Abbott Healthcare Products Limited

Section 4.2: amended;

FROM:

 If the granules are mixed with food it is important that they are taken immediately, 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.

TO:

If the granules are mixed with fluid or food it is important that they are taken immediately, 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.

Section 4.4: Following included;

As with all currently marketed porcine pancreatin products, Creon 40000 is sourced from pancreatic tissue from swine used for food consumption. Although the risk that Creon 40000 will transmit an infectious agent to humans has been reduced by the testing and inactivation of certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. The presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported, whereas they have been used for a long time.

4.8          Undesirable effects

From:

Skin and subcutaneous tissue disorders

Uncommon ( 1/1,000, 1/100): rash

Pruritus and urticaria have been additionally 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.

Multiple clinical trials were conducted in other patient populations: HIV, acute pancreatitis, diabetes mellitus. No additional adverse drug reactions were identified compared to the above three patient groups.

To:

Skin and subcutaneous tissue disorders

Uncommon(≥1/1,000, ≤1/100): rash

Frequency not known: pruritus, urticaria

Immune System Disorders:

Frequency not known: Hypersensitivity (anaphylactic reactions).

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.

Multiple clinical trials were conducted in other patient populations: HIV, acute pancreatitis, diabetes mellitus. No additional adverse drug reactions were identified compared to the above three patient groups.

 FROM:

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 meals.  The capsules should be swallowed whole. 

TO:

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 food it is important that they are taken immediately, 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.

Section 7: MARKETING AUTHORISATION HOLDER has been updated to Abbott Healthcare Products Limited

The following updates to the Creon 40000 SPC have been approved:

4.2       Posology and Method of Administration

From:

Colonic damage has been reported in patients with cystic fibrosis taking in excess of 10,000 units of lipase/kg/day (see Undesirable effects).

To:

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).

Section 4.3: Contraindications

From:

Patients with known hypersensitivity to porcine proteins.

To:

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

Section 4.4: Special warnings and special precautions for use

From:

The product is of porcine origin.

Oral medications should not be administered during the early stages of acute pancreatitis.

To:

Strictures of the ileo-caecum and large bowel (fibrosing colonopathy) have been reported in patients with cystic fibrosis taking high doses of pancreatin preparations.  Case control studies did not reveal evidence for an association between Creon and the appearance of fibrosing colonopathy.  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.

Section 4.5: Interaction with other medicinal products and other forms of interaction

From:

None known.

To:

No interaction studies have been performed.

Section 4.7: Effects on ability to drive and to use machines

From:

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

To:

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

Section 4.8: Undesirable effects

From:

Diarrhoea, constipation, gastric discomfort, nausea and skin reactions have been reported occasionally in patients receiving enzyme replacement therapy.

Rarely cases of hyper-uricosuria and hyperuricaemia have been reported with very high doses of pancreatin.

Stricture of the ileocaecum and large bowel and colitis has been reported in children with cystic fibrosis taking high doses of pancreatic enzyme supplements.  To date, Creon 10000 and 25000 have not been implicated in the development of colonic damage.  Experience with Creon 40000 in clinical use is limited.  Unusual abdominal symptoms or changes in abdominal symptoms should be reviewed to exclude the possibility of colonic damage - especially if the patient is taking in excess of 10,000 units of lipase/kg/day.

To:

In clinical trials, more than 600 patients with pancreatic exocrine insufficiency, due to cystic fibrosis, chronic pancreatitis, and pancreatic surgery 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 placebo-controlled clinical trials with the below indicated frequencies

Gastrointestinal disorders

Common (≥1/100, <1/10): nausea, vomiting, constipation, diarrhoea and abdominal distension

Gastrointestinal disorders are mainly associated with the underlying disease. Similar or lower incidences compared to placebo were reported for abdominal pain (very common, ≥1/10).

Skin and subcutaneous tissue disorders

Uncommon(≥1/1,000, ≤1/100): rash

Pruritus and urticaria have been additionally 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.

Multiple clinical trials were conducted in other patient populations: HIV, acute pancreatitis, diabetes mellitus. No additional adverse drug reactions were identified compared to the above three patient groups.

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.

Section 4.9: Overdose

From:

Most cases respond to supportive measures including stopping enzyme therapy, ensuring adequate rehydration.

To:

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

In section 4.6: In summary, the advice not to use creon whilst breast feeding has been removed. Also, a statement indicating that if required creon should be used to provide adequate nutritional balance has been added.

In section 6.1: the excipient dibutylphthalate and light liquid paraffin have been removed and replaced with cetyl alcohol and triethyl citrate

In section 9: following approval of the renewal the date has been updated

Previous

      Capsules:  Gelatin, Iron oxide E172, Titanium dioxide E171.

6.5      Nature and contents of container
          HDPE tablet container with LDPE closure.  Each container contains 100 capsules.

10.      Date of Revision of the Text

          August 2005

Amended

6.1      List of excipients

Gelatin

Anhydrous iron (III) oxide (E172)

Hydrated iron (III) oxide (E172)

Iron (II, III) oxide (E172)

Titanium dioxide E171

Sodium lauryl sulphate

6.5      Nature and contents of container
          HDPE container with tamper-evident PP cap. Each container contains 100 capsules.

10.      Date of Revision of the Text

          March 2007