PANCREAZE

1 INDICATIONS AND USAGE PANCREAZE is indicated for the treatment of exocrine pancreatic insufficiency in adult and pediatric patients. PANCREAZE ® is indicated for the treatment of exocrine pancreatic insufficiency in adult and pediatric patients. ( 1 )

2 DOSAGE AND ADMINISTRATION Important Dosing Information ( 2.1 ) PANCREAZE is a mixture of enzymes including lipases, proteases, and amylases and dosing is based on lipase units. Dosing scheme based on actual body weight or fat ingestion. Individualize the dosage based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet. Do not exceed 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or 4,000 lipase units/g fat ingested/day in adult and pediatric patients greater than 12 months of age without further investigation. ( 5.1 ) The total daily dosage in adult and pediatric patients greater than 12 months of age should reflect approximately three meals plus two or three snacks per day. With each snack, administer approximately half the prescribed dose for a meal. Do not substitute other pancreatic enzyme products for PANCREAZE. When switching from another pancreatic enzyme product to PANCREAZE, monitor patients for clinical symptoms of exocrine pancreatic insufficiency and titrate the dosage as needed. Recommended Dosage ( 2.2 ): Adult and Pediatric Patients Greater than 12 Months : The recommended initial starting dosage is: 500 lipase units/kg/meal for adult and pediatric patients 4 years and older. 1,000 lipase units/kg/meal for pediatric patients greater than 12 months to less than 4 years. Titrate the dosage to either 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or less than 4,000 lipase units/g fat ingested/day. Higher dosages may be administered if documented effective by fecal fat measures or improvement in malabsorption. Pediatric Patients Birth to 12 Months: The recommended dosage is 2,600 lipase units (one capsule) per 120 mL of formula or per breastfeeding. Preparation and Administration Instructions ( 2.3 ) Swallow capsules whole. For patients unable to swallow intact capsule(s), the capsule contents may be sprinkled on soft acidic food (e.g., applesauce). Do not crush or chew PANCREAZE capsules or capsule contents. Consume sufficient liquids to ensure complete swallowing of PANCREAZE. ( 5.2 ) See the full prescribing information for additional information on administering to pediatric patients birth to 12 months. 2.1 Important Dosing Information PANCREAZE is a mixture of enzymes including lipases, proteases, and amylases. PANCREAZE dosing is based on lipase units. Use either an actual body weight or fat ingestion-based dosing scheme. Start at the lowest recommended dosage and individualize the dosage based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet. Changes in dosage may require an adjustment period of several days. Do not exceed 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or 4,000 lipase units/g fat ingested/day in adult and pediatric patients greater than 12 months of age without further investigation [see Warnings and Precautions (5.1) ] . The total daily dosage in adult and pediatric patients greater than 12 months of age should reflect approximately three meals plus two or three snacks per day. With each snack, administer approximately half the prescribed PANCREAZE dose for a meal. Do not substitute other pancreatic enzyme products for PANCREAZE. When switching from another pancreatic enzyme product to PANCREAZE, monitor patients for clinical symptoms of exocrine pancreatic insufficiency and titrate the dosage as needed. 2.2 Recommended Dosage Adult and Pediatric Patients Greater than 12 Months of Age The recommended oral initial starting dosage is: 500 lipase units/kg/meal for adult and pediatric patients 4 years of age and older. 1,000 lipase units/kg/meal for pediatric patients greater than 12 months to less than 4 years of age. If signs and symptoms of malabsorption persist, increase the dosage. Titrate to either 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or less than 4,000 lipase units/grams of fat ingested/day. Higher dosages may be administered if they are documented to be effective b …

3 DOSAGE FORMS AND STRENGTHS Delayed-release capsules are available in the following strengths: 2,600 USP units of lipase; 8,800 USP units of protease; and 15,200 USP units of amylase in a two-piece hypromellose capsule with a light orange opaque body and clear cap, printed with "VIVUS" and "MT 2" 4,200 USP units of lipase; 14,200 USP units of protease; and 24,600 USP units of amylase in a two-piece hypromellose capsule with a yellow opaque body and clear cap, printed with "VIVUS" and "MT 4" 10,500 USP units of lipase; 35,500 USP units of protease; and 61,500 USP units of amylase in a two-piece hypromellose capsule with a flesh opaque body and clear cap, printed with "VIVUS" and "MT 10" 16,800 USP units of lipase; 56,800 USP units of protease; and 98,400 USP units of amylase in a two-piece hypromellose capsule with a flesh opaque body and clear cap, printed with "VIVUS" and "MT 16" 21,000 USP units of lipase; 54,700 USP units of protease; and 83,900 USP units of amylase in a two-piece hypromellose capsule with a white opaque body and cap, printed with "VIVUS" and "MT 20" 37,000 USP units of lipase; 97,300 USP units of protease; and 149,900 USP units of amylase in a two-piece hypromellose capsule with an iron grey opaque body and white opaque cap, printed with "VIVUS" and "MT 37" Delayed-release capsules ( 3 ): 2,600 USP units of lipase; 8,800 USP units of protease; and 15,200 USP units of amylase. 4,200 USP units of lipase; 14,200 USP units of protease; and 24,600 USP units of amylase 10,500 USP units of lipase; 35,500 USP units of protease; and 61,500 USP units of amylase 16,800 USP units of lipase; 56,800 USP units of protease; and 98,400 USP units of amylase 21,000 USP units of lipase; 54,700 USP units of protease; and 83,900 USP units of amylase 37,000 USP units of lipase; 97,300 USP units of protease; and 149,900 USP units of amylase

4 CONTRAINDICATIONS None. None.

6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are described elsewhere in the labeling: Fibrosing Colonopathy [see Warnings and Precautions (5.1) ] Irritation of the Oral Mucosa [see Warnings and Precautions (5.2) ] Hyperuricemia [see Warnings and Precautions (5.3) ] Risk of Viral Transmission [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] The data described below reflect exposure to PANCREAZE in 57 adult and pediatric patients with exocrine pancreatic insufficiency due to cystic fibrosis in two clinical trials. Study 1 was conducted in 40 patients, aged 8 years to 57 years; Study 2 was conducted in 17 pediatric patients, aged 6 months to 30 months [see Clinical Studies (14) ] . The most common adverse reactions were gastrointestinal, including diarrhea and vomiting. The following adverse reactions have been identified during post-approval use of PANCREAZE or other pancreatic enzyme products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Most common adverse reactions are gastrointestinal, including nausea and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact VIVUS LLC at 1-888-998-4887 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Eye Disorders blurred vision Gastrointestinal Disorders fibrosing colonopathy, distal intestinal obstruction syndrome abdominal pain, flatulence, constipation, and nausea Immune System Disorders anaphylaxis, asthma, hives, and pruritus Investigations asymptomatic elevations of liver enzymes Musculoskeletal System myalgia, muscle spasm Skin and Subcutaneous Tissue Disorders urticaria and rash

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Published data from case reports with pancrelipase use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Pancrelipase is minimally absorbed systematically; therefore, maternal use is not expected to result in fetal exposure to the drug. Animal reproduction studies have not been conducted with pancrelipase. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. 8.2 Lactation Risk Summary There are no data on the presence of pancrelipase in either human or animal milk, the effects on the breastfed infant or the effects on milk production. Pancrelipase is minimally absorbed systemically following oral administration, therefore maternal use is not expected to result in clinically relevant exposure of breastfed infants to the drug. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PANCREAZE and any potential adverse effects on the breastfed infant from PANCREAZE or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of PANCREAZE for the treatment of exocrine pancreatic insufficiency have been established in pediatric patients. Use of PANCREAZE for this indication is supported by an adequate and well-controlled trial in adult and pediatric patients 8 to 17 years of age (Study 1) along with supportive data from a randomized, investigator-blinded, dose-ranging study in 17 pediatric patients aged 6 to 30 months (Study 2). Both study populations consisted of patients with exocrine pancreatic insufficiency due to cystic fibrosis. The safety in pediatric patients in these studies was similar to that observed in adult patients [see Adverse Reactions ( 6 ) and Clinical Studies (14) ] . Dosages exceeding 6,000 lipase units/kg/meal have been reported postmarketing to be associated with fibrosing colonopathy and colonic strictures in pediatric patients less than 12 years of age. If there is a history of fibrosing colonopathy, monitor patients during treatment with PANCREAZE because some patients may be at risk of progressing to stricture formation. Do not exceed the recommended dosage of either 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or 4,000 lipase units/g fat ingested/day in pediatric patients greater than 12 months of age without further investigation . [see Dosage and Administration (2.2) and Warnings and Precautions (5.1) ] . Crushing or chewing PANCREAZE capsules or mixing the capsule contents in foods having a pH greater than 4.5 can disrupt the protective enteric coating on the capsule contents and result in early release of enzymes, irritation of the oral mucosa, and/or loss of enzyme activity. Instruct the patient or caregiver of the following: consume sufficient liquids (juice, water, breast milk, or formula) to ensure complete swallowing, and visually inspect the mouth of pediatric patients less than 12 months of age to ensure no drug is retained in the mouth and irritation of the oral mucosa has not occurred [see Dosage and Administration (2.3) and Warnings and Precautions (5.2) ]. 8.5 Geriatric Use Clinical studies of PANCREAZE did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between patients aged 65 years and over and younger adult patients.

12.1 Mechanism of Action Pancreatic enzyme products contain a mixture of lipases, proteases, and amylases that 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 maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.

11 DESCRIPTION Pancrelipase is a pancreatic enzyme product consisting of a mixture of enzymes including lipases, proteases, and amylases and is an extract derived from porcine pancreatic glands. The enteric-coated microtablets in PANCREAZE are formulated to release pancreatic enzymes at an approximate pH of 5.5 or greater. PANCREAZE (pancrelipase) delayed-release capsules are for oral administration and include a two-piece shell containing enteric-coated microtablets that are each approximately 2 mm in diameter and are available as follows: 2,600 USP units of lipase ; 8,800 USP units of protease; and 15,200 USP units of amylase; delayed-release capsules have a light orange opaque body and clear cap imprinted with "VIVUS" and "MT 2". The shells contain hypromellose, titanium dioxide, yellow iron oxide, red iron oxide and imprint ink contains black iron oxide, shellac, propylene glycol, strong ammonia solution, potassium hydroxide. 4,200 USP units of lipase ; 14,200 USP units of protease; and 24,600 USP units of amylase; delayed-release capsules have a yellow opaque body and clear cap imprinted with "VIVUS" and "MT 4". The shells contain hypromellose, titanium dioxide, yellow iron oxide, and imprint ink contains black iron oxide, shellac-glaze-45%, ammonium hydroxide, propylene glycol. 10,500 USP units of lipase; 35,500 USP units of protease; and 61,500 USP units of amylase; delayed-release capsules have a flesh opaque body and clear cap imprinted with "VIVUS" and "MT 10". The shells contain hypromellose, titanium dioxide, red iron oxide, and imprint ink contains black iron oxide, shellac-glaze-45%, ammonium hydroxide, propylene glycol. 16,800 USP units of lipase; 56,800 USP units of protease; 98,400 USP units of amylase; delayed-release capsules have a flesh opaque body and clear cap imprinted with "VIVUS" and "MT 16". The shells contain hypromellose, titanium dioxide, red iron oxide, yellow iron oxide, and imprint ink contains black iron oxide, shellac-glaze-45%, ammonium hydroxide, propylene glycol. 21,000 USP units of lipase; 54,700 USP units of protease; and 83,900 USP units of amylase; delayed-release capsules have a white opaque body and cap imprinted with "VIVUS" and "MT 20". The shells contain hypromellose, titanium dioxide, and imprint ink contains yellow iron oxide, shellac, strong ammonia solution, propylene glycol. 37,000 USP units of lipase; 97,300 USP units of protease; and 149,900 USP units of amylase; delayed-release capsules have an iron grey opaque body and white opaque cap imprinted with "VIVUS" and "MT 37". The shells contain hypromellose, titanium dioxide, black iron oxide and imprint ink contains black iron oxide, shellac-glaze-45%, ammonium hydroxide, propylene glycol. PANCREAZE (pancrelipase) delayed-release capsules include the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, methacrylic acid ethyl acrylate copolymer, microcrystalline cellulose, montan glycol wax, simethicone emulsion, talc and triethyl citrate.

10 OVERDOSAGE In Study 1, a 10 year-old patient was administered a PANCREAZE dose of 12,399 lipase units/kg/day for the duration of the open-label and randomized withdrawal periods (21 days). The patient experienced mild abdominal pain throughout both study periods. Abnormal chemistry data at the end of the study included mild elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum phosphate. Abnormal hematology data at the end of the study included mild elevations of hematocrit. No abnormalities from analyses of urinalysis or uric acid were noted. Chronic high dosages of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see Warnings and Precautions (5.1) ] . High dosages of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia [see Warnings and Precautions (5.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING PANCREAZE (pancrelipase) delayed-release capsules are supplied as follows: Strength Description Supplied As NDC Number 2,600 USP units of lipase; 8,800 USP units of protease; 15,200 USP units of amylase two-piece hypromellose capsule with a light orange opaque body and clear cap imprinted with "VIVUS" and "MT 2" Bottles of 100 NDC 62541-401-10 4,200 USP units of lipase; 14,200 USP units of protease; 24,600 USP units of amylase two-piece hypromellose capsule with a yellow opaque body and clear cap imprinted with "VIVUS" and "MT 4" Bottles of 100 NDC 62541-402-10 10,500 USP units of lipase; 35,500 USP units of protease; 61,500 USP units of amylase two-piece hypromellose capsule with a pink opaque body and clear cap imprinted with "VIVUS" and "MT 10" Bottles of 100 NDC 62541-403-10 16,800 USP units of lipase; 56,800 USP units of protease; 98,400 USP units of amylase two-piece hypromellose capsule with a flesh opaque body and clear cap imprinted with "VIVUS" and "MT 16" Bottles of 100 NDC 62541-404-10 21,000 USP units of lipase; 54,700 USP units of protease; 83,900 USP units of amylase two-piece hypromellose capsule with a white opaque body and cap imprinted with "VIVUS" and "MT 20" Bottles of 100 NDC 62541-405-10 37,000 USP units of lipase; 97,300 USP units of protease; 149,900 USP units of amylase Two-piece hypromellose capsule with an iron grey opaque body and white opaque cap imprinted with "VIVUS" and "MT 37" amylase 2 bottles of 50-(NDC 62541-406-50) inside a carton (NDC 62541-406-10) Storage and Handling Store PANCREAZE at room temperature between 15oC and 25oC (59°F to 77°F), excursion permitted up to 40oC (104°F) for 24 hours. After opening, keep bottle tightly closed between uses to protect from moisture. All PANCREAZE bottles contain a desiccant canister. Store and dispense PANCREAZE in the original container.