Creon (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.

14 CLINICAL STUDIES

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.

14.1 Cystic Fibrosis

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.

14.2 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. 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)

*p<0.0001

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)

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.

15 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.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

CREON (pancrelipase) Delayed-Release Capsules

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)

CREON (pancrelipase) Delayed-Release Capsules

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)

CREON (pancrelipase) Delayed-Release Capsules

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)

CREON (pancrelipase) Delayed-Release Capsules

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)

Storage and Handling

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.

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