Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

PANCREATIC ENZYMES

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pancreatic enzymes are standardized preparations of pancrelipase which contains various amounts of protease, amylase, and lipase. They are used in cases of pancreatic enzyme insufficiency, such as that found in cystic fibrosis, chronic pancreatitis and pancreatectomy.

Specific Substances

    1) Amylase
    2) Lipase
    3) Pancreatin
    4) Pancreatinum
    5) Pancrelipase
    6) Protease
    7) CAS 8049-47-6

Available Forms Sources

    A) FORMS
    1) There are 6 FDA-approved pancreatic enzyme products available: Creon(R), Zenpep(R), Pancreaze(R), Pertzye(TM), Ultresa(TM), and Viokace(TM). These products are not interchangeable (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012; Prod Info CREON oral delayed-release capsules, 2011; Prod Info ZENPEP(R) oral delayed-release capsules, 2011).
    2) Pancreatic enzymes may be available in capsules, delayed-release capsules, powder for oral administration. These products contain the active ingredient pancrelipase, which contains various amounts of digestive enzymes lipase, protease and amylase (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info ZENPEP(R) oral delayed-release capsules, 2011; Prod Info CREON oral delayed-release capsules, 2011).
    B) USES
    1) Pancrelipase (Pancreaze(R)) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info ZENPEP(R) oral delayed-release capsules, 2011; Prod Info CREON oral delayed-release capsules, 2011).
    2) Pancrelipase treatment with Creon(R) and Viokace(TM) is indicated for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy (Prod Info VIOKACE(TM) oral tablets, 2012; Prod Info CREON oral delayed-release capsules, 2011); Viokace(TM) must be used in combination with a proton pump inhibitor (Prod Info VIOKACE(TM) oral tablets, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Pancrelipase (Pancreaze(R)) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions. Pancrelipase treatment with Creon(R) and Viokace(TM) is indicated for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy. There are 6 FDA-approved pancreatic enzyme products available: Creon(R), Zenpep(R), Pancreaze(R), Pertzye(TM), Ultresa(TM), and Viokace(TM). These products are not interchangeable.
    B) PHARMACOLOGY: Pancreatic enzymes contain the active ingredient pancrelipase. Pancrelipase provides a replacement for digestive enzymes secreted by the pancreas with active porcine derived lipases, proteases and amylases to catalyze the hydrolysis of (1) fat into glycerol and fatty acids, (2) proteins into peptides and amino acids, and (3) starch into dextrins and sugars. The pancreatic enzymes are enteric-coated to prevent inactivation in gastric acid and to release most of the enzymes into the duodenum and proximal small intestines (which are the sites of action) at a pH of greater than 5.5.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Abdominal pain, diarrhea, flatulence, constipation and fatigue may occur. OTHER EFFECTS: Nausea, pruritus, urticaria, rash, dizziness, headache, lymphadenopathy, biliary tract stones, ear pain, dysuria and crystalluria and anal pruritus have also been reported. Patients with cystic fibrosis have also experienced pharyngitis, epistaxis, nasal congestion, cough, irritability and neck pain. Oral irritation when the tablets are held in the mouth have been reported with therapeutic use. Asthma, bronchial hypersensitivity and pulmonary hypersensitivity have been reported after exposure to the powder in both home and occupational settings. Hypersensitivity to pork or beef proteins may cause allergic reactions, due to the source of the enzymes. There have been several cases of these enzymes being contaminated by Salmonella. CHRONIC: Hyperuricemia, hyperuricosuria and urolithiasis have been reported in children taking large doses chronically. SERIOUS: Potentially serious adverse events may include asthma and anaphylaxis with therapeutic use of pancrelipase. Fibrosing colonopathy has been rarely reported with pancreatic enzymes usually during a prolonged period of use. Colonic stricture has been reported at doses exceeding 6000 lipase units/kg of body weight per meal.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Toxicity is uncommon. A 10-year-old patient received a Pancreaze dose of 12,399 lipase units/kg/day throughout the study period and developed mild abdominal pain. Laboratory results revealed mild elevations of AST, ALT, serum phosphate and hematocrit.
    0.2.20) REPRODUCTIVE
    A) Pancrelipase is classified as FDA pregnancy category C by the manufacturer. There are no data regarding the effects of pancrelipase on pregnancy or breastfeeding.

Laboratory Monitoring

    A) No specific laboratory tests are necessary following an overdose unless otherwise clinically indicated.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    D) Monitor patients for increased uric acid.
    E) Monitor urine for hyperuricosuria or crystalluria.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Pancreatic enzyme tablets are low in toxicity and are not expected to produce serious overdose effects. Treatment should be symptomatic and supportive. Patients should be monitored for irritation of the gastrointestinal tract, possible hypersensitivity reactions, and increased uric acid in the blood and urine. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after an overdose.
    C) DECONTAMINATION
    1) For large amounts, dilution to reduce irritation, may be indicated. Activated charcoal is generally NOT indicated because of low toxicity following an overdose.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress or acute allergic reactions.
    E) ANTIDOTES
    1) None.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    G) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    H) PHARMACOKINETICS
    1) The absorption of the pancreatic enzymes is negligible.
    0.4.3) INHALATION EXPOSURE
    A) Inhalation of the powder may cause hypersensitivity reactions.
    B) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: No specific toxic dose has been established. One or two tablets is unlikely to produce symptoms other than mild irritation. A 10-year-old patient received a Pancreaze dose of 12,399 lipase units/kg/day throughout the study period and developed mild abdominal pain. Laboratory results revealed mild elevations of AST, ALT, serum phosphate and hematocrit.
    B) THERAPEUTIC DOSE: The dose used is individualized based on the degree of steatorrhea present, fat content in the diet and clinical symptoms.

Clinical Effects

Summary Of Exposure

    A) USES: Pancrelipase (Pancreaze(R)) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions. Pancrelipase treatment with Creon(R) and Viokace(TM) is indicated for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy. There are 6 FDA-approved pancreatic enzyme products available: Creon(R), Zenpep(R), Pancreaze(R), Pertzye(TM), Ultresa(TM), and Viokace(TM). These products are not interchangeable.
    B) PHARMACOLOGY: Pancreatic enzymes contain the active ingredient pancrelipase. Pancrelipase provides a replacement for digestive enzymes secreted by the pancreas with active porcine derived lipases, proteases and amylases to catalyze the hydrolysis of (1) fat into glycerol and fatty acids, (2) proteins into peptides and amino acids, and (3) starch into dextrins and sugars. The pancreatic enzymes are enteric-coated to prevent inactivation in gastric acid and to release most of the enzymes into the duodenum and proximal small intestines (which are the sites of action) at a pH of greater than 5.5.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Abdominal pain, diarrhea, flatulence, constipation and fatigue may occur. OTHER EFFECTS: Nausea, pruritus, urticaria, rash, dizziness, headache, lymphadenopathy, biliary tract stones, ear pain, dysuria and crystalluria and anal pruritus have also been reported. Patients with cystic fibrosis have also experienced pharyngitis, epistaxis, nasal congestion, cough, irritability and neck pain. Oral irritation when the tablets are held in the mouth have been reported with therapeutic use. Asthma, bronchial hypersensitivity and pulmonary hypersensitivity have been reported after exposure to the powder in both home and occupational settings. Hypersensitivity to pork or beef proteins may cause allergic reactions, due to the source of the enzymes. There have been several cases of these enzymes being contaminated by Salmonella. CHRONIC: Hyperuricemia, hyperuricosuria and urolithiasis have been reported in children taking large doses chronically. SERIOUS: Potentially serious adverse events may include asthma and anaphylaxis with therapeutic use of pancrelipase. Fibrosing colonopathy has been rarely reported with pancreatic enzymes usually during a prolonged period of use. Colonic stricture has been reported at doses exceeding 6000 lipase units/kg of body weight per meal.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Toxicity is uncommon. A 10-year-old patient received a Pancreaze dose of 12,399 lipase units/kg/day throughout the study period and developed mild abdominal pain. Laboratory results revealed mild elevations of AST, ALT, serum phosphate and hematocrit.

Heent

    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) EAR PAIN: During an open label study of pediatric patients aged 7 to 11 years with exocrine pancreatic insufficiency due to cystic fibrosis, ear pain was reported in 11% of patients (n=7) receiving pancrelipase with a mean treatment dose of 6486 lipase units/kg of body weight (mean treatment duration: 5.7 days) (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) The powdered enzyme is irritating to the nasal mucosa (Prod Info Viokase(R), pancrelipase, 2000).
    2) ALLERGIC RHINITIS has been seen in those preparing it for use by patients (Sakula, 1977; Nakamura, 1972; Chignell, 1972).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Potentially serious adverse events may include asthma, anaphylaxis, hives, and pruritus with therapeutic use of pancrelipase (Prod Info CREON(R) oral capsule delayed release, 2009).
    b) Asthma attacks with wheezing have been induced after inhalation of the powder (Sakula, 1977a).
    1) These symptoms may occur in parents of children with cystic fibrosis (Dolan & Meyers, 1974; Twarog, 1977; Bergner & Bergner, 1975) or in health care professionals who prepare the enzymes (Nakamura, 1972; Nakamura, 1971; Lipkin & Vickers, 1987).
    c) Bronchial hyperreactivity, airway obstruction and disturbances of oxygen were seen in workers exposed to pancreatic enzyme dust (Wiessmann & Baur, 1985) (Hayes & Newman Taylor, 1991). Some of these workers developed mild fibrosis and acute alveolitis.
    d) Obstructive, reversible pulmonary and nasal hypersensitivity have been noted in individuals exposed to the powder in a non-industrial setting (Bergner & Bergner, 1975).
    e) The powder can be irritating to the nasal mucosa (Prod Info Viokase(R), pancrelipase, 2000).
    B) PHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind, placebo-controlled, crossover study of patients aged 8 to 37 years with exocrine pancreatic insufficiency due to cystic fibrosis, pharyngolaryngeal pain was reported in 7% of patients receiving pancrelipase (n=30) compared to 3% of patients receiving placebo (n=31) (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012).
    C) EPISTAXIS
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind, placebo-controlled, crossover study of patients aged 8 to 37 years with exocrine pancreatic insufficiency due to cystic fibrosis, epistaxis was reported in 7% of patients receiving pancrelipase (n=30) compared to 0% of patients receiving placebo (n=31) (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012).
    D) NASAL CONGESTION
    1) WITH THERAPEUTIC USE
    a) During an open label study of pediatric patients aged 7 to 11 years with exocrine pancreatic insufficiency due to cystic fibrosis, nasal congestion was reported in 14% of patients (n=7) receiving pancrelipase with a mean treatment dose of 6486 lipase units/kg of body weight (mean treatment duration: 5.7 days) (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012).
    E) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Pulmonary hypersensitivity is a rare complication after inhalation of powder (Wiessmann & Baur, 1985) (Khaw K, Adeniyl-Jones S & Pena-Cruz V et al, 1978).
    F) COUGH
    1) WITH THERAPEUTIC USE
    a) In a double-blind, crossover study evaluating cystic fibrosis patients (8 to 43 years of age) with exocrine pancreatic insufficiency, cough was reported in 10% (2 of 21) of patients who received pancrelipase (dose not greater than 2500 lipase units/kg/meal; total exposure, 20 to 28 days) compared to 4% (1 of 24) of patients who received placebo (Prod Info PERTZYE(TM) oral delayed-release capsules, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) During a single, multicenter, randomized, parallel, placebo-controlled, double-blind study of patients aged 24 to 70 years with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy, headache was reported in 3% of patients receiving pancrelipase (n=30) compared to 0% of patients receiving placebo (n=20) (Prod Info VIOKACE(TM) oral tablets, 2012).
    b) During a randomized, double-blind, placebo-controlled, crossover study of patients aged 8 to 37 years with exocrine pancreatic insufficiency due to cystic fibrosis, headache was reported in 7% of patients receiving pancrelipase (n=30) compared to 3% of patients receiving placebo (n=31) (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind, crossover study, dizziness was reported in 6% (2 of 32) of cystic fibrosis patients with exocrine pancreatic insufficiency who received pancrelipase (dose of 4000 lipase units per gram of fat ingested per day) compared to 0% of patients who received placebo (n=31). Each phase of treatment lasted 5 to 6 days (Prod Info CREON(R) oral delayed-release capsules, 2011).
    C) FEELING IRRITABLE
    1) WITH THERAPEUTIC USE
    a) In an open-label, single-arm study, irritability occurred with pancrelipase therapy (mean dose 7500 lipase units/kg/day) in 6% of patients aged 4 months to 6 years with exocrine pancreatic insufficiency due to cystic fibrosis (n=18). Patients were administered their usual pancreatic enzyme replacement therapy for a mean of 18.2 days (mean dose 7000 lipase units/kg/day) followed by pancrelipase for a mean of 12.6 days (Prod Info CREON(R) oral delayed-release capsules, 2011).
    D) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue has been commonly reported with both delayed- and immediate-release pancreatic enzyme products containing pancrelipase for the treatment of exocrine pancreatic insufficiency (Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Diarrhea, flatulence, constipation, decreased appetite, nausea, vomiting, dyspepsia and abdominal pain are reported adverse gastrointestinal events. Abdominal pain was one of the most common treatment emergent adverse events reported during clinical trials; however, in all studies the incidence rate was lower in the pancrelipase group compared with the placebo group (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info CREON oral delayed-release capsules, 2011).
    2) WITH POISONING/EXPOSURE
    a) In a randomized, double-blind, placebo-controlled study, a 10-year-old patient received a Pancreaze dose of 12,399 lipase units/kg/day for the duration of the open-label and randomized withdrawal periods, and developed mild abdominal pain. Laboratory results revealed mild elevations of AST, ALT, serum phosphate and hematocrit (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014).
    B) GASTROINTESTINAL IRRITATION
    1) WITH THERAPEUTIC USE
    a) ORAL irritation has been noted in children and infants who hold the pancreatic enzyme tablets in their mouths prior to swallowing. The medication should NOT be crushed or chewed or mixed in foods having a pH greater than 4.5 which can disrupt the protective coating (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info CREON oral delayed-release capsules, 2011).
    1) Events have included buccal irritation, severe mouth ulceration, and angular stomatitis resulting in weight loss and difficulty in swallowing. Irritation could be greatly reduced by enteric-coated formulations (Darby, 1970).
    C) STENOSIS OF INTESTINE
    1) WITH THERAPEUTIC USE
    a) Fibrosing colonopathy and distal intestinal obstruction syndrome (DIOS) have been reported in children with cystic fibrosis following long-term pancreatin therapy, with the majority of patients receiving high-dose preparations. It has been theorized that delayed gastrointestinal transit time and prolonged exposure of the colon to high-strength pancreatic enzymes in cystic fibrosis patients may be associated with the development of fibrosing colonopathy in these patients (Prod Info CREON(R) oral capsule delayed release, 2009; Powell, 1999; Prod Info Pancrease(R), pancrelipase, 1998; Taylor & Steiner, 1995).
    b) Distal intestinal obstruction syndrome has been reported in postmarketing surveillance with both delayed- and immediate-release pancreatic enzyme products containing pancrelipase for the treatment of exocrine pancreatic insufficiency (Prod Info ZENPEP(R) oral delayed-release capsules, 2013)
    2) WITH POISONING/EXPOSURE
    a) Although there are no reports of overdose, chronic high doses of pancreatic enzyme products may lead to fibrosing colonopathy (Prod Info CREON(R) oral capsule delayed release, 2009).
    D) PRURITUS ANI
    1) WITH THERAPEUTIC USE
    a) Perianal irritation, particularly in infants, has been reported with therapeutic use of pancreatic enzymes (S Sweetman , 2001; Lyon et al, 1998).
    b) During a single, multicenter, randomized, parallel, placebo-controlled, double-blind study of patients aged 24 to 70 years with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy, anal pruritus was reported in 7% of patients receiving pancrelipase (n=30) compared to 0% of patients receiving placebo (n=20) (Prod Info VIOKACE(TM) oral tablets, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) BILIARY CALCULUS
    1) WITH THERAPEUTIC USE
    a) During a single, multicenter, randomized, parallel, placebo-controlled, double-blind study of patients aged 24 to 70 years with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy, biliary tract stones were reported in 7% of patients receiving pancrelipase (n=30) compared to 0% of patients receiving placebo (n=20) (Prod Info VIOKACE(TM) oral tablets, 2012).
    B) INCREASED LIVER ENZYMES
    1) WITH POISONING/EXPOSURE
    a) In a randomized, double-blind, placebo-controlled study, a 10-year-old patient received a Pancreaze dose of 12,399 lipase units/kg/day for the duration of the open-label and randomized withdrawal periods and developed mild abdominal pain. Laboratory results revealed mild elevations of AST, ALT, serum phosphate and hematocrit (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) HYPERURICEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperuricemia has been observed following high doses of exogenous pancreatic enzymes of the active ingredient pancrelipase. Patients with gout, renal impairment, or preexisting hyperuricemia are at increased risk for hyperuricemia with administration of porcine-derived pancrelipase due to the purine content, which increases blood uric levels (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info ZENPEP(R) oral delayed-release capsules, 2011; Prod Info CREON oral delayed-release capsules, 2011).
    B) HYPERURICURIA
    1) WITH THERAPEUTIC USE
    a) Hyperuricosuria has been observed following high doses of exogenous pancreatic enzymes of the active ingredient pancrelipase. Patients with gout, renal impairment, or preexisting hyperuricemia are at increased risk for hyperuricuria with administration of porcine-derived pancrelipase due to the purine content, which increases blood uric levels (Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).
    C) KIDNEY STONE
    1) WITH THERAPEUTIC USE
    a) Urolithiasis has been noted in children with cystic fibrosis. Dose related hyperuricosuria and uric acid crystalluria have been reported (Stapleton et al, 1976) and thought to be due to the purine content of the product.
    2) WITH POISONING/EXPOSURE
    a) Although there are no reports of overdose, high doses of pancreatic enzymes may produce hyperuricosuria and hyperuricemia, and should be used with caution in patients with hyperuricemia, gout or renal impairment (Prod Info CREON(R) oral capsule delayed release, 2009).
    D) DYSURIA
    1) WITH THERAPEUTIC USE
    a) Dysuria and crystalluria have been seen in children with normal serum uric acid. Increases in uric acid resulted from increased pancreatic enzyme dosage and subsequent increases in purine intake (Stapleton et al, 1976).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOCRIT - FINDING
    1) WITH POISONING/EXPOSURE
    a) In a randomized, double-blind, placebo-controlled study, a 10-year-old patient received a Pancreaze dose of 12,399 lipase units/kg/day for the duration of the open-label and randomized withdrawal periods and developed mild abdominal pain. Laboratory results revealed mild elevations of AST, ALT, serum phosphate and hematocrit (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Pruritus, urticaria, and skin rash have been observed in patients receiving pancrelipase (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info CREON oral delayed-release capsules, 2011).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) NECK PAIN
    1) WITH THERAPEUTIC USE
    a) During an open label study of pediatric patients aged 7 to 11 years with exocrine pancreatic insufficiency due to cystic fibrosis, neck pain was reported in 14% of patients (n=7) receiving pancrelipase with a mean treatment dose of 6486 lipase units/kg of body weight (mean treatment duration: 5.7 days) (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Severe allergic reactions (ie, anaphylaxis, asthma, hives, pruritus) have rarely occurred with both delayed- and immediate-release pancreatic enzyme products containing pancrelipase for the treatment of exocrine pancreatic insufficiency (Prod Info ZENPEP(R) oral delayed-release capsules, 2013; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012).(Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009). Many of these products are made from hog pancrease. Individuals sensitive to pork protein may experience allergic reactions (Prod Info Pancrease MT(R), pancrelipase, 1998).
    b) Workers exposed to pancreatic enzyme dust for 1 to 18 years developed allergies determined by skin tests and bronchial provocation. Symptoms may appear as bronchial asthma (Hayes & Newman Taylor, 1991).
    1) Pancreatic alpha amylase and trypsin have been determined to be two of the causative allergens.
    2) There has been some immunologic cross-over demonstrated between pork and beef pancreatin (Wiessmann & Baur, 1985) (Baur et al, 1984).
    3) Not all workers are allergic to the same fraction of the enzymes, even within the same institution (van Toorenenbergen et al, 1991).
    B) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis and other severe allergic reactions (ie, asthma, hives, pruritus) have rarely occurred with both delayed- and immediate-release pancreatic enzyme products containing pancrelipase for the treatment of exocrine pancreatic insufficiency (Prod Info ZENPEP(R) oral delayed-release capsules, 2013; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012).(Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).
    C) LYMPHADENOPATHY
    1) WITH THERAPEUTIC USE
    a) During an open label study of pediatric patients aged 7 to 11 years with exocrine pancreatic insufficiency due to cystic fibrosis, lymphadenopathy was reported in 11% of patients (n=7) receiving pancrelipase with a mean treatment dose of 6486 lipase units/kg of body weight (mean treatment duration: 5.7 days) (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Pancrelipase is classified as FDA pregnancy category C by the manufacturer. There are no data regarding the effects of pancrelipase on pregnancy or breastfeeding.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012; Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).
    B) ANIMAL STUDIES
    1) There are no animal reproduction studies on the use of pancrelipase (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012; Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012; Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).
    B) PREGNANCY CATEGORY
    1) Pancrelipase is classified by the manufacturer as FDA pregnancy category C (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012; Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).
    C) ANIMAL STUDIES
    1) There are no animal reproduction studies on the use of pancrelipase (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012; Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012; Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) There are no animal fertility studies on the use of pancrelipase (Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012; Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are necessary following an overdose unless otherwise clinically indicated.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    D) Monitor patients for increased uric acid.
    E) Monitor urine for hyperuricosuria or crystalluria.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) No specific laboratory tests are necessary following an overdose unless otherwise clinically indicated.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    D) Monitor patients for increased uric acid.
    E) Monitor urine for hyperuricosuria or crystalluria.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) DILUTION
    1) For large amounts, dilution to reduce irritation, may be indicated.
    B) ACTIVATED CHARCOAL
    1) Activated charcoal is generally NOT indicated because of low toxicity following an overdose.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Activated charcoal is generally NOT indicated because of low toxicity following an overdose.
    B) DILUTION
    1) Dilution may be indicated following ingestion of large amounts in order to reduce irritation.
    2) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Pancreatic enzyme tablets are low in toxicity and are not expected to produce serious overdose effects. Treatment should be symptomatic and supportive. Patients should be monitored for irritation of the gastrointestinal tract, possible hypersensitivity reactions, and increased uric acid in the blood and urine. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Significant toxicity is not expected after an overdose.
    B) MONITORING OF PATIENT
    1) No specific laboratory tests are necessary following an overdose unless otherwise clinically indicated.
    2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    3) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    4) Monitor patients for increased uric acid.
    5) Monitor urine for hyperuricosuria or crystalluria.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Summary

    A) TOXICITY: No specific toxic dose has been established. One or two tablets is unlikely to produce symptoms other than mild irritation. A 10-year-old patient received a Pancreaze dose of 12,399 lipase units/kg/day throughout the study period and developed mild abdominal pain. Laboratory results revealed mild elevations of AST, ALT, serum phosphate and hematocrit.
    B) THERAPEUTIC DOSE: The dose used is individualized based on the degree of steatorrhea present, fat content in the diet and clinical symptoms.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) The dose used is individualized based on the degree of steatorrhea present, fat content in diet, and clinical symptoms (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012).
    B) PANCRELIPASE
    1) TABLETS AND DELAYED RELEASE CAPSULES
    a) Start dosing with 500 USP lipase units/kg/meal. The MAXIMUM dose is 2500 lipase units/kg/meal; OR less than or equal to 10,000 lipase units/kg/day; OR less than 4000 lipase units/g fat ingested per day (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012).
    b) SNACK: In general, half of the prescribed dose for a full meal should be given with each snack (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012).
    7.2.2) PEDIATRIC
    A) PANCRELIPASE
    1) GENERAL
    a) The dose used is individualized based on the degree of steatorrhea present, fat content in diet, and clinical symptoms (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info VIOKACE(TM) oral tablets, 2012; Prod Info CREON(R) oral capsule delayed release, 2009).
    2) INFANTS
    a) INFANTS UP TO 12 MONTHS OF AGE: 2600 units of lipase per 120 mL of formula or per breast feeding (Pancreaze(R)) (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014).
    b) INFANTS UP TO 12 MONTHS OF AGE: 2000 to 4000 USP units of lipase per 120 mL of formula or per breast feeding (Creon(R)) (Prod Info CREON(R) oral capsule delayed release, 2009).
    3) DELAYED RELEASE CAPSULE
    a) CHILDREN OLDER THAN 12 MONTHS AND YOUNGER THAN 4 YEARS WITH A WEIGHT OF AT LEAST 14 KG: Start dosing at 1000 USP lipase units/kg/meal orally. MAXIMUM dose is 2500 lipase units/kg/meal; OR less than or equal to 10,000 lipase units/kg/day; OR less than 4000 lipase units/g of fat per day (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012).
    1) For Pertzye (TM) oral delayed release capsules, this dosing in this age group is recommended for children weighing at least 8 kg (Prod Info PERTZYE(TM) oral delayed-release capsules, 2012).
    2) For Pancreaze(R) oral delayed release capsules, this dosing in this age group does not contain weight restrictions (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014).
    b) CHILDREN 4 YEARS OF AGE AND OLDER WITH A WEIGHT OF AT LEAST 28 KG: Start dosing at 500 USP lipase units/kg/meal orally. MAXIMUM dose is 2500 lipase units/kg/meal; OR less than or equal to 10,000 lipase units/kg/day; OR less than 4000 lipase units/g of fat per day (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012).
    1) For Pertzye (TM) oral delayed release capsules, this dosing in this age group is recommended for children weighing at least 16 kg (Prod Info PERTZYE(TM) oral delayed-release capsules, 2012).
    2) For Pancreaze(R) oral delayed release capsules, this dosing in this age group does not contain weight restrictions (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014).
    c) SNACK: In general, half of the prescribed dose for a full meal should be given with each snack (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014; Prod Info PERTZYE(TM) oral delayed-release capsules, 2012; Prod Info ULTRESA(TM) oral delayed-release capsules, 2012; Prod Info CREON(R) oral capsule delayed release, 2009).
    4) TABLETS
    a) Safety and efficacy of pancrelipase tablets have not been established in pediatric patients (Prod Info VIOKACE(TM) oral tablets, 2012).

Maximum Tolerated Exposure

    A) No specific toxic dose has been established.
    B) In a randomized, double-blind, placebo-controlled study, a 10-year-old patient received a Pancreaze dose of 12,399 lipase units/kg/day for the duration of the open-label and randomized withdrawal periods and developed mild abdominal pain. Laboratory results revealed mild elevations of AST, ALT, serum phosphate and hematocrit (Prod Info PANCREAZE(R) oral delayed-release capsules, 2014).
    C) Fibrosing colonopathy and colonic strictures have been reported following chronic high doses of pancreatic enzyme products. Patients with a history of hyperuricemia, gout or renal impairment may develop hyperuricosuria and hyperuricemia following high doses of pancreatic enzyme products (Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Pancrelipase provides a replacement for digestive enzymes secreted by the pancreas with active porcine derived lipases, proteases and amylases to catalyze the hydrolysis of (1) fat into glycerol and fatty acids, (2) proteins into peptides and amino acids, and (3) starch into dextrins and sugars. The pancreatic enzymes are enteric-coated to prevent inactivation in gastric acid and to release most of the enzymes into the duodenum and proximal small intestines (which are the sites of action) at a pH greater than 5.5 (Prod Info PANCREAZE(TM) delayed-release oral capsules, 2010; Prod Info CREON(R) oral capsule delayed release, 2009).

Physicochemical

Physical Characteristics

    A) Pancreatin: A white, cream, or buff colored amorphous solid with a characteristic odor (not unpleasant) (S Sweetman , 2001).
    B) Pancrelipase: A beige-white amorphous powder that is miscible in water and practically insoluble or insoluble in ether and alcohol (Prod Info CREON(R) oral capsule delayed release, 2009).

Molecular Weight

    A) Varies

References

General Bibliography

    1) Baur X, Wiessmann, & Wuthrich B: Enzyme sind die allergenwirksamen Komponenten von inhaliertem Pankreatin. Dtsch Med Wschr 1984; 109:257-260.
    2) Bergner A & Bergner RK: Pulmonary hypersensisitivity associated with pancreatin exposure. Pediatrics 1975; 55:814-817.
    3) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    4) Caravati EM: Alkali. In: Dart RC, ed. Medical Toxicology, Lippincott Williams & Wilkins, Philadelphia, PA, 2004.
    5) Chignell R: External influences on nose and throat. Proc R Soc Med 1972; 65:679.
    6) Darby CW: Pancreatic extracts (letter). BMJ 1970; 2:299.
    7) Dolan TF Jr & Meyers A: Bronchial asthma and allergic rhinitis associated with inhalation of pancreatic extracts. Am Rev Resp Dis 1974; 110:812.
    8) Glencross EJG: BMJ 1972; 2:376.
    9) Hayes JP & Newman Taylor AJ: Bronchial asthma in a paediatric nurse caused by inhaled pancreatic extracts. Br J Ind Med 1991; 48:355-356.
    10) JEF Reynolds : Martindale: The Extra Pharmacopoeia (electronic version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 1990; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    11) Khaw K, Adeniyl-Jones S & Pena-Cruz V et al: The affect of caloric supplementation on growth parameters in children with cyctic fibrosis. Cystic Fibrosis Club Abstr, 1978.
    12) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    13) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    14) Lipkin GW & Vickers DW: (letter). Lancet 1987; 1:392.
    15) Lipson A & Meikle H: Porcine pancreatin as a source of salmonella infection in children with cystic fibrosis. Arch Dis Child 1977; 52:569-572.
    16) Lyon CC, Yell J, & Beck MH: Irritant contact dermatitis from pancreatin exacerbating vulvodynia. Contact Dermatitis 1998; 38:362.
    17) Nakamura S: On occupational allergic asthma of different kinds newly found in our allergy clinic. J Asthma Res 1972; 10:37.
    18) Nakamura S: Studies on asthma bronchiale: 6. On the occupational allergy caused by pancreatic powder among pharmacists. Jap J Allergy 1971; 20:361.
    19) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    20) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    21) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    22) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    23) Powell CJ: Colonic toxicity from pancreatins: a contemporary safety issue. Lancet 1999; 353:911-915.
    24) Product Information: CREON oral delayed-release capsules, pancrelipase oral delayed-release capsules. Abbott Laboratories (per FDA), North Chicago, IL, 2011.
    25) Product Information: CREON(R) oral capsule delayed release, pancrelipase oral capsule delayed release. Solvay Pharmaceuticals, Inc., Marietta, GA, 2009.
    26) Product Information: CREON(R) oral delayed-release capsules, pancrelipase oral delayed-release capsules. AbbVie Inc. (per Manufacturer), North Chicago, IL, 2013.
    27) Product Information: CREON(R) oral delayed-release capsules, pancrelipase oral delayed-release capsules. Abbott Products GmbH (per FDA), Hannover, Germany, 2011.
    28) Product Information: PANCREAZE(R) oral delayed-release capsules, pancrelipase oral delayed-release capsules. Janssen Pharmaceuticals Inc. (per FDA), Titusville, NJ, 2014.
    29) Product Information: PANCREAZE(TM) delayed-release oral capsules, pancrelipase delayed-release oral capsules. McNeil Pediatrics, Titusville, NJ, 2010.
    30) Product Information: PERTZYE(TM) oral delayed-release capsules, pancrelipase oral delayed-release capsules. Digestive Care, Inc. (per Manufacturer), Bethlehem, PA, 2012.
    31) Product Information: Pancrease MT(R), pancrelipase. McNeil Labs, Spring House, PA, 1998.
    32) Product Information: Pancrease(R), pancrelipase. McNeil Labs, Spring House, PA, 1998.
    33) Product Information: ULTRESA(TM) oral delayed-release capsules, pancrelipase oral delayed-release capsules. Aptalis Pharma US, Inc (Per FDA), Birmingham, AL, 2012.
    34) Product Information: VIOKACE(TM) oral tablets, pancrelipase oral tablets. Aptalis Pharma US, Inc (Per FDA), Birmingham, AL, 2012.
    35) Product Information: Viokase(R), pancrelipase. Axcan Scandipharm Inc, Birmingham, AL, 2000.
    36) Product Information: ZENPEP(R) oral delayed-release capsules, pancrelipase oral delayed-release capsules. Aptalis Pharma US, Inc. (Per FDA), Bridgewater, NJ, 2013.
    37) Product Information: ZENPEP(R) oral delayed-release capsules, pancrelipase oral delayed-release capsules. Eurand Pharmaceuticals, Inc (Per FDA), Yardley, PA, 2011.
    38) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    39) S Sweetman : Martindale: The Complete Drug Reference. Pharmaceutical Press. London, UK (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    40) Sakula A: Bronchial asthma due to allergy to pancreatic extract. Lancet 1977; 2:193.
    41) Sakula A: Bronchial asthma due to allergy to pancreatic extract: a hazard in the treatment of cystic fibrosis. Br J Dis Chest 1977a; 71:295-299.
    42) Stapleton FB, Kennedy J, & Nousia-Arvanitakis S: Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis. N Engl J Med 1976; 295:246-248.
    43) Taylor CJ & Steiner GM: Fibrosing colonopathy in a child on low-dose pancreatin (letter). Lancet 1995; 346:1106-1107.
    44) Twarog FJ: J Allergy Clin Immunol 1977; 59:35.
    45) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    46) van Toorenenbergen AW, Huijskes-Heins MIE, & Dieges PH: Occupational allergy to pancreatic powder: characterization of IgE-binding antigens in pancreatic extract by immunoblotting. J Allergy Clin Immunol 1991; 87:65-654.