lly 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. 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. pertzye 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) ] . for patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents mixed with a small amount of acidic soft food with a ph of 4.5 or less, such as applesauce, or administered with applesauce via a gastrostomy tube with a diameter of 14 french or larger (only for the 4,000 usp lipase unit capsule strength) [see dosage and administration (2.2) ] . if administered orally, the pertzye-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion. 5.3 potential for risk of hyperuricemia porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels. consider monitoring serum uric acid levels in patients with hyperuricemia, gout, or renal impairment. 5.4 potential viral exposure from the product source pertzye is sourced from pancreatic tissue from swine used for food consumption. although the risk that pertzye 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 pertzye treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.

limitations on dosing dosing should not exceed the recommended maximum dosage set forth by the cystic fibrosis foundation consensus conferences guidelines. ( 2.1 ) administration ( 2.2 ) administer pertzye during meals or snacks, with sufficient fluid. swallow pertzye capsules whole. do not crush or chew the capsules or the capsule contents. for patients unable to swallow intact capsules, see the full prescribing information for instructions on opening the capsules and administering orally or via a gastrostomy tube. 2.1 dosage pertzye is not substitutable with any other pancrelipase products. pertzye is administered orally or via a gastrostomy tube. therapy should be initiated at the lowest recommended dose and gradually increased. the dosage of pertzye should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet ( see limitations on dosing below ). pertzye is a mixture of enzymes including lipases, proteases, and amylases and dosing is based on lipase units. dosage recommendations for pancreatic enzyme replacement therapy were published following the cystic fibrosis foundation consensus conferences. 1,2,3 pertzye should be administered in a manner consistent with the recommendations of the conferences provided in the following paragraphs. 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 4,000 lipase units (one capsule) per 120 ml of formula or breast-feeding. do not mix pertzye 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 pertzye 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 pertzye should always be taken as prescribed by a healthcare professional. infants (up to 12 months) pertzye should be administered to infants immediately prior to each feeding, using a dosage of 4,000 lipase units (one capsule) per 120 ml of formula or per breast-feeding. contents of the capsule may be mixed with approximately 10 ml of soft acidic food with a ph of 4.5 or less (e.g., applesauce). contents of the capsule may also be administered directly to the mouth. administration should be followed by breast milk or formula. do not mix contents of the capsule directly into formula or breast milk as this may diminish efficacy. care should be taken to ensure that the pertzye capsule contents (microspheres) are not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa [see warnings and precautions (5.2) ] . children and adults administer pertzye during meals or snacks, with sufficient fluid. swallow pertzye capsules whole. if a dose is missed, take the next dose with the next meal or snack as directed. do not take two doses at one time. do not crush or chew the capsules or the capsule contents (microspheres). for patients who are unable to swallow intact capsules, follow the instructions below for oral administration with soft foods with a ph of 4.5 or less (e.g., applesauce): place a small amount (approximately 10 ml) of applesauce into a clean container. carefully open the capsule(s). sprinkle the entire contents (microspheres) on the applesauce. mix the capsule contents (microspheres) with the applesauce being careful not to crush the microspheres when mixing. consume the entire mixture immediately. do not chew the capsule contents (microspheres). do not save the mixture for later use. follow with water or juice to ensure complete ingestion and to ensure nothing is retained in the mouth to avoid mucosal irritation [see warnings and precautions (5.2) ] . alternatively, the contents of one or two 4,000 usp lipase unit capsules can be administered with soft foods with a ph of 4.0 or less (e.g., applesauce) via a gastrostomy tube with a diameter of 14 french or larger. gastrostomy tube administration instructions (14 french gastrostomy tube or larger) only perform gastrostomy tube administration with the contents of the 4,000 usp lipase unit capsule of pertzye. the contents of no more than two capsules may be administered at a time. transfer a minimum of 10 ml of applesauce into a small bowl or medicine cup. carefully open one or two pertzye 4,000 lipase unit capsules. mix the capsule contents (microspheres) thoroughly with the transferred applesauce to create a uniform suspension. once mixed, administer the suspension immediately. care should be taken not to crush the microspheres when mixing. discard the empty capsules. remove the plunger from a 35 ml slip tip syringe. cover the tip of the syringe with your finger. transfer the pertzye-applesauce mixture into the syringe. replace the plunger partially back into the syringe. shake or tap the syringe lightly with the syringe tip facing upward so that the pertzye-applesauce mixture will move towards the plunger. carefully push the plunger slowly until the residual air is removed from the syringe tip. once the residual air is removed, connect the syringe directly into the gastrostomy tube feeding port. push the syringe contents into the gastrostomy tube feeding port using steady pressure until empty. draw up approximately 10 ml of water with the slip tip syringe and flush the gastrostomy tube feeding port with the water. discard any unused portion of the pertzye-applesauce mixture. do not save for later use. if dose requires more than two capsules, repeat steps 1-9 until prescribed dose is reached.

ystic fibrosis. in this study, patients were randomized to receive pertzye at individually titrated doses (not to exceed 2,500 lipase units per kilogram per meal) or matching placebo for 6 to 8 days of treatment, followed by crossover to the alternate treatment for an additional 6 to 8 days. the length of exposure to pertzye during this study was 20-28 days, including the treatment period of 6 to 8 days, and the open label titration and transition periods of 7 to 10 days. the most common adverse reactions (≥10%) were diarrhea, dyspepsia, and cough. table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 10%) treated with pertzye at a higher rate than with placebo. table 1. adverse reactions occurring in at least 2 patients (≥ 10%) adverse reaction pertzye n=21 n (%) placebo n=24 n (%) diarrhea 2 (10%) 1 (4%) dyspepsia 2 (10%) 1 (4%) cough 2 (10%) 1 (4%) 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of pertzye. 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. this formulation of pertzye has been marketed since 2004 under the trademark pancrecarb ® . two product complaints relating to an adverse drug reaction were reported. a mild allergic reaction (itching and red, blotchy rash on face) was reported by a patient with a known history of allergy to another pancrelipase product, and a dull headache was reported by another patient taking concomitant ursodeoxycholic acid. both events resolved without sequelae after discontinuation of treatment. 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. 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.

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 pertzye and any potential adverse effects on the breastfed infant from pertzye or from the underlying maternal condition. 8.4 pediatric use the short-term safety and efficacy of pertzye were assessed in a randomized, double- blind, placebo-controlled, crossover study of 24 patients with exocrine pancreatic insufficiency due to cystic fibrosis, including 10 patients between 8 and 17 years of age. the safety and efficacy in 8 to 17 year old patients in this study were similar to adult patients [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 ingredient (lipases, proteases, and amylases) for treatment of pediatric patients with exocrine pancreatic insufficiency due to cystic fibrosis have 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) ] .

ucts 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) ] .

fference in cfa was 36 percentage points in favor of pertzye treatment with 95% ci: (28, 45) and p<0.001. the coefficient of nitrogen absorption (cna) was determined by a 72-hour stool collection during both treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated (based on the assumption that proteins contain 16% nitrogen). each patient's cna during placebo treatment was used as their no-treatment cna value. mean cna was 79% with pertzye treatment compared to 47% with placebo treatment. the mean difference in cna was 32 percentage points in favor of pertzye treatment and this was a statistically significant change. there were no differences between children and adults in the severity of pancreatic insufficiency (placebo response) or in the magnitude of the response to pertzye.

rinted with a red circular stripe and "dci". delayed-release capsules are supplied in bottles of 100 (ndc 59767-016-01) or 250 (ndc 59767-016-02). pertzye (pancrelipase) delayed-release capsules 24,000 usp units of lipase; 86,250 usp units of protease; 90,750 usp units of amylase. each pertzye delayed-release capsule has a clear body printed in purple with "24" and a clear cap printed with a purple circular stripe and "dci". delayed-release capsules are supplied in bottles of 80 (ndc 59767-024-01) or 200 (ndc 59767-024-02). storage and handling store at room temperature 20°c to 25°c (68°f to 77°f), excursions permitted to 15°c to 40°c (59°f to 104°f) for up to 30 days. pertzye hard gelatin capsules should be stored in a dry place in the original container or equivalent air tight container. after opening, keep the container tightly closed between uses to protect from moisture. pertzye is dispensed in bottles containing a desiccant. the desiccant packet should not be eaten or thrown away. the desiccant packet will protect the product from moisture.

with the next meal or snack as directed. do not take two doses at one time [see dosage and administration (2) ]. after opening the bottle containing pertzye, keep it tightly closed between uses. do not eat or throw away the desiccant packet. fibrosing colonopathy high doses of pancreatic enzyme products have been associated with colonic strictures in children below the age of 12 years. advise patients and caregivers that if signs and symptoms of stricture formation occur (e.g., stomach area (abdominal) pain, bloating, trouble passing stool (constipation), nausea, vomiting, diarrhea) to immediately contact their healthcare provider [see dosage and administration (2) , warnings and precautions (5.1) ]. allergic reactions allergic reactions, including anaphylaxis, asthma, hives and pruritus may occur. advise patients and caregivers to immediately contact their healthcare provider if symptoms occur [see warnings and precautions (5.5) ].