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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Creon ® 40000 Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains pancreatin PhEur 400 mg equivalent to:

Lipase 40,000 PhEur units Amylase 25,000 PhEur units Protease 1,600 PhEur units

3 PHARMACEUTICAL FORM

Capsules.

Brown/clear size 00 capsules containing light brown, gastro-resistant granules.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of pancreatic exocrine insufficiency.

4.2 Posology and method of administration

Adults (including the elderly) and children:

Creon 40000 should only be used if the patient requires equal to or more than 40,000 lipase units per meal or snack. Creon 40000 should only be used in patients in whom the minimum effective dose has already been determined using lower strength pancreatic enzyme products.

Initially one or two capsules with each meal. The capsules should be swallowed whole or for ease of administration they may be opened and the granules taken with acidic fluid or soft food, but without chewing. This could be apple sauce or yoghurt or any fruit juice with a pH less than 5.5, e.g. apple, orange or pineapple juice. If the granules are mixed with fluid or food it is important that they are taken immediately and the mixture not stored, otherwise dissolution of the enteric coating may result. In order to protect the enteric coating, it is important that the granules are not crushed or chewed. 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 to ensure that no product is retained in the mouth.

Dose increases, if required, should be added slowly, with careful monitoring of response and symptomatology.

It is important to ensure adequate hydration of patients at all times whilst dosing Creon 40000.

Fibrosing colonopathy has been reported in patients with cystic fibrosis taking in excess of 10,000 units of lipase/kg/day (see section 4.4).

4.3 Contraindications

Hypersensitivity to pancreatin of porcine origin or to any of the excipients.

4.4 Special warnings and special precautions for use

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 10 000 units of lipase/kg/day.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6 Fertility, Pregnancy and lactation

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 or lactation Creon should be used in doses sufficient to provide adequate nutritional status.

4.7 Effects on ability to drive and use machines

Creon 40000 has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable effects

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 below indicated frequencies;

Organ system	Very common > 1/10	Common > 1/100 to < 1/10	Uncommon > 1/1000 to < 1/100	Frequency not known
Gastrointestinal disorders	abdominal pain*	nausea, vomiting, constipation, abdominal distention, diarrhoea*		strictures of the ileo-caecum and large bowel (fibrosing colonopathy)
Skin and subcutaneous tissue disorders			rash	pruritus, urticaria
Immune system disorders				hypersensitivity (anaphylactic reactions).

*Gastrointestinal disorders are mainly associated with the underlying disease. Similar or lower incidences compared to placebo were reported for abdominal pain and diarrhoea.

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 section 4.4 Special warnings and precautions for use.

Allergic reactions mainly but not exclusively limited to the skin have been observed and identified as adverse reactions during post-approval 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 paediatric population. Frequency, type and severity of adverse reactions were similar in children with cystic fibrosis as compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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

Supportive measures including stopping enzyme therapy and ensuring adequate rehydration are recommended.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Multienzymes (amylase, lipase, protease), ATC code: A09A A02

Creon contains porcine pancreatin formulated as enteric-coated (acid-resistant) minimicrospheres within gelatine 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, 25000 or 40000 Ph. Eur units of lipase and Creon 5000) 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 faecal fat excretion. In the placebo-controlled PEI studies, the mean CFA (%, mean ± SD) was higher with Creon treatment (83.0 ± 12.6%) as compared to placebo (62.6 ± 21.8%). The median treatment duration was 7 days on both treatments. 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.

5.2 Pharmacokinetic properties

Pharmacokinetic data are not available as the enzymes act locally in the gastrointestinal tract. After exerting their action, the enzymes are digested themselves in the intestine.

5.3 Preclinical safety data

None stated.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Granules:

Macrogol 4000 Hypromellose phthalate Dimeticone Cetyl alcohol Triethyl citrate

Capsules:

Gelatin

Anhydrous iron (III) oxide (E172) Hydrated iron (III) oxide (E172) Iron (II, III) oxide (E172) Titanium dioxide E171 Sodium lauryl sulfate

6.2 Incompatibilities

None known.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25°C. Keep container tightly closed.

6.5 Nature and contents of container

HDPE container with tamper-evident PP cap. Each container contains 100

capsules.