CREON MINIMICROSPHERES

1 Dosing Considerations • Patients with pancreatic exocrine insufficiency should consume a high-calorie, unrestricted fat diet appropriate for their age and clinical status. A nutritional assessment should be performed regularly as a component of routine care, and additionally when the dosage of pancreatic enzyme replacement is made.

• Dosage should be adjusted according to the severity of the pancreatic exocrine enzyme deficiency. The number of capsules or dosage strength given with meals and/or snacks should be estimated by assessing at which dose steatorrhea is minimized and good nutritional status is maintained.

• It is important to ensure adequate hydration at all times, 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 (see 7 WARNINGS AND PRECAUTIONS).

2 Recommended Dose and Dosage Adjustment • Cystic Fibrosis Based upon a recommendation of the Cystic Fibrosis (CF) 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.

CREON MINIMICROSPHERES® lipase/amylase/protease Page 6 of 21 Infants In infants, dosing should be initiated at a dose of 2,000 to 5,000 lipase units for each feeding (usually 120 mL) and adjusted up to a dose no greater than 2,500 lipase units per kilogram per feeding with a maximum daily dose of 10,000 lipase units per kilogram per day.

Children Younger Than 4 Years of Age In children less than 4 years of age, weight-based enzyme dosing should begin with 1,000 lipase units per kilogram body weight per meal. Usually, half the standard dose is given with snacks. Dosage should be adjusted according to the severity of the disease, control of steatorrhea and maintenance of good nutritional status.

Dosage should not exceed 10,000 lipase units per kilogram body weight per day or 4,000 lipase units/gram fat intake. Children Older Than 4 Years of Age and Adults In children older than age 4 years and in adults, weight-based enzyme dosing should begin with 500 lipase units per kilogram body weight per meal.

Usually, half the standard dose is given with snacks. Dosage should be adjusted according to the severity of the disease, control of steatorrhea and maintenance of good nutritional status. Dosage should not exceed 10,000 lipase units per kilogram body weight per day or 4,000 lipase units/gram fat intake.

• Other Conditions Associated With Pancreatic Exocrine Insufficiency Adults The required dose for a meal ranges from about 25,000 to 80,000 units of lipase and half of the required dose for snacks. Dosage should be individualized according to the degree of maldigestion and the fat content of the meal.

In certain conditions, such as with acute pancreatitis, CREON MINIMICROSPHERES® should be taken when food intake has started again. 4 Administration CREON MINIMICROSPHERES® MICRO is available as gastro-resistant granules (minimicrospheres) dosed with a spoon.

It is a specific dosage form with a small minimicrosphere size in particular for use in infants and children unable to swallow capsules. CREON MINIMICROSPHERES® MICRO allows improved individual dosing when low lipase doses are needed for adequate treatment of young children.

CREON MINIMICROSPHERES® 10, 20, 25 and 35 are available as capsules filled with gastro- resistant granules (minimicrospheres). The capsules should be swallowed intact, without CREON MINIMICROSPHERES® lipase/amylase/protease Page 7 of 21 crushing or chewing, with enough fluid during or after each meal or snack.

It is recommended to take the enzymes during or immediately after the meals. g. small children or elderly patients), the capsules may be opened. 5) such as apple, orange or pineapple juice (see 7 WARNINGS AND PRECAUTIONS). This mixture should not be stored.

Alternatively, the minimicrospheres can be mixed with a small amount of milk on a (weaning) spoon and administered to the infant immediately. The minimicrospheres should not be added to a baby’s bottle. The CREON MINIMICROSPHERES®- soft food or fluid mixture should be swallowed immediately without crushing, chewing or holding in the mouth, and followed with water or juice to ensure complete ingestion.

Mixtures with food or liquids should be used immediately and not stored, otherwise the protective enteric coating may dissolve. Care should be taken to ensure that no product is retained in the mouth. 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 (see 7 WARNINGS AND PRECAUTIONS). See 11 STORAGE, STABILITY AND DISPOSAL for further information.

5 Missed Dose If a dose is missed, the patient should take their next dose as usual with their next meal. The patient should not double the dose.

and 14 CLINICAL TRIALS). 2 Geriatrics (≥ 65 years of age) CREON MINIMICROSPHERES® was shown to be similarly effective and safe in elderly patients with PEI as compared to the overall population. 2 CONTRAINDICATIONS • CREON MINIMICROSPHERES® is contraindicated in patients who are hypersensitive to this drug (porcine protein or pancreatic enzymes) or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. CREON MINIMICROSPHERES® lipase/amylase/protease Page 5 of 21 3 SERIOUS WARNINGS AND PRECAUTIONS BOX Serious Warnings and Precautions • Pancreatic enzyme products, including CREON MINIMICROSPHERES® have been associated with fibrosing colonopathy (strictures of the ileo-caecum and large intestine) if given at high doses chronically to patients with cystic fibrosis.

It is not clear whether this complication is caused by high dosages of pancreatic enzymes, or whether the underlying disease is responsible. Unusual 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 body weight/day or more than 4,000 units of lipase/gram fat intake.

• CREON MINIMICROSPHERES® cannot be substituted (unit for unit) with other pancreatic enzyme products because they are biological products and, therefore, differ in their manufacturing processes, formulations, exact composition, enzymatic activities, stability and bioactivity in the small intestine, so the response of the patient to the estimated dose must be monitored and adjusted as necessary.

Special attention to the response of the patient is required during any change in treatment from one pancreatic enzyme product to another. 1 Dosing Considerations • Patients with pancreatic exocrine insufficiency should consume a high-calorie, unrestricted fat diet appropriate for their age and clinical status.

A nutritional assessment should be performed regularly as a component of routine care, and additionally when the dosage of pancreatic enzyme replacement is made. • Dosage should be adjusted according to the severity of the pancreatic exocrine enzyme deficiency.

The number of capsules or dosage strength given with meals and/or snacks should be estimated by assessing at which dose steatorrhea is minimized and good nutritional status is maintained. • It is important to ensure adequate hydration at all times, 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 (see 7 WARNINGS AND PRECAUTIONS). 2 Recommended Dose and Dosage Adjustment • Cystic Fibrosis Based upon a recommendation of the Cystic Fibrosis (CF) 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.

CREON MINIMICROSPHERES® lipase/amylase/protease Page 6 of 21 Infants In infants, dosing should be initiated at a dose of 2,000 to 5,000 lipase units for each feeding (usually 120 mL) and adjusted up to a dose no greater than 2,500 lipase units per kilogram per feeding with a maximum daily dose of 10,000 lipase units per kilogram per day.

Children Younger Than 4 Years of Age In children less than 4 years of age, weight-based enzyme dosing should begin with 1,000 lipase units per kilogram body weight per meal. Usually, half the standard dose is given with snacks. Dosage should be adjusted according to the severity of the disease, control of steatorrhea and maintenance of good nutritional status.

Dosage should not exceed 10,000 lipase units per kilogram body weight per day or 4,000 lipase units/gram fat intake. Children Older Than 4 Years of Age and Adults In children older than age 4 years and in adults, weight-based enzyme dosing should begin with 500 lipase units per kilogram body weight per meal.

Usually, half the standard dose is given with snacks. Dosage should be adjusted according to the severity of the disease, control of steatorrhea and maintenance of good nutritional status. Dosage should not exceed 10,000 lipase units per kilogram body weight per day or 4,000 lipase units/gram fat intake.

• Other Conditions Associated With Pancreatic Exocrine Insufficiency Adults The required dose for a meal ranges from about 25,000 to 80,000 units of lipase and half of the required dose for snacks. Dosage should be individualized according to the degree of maldigestion and the fat content of the meal.

In certain conditions, such as with acute pancreatitis, CREON MINIMICROSPHERES® should be taken when food intake has started again. 4 Administration CREON MINIMICROSPHERES® MICRO is available as gastro-resistant granules (minimicrospheres) dosed with a spoon.

It is a specific dosage form with a small minimicrosphere size in particular for use in infants and children unable to swallow capsules. CREON MINIMICROSPHERES® MICRO allows improved individual dosing when low lipase doses are needed for adequate treatment of young children.

CREON MINIMICROSPHERES® 10, 20, 25 and 35 are available as capsules filled with gastro- resistant granules (minimicrospheres). The capsules should be swallowed intact, without CREON MINIMICROSPHERES® lipase/amylase/protease Page 7 of 21 crushing or chewing, with enough fluid during or after each meal or snack.

It is recommended to take the enzymes during or immediately after the meals. g. small children or elderly patients), the capsules may be opened. 5) such as apple, orange or pineapple juice (see 7 […]

). 2 Recommended Dose and Dosage Adjustment • Cystic Fibrosis Based upon a recommendation of the Cystic Fibrosis (CF) 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.

CREON MINIMICROSPHERES® lipase/amylase/protease Page 6 of 21 Infants In infants, dosing should be initiated at a dose of 2,000 to 5,000 lipase units for each feeding (usually 120 mL) and adjusted up to a dose no greater than 2,500 lipase units per kilogram per feeding with a maximum daily dose of 10,000 lipase units per kilogram per day.

Children Younger Than 4 Years of Age In children less than 4 years of age, weight-based enzyme dosing should begin with 1,000 lipase units per kilogram body weight per meal. Usually, half the standard dose is given with snacks. Dosage should be adjusted according to the severity of the disease, control of steatorrhea and maintenance of good nutritional status.

Dosage should not exceed 10,000 lipase units per kilogram body weight per day or 4,000 lipase units/gram fat intake. Children Older Than 4 Years of Age and Adults In children older than age 4 years and in adults, weight-based enzyme dosing should begin with 500 lipase units per kilogram body weight per meal.

Usually, half the standard dose is given with snacks. Dosage should be adjusted according to the severity of the disease, control of steatorrhea and maintenance of good nutritional status. Dosage should not exceed 10,000 lipase units per kilogram body weight per day or 4,000 lipase units/gram fat intake.

• Other Conditions Associated With Pancreatic Exocrine Insufficiency Adults The required dose for a meal ranges from about 25,000 to 80,000 units of lipase and half of the required dose for snacks. Dosage should be individualized according to the degree of maldigestion and the fat content of the meal.

In certain conditions, such as with acute pancreatitis, CREON MINIMICROSPHERES® should be taken when food intake has started again. 4 Administration CREON MINIMICROSPHERES® MICRO is available as gastro-resistant granules (minimicrospheres) dosed with a spoon.

It is a specific dosage form with a small minimicrosphere size in particular for use in infants and children unable to swallow capsules. CREON MINIMICROSPHERES® MICRO allows improved individual dosing when low lipase doses are needed for adequate treatment of young children.

CREON MINIMICROSPHERES® 10, 20, 25 and 35 are available as capsules filled with gastro- resistant granules (minimicrospheres). The capsules should be swallowed intact, without CREON MINIMICROSPHERES® lipase/amylase/protease Page 7 of 21 crushing or chewing, with enough fluid during or after each meal or snack.

It is recommended to take the enzymes during or immediately after the meals. g. small children or elderly patients), the capsules may be opened. 5) such as apple, orange or pineapple juice (see 7 WARNINGS AND PRECAUTIONS). This mixture should not be stored.

Alternatively, the minimicrospheres can be mixed with a small amount of milk on a (weaning) spoon and administered to the infant immediately. The minimicrospheres should not be added to a baby’s bottle. The CREON MINIMICROSPHERES®- soft food or fluid mixture should be swallowed immediately without crushing, chewing or holding in the mouth, and followed with water or juice to ensure complete ingestion.

Mixtures with food or liquids should be used immediately and not stored, otherwise the protective enteric coating may dissolve. Care should be taken to ensure that no product is retained in the mouth. 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 (see 7 WARNINGS AND PRECAUTIONS). See 11 STORAGE, STABILITY AND DISPOSAL for further information.

5 Missed Dose If a dose is missed, the patient should take their next dose as usual with their next meal. The patient should not double the dose. 5 OVERDOSAGE Extremely high doses of pancreatic enzymes have been reported to cause hyperuricosuria and hyperuricaemia.

Most cases responded to supportive measures, including discontinuation of the enzyme therapy and ensuring adequate hydration. For management of a suspected drug overdose, contact your regional poison control centre. 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING To help ensure the traceability of biologic products, including biosimilars, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

CREON MINIMICROSPHERES® lipase/amylase/protease Page 8 of 21 Table – Dosage Forms, Strengths, Composition and Packaging CREON MINIMICROSPHERES® MICRO is available as round, light brown gastro-resistant granules (minimicrospheres). It is available in glass bottles of 20 grams.

The bottle comes in a carton box with a polystyrene dosing spoon. Eur. units): 5,000 units of lipase, 5,100 units of amylase, and 320 units of protease. CREON MINIMICROSPHERES® 10 is available as capsules with a brown opaque cap and a transparent body, filled with brownish granules.

It is available in HDPE bottles of 100 capsules. One capsule contains minimicrospheres corresponding to (Ph. Eur. units) 10,000 units of lipase, 11,200 units of amylase, and 730 units of protease. Route of Administration […]

• CREON MINIMICROSPHERES® is contraindicated in patients who are hypersensitive to this drug (porcine protein or pancreatic enzymes) or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. CREON MINIMICROSPHERES® lipase/amylase/protease Page 5 of 21