COTAZYM® (pancrelipase capsules, USP) contains pancrelipase obtained from the porcine pancreas. Pancrelipase is composed principally of lipase, amylase and protease and is used for oral digestive enzyme replacement. Each capsule contains not less than:

Lipase                   8,000 USP Units
Protease              30,000 USP Units
Amylase              30,000 USP Units

At release, up to 25% more lipase may be present.

Each capsule also contains the inactive ingredients: cornstarch, precipitated calcium carbonate, gelatin, magnesium stearate, talc, titanium dioxide, FD&C Green #3 and D&C Yellow #10 as coloring.

Pancrelipase, USP contains lipase, protease and amylase obtained from porcine pancreas. Normal pancreatic function includes secretion of proteolytic enzymes such as proteases (trypsin and chymotrypsin), nonproteolytic enzymes such as lipase and amylase, and electrolytes such as bicarbonate, chloride, sodium and potassium. Lipase, protease and amylase break down fat, protein, and starches, respectively, in the small intestine. Lipase hydrolyzes fats into glycerol and fatty acids. Protease converts proteins into proteoses and derived substances, while amylase converts starches into dextrins and sugars. Pancreatic enzymes are used to correct maldigestion, malabsorption and pain associated with pancreatic insufficiency. The major maldigestion/malabsorption problems arise from incomplete fat digestion. Exogenous pancrelipase reduces the amount of nitrogen and fat excreted in the stool. Activity of these products are dependent upon the amount of pancrelipase delivered to the small intestine. This delivery can be hampered by inactivation from low gastric pH, acidic precipitation of bile salts, and the proteolytic activity of the component protease. Pancreatic enzymes are more active at pH greater than 4, with lipase being the most sensitive of the pancreatic enzymes to inactivation by low pH. Malabsorption of fat is likely if an individual, ingesting 100 gm of fat per day, excretes more than 7 gm of fat (or 18 mmol) in a 24-hour period. Malabsorption of protein is likely if nitrogen excretion is greater than 2.5 gm per 24-hours (16% of protein by weight is nitrogen). In order for fat maldigestion to occur, a pancreas must secrete less than 10% of its normal output.

The enzymes contained in COTAZYM® (pancrelipase capsules, USP) are not absorbed systemically; therefore, pharmacokinetic studies of their absorption, distribution, metabolism, and excretion have not been conducted. The contents of COTAZYM® capsules are released in the stomach, whereupon some of the enzyme is inactivated by acid. The remaining enzymes traverse into the duodenum, where they facilitate digestion and subsequently are hydrolyzed to their constituent amino acids by proteases. Pancreatic extracts contain purines which are absorbed into the general circulation and are converted to uric acid. This uric acid could lead to hyperurticemia, hyperuticosuria, and possible kidney damage. Chymotrypsin activity in the stool is indicative of exocrine pancreatic function. Ingestion of pancrelipase enzymes result in an increase in chymotrypsin in the stool.

Clinical bioactivity and bioavaliability studies in patients with exocrine pancreatic insufficiency from cystic fibrosis or chronic alcoholic pancreatitis have shown that the enzymes from COTAZYM® are released at the duodenojejunal junction.

A study was conducted in 6 patients (ages 43-58) with pancrelipase insufficiency secondary to chronic alcoholic pancreatitis. Four of the patients received 4 capsules of COTAZYM® with a standard test meal. The mean (±SEM) percent of ingested dose of lipase and trypsin delivered to the duodenum postprandially was 15.1% (±2.1) and 11.3% (±1.6), respectively. A randomized 3-way crossover study was also performed on this group of patients to further ascertain bioavaliability. Each patient received 10 PANCREATIN® tablets per meal, 4 COTAZYM® capsules per meal, and 4 or 8 PANCREASE® capsules per meal in a randomized order. In patients who received COTAZYM®, PANCREASE®, or PANCREATIN® while on a 100 gm fat/day diet, the fat excretions were 15.0 gm, 13.0 gm, and 19.0 gm per 24 hours, respectively, while fat excretion was 31.0 gm/24 hours in the no enzyme treatment group. 1 An investigation was also conducted in 8 cystic fibrosis patients (ages 18-29) with steatorrhea who were already on some type of enzyme replacement therapy. Two patients were given a test meal together with 4 capsules of COTAZYM®. The mean delivery of lipase and trypsin to the duodenum postprandially was 7.6% (3.5-11.7%) and 14.5% (12-17%) of intake, respectively. A randomized 2-way crossover study was performed on 7 of these 8 patients. Each patient received 4 COTAZYM® capsules per meal or 8 PANCREASE® capsules per meal, while on a 100 gm fat/day diet. Steatorrhea was controlled with 19.2% of fat excreted (as % of fat intake) for COTAZYM® and 5.9% of fat excreted for PANCREASE®, reduced from 28% fat excreted with previous treatments. 2

SPECIAL POPULATIONS

Pediatric and Geriatric Patients

There is no evidence to suggest that the bioactivity or bioavailability of COTAZYM® would differ markedly in pediatric or geriatric patients from other patient populations.

CLINICAL STUDIES

Cystic Fibrosis

In a single center, unblinded, non-randomized, active-controlled, one sequence, 2-period (with no washout period) crossover Canadian study of 15 patients, under the age of 4 years, with exocrine pancreatic insufficiency secondary to cystic fibrosis, COTAZYM® (pancrelipase capsules, USP) was compared to another pancreatic enzyme preparation for the treatment of fat malabsorption. 3

COTAZYM® significantly reduced fecal fat as a percentage of intake when compared to baseline as follows:

Fecal Fat
(as % of intake)  
Baseline
Mean ± SEM
COTAZYM®
Mean ± SEM
29.5 ± 5.2 14.7 ± 1.8
P value = 0.088

In a single center, randomized, double-blind, placebo controlled, 2-period crossover, 5-day treatment U.S. study in 10 male patients, ages 10-16 years, with exocrine pancreatic insufficiency secondary to cystic fibrosis, COTAZYM® and other pancreatic enzyme preparation were compared to placebo for treatment of fat malasbsorption. 4

COTAZYM® significantly reduced fecal fat as compared to placebo as follows:

Fecal Fat
Excretion
(grams/day)
Placebo
Mean ± SEM
COTAZYM®
Mean ± SEM
67.9± 13.1 29.9 ± 7.0
P value < 0.005

Chronic Pancreatitis

In a multicenter, randomized, unblinded, 3-period crossover, 6-day treatment U.S. study in 6 male patients, ages 43-58 years, with exocrine pancreatic insufficiency from chronic alcoholic pancreatitis, COTAZYM® (pancrelipase capsules, USP) and two other pancreatic enzyme preparations were compared to a no treatment control for the treatment of fat malabsorption. 1

COTAZYM® significantly reduced fecal fat as compared to the no treatment control as follows:

Fecal Fat
Excretion
(grams/day)
Control
Mean ± SEM
COTAZYM®
Mean ± SEM
3.10 ± 2.0 15.0 ± 2.0
P value < 0.005

COTAZYM® (pancrelipase capsules, USP) capsules are indicated for treatment of steatorrhea due to exocrine pancreatic enzyme deficiency in such conditions as cystic fibrosis and chronic pancreatitis.

CONTRAINDICATIONS

COTAZYM® (pancrelipase capsules, USP) is contraindicated in those individuals who are hypersensitive to antigens of porcine origin.

(See PRECAUTIONS and DOSAGE AND ADMINISTRATION .)

PRECAUTIONS

General

Large doses of delayed release pancreatic enzyme preparations taken by patients with cystic fibrosis have been associated with fibrosing colonopathy (colonic stricture). While COTAZYM® (pancrelipase capsules, USP) is an immediate release product and such products have not generally been associated with the lesion, the dose recommended should not be exceeded unless justified by individual patient need and response (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS ). If capsules must be opened for any reason, care should be taken that the powder is not inhaled or spilled on hands; it may cause serious allergic reaction or be irritating to the skin or mucous membranes. A mask and gloves should be worn while handling opened capsules.

Folic acid supplementation during pregnancy is important. Daily oral supplementation with folic acid before conception and during pregnancy can substantially reduce the occurrence of neural tube defects (anencephaly and spina bifida). Women should take folic acid if they are pregnant, or are thinking of becoming pregnant during treatment with COTAZYM®.

Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe COTAZYM® (pancrelipase capsules, USP):

Taking the Capsules

Patients should be instructed not to increase their COTAZYM® (pancrelipase capsules, USP) dose without consulting their physician. If it becomes necessary to open the COTAZYM® capsules, inhalation of the powder or contact with the skin or mucous membranes should be avoided. It is suggested mask and gloves be worn when opening capsules. COTAZYM® should not be taken by patients with known hypersensitivity to antigens of porcine origin. Sensitive individuals may experience allergic reactions.

Folic acid supplementation during pregnancy is important. Daily oral supplementation with folic acid before conception and during pregnancy can substantially reduce the occurrence of neural tube defects (anencephaly and spina bifida). Women should take folic acid if they are pregnant, or are thinking of becoming pregnant during treatment with COTAZYM®.

Concomitant Medication

Patients should be advised not to take COTAZYM® (pancrelipase capsules, USP) together with a combination of calcium carbonate and magnesium hydroxide. Calcium carbonate and magnesium hydroxide may be found in certain antacids. Calcium carbonate can also be found in certain calcium or mineral supplements. COTAZYM® may interfere with the absorption of folic acid and iron. Patients should consult with their physician if taking folic acid or iron containing preparations.

Pregnancy

COTAZYM® (pancrelipase capsules, USP) may interfere with the absorption of folic acid. Folic acid supplementation during pregnancy is important. Daily oral supplementation with folic acid before conception and during pregnancy can substantially reduce the occurrence of neural tube defects (anencephaly and spina bifida). Patients should be advised to notify their physician if they are pregnant or are thinking of becoming pregnant during treatment with COTAZYM® (pancrelipase capsules, USP).

Nursing

Patients should be advised to notify their physician if they are breast-feeding an infant.

Drug Interactions

Antacids containing calcium carbonate and magnesium hydroxide should not be taken concurrently with pancrelipase. The combination of calcium carbonate and magnesium hydroxide with pancrelipase may precipitate glycine-conjugated bile acids and may form calcium and magnesium fatty acid soaps, causing a decrease in fat absorption and thus an increase in steatorrhea.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Long-term animal studies for carcinogenesis and studies evaluating the potential for impairment of fertility of mutagenesis have not been performed with COTAZYM® (pancrelipase capsules, USP).

Pregnancy

Pregnancy Category C

Animal reproductive studies have not been conducted with COTAZYM® (pancrelipase capsules, USP). It is not known whether COTAZYM® can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. COTAZYM® should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known if COTAZYM® (pancrelipase capsules, USP) is excreted in human milk.

Because many products are excreted in human milk, caution should be exercised when COTAZYM® is administered to nursing mothers.

ADVERSE REACTIONS

Adverse reactions to COTAZYM® (pancrelipase capsules, USP) have been reported uncommonly. The most frequent adverse reactions reported during clinical use are diarrhea and stool abnormalities, such as green stools. Other reactions reported include pharyngitis, vomiting, abdominal pain, gastric burning, syncope, mouth irritation, mouth ulcers, mild anemia, abnormal smell and taste, stomach trouble and belching. Hyperuricosuria and/or hyperuricemia have been reported in patients taking high doses of COTAZYM®, pancreatic extracts have high purine content. Renal damage has not been reported. Hypersensitivity reactions, such as anaphylaxis, allergy, nasal irritation, coughing spells and episodes of bronchospasm, can occur in people exposed to the enzyme powder from opened capsules. High doses of the powder may cause mouth or perianal excoriation. In addition, pancreatic enzyme preparations may interfere with folic acid and iron absorption.

There is a report of a child with cystic fibrosis who developed fibrosing colonopathy, and who has been treated with delayed-release pancreatic enzyme preparations as well as COTAZYM® prior to detection of the lesion.

OVERDOSAGE

No cases of acute overdose have been reported with COTAZYM® (pancrelipase capsules, USP). Hyperuricemia and/or hyperuricosuria have been reported in patients chronically taking high doses of COTAZYM® (pancrelipase capsules, USP). The minimum effective dose of COTAZYM® should be determined and adhered to for each patient. Large doses of delayed-release pancreatic enzyme preparations taken by patients with cystic fibrosis have been associated with fibrosing colonopathy (see PRECAUTIONS ).

DOSAGE AND ADMINISTRATION

Cystic Fibrosis

The dosage of COTAZYM® (pancrelipase capsules, USP) must be individualized according to the patient' remaining exocrine pancreatic function, pH of the gut lumen (if such measurements are routinely taken) and intake of fat and protein. Dosage should depend on nutritional intake as well as body weight, and varies with age. A high caloric diet with unrestricted fat appropriate to age and clinical status should be consumed. While the dose may need to be adjusted for control of steatorrhea, a total daily dose should not exceed 2500 lipase units/kg per meal without careful evaluation of the patient. A dose higher than 6000 lipase units/kg per meal should not be administered 5 (see PRECAUTIONS ).

Prior to treatment, the patient' stool should be evaluated microscopically for the presence of fat droplets. If visible, a 72-hour fat balance study should be performed while monitoring nutrient intake, to determine the extent of malabsorption. In patients with meconium ileus, a fat balance study is not required prior to establishing a dosage and beginning treatment with COTAZYM®. Do not exceed recommended dosage. Based on 2500 lipase units/kg per meal, the maximum recommended dosage for a 70 kg patient would be 20 capsules per meal (60 capsules/day for 3 meals). Dosages greater than 2500 lipase units/kg per meal should only be used with caution and only if safely tolerated by the patient and documented to be effective by 3 day fecal fat measures that indicate a significantly improved coefficient of absorption. 5 Infants should be given a total of 2000 to 4000 lipase units for each 120 mL (4 oz.) of formula or each breast feeding. For other children less than 4 years of age, dosing should begin with 1000 lipase units/kg for each meal. For children 4 years of age or older, 500 lipase units/kg for each meal should be initiated. For a snack, half the dose for a meal should be given.

Chronic Pancreatitis

One or two capsules should be administered for control of symptoms and adjusted as needed.

HOW SUPPLIED

COTAZYM® (pancrelipase capsules, USP) are opaque green capsules imprinted with "Organon" and "381". COTAZYM® is supplied in bottles of 100, NDC# 0052-0381-91, and bottles of 500, NDC# 0052-0381-95.

Storage:   Not to exceed 25°C (77°F). Store in dry place when opened.

Dispense:   In tight container as defined in the USP.

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.

images/pills/p01327c2.jpg

REFERENCES

  1. Dutta SK, Rubin J, Harvey J. Comparative Evaluation of the Therapeutic Efficacy of a pH-Sensitive Enteric Coated Pancreatic Enzyme Preparation with Conventional Pancreatic Enzyme Therapy in the Treatment of Exocrine Pancreatic Insufficiency. Gastroenterology 1983;84:476-482.
  2. Dutta SK, Hubbard VS, 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 and Sci 1988;33:1237-1244.
  3. Data on File at Organon Inc., W. Orange, NJ, USA
  4. Mischler EH, Parrell S, Farrell PM, Odell GB. Comparison of effectiveness of pancreatic enzyme preparations in cystic fibrosis. Am J Dis Child 1982;136:1060-1063.
  5. Borowitz DS, Grand RJ, Durie PR, and the Consensus Committee. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. J Ped 1995;127:681-684.

Caution:   Federal law prohibits dispensing without a prescription.

Organon' Inc.

375 Mt. Pleasant Avenue

West Orange, NJ 07052

                             Revision 8/97