2.1 Important Dosing Information

PERTZYE is a mixture of enzymes including lipases, proteases, and amylases. PERTZYE 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 PERTZYE dose for a meal.
• Do not substitute other pancreatic enzyme products for PERTZYE. When switching from another pancreatic enzyme product to PERTZYE, monitor patients for clinical symptoms of exocrine pancreatic insufficiency and titrate the dosage as needed.

2.2 Recommended Dosage

2.3 Preparation and Administration Instructions

5.1 Fibrosing Colonopathy

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

If there is a history of fibrosing colonopathy, monitor patients during treatment with PERTZYE 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)].

5.2 Irritation of the Oral Mucosa

Crushing or chewing PERTZYE 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). The 4,000 USP lipase unit capsule may also be administered with applesauce via a gastrostomy tube with a diameter of 14 French or larger.
• Do not crush or chew PERTZYE capsules or capsule contents.
• Consume sufficient liquids (juice, water, breast milk, or formula) immediately following administration of PERTZYE 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 no drug is retained in the mouth and irritation of the oral mucosa has not occurred [see Dosage and Administration (2.3)].

5.3 Hyperuricemia

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

5.4 Risk of Viral Transmission

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.

5.5 Hypersensitivity Reactions

Severe hypersensitivity reactions including anaphylaxis, asthma, hives, and pruritus have been reported with pancreatic enzyme products [see Adverse Reactions (6.2)]. If symptoms occur, initiate appropriate medical management.

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

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described below reflect exposure to PERTZYE in 21 patients, aged 8 to 43 years, with exocrine pancreatic insufficiency due to cystic fibrosis in a placebo-controlled clinical trial [see Clinical Studies (14)].

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of PERTZYE or other pancreatic enzyme products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye Disorders

• blurred vision

Gastrointestinal Disorders

• fibrosing colonopathy, 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

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of PERTZYE for the treatment of exocrine pancreatic insufficiency have been established in pediatric patients.

Use of PERTZYE for this indication is supported by a randomized, double-blind, placebo-controlled, crossover study of 24 pediatric patients, 8 years and older with exocrine pancreatic insufficiency due to cystic fibrosis. The safety in pediatric patients was similar to that observed in adult patients [see Adverse Reactions (6.1) 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 PERTZYE 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 (2.1) and Warnings and Precautions (5.1)].

Crushing or chewing PERTZYE 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 that 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 PERTZYE 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 maltotriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

Adult and Pediatric Patients

A randomized, double-blind, placebo-controlled, crossover study was conducted in 24 patients aged 8 to 43 years (mean age of 20 years) with exocrine pancreatic insufficiency due to cystic fibrosis. Patients were randomized to receive PERTZYE at individually titrated doses (not to exceed 2,500 lipase units/kg/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 mean lipase dosage during the treatment period was 1,565 lipase units/kg/meal and a controlled high-fat diet (approximately 2g fat/kg/day) was maintained throughout the study. The length of exposure to PERTZYE during this study was 20 to 28 days, including the treatment period of 6 to 8 days, and the open label titration and transition periods of 7 to 10 days each.

The efficacy analysis population included 21 patients who completed both double-blind treatment periods.

Storage and Handling

• Store PERTZYE at room temperature 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 40°C (59°F to 104°F) for up to 30 days. PERTZYE hard gelatin capsules should be stored in a dry place in the original container or equivalent airtight container. After opening, keep the container tightly closed between uses to protect from moisture.
• PERTZYE is dispensed in bottles containing a desiccant.

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 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 PERTZYE 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 PERTZYE with meals or snacks.
• Swallow capsules whole.
• For patients unable to swallow intact capsules:
  • the capsule contents may be sprinkled on a small amount of soft acidic food with a pH of 4.5 or less (e.g., applesauce). The 4,000 USP lipase unit capsule may also be administered with applesauce via gastrostomy tube 14 French or larger.
  • For pediatric patients birth to 12 months of age, PERTZYE capsules can be opened, and the capsule contents sprinkled directly into the infant's mouth.
  • See the Instructions for Use for a description of all preparation and administration instructions.
• Consume sufficient liquids (juice, water, breast milk, or formula) and visually inspect an infant's mouth to ensure complete swallowing of PERTZYE capsules or capsule contents [see Warnings and Precautions (5.2)].
• Do not crush or chew PERTZYE capsules or capsule contents.
• Do not mix the PERTZYE capsule contents directly into a bottle of breast milk or formula.

Storage

Instruct the patient or caregiver as follows:

• Keep PERTZYE in a dry place and protect from moisture and heat.
• After opening, keep the container tightly closed between uses to protect from moisture.
• The desiccant packet should not be eaten or thrown away.