Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action The pancreatic enzymes in VIOKACE catalyze the hydrolysis of fats to monoglycerides, glycerol and free fatty acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas. Pharmacokinetics Pancreatic enzymes are not absorbed from the gastrointestinal tract in appreciable amounts. Clinical Studies The short-term safety and efficacy of VIOKACE were evaluated in a randomized, double-blind, placebo-controlled, parallel group study comparing VIOKACE Tablets (20,880 USP units of lipase per tablet) to placebo in 50 patients, ages 24 to 70, with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis (CP) or pancreatectomy. Eighteen patients had a history of pancreatectomy (11 were treated with VIOKACE). All patients were maintained on a controlled high fat diet of 100 grams of fat per day. After a wash-out period (6 to 7 days), patients were randomized to a fixed dose of VIOKACE (22 tablets per day; 6 tablets per meal and 2 tablets with 2 of 3 snacks) or placebo, in combination with a proton pump inhibitor. Forty-nine patients completed the double-blind treatment period (6 to 7 days); 29 patients received VIOKACE, and 20 patients received placebo. The coefficient of fat absorption (CFA) was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat ingestion were measured. The wash-out period mean CFA was 48% in the VIOKACE treatment group and was 57% in the placebo group. At the end of the double-blind treatment period, the mean CFA was 86% with VIOKACE treatment compared to 58% with placebo. The mean difference in CFA at the end of the double-blind treatment period was 28 percentage points in favor of VIOKACE treatment with 95% Confidence Interval of (21, 37) and p ≤ 0.0001. Subgroup analyses of the CFA results showed that mean change in CFA with VIOKACE treatment (from the washout period to the end of the double-blind period) was greater in patients with lower wash-out period CFA values than in patients with higher wash-out period CFA values. Only 2 of the patients with a history of total pancreatectomy were treated with VIOKACE. One of these patients had a CFA of 12% during the wash-out period and a CFA of 90% at the end of the double-blind period; the other patient had a CFA of 38% during the wash-out period and a CFA of 77% at the end of the double-blind period. The remaining 9 patients with a history of partial pancreatectomy treated with VIOKACE had a mean CFA of 56% during the wash-out period and a mean CFA of 86% at the end of the double-blind period.

CLINICAL PHARMACOLOGY ULTRASE® (pancrelipase) Capsules are designed to prevent inactivation by gastric acid thereby resulting in the delivery of high levels of biologically active enzymes into the duodenum. The enzymes catalyze the hydrolysis of fats into glycerol and fatty acids, starch into dextrins and sugars, and protein into proteoses and derived substances.

CLINICAL PHARMACOLOGY Mechanism Of Action The pancreatic enzymes in PERTZYE catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and maltotriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas. Pharmacokinetics The pancreatic enzymes in PERTZYE are enteric-coated to minimize destruction or inactivation in gastric acid. PERTZYE is expected to release most of the enzymes in vivo at pH greater than 5.5. Pancreatic enzymes are not absorbed from the gastrointestinal tract in appreciable amounts. Clinical Studies The short-term safety and efficacy of PERTZYE were evaluated in a randomized, double-blind, placebo-controlled, crossover study conducted in 24 patients ages 8 to 43 years (mean age = 20 years) with exocrine pancreatic insufficiency due to cystic fibrosis.6 The efficacy analysis population included 21 patients who completed both double-blind treatment periods. 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 primary efficacy endpoint was the mean difference in coefficient of fat absorption (CFA) between PERTZYE and placebo treatment. The CFA was determined by a 72-hour stool collection during both treatments, when both fat ingestion and excretion were measured. Mean CFA was 83% with PERTZYE treatment compared to 46% with placebo treatment. The mean difference 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. REFERENCES 6. Konstan MW, et al. A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Cross-Over Study to Evaluate the Effectiveness and Safety of a Novel Pancrelipase (PANCRECARB® MS-16) in Reducing Steatorrhea in Children and Adults with Cystic Fibrosis. 2008 North American Cystic Fibrosis Conference. Abstract #618.

CLINICAL PHARMACOLOGY The buffer-stabilized pancreatic enzymes in PANCRECARB® (pancrelipase) Delayed-Release are enteric-coated with a gastric acid resistant polymer to protect the enzymes during gastric transit into the duodenum. After being swallowed, the gelatin capsules dissolve in the gastric juice within minutes and the released microspheres disperse with food in the stomach. Upon passing into the duodenum, the enteric-coated PANCRECARB® (pancrelipase) microspheres are activated at approximately pH 5.5, discharge their digestive enzymes and the released digestive enzymes help to re-establish the natural digestive conditions in the intestine. The digestive enzymes in PANCRECARB® (pancrelipase) act locally in the gastrointestinal tract. The digestive enzymes hydrolyze fats into glycerol and fatty acids, proteins into peptides and amino acids, and starch into dextrins and maltrose. Once the digestive enzymes accomplish their catalytic function to hydrolyze food, the digestive enzymes may be inactivated by anti-enzymes which are secreted by the intestinal mucosa or digested by proteases. The digested enzyme fragments may be absorbed from the intestine and subsequently excreted into the urine. The inactivated enzymes are excreted in the feces.

Find Lowest Prices on VIOKACE (pancrelipase) Tablets, for Oral Use DESCRIPTION VIOKACE is a pancreatic enzyme preparation for oral administration consisting of pancrelipase, an extract derived from porcine pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, amylases, and proteases. Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble in alcohol. The active ingredient evaluated in clinical trials is lipase. VIOKACE is dosed by lipase units. Other active ingredients include protease and amylase. Inactive ingredients in VIOKACE include: colloidal silicon dioxide, crosscarmellose sodium, lactose monohydrate, microcrystalline cellulose, stearic acid and talc. 10,440 USP units of lipase; 39,150 USP units of protease; 39,150 USP units of amylase tablets are tan, round biconvex and have VIO9111 engraved on one side and 9111 on the other side. 20,880 USP units of lipase; 78,300 USP units of protease; 78,300 USP units of amylase tablets are tan, oval, biconvex with V16 engraved on one side and 9116 on the other side.

ULTRASE® (pancrelipase) Capsules Enteric-Coated Microspheres DESCRIPTION ULTRASE® (pancrelipase) Capsules are orally administered and contain 250 mg of enteric-coated microspheres of porcine pancreatic enzyme concentrate, predominantly pancreatic lipase, amylase, and protease. Each ULTRASE® (pancrelipase) Capsule contains: Lipase .................................................. 4,500 U.S.P. Units Amylase .................................................. 20,000 U.S.P. Units Protease .................................................. 25,000 U.S.P. Units Inactive ingredients: povidone, talc, sugar, methacrylic acid copolymer (Type C), triethyl citrate, simethicone emulsion.

Find Lowest Prices on PERTZYE (pancrelipase) Hard Gelatin Capsules DESCRIPTION PERTZYE is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and amylases. Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble or insoluble in alcohol and ether. Each PERTZYE delayed-release capsule for oral administration contains bicarbonate-buffered enteric-coated microspheres ranging in size from 0.8 to1.4 mm in diameter for 4,000 USP units of lipase and 0.8 to 2.2 mm in diameter for 8,000 and 16,000 USP units of lipase. The active ingredient evaluated in clinical trials is lipase. PERTZYE is dosed by lipase units. Other active ingredients include protease and amylase. Inactive ingredients in PERTZYE include sodium bicarbonate, sodium carbonate, cellulose acetate phthalate, sodium starch glycolate, diethyl phthalate, ursodiol, polyvinylpyrrolidone, and talc and are contained in hard gelatin capsules. 4,000 USP units of lipase; 14,375 USP units of protease; 15,125 USP units of amylase. Delayed-Release Capsules have a clear body printed in green with “4” and a clear cap printed with a green circular stripe and “DCI”. The imprinting ink on the capsule contains FD&C Blue #1, D&C Yellow #10, black iron oxide, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, shellac and ammonium hydroxide. 8,000 USP units of lipase; 28,750 USP units of protease; 30,250 USP units of amylase. Delayed-Release Capsules have a clear body printed in blue with “8” and a clear cap printed with a blue circular stripe and “DCI”. The imprinting ink on the capsule contains FD&C Blue #1, ethanol, methanol, n-butyl alcohol, propylene glycol, shellac and ammonium hydroxide. 16,000 USP units of lipase; 57,500 USP units of protease; 60,500 USP units of amylase. Delayed-Release Capsules have a clear body printed in red with “16” and a clear cap printed with a red circular stripe and “DCI”. The imprinting ink on the capsule contains FD&C Red #40, povidone, titanium dioxide, dehydrated alcohol, sodium hydroxide, butyl alcohol, propylene glycol, isopropyl alcohol, and shellac.

PANCRECARB (pancrelipase) Delayed-Release Capsules, Buffered and Enteric-Coated Microspheres. DESCRIPTION PANCRECARB® (pancrelipase) contain buffered pancreatic enzymes: lipase, amylase and protease, isolated and concentrated from porcine pancreatic glands. The enzyme containing microspheres are coated with a pH sensitive enteric-coating to provide protection against gastric inactivation of the buffer-stabilized enzymes during gastric passage. EACH PANCRECARB® (pancrelipase) CONTAINS: MS-4 MS-8 Lipase 4,000 U.S.P. Units 8,000 U.S.P. Units Amylase 25,000 U.S.P. Units 40,000 U.S.P. Units Protease 25,000 U.S.P. Units 45,000 U.S.P. Units Inactive ingredients include sodium carbonate, sodium bicarbonate, cellulose acetate phthalate, diethyl phthalate, gelatin, sodium carboxymethyl starch, polyvinylpyrrolidone, talc, ursodiol, and other trace ingredients.

INDICATIONS VIOKACE (pancrelipase) tablets, in combination with a proton pump inhibitor, is indicated in adults for the treatment of exocrine paencratic insufficiency due to chronic pancreatitis or pancreatectomy. DOSAGE AND ADMINISTRATION VIOKACE is not interchangeable with any other pancrelipase product. VIOKACE is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of VIOKACE should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet as described in the Limitations on Dosing below [see WARNINGS AND PRECAUTIONS]. Administration Since VIOKACE is not enteric-coated, it should be taken in combination with a proton pump inhibitor [see INDICATIONS]. VIOKACE should be taken during meals or snacks, with sufficient fluid. Tablets should be swallowed whole. Do not crush or chew tablets. Care should be taken to ensure that no drug is retained in the mouth to avoid mucosal irritation. Dosage Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences.1,2,3 VIOKACE should be administered in a manner consistent with the recommendations of the Conferences provided in the following paragraph. Only the adult dosing guidelines are shown below. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme. Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations. Enzyme dosing should begin with 500 lipase units/kg of body weight per meal 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 VIOKACE dose for an individualized full meal should be given with each snack. The total daily dosage should reflect approximately three meals plus two or three snacks per day. In one clinical trial, patients received VIOKACE at a dose of 125,280 lipase units per meal while consuming 100 g of fat per day [see Clinical Studies]. Lower starting doses recommended in the literature are consistent with the 500 lipase units/kg of body weight per meal 1, 2, 3, 4 lowest starting dose recommended for adults in the Cystic Fibrosis Foundation Consensus Conferences Guidelines. The initial starting dose and increases in the dose per meal should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet. 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 the 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 stricture, indicative of fibrosing colonopathy, in children less than 12 years of age [see WARNINGS AND PRECAUTIONS]. 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. HOW SUPPLIED Dosage Forms and Strengths The active ingredient in VIOKACE evaluated in clinical trials is lipase. VIOKACE is dosed in lipase units. Other active ingredients include protease and amylase. Each VIOKACE tablet strength contains the specified amounts of lipase, protease, and amylase as follows: 10,440 USP units of lipase; 39,150 USP units of protease; 39,150 USP units of amylase tablets are tan, round, biconvex and have VIO9111 engraved on one side and 9111 on the other side. 20,880 USP units of lipase; 78,300 USP units of protease; 78,300 USP units of amylase tablets are tan, oval, biconvex with V16 engraved on one side and 9116 on the other side. VIOKACE tablets 10,440 USP units of lipase; 39,150 USP units of protease; 39,150 USP units of amylase Each VIOKACE tablet is available as a tan, round, biconvex tablet with VIO9111 engraved on one side and 9111 on the other side supplied in bottles of 100 tablets (NDC 58914-112-10). VIOKACE tablets 20,880 USP units of lipase; 78,300 USP units of protease; 78,300 USP units of amylase Each VIOKACE tablet is available as a tan, oval, biconvex tablet with V16 engraved on one side and 9116 on the other side supplied in bottles of 100 tablets (NDC 58914-117-10). Storage and Handling Avoid heat. VIOKACE tablets should be stored in a dry place in the original container. Store at room temperature (20-25°C, 68-77°F), brief excursion permitted up to 40°C (104°F) for up to 24 hrs. After opening, keep the container tightly closed between uses to protect from moisture. VIOKACE is dispensed in bottles containing a desiccant. The desiccant packet should not be eaten. The desiccant packet will protect the product from moisture. REFERENCES 1. Borowitz DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Journal of Pediatrics. 1995; 127: 681-684. 2. Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. Journal of Pediatric Gastroenterology Nutrition. 2002 Sep; 35: 246-259. 3. Stallings VA, Start LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. Journal of the American Dietetic Association. 2008; 108: 832-839. 4. Dominguez-Munoz JE, Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Current Gastroenterology Reports. 2007; 9: 116-122. 5Smyth RL, Ashby D, O'Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet. 1995; 346: 12471251. Marketed by: Aptalis Pharma US, Inc., 22 Inverness Center Parkway Birmingham, AL 35242 USA. Manufactured by: Confab Laboratories, Inc. St. Hubert, Canada. Revised: March 2012

INDICATIONS ULTRASE® (pancrelipase) Capsules are indicated for patients with partial or complete exocrine pancreatic insufficiency caused by: Cystic fibrosis (CF) Chronic pancreatitis due to alcohol use or other causes Surgery (pancreatico-duodenectomy or Whipple's procedure, with or without Wirsung duct injection, total pancreatectomy) Obstruction (pancreatic and biliary duct lithiasis, pancreatic and duodenal neoplasms, ductal stenosis) Other pancreatic disease (hereditary, post traumatic and allograft pancreatitis, hemochromatosis, Shwachman's Syndrome, lipomatosis, hyperparathyroidism) Poor mixing (Billroth II gastrectomy, other types of gastric bypass surgery, gastrinoma) Pancrelipase capsules are effective in controlling steatorrhea.1-9 DOSAGE AND ADMINISTRATION The enzymatic activity of ULTRASE® (pancrelipase) Capsules is expressed in U.S.P. units. The smallest effective dose should be used. Dosage should be adjusted according to the severity of the exocrine pancreatic insufficiency. Begin therapy with one or two capsules with meals or snacks and adjust dosage according to symptoms. The number of capsules or capsule strength given with meals and/or snacks should be estimated by assessing which dose minimizes steatorrhea and maintains good nutritional status. Dosages should be adjusted according to the response of the patient. Where swallowing of capsules is difficult, they may be opened and the microspheres added to a small quantity of a soft food (e.g., applesauce, gelatin, etc.) that does not require chewing, and swallowed immediately. It is recommended that the total dose of pancrelipase being ingested for a meal or snack be dispersed equally (with fluids) before, during, and after the meal or snack. SUGGESTIONS FOR THE USE OF PANCREATIC ENZYMES IN CYSTIC FIBROSIS12 Patients should be receiving optimal diet for age and clinical status, recognizing that those with failure to thrive or malnutrition require additional calories and other nutrients for catch-up growth. Nutrition assessment should be a part of routine clinical evaluations. Initial dosing of pancreatic enzyme supplements should begin with 500 lipase U/kg/meal using enteric-coated microsphere products. Patients should be reassessed 2-4 weeks after initiation of therapy. The following items should be assessed: Clinical status, e.g., abdominal symptoms and exam; Nutritional intake and growth (height, weight, head circumference); Character of stools - greasy, oily (for information, not for decision making); Quantitative 72-hour fecal fat when indicated but not less than annually (perform on a normal diet for age); Fat soluble vitamin measures. Corollaries to dosing suggestions: Dose may be altered in a stepwise fashion according to the response of the patient (see 4. above). Dose approaching 2,000 lipase U/kg/meal would indicate the need for further investigation (see below). Patients presently on higher doses should be reevaluated; either immediately decrease the dose or titrate down to a lower dose range at, or below, 2,000 lipase U/kg/meal. Doses > 6,000 lipase U/kg/meal have been associated with colonic strictures. Pancreatic supplements mixed with applesauce or other acidic food substances should be administered immediately, not stored. Enteric-coated microspheres should not be crushed. Enzyme doses (as lipase U/kg/meal) tend to decrease with advancing age. Patients should accept only product brands prescribed by their physician. Adjustment of dosage is the responsibility of the physician. Patients should be advised not to adjust doses without consulting their physician. Changes in product or dosage may require an adjustment period. Complaints transmitted by phone should be investigated thoroughly before dose is adjusted. If indicated, this investigation should include 72-hour fecal fat testing. Pancreatic supplements should be stored in a cool, dry place and checked regularly for expiration date. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. HOW SUPPLIED ULTRASE® (pancrelipase) Capsules Gelatin capsules (opaque white and opaque white), imprinted “ULTRASE (pancrelipase) ”. Bottles of 100 (NDC 58914-045-10). Store at controlled room temperature, between 15°C and 25°C (59°F and 77°F), in a dry place. Do not refrigerate. REFERENCES 1. Delchier JC, Vidon N, et al. Fate of orally ingested enzymes in pancreatic insufficiency: comparison of two pancreatic enzyme preparations. Aliment Pharmacol Therap. 1991;5:365-378. 2. Duhamel JP, Vidailhet M, et al. Étude multicentrique comparative d'une nouvelle présentation de pancréatine en microgranules gastrorésistants dans I'insuffisance pancréatique exocrine de la mucoviscidose chez l'enfant. Ann Pediatr. 1988;35:69-74. 3. Dutta SK, Tilley DK. The pH-sensitive enteric-coated pancreatic enzyme preparations: an evaluation of therapeutic efficacy in adult patients with pancreatic insufficiency. J Clin Gastroenterol. 1983;5:51-54. 4. Dutta SK, Rubin J, Harvey J. Comparative evaluation of the therapeutic efficacy of a pH-sensitive enteric-coated pancreatic enzyme preparation with conventional pancreatic enzyme therapy in the treatment of exocrine pancreatic insufficiency. Gastroenterol. 1983;84:476-482. 5. Gouerou H, Dain MP, et al. Alipase versus nonenteric-coated enzymes in pancreatic insufficiency. Int J Pancreatol. 1989;5:45-50. 6. Mischler EH, Parrell S, et al. Comparison of effectiveness of pancreatic enzyme preparations in cystic fibrosis. Am J Dis Child. 1982;136:1060-1063. 7. Salen G, Prakash A. Evaluation of enteric-coated microspheres for enzyme replacement therapy in adults with pancreatic insufficiency. Cur Ther Res. 1979;25:650-656. 8. Schneider MU, Knoll-Ruzicka ML, et al. Pancreatic enzyme replacement therapy: comparative effects of conventional and enteric-coated microspheric pancreatin and acid-stable fungal enzyme preparations on steatorrhea in chronic pancreatitis. Hepatogastroenterol. 1985;32:97-102. 9. Halgreen H, Thorsgaard Pedersen N, Worning H. Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis. Scand J Gastroenterol. 1986;21:104-108. 12. Cystic Fibrosis Foundation Conference on Pancreatic Enzyme Supplementation in the Context of Fibrosing Colonopathy; Washington, D.C., March 23-24, 1995. REV. June 2008. Marketed as ULTRASE® (pancrelipase) by: AXCAN PHARMA US, INC. 22 Inverness Center, Parkway, Birmingham, AL 35242 USA. www.axcan.com. ULTRASE® (pancrelipase) is manufactured by Eurand International, Milan, Italy using its DIFFUCAPS® technology for Axcan Pharma US, Inc., 22 Inverness Center Parkway, Birmingham, Alabama 35242 USA. FDA revision date: n/a

CLINICAL PHARMACOLOGY Mechanism Of Action The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR, HER2, HER3, and HER4. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Expression of EGFR is also detected in many human cancers including those of the head and neck, colon, and rectum. Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha. In vitro assays and in vivo animal studies have shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production. Signal transduction through the EGFR results in activation of wild-type Ras proteins, but in cells with activating Ras somatic mutations, the resulting mutant Ras proteins are continuously active regardless of EGFR regulation. In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express the EGFR. No anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression. The addition of cetuximab to radiation therapy or irinotecan in human tumor xenograft models in mice resulted in an increase in anti-tumor effects compared to radiation therapy or chemotherapy alone. Pharmacodynamics Effects On Electrocardiogram (ECG) The effect of cetuximab on QT interval was evaluated in an open-label, single-arm, monotherapy trial in 37 subjects with advanced malignancies who received an initial dose of 400 mg/m2 , followed by weekly infusions of 250 mg/m2 for a total of 5 weeks. No large changes in the mean QT interval of >20 ms from baseline were detected in the trial based on the Fridericia correction method. A small increase in the mean QTc interval of <10 ms cannot be excluded because of the limitations in the trial design. Pharmacokinetics Erbitux administered as monotherapy or in combination with concomitant chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area under the concentration time curve (AUC) increased in a greater than dose proportional manner while clearance of cetuximab decreased from 0.08 to 0.02 L/h/m2 as the dose increased from 20 to 200 mg/m2 , and at doses >200 mg/m2 , it appeared to plateau. The volume of the distribution for cetuximab appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following the recommended dose regimen (400 mg/m2 initial dose; 250 mg/m2 weekly dose), concentrations of cetuximab reached steady-state levels by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 to 235 and 41 to 85 μg/mL, respectively. The mean half-life of cetuximab was approximately 112 hours (range 63–230 hours). The pharmacokinetics of cetuximab were similar in patients with SCCHN and those with colorectal cancer. Erbitux had an approximately 22% (90% confidence interval; 6%, 38%) higher systemic exposure relative to the EU-approved cetuximab used in Studies 2 and 4 based on a population pharmacokinetic analysis. [See Clinical Studies.] A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. Animal Pharmacology And/Or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. Clinical Studies Studies 2 and 4 were conducted outside the U.S. using an EU-approved cetuximab as the clinical trial material. Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab used in Studies 2 and 4; these pharmacokinetic data, together with the results of Studies 2, 4, and other clinical trial data establish the efficacy of Erbitux at the recommended dose in SCCHN and mCRC [see CLINICAL PHARMACOLOGY]. Squamous Cell Carcinoma Of The Head And Neck (SCCHN) Study 1 was a randomized, multicenter, controlled trial of 424 patients with locally or regionally advanced SCCHN. Patients with Stage III/IV SCCHN of the oropharynx, hypopharynx, or larynx with no prior therapy were randomized (1:1) to receive either Erbitux plus radiation therapy or radiation therapy alone. Stratification factors were Karnofsky performance status (60–80 versus 90–100), nodal stage (N0 versus N+), tumor stage (T1–3 versus T4 using American Joint Committee on Cancer 1998 staging criteria), and radiation therapy fractionation (concomitant boost versus once-daily versus twice-daily). Radiation therapy was administered for 6–7 weeks as once-daily, twice-daily, or concomitant boost. Erbitux was administered as a 400 mg/m2 initial dose beginning one week prior to initiation of radiation therapy, followed by 250 mg/m2 weekly administered 1 hour prior to radiation therapy for the duration of radiation therapy (6–7 weeks). Of the 424 randomized patients, the median age was 57 years, 80% were male, 83% were Caucasian, and 90% had baseline Karnofsky performance status ≥80. There were 258 patients enrolled in U.S. sites (61%). Sixty percent of patients had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors; 28% had AJCC T4 tumor stage. Fifty-six percent of the patients received radiation therapy with concomitant boost, 26% received once-daily regimen, and 18% twice-daily regimen. The main outcome measure of this trial was duration of locoregional control. Overall survival was also assessed. Results are presented in Table 6. Table 6: Study 1: Clinical Efficacy in Locoregionally Advanced SCCHN Erbitux + Radiation (n=211) Radiation Alone (n=213) Hazard Ratio (95% CIa) Stratified Log-rank p-value Locoregional Control Median duration (months) 24.4 14.9 0.68 (0.52–0.89) 0.005 Overall Survival Median duration (months) 49.0 29.3 0.74 (0.57–0.97) 0.03 aCI = confidence interval Study 2 was an open-label, randomized, multicenter, controlled trial of 442 patients with recurrent locoregional disease or metastatic SCCHN. Patients with no prior therapy for recurrent locoregional disease or metastatic SCCHN were randomized (1:1) to receive EU-approved cetuximab plus cisplatin or carboplatin and 5-FU, or cisplatin or carboplatin and 5-FU alone. Choice of cisplatin or carboplatin was at the discretion of the treating physician. Stratification factors were Karnofsky performance status (<80 versus ≥80) and previous chemotherapy. Cisplatin (100 mg/m2 , Day 1) or carboplatin (AUC 5, Day 1) plus intravenous 5-FU (1000 mg/m2 /day, Days 1–4) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Cetuximab was administered at a 400 mg/m2 initial dose, followed by a 250 mg/m2 weekly dose in combination with chemotherapy. Patients demonstrating at least stable disease on cetuximab in combination with chemotherapy were to continue cetuximab monotherapy at 250 mg/m2 weekly, in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of platinum-based therapy. For patients where treatment was delayed because of the toxic effects of chemotherapy, weekly cetuximab was continued. If chemotherapy was discontinued for toxicity, cetuximab could be continued as monotherapy until disease progression or unacceptable toxicity. Of the 442 randomized patients, the median age was 57 years, 90% were male, 98% were Caucasian, and 88% had baseline Karnofsky performance status ≥80. Thirty-four percent of patients had oropharyngeal, 25% laryngeal, 20% oral cavity, and 14% hypopharyngeal primary tumors. Fifty-three percent of patients had recurrent locoregional disease only and 47% had metastatic disease. Fifty-eight percent had AJCC Stage IV disease and 21% had Stage III disease. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately fifteen percent of the patients in the cisplatin alone arm switched to carboplatin during the treatment period. The main outcome measure of this trial was overall survival. Results are presented in Table 7 and Figure 1. Table 7: Study 2: Clinical Efficacy in Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab + Platinum-based Therapy + 5-FU (n=222) Platinum based Therapy + 5-FU (n=220) Hazard Ratio (95% CIa) Stratified Log-rank p-value Overall Survival Median duration (months) 10.1 7.4 0.80 (0.64, 0.98) 0.034 Progression-free Survival Median duration (months) 5.5 3.3 0.57 (0.46, 0.72) <0.0001 EU-Approved Cetuximab + Platinum-based Therapy + 5-FU (n=222) Platinum based Therapy + 5-FU (n=220) Odds Ratio (95% CIa) CMHb test p-value Objective Response Rate 35.6% 19.5% 2.33 (1.50, 3.60) 0.0001 aCI = confidence interval bCMH = Cochran-Mantel-Haenszel Figure 1: Kaplan-Meier Curve for Overall Survival in Patients with Recurrent Locoregional Disease or Metastatic Squamous Cell Carcinoma of the Head and Neck CT = Platinum-based therapy with 5-FU CET = EU-approved cetuximab In exploratory subgroup analyses of Study 2 by initial platinum therapy (cisplatin or carboplatin), for patients (N=284) receiving cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival was 3.3 months (10.6 versus 7.3 months, respectively; HR 0.71; 95% CI 0.54, 0.93). The difference in median progression-free survival was 2.1 months (5.6 versus 3.5 months, respectively; HR 0.55; 95% CI 0.41, 0.73). The objective response rate was 39% and 23%, respectively (OR 2.18; 95% CI 1.29, 3.69). For patients (N=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months (9.7 versus 8.3 months; HR 0.99; 95% CI 0.69, 1.43). The difference in median progression-free survival was 1.7 months (4.8 versus 3.1 months, respectively; HR 0.61; 95% CI 0.42, 0.89). The objective response rate was 30% and 15%, respectively (OR 2.45; 95% CI 1.10, 5.46). Study 3 was a single-arm, multicenter clinical trial in 103 patients with recurrent or metastatic SCCHN. All patients had documented disease progression within 30 days of a platinum-based chemotherapy regimen. Patients received a 20-mg test dose of Erbitux on Day 1, followed by a 400 mg/m2 initial dose, and 250 mg/m2 weekly until disease progression or unacceptable toxicity. The median age was 57 years, 82% were male, 100% Caucasian, and 62% had a Karnofsky performance status of ≥80. The objective response rate was 13% (95% confidence interval 7%–21%). Median duration of response was 5.8 months (range 1.2–5.8 months). Colorectal Cancer Erbitux Clinical Trials In K-Ras Wild-Type, EGFR-Expressing, Metastatic Colorectal Cancer Study 4 was a randomized, open-label, multicenter, study of 1217 patients with EGFR-expressing, metastatic colorectal cancer. Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI or FOLFIRI alone as first-line treatment. Stratification factors were Eastern Cooperative Oncology Group (ECOG) performance status (0 and 1 versus 2) and region (sites in Western Europe versus Eastern Europe versus other). FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m2 administered intravenously on Day 1), folinic acid (400 mg/m2 [racemic] or 200 mg/m2 [L-form] administered intravenously on Day 1), and 5-FU (400 mg/m2 bolus on Day 1 followed by 2400 mg/m2 as a 46-hour continuous infusion). Cetuximab was administered as a 400 mg/m2 initial dose on Day 1, Week 1, followed by 250 mg/m2 weekly administered 1 hour prior to chemotherapy. Study treatment continued until disease progression or unacceptable toxicity occurred. Of the 1217 randomized patients, the median age was 61 years, 60% were male, 86% were Caucasian, and 96% had a baseline ECOG performance status 0–1, 60% had primary tumor localized in colon, 84% had 1–2 metastatic sites and 20% had received prior adjuvant and/or neoadjuvant chemotherapy. Demographics and baseline characteristics were similar between study arms. K-Ras mutation status was available for 1079/1217 (89%) of the patients: 676 (63%) patients had K-Ras wild-type tumors and 403 (37%) patients had K-Ras mutant tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D [see WARNINGS AND PRECAUTIONS]. Baseline characteristics and demographics in the K-Ras wild-type subset were similar to that seen in the overall population [see WARNINGS AND PRECAUTIONS]. The main outcome measure of this trial was progression-free survival assessed by an independent review committee (IRC). Overall survival and response rate were also assessed. A statistically significant improvement in PFS was observed for the cetuximab plus FOLFIRI arm compared with the FOLFIRI arm (median PFS 8.9 vs. 8.1 months, HR 0.85 [95% CI 0.74, 0.99], p-value=0.036). Overall survival was not significantly different at the planned, final analysis based on 838 events (HR=0.93, 95% CI [0.8, 1.1], p-value 0.327). Results of the planned PFS and ORR analysis in all randomized patients and post-hoc PFS and ORR analysis in subgroups of patients defined by K-Ras mutation status, and post-hoc analysis of updated OS based on additional follow-up (1000 events) in all randomized patients and in subgroups of patients defined by K-Ras mutation status are presented in Table 8 and Figure 2. The treatment effect in the allrandomized population for PFS was driven by treatment effects limited to patients who have K-Ras wildtype tumors. There is no evidence of effectiveness in the subgroup of patients with K-Ras mutant tumors. Table 8: Clinical Efficacy in First-line EGFR-expressing, Metastatic Colorectal Cancer (All Randomized and K-Ras Status ) All Randomized K-Ras Wild-type K-Ras Mutant EUApproved Cetuximab plus EUApproved Cetuximab plus EUApproved Cetuximab plus FOLFIRI (n=608) FOLFIRI (n=609) FOLFIRI (n=320) FOLFIRI (n=356) FOLFIRI (n=216) FOLFIRI (n=187) Progression-Free Survival Number of Events (%) 343 (56) 371 (61) 165 (52) 214 (60) 138 (64) 112 (60) Median (months) 8.9 8.1 9.5 8.1 7.5 8.2 (95% CI) (8.0, 9.4) (7.6, 8.8) (8.9, 11.1) (7.4, 9.2) (6.7, 8.7) (7.4, 9.2) HR (95% CI) 0.85 (0.74, 0.99) 0.70 (0.57, 0.86) 1.13 (0.88, 1.46) p-valuea 0.0358 Overall Survivalb Number of Events (%) 491 (81) 509 (84) 244 (76) 292 (82) 189 (88) 159 (85) Median (months) 19.6 18.5 23.5 19.5 16.0 16.7 (95% CI) (18, 21) (17, 20) (21, 26) (17, 21) (15, 18) (15, 19) HR (95% CI) 0.88 (0.78, 1.0) 0.80 (0.67, 0.94) 1.04 (0.84, 1.29) Objective Response Rate ORR (95% CI) 46% (42, 50) 38% (34, 42) 57% (51, 62) 39% (34, 44) 31% (25, 38) 35% (28, 43) aBased on the Stratified Log-rank test. bPost-hoc updated OS analysis, results based on an additional 162 events. Figure 2: Kaplan-Meier Curve for Overall Survival in the K-Ras Wild-type Population in Study 4 Study 5 was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFRexpressing, previously treated, recurrent mCRC. Patients were randomized (1:1) to receive either Erbitux plus best supportive care (BSC) or BSC alone. Erbitux was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. Of the 572 randomized patients, the median age was 63 years, 64% were male, 89% were Caucasian, and 77% had baseline ECOG performance status of 0–1. Demographics and baseline characteristics were similar between study arms. All patients were to have received and progressed on prior therapy including an irinotecan-containing regimen and an oxaliplatin-containing regimen. K-Ras status was available for 453/572 (79%) of the patients: 245 (54%) patients had K-Ras wild-type tumors and 208 (46%) patients had K-Ras mutant tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D [see WARNINGS AND PRECAUTIONS]. The main outcome measure of the study was overall survival. Results are presented in Table 9 and Figure 3. Table 9: Overall Survival in Previously Treated EGFR-expressing, Metastatic Colorectal Cancer (All Randomized and K-Ras Status ) All Randomized K-Ras Wild-type K-Ras Mutant Erbitux plus BSC (N=287) BSC (N=285) Erbitux plus BSC (N=117) BSC (N=128) Erbitux plus BSC (N=108) BSC (N=100) Median (months) 6.1 4.6 8.6 5.0 4.8 4.6 (95% CI) (5.4, 6.7) (4.2, 4.9) (7.0, 10.3) (4.3, 5.7) (3.9, 5.6) (3.6, 4.9) HR 0.77 0.63 0.91 (95% CI) (0.64, 0.92) (0.47, 0.84) (0.67, 1.24) p-valuea 0.0046 aBased on the Stratified Log-rank test. Figure 3: Kaplan-Meier Curve for Overall Survival in Patients with K-Ras Wild-type Metastatic Colorectal Cancer in Study 5 Study 6 was a multicenter, clinical trial conducted in 329 patients with EGFR-expressing recurrent mCRC. Tumor specimens were not available for testing for K-Ras mutation status. Patients were randomized (2:1) to receive either Erbitux plus irinotecan (218 patients) or Erbitux monotherapy (111 patients). Erbitux was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. In the Erbitux plus irinotecan arm, irinotecan was added to Erbitux using the same dose and schedule for irinotecan as the patient had previously failed. Acceptable irinotecan schedules were 350 mg/m2 every 3 weeks, 180 mg/m2 every 2 weeks, or 125 mg/m2 weekly times four doses every 6 weeks. Of the 329 patients, the median age was 59 years, 63% were male, 98% were Caucasian, and 88% had baseline Karnofsky performance status ≥80. Approximately twothirds INDICATIONS PERTZYE® is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions. DOSAGE AND ADMINISTRATION 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). 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 breastfeeding. Do not mix PERTZYE capsule contents directly into formula or breast milk prior to administration [see Administration]. 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]. 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. 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 microspheres are not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa [see WARNINGS AND PRECAUTIONS]. 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. 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 intact microspheres on the applesauce. Mix the microspheres with the applesauce being careful not to crush the microspheres when mixing. Consume the entire contents immediately. Do not chew the microspheres. Do not save the applesauce and microspheres 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]. 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 thoroughly with the transferred applesauce to create a uniform suspension. Once mixed, administer the suspension immediately. Care should be taken not to crush the enzyme microspheres. 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. HOW SUPPLIED Dosage Forms And Strengths The active ingredient in PERTZYE evaluated in clinical trials is lipase. PERTZYE is dosed by lipase units. PERTZYE is available in 3 color coded capsule strengths. Each PERTZYE delayed-release capsule strength contains the specified amounts of lipase, protease and amylase as follows: 4,000 USP units of lipase; 14,375 USP units of protease; 15,125 USP units of amylase. Delayed-release capsules have a clear body printed in green with “4” and a clear cap printed with a green circular stripe and “DCI” 8,000 USP units of lipase; 28,750 USP units of protease; 30,250 USP units of amylase. Delayed-release capsules have a clear body printed in blue with “8” and a clear cap printed with a blue circular stripe and “DCI” 16,000 USP units of lipase; 57,500 USP units of protease; 60,500 USP units of amylase. Delayed-release capsules have a clear body printed in red with “16” and a clear cap printed with a red circular stripe and “DCI” PERTZYE (pancrelipase) Delayed-Release Capsules 4,000 USP units of lipase; 14,375 USP units of protease; 15,125 USP units of amylase. Each PERTZYE delayed-release capsule has a clear body printed in green with “4” and a clear cap printed with a green circular stripe and “DCI”. Capsules are supplied in bottles of 100 (NDC 59767-004-01). PERTZYE (pancrelipase) Delayed-Release Capsules 8,000 USP units of lipase; 28,750 USP units of protease; 30,250 USP units of amylase. Each PERTZYE delayed-release capsule has a clear body printed in blue with “8” and a clear cap printed with a blue circular stripe and “DCI”. Capsules are supplied in bottles of 100 (NDC 59767-008-01) or 250 (NDC 59767-008-02). PERTZYE (pancrelipase) Delayed-Release Capsules 16,000 USP units of lipase; 57,500 USP units of protease; 60,500 USP units of amylase. Each PERTZYE delayed-release capsule has a clear body printed in red with “16” and a clear cap printed with a red circular stripe and “DCI”. Capsules are supplied in bottles of 100 (NDC 59767-016-01) or 250 (NDC 59767-016-02). Storage And Handling Store at room temperature 20-25°C (68-77°F), brief excursions permitted to 15-40°C (59104°F). PERTZYE hard gelatin 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. 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. REFERENCES 1. Borowitz DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Journal of Pediatrics. 1995; 127: 681-684. 2. Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. Journal of Pediatric Gastroenterology Nutrition. 2002 Sep; 35: 246-259. 3. Stallings VA, Start LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. Journal of the American Dietetic Association. 2008; 108: 832-839. Manufactured in the USA by: Digestive Care, Inc. Bethlehem, PA 18017. Revised: Jul 2017 had previously failed oxaliplatin treatment. The efficacy of Erbitux plus irinotecan or Erbitux monotherapy, based on durable objective responses, was evaluated in all randomized patients and in two pre-specified subpopulations: irinotecan refractory patients, and irinotecan and oxaliplatin failures. In patients receiving Erbitux plus irinotecan, the objective response rate was 23% (95% confidence interval 18%–29%), median duration of response was 5.7 months, and median time to progression was 4.1 months. In patients receiving Erbitux monotherapy, the objective response rate was 11% (95% confidence interval 6%–18%), median duration of response was 4.2 months, and median time to progression was 1.5 months. Similar response rates were observed in the pre-defined subsets in both the combination arm and monotherapy arm of the study.

INDICATIONS PANCRECARB® (pancrelipase) Delayed-Release Capsules, Buffered and Enteric-Coated Microspheres are indicated for patients with exocrine pancreatic enzyme insufficiency such as: cystic fibrosis, chronic pancreatitis due to alcohol use or other causes, post-pancreatectomy and post-gastrointestinal bypass surgery (e.g. Billroth II gastroenterostomy). DOSAGE AND ADMINISTRATION Dosing, Duration Of Therapy Dosage should be individualized and adjusted according to fat intake, severity of steatorrhea and the severity of the exocrine pancreatic insufficiency. Begin therapy with one or two capsules with meals or snacks and adjust dosage according to symptoms. Dose increases, if required, should be made slowly, with careful monitoring of response and symptomatology. It is important to ensure adequate hydration of patients at all times while taking PANCRECARB® (pancrelipase) . Patients with pancreatic enzyme insufficiency should consume a high-caloric diet with unrestricted fat intake, which is appropriate for age and clinical symptomology. HOW SUPPLIED PANCRECARB® (pancrelipase) are supplied as follows: PANCRECARB® (pancrelipase) MS-4 (clear, hard gelatin capsule imprinted in blue with "DCI" and "PANCRECARB® (pancrelipase) MS-4") in bottles of 100 (NDC 59767-002-01). PANCRECARB® (pancrelipase) MS-8 (clear, hard gelatin capsule imprinted in blue with "DCI" and "PANCRECARB® (pancrelipase) MS-8") in bottles of 100 (NDC 59767-001-01). PANCRECARB® (pancrelipase) MS-16 (clear, hard gelatin capsule imprinted in blue with "DCI" and "PANCRECARB® (pancrelipase) MS-16") in bottles of 100 (NDC 59767-003-01). Storage Store at controlled room temperature 25ºC (77ºF) in a dry place. Do not refrigerate. Do not expose capsules to humid air. Keep bottle tightly closed. Dispense capsules in a tight container. Manufacturer information. n/a. FDA rev date: n/a

PATIENT INFORMATION MEDICATION GUIDE VIOKACE™ (vye-oh-kase) (pancrelipase) tablets Read this Medication Guide before you start taking VIOKACE and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. What is the most important information I should know about VIOKACE? VIOKACE may increase your chance of having a rare bowel disorder called fibrosing colonopathy. This condition is serious and may require surgery. The risk of having this condition may be reduced by following the dosing instructions that your doctor gave you. Call your doctor right away if you have any unusual or severe: stomach area (abdominal) pain bloating trouble passing stool (having bowel movements) nausea, vomiting, or diarrhea Take VIOKACE exactly as prescribed by your doctor. Do not take more or less VIOKACE than directed by your doctor. What is VIOKACE? VIOKACE is a prescription medicine used with a proton pump inhibitor medicine (PPI) to treat adults who cannot digest food normally. Adults with swelling of the pancreas that lasts a long time (chronic pancreatitis), or who have had some or all of their pancreas removed (pancreatectomy) may not digest food normally because they do not make enough enzymes or because their enzymes are not released into the bowel (intestine). VIOKACE contains a mixture of digestive enzymes (including lipases, proteases, and amylases) from pig pancreas. It is not known if VIOKACE is safe and effective in children. Use of VIOKACE in children may result in poor nutrition and slowing of growth. What should I tell my doctor before taking VIOKACE? Before taking VIOKACE, tell your doctor about all your medical conditions, including if you: are allergic to pork (pig) products have a history of blockage of your intestines, or scarring or thickening of your bowel wall (fibrosing colonopathy) have gout, kidney disease, or a condition called high blood uric acid (hyperuricemia) have trouble swallowing tablets are lactose intolerant have any other medical condition are pregnant or plan to become pregnant. It is not known if VIOKACE will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if VIOKACE passes into your breast milk. You and your doctor should decide if you will take VIOKACE or breastfeed. Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, or herbal supplements. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. How should I take VIOKACE? Take VIOKACE tablets exactly as your doctor tells you. You should not switch VIOKACE with any other pancreatic enzyme product without first talking to your doctor. Do not take more tablets in a day than the number your doctor tells you to take (total daily dose). Always take VIOKACE with a meal or a snack and enough liquid to swallow VIOKACE completely. If you eat a lot of meals or snacks in a day, be careful not to go over your total daily dose. Your doctor may change your dose based on the amount of fatty foods you eat or based on your weight. Your doctor should also prescribe a medicine for you called a proton pump inhibitor (PPI) to decrease stomach acid. VIOKACE should be taken with a PPI to help prevent VIOKACE from breaking down in your stomach. Swallow VIOKACE tablets whole. Do not crush or chew the tablets. Be careful to make sure that no VIOKACE is left in your mouth. Crushing, chewing or holding the VIOKACE tablets in your mouth may cause irritation in your mouth, or change the way VIOKACE works in your body.. If you forget to take VIOKACE, wait until your next meal and take your usual number of tablets. Take your next dose at your usual time. Do not take two doses at one time. What are the possible side effects of VIOKACE? VIOKACE may cause serious side effects, including: See "What is the most important information I should know about VIOKACE?" Irritation of the inside of your mouth. This can happen if VIOKACE is not swallowed completely. Increase in blood uric acid levels. This may cause worsening of swollen, painful joints (gout) caused by an increase in your blood uric levels. Allergic reactions, including trouble with breathing, skin rashes, or swollen lips. Call your doctor right away if you have any of these symptoms. The most common side effects of VIOKACE include: you can develop stones that form in your gallbladder and the tubes that carry bile to your small intestines. anal itching Other possible side effects: VIOKACE and other pancreatic enzyme products are made from the pancreas of pigs, the same pigs people eat as pork. These pigs may carry viruses. Although it has never been reported, it may be possible for a person to get a viral infection from taking pancreatic enzyme products that come from pigs. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the side effects of VIOKACE. For more information ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Aptalis Pharma US, Inc. at 1-800-472-2634. How should I store VIOKACE? Store VIOKACE at room temperature, 68°F to 77°F (20°C to 25°C). Avoid heat. Keep VIOKACE in a dry place and in its original container. After opening the bottle, keep it closed tightly between uses to protect from moisture. The VIOKACE bottle contains a desiccant packet to help keep your medicine dry (protect it from moisture). Do not eat or throw away the desiccant packet. Keep VIOKACE and all medicines out of reach of children. General information about the safe and effective use of VIOKACE Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VIOKACE for a condition for which it was not prescribed. Do not give VIOKACE to other people to take, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about VIOKACE. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about VIOKACE that is written for healthcare providers. For more information, go to www.aptalispharma.com or call toll-free 1-800-472-2634. What are the ingredients in VIOKACE? Active ingredient: lipase, protease and amylase Inactive ingredients: colloidal silicon dioxide, crosscarmellose sodium, lactose monohydrate, microcrystalline cellulose, stearic acid and talc. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued March 2012

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

PATIENT INFORMATION PERTZYE (pert-zye) (pancrelipase) delayed-release capsules, for oral use What is the most important information I should know about PERTZYE? PATIENT INFORMATION PERTZYE (pert-zye) (pancrelipase) delayed-release capsules What is the most important information I should know about PERTZYE? PERTZYE may increase the risk of having a rare bowel disorder called fibrosing colonopathy, especially if taken at a high dose in children with cystic fibrosis who are less than 12 years of age. This condition is serious and may require surgery. The risk of having fibrosing colonopathy may be reduced by following the dosing instructions that your doctor gives you. Call your doctor right away if you have any unusual or severe: stomach area (abdominal) pain bloating trouble passing stool (constipation) nausea vomiting diarrhea Take PERTZYE exactly as prescribed by your doctor. Do not take more PERTZYE than your doctor tells you to. What is PERTZYE? PERTZYE is a prescription medicine used to treat people who cannot digest food normally because their pancreas does not make enough enzymes due to cystic fibrosis or other conditions. PERTZYE capsules contain a mixture of digestive enzymes including lipases, proteases and amylases from pig pancreas. PERTZYE is safe and effective in children when taken as prescribed by their doctor. Before taking PERTZYE, tell your doctor about all of your medical conditions, including if you: are allergic to pork (pig) products. have a history of blockage of your intestines, or scarring or thickening of your bowel wall (fibrosing colonopathy). have gout, kidney disease, or high blood uric acid (hyperuricemia). have trouble swallowing capsules. are pregnant or plan to become pregnant. It is not known if PERTZYE can harm your unborn baby. It is not known if PERTZYE can affect your ability to become pregnant. are breastfeeding or plan to breastfeed. It is not known if PERTZYE passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take PERTZYE. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. How should I take PERTZYE? See the Instructions for Use at the end of this Medication Guide for detailed instructions about how to give PERTZYE by mouth and through a gastrostomy tube. Take PERTZYE capsules exactly as your doctor tells you. You should not switch PERTZYE with any other pancreatic enzyme product without first talking with your doctor. Do not take more capsules in a day than the number your doctor tells you to take (total daily dose). Always take PERTZYE with a meal or snack and plenty of fluid. If you eat a lot of meals or snacks in a day, be careful not to go over your total daily dose. Your doctor may change your dose based on the amount of fatty foods you eat or based on your weight. PERTZYE capsules should be swallowed whole. Do not crush or chew the PERTZYE capsules or their contents, and do not hold the capsule or capsule contents in your mouth. Crushing, chewing or holding the PERTZYE capsules in your mouth may cause irritation in your mouth or change the way PERTZYE works in your body. Throw away the PERTZYE capsule contents-food mixture that is not used. Do not save this mixture for later use. If you miss a dose of PERTZYE, wait until your next meal or snack and take your prescribed dose. Take your next dose at your usual time. Do not take two doses at one time. What are the possible side effects of PERTZYE? See “What is the most important information I should know about PERTZYE?” Irritation of the inside of your mouth. This can happen if PERTZYE is not swallowed completely, is crushed or chewed, or is mixed in foods that are not recommended. Increase in blood uric acid levels. This may cause worsening of swollen, painful joints (gout) caused by an increase in your blood uric acid levels. Allergic reactions, including trouble swallowing or breathing, skin rash, itching, or swelling of your face, eyes, lips, tongue, or throat. Call your doctor right away if you have any of these symptoms. The most common side effects of PERTZYE include: diarrhea upset stomach (indigestion) cough Other possible side effects: PERTZYE and other pancreatic enzyme products are made from the pancreas of pigs, the same pigs people eat as pork. These pigs may carry viruses. Although it has never been reported, it may be possible for a person to get a viral infection from taking pancreatic enzyme products that come from pigs. These are not all of the possible side effects of PERTZYE. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store PERTZYE? Store PERTZYE at room temperature between 68°F to 77°F (20°C to 25°C). Keep PERTZYE in a dry place and in the original container. After opening the bottle, keep it tightly closed between uses to keep your medicine dry (protect it from moisture). The PERTZYE bottle contains a desiccant packet to help keep your medicine dry. Do not eat or throw away the desiccant packet in your medicine bottle. Keep PERTZYE and all medicines out of the reach of children. General information about the safe and effective use of PERTZYE. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PERTZYE for a condition for which it was not prescribed. Do not give PERTZYE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about PERTZYE that is written for health professionals. What are the ingredients in PERTZYE? Active ingredients: lipase, protease, and amylase. Inactive ingredients: sodium bicarbonate, sodium carbonate, cellulose acetate phthalate, sodium starch glycolate, diethyl phthalate, ursodiol, polyvinylpyrrolidone, and talc. The hard gelatin capsule shells contain: gelatin and water. The green imprinting ink on the 4,000 units of lipase; 14,375 units of protease; 15,125 units of amylase capsules contain: FD&C Blue #1, D&C Yellow #10, black iron oxide, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, shellac and ammonium hydroxide. The blue imprinting ink on the 8,000 units of lipase; 28,750 units of protease; 30,250 units of amylase capsules contain: FD&C Blue #1, ethanol, methanol, n-butyl alcohol, propylene glycol, shellac and ammonium hydroxide. The red imprinting ink on the 16,000 units of lipase; 57,500 units of protease; 60,500 units of amylase capsules contain: FD&C Red #40, povidone, titanium dioxide, dehydrated alcohol, sodium hydroxide, butyl alcohol, propylene glycol, isopropyl alcohol, and shellac. For more information, go to www.digestivecare.com or call 1-877-882-5950. Instructions For Use PERTZYE (pert-zye) (pancrelipase) delayed-release capsules Important information: Always take PERTZYE with a meal or snack and plenty of fluid. PERTZYE capsules should be swallowed whole. Do not crush or chew the PERTZYE capsules or their contents, and do not hold the capsule or capsule contents in your mouth. Throw away the PERTZYE capsule contents-food mixture that is not used. Do not save this mixture for later use. Giving PERTZYE to infants (up to 12 months of age) by mouth: Give the contents of 1 PERTZYE capsule right before each feeding of formula or breast milk. Do not mix PERTZYE capsule contents directly into formula or breast milk. PERTZYE capsule contents may be given directly into your infant's mouth or mixed with food. Giving PERTZYE capsule contents directly into your infant's mouth: Carefully open the PERTZYE capsule by grasping and slightly squeezing both ends of the capsule and then twisting and pulling the capsule apart. Empty the capsule contents into your infant's mouth. Give your infant 4 ounces (120 mL) of formula or breastfeed right away. Look in your infant's mouth to make sure that all of the medicine is swallowed and there is no PERTZYE capsule contents left in your infant's mouth. Throw away the empty PERTZYE capsule. Giving PERTZYE capsule contents mixed in food: Place about 2 teaspoons of applesauce, the kind found in baby food jars that you buy at the store, or other food recommended by your doctor, into a clean container. Carefully open the PERTZYE capsule by grasping and slightly squeezing both ends of the capsule and then twisting and pulling the capsule apart. Pour the capsule contents onto the food in the clean container. Throw away the empty PERTZYE capsule. Carefully mix the capsule contents evenly through the food. Be careful not to crush the PERTZYE capsule contents when mixing. Give the PERTZYE capsule contents-food mixture to your infant right away. Give your infant 4 ounces (120 mL) of formula or breastfeed your infant right away. Look in your infant's mouth to make sure that all of the medicine is swallowed and there is no PERTZYE capsule contents-food mixture left in your infant's mouth. Giving PERTZYE to children and adults by mouth: Swallow PERTZYE capsules whole and take them with enough liquid to swallow them right away. If you have trouble swallowing capsules, follow these instructions for taking PERTZYE with food: Place about 2 teaspoons of applesauce, or other food recommended by your doctor, into a clean container. Carefully open the capsules that you will need for the prescribed dose by grasping and slightly squeezing both ends of the capsule and then twisting and pulling the capsule apart. Pour the capsule contents onto the food in the clean container. Throw away the empty PERTZYE capsules. Carefully mix the capsule contents evenly through the food. Be careful not to crush the PERTZYE capsule contents when mixing. Swallow all of the PERTZYE capsule contents-food mixture right away. Drink plenty of water or juice to make sure that all of the medicine is swallowed and there is no PERTZYE capsule contents-food mixture left in the mouth. Giving PERTZYE through a gastrostomy tube: PERTZYE 4,000 lipase units capsule contents may be given through a gastrostomy tube that is size 14 French or larger. Do not give PERTZYE through a gastrostomy tube smaller than size 14 French. Do not give more than the contents of 2 PERTZYE 4,000 lipase units capsules through a gastrostomy tube at a time. Give the PERTZYE capsule contents-food mixture right away after it is prepared. Place at least 2 teaspoons of applesauce, or other food recommended by your doctor, into a clean container. Carefully open 1 or 2 of the PERTZYE capsules, depending on your prescribed dose, by grasping and slightly squeezing both ends of the capsule and then twisting and pulling the capsule apart. Pour the capsule contents onto the food in the clean container. Throw away the empty PERTZYE capsules. Carefully mix the capsule contents evenly through the food. Be careful not to crush the PERTZYE capsule contents when mixing. Remove the plunger from a 35 mL slip tip syringe. Cover the tip of the syringe with your finger. Carefully spoon the PERTZYE capsule contents-food mixture into the slip tip syringe. Replace the plunger partially back into the slip tip syringe. Turn the slip tip syringe so the syringe tip is facing upward. Remove your finger from the tip of the slip tip syringe. Gently shake or tap the slip tip syringe so that the PERTZYE capsule contents-food mixture moves down towards the plunger. Carefully push up slowly on the plunger until the PERTZYE capsule contents-food mixture fills the syringe tip. Connect the slip tip syringe directly into the gastrostomy tube feeding port. Press on the plunger of the slip tip syringe using steady pressure to push all of the PERTZYE capsule contents-food mixture into the gastrostomy tube feeding port over 10 seconds to 12 seconds. Flush the gastrostomy tube feeding port with about 10 mL of water. If your prescribed dose is more than 2 capsules of PERTZYE, repeat steps 1 through 12, using only 1 or 2 PERTZYE capsules at a time, until the prescribed dose is given. How should I store PERTZYE? Store PERTZYE at room temperature between 68°F to 77°F (20°C to 25°C). Keep PERTZYE in a dry place and in the original container. After opening the bottle, keep it tightly closed between uses to keep your medicine dry (protect it from moisture). The PERTZYE bottle contains a desiccant packet to help keep your medicine dry. Do not eat or throw away the desiccant packet in your medicine bottle. Keep PERTZYE and all medicines out of the reach of children. PERTZYE may increase your chance of having a rare bowel disorder called fibrosing colonopathy. This condition is serious and may require surgery. The risk of having fibrosing colonopathy may be reduced by following the dosing instructions that your doctor gave you. Call your doctor right away if you have any unusual or severe: stomach area (abdominal pain) bloating trouble passing stool (constipation) nausea vomiting diarrhea Take PERTZYE exactly as prescribed by your doctor. Do not take more or less PERTZYE than your doctor tells you to. What is PERTZYE? PERTZYE is a prescription medicine used to treat people who cannot digest food normally because their pancreas does not make enough enzymes due to cystic fibrosis or other conditions. PERTZYE capsules contain a mixture of digestive enzymes including lipases, proteases and amylases from pig pancreas. PERTZYE is safe and effective in children when taken as prescribed by your doctor. Before taking PERTZYE, tell your doctor about all of your medical conditions, including if you: are allergic to pork (pig) products. have a history of blockage of your intestines, or scarring or thickening of your bowel wall (fibrosing colonopathy). have gout, kidney disease, or high blood uric acid (hyperuricemia). have trouble swallowing capsules. are pregnant or plan to become pregnant. It is not known if PERTZYE will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if PERTZYE passes into your breast milk. You and your doctor should decide if you will take PERTZYE or breastfeed. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. How should I take PERTZYE? Take PERTZYE capsules exactly as your doctor tells you. You should not switch PERTZYE with any other pancreatic enzyme product without first talking with your doctor. Do not take more capsules in a day than the number your doctor tells you to take (total daily dose). Always take PERTZYE with a meal or snack and plenty of fluid. If you eat a lot of meals or snacks in a day, be careful not to go over your total daily dose. Your doctor may change your dose based on the amount of fatty foods you eat or based on your weight. PERTZYE capsules should be swallowed whole. Do not crush or chew the PERTZYE capsules or their contents, and do not hold the capsule or capsule contents in your mouth. Crushing, chewing or holding the PERTZYE capsules in your mouth may cause irritation in your mouth or change the way PERTZYE works in your body. Giving PERTZYE to children and adults: You should not divide the capsule contents into small amounts to give small doses of PERTZYE. Swallow PERTZYE capsules whole and take them with enough liquid to swallow them right away. If you have trouble swallowing capsules, open the capsules and mix the contents with a small amount of soft acidic food such as applesauce. Ask your doctor about other foods you can mix with PERTZYE. If you mix PERTZYE with food, swallow it right after you mix it and drink plenty of water or juice to make sure the medicine is swallowed completely. Do not store PERTZYE that is mixed with food. Throw away any unused portion of the capsule contents. If you forget to take PERTZYE, wait until your next meal or snack and take your usual number of capsules. Take your next dose at your usual time. Do not take two doses at one time. What are the possible side effects of PERTZYE? PERTZYE may cause serious side effects, including: See “What is the most important information I should know about PERTZYE?” Irritation of the inside of your mouth. This can happen if PERTZYE is not swallowed completely. Increase in blood uric acid levels. This may cause worsening of swollen, painful joints (gout) caused by an increase in your blood uric acid levels. Allergic reactions, including trouble breathing, skin rash, itching, or swollen lips. Call your doctor right away if you have any of these symptoms. The most common side effects of PERTZYE include: diarrhea upset stomach (indigestion) cough Other possible side effects: PERTZYE and other pancreatic enzyme products are made from the pancreas of pigs, the same pigs people eat as pork. These pigs may carry viruses. Although it has never been reported, it may be possible for a person to get a viral infection from taking pancreatic enzyme products that come from pigs. These are not all of the possible side effects of PERTZYE. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Digestive Care, Inc. at 1-877-882-5950. How do I store PERTZYE? Store PERTZYE at room temperature between 68°F to 77°F (20°C to 25°C). Keep PERTZYE in a dry place and in the original container. After opening the bottle, keep it tightly closed between uses to keep your medicine dry (protect it from moisture). The PERTZYE bottle contains a desiccant packet to help keep your medicine dry (protect it from moisture). Do not eat or throw away the packet (desiccant) in your medicine bottle. Keep PERTZYE and all medicines out of the reach of children. General information about the safe and effective use of PERTZYE. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PERTZYE for a condition for which it was not prescribed. Do not give PERTZYE to other people to take, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about PERTZYE that is written for health professionals. What are the ingredients in PERTZYE? Active ingredients: lipase, protease, and amylase. Inactive ingredients: sodium bicarbonate, sodium carbonate, cellulose acetate phthalate, sodium starch glycolate, diethyl phthalate, ursodiol, polyvinylpyrrolidone, and talc. The hard gelatin capsule shells contain: gelatin and water. The green imprinting ink on the 4,000 units of lipase; 14,375 units of protease; 15,125 units of amylase capsules contain: FD&C Blue #1, D&C Yellow #10, black iron oxide, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, shellac and ammonium hydroxide. The blue imprinting ink on the 8,000 units of lipase; 28,750 units of protease; 30,250 units of amylase capsules contain: FD&C Blue #1, ethanol, methanol, n-butyl alcohol, propylene glycol, shellac and ammonium hydroxide. The red imprinting ink on the 16,000 units of lipase; 57,500 units of protease; 60,500 units of amylase capsules contain: FD&C Red #40, povidone, titanium dioxide, dehydrated alcohol, sodium hydroxide, butyl alcohol, propylene glycol, isopropyl alcohol, and shellac.

OVERDOSE There have been no reports of overdose in clinical trials or post-marketing surveillance with VIOKACE. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment [see WARNINGS AND PRECAUTIONS]. CONTRAINDICATIONS None.

OVERDOSE No information provided. CONTRAINDICATIONS Pancrelipase capsules are contraindicated in patients known to be hypersensitive to pork protein. Pancrelipase capsules are contraindicated in patients with acute pancreatitis or with acute exacerbations of chronic pancreatic diseases.

OVERDOSE In a clinical study, a 10 year-old patient was administered lipase doses over the maximum lipase dose of 2500 lipase units/kg/meal (Dose Stabilization 2799 lipase units/kg/meal; Wash-out/Re-Stabilization 2783 lipase units/kg/meal; and PERTZYE 2720 lipase units/kg/meal). Despite the administration of this slightly (10%) higher than recommended dose, no gastrointestinal AEs were reported for this subject. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment [see WARNINGS AND PRECAUTIONS]. CONTRAINDICATIONS None.

OVERDOSE No information provided. CONTRAINDICATIONS PANCRECARB® (pancrelipase) Delayed-Release Capsules, Buffered and Enteric-Coated Microspheres are contraindicated in patients known to be hypersensitive to pork protein or any other ingredient of this product.

SIDE EFFECTS 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]. 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 Reactions 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 and Administration Site Conditions Edema peripheral 1 ( 3%) 0 Hepatobiliary Disorders Biliary tract stones 2 ( 7%) 0 Hydrocholecystis 1 ( 3%) 0 Infections and Infestations Viral infection 1 ( 3%) 0 Nervous System Disorders Headache 1 ( 3%) 0 Renal and Urinary Disorders Renal cyst 1 ( 3%) 0 Skin and Subcutaneous Tissue Disorders Rash 1 ( 3%) 0 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. DRUG INTERACTIONS No drug interactions have been identified. No formal interaction studies have been conducted.

SIDE EFFECTS The most frequently reported adverse reactions to products containing pancrelipase are gastrointestinal in nature. Less frequently, allergic-type reactions have also been observed. Extremely high doses of exogenous pancreatic enzymes have been associated with hyperuricosuria and hyperuricemia when the preparations given were pancrelipase in powdered or capsule form, or pancreatin in tablet form. Colonic strictures have been reported in cystic fibrosis patients treated with both high- and lower-strength enzyme supplements.10 A causal relationship has not been established. The possibility of bowel stricture should be considered if symptoms suggestive of gastrointestinal obstruction occur. Since impaired fluid secretion may be a factor in the development of intestinal obstruction, care should be taken to maintain adequate hydration, particularly in warm weather.11 “Fibrosing colonopathy” is a term used to describe a condition seen in patients with CF who have taken high amounts of pancreatic enzyme supplements ( > 6,000 lipase U/kg/meal). At its most advanced, this condition leads to colonic strictures. In whom should one consider the diagnosis of fibrosing colonopathy? Patients with cystic fibrosis who have evidence of partial or complete obstruction, bloody diarrhea or chylous ascites. Patients who have two of the following three symptoms: abdominal pain ongoing diarrhea poor weight gain ESPECIALLY if they have: taken > 6,000 lipase U/kg/meal age less than twelve years history of meconium ileus prior intestinal surgery history of recurrent DIOS “inflammatory bowel disease”12 DRUG INTERACTIONS No information provided. REFERENCES 10. Smyth RL, van Velzen D, et al. Strictures of ascending colon in cystic fibrosis and high-strength pancreatic enzymes. The Lancet. 1994; 343:85-86. 11. Lands L, Zinman R, et al. Pancreatic function testing in meconium disease in CF: two case reports. J Ped Gastroenterol and Nut. 1988; 7:276-279. 12. Cystic Fibrosis Foundation Conference on Pancreatic Enzyme Supplementation in the Context of Fibrosing Colonopathy; Washington, D.C., March 23-24, 1995.

SIDE EFFECTS 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]. 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 PERTZYE was assessed in a randomized, double-blind, placebo-controlled, crossover study of 24 patients, ages 8 to 43 years, with exocrine pancreatic insufficiency due to cystic 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%) 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. DRUG INTERACTIONS No drug interactions have been identified. No formal interaction studies have been conducted.

SIDE EFFECTS The most frequently reported adverse reactions to pancrelipase-containing products are gastrointestinal in nature, which may include nausea, vomiting, bloating, cramping, constipation or diarrhea. Less frequently, allergic-type reactions have also been observed. Extremely high doses of exogenous pancreatic enzymes have been reported to be associated with hyperuricosuria and hyperuricemia. High strength pancrelipase preparation (i.e., those labeled as containing more than 20,000 lipase units per capsule) has been associated with colonic strictures. DRUG INTERACTIONS No information provided.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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]. 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. 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 and PATIENT INFORMATION]. 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. 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. 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. 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. Patient Counseling Information "See FDA-approved patient labeling (Medication Guide)" Dosing and Administration Instruct patients and caregivers that VIOKACE should only be taken as directed by their doctor. Patients should be advised that the total daily dose should not exceed 10,000 lipase units/kg body weight/day unless clinically indicated. This needs to be especially emphasized for patients eating multiple snacks and meals per day. Patients should be informed that if a dose is missed, the next dose should be taken with the next meal or snack as directed. Doses should not be doubled [see DOSAGE AND ADMINISTRATION]. Instruct patients and caregivers that VIOKACE should always be taken with food. Patients should swallow the intact tablets with adequate amounts of liquid at mealtimes [see DOSAGE AND ADMINISTRATION]. 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 have been associated with colonic strictures in children below the age of 12 years [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Allergic Reactions Advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to VIOKACE develop [see WARNINGS AND PRECAUTIONS]. Pregnancy and Breast Feeding Instruct patients to notify their healthcare professional if they are pregnant or are thinking of becoming pregnant during treatment with VIOKACE [see Use in Specific Populations]. Instruct patients to notify their healthcare professional if they are breast feeding or are thinking of breast feeding during treatment with VIOKACE [see Use In Specific Populations]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase. Use In Specific Populations Pregnancy Teratogenic effects Pregnancy Category C. Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. VIOKACE should be given to a pregnant woman only if clearly needed. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when VIOKACE is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency. Pediatric Use The safety and effectiveness of VIOKACE in pediatric patients have not been established. In general, delayed-release (enteric-coated) capsules should be used for pediatric patients. Due to greater degradation in the gastric environment, VIOKACE, a non-enteric-coated, pancreatic enzyme replacement product, may have decreased bioavailability and therefore may be less efficacious than enteric-coated formulations.7, 8 Thus, use of VIOKACE in pediatric patients may increase the risk of inadequate treatment of pancreatic insufficiency and result in suboptimal weight gain, malnutrition and/or need for larger doses of pancreatic enzyme replacement [See WARNINGS AND PRECAUTIONS] The efficacy of VIOKACE was established in adult patients with concomitant proton pump inhibitor (PPI) therapy. The long-term safety of PPI use in pediatric patients has not been established. Geriatric Use Clinical studies of VIOKACE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. REFERENCES 1. Borowitz DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Journal of Pediatrics. 1995; 127: 681-684. 5. Smyth RL, Ashby D, O'Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet. 1995; 346: 12471251. 6. FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. New England Journal of Medicine. 1997; 336: 1283-1289. 7. Gow R, Francis P, Bradbear R, et al. Comparative study of varying regimens to improve steatorrhoea and creatorrhoea in cystic fibrosis: effectiveness of an enteric-coated preparation with and without antacids and cimetidine. Lancet. November 14, 1981: 1071-1074. 8. Ansaldi-Balocco N, Santini B, Sarchi C. Efficacy of pancreatic enzyme supplementation in children with cystic fibrosis: comparison of two preparations by random crossover study and a retrospective study of the same patients at two different ages. J Pediatr Gastroenterol Nutr. 1988;7 Suppl 1:S40-5.

WARNINGS Should hypersensitivity occur, discontinue medication and treat symptomatically. PRECAUTIONS General TO PROTECT ENTERIC COATING, MICROSPHERES MUST NOT BE CRUSHED OR CHEWED. Where swallowing of capsules is difficult, they may be opened and the microspheres added to a small quantity of a soft food (e.g., applesauce, gelatin, etc.) that does not require chewing, and swallowed immediately. Contact of the microsphere with foods having a pH greater than 5.5 can dissolve the protective enteric shell. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Methacrylic acid, a minor component of the methacrylic acid copolymer enteric-coating contained in ULTRASE® (pancrelipase) Capsules, has been reported to act as a teratogen in rat embryo cultures. However, the copolymer enteric-coating of ULTRASE® (pancrelipase) Capsules was not mutagenic by the Ames test, and it did not produce chromosome damage in a test for unscheduled DNA synthesis in rat hepatocytes. Pregnancy: Category C. Animal reproduction studies have not been conducted with ULTRASE® (pancrelipase) Capsules. It is not known whether ULTRASE® (pancrelipase) Capsules can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ULTRASE® (pancrelipase) Capsules should be given to a pregnant woman only if the potential benefit outweighs the potential risk to the fetus. Nursing Mothers It is not known whether ULTRASE® (pancrelipase) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULTRASE® (pancrelipase) Capsules are administered to a nursing mother.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Fibrosing Colonopathy Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products.4,5 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 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]. 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. 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]. 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]. If administered orally, the PERTZYE-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion. 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. 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. 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. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Dosing And Administration Instruct patients and caregivers: Administer PERTZYE during meals or snacks, with sufficient fluid. Swallow PERTZYE capsules whole. Do not crush or chew the capsules or the capsule contents [see WARNINGS AND PRECAUTIONS]. For patients who are unable to swallow intact capsules, follow the instructions in the Medication Guide for: oral administration with soft foods with a pH of 4.5 or less (e.g., applesauce); or administration via a gastrostomy tube with a diameter of 14 French or larger with soft foods with a pH of 4.0 or less (e.g., applesauce). 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 [see DOSAGE AND ADMINISTRATION]. If a dose is missed the next dose should be taken with the next meal or snack as directed. Do not take two doses at one time [see DOSAGE AND ADMINISTRATION]. 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, WARNINGS AND PRECAUTIONS]. 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]. Pregnancy And Breast Feeding To notify their healthcare provider if they are pregnant or are thinking of becoming pregnant during treatment with PERTZYE. [see Use in Specific Populations] To notify their healthcare provider if they are breast feeding or are thinking of breast feeding during treatment with PERTZYE. [see Use in Specific Populations] Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase. Use In Specific Populations Pregnancy Teratogenic Effects Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PERTZYE should be given to a pregnant woman only if clearly needed. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PERTZYE is administered to a nursing mother. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency. 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 and Clinical Studies]. 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]. 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]. REFERENCES 4. Smyth RL, Ashby D, O'Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet. 1995; 346: 1247-1251. 5. FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. New England Journal of Medicine. 1997; 336: 1283-1289.

WARNINGS Should hypersensitivity occur during the course of treatment, discontinue medication and treat symptomatically. Cases of intestinal stricture and blockage requiring surgical decompression have been reported in cystic fibrosis patients, especially in patients with a history of intestinal complications such as meconium ileus equivalent, short bowel syndrome, surgery or Crohn's disease, who were taking high potency lipase pancreatic enzyme preparations (i.e., those labeled as containing more than 20,000 lipase units per capsule). If symptoms suggestive of gastrointestinal obstruction occur, the possibility of bowel strictures should be considered including the evaluation of pancreatic enzyme therapy. Patients receiving lipase dose of > 2,500 USP units per kilogram per meal should be re-evaluated and the lipase dose either be reduced by 50% or titrated down gradually to the lowest clinically effective dose as determined by 72-hour fecal fat excretion. PRECAUTIONS GENERAL - TO PROTECT ENTERIC COATING, MICROSPHERES SHOULD NOT BE CRUSHED OR CHEWED. The microsphere-containing capsules should be swallowed with liquids at the start of a meal. Where swallowing of capsules is difficult, the capsules may be carefully opened and the microspheres shaken into a small quantity of soft food such as applesauce, jelly, jello, etc., which does not require chewing, and swallowed immediately, followed by a glass of water or juice to ensure complete swallowing. Prolonged contact of the microspheres with foods having a pH greater than 5.5 can weaken the integrity of the protective enteric coat and compromise the potency of the enzymes. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed with PANCRECARB® (pancrelipase) delayed-release capsules. Pregnancy/Reproduction Pregnancy Category C. Diethylphthalate, an enteric coating component of PANCRECARB® (pancrelipase) have been shown to be teratogenic in rats following high intraperitoneal dosing. When this coating was given orally to rats up to 100 times the human dose, however, no teratogenic or embryocidal effects were observed.