Ultresa Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

ULTRESA (pancrelipase) is indicated in pediatric and adult patients for the treatment of exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF) or any other medically defined pancreatic disease that might require pancreatic enzyme therapy, including but not limited to:

• Cystic fibrosis
• Chronic pancreatitis
• Post-pancreatectomy
• Post-gastrointestinal bypass surgery (e.g. Billroth II gastroenterostomy)
• Ductal obstruction from neoplasm (e.g. of the pancreas or common bile duct)
• Pancreatic Cancer
• Gastrectomy
• Swachman-Diamond Syndrome

Geriatrics (> 65 years of age):

Clinical studies with ULTRESA capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pediatrics (< 16 years of age):

The short-term safety and efficacy of ULTRESA were assessed in two clinical studies in pediatric patients with EPI due to CF (see WARNINGS AND PRECAUTIONS, Special populations).

CONTRAINDICATIONS

ULTRESA (pancrelipase) should not be used in patients who are hypersensitive to porcine protein, pancreatic enzymes or any excipient.

ULTRESA should not be used during acute pancreatitis or the acute exacerbation of chronic pancreatitis.

WARNINGS AND PRECAUTIONS

General

Should hypersensitivity develop, discontinue medication and treat the patient symptomatically.

It is important to ensure adequate hydration in patients at all times during therapy with pancreatic enzymes.

The capsules should not be chewed or crushed because the coating (that is formulated to deliver the enzymes to the correct place in the intestines) will be destroyed. If the capsules are opened and the contents shaken onto soft food, it should not have an alkaline pH (e.g., milk, custard, ice cream, other dairy products) because the enteric coating will dissolve prematurely and limit absorption (see DOSAGE AND ADMINISTRATION).

To avoid irritation of the mouth, lips and tongue, opened capsules should be swallowed immediately before meals or snacks to minimize the probability of retaining some of the drug in the mouth. Proteolytic enzymes present in ULTRESA, when retained in the mouth, may begin to digest the mucous membranes and cause ulcerations.

Any change in pancreatic enzyme replacement therapy (e.g., dose or brand of medication) should be made cautiously and only under medical supervision. Pancreatic extracts can form insoluble complexes with folic acid, resulting in folic acid deficiency.

Endocrine and Metabolism

Pancreatic enzyme replacement therapy, in patients in whom both the exocrine and endocrine pancreas are not functioning, may interact with insulin therapy of diabetes. High-dose pancreatin may improve, but not fully normalize fat absorption, possibly because of the residual influence of diabetes and malnutrition on absorptive function. Since control of blood glucose may be brittle in malnourished, insulin-dependent patients, enzyme adjustment should be carefully supervised in-hospital to avoid exacerbation of pancreatic dysfunction

Hepatic/Biliary/Pancreatic

ULTRESA may cause hyperuricosuria and hyperuricemia with very high doses.

Potential Viral Exposure from Product Source

As with all currently marketed porcine pancreatin products, ULTRESA is sourced from pancreatic tissue from pigs used for food consumption. Although the risk that ULTRESA will transmit an infectious agent to humans has been reduced by testing for 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.

Special Populations

Pregnant Women:

There is insufficient data from the use of ULTRESA in pregnant women. Although some animal studies have been conducted, no adequate, well controlled studies have been conducted in pregnant women. ULTRESA should only be used during pregnancy if, in the opinion of the physician, the potential benefits outweigh the potential risks.

Nursing Women:

There is insufficient data to assess the risks. Pancreatic enzymes act locally in the gastrointestinal tract, and cannot be absorbed in their intact state systemically. Some of the constituent amino acids and nucleic acids are probably absorbed with dietary protein. However, the possibility of protein constituents being secreted into breast milk cannot be excluded. ULTRESA should be used only if, in the opinion of the physician, the potential benefits outweigh the potential risks.

Pediatrics (≤ 18 years of age):

There are no special warnings or precautions for use in pediatrics.

Geriatrics (> 65 years of age):

There are no special warnings or precautions for use in elderly patients

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most common adverse reactions are abdominal discomfort and pain. Other gastrointestinal reactions are less common and include abnormal stool and diarrhea. Nausea and vomiting have been reported, but these are not common.

At extremely high doses, hyperuricosuria and hyperuricaemia have been reported. Fibrosing colonopathy have been reported in CF patients (see WARNINGS AND PRECAUTIONS).

Allergic or hypersensitivity reactions have been reported.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

The short-term safety of ULTRESA (pancrelipase) was assessed in two clinical trials conducted in patients with EPI due to CF. Study 1 (UMT20CF05-01) was conducted in 30 patients, ages 8 years to 37 years and Study 2 (UMT20CF07-01) conducted in 9 patients, ages 7 years to 11 years.

All the adverse reactions mentioned in Table 1 and Table 2 below occurred in at least 1 of the total 39 patients studied during these studies with frequencies from 3.3% to 11.1%. As such, they are to be considered as common (>1% and <10%) to very common (>10%) adverse reactions.

Table 1 Adverse Reactions Occurring in at Least 1 Patient in UMT20CF05-01 a Multicenter, Randomized, Double-Blind, Crossover Study

Table 2 Adverse Reactions Occurring in at Least 1 Patient in UMT20CF07-01 a Multicenter, Phase III, Open-Label Study

Post-Market Adverse Drug Reactions

The following adverse reactions have been identified during marketed use of ULTRESA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.

Post-marketing data for ULTRESA has been available since 1992. The safety data is similar to that described below.

The adverse drug reactions seen with ULTRESA are:

Gastrointestinal disorders: Abdominal discomfort, Abdominal distension, Abdominal pain, Abdominal pain upper, Abnormal faeces (LLT: Feces abnormal smell of), Diarrhea, Flatulence, Frequent bowel movements, Nausea, Vomiting.

Immune system disorders: Hypersensitivity.

Investigations: Blood glucose increased.

Nervous system disorders: Headache.

Skin and subcutaneous tissue disorders: Blister, Pruritus generalised, Rash, Skin irritation, Urticaria.

DRUG INTERACTIONS

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

DOSAGE AND ADMINISTRATION

Dosing Considerations

Patients with pancreatic insufficiency should consume a high-calorie, unrestricted fat diet appropriate for their age and clinical status. A nutritional assessment should be performed regularly as a component of routine care, and additionally when the dosage of pancreatic enzyme replacement is made.

Dosage should be adjusted according to the severity of the exocrine pancreatic enzyme deficiency. The number of capsules, or dosage strength given with meals and/or snacks should be estimated by assessing at which dose steatorrhea is minimized and good nutritional status is maintained.

It is important to ensure adequate hydration at all times, especially during periods of increased loss of fluids. Inadequate hydration may aggravate constipation. Any mixture of the medication with food or liquid should be used immediately and not be stored.

Recommended Dose and Dosage Adjustment

Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences. ULTRESA (pancrelipase) should be administered in a manner consistent with the recommendations of the Conferences provided in the following paragraph. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.

Children Older than 12 months and Younger than 4 Years and Weight 14 kg or Greater

Children older than 12 months and younger than 4 years, weighing under 14 kg should not be dosed with this product because capsule dosage strengths cannot adequately provide dosing for these children.

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 Weight 28 kg or Greater and Adults

Children 4 years and older, weighing under 28 kg should not be administered this product because capsule dosage strengths cannot be adequately titrated for children in this weight range.

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 ULTRESA dose for an individualized full meal should be given with each snack. The total daily dosage 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. If symptoms and signs of steatorrhea persist, the dosage may be increased by a physician. 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 stricture, indicative of fibrosing colonopathy, in children 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.

Use of ULTRESA in children is limited by the available capsule dosage strengths and their ability to provide the recommended dose based on age and weight. Attempting to divide the capsule contents in small fractions to deliver small doses of lipase is not recommended.

Missed Dose

If a dose of ULTRESA is missed, the next dose should be taken with the next meal or snack as directed. Doses should not be doubled.

Administration

ULTRESA is not interchangeable with any other pancrelipase product.

ULTRESA is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of ULTRESA should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet.

ULTRESA should be taken during meals or snacks, with sufficient fluid. ULTRESA capsules should be swallowed whole. ULTRESA capsules and capsule contents should not be crushed or chewed.

For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents sprinkled on a small amount of applesauce, yogurt and other acidic soft food with a pH of 4.5 or less at room temperature.

The ULTRESA–soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth to avoid mucosal irritation.

Any unused portion of capsule contents should be discarded, and not used for subsequent dosing. The remaining exposed contents may lose potency and become less effective.

OVERDOSAGE

Extremely high dosages of pancreatic enzymes have been reported to cause hyperuricosuria and hyperuricaemia. Most cases responded to supportive measures, including discontinuation of the enzyme therapy and ensuring adequate hydration.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

The pancreatic enzymes in ULTRESA (pancrelipase) catalyze the hydrolysis of fats to monoglycerides, 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 ULTRESA are enteric-coated to minimize destruction or inactivation in gastric acid. ULTRESA is designed 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.

STORAGE AND STABILITY

Store at room temperature (20-25°C). Protect from heat and moisture.

ULTRESA (pancrelipase) should be stored in a dry place in the original container. After opening, keep the container tightly closed between uses to protect from moisture. ULTRESA is dispensed in bottles containing a desiccant. The dessicant packet will protect the product from moisture.

Keep ULTRESA in a safe place out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

ULTRESA (pancrelipase) is available as orally administered delayed-release capsules containing enteric-coated minitablets of porcine pancreatic enzyme concentrate, predominantly pancreatic lipase, amylase, and protease. ULTRESA is dosed by lipase units and is available in 3 color coded delayed-release capsule strengths.

ULTRESA 13,800 USP units lipase

Each white and yellow capsule printed "13800UL" and "AXCA" of enteric-coated minitablet contains 13,800 USP units of lipase, 58,800 USP units of amylase, and 53,400 USP units of protease.

Non-medicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, gelatin, hydrogenated castor oil, hydroxypropyl methylcellulose phthalate (HP 55) (as dry substance), iron oxide (yellow), magnesium stearate, microcrystalline cellulose, talc, triethyl citrate and titanium dioxide. Bottles of 100.

ULTRESA 20,700 USP units of lipase

Each grey and white capsule printed "20700UL" and "AXCA" of enteric-coated minitablet contains 20,700 USP units of lipase, 88,200 USP units of amylase, and 80,000 USP units of protease.

Non-medicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, gelatin, hydrogenated castor oil, hydroxypropyl methylcellulose phthalate (HP 55) (as dry substance), iron oxide (black), magnesium stearate, microcrystalline cellulose, talc, triethyl citrate and titanium dioxide. Bottles of 100.

ULTRESA 23,000 USP units of lipase

Each grey and yellow capsule printed "23000UL" and "AXCA" of enteric-coated minitablet contains 23,000 USP units of lipase, 98,000 USP units of amylase, and 88,900 USP units of protease.

Non-medicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, gelatin, hydrogenated castor oil, hydroxypropy l methylcellulose phthalate (HP 55) (as dry substance), iron oxides (black and yellow), magnesium stearate, microcrystalline cellulose, talc, triethyl citrate and titanium dioxide. Bottles of 100.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Proper name: Pancrelipase

Chemical name: Not applicable

Molecular formula and molecular mass: Not applicable

Structural formula: Not applicable

Physicochemical properties: The active pharmaceutical ingredient of ULTRESA^® is pancrelipase, an extract from porcine pancreas glands containing enzymes with lipolytic, amyolytic and proteolytic activity.

Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble or insoluble in alcohol and ether.

CLINICAL TRIALS

Exocrine Pancreatic Insufficiency:

The short-term efficacy and safety of ULTRESA (pancrelipase) were evaluated in 2 studies conducted in 40 patients, ages 7 to 37 years, with EPI associated with CF.

The primary endpoint was the coefficient of fat absorption (CFA). The CFA determines the percentage of fat that is absorbed into the body taking into account fat intake and fecal excretion.

Study UMT20CF05-01

Study UMT20CF05-01 was a randomized, double-blind, placebo-controlled, crossover study of 31 patients, ages 8 to 37 years, with EPI due to CF. The final analysis population was limited to 24 patients, who completed both treatment periods and had stool results available for each treatment period.

Patients were randomized to receive ULTRESA (at a dose not to exceed 2,500 lipase units per kilogram per meal or snack) or matching placebo for 6 to 7 days of treatment followed by crossover to the alternate treatment for an additional 6 to 7 days. The mean dose during the controlled treatment periods was 6,270 lipase units per kilogram per day. All patients consumed a high-fat diet (2 grams of fat per kilogram of body weight per day) during the treatment periods.

The CFA was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat ingestion were measured. Each patient’s CFA during placebo treatment was used as their no-treatment CFA value. Mean CFA was 89% with ULTRESA treatment compared to 56% with placebo treatment. The mean difference in CFA was 35 percentage points in favor of ULTRESA treatment with 95% CI: (25, 45) and p<0.0001.

Study UMT20CF07-01

Study UMT20CF07-01 was an open-label study of 9 patients, ages 7 years to 11 years (mean 10 years), with EPI due to CF. The final analysis population was limited to 7 patients who completed both the washout and treatment phases of the study.

After a 15 day screening period on individually-titrated doses of ULTRESA not to exceed 2,500 lipase units per kilogram per meal, patients entered a 7-day washout phase (no treatment) before returning to a 12-day treatment phase on the same individually-titrated dose of ULTRESA. The mean daily dose of ULTRESA during the treatment phase was 6,846 lipase units per kilogram body weight per day. All patients consumed a high-fat diet (2 grams of fat per kilogram of body weight per day) during both the washout phase and the treatment phase.

The mean CFA was determined during the washout phase (no treatment) and during the ULTRESA treatment phase. Mean CFA was 35% during the washout phase and was 83% during the ULTRESA treatment phase.

TOXICOLOGY

Non-clinical data show no relevant acute, subchronic or chronic toxicity. Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed.

REFERENCES

1. 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. 2. Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002 Sep;35:246-259.
3. 3. FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. N Engl J Med.1997;336:1283-1289.
4. 4. Halgreen H, Thorsgaard Pedersen N, Worning H. Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis. Scand J Gastroenterol 1986;21:104-108.
5. 5. Lands L, Zinman R, et al. Pancreatic function testing in meconium disease in CF: two case reports. J Ped Gastroenterol and Nutri 1988;7:276-279.
6. 6. Stallings VA, Start LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related 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.
7. 7. Smyth RL, Ashby D, O’Hea U. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet. 1995;345:1247-1251.