CREON 25000

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

CREON 25,000

Capsules

Each capsule contains: Pancreatin 300 mg, comprising:

Lipase 25,000 Ph. Eur. Units

Amylase 18,000 Ph. Eur. Units

Protease 1,000 Ph. Eur. Units

For a list of the inactive ingredients in the medicine, see

section 6.

Read this leaflet carefully in its entirety before using the

medicine. This leaflet contains concise information about the

medicine. If you have further questions, refer to the doctor

or pharmacist.

This medicine has been prescribed for you. Do not pass it on

to others. It may harm them, even if it seems to you that their

medical condition is similar.

- Creon 25,000 is a high-dosage pancreatic enzyme

supplement indicated for people whose bodies cannot

produce enough enzymes required to digest food.

- The capsules contain a mix of natural enzymes used to

digest food.

- The enzymes are extracted from pig pancreas.

- The medicine should be taken as per the doctor’s

instructions.

- Take the medicine together with a meal or snack, with a lot

of water (see section 3).

- Do not take the medicine if you are allergic to pig-derived

ingredients, pig proteins (see section 2).

- If you experience severe abdominal pains during the

course of treatment with the medicine, refer to the doctor

immediately (see section 4).

1. WHAT IS THE MEDICINE INTENDED fOR?

The medicine is intended to treat exocrine pancreatic

insufficiency.

The medicine contains pancreatic enzymes which aid

digestion, in cases where the pancreas does not produce these

enzymes, or does not produce enough of them. The medicine

is intended to balance low enzymatic activity in the intestine, in

cases of pancreatic insufficiency, e.g., cystic fibrosis, chronic

pancreatitis, excision of the pancreas and partial excision of

the digestive system in adults and children.

Therapeutic group: Digestive enzymes.

2. BEfORE USING THE MEDICINE

Do not use the medicine if:

you are sensitive (allergic) to the active ingredient, pancreatin

of porcine origin, to products of pig origin, pig proteins or to

any of the additional ingredients contained in the medicine

(see section 6).

If this section applies to you, do not take the medicine. Consult

with the doctor again.

Special warnings regarding use of this medicine

Before using the medicine, inform the doctor if you are

sensitive to any food or medicine.

Additional warnings

A rare bowel condition called fibrosing colonopathy (narrowing

of the large intestine) has been reported in patients with cystic

fibrosis taking high dosages of preparations containing

pancreatin.

If you have cystic fibrosis and take doses higher than 10,000

lipase units per kilogram body weight per day, refer to a

doctor if you have unusual abdominal symptoms or changes

in regular abdominal symptoms.

If you are taking, or have recently taken, other medicines,

including non-prescription medicines and nutritional

supplements, tell the doctor or pharmacist.

Use of the medicine and food

The digestive enzymes in the medicine act when food is

passing through the intestine, and therefore, the medicine

should be taken with a meal or snack. This will allow the

enzymes to effectively mix with the food (see section 3).

Pregnancy and breastfeeding

If you are pregnant or trying to become pregnant, consult the

doctor or pharmacist before using the medicine.

This medicine can be used when breastfeeding.

Driving and use of machinery

It is unlikely that the medicine will affect your ability to drive

or operate dangerous machinery.

Important information regarding some of the ingredients

in the medicine

The amount of sodium in each capsule: 3.9 mg.

This medicine does not contain sugar or lactose.

3. HOW SHOULD yOU USE THE MEDICINE?

Always use according to the doctor’s instructions.

Check with the doctor or pharmacist if you are uncertain.

The dosage and treatment regimen will be determined by

the doctor only.

If the doctor has told you to increase the dose (to increase

the number of capsules), do so gradually. If you still have fatty

stools or abdominal pains, inform the doctor.

Do not exceed the recommended dose.

Take the medicine during or immediately after a meal or a

snack.

Swallow the medicine with a lot of water.

Do not chew or crush the medicine, so as not to destroy the

inner coating, within which the enzymes are enclosed, thereby

abolishing the enzymatic activity of the medicine.

How should the medicine be taken

Swallow the capsule whole, or, if you have a hard time

swallowing whole capsules, the capsule can be carefully

opened and its contents can be mixed (without mashing) with

an acidic liquid (e.g., apple, orange or pineapple juice) or with

a soft acidic food (e.g., apple sauce or yogurt). If the contents

of the capsule are mixed with food or a beverage, take the

mixture immediately, without mashing or chewing, so that the

inner coating will not dissolve. Do not store the mixture.

Note:

Be sure to maintain adequate fluid intake at all times during

the course of treatment with the medicine, especially when

there is increased fluid loss (e.g., vomiting and diarrhea).

failure to drink adequately may worsen constipation. It

is important to drink a lot every day!

Mashing/chewing the granules in the capsule or mixing the

contents of the capsule with food or a nonacidic beverage

may cause irritation in the mouth or change the way Creon

works in the body.

Do not hold the whole capsule or mixture in the mouth for

more than the time necessary to swallow it.

∙ The bottle is closed with a child-proof cap. Press down and

turn to open it.

Child-proof caps have significantly lowered the number of

poisoning incidents caused by medicines each year. However,

if you are having a hard time opening the package, you can

refer to a pharmacist to have the safety mechanism removed

from the cap and to turn it into a regular, easy-to-open cap.

∙ The capsule can be opened and its contents dispersed.

∙ Do not crush, mash or chew the medicine.

∙ Duration of treatment - continue taking the medicine until

your doctor tells you to stop. Many patients need to take

pancreatic enzyme supplements throughout their lifetime.

If you accidentally took a higher dosage, drink lots of water.

If you took an overdose, or if a child accidentally swallowed

the medicine, immediately refer to a doctor or proceed to

a hospital emergency room, and bring the package of the

medicine with you.

If you forgot to take this medicine at the required time, do not

take a double dose to compensate for the forgotten dose. Take

the next dose with the next meal.

Adhere to the treatment regimen recommended by the

doctor.

Even if there is an improvement in your health, do not stop

treatment with the medicine, without consulting with the

doctor or pharmacist.

Do not take medicines in the dark! Check the label and the

dose each time you take medicine. Wear glasses if you need

them.

If you have further questions regarding use of the medicine,

consult the doctor or pharmacist.

4. SIDE EffECTS

As with any medicine, use of Creon 25,000 may cause side

effects in some users. Do not be alarmed when reading the list

of side effects. You may not suffer from any of them.

If you have severe and long-lasting abdominal pains or

abnormal abdominal symptoms, consult with the doctor

immediately.

The following side effects were reported in clinical trials

conducted among more than 900 patients who took Creon:

Side effects occurring very frequently (affect more than 1

in 10 users):

- stomach pains

Side effects occurring frequently (affect 1-10 in 100 users):

- diarrhea

- constipation

- nausea or vomiting

- bloating

Side effects occurring infrequently (affect 1-10 in 1,000

users):

- Skin reactions, such as a rash

During use, some patients have also experienced the following

effects, the frequency of which is unknown:

- itching with or without a rash

- allergic reactions (which may be severe, such as breathing

difficulties or swelling of the lips)

- severe or long-lasting abdominal pains (fibrosing

colonopathy)

Severe or long-lasting abdominal pains caused by narrowing of

the large intestine (fibrosing colonopathy) have been reported

in cystic fibrosis patients taking preparations containing high

dosages of pancreatin.

Very high dosages of pancreatin have sometimes caused high

levels of uric acid in the blood and urine.

If a side effect occurs, if any of the side effects worsen or

if you suffer from a side effect not mentioned in this leaflet,

consult with the doctor.

Side effects can be reported to the Ministry of Health via

the online form in the following link:

http://forms.gov.il/globaldata/getsequence/getsequence.

aspx?formType=AdversEffectMedic%40moh.health.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

∙ Avoid poisoning! This medicine, and any other medicine,

should be kept in a safe place out of the sight and reach of

children and/or infants in order to avoid poisoning. Do not

induce vomiting unless explicitly instructed to do so by the

doctor.

∙ Do not use the medicine after the expiry date (exp. date)

that appears on the package. The expiry date refers to the

last day of that month.

∙ Do not store at a temperature that exceeds 25°C. Close

tightly to prevent penetration of air and moisture. Store in

the original package.

Can be used for 3 months from the time the bottle is first

opened.

∙ The enzymes in the medicine are natural enzymes, whose

capacity to digest food declines with time. If the medicine

is stored in hot temperatures (e.g., the glove box in the car),

the digestive capacities of the enzymes in the medicine will

decline faster.

6. fURTHER INfORMATION

∙ In addition to the active ingredient, the medicine also

contains -

Hypromellose phthalate, Macrogol 4,000, Triethyl citrate,

Dimeticone 1,000, Cetyl alcohol.

Capsule: Gelatine, Iron oxides (red, yellow) (E172), Sodium

lauryl sulphate, Titanium dioxide (E171).

Each capsule contains 3.9 mg sodium

∙ What the medicine looks like and the contents of the

package - the medicine is composed of brownish granules

in hard gelatin capsules.

The medicine is marketed in a carton box that contains a

bottle with a child-safety cap.

Package sizes - 100 capsules, 50 capsules.

Not all package sizes are marketed.

∙ Registration holder and address: Abbott Medical

Laboratories Ltd., Kiryat Atidim P.O.B. 58099, Tel-Aviv.

∙ Manufacturer: Abbott Laboratories GmbH, Hanover,

Germany.

∙ This leaflet was checked and approved by the Ministry of

Health in June 2015.

∙ Registration number of the medicine in the National Drug

Registry of the Ministry of Health: 119-75-29972-00.

Summary of Product Characteristics

CREON

®

25000

1.

NAME OF THE MEDICINAL PRODUCT

CREON

®

25000, capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule Creon 25000 contains 300 mg pancreatin (pancreas powder) corresponding

Amylase

18,000 Ph.Eur. units

Lipase

25,000 Ph.Eur. units

Protease

1,000 Ph.Eur. units

3.

PHARMACEUTICAL FORM

Gastro-resistant

capsule,

hard

(hard

gelatin

capsules

filled

with

gastro-resistant

pellets

(=Minimicrospheres™).

Bicoloured capsule with Swedish orange opaque cap and transparent body.

4.

CLINICAL PARTICULARS

4.1

Therapeutic Indications

For the treatment of pancreatic exocrine deficiency.

Enzyme replacement therapy in patients with deficient exocrine pancreatic secretions, cystic

fibrosis, chronic pancreatitis, postpancreatectomy, ductal obstructions caused by cancer of the

pancreas,

pancreatic

insufficiency

steatorrhea

malabsorption

syndrome

postgastrectomy (Billroth II and Total).

Presumptive test for pancreatic function, especially in pancreatic insufficiency due to chronic

pancreatitis.

4.2

Posology and method of administration

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 each meal or snack.

Adults (including the elderly) and children:

Initially one capsule with meals. Dose increases, if required, should be added slowly with

careful monitoring of response and symptomatology.

For infants and children a median lipase intake of 10,000 Ph.Eur. units per kg body weight a day

is recommended. A daily lipase intake of 15,000 - 20,000 Ph.Eur. units per kg body weight

should not be exceeded.

The capsules can 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.

It is important to ensure adequate hydration of patients at all times whilst dosing Creon 25000,

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 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 U/kg body

weight per day or 4000 lipase unite/gram fat intake.

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).

Dosing in other conditions associated with exocrine pancreatic insufficiency

Dosage should be individualized by patient according to the degree of maldigestion and the fat

content of the meal. The required dose for a main meal (breakfast, lunch or dinner) ranges from

about 25000 to 80000 Ph. Eur. U of lipase and half of the individual dose for snacks.

4.3

Contraindications

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

4.4

Special warnings and precautions for use

The product is of porcine origin.

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

Interactions with other medicaments 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 of 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.

4.7

Effects on ability to drive and use machines

Creon 25000 has no or negligible influence on the ability to drive or operate 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

were

primarily

mild

moderate in severity.

The following adverse reactions have been observed during clinical trials with the below

indicated frequencies

*Gastrointestinal disorders are mainly associated with the underlying disease. Similar or

lower incidences compared to placebo were reported for abdominal pain and diarrhea.

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

adverse

reactions

during

postapproval

use.

Because

these

reactions

were

reported spontaneously form 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.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic

@moh.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL)

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.

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,

diarrhea*

strictures of the

ileo-caecum and

large bowel

(fibrosing

colonopathy)

Skin and

subcutaneous

tissue disorders

rash

pruritus,

urticaria

Immune system

disorders

hypersensitivity

(anaphylactic

reactions).

5. Pharmacological Properties

5.1

Pharmacodynamic Properties

Pharmacotherapeutic group: Multienzymes (amylase, lipase, protease), ATC code: A09A

Creon

25000

contains

porcine

pancreatin

formulated

enteric-coated

(acid-resistant)

minimicrospheres

within gelatine

capsules. The

capsules

dissolve

rapidly

stomach

releasing plenty of 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 fecal 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 gastro-intestinal tract.

After exerting their action, the enzymes are digested themselves in the intestine.

5.3

Preclinical Safety Data

Not applicable.

6 Pharmaceutical Particulars

6.1

List of excipients

Granules core:

Macrogol 4000,

Granules coating: Hypromellose phthalate, cetyl alcohol, triethyl citrate, dimeticone 1000

Capsule shell:

Gelatin, iron oxides (red, yellow) (E172), titanium dioxide (E171), sodium

lauryl sulphate,

6.2

Incompatibilities

None known.

6.3

Shelf Life

3 years . Shelf life after first opening: 3 months or expiry date, whichever comes first.

6.4

Special Precautions for Storage

Do not Store above 25°C, keep the container tightly closed in order to protect from moisture.

6.5

Nature and Contents of Container

HDPE container with tamper-evident child resistant PP cap. Each container contains 50 or 100

capsules.

Manufacturer: Abbott Laboratories GmbH, Hannover, Germany

Registration Holder: Abbott Medical Laboratories Ltd., Kiryat Atidim, POB 58099,

Tel – Aviv