FDA label eaa6c757-097c-4e9a-84b4-e4dfc403e18a

5 WARNINGS AND PRECAUTIONS Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme replacement. Exercise caution when doses of ZENPEP exceed 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day). ( 5.1 ) To avoid irritation of oral mucosa, do not chew ZENPEP or retain in the mouth. ( 5.2 ) Exercise caution when prescribing ZENPEP to patients with gout, renal impairment, or hyperuricemia. ( 5.3 ) There is theoretical risk of viral transmission with all pancreatic enzyme products including ZENPEP. ( 5.4 ) Exercise caution when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. ( 5.5 ) 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 6000 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 )] The most common adverse events (≥6% of patients treated with ZENPEP) are abdominal pain, flatulence, headache, cough, decreased weight, early satiety, and contusion. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aptalis Pharma at 1-888-936-7371 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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) MedDRA Primary System Organ Class Preferred Term ZENPEP (N=34) % Placebo (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 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). 6.2 Postmarketing Experience Postmarketing data for ZENPEP have been available since 2009. The following adverse reactions have been identified during post-approval use of Zenpep. 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.

<table width="700" ID="i8645a5a1-628f-4968-895b-868e315cceff"> <tbody> <tr> <td>MedDRA Primary System Organ Class Preferred Term</td> <td>ZENPEP (N=34) %</td> <td>Placebo (N=32) %</td> </tr> <tr> <td> <content styleCode="Bold Italics">Gastrointestinal Disorders</content> </td> <td> </td> <td> </td> </tr> <tr> <td> Abdominal pain</td> <td> <content styleCode="italics">6 (18%)</content> </td> <td> <content styleCode="italics">9 (28%)</content> </td> </tr> <tr> <td> Flatulence</td> <td>2 (6%)</td> <td>3 (9%)</td> </tr> <tr> <td> <content styleCode="Bold Italics">Nervous System Disorders</content> </td> <td> </td> <td> </td> </tr> <tr> <td> Headache</td> <td>5 (15%)</td> <td>0</td> </tr> <tr> <td> <content styleCode="Bold Italics">Injury, Poisoning and Procedural Complications</content> </td> <td> </td> <td> </td> </tr> <tr> <td> Contusion</td> <td>2 (6%)</td> <td>0</td> </tr> <tr> <td> <content styleCode="Bold Italics">Investigations</content> </td> <td> </td> <td> </td> </tr> <tr> <td> Weight decreased</td> <td>2 (6%)</td> <td>2 (6%)</td> </tr> <tr> <td> <content styleCode="Bold Italics">Respiratory, Thoracic and Mediastinal Disorders</content> </td> <td> </td> <td> </td> </tr> <tr> <td> Cough</td> <td>2 (6%)</td> <td>0</td> </tr> <tr> <td> <content styleCode="Bold Italics">General Disorders and Administration Site Conditions</content> </td> <td> </td> <td> </td> </tr> <tr> <td> Early Satiety</td> <td>2 (6%)</td> <td>0</td> </tr> </tbody> </table>