Viokace Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

VIOKACE (pancrelipase tablets) is indicated in adult patients for:

• treatment of exocrine pancreatic insufficiency (EPI) attributed to cystic fibrosis, chronic pancreatitis, or any other medically defined pancreatic disease that might require pancreatic enzyme therapy.

VIOKACE tablets are used in conjunction with a proton pump inhibitor.

PATIENT SUBSETS

Geriatrics (> 65 years of age):

Clinical studies conducted with VIOKACE tablets 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 (< 18 years of age):

The safety and efficacy of VIOKACE in pediatric patients have not been established.

In general, delayed-release (enteric-coated) capsules should be used for pediatric patients. Due to greater degradation in the gastric environment, VIOKACE, a non-enteric-coated, pancreatic enzyme replacement product, may have decreased bioavailability and therefore may be less efficacious than enteric-coated formulations. Thus, use of VIOKACE in pediatric patients may increase the risk of inadequate treatment of pancreatic insufficiency and result in suboptimal weight gain, malnutrition and/or need for larger doses of pancreatic enzyme replacement (See WARNINGS and PRECAUTIONS). The efficacy of VIOKACE was established in adult patients with concomitant proton pump inhibitor (PPI) therapy. The long-term safety of PPI use in pediatric patients has not been established.

CONTRAINDICATIONS

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

VIOKACE 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.

VIOKACE should always be taken with food. Tablets should be swallowed whole with adequate amounts of liquid at mealtimes. VIOKACE should not be crushed or chewed. Since VIOKACE is not enteric-coated, it should not be mixed with food. Patients who cannot swallow VIOKACE tablets whole should not use VIOKACE. Care should be taken to ensure that no drug is retained in the mouth to avoid irritation of oral mucosa, and or loss of enzyme activity (See DOSAGE AND ADMINISTRATION).

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.

Potential Viral Exposure from Product Source

VIOKACE is sourced from pancreatic tissue from pigs used for food consumption. Although the risk that VIOKACE 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.

Respiratory

The fine powder of pancreatic enzyme tablets such as VIOKACE may be irritating to the nasal mucosa and the respiratory tract.

Hepatic/Biliary/Pancreatic

VIOKACE may cause hyperuricosuria and hyperuricemia with very high doses.

Special Populations

Pregnant Women:

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

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 cystic fibrosis patients

Allergy or hypersensitivity reactions of the skin 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. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The short-term safety and efficacy of VIOKACE (pancrelipase tablets) were evaluated in a randomized, double-blind, placebo-controlled, parallel group study comparing VIOKACE Tablets (20,880 USP units of lipase per tablet) to placebo in 50 patients, ages 24 to 70, with exocrine pancreatic insufficiency (EPI). VIOKACE Tablets (20,880 USP units of lipase per tablet) or placebo were administered as 22 tablets per day (6 tablets with 3 meals and 2 tablets with 2 of 3 snacks). Duration of exposure ranged from 6 to 7 days. The majority of the subjects were Caucasian (96%) and male (82%).

Table 1 presents adverse reactions that occurred in at least 1 patient (≥ 3%) treated with VIOKACE at a higher rate than with placebo. As such, all the adverse reactions mentioned in Table 1 were to be considered as common (frequent) adverse reactions (>1%).

Adverse Reactions

Post-Market Adverse Drug Reactions

Post-marketing data for VIOKACE have been available since 2000. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The Adverse Drug Reactions seen with VIOKACE are:

Gastrointestinal disorders: Abdominal discomfort, Abdominal distension, Abdominal pain, Abdominal pain upper, Constipation, Diarrhoea, Dyspepsia, Flatulence, Frequent bowel movements, Nausea.

Immune system disorders: Hypersensitivity.

Respiratory, thoracic and mediastinal disorders: Oropharyngeal pain, Rhinorrhoea.

Skin and subcutaneous tissue disorders: Rash, 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 tablets, or dosage strength given with meals and/or snacks should be determined 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.

Take the medication immediately. Do not store it to be taken later.

Recommended Dose and Dosage Adjustment

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

Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.

Enzyme dosing should begin with 500 lipase units/kg of body weight per meal 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 VIOKACE 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.

In one clinical trial, patients received VIOKACE at a dose of 125,280 lipase units per meal while consuming 100 g of fat per day. Lower starting doses recommended in the literature are consistent with the 500 lipase units/kg of body weight per meal lowest starting dose recommended for adults in the Cystic Fibrosis Foundation Consensus Conferences Guidelines. The initial starting dose and increases in the dose per meal should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet.

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 the healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase unit/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.

Missed Dose

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

Administration

VIOKACE is not interchangeable with any other pancrelipase product.

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

Since VIOKACE is not enteric-coated, it should be taken in combination with a proton pump inhibitor.

VIOKACE should be taken during meals or snacks, with sufficient fluid. Tablets should be swallowed whole. Patients should only take VIOKACE if they can swallow the tablets whole as VIOKACE should not be crushed or chewed. Care should be taken to ensure that no drug is retained in the mouth to avoid mucosal irritation

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

VIOKACE (pancrelipase tablets) tablets are not enteric-coated. The pancreatic enzymes in VIOKACE 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 (e.g., maltose, maltriose) in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the normally functioning pancreas.

Pharmacokinetics

Pancreatic enzymes are not absorbed from the gastrointestinal tract in appreciable amounts.

STORAGE AND STABILITY

Store in a dry place. Do not store above 25° C.. Protect from heat and moisture. Do not refrigerate or freeze.

VIOKACE (pancrelipase tablets) tablets should be stored in a dry place in the original container. After opening, keep the container tightly closed between uses to protect from moisture.

VIOKACE is dispensed in bottles containing a desiccant. The desiccant packet should not be eaten. The desiccant packet will protect the product from moisture.

SPECIAL HANDLING INSTRUCTIONS

Dispense VIOKACE (pancrelipase tablets) tablets in tight container, preferably with a desiccant.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Each VIOKACE (pancrelipase tablets) tablet strength contains the specific amount of lipase, protease and amylase

• VIOKACE tablets (10,440 USP lipase units / tablet) : 10,440 USP units of lipase; 57,100 USP units of protease; 56,400 USP units of amylase
• VIOKACE tablets (20,880 USP lipase units / tablet) : 20,880 USP units of lipase; 112,500 USP units of protease; 113,400 USP units of amylase

VIOKACE (10,440 USP lipase units) is supplied in bottles of 100 tablets each (DIN 02230019). Tablets are tan, round, compressed and have the inscription VIO9111 on one side and 9111 on the other side. Tablets contain the following non-medicinal ingredients: colloidal silicone dioxide, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, stearic acid and talc.

VIOKACE (20,880 USP lipase units) is supplied in bottles of 100 tablets each (DIN 02241933). Tablets are tan, oval, biconvex and have the inscription V¹⁶ engraved on one side and 9116 on the other side. Tablets contain the following non-medicinal ingredients (in alphabetical order): colloidal silicone dioxide, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, stearic acid and talc.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Proper name: Pancrelipase

Chemical name: Not applicable

Molecular formula Not applicable

and molecular mass:

Structural formula: Not applicable

Physicochemical properties: The active pharmaceutical ingredient of VIOKACE^TM 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 in alcohol.

CLINICAL TRIALS

Exocrine Pancreatic Insufficiency:

A single Phase III study VIO16EPI07-01 investigating the efficacy of VIOKACE (pancrelipase tablets) tablets in patients with exocrine pancreatic insufficiency (EPI) was conducted. Study VIO16EPI07-01was a multicenter, randomized, double-blind, parallel, placebo-controlled study performed in chronic pancreatitis (CP) patients with EPI.

In this placebo-controlled study, the primary objective was to show superiority of VIOKACE compared to placebo on the primary efficacy endpoint, 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.

The wash-out period mean CFA was 48% in the VIOKACE treatment group and was 57% in the placebo group. At the end of the double-blind treatment period, the mean CFA was 86% with VIOKACE treatment compared to 58% with placebo. The mean difference in 270 CFA at the end of the double-blind treatment period was 28 percentage points in favor of VIOKACE treatment with 95% Confidence Interval of (21, 37) and p < 0.0001.

Subgroup analyses of the CFA results showed that mean change in CFA with VIOKACE treatment (from the washout period to the end of the double-blind period) was greater in patients with lower wash-out period CFA values than in patients with higher wash-out period CFA values.

Only 2 of the patients with a history of total pancreatectomy were treated with VIOKACE. One of these patients had a CFA of 12% during the wash-out period and a CFA of 90% at the end of the double-blind period; the other patient had a CFA of 38% during the wash-out period and a CFA of 77% at the end of the double-blind period. The remaining 9 patients with a history of partial pancreatectomy treated with VIOKACE had a mean CFA of 56% during the wash-out period and a mean CFA of 86% at the end of the double-blind period.

TOXICOLOGY

Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.

REFERENCES

1. 1. Ansaldi-Balocco N, Santini B, Sarchi C. Efficacy of pancreatic enzyme supplementation in children with cystic fibrosis: comparison of two preparations by random crossover study and retrospective study of the same patients at two different ages. J Pediatr Gastroenterol Nutr. 1099;7 Suppl 1:S40-5.
2. 2. 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.
3. 3. 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.
4. 4. Clinical Study Report Protocol No. VIO16EPI07-01: A Multicenter, Randomized, Double-Blind, parallel, Placebo-Controlled, Phase III Study to assess the Safety and Efficacy of VIOKACE for the Correction of Steatorrhea in Patients with Exocrine Pancreatic Insufficiency (2009).
5. 5. Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Current Gastroenterology Reports. 2007;9:116-122.
6. 6. 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.
7. 7. Gow R, Francis P, Bradbear R, et al. Comparative study of varying regiments to improve steatorrhoea and creatorrhoea in cystic fibrosis: effectiveness of an enteric-coated preparation with and without antacids and cimetidine. Lancet. Nov 1981;1071-1074.
8. 8. NCT00559364 : Safety and Efficacy Study of VIOKASE 16 for the Correction of Steatorrhea (2010).
9. 9. 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.
10. 10. Smyth RL, Ashby D, O’Hea U. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet. 1995;345:1247-1251.