PANCREAZE

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.

Instruct adult and pediatric patients greater than 12 months of age, or their caregivers, of the following:

• Take PANCREAZE with meals or snacks. If a dose is missed, take the next dose with the next meal or snack.
• Swallow capsules whole.
• For patients who are unable to swallow intact capsules, carefully open the capsules and sprinkle the entire contents on a small amount of acidic soft food with a pH of 4.5 or less (e.g., applesauce). Consume the entire mixture immediately.
• Do not crush or chew PANCREAZE capsules or capsule contents.
• Consume sufficient liquids (water or juice) to ensure complete swallowing of PANCREAZE capsules [see Warnings and Precautions (5.2)] .

Instruct caregivers of pediatric patients birth to 12 months of age of the following:

• Immediately prior to each breast-feeding session or each administration of 120 mL of formula, carefully open one PANCREAZE capsule (containing 2,600 USP units of lipase) and administer the entire contents using one of the following two methods:
  • Sprinkle on a small amount of acidic soft food with a pH of 4.5 or less (e.g., applesauce) being careful not to crush the capsule contents. The entire mixture should be given to the infant immediately.
  • Sprinkle the capsule contents directly into the infant's mouth.
• Immediately administer additional breast milk or formula after PANCREAZE to ensure complete swallowing of the capsule contents.
• Do not mix PANCREAZE capsule contents directly into a bottle of breast milk or formula.
• Do not crush PANCREAZE capsule contents, and visually inspect the infant's mouth to ensure that no drug is retained in the mouth [see Warnings and Precautions (5.2)] .
• If a dose is missed, administer the next dose with the next feeding.

Fibrosing colonopathy has been reported following treatment with pancreatic enzyme products. Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with use of high-dose pancreatic enzyme products, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. Pancreatic enzyme products exceeding 6,000 lipase units/kg/meal have been associated with colonic strictures, a complication of fibrosing colonopathy, in pediatric patients less than 12 years of age. The underlying mechanism of fibrosing colonopathy remains unknown.

If there is a history of fibrosing colonopathy, monitor patients during treatment with PANCREAZE because some patients may be at risk of progressing to colonic stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs. Do not exceed the recommended dosage of either 2,500 lipase units/kg/meal, 10,000 lipase units/kg/day, or 4,000 lipase units/g fat ingested/day in adult and pediatric patients greater than 12 months of age without further investigation . Higher dosages may be administered if they are documented to be effective by fecal fat measures or an improvement in signs and symptoms of malabsorption including measures of nutritional status . Patients receiving dosages higher than 6,000 lipase units/kg/meal should be frequently monitored for symptoms of fibrosing colonopathy and the dosage decreased or titrated downward to a lower range if clinically appropriate [see Dosage and Administration (2.1)] .

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:

• Swallow capsules whole. For patients who cannot swallow the capsules whole, the capsules can be opened, and the contents sprinkled on a small amount of acidic soft food with a pH of 4.5 or less (e.g., applesauce).
• Do not crush or chew PANCREAZE capsules or capsule contents.
• Consume sufficient liquids (juice, water, breast milk, or formula) immediately following administration of PANCREAZE to ensure complete swallowing.
• Visually inspect the mouth of pediatric patients less than 12 months of age and of patients who are unable to swallow intact capsules to ensure that no drug is retained in the mouth and irritation of the oral mucosa has not occurred [see Dosage and Administration (2.3)] .

Pancreatic enzyme products contain purines that may increase blood uric acid levels. High dosages have been associated with hyperuricosuria and hyperuricemia [see Overdosage (10)]. Consider monitoring blood uric acid levels in patients with gout, renal impairment, or hyperuricemia during treatment with PANCREAZE.

PANCREAZE is sourced from pancreatic tissue from swine used for food consumption. Although the risk that PANCREAZE 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.

Serious hypersensitivity reactions including anaphylaxis, asthma, hives, and pruritus have been reported with pancreatic enzyme products [see Adverse Reactions ( 6)] . If symptoms occur, initiate appropriate medical management.

Monitor patients with a known hypersensitivity reaction to proteins of porcine origin for hypersensitivity reactions during treatment with PANCREAZE. The risks and benefits of continued PANCREAZE treatment in patients with serious hypersensitivity reactions should be taken into consideration with the overall clinical needs of the patient.

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

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)].

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.

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.

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.

For patients consuming a high fat diet in the clinical trials, the coefficient of fat absorption (CFA) was higher in patients who received PANCREAZE compared to the placebo treatment group, indicating improved fat absorption [see Clinical Studies (14)] .

Following oral administration, the lipases, proteases, and amylases released from PANCREAZE are not absorbed from the gastrointestinal tract in appreciable amounts.

Study 1

Study 1 was a randomized, double-blind, placebo-controlled study of 40 patients, ages 8 to 57 years. In this study, patients received PANCREAZE at individually titrated doses (not to exceed 2,500 lipase units/kg/meal) for 14 days (open-label period) followed by randomization to PANCREAZE or matching placebo for 7 days of treatment (double-blind withdrawal period). Only patients with coefficient of fat absorption (CFA) ≥80% in the open-label period were randomized to the double-blind withdrawal period. The mean dosage during the 70day placebo-controlled treatment period was 6,400 lipase units/kg/day. All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the treatment period. The population was nearly evenly distributed in biological sex and approximately 96% of patients were White.

Study 2

Study 2 was a randomized, investigator-blinded, dose-ranging study of 17 pediatric patients, ages 6 months to 30 months (mean 18 months). The final analysis population was limited to 16 patients; 1 patient was excluded due to withdrawal of consent. All patients were transitioned from their usual pancreatic enzyme treatment to PANCREAZE at 375 lipase units/kg/meal for a 6-day run-in period. Patients were then randomized to receive PANCREAZE at one of four dosages (375, 750, 1,125, and 1,500 lipase units/kg/meal) for 5 days.

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.

Fibrosing Colonopathy

Advise the patient or caregiver that fibrosing colonopathy has been reported with high dosages of pancreatic enzyme products, usually with use over a prolonged period of time and in pediatric patients with cystic fibrosis. Colonic stricture has been reported in pediatric patients less than 12 years of age. Advise patients and caregivers that if signs and symptoms of colon stricture formation occur (e.g., stomach area (abdominal) pain, bloating, trouble passing stool (constipation), nausea, vomiting, diarrhea) to immediately contact their healthcare provider [see Warnings and Precautions (5.1)] .

Hyperuricemia

Advise the patient or caregiver that hyperuricemia may occur in patients with gout or renal impairment and to contact the healthcare provider if they experience pain, stiffness, redness or swelling of their joints [see Warnings and Precautions (5.3)] .

Hypersensitivity Reactions

Inform the patient or caregiver that severe hypersensitivity reactions, including anaphylaxis asthma, hives, and pruritus, have been reported with use of pancreatic enzyme products. Seek medical attention if signs or symptoms of a hypersensitivity reaction develop [see Warnings and Precautions (5.5)] .

Dosage

Advise the patient or caregiver to take or administer PANCREAZE as prescribed, and to contact the healthcare provider if signs and symptoms of malabsorption persist [see Dosage and Administration (2.2)] .

Administration

Instruct the patient or caregiver to:

• Take PANCREAZE with meals or snacks.
• Swallow capsules whole.
• For adult and pediatric patients unable to swallow intact capsules, the capsule contents may be sprinkled on a small amount soft acidic food with a pH of 4.5 or less (e.g., applesauce). For pediatric patients birth to 12 months of age, PANCREAZE capsules can also be opened, and the capsule contents sprinkled directly into the infant's mouth.
• Consume sufficient liquids (juice, water, breast milk, or formula) and visually inspect an infant's mouth to ensure complete swallowing of PANCREAZE capsules or capsule contents [see Warnings and Precautions (5.2)].
• Do not crush or chew PANCREAZE capsules or capsule contents.
• Do not mix the PANCREAZE capsule contents directly into a bottle of breast milk or formula.

Storage

Instruct the patient or caregiver as follows:

• Keep PANCREAZE in a dry place and protect from moisture and heat.
• After opening, keep bottle tightly closed between uses to protect from moisture.
• Keep PANCREAZE in the original container.
• Do not eat or throw away the desiccant canister in the bottle.