Prescription Drug Information: Esomeprazole Magnesium (Page 6 of 9)

12.4 Microbiology

Esomeprazole magnesium delayed-release capsules, 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 the Table 8:

Table 8: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes 1 for Triple Therapy — (Esomeprazole magnesium 40 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
S 2 I 2 R 2 No MIC
Susceptible 2 182 162 4 0 2 14
Intermediate 2 1 1 0 0 0 0
Resistant 2 29 13 1 0 13 2

1. Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test results

2. Susceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC = 0.5 mcg/mL, Resistant (R) MIC ≥ 1 mcg/mL

Patients not eradicated of H. pylori following esomeprazole magnesium delayed-release capsules/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 delayed-release capsules/amoxicillin/clarithromycin clinical trials, 83% (176/212) of the patients in the esomeprazole magnesium delayed-release capsules/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 magnesium delayed-release capsules 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 140.8 mg/kg/day (about 0.4 to 34 times the human dose of 40 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 3.4 times the human dose of 40 mg/day 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 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, 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 on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times the human dose of 40 mg/day 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

Reproduction Studies

Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole [see Use in Specific Populations (8.1)].

Juvenile Animal Study

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 68 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose 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. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

14 CLINICAL STUDIES

14.1 Healing of Erosive Esophagitis

The healing rates of esomeprazole magnesium delayed-release capsules 40 mg, esomeprazole magnesium delayed-release capsules 20 mg, and omeprazole 20 mg (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 the Table 9:

Table 9: Erosive Esophagitis Healing Rate (Life-Table Analysis)
Study No. of Patients Treatment Groups Week 4 Week 8 Significance Level 1
1 588 Esomeprazole magnesium delayed-release capsules 20 mg 68.7% 90.6% N.S.
588 Omeprazole 20 mg 69.5% 88.3%
2 654 Esomeprazole magnesium delayed-release capsules 40 mg 75.9% 94.1% p < 0.001
656 Esomeprazole magnesium delayed-release capsules 20 mg 70.5% 89.9% p < 0.05
650 Omeprazole 20 mg 64.7% 86.9%
3 576 Esomeprazole magnesium delayed-release capsules 40 mg 71.5% 92.2% N.S.
572 Omeprazole 20 mg 68.6% 89.8%
4 1216 Esomeprazole magnesium delayed-release capsules 40 mg 81.7% 93.7% p < 0.001
1209 Omeprazole 20 mg 68.7% 84.2%

1. 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 the Table 10:

Table 10: Sustained Resolution 1 of Heartburn (Erosive Esophagitis Patients)
Study No. of Patients Treatment Groups Cumulative Percent 2 with Sustained Resolution Significance Level 3
Day 14 Day 28
1 573 Esomeprazole magnesium delayed-release capsules 20 mg 64.3% 72.7% N.S.
555 Omeprazole 20 mg 64.1% 70.9%
2 621 Esomeprazole magnesium delayed-release capsules 40 mg 64.8% 74.2% p < 0.001
620 Esomeprazole magnesium delayed-release capsules 20 mg 62.9% 70.1% N.S.
626 Omeprazole 20 mg 56.5% 66.6%
3 568 Esomeprazole magnesium delayed-release capsules 40 mg 65.4% 73.9% N.S.
551 Omeprazole 20 mg 65.5% 73.1%
4 1187 Esomeprazole magnesium delayed-release capsules 40 mg 67.6% 75.1% p < 0.001
1188 Omeprazole 20 mg 62.5% 70.8%

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

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

3. 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 delayed-release capsules 40 mg, 7 to 8 days for esomeprazole magnesium delayed-release capsules 20 mg and 7 to 9 days for omeprazole 20 mg.

There are no comparisons of 40 mg of esomeprazole magnesium delayed-release capsules 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 40 mg (n=174), 20 mg (n=180), 10 mg (n=168) or placebo (n=171) once daily over six months of treatment.

No additional clinical benefit was seen with esomeprazole magnesium delayed-release capsules 40 mg over esomeprazole magnesium delayed-release capsules 20 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)
(click image for full-size original)

Figure 3: Maintenance of Healing Rates by Month (Study 178)
(click image for full-size original)

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

In both studies, the proportion of patients on esomeprazole magnesium delayed-release capsules 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 delayed-release capsules 40 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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