Viokace

5. WARNINGS AND PRECAUTIONS Fibrosing Colonopathy : Associated with high doses, usually over prolonged use and in pediatric patients with cystic fibrosis. Colonic stricture reported in pediatric patients less than 12 years of age with dosages exceeding 6,000 lipase units/kg/meal. Monitor during treatment for progression of preexisting disease. Do not exceed the recommended dosage, unless clinically indicated. ( 2.1 , 5.1 ) Irritation of the Oral Mucosa : May occur if tablets are crushed or chewed. ( 5.2 ) Hyperuricemia : Reported with high dosages, consider monitoring blood uric acid levels in patients with gout, renal impairment, or hyperuricemia. ( 5.3 ) Risk of Viral Transmission : The presence of porcine viruses that might infect humans cannot be definitely excluded. ( 5.4 ) Hypersensitivity Reactions : Monitor patients with known reactions to proteins of porcine origin. If symptoms occur, initiate appropriate medical management; consider the risks and benefits of continued treatment. ( 5.5 ) Potential for Exacerbation of Symptoms of Lactose Intolerance : tablets contain lactose monohydrate. Patients who have lactose intolerance may not be able to tolerate VIOKACE. ( 5.6 ) 5.1. Fibrosing Colonopathy Fibrosing colonopathy has been reported following treatment with pancreatic enzyme products. Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with use of high-dose pancreatic enzyme products, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. Pancreatic enzyme products exceeding 6,000 lipase units/kg/meal have been associated with colonic stricture, a complication of fibrosing colonopathy, in pediatric patients less than 12 years of age. The underlying mechanism of fibrosing colonopathy remains unknown. If there is a history of fibrosing colonopathy, monitor patients during treatment with VIOKACE because some patients may be at risk of progressing to colonic stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs. Do not exceed the recommended dosage of either 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or 4,000 lipase units/g fat ingested/day without further investigation . Higher dosages may be administered if they are documented to be effective by fecal fat measures or an improvement in signs or symptoms of malabsorption including measures of nutritional status. Patients receiving dosages higher than 6,000 lipase units/kg/meal should frequently monitored for symptoms of fibrosing colonopathy and the dosage decreased or titrated downward to a lower range if clinically appropriate [see Dosage and Administration (2.1) ] . 5.2. Irritation of the Oral Mucosa Crushing or chewing VIOKACE tablets can result in irritation of the oral mucosa, and/or loss of enzyme activity. Instruct the patient to swallow tablets whole. Do not crush or chew VIOKACE tablets. Consume sufficient liquids immediately following administration of VIOKACE to ensure complete swallowing [see Dosage and Administration (2.3) ] . 5.3. Hyperuricemia Pancreatic enzyme products contain purines that may increase blood uric acid levels. High dosages have been associated with hyperuricosuria and hyperuricemia [see Overdosage (10) ]. Consider monitoring blood uric acid levels in patients with gout, renal impairment, or hyperuricemia during treatment with VIOKACE. 5.4. Risk of Viral Transmission 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. Hypersensitivity Reactions Severe hypersensitivity reactions including anaphylaxis, asthma, hives, and pruritus have been reported with pancreatic enzyme products [see Adverse Reactions (6.2) ] . If symptoms occur, initiate appropriate medical management. Monitor patients with a known hypersensitivity reaction to proteins of porcine origin for hypersensitivity reactions during treatment with VIOKACE. The risks and benefits of continued VIOKACE treatment in patients with severe hypersensitivity reactions 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 [see Description (11) ] . Patients who have lactose intolerance may not be able to tolerate VIOKACE.

6. ADVERSE REACTIONS The following serious or otherwise important adverse reactions are described elsewhere in the labeling: Fibrosing Colonopathy [see Warnings and Precautions (5.1) ] Irritation of the Oral Mucosa [see Warnings and Precautions (5.2) ] Hyperuricemia [see Warnings and Precautions (5.3) ] Risk of Viral Transmission [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Potential for Exacerbation of Symptoms of Lactose Intolerance [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥7%) are: anal pruritus and biliary tract stones. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aimmune Therapeutics, Inc at 1-833-AIM2KNO (1-833-246-2566) 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 data described below reflect exposure to VIOKACE in 30 adult patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy in a single, multicenter, randomized, parallel, placebo-controlled, double-blind study [see Clinical Studies (14) ] . Adverse reactions that were reported in at least 2 VIOKACE-treated patients (greater than or equal to 7%) are shown in Table 1. There were no adverse reactions reported in two or more patients in the placebo group (N=20). Table 1: Adverse Reactions Reported in at least 2 VIOKACE-treated patients (greater than or equal to 7%) and at a higher rate than placebo-treated patients. in a Clinical Trial of Adult Patients with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy Adverse Reaction VIOKACE N = 30 (%) Anal pruritus 2 (7%) Biliary tract stones 2 (7%) The following adverse reactions were reported in one VIOKACE-treated patient each: anemia, abdominal pain, ascites, flatulence, headache, hydocholecystis, peripheral edema, rash, renal cyst, and viral infection. 6.2. Postmarketing Experience The following adverse reactions have been identified during post-approval use of VIOKACE or other pancreatic enzyme products. 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. Eye Disorders blurred vision Gastrointestinal Disorders fibrosing colonopathy and distal intestinal obstruction syndrome abdominal pain, diarrhea, flatulence, constipation, and nausea Immune System Disorders anaphylaxis, asthma, hives and pruritis Investigations asymptomatic elevations of liver enzymes Musculoskeletal System myalgia, muscle spasm Skin and Subcutaneous Tissue Disorders urticaria and rash

<table width="80%"><caption>Table 1: Adverse Reactions<footnote>Reported in at least 2 VIOKACE-treated patients (greater than or equal to 7%) and at a higher rate than placebo-treated patients.</footnote> in a Clinical Trial of Adult Patients with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy</caption><col width="50%" align="center" valign="middle"/><col width="50%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction</th><th styleCode="Rrule">VIOKACE N = 30 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anal pruritus</td><td styleCode="Rrule">2 (7%)</td></tr><tr><td styleCode="Lrule Rrule">Biliary tract stones</td><td styleCode="Rrule">2 (7%)</td></tr></tbody></table>