Creon 25000

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KREON® 10000 (KREON® 10000) KREON® 25000 (KREON® 25000) KREON® 40000 (KREON® 40000)

Composition:

Active substance: pancreatin;

KREON® 10000: 1 capsule contains 150 mg of pancreatin in gastroresistant granules (Creon minimicrospheres®), having enzymatic activity: lipase 10,000 IU Ph. Eur., amylase 8,000 IU Ph. Eur., protease 600 IU Ph. Eur.;

KREON® 25000: 1 capsule contains 300 mg of pancreatin in gastroresistant granules (Creon minimicrospheres®), having enzymatic activity: lipase 25,000 IU Ph. Eur., amylase 18,000 IU Ph. Eur., protease 1,000 IU Ph. Eur.;

KREON® 40000: 1 capsule contains 400 mg of pancreatin in gastroresistant granules (Creon minimicrospheres®), having enzymatic activity: lipase 40,000 IU Ph. Eur., amylase 25,000 IU Ph. Eur., protease 1,600 IU Ph. Eur.;

Excipients:

KREON® 10000, KREON® 40000: macrogol 4000, hypromellose phthalate, cetyl alcohol, triethyl citrate, dimethicone 1000; hard capsule: gelatin, iron oxide (E 172), titanium dioxide (E 171), sodium lauryl sulfate;

KREON® 25000: macrogol 4000, hypromellose phthalate, cetyl alcohol, triethyl citrate, dimethicone 1000; hard capsule: gelatin, iron oxide (E 172), sodium lauryl sulfate.

Pharmaceutical form. Hard capsules with gastroresistant granules.

Main physicochemical characteristics:

KREON® 10000 − two-colored hard gelatin capsules of size 2 with an opaque brown cap and a colorless transparent body, filled with brownish granules (Creon minimicrospheres®);

KREON® 25000 − two-colored hard gelatin capsules of size 0el with an opaque orange cap and a colorless transparent body, filled with brownish granules (Creon minimicrospheres®);

KREON® 40000 − two-colored hard gelatin capsules of size 00 with an opaque brown cap and a colorless transparent body, filled with brownish granules (Creon minimicrospheres®).

Pharmacotherapeutic group. Digestive agents, including enzymes. Pancreatic enzyme preparations. ATC code A09AA02.

Pharmacological properties.

Pharmacodynamics.

CREON® contains porcine pancreatin in the form of enteric-coated (acid-resistant) granules in gelatin capsules. The capsules dissolve rapidly in the stomach, releasing a large number of granules according to the multi-dose principle, ensuring good mixing with gastric contents, transport from the stomach together with its contents, and after release, good distribution of enzymes within the intestinal contents. When the granules reach the small intestine, the coating dissolves rapidly (at pH > 5.5), releasing enzymes with lipolytic, amylolytic, and proteolytic activity, which ensures the breakdown of fats, carbohydrates, and proteins. The products of pancreatic digestion are then absorbed either directly or after further hydrolysis by intestinal enzymes.

Clinical efficacy.

A total of 30 efficacy studies of CREON® have been conducted involving patients with exocrine pancreatic insufficiency (EPI). Ten of these were placebo-controlled. These studies included patients with cystic fibrosis, chronic pancreatitis, or post-surgical conditions.

In all randomized, placebo-controlled efficacy studies, the pre-defined primary objective was to demonstrate superior efficacy of CREON® compared to placebo for the primary efficacy endpoint – the coefficient of fat absorption (CFA).

The coefficient of fat absorption determines the percentage of fat absorbed by the body, taking into account dietary fat intake and fecal fat excretion. In placebo-controlled studies involving patients with EPI, the mean CFA (%) was higher in patients receiving CREON® (83.0%) compared to the placebo group (62.6%). Across all studies, regardless of study design, mean CFA (%) at the end of treatment with CREON® was similar to the mean CFA values observed for CREON® in the placebo-controlled studies.

Treatment with CREON® significantly reduces symptoms caused by impaired exocrine pancreatic function, including stool consistency, abdominal pain, flatulence, and stool frequency, regardless of the underlying disease.

Children.

The efficacy of CREON® has been demonstrated in 288 children from newborn to adolescent age with cystic fibrosis. Across all studies, mean CFA values at the end of treatment with CREON® exceeded 80% in children of all age groups.

Preclinical safety data.

Preclinical studies did not reveal evidence of relevant acute, subchronic, or chronic toxicity. Studies on genotoxicity, carcinogenicity, or toxic effects on reproduction were not conducted.

Pharmacokinetics.

Animal studies did not detect evidence of absorption of enzymes in unchanged form, and therefore classical pharmacokinetic studies were not performed. Pancreatic enzyme preparations do not require absorption to achieve their effect. On the contrary, their full therapeutic action occurs within the lumen of the gastrointestinal tract. Moreover, as proteins, they undergo proteolytic digestion while passing through the gastrointestinal tract before being absorbed as peptides and amino acids.

Clinical characteristics.

Indications.

Treatment of exocrine pancreatic insufficiency in adults and children caused by various diseases and conditions, including but not limited to those listed below:

• cystic fibrosis;
• chronic pancreatitis;
• pancreatectomy;
• gastrectomy;
• gastrointestinal anastomosis surgery (e.g., gastroenterostomy according to Billroth II);
• Shwachman–Diamond syndrome;
• condition following an acute pancreatitis attack and restoration of enteral or oral nutrition.

Contraindications.

Hypersensitivity to the active substance or to any of the other components of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been performed.

Special precautions for use

In patients with cystic fibrosis who have received high doses of pancreatin preparations, narrowing of the ileocecal region and large intestine (fibrosing colonopathy) has been observed. As a precautionary measure, it is recommended that, in case of onset of unusual abdominal symptoms or changes in the nature of existing abdominal symptoms, medical advice should be sought to exclude the possibility of fibrosing colonopathy, particularly if the patient is receiving more than 10,000 IU of lipase/kg/day.

Use during pregnancy or breastfeeding

Due to the lack of clinical data on the effects of pancreatic enzymes on pregnancy, the drug should be administered with caution to pregnant women. Animal studies have shown no evidence of absorption of pancreatic enzymes. Therefore, toxic effects on reproductive function or fetal development are not expected.

Animal studies indicate no systemic exposure to pancreatic enzymes in lactating women; thus, no effects on the breastfed infant are anticipated. Therefore, pancreatic enzymes may be used in women during breastfeeding.

If necessary, pregnant women or women who are breastfeeding may take CREON® at doses sufficient to ensure adequate nutritional status.

Ability to influence reaction speed when driving or operating machinery

The effect of CREON® on the ability to drive vehicles or operate machinery is absent or negligible.

Dosage and Administration

The dosage of the drug is based on individual patient needs and depends on the severity of the disease and dietary composition.

The drug should be taken during or immediately after a meal.

Capsules and granules should be swallowed whole, without breaking or chewing, and taken with an adequate amount of liquid during or after meals, including light snacks. If a patient is unable to swallow the capsule whole (e.g., children or elderly patients), it may be carefully opened and the granules mixed with soft food with an acidic environment (pH < 5.5) that does not require chewing, or with an acidic liquid (pH < 5.5). Suitable options include apple puree, yogurt, or fruit juice with pH < 5.5, such as apple, orange, or pineapple juice. This mixture should not be stored. Breaking or chewing the granules or mixing them with food or liquids with pH > 5.5 may damage their protective enteric coating, potentially leading to premature release of enzymes in the oral cavity, reduced efficacy of the drug, and irritation of mucous membranes.

Care must be taken to ensure that no residue of the drug remains in the oral cavity.

Adequate fluid intake is very important during treatment with PANCREAZE® 10000, PANCREAZE® 25000, and PANCREAZE® 40000, especially during periods of increased fluid loss. Fluid deficiency may worsen constipation. Any mixture of granules with food or liquids should be taken immediately and not stored.

Dosage in cystic fibrosis.

Based on recommendations from the Cystic Fibrosis (CF) Consensus Conference, the US CF Association case-control study, and the UK case-control study, the following general dosage guidelines for pancreatic enzyme replacement therapy are recommended:

• Initial dose for children under 4 years of age: 1000 IU of lipase per kg of body weight per meal; for children aged 4 years and older: 500 IU of lipase per kg of body weight per meal;
• Dosage should be individually adjusted based on disease severity, control of steatorrhea, and maintenance of adequate nutritional status;
• The maintenance dose for most patients should not exceed 10,000 IU of lipase per kg of body weight per day or 4,000 IU of lipase per gram of dietary fat intake.

Dosage in other forms of exocrine pancreatic insufficiency:

• Dosage should be individually adjusted depending on the degree of digestive impairment and fat content of the diet. Doses ranging from 25,000 to 80,000 IU of lipase are typically required with meals, and half the individual dose should be taken with a light snack.

Children.

PANCREAZE® can be used in children.

Overdose.

Cases of hyperuricosuria and hyperuricemia have been reported and were associated with the intake of extremely high doses of pancreatin.

Side effects.

The effect of CREON® has been studied in more than 900 patients during clinical trials. Gastrointestinal disorders, mostly mild to moderate in severity, were the most frequently reported.

The side effects observed during clinical trials and their frequencies are listed below.

Gastrointestinal disorders: very common (≥ 1/10) – abdominal pain*; common (≥ 1/100 to < 1/10) – nausea, vomiting, constipation, bloating, diarrhea*; frequency not known – narrowing of the ileocecal region and colon (fibrosing colonopathy).

*Gastrointestinal disorders were mainly related to the underlying disease. Reports of diarrhea and abdominal pain occurred at a frequency similar to or less than that with placebo.

Skin and subcutaneous tissue disorders: uncommon (≥ 1/1,000 to < 1/100) – rash; frequency not known – pruritus, urticaria.

Immune system disorders: frequency not known – hypersensitivity (anaphylactic reactions).

Cases of narrowing of the ileocecal region and colon (fibrosing colonopathy) have been reported in patients with cystic fibrosis who were receiving high doses of pancreatic enzyme products (see section "Special precautions").

Allergic reactions, mainly manifesting as skin reactions but not exclusively, have been reported during post-marketing use. Since these reports were spontaneous and derived from an undefined number of patients, the exact frequency of these reactions cannot be determined.

Children

No specific side effects have been identified in children. The frequency, type, and severity of adverse reactions in children with cystic fibrosis were similar to those in adults.

Shelf life.

2 years. Shelf life after first opening – 6 months.

Storage conditions.

Store at a temperature not exceeding 25 °C in a tightly closed container.

Keep out of reach of children.

Packaging.

20, 50, or 100 capsules in a high-density polyethylene bottle, 1 bottle in a cardboard box.

CREON® 25000, CREON® 40000: 10 capsules in a blister, 2 blisters in a cardboard box.

CREON® 10000: 10 capsules in a blister, 1, 2, or 3 blisters in a cardboard box.

Prescription status.

Over-the-counter.

Manufacturer.

Abbott Laboratories GmbH, Germany.

Manufacturer's address and place of business.

Justus-von-Liebig-Strasse 33, Neustadt, Niedersachsen, 31535, Germany.