ver 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. 1 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. pancreaze 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 of enzyme activity [see dosage and administration (2.2) and patient counseling information (17) ] . for patients who are unable to swallow intact delayed-release capsules, the delayed-release capsules may be carefully opened and the contents sprinkled to a small amount of acidic soft food with a ph of 4.5 or less, such as applesauce. the pancreaze-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 pancreaze 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 pancreaze is sourced from pancreatic tissue from swine used for food consumption. although the risk that pancreaze 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 pancreaze treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.

ations on dosing dosing should not exceed the recommended maximum dosage set forth by the cystic fibrosis foundation consensus conferences guidelines. ( 2.1 ) administration pancreaze should be swallowed whole. for infants or patients unable to swallow intact capsules, the contents may be sprinkled on soft acidic food with a ph of 4.5 or less, e.g., applesauce. ( 2.2 ) 2.1 dosage pancreaze is not interchangeable with other pancrelipase products. pancreaze is orally administered. therapy should be initiated at the lowest recommended dose and gradually increased. the dosage of pancreaze 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 pancreaze 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. pancreaze is available in a 2,600 lipase unit delayed-release capsule. the recommended dose of pancreaze in infants up to 12 months is 2,600 lipase units per 120 ml of formula or per breast-feeding. 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 2,600 lipase units per 120 ml of formula or per breast-feeding. do not mix pancreaze delayed-release 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 pancreaze 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 6,000 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 [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 pancreaze should always be taken as prescribed by a healthcare professional. infants (up to 12 months) pancreaze should be administered to infants immediately prior to each feeding, using a dosage of 2,600 lipase units per 120 ml of formula or per breast-feeding (i.e., one delayed-release capsule with 2,600 usp units of lipase). contents of the delayed-release capsule may be sprinkled on small amounts of acidic soft food with a ph of 4.5 or less (e.g., applesauce) and given to the infant within 15 minutes. contents of the delayed-release capsule may also be administered directly to the mouth. administration should be followed by breast milk or formula. contents of the delayed-release capsule should not be mixed directly into formula or breast milk as this may diminish efficacy. care should be taken to ensure that pancreaze is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa. children and adults pancreaze should be taken during meals or snacks, with sufficient fluid. pancreaze delayed-release capsules and delayed-release capsule contents should not be crushed or chewed. delayed-release capsules should be swallowed whole. for patients who are unable to swallow intact delayed-release capsules, the delayed-release capsules may be carefully opened and the contents sprinkled on small amounts of acidic soft food with a ph of 4.5 or less (e.g., applesauce). the pancreaze-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.

n 57 patients with exocrine pancreatic insufficiency (epi) due to cf. study 1 was conducted in 40 patients, ages 8 years to 57 years; study 2 was conducted in 17 patients, ages 6 months to 30 months. in study 1, pancreaze was administered in a dose of approximately 6,300 lipase units per kilogram per day for lengths of treatment ranging from 8 to 26 days; in study 2, pancreaze was administered in four treatment arms (doses of 1,375, 2,875, 4,735, and 5,938 lipase units per kilogram per day) for lengths of treatment ranging from 6 to 11 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 study of 40 patients, ages 8 to 57 years, with epi due to cf. in this study, patients received pancreaze at individually titrated doses (not to exceed 2,500 lipase units per kilogram per meal) for 14 days, followed by randomization to pancreaze or matching placebo for 7 days of treatment. the mean exposure to pancreaze during this study, including titration period and randomized withdrawal period, was 18 days. the incidence of adverse events (regardless of causality) was higher during placebo treatment (60%) than during pancreaze treatment (40%). the most common adverse events reported during the study were gastrointestinal complaints, which were reported more commonly during placebo treatment (55%) than during pancreaze treatment (30%). the type and incidence of adverse events were similar in children (8 to 11 years), adolescents (12 to 17 years), and adults (greater than 18 years). table 1 enumerates treatment-emergent adverse events that occurred in at least 2 patients (greater than or equal to 10%) treated with either pancreaze 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 10%) in either treatment group of the placebo-controlled, clinical study of pancreaze meddra primary system organ class preferred term pancreaze (n=20) n (%) placebo (n=20) n (%) gastrointestinal disorders abdominal pain 2 (10%) 3 (15%) abdominal pain upper 1 (5%) 3 (15%) flatulence 1 (5%) 3 (15%) diarrhea 0 (0%) 4 (20%) abnormal feces 0 (0%) 3 (15%) general disorders and administration site conditions fatigue 0 (0%) 2 (10%) study 2 was a randomized, investigator-blinded, dose-ranging study of 17 patients, ages 6 months to 30 months, with epi due to cf. all patients were transitioned from their usual pep treatment to pancreaze at 375 lipase units per kilogram body weight per meal for a 6 day run-in period. patients were then randomized to receive pancreaze at one of four doses (375, 750, 1,125, and 1,500 lipase units per kilogram body weight per meal) for 5 days. adverse events were collected on patient diary entries and at each study visit. the most commonly reported adverse events were gastrointestinal, including diarrhea and vomiting, and were similar in type and frequency across treatment arms and to those reported in the double-blind, placebo-controlled trial (study 1). 6.2 postmarketing experience postmarketing data for pancreaze have been available since 1988. the safety data are similar to those described below. 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 included fibrosing colonopathy, distal intestinal obstruction syndrome (dios), recurrence of pre-existing carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus. the most commonly reported adverse events were gastrointestinal disorders, including abdominal pain, diarrhea, flatulence, constipation and nausea, and skin disorders including pruritus, urticaria and rash. in general, these products have a well-defined and favorable risk-benefit profile in exocrine pancreatic insufficiency. 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.

er adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. 8.2 lactation risk summary there are no data on the presence of pancrelipase in either human or animal milk, the effects on the breastfed infant or the effects on milk production. pancrelipase is minimally absorbed systemically following oral administration, therefore maternal use is not expected to result in clinically relevant exposure of breastfed infants to the drug. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pancreaze and any potential adverse effects on the breastfed infant from pancreaze or from the underlying maternal condition. 8.3 pediatric use the short-term safety and effectiveness of pancreaze were assessed in two clinical studies in pediatric patients with epi due to cf; one study included patients ages 6 to 30 months, and the other included patients ages 8 years to 17 years. study 1 was a randomized, double-blind, placebo-controlled study in 40 patients, 14 of whom were pediatric patients, including 7 children aged 8 to 11 years, and 7 adolescents aged 12 to 17 years. the safety and efficacy in pediatric patients in this study were similar to adult patients [see adverse reactions (6.1) and clinical studies (14) ] . study 2 was a randomized, investigator-blinded, dose-ranging study in 17 pediatric patients aged 6 to 30 months. when patient regimen was switched from their usual pep regimen to pancreaze, patients showed similar control of their fat malabsorption [see adverse reactions (6.1) and clinical studies (14) ] . the safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredients (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 [see dosage and administration (2.1) ]. 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 [see warnings and precautions (5.1) ].

ncrelipase consisting of the same active ingredients (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 [see dosage and administration (2.1) ]. 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 [see warnings and precautions (5.1) ].

e change in cfa from the open label period to the end of the double-blind withdrawal period. the cfa was determined by a 72-hour stool collection period during both treatment periods, when both fat excretion and fat ingestion were measured (table 2). table 2. change in cfa in study 1 (open-label period to end of double-blind withdrawal period) pancreaze n=20 placebo n=20 cfa [%] open-label period minimum of 72 hours from start of open label period. (mean, sd) 88 (5) 91 (5) end of double-blind withdrawal period double-blind withdrawal period ranged from 4 to 7 days. (mean, sd) 87 (8) 56 (25) change in cfa p<0.001 [%] open-label period to end of double-blind withdrawal period (mean, sd) -2 (6) -34 (23) treatment difference point estimate (95% ci) 33 (25, 40) at the end of the double-blind withdrawal period, the mean change in cfa from the open-label period to the end of the double-blind withdrawal period was -2% with pancreaze treatment compared to -34% with placebo treatment. there were similar responses to pancreaze by age and gender. study 2 was a randomized, investigator-blinded, dose-ranging study of 17 patients, ages 6 months to 30 months (mean 18 months) with epi due to cf. the final analysis population was limited to 16 patients; 1 patient was excluded due to withdrawal of consent. all patients were transitioned from their usual pep treatment to pancreaze at 375 lipase units per kilogram body weight per meal for a 6-day run-in period. patients were then randomized to receive pancreaze at one of four doses (375, 750, 1,125, and 1,500 lipase units per kilogram body weight per meal) for 5 days. the cfa was measured at the end of the run-in period and at the end of the randomized period (table 3). table 3. change in cfa in study 2 (end of run-in period to end of study) 375 units lipase/kg/meal n=4 750 units lipase/kg/meal n=4 1,125 units lipase/kg/meal n=4 1,500 units lipase/kg/meal n=4 cfa (%) day 6 end of run-in period; (mean, sd) 93 (2) 90 (5) 81 (11) 93 (3) day 11 end of study (mean, sd) 92 (3) 91 (4) 80 (13) 91 (2) change in cfa (%) day 6 to day 11 (mean, sd) -2 (3) 1 (3) -1 (3) -2 (3) overall, patients showed similar cfa at the end of the run-in period (mean pancreaze dose of 1,600 lipase units per kilogram body weight per day) as at the end of the study across the four treatment arms.

1-403-10). pancreaze (pancrelipase) delayed-release capsules 16,800 usp units of lipase; 56,800 usp units of protease; 98,400 usp units of amylase. pancreaze (pancrelipase) is supplied as hypromellose capsules with a flesh opaque body and clear cap imprinted with "vivus" and "mt 16" and packaged in bottles of 100-(ndc 62541-404-10). pancreaze (pancrelipase) delayed-release capsules 21,000 usp units of lipase; 54,700 usp units of protease; 83,900 usp units of amylase. pancreaze (pancrelipase) is supplied as hypromellose capsules with a white opaque body and cap imprinted with "vivus" and "mt 20" and packaged in bottles of 100-(ndc 62541-405-10). pancreaze (pancrelipase) delayed-release capsules 37,000 usp units of lipase; 97,300 usp units of protease; 149,900 usp units of amylase. pancreaze (pancrelipase) is supplied as hypromellose capsules with an iron grey opaque body and white opaque cap imprinted with "vivus" and "mt 37" and packaged in 2 bottles of 50-(ndc 62541-406-50) inside a carton (ndc 62541-406-10). storage and handling avoid heat. pancreaze capsules should be stored in a dry place in the original container. after opening, keep the container tightly closed between uses to protect from moisture. do not store above 25°c (77°f). all pancreaze bottles contain a desiccant canister. do not eat or throw away the desiccant canister in your medicine bottle. this canister will protect your medicine from moisture. do not crush pancreaze delayed-release capsules or the capsule contents.

te amounts of liquid at mealtimes. if necessary, the delayed-release capsule contents can also be sprinkled on soft acidic foods. [see dosage and administration (2) ] . instruct patients to notify their healthcare professional if they are pregnant or are thinking of becoming pregnant during treatment with pancreaze [see use in specific populations (8.1) ]. instruct patients to notify their healthcare professional if they are breastfeeding or are thinking of breastfeeding during treatment with pancreaze [see use in specific populations (8.2) ]. 17.2 fibrosing colonopathy advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal (10,000 lipase units/kg of body weight/day) have been associated with colonic strictures in children below the age of 12 years [see dosage and administration (2) ] . 17.3 allergic reactions advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to pancreaze develop [see warnings and precautions (5.5) ] .