Norzyme 25,000 Gastro-resistant capsule

For the treatment of pancreatic exocrine insufficiency.

Adults (including the elderly) and children:

Initially one or two capsules during or immediately after each meal.

Dose increases, if required, should be added slowly, with careful monitoring of response and symptomatology.

The capsules can be swallowed whole, or for ease of administration they may be opened and the micropellets 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 micropellets 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 micropellets are not crushed or chewed. Crushing and chewing of the micropellets 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 Norzyme.

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).

Hypersensitivity to pancreas powder (pancreatic extract) of porcine origin or to any of the excipients.

Strictures of the ileo-caecum and large bowel (fibrosing colonopathy) have been reported in patients with cystic fibrosis taking high doses of preparations containing pancreas powder (pancreatic extract). 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.

Hepatitis E virus infection

Despite measures taken during manufacturing to reduce the risk, the presence of hepatitis E virus (HEV) in medicinal products containing pancreas powder extracts of animal (porcine) origin is possible. A cross-sectional study has suggested a higher HEV seroprevalence in patients with cystic fibrosis using pancreatic enzyme replacement therapy than in individuals who do not use pancreatin. This study is subject to important limitations including uncertainty with regards to the timing of past infection, as well as the potential for other sources of HEV. As a precaution, immunosuppressed patients receiving high daily dosing should be advised about symptoms of viral hepatitis and to seek medical attention if such symptoms occur.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

No interaction studies have been performed.

Pregnancy

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.

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 or lactation Norzyme should be used in doses sufficient to provide adequate nutritional status.

Norzyme has no or negligible influence on the ability to drive and use machines.

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

The following adverse reactions have been observed 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 diarrhoea.

Strictures of the ileo-caecum and large bowel (fibrosing colonopathy) have been reported in patients with cystic fibrosis taking high doses of preparations containing pancreas powder (pancreatic extract), 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 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.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system “the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.”

Extremely high doses of pancreas powder (pancreatic extract) have been reported to be associated with hyperuricosuria and hyperuricaemia.

Supportive measures including stopping enzyme therapy and ensuring adequate rehydration are recommended.

Multienzymes (amylase, lipase, protease), ATC code: A09A A02

Norzyme contains porcine pancreas powder formulated as enteric-coated (acid-resistant) micropellets within gelatine capsules.

The capsules dissolve rapidly in the stomach releasing plenty of micropellets, a multidose 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 micropellets 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 pancreas powder (pancreatic extract) containing preparations of different strengths 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 randomised, placebo-controlled, efficacy studies, the pre-defined primary objective was to show superiority of pancreas powder (pancreatic extract) 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 faecal fat excretion. In the placebo controlled PEI studies, the mean CFA (%, mean ± SD) was higher with treatment with pancreas powder (pancreatic extract) (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 pancreas powder (pancreatic extract) was similar to the mean CFA values for preparations containing pancreas powder (pancreatic extract) in the placebo controlled studies.

Treatment with pancreas powder (pancreatic extract) markedly improves the symptoms of pancreatic exocrine insufficiency including stool consistency, abdominal pain, flatulence and stool frequency, independent of the underlying disease.

In placebo-controlled studies in which symptoms have been collected on diaries, the percentage of subjects with 'no abdominal pain' as most frequently reported rating was higher (73 %) during treatment with pancreas powder (pancreatic extract) than during placebo treatment (52 %). The most frequently reported stool consistency was 'formed/normal' in 63 % of the subjects during treatment with pancreas powder (pancreatic extract) and in 17 % of the subjects during placebo treatment. During treatment with pancreas powder (pancreatic extract), the percentage of subjects with 'no flatulence' as most frequently reported rating was higher (30 %) than during placebo treatment (19 %). The average number of daily stools was lower during treatment with pancreas powder (pancreatic extract) than during placebo treatment (mean ± SD: 1.89 ± 0.87 vs 3.16 ± 1.51).

In subjects with PEI due to CF in these studies, the percentage of subjects with 'no abdominal pain' as most frequently reported rating was 94 % during treatment with pancreas powder (pancreatic extract) and 60 % during placebo treatment. The most frequently reported stool consistency was 'formed/normal' in 73 % of the subjects during treatment with pancreas powder (pancreatic extract) and in 18 % of the subjects during placebo treatment. The percentage of subjects with 'no flatulence' as most frequently reported rating was 37 % during treatment with pancreas powder (pancreatic extract) and 26 % during placebo treatment. The average number of daily stools (mean ± SD) was 1.78 ± 0.78 during treatment with pancreas powder (pancreatic extract) and 3.24 ± 1.49 during placebo treatment.

In subjects with PEI due to CP in these studies, the percentage of subjects with 'no abdominal pain' as most frequently reported rating was 55 % during treatment with pancreas powder (pancreatic extract) and 46 % during placebo treatment. The most frequently reported stool consistency was 'formed/normal' in 45 % of the subjects during treatment with pancreas powder (pancreatic extract) and in 18 % of the subjects during placebo treatment. The percentage of subjects with 'no flatulence' as most frequently reported rating was 26 % during treatment with pancreas powder (pancreatic extract) and 13 % during placebo treatment. The average number of daily stools (mean ± SD) was 2.07 ± 1.08 during treatment with pancreas powder (pancreatic extract) and 2.89 ± 1.55 during placebo treatment.

Paediatric population

In cystic fibrosis (CF) the efficacy of pancreas powder (pancreatic extract) 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 treatment with pancreas powder (pancreatic extract) comparably in all paediatric age groups.

Pancreas powder (pancreatic extract) and the enzymes contained therein are not absorbed from the gastrointestinal tract. They are eliminated through the stool or largely degraded or denatured by digestive juice or bacteria. The resulting amino acids and short-chain peptides can be taken up by the body.

No preclinical studies have been performed.

Capsule contents:

  Crospovidone

  Microcrystalline cellulose

  Highly dispersed silica

  Magnesium stearate

  Methacrylic acid-ethyl acrylate copolymer (1:1) dispersion 30 % (contains Methacrylic acid-ethyl acrylate copolymer (1:1), polysorbate 80, sodium laurilsulfate and water)

  Triethyl citrate

  Talc

  Simeticon emulsion (contains simeticon, methyl cellulose, sorbic acid and water)

  Montan glycol wax

Capsule shells:

  Gelatine

  Titanium dioxide (E171)

  Iron oxides and hydroxides (E172

None known.

2 years

after opening: 4 months

Store below 25 °C.

Keep the container tightly closed in order to protect from moisture.

Amber glass bottle(s) in outer carton with

• 50 gastro-resistant capsules, hard

• 100 gastro-resistant capsules, hard

• 200 (2x100) gastro-resistant capsules, hard

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.