Enzepi - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

Gastro-resistant hard capsule.

Enzepi 5,000 units gastro-resistant hard capsules

Hard capsules with a white opaque cap and a white opaque body, printed with “Enzepi 5” and containing light-brown gastro-resistant granules.

Enzepi 10,000 units gastro-resistant hard capsules

Hard capsule with a yellow opaque cap and a white opaque body, printed with “Enzepi 10” and containing light-brown gastro-resistant granules.

Enzepi 25,000 units gastro-resistant hard capsules

Hard capsule with a green opaque cap and a white opaque body, printed with “Enzepi 25” and containing light-brown gastro-resistant granules.

Enzepi 40,000 units gastro-resistant hard capsules

Hard capsule with a blue opaque cap and a white opaque body, printed with “Enzepi 40” and containing light-brown gastro-resistant granules.

4. CLINICAL PARTICULARS4.1 Therapeutic indicationsic fibrosis or other

Pancreatic enzyme replacement treatment in exocrine pancreatic insufficiency due to conditions (e.g. chronic pancreatitis, post pancreatectomy or pancreatic cancer).

Enzepi is indicated in infants, children, adolescents and adults.

4.2 Posology and method of administration

Posology

The dosage of Enzepi should be individualised based on clinical symptoms, the degree of steatorrhoea present, the fat content of the diet, or actual body weight. Therapy should be initiated at the lowest recommended dose and gradually increased under medical supervision with careful monitoring of the patient’s response and symptoms. Patients should be instructed not to increase the dosage on their own. Changes in dosage may require an adjustment period of several days.

Maximum recommended dose

The maximum recommended total dose is 2,500 lipase units/kg of body weight per meal (or 10,000 lipase units/kg of body weight per day), or 4,000 lipase units/g fat ingested per day. Higher doses should be used with caution if warranted (see sections 4.4 and 4.9) and only if they are documented to be effective by 3day faecal fat measurements that indicate a significantly improved coefficient of fat absorption.

For each snack, half of the prescribed Enzepi dose for a full meal should be given. Enzyme doses expressed as lipase units/kg of body weight per meal must be reduced in older patients because they tend to ingest less fat per kilogram of body weight.

Starting dose

Paediatric population below 1 year of age

For infants below 1 year of age the recommended starting dose is 5,000 lipase units per meal (generally 120 ml of milk) (see section Method of administration).

Paediatric population between 1 and less than 4 years of age

For children between 1 and less than 4 years of age the recommended starting dose is 1,000 lipase units/kg of body weight per meal.

Paediatric population aged 4 years or older and adults (including elderly)

For children aged 4 years or older, adolescents and adults the recommended starting dose is 500 lipase units/kg of body weight per meal.

Method of administration

For oral use.

Enzepi should be taken during meals or snacks, with a drink of water or juice.

Capsules should be swallowed whole and not chewed or crushed. Crushing, chewing, or mixing capsule contents with food or fluid with a pH greater than 5 or storing the food mixture (see below), can lead to a disruption of the protective gastro-resistant coating. This can result in early release of the enzymes in the oral cavity, irritation of the mucous membranes and may lead to loss of enzyme activity.

Patients unable to swallow capsules whole

For patients who are unable to swallow capsules whole, the capsules may be carefully opened and the contents mixed (without crushing) with small amounts of acidic soft food of pH 5 or less (e.g., fruit puree [apple/ pear], yoghurt, juice [orange/pineap­ple/apple]). Do not mix with water, milk, breast-milk, formula, flavoured milk or hot food. The Enzepi soft food mixture should be swallowed immediately without chewing and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that Enzepi is not retained in the mouth. The mixture must not be stored.

Paediatric population

For paediatric patients below 1 year of age, Enzepi must be administered immedi

The capsule should be carefully opened to empty the content (granules). Th with a small amount of appropriate acidic food or directly into the mouth. A by breast-milk or formula to ensure complete ingestion. The contents of the capsule should not be mixed directly into formula or breast-milk as this may diminish efficacy. Care should be taken to ensure that Enzepi is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• 4.4 Special warnings and precautions

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Pancreatic enzyme medicinal products do not cause pharmacokinetic and pharmacodynamic interactions based on their pharmacology, as they are not absorbed from the gastrointestinal tract. No clinically relevant interactions are expected.

4.6 Fertility, pregnancy and lactation

Pregnancy                                                   ­¿V

There are no adequate data from the use of this medicinal product in pregnant women. It is also not known whether this medicinal product can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Although, no preclinical investigations were carried out with Enzepi there is no evidence for any absorption of this medicinal product. Therefore, no reproductive or developmental toxicity is to be expected. The risk and benefit of this medicinal product should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and foetal growth.

Reduced maternal weight gain and malnutrition can be associ

Breast-feeding

It is unknown whether this medicinal product is excreted in human milk. Nevertheless, undersirable effects on the breastfed newborn/infant are not anticipated since systemic exposure in breast-feeding women to the pancreatic enzymes present in Enzepi is not expected.

As a risk to newborns/infants cannot be excluded, a decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Enzepi therapy taking into account the benefit of breast-feeding for the child and the benefit of continued Enzepi therapy for the breastfeeding wo­man.

Fertility

No human data on the effect of Enzepi on fertility are available.

4.7 Effects on a

drive and use machines

Enzepi has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most important serious adverse reactions observed with pancreatic enzyme medicinal products are anaphylactic reactions (see section 4.4) and fibrosing colonopathy (see section 4.4).

The most common adverse reactions reported with Enzepi were gastrointestinal complaints [abdominal pain (16%); flatulence (12%); abdominal distention (7%); diarrhoea and vomiting (6%); constipation (5%); nausea (3%)], and headache occurring in approximately 6% of patients. In clinical trials, most of them were mild to moderate in severity.

Tabulated list of adverse reactions

Adverse reactions associated with pancreas powder obtained from clinical studies, post-marketing surveillance and some additional class effects are tabulated below. They are presented according to the

MedDRA System Organ Classification and are ranked under headings of frequency, using the following categories: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Class	Very common	Common	Not known
Immune system disorders			Anaphylactic reaction** Drug hypersensitivity/ Hypersensitivity
Metabolism and nutrition disorders			Hyperuricaemia/ hyperuricosuria** Decreased appetite
Nervous system disorders		Headache	Dizziness
Respiratory, thoracic and mediastinal disorders			Dyspnoea*
Gastrointestinal disorders	Abdominal pain	Diarrhoea Vomiting Nausea Constipation Abdominal distension Flatulence Abdominal discomfort	Fibrosing colonopathy** Lip swelling and swollen tongue* Stomatitis Abdominal pain upper Dyspepsia Abnormal faeces Faeces discoloured Frequent bowel movements
Skin and subcutaneous tissue disorders	X		Swelling face Urticaria Rash generalised Rash Rash erythematous Pruritus
General disorders and £ administration site conditions			Fatigue Malaise
Investigations'^?			Blood glucose decreased Blood glucose increased Weight decreased Weight increased

*Symptoms of allergic reactions.

**Class effects

Description of selected adverse reactions

In patients at risk of abnormal blood glucose levels glycaemic control may be affected by administration of pancreatic enzyme replacement therapy (see section 4.4). Cases of blood glucose fluctuations have been reported with Enzepi, most of them non-serious and recovered after diabetic treatment adjustment.

The most relevant class effects of the pancreatic enzyme products include fibrosing colonopathy, hyperuricaemia/ hyperuricosuria and anaphylactic reactions.

Paediatric population

In clinical trials, 110 children with CF (cystic fibrosis) aged 1 month and older received Enzepi at a dose that ensured stabilization of symptoms. The safety profile of Enzepi in the paediatric population was similar to that observed in adults.

Elderly people

No specific adverse reactions were identified in the elderly population. Frequency, type and severity of adverse reactions were similar in elderly people with pancreatic exocrine insufficiency 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 listed in Appendix V.

4.9 Overdose

Chronic high doses of pancreatic enzyme products have been associated with fibr

result in some cases colonic strictures (see sections 4.2 and 4.4). High doses have been associated with hyperuricosuria and hyperuricaemia, and should b with a history of gout, renal impairment or hyperuricaemia (see section 4.4). Supportive measures including stopping pancreatic enzyme therapy and ensuring adequate rehydration are recommended.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Digestives, incl. enzymes, Enzyme preparations, ATC code: A09AA02

Mechanism of action

Enzepi belongs to the family of pancreatic enzyme products and contains a defined amount of lipase, amylase and protease that have been extracted from porcine pancreas and purified using a process designed to inactivate viruses.

Gastro-resistant granules are thoroughly mixed with chyme when the capsule dissolves in the stomach, without inactivating the acid-sensitive enzymes. It is only in the duodenum, which has a different environment with a p e greater than 5, that these digestive enzymes are released from the granules.

he hydrolysis of fats to monoglycerides, glycerol, and free fatty acids, protein into cids, and starch into dextrins and short chain sugars such as maltose and maltotriose in proximal small intestine, thereby acting like digestive enzymes physiologically secreted

Clinical efficacy

The efficacy of Enzepi has been evaluated in one active-comparator study and one placebo-controlled study conducted in 130 patients with EPI (exocrine pancreatic insufficiency) associated with CF. Moreover three supportive studies were conducted in 34 paediatric patients.

Data generated in the CF population with EPI can be extrapolated to the other causes of EPI such as chronic pancreatitis, post pancreatectomy or pancreatic cancer.

Study PR-005

The pivotal study PR-005 was conducted in Europe. It was a randomized, double-blind, active controlled, two-treatment, crossover study, comparing Enzepi to standard pancreatic enzyme treatment during

2 treatments periods. During the first treatment period, patients received either Enzepi or the comparator for 28 days, followed by a cross-over to the alternate treatment for a second 28 day period. For both treatment periods, patients received a dose as close as possible to their stabilized existing pancreatic enzyme product dose on the first day. Then, starting on the second day, the dose of assigned treatment could be changed (titrated up and/or titrated down) to stabilize the symptoms of EPI. Stabilization of the symptoms had to be obtained before the end of the first 14 days of each treatment period.

A total of 96 patients, aged 12 to 43 years, were randomized in the intent-to-treat population. During the study, patients were instructed to consume 100 g (± 15 g) of fat per day and to maintain a consistent dietary fat intake for meals and snacks. The primary efficacy endpoint was the coefficient of fat absorption over 72 hours (CFA-72h) which was calculated at the end of each treatment period, from the stools collected during the last 3 days of each treatment period. The collection was performed in an approved, controlled environment that enabled supervised dietary intake and quantitative stool collection.

Subjects achieved a mean CFA-72h of 84.08 with Enzepi and of 85.33 with comparator. The difference in means was –1.25 (95% CI, –3.62 to 1.12), with p=0.2972. Thus, Enzepi demonstrated both non-inferiority and equivalence to the comparator in fat absorption control (measured as CFA-72h) in adolescents and adults with CF-associated EPI.

Analysis of coefficient of fat absorption over 72 hours population (study : PR005)

Model-based statistics (Enzepi minus Creon) LS mean (standard error)

Difference in LS means (95% confidence

p-value

N: number of patients; SD: standard deviation; LS: least squares.

Model-based statistics are from a mixed effects linear model using CFA-72h as the response variable, fixed effect factors for treatment, period and treatment sequence, and subject within treatment sequence as a random effect.

Study EUR-1008-M

The supportive EUR-1008-M, conducted in the US, was a randomized, double-blind, placebo-controlled, crossover study of 34 patients, ages 7 to 23 years, with EPI due to CF. Patients were randomized to receive Enzepi or matching placebo for 6 to 7 days of treatment, followed by cross-over to the alternate treatment for an additional 6 to 7 days. All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the treatment period.

The primary efficacy endpoint was the mean difference in the coefficient of fat absorption (CFA-72h) between Enzepi and placebo treatment. The CFA-72h was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat ingestion were measured. Each patient’s CFA-72h during placebo treatment was used as their no-treatment CFA-72h value.

Mean CFA-72h was 88% with Enzepi treatment compared to 63% with placebo treatment. The mean difference in CFA-72h was 26 percentage points greater with Enzepi treatment with a 95% Confidence Interval of (19, 32) and p<0.001.

Paediatric population

The short-term efficacy and safety of Enzepi were assessed in clinical studies in paediatric patients, ages 1 to 17 years, with EPI due to CF.

Study EUR-1008-M

EUR-1008-M was conducted in 34 patients with EPI due to CF, 26 of whom were children, including 8 children aged 7 to 11 years, and 18 adolescents aged 12 to 17 years. Results are presented above.

The safety and efficacy in the paediatric patients in this study was similar to the adult patients.

Study EUR 1009-M

EUR 1009-M was an open-label, single arm study in 19 patients, ages 1 to 6 years, with EPI due to CF. Approximately half of the patients were ages 1 to 3 years. Patients were transitioned to Enzepi from their usual PEP (pancreatic enzyme product) treatment. After a 4–14 days screening period on their usual PEP, patients received Enzepi at individually titrated doses ranging between 2,300 and 10,000 lipase units per kg body weight per day, with a mean of approximately 5,000 lipase units per kg body weight per day (not to exceed 2,500 lipase units per kilogram per meal) for 14 days. There was no wash-out period.

The primary efficacy endpoint was the percentage of “responders”, defined as those patients without steatorrhoea (<30% faecal fat content) and without signs and symptoms of malabsorption after one and two weeks of treatment with Enzepi. Steatorrhoea was assessed from the faecal fat content measured by spot faecal fat testing on Days 11 and 18 compared with baseline (under usual PEPs).

The number of responders (patients with less than 30% faecal fat content and without signs and symptoms of malabsorption) at baseline was 10/19 (52.6%), 13/19 (68.4%) after 1 week of treatment (stabilization) and 11/19 (57.9%) after the second week of open-label treatment with Enzepi. The mean faecal fat content was (27.3%).

Study PR-011

Study PR-011 was an open-label crossover study in 15 patients, ages 1 to 11 months, with EPI due to CF.

Patients were randomized to receive Enzepi from an opened capsule mixed and administered with apple juice (in a syringe nurser) or apple sauce (using a spoon) for 10 days of treatment, followed by a cross-over

to the alternate mode of administration fo

The primary objective was to assess the acceptability of 2 modes of administration using an acceptability questionnaire that was completed by the caregiver. Twelve patients completed both assigned treatment arms and were evaluated. Overall, caregivers were satisfied with using apple sauce as a dosing method compared with apple juice.

-month open-label extension of Study PR-011. Patients were administered Enzepi at e taking at the end of Study PR-011. The dose of Enzepi was adjusted during the 12-month study as the patient’s grew and gained weight.

Twelve patients completed the study. Overall, an improvement was observed from baseline to study completion for growth indices including weight-for-age, length-for-age, and weight-for-length percentiles.

Elderly people

Clinical studies of Enzepi did not include sufficient numbers of subjects aged 65 and over to determine whether they respond different from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and young patients.

5.2 Pharmacokinetic properties

The pancreatic enzymes in Enzepi are gastro-resistant to minimise destruction or inactivation in gastric acid. Enzepi is designed to release most of the enzymes in vivo at pH greater than 5.5. Pancreatic enzymes are not absorbed from the gastrointesti­nal tract.

5.3 Preclinical safety data

No preclinical investigations were carried out with Enzepi. However as pancreatic enzymes are not absorbed from the gastrointestinal tract, no systemic toxicity is expected following oral administration of pancreas powder.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule content (gastro-resistant granules)

Croscarmellose sodium

Hydrogenated castor oil

Colloidal anhydrous silica

Microcrystalline cellulose

Magnesium stearate

Hypromellose phthalate

Talc

Triethyl citrate

Capsule shell

Hypromellose

Carrageenan (E407)

Potassium chloride

Titanium dioxide (E171)

Carnauba wax

Purified water

Additionally for Enzepi 10,000 units gastro-resistant granules

Yellow iron oxide (E172)

Additionally for Enzepi 25,000 units gastro-resistant granules

Yellow iron oxide (E172)

Indigotine (E132)

Additionally for Enzepi 40,000 units gastro-resistant granules

Indigotine (E132)

Printing ink

Shellac

Propylene glycol

Indigotine (E132)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

After first opening: 6 months when stored below 25°C. Keep the bottle tightly closed and the desiccant in the bottle in order to protect from moisture.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

HDPE bottle containing desiccant sachets, closed with a lined polypropylene childresistant closure and a peel-off sealing liner.

Pack size of 20, 50, 100, and 200 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Use in paediatric population

If required, carefully open the capsule and administer the contents (granules) to the patient as described in section 4.2.

Dispose of any accidentally crushed capsule.

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

7. MARKETING AUTHORISATION HOLDER

Allergan Pharmaceuticals International Limited

Clonshaugh Industrial Estate

Coolock

Dublin 17

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1113/001–016

ST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

Date of first authorisation: