PANCREAZE (Page 3 of 6)

7 DRUG INTERACTIONS

No drug interactions have been identified. No formal interaction studies have been conducted.

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 estimated 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.

8.3 Pediatric Use

The short-term safety and effectiveness of PANCREAZE were assessed in two clinical studies in pediatric patients with EPI due to CF; one study included patients ages 6 to 30 months, and the other included patients ages 8 years to 17 years.

Study 1 was a randomized, double-blind, placebo-controlled study in 40 patients, 14 of whom were pediatric patients, including 7 children aged 8 to 11 years, and 7 adolescents aged 12 to 17 years. The safety and efficacy in pediatric patients in this study were similar to adult patients [see Adverse Reactions (6.1) and Clinical Studies (14)] .

Study 2 was a randomized, investigator-blinded, dose-ranging study in 17 pediatric patients aged 6 to 30 months. When patient regimen was switched from their usual PEP regimen to PANCREAZE, patients showed similar control of their fat malabsorption [see Adverse Reactions (6.1) and Clinical Studies (14)] .

The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredients (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis has 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 (2.1)]. 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 (5.1)].

10 OVERDOSAGE

In Study 1, a 10 year-old patient was administered a PANCREAZE dose of 12,399 lipase units per kilogram per day for the duration of the open-label and randomized withdrawal periods. 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 doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)] . 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 (5.3)] .

11 DESCRIPTION

Pancrelipase is a pancreatic enzyme preparation consisting of an extract derived from porcine pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and amylases. The minimum potency in each mg of pancrelipase, as described per USP, is not less than 24 units of lipase activity, not less than 100 units of amylase activity, and not less than 100 units of protease activity.

Each PANCREAZE (pancrelipase) delayed-release capsule for oral administration contains enteric-coated microtablets that are each approximately 2 mm in diameter.

The active ingredient evaluated in clinical trials is lipase. PANCREAZE is dosed by lipase units. Other active ingredients include protease and amylase.

Inactive ingredients in all PANCREAZE strengths include colloidal silicon dioxide, crospovidone, magnesium stearate, methacrylic acid ethyl acrylate copolymer, microcrystalline cellulose, montan glycol wax, simethicone emulsion, talc and triethyl citrate.

PANCREAZE is available in five color coded strengths. Each PANCREAZE delayed-release capsule strength contains the specified amounts of lipase, protease, and amylase as follows:

2,600 USP units of lipase; 8,800 USP units of protease; 15,200 USP units of amylase. The hypromellose capsules have a light orange opaque body and clear cap imprinted with “VIVUS” and “MT 2”. The capsule shell contains 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; 24,600 USP units of amylase. The hypromellose capsules have a yellow opaque body and clear cap imprinted with “VIVUS” and “MT 4”. The capsule shell contains 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; 61,500 USP units of amylase. The hypromellose capsules have a flesh opaque body and clear cap imprinted with “VIVUS” and “MT 10”. The capsule shell contains 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. The hypromellose capsules have a flesh opaque body and clear cap imprinted with “VIVUS” and “MT 16”. The capsule shell contains 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; 83,900 USP units of amylase. The hypromellose capsules have a white opaque body and cap imprinted with “VIVUS” and “MT 20”. The capsule shell contains 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; 149,900 USP units of amylase. The hypromellose capsules have an iron grey opaque body and white opaque cap imprinted with “VIVUS” and “MT 37”. The capsule shell contains hypromellose, titanium dioxide, black iron oxide and imprint ink contains black iron oxide, shellac-glaze-45%, ammonium hydroxide, propylene glycol.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The pancreatic enzymes in PANCREAZE 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.

12.3 Pharmacokinetics

The pancreatic enzymes in PANCREAZE are enteric-coated to minimize destruction or inactivation in gastric acid. PANCREAZE 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.