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].
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 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(%)
n = 47(%)
|Vomiting||3 (6)||1 (2)|
|Dizziness||2 (4)||1 (2)|
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.
Chronic Pancreatitis or Pancreatectomy
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(%)
n = 29 (%)
|Hyperglycemia||2 (8)||2 (7)|
|Hypoglycemia||1 (4)||1 (3)|
|Abdominal Pain||1 (4)||1 (3)|
|Abnormal Feces||1 (4)||0|
|Frequent Bowel Movements||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.