PRODUCT MONOGRAPH. Pr ULTRESA. (Pancrelipase USP) Capsule (Delayed- Release) 13,800, 20,700 and 23,000 USP units of lipase USP

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PRODUCT MONOGRAPH Pr ULTRESA (Pancrelipase USP) Capsule (Delayed- Release) 13,800, 20,700 and 23,000 USP units of lipase USP Pancreatic enzymes A09AA02 Aptalis Pharma Canada Inc. 597 Sir-Wilfrid-Laurier
PRODUCT MONOGRAPH Pr ULTRESA (Pancrelipase USP) Capsule (Delayed- Release) 13,800, 20,700 and 23,000 USP units of lipase USP Pancreatic enzymes A09AA02 Aptalis Pharma Canada Inc. 597 Sir-Wilfrid-Laurier Blvd. Mont-Saint-Hilaire, Québec Canada J3H 6C4 Date of Approval: June 5, 2015 Submission Control No: ULTRESA Pancrelipase Capsules Page 1 of 18 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION...3 SUMMARY PRODUCT INFORMATION...3 INDICATIONS AND CLINICAL USE...3 CONTRAINDICATIONS...4 WARNINGS AND PRECAUTIONS...4 ADVERSE REACTIONS...6 DRUG INTERACTIONS...8 DOSAGE AND ADMINISTRATION...8 OVERDOSAGE...10 ACTION AND CLINICAL PHARMACOLOGY...10 STORAGE AND STABILITY...11 DOSAGE FORMS, COMPOSITION AND PACKAGING...11 PART II: SCIENTIFIC INFORMATION...13 PHARMACEUTICAL INFORMATION...13 CLINICAL TRIALS...13 TOXICOLOGY...14 REFERENCES...15 PART III: CONSUMER INFORMATION...16 ULTRESA Pancrelipase Capsules Page 2 of 18 ULTRESA Pancreatic enzymes PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Oral Oral Oral Dosage Form / Strength Capsule (Delayed-Release):13,800 USP units of lipase Lipase: 13,800 USP units Amylase: 58,800 USP units Protease: 53,400 USP units Capsule (Delayed-Release):20,700 USP units of lipase Lipase: 20,700 USP units Amylase: 88,200 USP units Protease: 80,000 USP units Capsule (Delayed-Release):23,000 USP units of lipase Lipase: 23,000 USP units Amylase: 98,000 USP units Protease: 88,900 USP units Clinically Relevant Non- Medicinal Ingredients For a complete listing see Dosage Forms, Composition and Packaging section. For a complete listing see Dosage Forms, Composition and Packaging section. For a complete listing see Dosage Forms, Composition and Packaging section. 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 ULTRESA Pancrelipase Capsules Page 3 of 18 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 Serious Warnings and Precautions Pancreatic enzymes products, including ULTRESA (pancrelipase) have been associated with fibrosing colonopathy (strictures of the ileo-caecum and large intestine) if given at high doses chronically to patients with cystic fibrosis. It is not clear whether this complication is caused by high dosages of pancreatic enzymes, or whether the underlying disease is responsible. Unusual abdominal symptoms should be reviewed to exclude the possibility of colonic damage, especially if the patient is taking in excess of 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) or greater than 4,000 lipase units/g fat ingested per day. ULTRESA cannot be substituted (unit for unit) with other pancreatic enzyme products because they are biological products, and therefore, differ in their manufacturing processes, formulations, exact composition, enzymatic activities, stability and bioactivity in the small intestine, the response of the patient to the estimated dose must be monitored and adjusted as necessary. Special attention to the response of the patient is required during any change in treatment from one pancreatic enzyme to another. General Should hypersensitivity develop, discontinue medication and treat the patient symptomatically. ULTRESA Pancrelipase Capsules Page 4 of 18 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. ULTRESA Pancrelipase Capsules Page 5 of 18 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. ULTRESA Pancrelipase Capsules Page 6 of 18 Table 1 Adverse Reactions Occurring in at Least 1 Patient in UMT20CF05-01 a Multicenter, Randomized, Double-Blind, Crossover Study ULTRASE Placebo Capsules MedDRA SOC Preferred Term N=30 N=31 n (%) n (%) Abdominal pain 2 (6.7) 12 (38.7%) Gastrointestinal disorders Abdominal pain upper 1 (3.3) 4 (12.9%) Constipation 2 (6.7) 1 (3.2%) Investigations Alanine aminotransferase increased 1 (3.3) 0 (0) Table 2 Adverse Reactions Occurring in at Least 1 Patient in UMT20CF07-01 a Multicenter, Phase III, Open-Label Study ULTRASE Capsules MedDRA SOC Preferred Term N=9 n (%) Abdominal discomfort 1 ( 11.1) Gastrointestinal disorders Abdominal pain 1 (11.1 ) Investigations Nausea Weight decreased 1 (11.1 ) 1 ( 11.1) 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 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. ULTRESA Pancrelipase Capsules Page 7 of 18 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 weightbased 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 ULTRESA Pancrelipase Capsules Page 8 of 18 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 Pancrelipase Capsules Page 9 of 18 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 For management of a suspected drug overdose, contact your regional Poison Control Centre. 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. ULTRESA Pancrelipase Capsules Page 10 of 18 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
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