Pertzye

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.

Indications

PERTZYE^® (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions.

Dosage And Admintisration

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 breast-feeding. 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):
  1. Place a small amount (approximately 10 mL) of applesauce into a clean container.
  2. Carefully open the capsule(s).
  3. Sprinkle the intact microspheres on the applesauce.
  4. Mix the microspheres with the applesauce being careful not to crush the microspheres when mixing.
  5. Consume the entire contents immediately. Do not chew the microspheres. Do not save the applesauce and microspheres for later use.
  6. 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.

1. Transfer a minimum of 10 mL of applesauce into a small bowl or medicine cup.
2. Carefully open one or two PERTZYE 4,000 lipase unit capsules.
3. 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.
4. 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.
5. 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.
6. Once the residual air is removed, connect the syringe directly into the gastrostomy tube feeding port.
7. Push the syringe contents into the gastrostomy tube feeding port using steady pressure until empty.
8. Draw up approximately 10 mL of water with the slip tip syringe and flush the gastrostomy tube feeding port with the water.
9. Discard any unused portion of the PERTZYE-applesauce mixture. Do not save for later use.
10. If dose requires more than two capsules, repeat steps 1-9 until prescribed dose is reached.

Dosage

PERTZYE is not substitutable with 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 breast-feeding. 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 responses 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):
  1. Place a small amount (approximately 10 mL) of applesauce into a clean container.
  2. Carefully open the capsule(s).
  3. Sprinkle the intact microspheres on the applesauce.
  4. Mix the microspheres with the applesauce being careful not to crush the microspheres when mixing.
  5. Consume the entire contents immediately. Do not chew the microspheres. Do not save the applesauce and microspheres for later use.
  6. 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.

1. Transfer a minimum of 10 mL of applesauce into a small bowl or medicine cup.
2. Carefully open one or two PERTZYE 4,000 lipase unit capsules.
3. 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.
4. 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.
5. 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.
6. Once the residual air is removed, connect the syringe directly into the gastrostomy tube feeding port.
7. Push the syringe contents into the gastrostomy tube feeding port using steady pressure until empty.
8. Draw up approximately 10 mL of water with the slip tip syringe and flush the gastrostomy tube feeding port with the water.
9. Discard any unused portion of the PERTZYE-applesauce mixture. Do not save for later use.
10. 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. Delayedrelease 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. Delayedrelease 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. Delayedrelease capsules have a clear body printed in red with “16” and a clear cap printed with a red circular stripe and “DCI”
• 24,000 USP units of lipase; 86,250 USP units of protease; 90,750 USP units of amylase. Delayedrelease capsules have a clear body printed in purple with “24” and a clear cap printed with a purple circular stripe and “DCI”

Storage And Handling

PERTZYE (Pancrelipase) Delayed-Release Capsules

4,000 USP units of lipase; 14,375 USP units of protease; 15,125 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”. Delayed-release 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 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”. Delayed-release 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 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”. Delayed-release capsules are supplied in bottles of 100 (NDC 59767-016-01) or 250 (NDC 59767-016-02).

PERTZYE (Pancrelipase) Delayed-Release Capsules

24,000 USP units of lipase; 86,250 USP units of protease; 90,750 USP units of amylase.

Each PERTZYE delayed-release capsule has a clear body printed in purple with “24” and a clear cap printed with a purple circular stripe and “DCI”. Delayed-release capsules are supplied in bottles of 80 (NDC 59767-024-01) or 200 (NDC 59767-024-02).

Storage and Handling

Store at room temperature 20-25°C (68-77°F), brief excursions permitted to 15-40°C (59-104°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 dessicant. The dessicant packet should not be eaten or thrown away. The dessicant 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 nutritionrelated 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: Oct 201

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 (≥ 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 preexisting 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.

WarningS

Included as part of the “PRECAUTIONS” Section

Preauctions

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.

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 age¹. 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 and PATIENT INFORMATION] . 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. 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 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 and 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 casecontrol 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.

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.

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.