Creon (Page 3 of 5)

6.2 Postmarketing Experience

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.

7 DRUG INTERACTIONS

No drug interactions have been identified. No formal interaction studies have been conducted.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic effects

Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CREON should be given to a pregnant woman only if clearly needed. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when CREON is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency.

8.4 Pediatric Use

The short-term safety and effectiveness of CREON were assessed in two randomized, double-blind, placebo-controlled, crossover studies of 49 patients with EPI due to cystic fibrosis, 25 of whom were pediatric patients. Study 1 included 8 adolescents between 12 and 17 years of age. Study 2 included 17 children between 7 and 11 years of age. The safety and efficacy in pediatric patients in these studies were similar to adult patients [see Adverse Reactions (6.1) and Clinical Studies (14)].

An open-label, single-arm, short-term study of CREON was conducted in 18 infants and children, ages 4 months to six years of age, 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). The mean daily fat intake was 48 grams during treatment with usual pancreatic enzyme replacement therapy and 47 grams during treatment with CREON. When patients were switched from their usual pancreatic enzyme replacement therapy to CREON, they demonstrated similar spot fecal fat testing results; the clinical relevance of spot fecal fat testing has not been demonstrated. Adverse reactions that occurred in patients during treatment with CREON were vomiting, irritability, and decreased appetite [see Adverse Reactions (6.1)].

The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience.

Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation Consensus Conferences [see Dosage and Administration (2.1)]. Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years of age [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Clinical studies of CREON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

10 OVERDOSAGE

There have been no reports of overdose in clinical trials or postmarketing surveillance with this formulation of CREON. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment [see Warnings and Precautions (5.3)].

11 DESCRIPTION

CREON is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and amylases.

Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble or insoluble in alcohol and ether.

Each delayed-release capsule for oral administration contains enteric-coated spheres (0.71–1.60 mm in diameter).

The active ingredient evaluated in clinical trials is lipase. CREON is dosed by lipase units.

Other active ingredients include protease and amylase.

CREON contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate, polyethylene glycol, and triethyl citrate.

3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase delayed-release capsules have a white opaque cap with imprint “CREON 1203” and a white opaque body. The shells contain titanium dioxide and hypromellose.

6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase delayed-release capsules have a Swedish-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.

12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase delayed-release capsules have a brown 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.

24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase delayed-release capsules have a Swedish-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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The pancreatic enzymes in CREON catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.

12.3 Pharmacokinetics

The pancreatic enzymes in CREON are enteric-coated to minimize destruction or inactivation in gastric acid. CREON is designed to release most of the enzymes in vivo at an approximate pH of 5.5 or greater. Pancreatic enzymes are not absorbed from the gastrointestinal tract in appreciable amounts.

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