DESCRIPTION SECTION

11 DESCRIPTION

Pancrelipase is a pancreatic enzyme product consisting of a mixture of enzymes including lipases, proteases, and amylases and is an extract derived from porcine pancreatic glands. The enteric-coated spheres in CREON are formulated to release pancreatic enzymes at an approximate pH of 5.5 or greater.

CREON (pancrelipase) delayed-release capsules are for oral administration, include a two-piece shell containing tan-colored enteric-coated spheres (0.71 mm to 1.60 mm in diameter), and are available as follows:

3,000 USP units of lipase; 9,500 USP units of protease; and 15,000 USP units of amylase; delayed-release capsules with shells that contain hypromellose and titanium dioxide, and that also may contain carrageenan and potassium chloride.

6,000 USP units of lipase; 19,000 USP units of protease; and 30,000 USP units of amylase; delayed-release capsules with shells that may contain gelatin, hypromellose, carrageenan, potassium chloride, sodium lauryl sulfate, titanium dioxide, FD&C Blue No. 1, and FD&C Blue No. 2, red iron oxide, and yellow iron oxide.

12,000 USP units of lipase; 38,000 USP units of protease; and 60,000 USP units of amylase; delayed-release capsules with shells that may contain gelatin, hypromellose, carrageenan, potassium chloride, sodium lauryl sulfate, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide.

24,000 USP units of lipase; 76,000 USP units of protease; and 120,000 USP units of amylase; delayed-release capsules with shells that may contain gelatin, hypromellose, carrageenan, potassium chloride, sodium lauryl sulfate, titanium dioxide, red iron oxide, and yellow iron oxide.

36,000 USP units of lipase; 114,000 USP units of protease; and 180,000 USP units of amylase; delayed-release capsules with shells that may contain gelatin, hypromellose, carrageenan, potassium chloride, sodium lauryl sulfate, titanium dioxide, FD&C Blue No. 1, and FD&C Blue No. 2.

CREON (pancrelipase) delayed-release capsules include the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate, polyethylene glycol, and triethyl citrate.

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INDICATIONS & USAGE SECTION

Highlight: CREON is indicated for the treatment of exocrine pancreatic insufficiency in adult and pediatric patients. (1)

1 INDICATIONS****AND USAGE

CREON® is indicated for the treatment of exocrine pancreatic insufficiency in adult and pediatric patients.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: 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

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.

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CONTRAINDICATIONS SECTION

Highlight: None (4)

4 CONTRAINDICATIONS

None.

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USE IN SPECIFIC POPULATIONS SECTION

8 USE IN SPECIFIC POPULATIONS

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.

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ADVERSE REACTIONS SECTION

Highlight: Most Common Adverse Reactions (6.1)

Cystic fibrosis adult and pediatric patients:

• 7 years and older (≥4%): vomiting, dizziness, cough.

• 4 months to 6 years (6%): vomiting, irritability, decreased appetite.

Chronic pancreatitis or pancreatectomy patients:

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

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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 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)]

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)

• 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)

• 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 Disorders

• 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

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1Exocrine Pancreatic Insufficiency Due toCystic Fibrosis

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.

Coefficient of Fat Absorption 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.

**14.2Exocrine Pancreatic Insufficiency Due toChronic

Pancreatitis or Pancreatectomy**

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.

Coefficient of Fat Absorption 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)

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.

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OVERDOSAGE SECTION

10 OVERDOSAGE

Chronic high dosages of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see Warnings and Precautions (5.1)]. High dosages of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia [see Warnings and Precautions (5.3)].

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INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide).

Fibrosing Colonopathy

Advise the patient or caregiver that fibrosing colonopathy has been reported with high dosages of pancreatic enzyme products, usually with use over a prolonged period of time and in pediatric patients with cystic fibrosis. Colonic stricture has been reported in pediatric patients less than 12 years of age. Advise patients and caregivers that if signs and symptoms of colon stricture formation occur (e.g., stomach area (abdominal) pain, bloating, trouble passing stool (constipation), nausea, vomiting, diarrhea) to immediately contact their healthcare provider [see Warnings and Precautions (5.1)].

Hyperuricemia

Advise the patient or caregiver that hyperuricemia may occur in patients with gout or renal impairment and to contact the healthcare provider if they experience pain, stiffness, redness or swelling of their joints [see Warnings and Precautions (5.3)].

Hypersensitivity Reactions

Inform the patient or caregiver that severe hypersensitivity reactions, including anaphylaxis, asthma, hives, and pruritus, have been reported with use of pancreatic enzyme products. Seek medical attention if signs or symptoms of a hypersensitivity reaction develop [see Warnings and Precautions (5.5)].

Dosage

Advise the patient or caregiver to take or administer CREON as prescribed, and to contact the healthcare provider if signs and symptoms of malabsorption persist [see Dosage and Administration (2.2)].

Administration

Instruct the patient or caregiver as follows:

• Take CREON during meals and snacks.

• Swallow capsules whole.

• For adult and pediatric patients unable to swallow intact capsules, the capsule contents may be sprinkled on a small amount of soft acidic food with a pH of 4.5 or less (e.g., applesauce, bananas, plain Greek yogurt). For pediatric patients birth to 12 months of age, CREON capsules can also be opened, and the capsule contents sprinkled directly into the infant’s mouth.

• Consume sufficient liquids (juice, water, breast milk, or formula) and visually inspect an infant’s mouth to ensure complete swallowing of CREON capsules or capsule contents [see Warnings and Precautions (5.2)].

• Do not crush or chew CREON capsules or capsule contents.

• Do not mix the CREON capsule contents directly into a bottle of breast milk or formula.

Storage

Instruct the patient or caregiver as follows:

• Keep CREON in a dry place and protect from heat.

• After opening, keep the bottle tightly closed between uses to protect from moisture.

• Keep CREON in the original container.

• If there is a desiccant packet in the bottle, keep it in the bottle. Do not eat or throw away the desiccant.

© 2009-2024 AbbVie. All rights reserved.

CREON® is a registered trademark of AbbVie Products LLC.

Manufactured by:

AbbVie Inc.

North Chicago, IL 60064, U.S.A.

US License Number 1889

20082735 February, 2024

SPL MEDGUIDE SECTION

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 2/2024

20082735

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

CREON (pancrelipase) delayed-release capsules, containing tan-colored enteric- coated pancrelipase spheres, are supplied as follows:

Storage and Handling

• Store CREON at room temperature, 15°C to 25°C (59°F to 77°F), and protect from moisture. Temperature excursions are permitted between 25°C to 40°C (77°F to 104°F) for up to 30 days. Discard CREON if exposed to higher temperature and moisture conditions higher than 70%.

• After opening, keep bottle tightly closed between uses to protect from moisture. Keep the desiccant in the bottle if present.

• Store and dispense CREON in the original container.

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