Creon Minimicrospheres 6 Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

CREON MINIMICROSPHERES^® (pancreatin) is indicated in pediatric and adult patients for:

• treatment of pancreatic exocrine insufficiency (PEI) attributed to cystic fibrosis, chronic pancreatitis, or any other medically defined pancreatic disease that might require pancreatic enzyme therapy

including, but not limited to:

• cystic fibrosis
• chronic pancreatitis
• pancreatic surgery
• gastrectomy
• pancreatic cancer
• gastrointestinal bypass surgery (e.g. Billroth II gastroenterostomy)
• ductal obstruction of the pancreas or common bile duct (e.g. from neoplasm)
• Shwachman-Diamond Syndrome
• status after an attack of acute pancreatitis and initiation of enteral or oral feeding

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.

Pediatrics (≤ 18 years of age):

CREON MINIMICROSPHERES^® was shown to be effective in pediatric populations with PEI due to cystic fibrosis, independent of age and severity of the disease. The efficacy and safety observed during CREON MINIMICROSPHERES^® treatment in these patients was similar to that in adult patients (see ADVERSE REACTIONS and CLINICAL TRIALS).

CONTRAINDICATIONS

• Patients who have known hypersensitivity to porcine protein, pancreatic enzymes or to any other ingredient in this product. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section.

WARNINGS AND PRECAUTIONS

General

Should hypersensitivity develop, discontinue medication and treat the patient symptomatically.

It is important to ensure adequate hydration in patients at all times during therapy with pancreatic enzymes.

Capsules should be swallowed whole without crushing or chewing, with enough fluid during or after each meal or snack.

Where swallowing the capsules is difficult they may be opened. The minimicrospheres can be added to small amounts of acidic soft food (pH < 5.5) that do not require chewing such as apple sauce or yogurt, or be taken with acidic liquid (pH < 5.5) such as apple, orange, or pineapple juice (see DOSAGE AND ADMINISTRATION).

Mixtures with foods or liquids should be used immediately and not stored, otherwise the protective enteric coating may dissolve. 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.

Any change in pancreatic enzyme replacement therapy (e.g. dose or brand of medication) should be made cautiously and only under medical supervision.

Potential Viral Exposure from the Product Source

As with all currently marketed porcine pancreatin products, CREON MINIMICROSPHERES^® is sourced from pancreatic tissue from swine used for food consumption. Although the risk that CREON MINIMICROSPHERES^® 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.

Hepatic/Biliary/Pancreatic

CREON MINIMICROSPHERES^® may cause hyperuricosuria and hyperuricemia with extremely high doses.

Special Populations

Pregnant Women

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. CREON MINIMICROSPHERES^® should only be used during pregnancy if, in the opinion of the healthcare practitioner, the potential benefits outweigh the potential risks.

If required during pregnancy CREON MINIMICROSPHERES^® should be used in doses sufficient to provide adequate nutritional status.

Nursing Women

There is insufficient data to assess the risks however animal studies suggest no systemic exposure of the breastfeeding woman to pancreatic enzymes. CREON MINIMICROSPHERES^® should only be used, in the opinion of the healthcare practitioner, the potential benefits outweigh the potential risks.

If required during breastfeeding CREON MINIMICROSPHERES^® should be used in doses sufficient to provide adequate nutritional status.

Pediatrics (≤ 18 years of age):

There are no special warnings or precautions for use in pediatrics.

Geriatrics (> 65 years of age):

There are no special warnings or precautions for use in elderly patients.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most commonly reported adverse reactions were gastrointestinal disorders and were primarily mild or moderate in severity.

At extremely high doses, hyperuricosuria and hyperuricaemia have been reported. Fibrosing colonopathy have been reported in cystic fibrosis patients (see WARNINGS AND PRECAUTIONS).

Allergic or hypersensitivity reactions have been reported.

Pediatrics

No specific adverse reactions have been identified in the pediatric population. Frequency, type and severity of adverse reactions were similar in children with cystic fibrosis as compared to adults.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In clinical trials, more than 900 patients were exposed to CREON MINIMICROSPHERES^® (pancreatin).

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

Post-Market Adverse Drug Reactions

The following adverse events have been reported during post-marketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency.

DRUG INTERACTIONS

Drug-Drug Interactions

No interaction studies have been performed.

DOSAGE AND ADMINISTRATION

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 WARNINGS AND PRECAUTIONS).

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.

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.

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.

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^® 6, 10, and 25 are available as capsules filled with gastro-resistant granules (minimicrospheres). The capsules should be swallowed intact, without 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.

When swallowing of capsules is difficult (e.g. small children or elderly patients), the capsules may be opened.

The minimicrospheres can be added to small amounts of acidic soft food (pH < 5.5) that do not require chewing such as apple sauce or yogurt, or be taken with acidic liquid (pH < 5.5) such as apple, orange or pineapple juice (see WARNINGS AND PRECAUTIONS). This mixture should not be stored.

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. 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 (see WARNINGS AND PRECAUTIONS).

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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

When the minimicrospheres reach the small intestine the coating rapidly disintegrates (at pH > 5.5) to release pancreatic enzymes. These enzymes catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.

Pharmacokinetics

Absorption

Animal studies showed no evidence for absorption of intact enzymes and therefore classical pharmacokinetic studies have not been performed. Pancreatic enzyme supplements do not require absorption to exert their effects. On the contrary, their full therapeutic activity is exerted from within the lumen of the gastrointestinal tract. Pancreatic enzymes are proteins, as such they undergo proteolytic digestion while passing along the gastrointestinal tract before being absorbed as peptides and amino acids.

Distribution

No information is available.

Metabolism

No information is available.

Excretion

No information is available.

STORAGE AND STABILITY

Store CREON MINIMICROSPHERES^® (pancreatin) between 15 and 30ºC in a tightly-closed container to protect from moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

CREON MINIMICROSPHERES^® MICRO

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.

One spoonful (100 mg) contains minimicrospheres corresponding to (Ph.Eur. units): 5,000 units of lipase, 5,100 units of amylase, and 320 units of protease.

Listing of Non-Medicinal Ingredients

CREON MINIMICROSPHERES^® MICRO contains the following non-medicinal ingredients: cetyl alcohol, dimethicone 1000, hypromellose phthalate, macrogol 4000 and triethyl citrate.

CREON MINIMICROSPHERES^® 6

CREON MINIMICROSPHERES^® 6 is available as capsules with a Swedish orange opaque cap with imprint “CREON 1206” and a blue opaque body, filled with brownish granules. It is available in HDPE bottles of 100 capsules. One capsule contains minimicrospheres corresponding to (USP units) 6,000 units of lipase, 30,000 units of amylase, and 19,000 units of protease.

Listing of Non-Medicinal Ingredients

CREON MINIMICROSPHERES^® 6 contains the following non-medicinal ingredients: cetyl alcohol, dimethicone 1000, FD&C Blue No. 2, gelatin, hypromellose phthalate, iron oxides, macrogol 4000, sodium lauryl sulphate, titanium dioxide and triethyl citrate.

CREON MINIMICROSPHERES^® 10

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.

Listing of Non-Medicinal Ingredients

CREON MINIMICROSPHERES^® 10 contains the following non-medicinal ingredients: cetyl alcohol, dimethicone 1000, gelatin, hypromellose phthalate, iron oxides, macrogol 4000, sodium lauryl sulphate, titanium dioxide and triethyl citrate.

CREON MINIMICROSPHERES^® 25

CREON MINIMICROSPHERES^® 25 is available as capsules with a Swedish orange 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) 25,000 units of lipase, 25,500 units of amylase, and 1,600 units of protease.

Listing of Non-Medicinal Ingredients

CREON MINIMICROSPHERES^® 25 contains the following non-medicinal ingredients: cetyl alcohol, dimethicone 1000, gelatin, hypromellose phthalate, iron oxides, macrogol 4000, sodium lauryl sulphate, titanium dioxide and triethyl citrate.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

CLINICAL TRIALS

Pancreatic Exocrine Insufficiency

Overall 30 studies investigating the efficacy of CREON MINIMICROSPHERES^® capsules 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 MINIMICROSPHERES^® over placebo on the primary efficacy parameter, the coefficient of fat absorption (CFA).

The CFA determines the percentage of fat that is absorbed into the body taking into account fat intake and fecal fat excretion. In the placebo-controlled pancreatic exocrine insufficiency studies, the mean CFA (%) was higher with CREON MINIMICROSPHERES^® treatment (83.0%) as compared to placebo (62.6%). In all studies, irrespective of the design, the mean CFA (%) at the end of the treatment period with CREON MINIMICROSPHERES^® was similar to the mean CFA values for CREON MINIMICROSPHERES^® in the placebo-controlled studies.

In the placebo-controlled studies, the mean percentage of days without the clinical symptoms of abdominal pain and flatulence was highest in the CREON MINIMICROSPHERES^® group as compared to placebo. Vice versa, the mean percentage of days with abdominal pain or flatulence of most different intensities (mild, moderate, severe) was lowest with CREON MINIMICROSPHERES^® compared to placebo. The mean percentage of days with hard and formed/normal stools was highest with CREON MINIMICROSPHERES^® treatment (6.6% and 59.8%, respectively) compared with placebo (4.8% and 38.1%, respectively). The percentage of days with soft and watery stools was always lowest with CREON MINIMICROSPHERES^® treatment compared to placebo. In all performed studies, irrespective of etiology, an improvement was also shown in disease specific symptomatology (stool frequency, stool consistency, flatulence).

Pediatric Population

In cystic fibrosis (CF) the efficacy of CREON MINIMICROSPHERES^® was demonstrated in 288 pediatric patients covering an age range from newborns to adolescents. In all studies, the mean end-of-treatment CFA values exceeded 80% on CREON MINIMICROSPHERES^® comparably in all pediatric age groups.

Additional Data in Pediatric Population for CREON MINIMICROSPHERES^® MICRO

CREON MINIMICROSPHERES^® MICRO has been specifically developed to offer a dosage form for infants and children. One baseline-adjusted specific study performed over 8 weeks in 12 infants, aged 1 to 23 months, demonstrated that CREON MINIMICROSPHERES^® MICRO was effective regarding the improvement of CFA and stool fat excretion as well as fecal energy loss after two weeks of treatment. 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%, p = 0.0013, paired t-test). Height and weight increased, but the weight for height percentile remained nearly constant and close to 100%.

TOXICOLOGY

Non-clinical data show no relevant acute, subchronic or chronic toxicity. Studies on genotoxicity, carcinogenicity or toxicity to reproduction have not been performed.

REFERENCES

1. 1. Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. Journal of Pediatric Gastroenterology Nutrition 2002 Sep; 35:246-259.
2. 2. Borowitz D, Robinson KA, Rosenfeld M. et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr 2009; 155(6, suppl):S73-S93.
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