Ultresa - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Ultresa - Scientific Information

Manufacture: Forest Laboratories, Inc.
Country: United States
Condition: Cystic Fibrosis, Chronic Pancreatitis, Pancreatic Exocrine Dysfunction
Class: Digestive enzymes
Form: Capsules
Ingredients: lipase, protease, amylase, colloidal silicon dioxide, croscarmellose sodium, hydrogenated castor oil, hypromellose phthalate, magnesium stearate, microcrystalline cellulose, talc, triethyl citrate

Description

ULTRESA is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, amylases, and proteases.

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

Each delayed-release capsule for oral administration contains enteric-coated beads (1.7 mm in diameter and 1.9 mm thick for 4,000 USP lipase units, approximately 2.0 mm in diameter and 2.0 – 2.4 mm thick for 13,800, 20,700, and 23,000 USP lipase units).

The active ingredient evaluated in clinical trials is lipase. ULTRESA is dosed by lipase units. Other active ingredients include protease and amylase.

ULTRESA contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydrogenated castor oil, hypromellose phthalate, magnesium stearate, microcrystalline cellulose, talc, and triethyl citrate.

4,000 USP units of lipase; 8,000 USP units of protease; 8,000 USP units of amylase. The hypromellose delayed-release capsules have a flesh opaque cap and blue opaque body, printed with “ULTRESA” on the cap and “4000” on the body in black ink. The capsule shell contains hypromellose, titanium dioxide, FD&C Blue 1, red iron oxide, and capsule imprint ink.

13,800 USP units of lipase; 27,600 USP units of protease; 27,600 USP units of amylase. The hard gelatin delayed-release capsules have a white cap and yellow body printed with “13800UL” on cap and “AXCA” on the body in black ink. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and capsule imprint ink.

20,700 USP units of lipase; 41,400 USP units of protease; 41,400 USP units of amylase. The hard gelatin delayed-release capsules have a gray cap and white body printed with “20700UL” on cap and “AXCA” on the body in black ink. The capsule shell contains gelatin, titanium dioxide, black iron oxide, and capsule imprint ink.

23,000 USP units of lipase; 46,000 USP units of protease; 46,000 USP units of amylase. The hard gelatin delayed-release capsules have a light gray cap and yellow body printed with “23000UL” on cap and “AXCA” on the body in black ink. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide, and capsule imprint ink.

The black radial imprinting on the capsule contains iron oxide black as colorant, shellac, and propylene glycol. It may also contain strong ammonia solution, and potassium hydroxide.

Clinical Pharmacology

Mechanism of Action

The pancreatic enzymes in ULTRESA 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Clinical Studies

The short-term efficacy and safety of ULTRESA were evaluated in 2 studies conducted in 40 patients, ages 7 to 37 years, with exocrine pancreatic insufficiency associated with cystic fibrosis.

Study 1 was a randomized, double-blind, placebo-controlled, crossover study of 31 patients, ages 8 to 37 years, with exocrine pancreatic insufficiency due to cystic fibrosis. 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 coefficient of fat absorption (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.

Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher no-treatment (placebo) CFA values. There were similar responses to ULTRESA by age and gender.

The coefficient of nitrogen absorption (CNA) was determined by a 72 hour stool collection during both treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated (based on the assumption that proteins contain 16% nitrogen). Each patient’s CNA during placebo treatment was used as their no treatment CNA value.

In Study 1, mean CNA was 84% with ULTRESA treatment compared to 59% with placebo treatment. The mean difference in CNA was 26 percentage points in favor of ULTRESA treatment with 95% CI: (18, 33) and p<0.0001.

Study 2 was an open-label study of 9 patients, ages 7 years to 11 years (mean 10 years), with exocrine pancreatic insufficiency due to cystic fibrosis. 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 in Study 2 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 coefficient of fat absorption (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.