Creon 10000/Creon 40000

Pancreatin.

1 capsule Creon 10000 contains 150 mg Pancreatin (Pancreas Powder) corresponding to Amylase 8000 Ph.Eur. units, Lipase 10000 Ph.Eur. units, Protease 600 Ph.Eur. units produced from porcine pancreatic tissue.
1 capsule Creon 40000 contains 400 mg Pancreatin (Pancreas Powder) corresponding to Amylase 25000 Ph.Eur. units, Lipase 40000 Ph.Eur. units, Protease 1600 Ph.Eur. units produced from porcine pancreatic tissue.
Excipients/Inactive Ingredients: Core pellet: macrogol 4000.
Coating: hypromellose phthalate, dimethicone 1000, triethyl citrate, cetyl alcohol.
Capsule: iron oxide (E 172), titanium dioxide (E 171), sodium lauryl sulphate, gelatin.

Pharmacotherapeutic Group: Multienzymes (amylase, lipase, protease). ATC code: A09A A02.
Pharmacology: Pharmacodynamics: Creon contains porcine pancreatin formulated as enteric-coated (acid-resistant) minimicrospheres within gelatin capsules.
The capsules dissolve rapidly in the stomach releasing plenty of minimicrospheres, a multidose principle which is designed to achieve good mixing with the chyme, emptying from the stomach together with the chyme and after release, good distribution of enzymes within the chyme.
When the minimicrospheres reach the small intestine the coating rapidly disintegrates (at pH > 5.5) to release enzymes with lipolytic, amylolytic and proteolytic activity to ensure the digestion of fats, starches and proteins. The products of pancreatic digestion are then either absorbed directly, or following further hydrolysis by intestinal enzymes.
Clinical efficacy: Overall 30 studies investigating the efficacy of Creon (Creon capsules with 10000 or 40000 Ph. Eur units of lipase) in patients with pancreatic exocrine insufficiency have been conducted. Ten of these were placebo controlled studies performed in patients with cystic fibrosis, chronic pancreatitis or post surgical conditions.
In all randomized, placebo-controlled, efficacy studies, the pre-defined primary objective was to show superiority of Creon over placebo on the primary efficacy parameter, the coefficient of fat absorption (CFA).
The coefficient of fat absorption determines the percentage of fat that is absorbed into the body taking into account fat intake and fecal fat excretion. In the placebo-controlled Pancreatic Exocrine Insufficiency (PEI) studies, the mean CFA (%) was higher with Creon treatment (83.0%) as compared to placebo (62.6%). In all studies, irrespective of the design, the mean CFA (%) at the end of the treatment period with Creon was similar to the mean CFA values for Creon in the placebo controlled studies.
In all performed studies, irrespective of etiology, an improvement was also shown in disease specific symptomatology (stool frequency, stool consistency, flatulence).
Paediatric population: In cystic fibrosis (CF) the efficacy of Creon was demonstrated in 288 paediatric patients covering an age range from newborns to adolescents. In all studies, the mean end-of treatment CFA values exceeded 80% on Creon comparably in all paediatric age groups.
Pharmacokinetics: Animal studies showed no evidence for absorption of intact enzymes and therefore classical pharmacokinetic studies have not been performed. Pancreatic enzyme supplements do not require absorption to exert their effects. On the contrary, their full therapeutic activity is exerted from within the lumen of the gastrointestinal tract. Furthermore, they are proteins, and as such undergo proteolytic digestion while passing along the gastrointestinal tract before being absorbed as peptides and amino acids.
Toxicology: Preclinical Safety data: Preclinical data show no relevant acute, subchronic or chronic toxicity. Studies on genotoxicity, carcinogenicity or toxicity to reproduction have not been performed.

Treatment of pancreatic exocrine insufficiency (PEI) in paediatric and adult patients often associated with, but not limited to: cystic fibrosis, chronic pancreatitis, pancreatic surgery gastrectomy, pancreatic cancer, gastrointestinal bypass surgery (e.g. Billroth II gastroenterostomy), ductal obstruction of the pancreas or common bile duct (e.g. from neoplasm), Shwachman-Diamond Syndrome, status after an attack of acute pancreatitis and initiation of enteral or oral feeding.

The posology aims at individual needs and depends on the severity of the disease and the composition of food.
It is recommended to take the enzymes during or immediately after the meals.
The capsules should be swallowed intact, without crushing or chewing, with enough fluid during or after each meal or snack.
When swallowing of capsules is difficult (e.g. small children or elderly patients), the capsules may be carefully opened and the minimicrospheres added to acidic soft food [pH < 5.5] that does not require chewing, or the minimicrospheres will be taken with acidic liquid [pH < 5.5]. This could be apple sauce or yogurt or fruit juice with a pH less than 5.5, e.g. apple, orange or pineapple juice. This mixture should not be stored. Crushing and chewing of the minimicrospheres or mixing with food or fluid with a pH greater than 5.5 can disrupt the protective enteric coating. This can result in early release of enzymes in the oral cavity and may lead to reduced efficacy and irritation of the mucous membranes. Care should be taken that no product is retained in the mouth.
It is important to ensure adequate hydration at all times, especially during periods of increased loss of fluids. Inadequate hydration may aggravate constipation. Any mixture of the minimicrospheres with food or liquids should be used immediately and should not be stored.
Dosing In Paediatric and Adult Patients With Cystic Fibrosis: Based upon a recommendation of the Cystic Fibrosis (CF) Consensus Conference, the US CF Foundation case-control study, and the UK case-control study, the following general dosage recommendation for pancreatic enzyme replacement therapy can be proposed: Weight-based enzyme dosing should begin with 1000 lipase units/kg/meal for children less than four years of age and with 500 lipase units/kg/meal for those over age four.
Dosage should be adjusted according to the severity of the disease, control of steatorrhea and maintenance of good nutritional status.
Most patients should remain below or should not exceed 10000 lipase units/kg body weight per day or 4000 lipase units/gram fat intake.
Dosing In Other Conditions Associated With Exocrine Pancreatic Insufficiency: Dosage should be individualized by patients according to the degree of maldigestion and the fat content of the meal. The required dose for a meal ranges from about 25000 to 80000 Ph. Eur. units of lipase and half of the individual dose for snacks.

Extremely high doses of pancreatin have been reported to be associated with hyperuricosuria and hyperuricaemia.

Hypersensitivity to the active substance or to any of the excipients.

Strictures of the ileo-caecum and large bowel (fibrosing colonopathy) have been reported in patients with cystic fibrosis taking high doses of pancreatin preparations. As a precaution, unusual abdominal symptoms or changes in abdominal symptoms should be medically assessed to exclude the possibility of fibrosing colonopathy, especially if the patient is taking in excess of 10000 units of lipase/kg/day.
Effects on ability to drive and use machine: Creon has no or negligible influence on the ability to drive and use machines.

Fertility and pregnancy: For pancreatic enzymes no clinical data on exposed pregnancies are available. Animal studies show no evidence for any absorption of porcine pancreatic enzymes. Therefore, no reproductive or developmental toxicity is to be expected. Caution should be exercised when prescribing to pregnant women.
Lactation: No effects on the suckling child are anticipated since animal studies suggest no systemic exposure of the breastfeeding woman to pancreatic enzymes. Pancreatic enzymes can be used during breastfeeding.
If required during pregnancy and lactation Creon should be used in doses sufficient to provide adequate nutritional status.

In clinical trials, more than 900 patients were exposed to Creon.
The most commonly reported adverse reactions were gastrointestinal disorders and were primarily mild or moderate in severity.
The following adverse reactions have been observed during clinical trials with the following indicated frequencies. (See table.)

Click on icon to see table/diagram/image

Strictures of the ileo-caecum and large bowel (fibrosing colonopathy) have been reported in patients with cystic fibrosis taking high doses of pancreatin preparations, see Precautions.
Allergic reactions mainly but not exclusively limited to the skin have been observed and identified as adverse reactions during postapproval use. Because these reactions were reported spontaneously from a population of uncertain size, it is not possible to reliably estimate their frequency.
Paediatric population: No specific adverse reactions were identified in the pediatric population. Frequency, type and severity of adverse reactions were similar in children with cystic fibrosis as compared to adults.

No interaction studies have been performed.

Incompatibilities: Not applicable.
Special precautions for disposal: No special requirements.

Do not store above 30°C.
Keep the container tightly closed in order to protect from moisture.
After opening do not store above 25°C and use within 6 months.
Shelf life: 2 years.

Digestives

A09AA02 - multienzymes (lipase, protease etc.) ; Belongs to the class of enzyme preparations used as digestives.

NDD