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warnings and cautions
5 WARNINGS AND PRECAUTIONS Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme replacement. Exercise caution when doses of VIOKACE 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 VIOKACE or retain in the mouth. ( 5.2 ) Exercise caution when prescribing VIOKACE to patients with gout, renal impairment, or hyperuricemia. ( 5.3 ) There is theoretical risk of viral transmission with all pancreatic enzyme products including VIOKACE. ( 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. 5 ,6 Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually 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 stricture 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 ( 2.2 ) ]. 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 to avoid irritation of oral mucosa, and/or loss of enzyme activity. VIOKACE should not be crushed or chewed [see Dosage and Administration ( 2.1 ) and Pati ent Counseling Information ( 17.1 ) ] . 5.3 Potential for Risk of Hyperuricemia Caution should be exercised when prescribing VIOKACE 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 for Viral Exposure from the Product Source VIOKACE is sourced from pancreatic tissue from pigs used for food consumption. Although the risk that VIOKACE 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 VIOKACE treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient. 5.6 Potential for Exacerbation of Symptoms of Lactose Intolerance VIOKACE tablets contain lactose monohydrate. Patients who have lactose intolerance may not be able to tolerate VIOKACE.
6 ADVERSE REACTIONS The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and allergic reactions [ see Warnings and Precautions ( 5.1 , 5.3 and 5.5 ) ]. Adverse reactions occurring in at least 2 chronic pancreatitis or pancreatectomy patients (greater than or equal to 7%) receiving VIOKACE are biliary tract stones and anal pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Allergan USA, Inc. at 1-800-678-1605 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 practice. The short-term safety of VIOKACE was assessed in a single, multicenter, randomized, parallel, placebo-controlled, double-blind study of 50 patients, ages 24-70 years, with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis or pancreatectomy. VIOKACE Tablets (20,880 USP units of lipase per tablet) or placebo were administered as 22 tablets per day (6 tablets with 3 meals and 2 tablets with 2 of 3 snacks). Duration of exposure ranged from 6 to 7 days. The majority of the subjects were Caucasian (96%) and male (82%). The most common adverse reactions (greater than or equal to 7%) were biliary tract stones and anal pruritus. Table 1 enumerates adverse reactions that occurred in at least 1 patient (greater than or equal to 3%) treated with VIOKACE at a higher rate than with placebo. Two adverse reactions reported in greater than one patient were biliary tract stones and anal pruritus. TABLE 1 Adverse Reaction s Occurring in at Least 1 Patient ( greater than or equal to 3%) in Chronic Pancreatitis or Pancreatectomy Treatment Group MedDRA Primary System Organ Class / Adverse Reactions VIOKACE (N=30) Placebo (N=20) Blood And Lymphatic System Disorders Anemia 1 ( 3%) 0 Gastrointestinal Disorders Anal pruritus 2 ( 7%) 0 Abdominal pain 1 ( 3%) 0 Ascites 1 ( 3%) 0 Flatulence 1 ( 3%) 0 General Disorders a nd Administration Site Conditions Edema peripheral 1 ( 3%) 0 Hepatobiliary Disorders Biliary tract stones 2 ( 7%) 0 Hydrocholecystis 1 ( 3%) 0 Infections a nd Infestations Viral infection 1 ( 3%) 0 Nervous System Disorders Headache 1 ( 3%) 0 Renal a nd Urinary Disorders Renal cyst 1 ( 3%) 0 Skin a nd Subcutaneous Tissue Disorders Rash 1 ( 3%) 0 6.2 Postmarketing Experience Post-marketing data for VIOKACE have been available since 2003. The safety data are similar to that described below. 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. Pancreatic enzyme products (delayed and immediate-release) 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.