Geriatric

The AUC and C_max values were slightly higher (25% and 18%, respectively) in the elderly as compared

to younger subjects at steady state. Dosage adjustment based on age is not necessary.

Pediatric

The pharmacokinetics of esomeprazole have not been studied in patients < 18 years of age.

Gender

The AUC and C_max values were slightly higher (13%) in females than in males at steady state. Dosage

adjustment based on gender is not necessary.

Hepatic Insufficiency

The steady state pharmacokinetics of esomeprazole obtained after administration of 40 mg once daily to 4 patients each with mild (Child Pugh A), moderate (Child Pugh Class B), and severe (Child Pugh Class C) liver insufficiency were compared to those obtained in 36 male and female GERD patients with normal liver function. In patients with mild and moderate hepatic insufficiency, the AUCs were within the range that could be expected in patients with normal liver function. In patients with severe hepatic insufficiency the AUCs were 2 to 3 times higher than in the patients with normal liver function. No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency (Child Pugh Classes A and B). However, in patients with severe hepatic insufficiency (Child Pugh Class C) a dose of 20 mg once daily should not be exceeded (See DOSAGE AND ADMINISTRATION).

Renal Insufficiency

The pharmacokinetics of esomeprazole in patients with renal impairment are not expected to be altered

relative to healthy volunteers as less than 1% of esomeprazole is excreted unchanged in urine.

Pharmacokinetics: Combination Therapy with Antimicrobials

Esomeprazole magnesium 40 mg once daily was given in combination with clarithromycin 500 mg twice daily and amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady state AUC and C_max of esomeprazole increased by 70% and 18%, respectively during triple combination therapy compared to treatment with esomeprazole alone. The observed increase in esomeprazole exposure during co-administration with clarithromycin and amoxicillin is not expected to produce significant safety concerns.

The pharmacokinetic parameters for clarithromycin and amoxicillin were similar during triple combination therapy and administration of each drug alone. However, the mean AUC and C_max for 14-hydroxyclarithromycin increased by 19% and 22%, respectively, during triple combination therapy compared to treatment with clarithromycin alone. This increase in exposure to 14-hydroxyclarithromycin is not considered to be clinically significant.

Pharmacodynamics

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 finaÅ? 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.

Antisecretory Activity

The effect of esomeprazole 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:

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

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, (% time with pH>4 was 68% or 16.3 hours).

Serum Gastrin Effects

The effect of NEXIUM on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6-12 months. The mean fasting gastrin level increased in a dose-related manner. This increase reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.

Enterochromaffin-like (ECL) Cell Effects

In 24-month carcinogenicity studies of omeprazole in rats, a dose-related significant occurrence of gastric ECL cell carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility). Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H₂-receptor antagonists.

Human gastric biopsy specimens have been obtained from more than 3,000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients.

In over 1,000 patients treated with NEXIUM (10, 20 or 40 mg/day) up to 6-12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.

NEXIUM had no effect on thyroid function when given in oraÅ? doses of 20 or 40 mg for 4 weeks. Other effects of NEXIUM on the endocrine system were assessed using omeprazole studies. Omeprazole given in oraÅ? doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin.

Microbiology

Esomeprazole magnesium, amoxicillin and clarithromycin triple therapy has been shown to be active against most strains of Helicobacter pylori (H. pylori) in vitro and in clinical infections as described in the Clinical Studies and INDICATIONS AND USAGE sections.

Helicobacter

Helicobacter pylori: Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology, and minimum inhibitory concentrations (MICs) were determined.

Pretreatment Resistance: Clarithromycin pretreatment resistance ratÄ? (MIC > 1 |lg/mL) to H. pylori was 15% (66/445) at baseline in all treatment groups combined. A total of > 99% (394/395) of patients had H. pylori isolates which were considered to be susceptible (MIC < 0.25 |ig/mL) to amoxicillin at baseline. One patient had a baseline H. pylori isolate with an amoxicillin MIC = 0.5 |lg/mL.

Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes: The baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results at the Day 38 visit are shown in the table below:

Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes ^a for Triple

Therapy - (Esomeprazole magnesium 40 mg once daily/amoxicillin 1000 mg twice daily/clarithromycin 500 mg twice daily for 10 days)

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes:

In the esomeprazole magnesium/amoxicillin/clarithromycin clinical trials, 83% (176/212) of the patients in the esomeprazole magnesium/amoxicillin/clarithromycin treatment group who had pretreatment amoxicillin susceptible MICs (< 0.25 |ig/mL) were eradicated of H. pylori, and 17% (36/212) were not eradicated of H. pylori. Of the 36 patients who were not eradicated of H. pylori on triple therapy, 16 had no post-treatment susceptibility test results and 20 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Fifteen of the patients who were not eradicated of H. pylori on triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. There were no patients with H. pylori isolates who developed treatment emergent resistance to amoxicillin.

Susceptibility Test for Helicobacter pylori: The reference methodology for susceptibility testing of H. pylori is agar dilution MICs. One to three microliters of an inoculum equivalent to a No.2 McFarland standard (1 x 10⁷ - 1 x 10⁸ CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (> 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent reÄ?uired to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

These are breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative methods.

There were not enough organisms with MICs > 0.25 µg/mL to determine a resistance breakpoint.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:

^a These are Ä?uality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.