Prescription Drug Information: Esomeprazole Strontium (Page 5 of 8)

12.4 Microbiology

Esomeprazole, 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 [see Indications and Usage (1) and Clinical Studies (14)].

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 rate (MIC ≥1 mcg/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 that were considered to be susceptible (MIC ≤0.25 mcg/mL) to amoxicillin at baseline. One patient had a baseline H. pylori isolate with an amoxicillin MIC = 0.5 mcg/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 Table 5:

Table 5: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes a for Triple Therapy — (esomeprazole magnesium 44.6 mg# once daily/amoxicillin 1000 mg twice daily/clarithromycin 500 mg twice daily for 10 days)

Clarithromycin Pretreatment Results

H. pylori negative (Eradicated)

H. pylori positive (Not Eradicated) Post-treatment susceptibility results

Sb

Ib

Rb

No MIC

Susceptibleb 182

162

4

0

2

14

Intermediateb 1

1

0

0

0

0

Resistantb 29

13

1

0

13

2

a Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test results
b Susceptible (S) MIC ≤0.25 mcg/mL, Intermediate (I) MIC = 0.5 mcg/mL, Resistant (R) MIC ≥1.0 mcg/mL
# 44.6 mg of esomeprazole magnesium is equivalent to 40 mg of esomeprazole

Patients not eradicated of H. pylori following esomeprazole magnesium/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, when possible. Patients with clarithromycin resistant H. pylori should not be re-treated with a clarithromycin-containing regimen.

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 mcg/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: For susceptibility testing information about Helicobacter pylori , see Microbiology section in prescribing information for clarithromycin and amoxicillin.

Effects on Gastrointestinal Microbial Ecology: Decreased gastric acidity due to any means, including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile in hospitalized patients.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of esomeprazole was assessed using studies of omeprazole, of which esomeprazole is an enantiomer. In two 24-month oral carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44, and 141 mg/kg/day (about 0.7 to 57 times the human dose of 20 mg/day expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 5.6 times the human dose on a body surface area basis) for 1 year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of 1 year (94% treated vs. 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for 2 years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive.

Esomeprazole strontium was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Esomeprazole magnesium, however, was positive in the in vitro human lymphocyte chromosome aberration test. Omeprazole was positive in the in vitro human lymphocyte chromosome aberration test, the in vivo mouse bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test.

The potential effects of esomeprazole strontium on fertility and reproductive performance were not directly studied. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 33.6 times the daily MRHD of 40 mg on a body surface area basis) was found to have no effect on reproductive performance of parental animals.

13.2 Animal Toxicology and/or Pharmacology

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole strontium or esomeprazole magnesium at equimolar oral doses of 70 to 280 mg esomeprazole/kg/day (about 17 to 57 times the daily MRHD of 40 mg on a body surface area basis). When administered as either the strontium or magnesium salt from postnatal day 7 through postnatal day 35, the dose of 280 mg esomeprazole/kg/day produced an increase in the number of deaths. In addition, when administered as either the strontium or magnesium salt, doses equal to or greater than 140 mg esomeprazole/kg/day (about 34 times the daily MRHD of 40 mg on a body surface area basis) produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth.

14 CLINICAL STUDIES

The safety and efficacy of esomeprazole strontium has been established based on adequate and well-controlled adult studies of esomeprazole magnesium in the healing and maintenance of erosive esophagitis, symptomatic GERD, risk reduction of NSAID-associated gastric ulcer, H. pylori eradication to reduce the risk of duodenal ulcer recurrence, and pathological hypersecretory conditions including Zollinger-Ellison Syndrome. Below is a display of the results of the adequate and well-controlled studies of esomeprazole magnesium in these conditions.

14.1 Healing of Erosive Esophagitis

The healing rates of 44.6 mg of esomeprazole magnesium (equivalent to 40 mg of esomeprazole), 22.3 mg of esomeprazole magnesium (equivalent to 20 mg of esomeprazole), and 20 mg of omeprazole (the approved dose for this indication) were evaluated in patients with endoscopically diagnosed erosive esophagitis in four multicenter, double-blind, randomized studies. The healing rates at Weeks 4 and 8 were evaluated and are shown in Table 6:

Table 6: Erosive Esophagitis Healing Rate (Life-Table Analysis)

Study

No. of Patients

Treatment Groups

Week 4

Week 8

Significance Level*

1

588

Esomeprazole magnesium 22.3 mg

68.7%

90.6%

N.S.

588

Omeprazole 20 mg

69.5%

88.3%

2

654

Esomeprazole magnesium 44.6 mg

75.9%

94.1%

p < 0.001

656

Esomeprazole magnesium 22.3 mg

70.5%

89.9%

p < 0.05

650

Omeprazole 20 mg

64.7%

86.9%

3

576

Esomeprazole magnesium 44.6 mg

71.5%

92.2%

N.S.

572

Omeprazole 20 mg

68.6%

89.8%

4

1216

Esomeprazole magnesium 44.6 mg

81.7%

93.7%

p < 0.001

1209

Omeprazole 20 mg

68.7%

84.2%

* log-rank test vs. omeprazole 20 mg

N.S. = not significant (p >0.05)

In these same studies of patients with erosive esophagitis, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in Table 7:

Table 7: Sustained Resolution of Heartburn (Erosive Esophagitis Patients)

Cumulative Percent# with Sustained Resolution

Study

No. of Patients

Treatment Groups

Day 14

Day 28

Significance Level*

1

573

Esomeprazole magnesium 22.3 mg

64.3%

72.7%

N.S.

555

Omeprazole 20 mg

64.1%

70.9%

2

621

Esomeprazole magnesium 44.6 mg

64.8%

74.2%

p <0.001

620

Esomeprazole magnesium 22.3 mg

62.9%

70.1%

N.S.

626

Omeprazole 20 mg

56.5%

66.6%

3

568

Esomeprazole magnesium 44.6 mg

65.4%

73.9%

N.S.

551

Omeprazole 20 mg

65.5%

73.1%

4

1187

Esomeprazole magnesium 44.6 mg

67.6%

75.1%

p <0.001

1188

Omeprazole 20 mg

62.5%

70.8%

Defined as 7 consecutive days with no heartburn reported in daily patient diary.

# Defined as the cumulative proportion of patients who have reached the start of sustained resolution

* log-rank test vs omeprazole 20 mg

N.S. = not significant (p > 0.05)

In these four studies, the range of median days to the start of sustained resolution (defined as 7 consecutive days with no heartburn) was 5 days for esomeprazole magnesium 44.6 mg, 7 to 8 days for esomeprazole magnesium 22.3 mg and 7 to 9 days for omeprazole 20 mg.

There are no comparisons of 44.6 mg of esomeprazole magnesium with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of erosive esophagitis.

Long-Term Maintenance of Healing of Erosive Esophagitis

Two multicenter, randomized, double-blind placebo-controlled 4-arm trials were conducted in patients with endoscopically confirmed, healed erosive esophagitis to evaluate esomeprazole magnesium 44.6 mg (n=174), 22.3 mg (n=180), 11.15 mg (n=168) or placebo (n=171) once daily over six months of treatment.

No additional clinical benefit was seen with esomeprazole magnesium 44.6 mg over esomeprazole magnesium 22.3 mg.

The percentages of patients that maintained healing of erosive esophagitis at the various time points are shown in the Figures 2 and 3:

Figure 2: Maintenance of Healing Rates by Month (Study 177) — Esomeprazole Magnesium

figure2
(click image for full-size original)

s = scheduled visit

Figure 3: Maintenance of Healing Rates by Month (Study 178) — Esomeprazole Magnesium

figure3
(click image for full-size original)

s= scheduled visit

Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with esomeprazole magnesium compared to placebo.

In both studies, the proportion of patients on esomeprazole magnesium who remained in remission and were free of heartburn and other GERD symptoms was well differentiated from placebo.

In a third multicenter open label study of 808 patients treated for 12 months with esomeprazole magnesium 44.6 mg, the percentage of patients that maintained healing of erosive esophagitis was 93.7% for six months and 89.4% for one year.

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