Zenpep: Package Insert and Label Information

ZENPEP- pancrelipase lipase, pancrelipase protease and pancrelipase amylase capsule, delayed release
Allergan, Inc.

1 INDICATIONS AND USAGE

ZENPEP ® is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

ZENPEP is not interchangeable with other pancrelipase products.

ZENPEP is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of ZENPEP should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet (see Limitations on Dosing below).

Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences.1, 2, 3 ZENPEP should be administered in a manner consistent with the recommendations of the Conferences provided in the following paragraphs, with one exception. The Conferences recommend doses of 2,000 to 4,000 lipase units in infants up to 12 months. ZENPEP is available in a 3,000 lipase unit capsule. The recommended dose of ZENPEP in infants up to 12 months is 3,000 lipase units. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.

Infants (up to 12 months)

Infants may be given 3,000 lipase units (one capsule) per 120 mL of formula or breast-feeding. Do not mix ZENPEP capsule contents directly into formula or breast milk prior to administration [see Dosage and Administration ( 2.2)].

Children Older than 12 Months and Younger than 4 Years

Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

Children 4 Years and Older and Adults

Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

Usually, half of the prescribed ZENPEP dose for an individualized full meal should be given with each snack. The total daily dose should reflect approximately three meals plus two or three snacks per day.

Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight.

Limitations on Dosing

Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3

If symptoms and signs of steatorrhea persist, the dosage may be increased by a healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted.

Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses greater than 6,000lipase units/kg of body weight per meal have been associated with colonic strictures, indicative of fibrosing colonopathy, in children with cystic fibrosis less than 12 years of age [see Warnings and Precautions ( 5.1)]. Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.

2.2 Administration

ZENPEP should always be taken as prescribed by a healthcare professional.

Infants (up to 12 months)

ZENPEP should be administered to infants immediately prior to each feeding, using a dosage of 3,000 lipase units (one capsule) per 120 mL of formula or per breast-feeding. Contents of the capsule may be administered with a small amount of applesauce, or other acidic food with a pH of 4.5 or less (e.g., commercially available preparations of bananas, or pears). Contents of the capsule may also be administered directly to the mouth. Administration should be followed by breast milk or formula. 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 ZENPEP is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa.

Children and Adults

ZENPEP should be taken during meals or snacks, with sufficient fluid. ZENPEP capsules and capsule contents should not be crushed or chewed. Capsules should be swallowed whole.

For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents sprinkled on small amounts of acidic soft food of pH 4.5 or less (e.g., commercially available preparations of bananas, pears and applesauce).

The ZENPEP -soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth.

3 DOSAGE FORMS AND STRENGTHS

The active ingredient in ZENPEP evaluated in clinical trials is lipase. ZENPEP is dosed by lipase units.

ZENPEP is available in 7 color coded capsule strengths.

Other active ingredients include protease and amylase. Each ZENPEP capsule strength contains the specified amounts of lipase, protease, and amylase.

Capsules of all strengths are colored as follows:

  • 3,000 USP units of lipase; 10,000 USP units of protease; 14,000 USP units of amylase capsules have a white opaque cap and white opaque body, red imprint with “APTALIS 3”
  • 5,000 USP units of lipase; 17,000 USP units of protease; 24,000 USP units of amylase capsules have a white opaque cap and white opaque body, blue imprint with “APTALIS 5”
  • 10,000 USP units of lipase; 32,000 USP units of protease; 42,000 USP units of amylase capsules have a yellow opaque cap and white opaque body, blue imprint with “APTALIS 10”
  • 15,000 USP units of lipase; 47,000 USP units of protease; 63,000 USP units of amylase capsules have a red opaque cap and white opaque body, blue imprint with “APTALIS 15”
  • 20,000 USP units of lipase; 63,000 USP units of protease; 84,000 USP units of amylase capsules have a green opaque cap and white opaque body, blue imprint with “APTALIS 20”
  • 25,000 USP units of lipase; 79,000 USP units of protease; 105,000 USP units of amylase capsules have a blue opaque cap and white opaque body, blue imprint with “APTALIS 25”
  • 40,000 USP units of lipase; 126,000 USP units of protease; 168,000 USP units of amylase capsules have a orange opaque cap and white opaque body, blue imprint with “APTALIS 40”

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Fibrosing Colonopathy

Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. Fibrosing colonopathy is a rare serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually with use over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis.The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic strictures in children less than 12 years of age.1 Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs. It is generally recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day [see Dosage and Administration ( 2.1)].

Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.

5.2 Potential for Irritation to Oral Mucosa

Care should be taken to ensure that no drug is retained in the mouth. ZENPEP should not be crushed or chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss or enzyme activity [see Dosage and Administration ( 2.2) and Patient Counseling Information ( 17.1)]. For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce. The ZENPEP-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion.

5.3 Potential for Risk of Hyperuricemia

Caution should be exercised when prescribing ZENPEP to patients with gout, renal impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.

5.4 Potential Viral Exposure from the Product Source

ZENPEP is sourced from pancreatic tissue from swine used for food consumption. Although the risk that ZENPEP will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Thus, 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.

5.5 Allergic Reactions

Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued ZENPEP treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.

6 ADVERSE REACTIONS

The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) include fibrosing colonopathy, hyperuricemia and allergic reactions [see Warnings and Precautions ( 5)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The short-term safety of ZENPEP was assessed in two clinical trials conducted in 53 patients, ages 1 to 23 years, with exocrine pancreatic insufficiency (EPI) due to CF. In both studies, ZENPEP was administered in doses of approximately 5,000 lipase units per kilogram per day, for lengths of treatment ranging from 19 to 42 days. The population was nearly evenly distributed in gender, and approximately 96% of patients were Caucasian.

Study 1 was a randomized, double-blind, placebo-controlled, 2-treatment, crossover study of 34 patients, ages 7 to 23 years, with EPI due to CF. In this study, patients were randomized to receive ZENPEP at individually titrated doses (not to exceed 2,500 lipase units per kilogram per meal) or matching placebo for 6 to 7 days of treatment, followed by crossover to the alternate treatment for an additional 6 to 7 days. The mean exposure to ZENPEP during this study, including titration period and open label transition, was 30 days.

The incidence of adverse events (regardless of causality) was similar during double blind ZENPEP treatment (56%) and placebo treatment (50%). The most common adverse events reported during the study were gastrointestinal complaints, which were reported more commonly during placebo treatment (41%) than during ZENPEP treatment (32%), and headache, which was reported more commonly during ZENPEP treatment (15%) than during placebo treatment (0). The type and incidence of adverse events were similar in children (7-11 years), adolescents (12-16 years), and adults (greater than 18 years).

Because clinical trials are conducted under controlled conditions, the observed adverse event rates may not reflect the rates observed in clinical practice.

Table 1 enumerates treatment-emergent adverse events that occurred in at least 2 patients (greater than or equal to 6%) treated with either ZENPEP or placebo in Study 1. Adverse events were classified by Medical Dictionary for Regulatory Activities (MedDRA) terminology.

Table 1: Treatment-Emergent Adverse Events Occurring in at least 2 Patients (greater than or equal to 6%) During Treatment Period and Crossover Treatment Period of the Placebo-Controlled, Crossover Clinical Study of ZENPEP (Study 1)
ZENPEP Placebo
MedDRA Primary System Organ Class Preferred Term (N=34) % (N=32) %
Gastrointestinal Disorders
Abdominal pain 6 (18%) 9 (28%)
Flatulence 2 (6%) 3 (9%)
Nervous System Disorders
Headache 5 (15%) 0
Injury, Poisoning and Procedural Complications
Contusion 2 (6%) 0
Investigations
Weight decreased 2 (6%) 2 (6%)
Respiratory, Thoracic and Mediastinal Disorders
Cough 2 (6%) 0
General Disorders and Administration Site Conditions
Early Satiety 2 (6%) 0

Study 2 was an open-label, uncontrolled study of 19 patients, ages 1 to 6 years, with EPI due to CF. After a 4-14 days screening period on the current PEP, patients in Study 2 received ZENPEP 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 14days. There was no comparator treatment, and adverse events were collected on patient diary entries and at each study visit.

The most commonly reported adverse events were gastrointestinal, including abdominal pain and steatorrhea, and were similar in type and frequency to those reported in the double-blind, placebo-controlled trial (Study 1).

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