therapeutic approach to pancreatic extract-induced hyperuricosuria in cystic fibrosis, J Pediatr, 1977, 90[2]: 302-305.
  1. Davidson G, Hassel M, Crozier D, Corey M, Forstner G, Iatrogenic hyperuricemia in children with cystic fibrosis, J Pediatr, 1978, 93[6]: 976-978.
  1. Dutta S, Hubbard V, Appler M, Critical examination of therapeutic efficacy of a pH-sensitive enteric-coated pancreatic enzyme preparation in treatment of exocrine pancreatic insufficiency secondary to cystic fibrosis, Dig Dis Sci, 1988, 33[10]: 1237-1244.
  1. Panelist comment, 1991 revision cycle, second round.
  1. Smyth R, van Velzen D, Smyth A, Lloyd D, Heaf D. Stricture of ascending colon in cystic fibrosis and high-strength pancreatic enzymes. Lancet 1994; 343: 85-6.
  1. Comments from FDA Gastrointestinal Drugs Advisory Committee meeting on February 17, 1994 in Bethesda, MD.
  1. Panokase product information (Rugby—US), Rev 6/88, Rec 4/95.
  1. Pancrelipase product information (Jones Medical Industries—US), Rev 6/88, Rec 5/95.
  1. Pancrease MT 20 product information (Ortho McNeil—US), Rev 3/94, Rec 4/95.
  1. Product Information: Creon 5® Minimicrospheres®, pancrelipase delayed–release capsules, USP. Solvay Pharmaceuticals, Inc. Marietta, GA (PI revised 6/1998) PI reviewed 3/2001.
  1. Product Information: Creon 10® Minimicrospheres®, pancrelipase delayed–release capsules, USP. Solvay Pharmaceuticals, Inc. Marietta, GA (PI revised 6/1998) PI reviewed 3/2001.
  1. Product Information: Creon 20® Minimicrospheres®, pancrelipase delayed–release capsules, USP. Solvay Pharmaceuticals, Inc. Marietta, GA (PI revised 6/1998) PI reviewed 3/2001.
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