Creon

2.1 Important Dosing Information 

CREON is a mixture of enzymes including lipases, proteases, and amylases. CREON dosing is based on lipase units.

• Use either an actual body weight or fat ingestion-based dosing scheme.
  
• Start at the lowest recommended dosage and individualize the dosage based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet. Changes in dosage may require an adjustment period of several days.
  
• Do not exceed 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or 4,000 lipase units/g fat ingested/day in adult and pediatric patients greater than 12 months of age without further investigation [see Warnings and Precautions ( 5.1)].
  
• The total daily dosage in adult and pediatric patients greater than 12 months of age should reflect approximately three meals plus two or three snacks per day. With each snack, administer approximately half the prescribed CREON dose for a meal.
  
• Do not substitute other pancreatic enzyme products for CREON. When switching from another pancreatic enzyme product to CREON, monitor patients for clinical symptoms of exocrine pancreatic insufficiency and titrate the dosage as needed.

2.2 Recommended Dosage

Adult and Pediatric Patients Greater than 12 Months of Age

The recommended oral initial starting dosage is:

• 500 lipase units/kg/meal for adult and pediatric patients 4 years of age and older.
  
• 500 to 1,000 lipase units/kg/meal for adult patients with chronic pancreatitis or pancreatectomy.
  
• 1,000 lipase units/kg/meal for pediatric patients greater than 12 months to less than 4 years of age.

If signs and symptoms of malabsorption persist, increase the dosage. Titrate to either 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or 4,000 lipase units/gram of fat ingested/day. Higher dosages may be administered if they are documented to be effective by fecal fat measures or an improvement in signs or symptoms of malabsorption including measures of nutritional status.

Pediatric Patients Birth to 12 Months of Age

The recommended oral dosage is 3,000 lipase units per 120 mL of formula or per breast-feeding.

2.3 Preparation and Administration Instructions

Instruct adult and pediatric patients greater than 12 months of age, or their caregivers, of the following:

• Take CREON during meals and snacks. If a dose is missed, take the next dose with the next meal or snack.
  
• Swallow capsules whole.
  
• For patients who are unable to swallow intact capsules, carefully open the capsules and sprinkle the entire contents on a small amount of acidic soft food with a pH of 4.5 or less (e.g., applesauce, bananas, plain Greek yogurt). Consume the entire mixture immediately.
  
• Do not crush or chew CREON capsules or capsule contents.
  
• Consume sufficient liquids (water or juice) to ensure complete swallowing of CREON [see Warnings and Precautions ( 5.2)].

Instruct caregivers of pediatric patients birth to 12 months of age of the following:

• Immediately prior to each breast-feeding session or each administration of 120 mL of formula, carefully open one CREON capsule (containing 3,000 USP units of lipase) and administer the entire contents using one of the following two methods:
  • Sprinkle on a small amount of acidic soft food with a pH of 4.5 or less (e.g., applesauce, bananas, plain Greek yogurt) being careful not to crush the capsule contents. The entire mixture should be given to the infant immediately.
    
  • Sprinkle the capsule contents directly into the infant’s mouth.
  
  
• Immediately administer additional breast milk or formula after CREON to ensure complete swallowing of the capsule contents.
  
• Do not mix CREON capsule contents directly into a bottle of breast milk or formula.
  
• Do not crush CREON capsule contents, and visually inspect the infant’s mouth to ensure that no drug is retained in the mouth [see Warnings and Precautions ( 5.2)].
  
• If a dose is missed, administer the next dose with the next feeding.

8.1 Pregnancy

Risk Summary

Published data from case reports with pancrelipase use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Pancrelipase is minimally absorbed systematically; therefore, maternal use is not expected to result in fetal exposure to the drug. Animal reproduction studies have not been conducted with pancrelipase.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of pancrelipase in either human or animal milk, the effects on the breastfed infant or the effects on milk production. Pancrelipase is minimally absorbed systemically following oral administration; therefore, maternal use is not expected to result in clinically relevant exposure of breastfed infants to the drug. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CREON and any potential adverse effects on the breastfed infant from CREON or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of CREON for the treatment of exocrine pancreatic insufficiency have been established in pediatric patients.

Use of CREON for this indication is supported by two adequate and well-controlled trials in adult and pediatric patients 12 years and older (Study 1) and in pediatric patients 7 to 11 years of age (Study 2) along with supportive data from an open-label, single-arm, study in 18 pediatric patients 4 months to six years of age (Study 3). All three study populations consisted of patients with exocrine pancreatic insufficiency due to cystic fibrosis. The safety in pediatric patients 7 years of age and older in Studies 1 and 2 were similar to that observed adult patients [see Adverse Reactions ( 6.1) and Clinical Studies ( 14)].

In Study 3, patients received their usual pancreatic enzyme replacement therapy (mean dose of 7,000 lipase units/kg/day for a mean duration of 18.2 days) followed by CREON (mean dose of 7,500 lipase units/kg/day for a mean duration of 12.6 days). The mean daily fat intake was 48 grams during treatment with usual pancreatic enzyme replacement therapy and 47 grams during treatment with CREON. Adverse reactions that occurred in patients during treatment with CREON in Study 3 were vomiting, irritability, and decreased appetite [see Adverse Reactions ( 6.1)].

Dosages exceeding 6,000 lipase units/kg/meal have been reported postmarketing to be associated with fibrosing colonopathy and colonic strictures in pediatric patients less than 12 years of age. If there is a history of fibrosing colonopathy, monitor patients during treatment with CREON because some patients may be at risk of progressing to stricture formation. Do not exceed the recommended dosage of either 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or 4,000 lipase units/g fat ingested/day in pediatric patients greater than 12 months of age without further investigation [see Dosage and Administration ( 2.2) and Warnings and Precautions ( 5.1)].

Crushing or chewing CREON capsules or mixing the capsule contents in foods having a pH greater than 4.5 can disrupt the protective enteric coating on the capsule contents and result in early release of enzymes, irritation of the oral mucosa, and/or loss of enzyme activity. Instruct the patient or caregiver of the following: consume sufficient liquids (juice, water, breast milk, or formula) to ensure complete swallowing, and visually inspect the mouth of pediatric patients less than 12 months of age to ensure no drug is retained in the mouth and irritation of the oral mucosa has not occurred [see Dosage and Administration ( 2.3) and Warnings and Precautions ( 5.2)].

8.5 Geriatric Use

Clinical studies of CREON did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between patients aged 65 years and over and younger adult patients.

5.1 Fibrosing Colonopathy

Fibrosing colonopathy has been reported following treatment with pancreatic enzyme products. Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with use of high-dose pancreatic enzyme products, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. Pancreatic enzyme products exceeding 6,000 lipase units/kg/meal have been associated with colonic stricture, a complication of fibrosing colonopathy, in pediatric patients less than 12 years of age. The underlying mechanism of fibrosing colonopathy remains unknown.

If there is history of fibrosing colonopathy, monitor patients during treatment with CREON because some patients may be at risk of progressing to colonic stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs. Do not exceed the recommended dosage of either 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or 4,000 lipase units/g fat ingested/day in adult and pediatric patients greater than 12 months of age without further investigation. Higher dosages may be administered if they are documented to be effective by fecal fat measures or an improvement in signs or symptoms of malabsorption including measures of nutritional status. Patients receiving dosages higher than 6,000 lipase units/kg/meal should be frequently monitored for symptoms of fibrosing colonopathy and the dosage decreased or titrated downward to a lower range if clinically appropriate [see Dosage and Administration ( 2.1)].

5.2 Irritation of the Oral Mucosa

Crushing or chewing CREON capsules or mixing the capsule contents in foods having a pH greater than 4.5 can disrupt the protective enteric coating on the capsule contents and result in early release of enzymes, irritation of the oral mucosa, and/or loss of enzyme activity.

Instruct the patient or caregiver of the following:

• Swallow capsules whole. For patients who cannot swallow the capsules whole, the capsules can be opened, and the contents sprinkled in a small amount of acidic soft food with a pH of 4.5 or less (e.g., applesauce, bananas, plain Greek yogurt).
  
• Do not crush or chew CREON capsules or capsule contents.
  
• Consume sufficient liquids (juice, water, breast milk, or formula) immediately following administration of CREON to ensure complete swallowing.
  
• Visually inspect the mouth of pediatric patients less than 12 months of age and of patients who are unable to swallow intact capsules to ensure no drug is retained in the mouth and irritation of the oral mucosa has not occurred [see Dosage and Administration ( 2.3)].

5.3 Hyperuricemia

Pancreatic enzyme products contain purines that may increase blood uric acid levels. High dosages have been associated with hyperuricosuria and hyperuricemia [see Overdosage ( 10)]. Consider monitoring blood uric acid levels in patients with gout, renal impairment, or hyperuricemia during treatment with CREON.

5.4 Risk of Viral Transmission 

CREON is sourced from pancreatic tissue from swine used for food consumption. Although the risk that CREON will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported.

5.5 Hypersensitivity Reactions

Severe hypersensitivity reactions including anaphylaxis, asthma, hives, and pruritus have been reported with pancreatic enzyme products [see Adverse Reactions ( 6.2)]. If symptoms occur, initiate appropriate medical management.

Monitor patients with a known hypersensitivity reaction to proteins of porcine origin for hypersensitivity reactions during treatment with CREON. The risks and benefits of continued CREON treatment in patients with severe hypersensitivity reactions should be taken into consideration with the overall clinical needs of the patient.