This information is intended for use by health professionals

1. Name of the medicinal product

Creon® Micro Pancreatin 60.12 mg Gastro-resistant Granules

2. Qualitative and quantitative composition

Each 100 mg of gastro-resistant granules (equivalent to one measuring spoonful) contains 60.12mg of pancreatin, containing the following pancreatic enzymes:

Lipase

5,000 PhEur units

Amylase

3,600 PhEur units

Protease

   200 PhEur units

For excipients, see 6.1.

3. Pharmaceutical form

Gastro-resistant granules.

Round, 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

Initially 100 mg (5000 lipase units) of gastro-resistant granules (one measure) should be taken with each feed or meal or immediately after. Dose increases, if required, should be added slowly, with careful monitoring of response and symptomatology. The maximum daily dosage should not exceed 10,000 units lipase/kg/day. The required quantity of gastro-resistant granules should be dispensed using the measuring scoop contained in the pack which holds 100 mg.

In young infants, Creon Micro granules should be mixed with a small amount of apple juice and given from a spoon directly before the feed. In weaned infants, granules should be taken with acidic liquids or soft foods (e.g. mixed with apple juice or apple puree), but without chewing, directly before the meal. When giving Creon Micro to young or weaned infants the apple juice should not be diluted. Alternatively, the granules can be mixed with a small amount of milk on a spoon and administered to the infant immediately. The granules should not be added to the baby's bottle.

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.

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

Fibrosing colonopathy has been reported in patients with cystic fibrosis taking in excess of 10000 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 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 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 has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable effects

In clinical trials, more than 900 patients with 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 Micro contains porcine pancreatin formulated as enteric-coated (acid-resistant) minimicrospheres, a multi-dose 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.

Treatment with Creon markedly improves the symptoms of pancreatic exocrine insufficiency including stool consistency, abdominal pain, flatulence and stool frequency, independent of the underlying disease.

In placebo-controlled studies in which symptoms have been collected on diaries, the percentage of subjects with 'no abdominal pain' as most frequently reported rating was higher (73%) during Creon treatment than during placebo treatment (52%). The most frequently reported stool consistency was 'formed/normal' in 63% of the subjects during Creon treatment and in 17% of the subjects during placebo treatment. During Creon treatment, the percentage of subjects with 'no flatulence' as most frequently reported rating was higher (30%) than during placebo treatment (19%). The average number of daily stools was lower during Creon treatment than during placebo treatment (mean±SD: 1.89±0.87 vs 3.16±1.51).

In subjects with PEI due to CF in these studies, the percentage of subjects with 'no abdominal pain' as most frequently reported rating was 94% during Creon treatment and 60% during placebo treatment. The most frequently reported stool consistency was 'formed/normal' in 73% of the subjects during Creon treatment and in 18% of the subjects during placebo treatment. The percentage of subjects with 'no flatulence' as most frequently reported rating was 37% during Creon treatment and 26% during placebo treatment. The average number of daily stools (mean±SD) was 1.78±0.78 during Creon treatment and 3.24±1.49 during placebo treatment.

In subjects with PEI due to CP in these studies, the percentage of subjects with 'no abdominal pain' as most frequently reported rating was 55% during Creon treatment and 46% during placebo treatment. The most frequently reported stool consistency was 'formed/normal' in 45% of the subjects during Creon treatment and in 18% of the subjects during placebo treatment. The percentage of subjects with 'no flatulence' as most frequently reported rating was 26% during Creon treatment and 13% during placebo treatment. The average number of daily stools (mean±SD) was 2.07±1.08 during Creon treatment and 2.89±1.55 during placebo treatment.

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.

Additional data in paediatric population for Creon Micro:

Creon Micro has been specifically developed to offer a dosage form for infants and children.

One baseline-adjusted specific study performed over 8 weeks in infants demonstrated that Creon Micro was effective regarding the improvement of CFA and stool fat excretion as well as faecal energy loss after two weeks of treatment.

This study was designed mainly to evaluate the efficacy of Creon Micro in 12 infants, aged 1-23 months. The analysis of the results showed that the primary efficacy parameter, CFA, significantly increased from a baseline mean of 58.0% to a mean of 84.7% (mean increase 26.7%, 95% CI [12.9; 40.4], p = 0.0013, paired t-test). Height and weight increased, but the weight for height percentile remained nearly constant and close to 100%.

5.2 Pharmacokinetic properties

Pharmacokinetic data are not available as the enzymes act locally in the gastro-intestinal 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

Hypromellose phthalate

Macrogol 4000

Dimeticone

Cetyl alcohol

Triethyl citrate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years. 12 weeks after first opening.

6.4 Special precautions for storage

Do not store above 30°C.

Keep the container tightly closed in order to protect from moisture.

6.5 Nature and contents of container

Glass bottle with LDPE stopper. Containers hold 20 g of gastro-resistant granules.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Mylan Products Ltd

20 Station Close

Potters Bar

Herts

EN6 1TL

UK

8. Marketing authorisation number(s)

PL 46302/0031

9. Date of first authorisation/renewal of the authorisation

August 2004

10. Date of revision of the text

17 November 2016

Legal category

P