Creon (pancrelipase lipase 36000 [usp'u] pancrelipase amylase 180000 [usp'u] pancrelipase protease 114000 [usp'u]) Dailymed

3 Dosage Forms And Strengths

Delayed-release capsules are available in the following strengths:

• 3,000 USP units of lipase; 9,500 USP units of protease; and 15,000 USP units of amylase in a two-piece capsule with a white opaque cap imprinted with “CREON 1203” and a white opaque body.
• 6,000 USP units of lipase; 19,000 USP units of protease; and 30,000 USP units of amylase in a two-piece capsule with an orange opaque cap imprinted with “CREON 1206” and a blue opaque body.
• 12,000 USP units of lipase; 38,000 USP units of protease; and 60,000 USP units of amylase in a two-piece capsule with a brown opaque cap imprinted with “CREON 1212” and a colorless transparent body.
• 24,000 USP units of lipase; 76,000 USP units of protease; and 120,000 USP units of amylase in a two-piece capsule with an orange opaque cap imprinted with “CREON 1224” and a colorless transparent body.
• 36,000 USP units of lipase; 114,000 USP units of protease; and 180,000 USP units of amylase in a two-piece capsule with a blue opaque cap imprinted with “CREON 1236” and a colorless transparent body.

Delayed-Release Capsules (3):

• 3,000 USP units of lipase; 9,500 USP units of protease; and 15,000 USP units of amylase
• 6,000 USP units of lipase; 19,000 USP units of protease; and 30,000 USP units of amylase
• 12,000 USP units of lipase; 38,000 USP units of protease; and 60,000 USP units of amylase
• 24,000 USP units of lipase; 76,000 USP units of protease; and 120,000 USP units of amylase
• 36,000 USP units of lipase; 114,000 USP units of protease; and 180,000 USP units of amylase

4 Contraindications

None.


None (4)

5 Warnings And Precautions

• Fibrosing C olonopathy: Associated with high doses, usually over prolonged use and in pediatric patients with cystic fibrosis. Colonic stricture reported in pediatric patients less than 12 years of age with dosages exceeding 6,000 lipase units/kg/meal. Monitor during treatment for progression of preexisting disease. Do not exceed the recommended dosage, unless clinically indicated. (2.1, 5.1)
• I rritation of the O ral M ucosa: May occur due to loss of protective enteric coating on the capsule contents. (2.3, 5.2)
• Hyperuricemia: Reported with high dosages; consider monitoring blood uric acid levels in patients with gout, renal impairment, or hyperuricemia. (5.3)
• Risk of Viral Transmission: The presence of porcine viruses that might infect humans cannot be definitely excluded. (5.4)
• Hypersensitivity Reactions: Monitor patients with known reactions to proteins of porcine origin. If symptoms occur, initiate appropriate medical management; consider the risks and benefits of continued treatment. (5.5)

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

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

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

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.

6 Adverse Reactions

The following serious or otherwise important adverse reactions are described elsewhere in the labeling:

• Fibrosing Colonopathy [see Warnings and Precautions ( 5.1 )]
• Irritation of the Oral Mucosa [see Warnings and Precautions ( 5.2 )]
• Hyperuricemia [see Warnings and Precautions ( 5.3 )]
• Risk of Viral Transmission [see Warnings and Precautions ( 5.4 )]
• Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )]

Most Common Adverse R eactions (6.1)

C ystic fibrosis adult and pediatric patients : 

• 7 years and older (≥4%): vomiting, dizziness, cough.
• 4 months to 6 years (6%): vomiting, irritability, decreased appetite.

C hronic pancreatitis or pancreatectomy patient s: 

• Adults (≥ 4%): hyperglycemia, hypoglycemia, abdominal pain, abnormal feces, flatulence, frequent bowel movements, nasopharyngitis.

To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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 data described below reflect exposure to CREON in 92 patients: 67 patients aged 4 months to 43 years with exocrine pancreatic insufficiency due to cystic fibrosis (Studies 1, 2, and 3) and 25 adults with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy (Study 4) [see Use in Specific Populations ( 8.4 ) and Clinical Studies ( 14.1 , 14.2 )].

Exocrine Pancreatic Insufficiency Due to Cystic Fibrosis in Adult and Pediatric Patients

Adult and Pediatric Patients 7 Years of Age and Older

The most common adverse reactions, reported in at least 2 CREON-treated patients (greater than or equal to 4%) and at a higher rate than in placebo-treated patients in Studies 1 and 2, are shown in Table 1.

Table 1: Adverse Reactions* in Clinical Trials of Adult and Pediatric Patients 7 Years of Age and Older with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis (Studies 1 and 2)

Adverse Reaction	CREON N = 49 n (%)	Placebo N = 47 n (%)
Vomiting	3 (6%)	1 (2%)
Dizziness	2 (4%)	1 (2%)
Cough	2 (4%)	0 (0%)

* Reported in at least 2 CREON-treated patients (greater than or equal to 4%) and at a higher rate than placebo-treated patients.

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.

Pediatric Patients 4 Months to 6 Years of Age

Adverse reactions reported in 18 CREON-treated pediatric patients aged 4 months to 6 years in Study 3 were vomiting, irritability, and decreased appetite, each occurring in 6% of patients [see Use in Specific Populations ( 8.4 )].

Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy in Adults

Adverse reactions reported in at least 1 adult CREON-treated patient (greater than or equal to 4%) and at a higher rate than in placebo-treated patients in Study 4 is shown in Table 2.

Table 2: Adverse Reactions* in a Clinical Trial of Adult Patients with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy (Study 4) 

Adverse Reaction	CREON N = 25 n (%)	Placebo N = 29 n (%)
Hyperglycemia	2 (8%)	2 (7%)
Hypoglycemia	1 (4%)	1 (3%)
Abdominal Pain	1 (4%)	1 (3%)
Abnormal Feces	1 (4%)	0 (0%)
Flatulence	1 (4%)	0 (0%)
Frequent Bowel Movements	1 (4%)	0 (0%)
Nasopharyngitis	1 (4%)	0 (0%)

 * Reported in at least 1 CREON-treated patient (greater than or equal to 4%) and at a higher rate than placebo-treated patients.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of CREON or other pancreatic enzyme products. 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.

Eye Disorders

• blurred vision

Gastrointestinal D isorders

• fibrosing colonopathy and distal intestinal obstruction syndrome
• abdominal pain, diarrhea, flatulence, constipation, and nausea

Immune System Disorders

• anaphylaxis, asthma, hives, and pruritus 

Investigations

• asymptomatic elevations of liver enzymes

Musculoskeletal System

• myalgia, muscle spasm

Skin and Subcutaneous Tissue Disorders

• urticaria and rash

14.1

Adult and Pediatric Patients

Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies in 49 patients, aged 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/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.

C oefficient of F at A bsorption Endpoint and Results

The primary efficacy endpoint was the coefficient of fat absorption (CFA) in CREON and placebo treatment groups. 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 biological sex, with similar responses to CREON observed in male and female patients, and in younger (under 18 years of age) and older patients.

Coefficient of Nitrogen Absorption Endpoint and Results

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.

14.2

A randomized, double-blind, placebo-controlled, parallel group study was conducted in 54 adult patients, aged 32 to 75 years, with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy (Study 4). 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. All patients were to consume a high-fat diet (greater than or equal to 100 grams of fat/day) during the treatment period. The dosage 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) [approximately 1,000 lipase units/kg/meal]. The mean exposure to CREON during this study was 7 days in the 25 patients that received CREON. 

C oefficient of F at A bsorption Endpoint and Results

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 Coefficient of Fat Absorption in Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis and Pancreatectomy (Study 4) 

	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<0.0001

Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower run-in period CFA values than in patients with higher run-in period CFA values. Only 1 of the patients with a history of total pancreatectomy was treated with CREON in the study. That patient had a CFA of 26% during the run-in period and a CFA of 73% at the end of the double-blind period. The remaining 6 patients with a history of partial pancreatectomy treated with CREON on the study had a mean CFA of 42% during the run-in period and a mean CFA of 84% at the end of the double-blind period.