Figure 1

The magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of solvation and is slightly soluble in water. The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium salt is about 19 hours at 25°C and about 8 hours at 37°C.

NEXIUM is supplied in delayed-release capsules and in packets for a delayed-release oral suspension. Each delayed-release capsule contains 20 mg, or 40 mg of esomeprazole (present as 22.3 mg, or 44.5 mg esomeprazole magnesium trihydrate) in the form of enteric-coated granules with the following inactive ingredients: glyceryl monostearate 40-55, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, and triethyl citrate. The capsule shells have the following inactive ingredients: gelatin, FD&C Blue #1, FD&C Red #40, D&C Red #28, titanium dioxide, shellac, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, sodium hydroxide, polyvinyl pyrrolidone, and D&C Yellow #10.

Each packet of NEXIUM For Delayed-Release Oral Suspension contains 10 mg, 20 mg, or 40 mg of esomeprazole, in the form of the same enteric-coated granules used in NEXIUM Delayed-Release Capsules, and also inactive granules. The inactive granules are composed of the following ingredients: dextrose, xanthan gum, crospovidone, citric acid, iron oxide, and hydroxypropyl cellulose. The esomeprazole granules and inactive granules are constituted with water to form a suspension and are given by oral, nasogastric, or gastric administration.

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion.

12.2 Pharmacodynamics
Antisecretory Activity

The effect of NEXIUM on intragastric pH was determined in patients with symptomatic gastroesophageal reflux disease in two separate studies. In the first study of 36 patients, NEXIUM 40 mg and 20 mg capsules were administered over 5 days. The results are shown in the following table:

Table 3

Effect on Intragastric pH on Day 5 (N=36)

 *
Gastric pH was measured over a 24-hour period
†
p< 0.01 NEXIUM 40 mg vs. NEXIUM 20 mg
Parameter
 NEXIUM

40 mg
 NEXIUM

20 mg
 
% Time Gastric pH >4*(Hours)
 70%†

(16.8 h)
 53%

(12.7 h)
 
Coefficient of variation
 26%
 37%
 
Median 24 Hour pH
 4.9†
 4.1
 
Coefficient of variation
 16%
 27%
 

In a second study, the effect on intragastric pH of NEXIUM 40 mg administered once daily over a five day period was similar to the first study, (% tim