Status: NDA approved in 2009; long on the market before recent formal approval

Organizations Involved:

Abbvie – Manuf.; R&D; Tech.; World mark.

Abbott Labs. – Former

Solvay Pharmaceuticals, Inc. – Former

Solvay Pharmaceuticals S.A. – Former; Parent

Cross ref: See the entry for Pancreatic Enzyme Products.

Description: Creon is a lyophilized (freeze-dried) formulation of pancrelipase, an extract derived from porcine pancreatic glands, packaged within digestion-resistant microspheres (0.71–1.60 mm in diameter; enteric coating) for enteric delivery. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and amylases. The primary active ingredient and the one evaluated in clinical trials is lipase. Creon is dosed by lipase units.

Creon has long been available as capsules containing:

a) 5,000 USP Units of lipase, protease 18,750 USP Units and amylase 16,600 USP Units (Creon 5). Each Creon 5 Capsule is filled with 124 mg of delayed-release Minimicrospheres. Inactive ingredients include dibutyl phthalate, dimethicone, hydroxypropylmethyl cellulose phthalate, light mineral oil and polyethylene glycol. The capsule shells contain gelatin, red iron oxide, titanium dioxide, yellow iron oxide and FD&C blue No.2. The capsule imprinting ink contains dimethicone, 2-ethoxyethanol, shellac, soya lecithin,and titanium dioxide.

b) 10,000 USP Units of lipase, protease 37,500 USP Units, and amylase 33,200 USP Units per capsule (Creon 10). Each Creon 10 Capsule is filled with 249 mg of delayed-release Minimicrospheres. Inactive agent are the same as Creon 5. The capsule contains the same ingredients as that of Creon 5, except black iron oxide (rather than red) and no blue dye.

c) 20,000 USP Units lipase, protease 75,000 USP Units, andamylase 66,400 USP Units per capsule (Creon 20). Each Creon 10 Capsule is filled with 497 mg of delayed-release Minimicrospheres. Inactive ingredients and the shells contain the same ingredients as Creon 5.

The newer formulations being phased-in provide capsules containing:

a) 6,000 USP units of lipase, 19,000 USP units of protease and 30,000 USP units of amylase, with capsules having an 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.

b) 12,000 USP units of lipase, 38,000 USP units of protease and 60,000 USP units of amylase, with capsules having an orange 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.

c) 24,000 USP units of lipase, 76,000 USP units of protease and 120,000 USP units of amylase, with capsules having an 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

The newer Creon capsultes also contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate, polyethylene glycol, and triethyl citrate. The enteric digestion-resistant shells contain FD&C Blue No. 2, gelatin (porcine-derived), red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide. The imprinting ink on the capsule contains dimethicone, 2-ethoxyethanol, shellac, soya lecithin, and titanium dioxide. The updated formulation no longer contains dibutyl phthalate in the enteric coating, or mineral oil, which should not affect efficacy.

Also, 3,000 units pediatric doses are available.

Creon is 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.

The newly approved capsules are longer be overfilled and contain the exact amount of lipase indicated on the label.

Nomenclature: Pancrelipase/ Abbott [BIO]; (pancrelipase) Capsules, Delayed Release for Oral Use [FDA]; Creon [TR]; Creon Delayed-release Capsules [TR]; Creon Minimicrospheres [TR]; Lipacreon [TR Japan]; pancrelipase [USAN]; (NDC 0032-1206-01; NDC 0032-1206-07; NDC 0032-1212-01; NDC 0032-1212-07; NDC 0032-1224-01; NDC 0032-1224-07 [NDC]

Biological.: Creon Minimicrospheres combine the features of fast, homogeneous distribution in the stomach with complete protection against inactivation by gastric juices. Creon is designed to enable a simultaneous passage through the stomach and further into the duodenum together with the food, and a rapid release of the digestive pancreatic enzymes in the duodenum.

Creon enzymes are enteric-coated to resist destruction or inactivation in gastric acid, and to release most of the enzymes in vivo in the duodenum at a pH greater than 5.5. In the duodenum and proximal small intestine, the Creon enzymes catalyze the hydrolysis of fats to monoglycerol, glycerol and fatty acids, protein into peptides and amino acids, and starch into dextrins and short chain sugars, thereby acting as a replacement for digestive enzymes physiologically secreted by the pancreas. Pancreatic enzymes are not absorbed from the gastrointestinal tract in any appreciable amount, and are not systemically active.

Pancrelipase/ Solvay [BIO] (pancrelipase) Capsules, Delayed Release for Oral Use [FDA] Creon [TR] Creon Delayed-release Capsules [TR] Creon Minimicrospheres [TR] Lipacreon [TR Japan] pancrelipase [USAN] (NDC 0032-1206-01; NDC 0032-1206-07; NDC 0032-1212-01; NDC 0032-1212-07; NDC 0032-1224-01; NDC 0032-1224-07 [NDC] Companies.: Upon approval, Creon was manufactured by Solvay Pharmaceuticals GmbH, marketed in the U.S. by Solvay Pharmaceuticals, Inc., with both companies subsidiaries of Solvay S.A The pharmaceutical business of Solvay was acquired by Abbott Labs. in Sept. 2009. On Jan. 1, 2013, Abbott Labs. spun off its innovative pharmaceuticals business to Abbvie.

FDA class: Drug NDA

Approvals: Date = 20090501; NDA

Date = 20109503; NDA supplement; Indication = added dosing guidance in the prescribing information specific to patients with limited production of enzymes in the pancreas (exocrine pancreatic insufficiency) due to chronic pancreatitis (CP) or removal of the pancreas (pancreatectomy). Prior to this FDA approval, dosing guidance for medications such as CREON was based on patients with cystic fibrosis. With this FDA approval, CREON became the first medication in its class to have this guidance and information in its prescribing information for use in treating EPI due to CP and pancreatectomy.

Date = 20110614; NDA supplement; Indication = infant-specific dose of CREON Delayed-Release Capsules to treat exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF)

Indications: [Full text of the "INDICATIONS AND USAGE” of the product labeling/insert]:

CREON (pancrelipase) Delayed-Release Capsules is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions.

Status: Creon pancrelipase is the first drug in the pancreatic enzyme class to meet the FDA’s 2004 requirement that these agents go through the New Drug Application process in order to remain on the market. Approval for Creon was based on demonstration of efficacy in a randomized, double-blind, placebo-controlled cross-over study. At least five companies market pancrelipase under different names, and Creon was the first to complete the FDA process. As the first FDA-approved pancreatic enzyme replacement therapy (PERT), CREON was also the first product in the class to provide a Medication Guide with dosing information, including instructions for administration to infants and toddlers (consistent with the CF Foundation Consensus Conference Guidelines).

Backgournd: PEPs have a long and interesting regulatory history.  PEPs have been available in the U.S. since before the enactment of the 1938 FDC Act.  In 1995, FDA concluded as part of its Over-the-Counter (OTC) Drug Review for PEPs that OTC PEPs are not generally recognized as safe and effective.  In Dec. 1996, FDA approved one PEP – Organon Inc.’s COTAZYM (pancrelipase [amylase; lipase; protease]) Capsules (NDA No. 20-580) – for the treatment of EPI.  That drug product has since been discontinued from marketing, and approval was apparently not granted any period of market exclusivity. In April 2004, FDA announced in a Federal Register notice that all PEPs are new drugs and described the conditions for continued marketing of these drug products.  In particular, FDA announced that manufacturers who wish to continue to market PEP drug products must submit NDAs.  In April 2008, FDA published a guidance document to assist manufacturers in preparing and submitting NDAs and stating that the Agency would exercise enforcement discretion for firms who submitted INDs by April 28, 2008 and NDAs by April 28, 2009.  CREON is the first PEP approved under the process described in FDA’s guidance document.

Creon is registered in more than 80 countries and is used by thousands of patients worldwide.

Trials: The efficacy of FDA-approved Creon was demonstrated in a randomized, double-blind, placebo-controlled crossover study which enrolled 32 patients with cystic fibrosis. The primary efficacy endpoint was the coefficient of fat absorption (CFA), which measures the percentage of fat absorption relative to dietary fat intake. Creon produced significantly greater mean CFA values compared to placebo in this study. The mean CFA during treatment was 89% versus 49% during treatment with placebo, representing a mean difference in CFA of 41%. Creon showed statistically-significant increases in CFA for both adults (age >18 years) and adolescents (age 12-18 years). There was no relevant difference in the magnitude of response between the age groups. The incidence of adverse events (regardless of causality) was higher during placebo treatment (71%) than during Creon treatment (50%). Treatment-emergent adverse events occurring in at least two patients (greater than or equal to 6%) receiving Creon or placebo were abdominal pain, abdominal pain upper, abnormal feces, cough, dizziness, flatulence, headache and weight decreased. The study also showed significantly better fat absorption across age groups, with similar benefits for adults and adolescents age 12 to 18.

Overall, the drug was well tolerated compared with placebo. Treatment-emergent adverse events occurring in at least 6% of patients, including abdominal pain, abdominal pain upper, abnormal feces, cough, dizziness, flatulence, headache, and weight loss.

In the Oct. 9, 2009 issue of the Journal of Cystic Fibrosis, Solvay reported results from the pivotal Phase III study of Creon showing that it significantly improved a key measure of fat absorption in patients with cystic fibrosis, (CF) with exocrine pancreatic insufficiency (EPI). EPI is a condition resulting from a deficiency in the production and/or secretion of pancreatic enzymes that are necessary to digest nutrients in food and, if untreated, can lead to poor growth, poor weight gain and failure to thrive in children with CF. Patients with CF and confirmed EPI had an improved coefficient of fat absorption (CFA) during treatment with Creon compared to treatment with placebo. CFA is calculated based on measures of fat ingestion and fat excretion; and assessing the CFA of a patient is a way to measure the absorption of fat as a percentage of fat intake in patients being tested for EPI. The trial reached statistical significance on its primary endpoint, CFA.

In Aug. 2011, Dermagraft failed its pivotal Phase III clinical trial for treating venous leg ulcers (VLU), an indictaion that UBS had projected would add about $160 million/year in sales. Following preliminary analysis of the top-line results, the decision has been made not to pursue the venous leg ulcer indication. The international pivotal trial, which enrolled more than 500 patients in eight countries, was designed as a prospective, multicenter, randomized, controlled clinical study to assess the product’s safety and efficacy in the promotion of healing venous leg ulcers.

Medical: Creon is orally administered. Therapy should be initiated at the lowest recommended dose and gradually

increased. The dosage should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet. Dosage recommendations for pancreatic enzyme replacement therapy have been published by through Cystic Fibrosis Foundation Consensus Conferences. Patients may be dosed on a fat ingestion-based or an actual body weight-based dosing scheme.

Market: Creon is the most popular (largest market share) pancreatic enzyme replacement therapy (PERT) in the U.S. In June 2011, Abbott reported "CREON is the pancreatic enzyme chosen to treat three out of four CF patients in the United States."

The 2009 Average Wholesale Price (AWP) for Creon 20 is $271.99/100 and $660.57/250, and AWP for Creon 5 is $79.39/100 and $194.46.57/250 (2009 Red Book).

The FDA-approved formulation of Creon is targeted to be launched in the U.S. in the third quarter of 2009. The currently-marketed formulation of will continue to be commercially available until the launch of the FDA-approved product.