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CREON
(pancrelipase) Delayed-Release Capsules
CREON is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and amylases.
Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble or insoluble in alcohol and ether.
Each delayed-release capsule for oral administration contains enteric-coated spheres (0.71–1.60 mm in diameter).
The active ingredient evaluated in clinical trials is lipase. CREON is dosed by lipase units.
Other active ingredients include protease and amylase.
CREON contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate, polyethylene glycol, and triethyl citrate.
3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase delayed-release capsules have a white opaque cap with imprint “CREON 1203” and a white opaque body. The shells contain titanium dioxide and hypromellose.
6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase delayed-release capsules have a Swedish-orange opaque cap with imprint “CREON 1206” and a blue opaque body. The shells contain FD&C Blue No. 2, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase delayed-release capsules have a brown opaque cap with imprint “CREON 1212” and a colorless transparent body. The shells contain black iron oxide, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase delayed-release capsules have a Swedish-orange opaque cap with imprint “CREON 1224” and a colorless transparent body. The shells contain gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
36,000 USP units of lipase; 114,000 USP units of protease; 180,000 USP units of amylase delayed-release capsules have a blue opaque cap with imprint “CREON 1236” and a colorless transparent body. The shells contain gelatin, titanium dioxide, FD&C Blue No. 2 and sodium lauryl sulfate.
CREON® (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.
CREON is not interchangeable with other pancrelipase products.
CREON is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet as described in the Limitations on Dosing below [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
CREON should be administered to infants immediately prior to each feeding, using a dosage of 3,000 lipase units per 120 mL of formula or prior to breast-feeding. Contents of the capsule may be administered directly to the mouth or with a small amount of applesauce. Administration should be followed by breast milk or formula. Contents of the capsule should not be mixed directly into formula or breast milk as this may diminish efficacy. Care should be taken to ensure that CREON is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa.
CREON should be taken during meals or snacks, with sufficient fluid. CREON capsules and capsule contents should not be crushed or chewed. Capsules should be swallowed whole.
For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth.
Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences.1, 2, 3 CREON should be administered in a manner consistent with the recommendations of the Cystic Fibrosis Foundation Consensus Conferences (also known as Conferences) provided in the following paragraphs, except for infants. Although the Conferences recommend doses of 2,000 to 4,000 lipase units in infants up to 12 months, CREON is available in a 3,000 lipase unit capsule. Therefore, the recommended dose of CREON in infants up to 12 months is 3,000 lipase units per 120 mL of formula or per breast-feeding. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.
Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.
CREON is available in the strength of 3,000 USP units of lipase thus infants may be given 3,000 lipase units (one capsule) per 120 mL of formula or per breast-feeding. Do not mix CREON capsule contents directly into formula or breast milk prior to administration [see ADMINISTRATION].
Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack. The total daily dose should reflect approximately three meals plus two or three snacks per day.
Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight.
The initial starting dose and increases in the dose per meal should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet.
In one clinical trial, patients received CREON at a dose of 72,000 lipase units per meal while consuming at least 100 g of fat per day [see Clinical Studies]. Lower starting doses recommended in the literature are consistent with the 500 lipase units/kg of body weight per meal lowest starting dose recommended for adults in the Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3, 4 Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.
Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3 If symptoms and signs of steatorrhea persist, the dosage may be increased by the healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of fibrosing colonopathy, in children less than 12 years of age [see WARNINGS AND PRECAUTIONS]. Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.
The active ingredient in CREON evaluated in clinical trials is lipase. CREON is dosed by lipase units.
Other active ingredients include protease and amylase. Each CREON delayed-release capsule strength contains the specified amounts of lipase, protease, and amylase as follows:
3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase
Each CREON capsule is available as a two piece hypromellose capsule with a white opaque cap with imprint “CREON 1203” and a white opaque body that contains tan colored, delayed-release pancrelipase supplied in bottles of:
70 capsules (NDC 0032-1203-70)
6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint “CREON 1206” and a blue opaque body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
100 capsules (NDC 0032-1206-01)
250 capsules (NDC 0032-1206-07)
12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with a brown opaque cap with imprint “CREON 1212” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
100 capsules (NDC 0032-1212-01)
250 capsules (NDC 0032-1212-07)
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint “CREON 1224” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
100 capsules (NDC 0032-1224-01)
250 capsules (NDC 0032-1224-07)
36,000 USP units of lipase; 114,000 USP units of protease; 180,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with blue opaque cap with imprint “CREON 1236” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
100 capsules (NDC 0032-3016-13)
250 capsules (NDC 0032-3016-28)
CREON must be stored at room temperature up to 25°C (77°F) and protected from moisture. Temperature excursions are permitted between 25°C to 40°C (77°F and 104°F) for up to 30 days. Product should be discarded if exposed to higher temperature and moisture conditions higher than 70%. After opening, keep bottle tightly closed between uses to protect from moisture.
Bottles of CREON 3,000 USP units of lipase must be stored and dispensed in the original container.
Do not crush CREON delayed-release capsules or the capsule contents.
REFERENCES
1 Borowitz DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Journal of Pediatrics. 1995; 127: 681-684.
2 Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. Journal of Pediatric Gastroenterology Nutrition. 2002 Sep; 35: 246-259.
3 Stallings VA, Stark LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. Journal of the American Dietetic Association. 2008; 108: 832-839.
4 Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Current Gastroenterology Reports. 2007; 9: 116-122.
Manufactured by: Abbott Laboratories GmbH, Hannover, Germany. Marketed by: AbbVie Inc., North Chicago, IL 60064, U.S.A. Revised: September, 2012
The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and allergic reactions [see WARNINGS AND PRECAUTIONS].
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The short-term safety of CREON was assessed in clinical trials conducted in 121 patients with exocrine pancreatic insufficiency (EPI): 67 patients with EPI due to cystic fibrosis (CF) and 25 patients with EPI due to chronic pancreatitis or pancreatectomy were treated with CREON.
Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies of 49 patients, ages 7 to 43 years, with EPI due to CF. Study 1 included 32 patients ages 12 to 43 years and Study 2 included 17 patients ages 7 to 11 years. In these studies, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. The mean exposure to CREON during these studies was 5 days.
In Study 1, one patient experienced duodenitis and gastritis of moderate severity 16 days after completing treatment with CREON. Transient neutropenia without clinical sequelae was observed as an abnormal laboratory finding in one patient receiving CREON and a macrolide antibiotic.
In Study 2, adverse reactions that occurred in at least 2 patients (greater than or equal to 12%) treated with CREON were vomiting and headache. Vomiting occurred in 2 patients treated with CREON and did not occur in patients treated with placebo; headache occurred in 2 patients treated with CREON and did not occur in patients treated with placebo.
The most common adverse reactions (greater than or equal to 4%) in Studies 1 and 2 were vomiting, dizziness, and cough. Table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 4%) treated with CREON at a higher rate than with placebo in Studies 1 and 2.
Table 1: Adverse Reactions Occurring in at Least 2
Patients (greater than or equal to 4%) in Cystic Fibrosis (Studies 1 and 2)
| Adverse Reaction | CREON Capsules n = 49(%) |
Placebo n = 47(%) |
| Vomiting | 3 (6) | 1 (2) |
| Dizziness | 2 (4) | 1 (2) |
| Cough | 2 (4) | 0 |
An additional open-label, single-arm study assessed the short-term safety and tolerability of CREON in 18 infants and children, ages 4 months to 6 years, with EPI due to cystic fibrosis. 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). There were no serious adverse reactions. Adverse reactions that occurred in patients during treatment with CREON were vomiting, irritability, and decreased appetite, each occurring in 6% of patients.
A randomized, double-blind, placebo-controlled, parallel group study was conducted in 54 adult patients, ages 32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. Patients received single-blind placebo treatment during a 5-day run-in period followed by an intervening period of up to 16 days of investigatordirected treatment with no restrictions on pancreatic enzyme replacement therapy. Patients were then randomized to receive CREON or matching placebo for 7 days. The CREON dose was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks). The mean exposure to CREON during this study was 6.8 days in the 25 patients that received CREON.
The most common adverse reactions reported during the study were related to glycemic control and were reported more commonly during CREON treatment than during placebo treatment.
Table 2 enumerates adverse reactions that occurred in at least 1 patient (greater than or equal to 4%) treated with CREON at a higher rate than with placebo.
Table 2: Adverse Reactions in at Least 1 Patient
(greater than or equal to 4%) in the Chronic Pancreatitis or Pancreatectomy Trial
| Adverse Reaction | CREON Capsules n = 25(%) |
Placebo n = 29 (%) |
| Hyperglycemia | 2 (8) | 2 (7) |
| Hypoglycemia | 1 (4) | 1 (3) |
| Abdominal Pain | 1 (4) | 1 (3) |
| Abnormal Feces | 1 (4) | 0 |
| Flatulence | 1 (4) | 0 |
| Frequent Bowel Movements | 1 (4) | 0 |
| Nasopharyngitis | 1 (4) | 0 |
Postmarketing data from this formulation of CREON have been available since 2009. The following adverse reactions have been identified during post approval use of this formulation of CREON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders (including abdominal pain, diarrhea, flatulence, constipation and nausea), skin disorders (including pruritus, urticaria and rash), blurred vision, myalgia, muscle spasm, and asymptomatic elevations of liver enzymes have been reported with this formulation of CREON.
Delayed- and immediate-release pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature. The most serious adverse reactions included fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus.
No drug interactions have been identified. No formal interaction studies have been conducted.
Included as part of the PRECAUTIONS section.
Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products.5, 6 Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age.1 Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs.1 It is generally recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day [see DOSAGE AND ADMINISTRATION].
Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.
Care should be taken to ensure that no drug is retained in the mouth. CREON should not be crushed or chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity [see DOSAGE AND ADMINISTRATION and PATIENT INFORMATION]. For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion.
Caution should be exercised when prescribing CREON to patients with gout, renal impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.
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.
Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued CREON treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.
See FDA-approved patient labeling (Medication Guide)
Advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic strictures in children below the age of 12 years [see DOSAGE AND ADMINISTRATION].
Advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to CREON develop [see WARNINGS AND PRECAUTIONS].
Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.
Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CREON should be given to a pregnant woman only if clearly needed. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when CREON is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency.
The short-term safety and effectiveness of CREON were assessed in two randomized, double-blind, placebocontrolled, crossover studies of 49 patients with EPI due to cystic fibrosis, 25 of whom were pediatric patients. Study 1 included 8 adolescents between 12 and 17 years of age. Study 2 included 17 children between 7 and 11 years of age. The safety and efficacy in pediatric patients in these studies were similar to adult patients [see ADVERSE REACTIONS and Clinical Studies].
An open-label, single-arm, short-term study of CREON was conducted in 18 infants and children, ages 4 months to six years of age, with EPI due to cystic fibrosis. 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. When patients were switched from their usual pancreatic enzyme replacement therapy to CREON, they demonstrated similar spot fecal fat testing results; the clinical relevance of spot fecal fat testing has not been demonstrated. Adverse reactions that occurred in patients during treatment with CREON were vomiting, irritability, and decreased appetite [see ADVERSE REACTIONS].
The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience.
Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation Consensus Conferences [see DOSAGE AND ADMINISTRATION]. Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years of age [see WARNINGS AND PRECAUTIONS].
Clinical studies of CREON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
REFERENCES
5 Smyth RL, Ashby D, O'Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet. 1995; 346: 1247-1251.
6 FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. New England Journal of Medicine. 1997; 336: 1283-1289.
There have been no reports of overdose in clinical trials or postmarketing surveillance with this formulation of CREON. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment [see WARNINGS AND PRECAUTIONS].
None.
The pancreatic enzymes in CREON catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.
The pancreatic enzymes in CREON are enteric-coated to minimize destruction or inactivation in gastric acid. CREON is designed to release most of the enzymes in vivo at an approximate pH of 5.5 or greater. Pancreatic enzymes are not absorbed from the gastrointestinal tract in appreciable amounts.
The short-term efficacy of CREON was evaluated in three studies conducted in 103 patients with exocrine pancreatic insufficiency (EPI). Two studies were conducted in 49 patients with EPI due to cystic fibrosis (CF); one study was conducted in 54 patients with EPI due to chronic pancreatitis or pancreatectomy.
Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies in 49 patients, ages 7 to 43 years, with exocrine pancreatic insufficiency due to cystic fibrosis. Study 1 included patients aged 12 to 43 years (n = 32). The final analysis population was limited to 29 patients; 3 patients were excluded due to protocol deviations. Study 2 included patients aged 7 to 11 years (n = 17). The final analysis population was limited to 16 patients; 1 patient withdrew consent prior to stool collection during treatment with CREON. In each study, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. All patients consumed a high-fat diet (greater than or equal to 90 grams of fat per day, 40% of daily calories derived from fat) during the treatment periods.
The coefficient of fat absorption (CFA) was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat ingestion were measured. Each patient's CFA during placebo treatment was used as their no-treatment CFA value.
In Study 1, mean CFA was 89% with CREON treatment compared to 49% with placebo treatment. The mean difference in CFA was 41 percentage points in favor of CREON treatment with 95% CI: (34, 47) and p < 0.001.
In Study 2, mean CFA was 83% with CREON treatment compared to 47% with placebo treatment. The mean difference in CFA was 35 percentage points in favor of CREON treatment with 95% CI: (27, 44) and p < 0.001.
Subgroup analyses of the CFA results in Studies 1 and 2 showed that mean change in CFA with CREON treatment was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher no-treatment (placebo) CFA values. There were no differences in response to CREON by age or gender, with similar responses to CREON observed in male and female patients, and in younger (under 18 years of age) and older patients.
The coefficient of nitrogen absorption (CNA) was determined by a 72-hour stool collection during both treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated (based on the assumption that proteins contain 16% nitrogen). Each patient's CNA during placebo treatment was used as their no-treatment CNA value.
In Study 1, mean CNA was 86% with CREON treatment compared to 49% with placebo treatment. The mean difference in CNA was 37 percentage points in favor of CREON treatment with 95% CI: (31, 42) and p < 0.001.
In Study 2, mean CNA was 80% with CREON treatment compared to 45% with placebo treatment. The mean difference in CNA was 35 percentage points in favor of CREON treatment with 95% CI: (26, 45) and p < 0.001.
A randomized, double-blind, placebo-controlled, parallel group study was conducted in 54 adult patients, ages 32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. The final analysis population was limited to 52 patients; 2 patients were excluded due to protocol violations. Ten patients had a history of pancreatectomy (7 were treated with CREON). In this study, patients received placebo for 5 days (run-in period), followed by pancreatic enzyme replacement therapy as directed by the investigator for 16 days; this was followed by randomization to CREON or matching placebo for 7 days of treatment (double-blind period). Only patients with CFA less than 80% in the run-in period were randomized to the double-blind period. The dose of CREON during the double-blind period was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks). All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the treatment period.
The CFA was determined by a 72-hour stool collection during the run-in and double-blind treatment periods, when both fat excretion and fat ingestion were measured. The mean change in CFA from the run-in period to the end of the double-blind period in the CREON and Placebo groups is shown in Table 3.
Table 3: Change in CFA in the Chronic Pancreatitis and
Pancreatectomy Trial (Run-in Period to End of Double-Blind Period)
| CREON n = 24 |
Placebo n = 28 |
|
| CFA [%] | ||
| Run-in Period (Mean, SD) | 54 (19) | 57 (21) |
| End of Double-Blind Period (Mean, SD) | 86 (6) | 66 (20) |
| Change in CFA * [%] | ||
| Run-in Period to End of Double-Blind Period (Mean, SD) | 32 (18) | 9 (13) |
| Treatment Difference (95% CI) | 21 (14, 28) | |
*p
PATIENT INFORMATIONMEDICATION GUIDE CREON® Read this Medication Guide before you start taking CREON and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or treatment. What is the most important information I should know about CREON? CREON may increase your chance of having a rare bowel disorder called fibrosing colonopathy. This condition is serious and may require surgery. The risk of having this condition may be reduced by following the dosing instructions that your doctor gave you. Call your doctor right away if you have any unusual or severe:
Take CREON exactly as prescribed. Do not take more or less CREON than directed by your doctor. What is CREON? CREON is a prescription medicine used to treat people who cannot digest food normally because their pancreas does not make enough enzymes due to cystic fibrosis, swelling of the pancreas that lasts a long time (chronic pancreatitis), removal of some or all of the pancreas (pancreatectomy), or other conditions. CREON may help your body use fats, proteins, and sugars from food. CREON contains a mixture of digestive enzymes including lipases, proteases, and amylases from pig pancreas. What should I tell my doctor before taking CREON? Before taking CREON, tell your doctor about all your medical conditions, including if you:
Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. How should I take CREON?
Giving CREON to infants (children up to 12 months) Giving CREON to children and adults What are the possible side effects of CREON? CREON may cause serious side effects, including:
Call your doctor right away if you have any of these symptoms. The most common side effects of CREON include:
Other Possible Side Effects: CREON and other pancreatic enzyme products are made from the pancreas of pigs, the same pigs people eat as pork. These pigs may carry viruses. Although it has never been reported, it may be possible for a person to get a viral infection from taking pancreatic enzyme products that come from pigs. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the side effects of CREON. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA- 1088. You may also report side effects to AbbVie Inc. at 1-800-633-9110. How should I store CREON?
Keep CREON and all medicines out of the reach of children. General information about CREON Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CREON for a condition for which it was not prescribed. Do not give CREON to other people to take, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about CREON. If you would like more information, talk to your doctor. You can ask your doctor or pharmacist for information about CREON that is written for healthcare professionals. For more information, go to www.creon-us.com or call toll-free [1-800-633-9110]. What are the ingredients in CREON? Active Ingredient: lipase, protease, amylase Inactive Ingredients: cetyl alcohol, dimethicone, hypromellose phthalate, polyethylene glycol, and triethyl citrate. The shells of the CREON 6,000 USP units of lipase, 12,000 USP units of lipase, and 24,000 USP units of lipase strengths contain: gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide. In addition: The shells for the CREON 3,000 USP units of lipase strength capsules contain titanium dioxide and hypromellose. The shells of the CREON 6,000 USP units of lipase strength capsules contain FD&C Blue No. 2. The shells of the CREON 12,000 USP units of lipase strength capsules contain black iron oxide. The shells of the CREON 36,000 USP units of lipase strength capsules contain gelatin, titanium dioxide, sodium lauryl sulfate and FD&C Blue No. 2. This Medication Guide has been approved by the U.S. Food and Drug Administration. From
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