Zenpep Information
Zenpep () Indications And Usage
Zenpep () (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions.
Zenpep () Dosage And Administration
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 below).
Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences. 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.
Children Older than 12 Months and Younger than 4 Years
Children 4 Years and Older and Adults
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
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 6000 lipase 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 . 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.
Zenpep () should always be taken as prescribed by a healthcare professional.
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.
Zenpep () 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 6 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 have a blue radial print on the capsule body and are colored as follows:
Zenpep () Contraindications
Zenpep () Warnings And Precautions
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. of pancreatic enzyme products exceeding 6000 lipase units/kg of body weight per meal have been associated with colonic strictures in children less than 12 years of age. 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
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.
Zenpep () 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
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)
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 5000 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 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).
Postmarketing data for Zenpep () have been available since 2009. The following adverse reactions were reported postapproval. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The most commonly reported adverse events are gastrointestinal disorders (including abdominal distension, abdominal pain, diarrhea, flatulence, constipation and nausea) and skin disorders (including pruritus, urticaria, and rash).
In patients at risk for abnormal blood glucose levels glycemic control may be affected by administration of pancreatic enzyme replacement therapy. Consideration should be given to additional glucose monitoring in these patients.
Delayed- and immediate-release pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature. The most serious adverse events include fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus.
In general, pancreatic enzyme products have a well defined and favorable risk-benefit profile in exocrine pancreatic insufficiency.
Zenpep () Drug Interactions
No drug interactions have been identified. No formal interaction studies have been conducted.
Zenpep () Use In Specific Populations
The short-term safety and effectiveness of Zenpep () were assessed in 2 clinical studies in pediatric patients, ages 1 to 17 years, with EPI due to CF.
Study 1 was a randomized, double-blind, placebo-controlled, crossover study in 34 patients 26 of whom were children, including 8 children aged 7 to 11 years, and 18 adolescents aged 12 to 17 patients.. The safety and efficacy in pediatric patients in this study were similar to adult patients
Study 2 was an open-label, single arm study in 19 patients, ages 1 to 6 years, with EPI due to CF. When patient regimen was switched from their usual PEP regimen to Zenpep () at similar doses, patients showed similar control of their clinical symptoms.
The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis has been described in the medical literature and through clinical experience.
Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation Consensus Conferences Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years of age
Zenpep () Overdosage
In Study 1, a 10 year-old patient was administered a dose of 10,856 lipase units per kg body weight of Zenpep () for a period of one day. The patient did not experience any adverse events as a result of the dose increase, nor did this patient experience any adverse events during a 44-day follow-up period. No abnormalities from analyses of safety labs (chemistry, hematology, urinalysis or uric acid) were noted.
Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures . High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment .
Zenpep () Description
Zenpep () is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine derived lipases, proteases, and amylases.
Pancrelipase is a cream-colored powder. It is miscible in water and practically insoluble or insoluble in alcohol and ether.
Each capsule for oral administration contains enteric coated beads (1.8-1.9mm for 3,000 and 5,000 USP units of lipase, 2.2-2.5mm for 10,000, 15,000, 20,000 and 25,000 USP units of lipase).
The active ingredient evaluated in clinical trials is lipase. Zenpep () is dosed by lipase units. Other active ingredients include protease and amylase.
Inactive ingredients in Zenpep () include colloidal silicon dioxide, croscarmellose sodium, hydrogenated castor oil, hypromellose phthalate, magnesium stearate, microcrystalline cellulose, talc, and triethyl citrate and are contained in hypromellose capsules. The imprinting red ink on the 3,000 capsules strength contains, antifoam DC 1510, industrial methylated spirit, iron oxide red C.I. 77491-E172, n-butyl alcohol, shellac and soya lecithin.
The imprinting blue ink on the capsules strengths 5,000, 10,000, 15,000, 20,000 and 25,000 contains dehydrated alcohol, FD&C Blue #2 aluminum lake C.I. 73015-E132, isopropyl alcohol, n-butyl alcohol, propylene glycol, shellac and strong ammonia solution.
Zenpep () Clinical Studies
The short-term safety and efficacy of Zenpep () were evaluated in 2 studies conducted in 53 patients, ages 1 to 23 years, with exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF).
Study 1, was a randomized, double-blind, placebo-controlled, crossover study of 34 patients, ages 7 to 23 years, with EPI due to CF. The final analysis population was limited to 32 patients, who completed both double-blind treatment periods, and were included in the efficacy analysis population. Patients were randomized to receive Zenpep () 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 dose during the controlled treatment periods ranged from a mean dose of 3,900 lipase units per kilogram per day to 5,700 lipase units per kilogram per day. 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) between Zenpep () and placebo treatment. The CFA was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat ingestion were measured. Each patient’s CFA during placebo treatment was used as their no-treatment CFA value.
Mean CFA was 88% with Zenpep () treatment compared to 63% with placebo treatment. The mean difference in CFA was 26 percentage points in favor of Zenpep () treatment with 95% Confidence Interval of (19, 32) and p≤0.001.
Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher no-treatment (placebo) CFA values. There were similar responses to Zenpep () by age and gender.
Study 2, was an open-label, uncontrolled study of 19 patients, ages 1 to 6 years (mean age 4 years), with EPI due to CF. Approximately half of the patients were ages 1 to 3 years. Study 2 compared a measurement of fat malabsorption, spot fecal fat testing, before (while receiving therapy with another commercial PEP) and after oral administration of Zenpep () capsules with each meal or snack.
All patients in Study 2 were transitioned to Zenpep () from their usual PEP treatment. 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 5000 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. Overall, patients showed similar control of fat malabsorption by spot fecal fat testing when switched to Zenpep () treatment at similar doses.
Zenpep () How Supplied/storage And Handling
Each Zenpep () capsule is available as a two piece hypromellose capsule with yellow opaque cap and white body with a blue radial print and printed with “EURAND 10”, that contains 2.2-2.5mm enteric-coated beads. Capsules are supplied in bottles of:
Each Zenpep () capsule is available as a two piece hypromellose capsule with red opaque cap and white body with a blue radial print and printed with “EURAND 15”, that contains 2.2-2.5mm enteric-coated beads. Capsules are supplied in bottles of:
Each Zenpep () capsule is available as a two piece hypromellose capsule with green opaque cap and white body with a blue radial print and printed with “EURAND 20”, that contains 2.2-2.5mm enteric-coated beads. Capsules are supplied in bottles of:
Each Zenpep () capsule is available as a two piece hypromellose capsule with blue opaque cap and white body with a blue radial print and printed with “EURAND 25”, that contains 2.2-2.5mm enteric-coated beads. Capsules are supplied in bottles of:
Zenpep () Patient Counseling Information
See
Zenpep () is subject of US Patent No. 7,658,918.
Manufactured by: Eurand S.p.A. Via Martin Luther King, 13 20060, Pessano con Bornago Milan, Italy
Marketed by: Eurand Pharmaceuticals, Inc. 790 Township Line Road, Suite 250 Yardley, PA 19067
For further information, please call Eurand toll-free at 1-888-936-7371.
©2011 Eurand Pharmaceuticals, Inc. PKG-102807/11 rev. 3
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