ESOMEPRAZOLE STRONTIUM (Page 5 of 6)

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.

16.HOW SUPPLIED/STORAGE AND HANDLING

Esomeprazole strontium delayed-release capsules, 24.65 mg (equivalent to 20 mg of esomeprazole), are hard capsules with light pink cap and body containing off-white to pale brown granules with HMP 20 printed in black ink.

They are available as follows:

Unit of use bottles of 30 NDC 70849-200-30

Esomeprazole strontium delayed-release capsules, 49.3 mg (equivalent to 40 mg of esomeprazole), are hard capsules with dark pink cap and body containing off-white to pale brown granules with HMP 40 printed in black ink.

They are available as follows:

Unit of use bottles of 30 NDC 70849-400-30

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Keep esomeprazole strontium delayed-release capsules container tightly closed. Dispense in a tight container if the esomeprazole strontium delayed-release capsules product package is subdivided.

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:

TABLE6
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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:

table7
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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:

FIGURE2

FIGURE2
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FIGURE3

FIGURE3
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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.


14.2 Symptomatic Gastroesophageal Reflux Disease (GERD)
Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 717 patients comparing four weeks of treatment with 22.3 mg or 44.6 mg of esomeprazole magnesium (equivalent to 20 mg or 40 mg of esomeprazole, respectively) once daily versus placebo for resolution of GERD symptoms. Patients had ≥ 6-month history of heartburn episodes, no erosive esophagitis by endoscopy, and heartburn on at least four of the seven days immediately preceding randomization.


The percentage of patients that were symptom-free of heartburn was significantly higher in the esomeprazole magnesium groups compared to placebo at all follow-up visits (Weeks 1, 2, and 4).


No additional clinical benefit was seen with esomeprazole magnesium 44.6 mg over esomeprazole magnesium 22.3 mg. The percent of patients symptom-free of heartburn by day are shown in the Figures 4 and 5:

Figure4

figure4
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Figure5

figure5
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In three European symptomatic GERD trials, esomeprazole magnesium 22.3 mg and 44.6 mg and omeprazole 20 mg were evaluated. No significant treatment related differences were seen.


14.3 Risk Reduction of NSAID-Associated Gastric Ulcer Two multicenter, double-blind, placebo-controlled studies were conducted in patients at risk of developing gastric and/or duodenal ulcers associated with continuous use of non-selective and COX-2 selective NSAIDs. A total of 1429 patients were randomized across the 2 studies. Patients ranged in age from 19 to 89 (median age 66.0 years) with 70.7% female, 29.3% male, 82.9% Caucasian, 5.5% Black, 3.7% Asian, and 8% Others. At baseline, the patients in these studies were endoscopically confirmed not to have ulcers but were determined to be at risk for ulcer occurrence due to their age (≥60 years) and/or history of a documented gastric or duodenal ulcer within the past 5 years. Patients receiving NSAIDs and treated with 22.3 mg or 44.6 mg of esomeprazole magnesium (equivalent to 20 mg or 40 mg of esomeprazole, respectively) once a day experienced significant reduction in gastric ulcer occurrences relative to placebo treatment at 26 weeks. See Table 8. No additional benefit was seen with esomeprazole magnesium 44.6 mg over esomeprazole magnesium 22.3 mg. These studies did not demonstrate significant reduction in the development of NSAID-associated duodenal ulcer. The incidence of duodenal ulcers in these trials was low.

table8
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14.4 Helicobacter pylori (H. pylori) Eradication in Patients with Duodenal Ulcer Disease Triple Therapy (esomeprazole magnesium/amoxicillin/clarithromycin): Two multicenter, randomized, double-blind studies were conducted using a 10 day treatment regimen. The first study (191) compared 44.6 mg of esomeprazole magnesium (equivalent to 40 mg of esomeprazole) once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to 44.6 mg of esomeprazole magnesium once daily plus clarithromycin 500 mg twice daily. The second study (193) compared 44.6 mg of esomeprazole magnesium once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to 44.6 mg of esomeprazole magnesium once daily. H. pylori eradication rates, defined as at least two negative tests and no positive tests from CLOtest®, histology and/or culture at 4 weeks post-therapy, were significantly higher in the esomeprazole magnesium plus amoxicillin and clarithromycin group than in the esomeprazole magnesium plus clarithromycin or esomeprazole magnesium alone group. The results are shown in Table 9:

table9
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The percentage of patients with a healed baseline duodenal ulcer by 4 weeks after the 10 day treatment regimen in the esomeprazole magnesium plus amoxicillin and clarithromycin group was 75% (n=156) and 57% (n=60) respectively, in the studies 191 and 193 (per-protocol analysis).


14.5 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome In a multicenter, open-label dose-escalation study of 21 patients (15 males and 6 females, 18 Caucasian and Black, mean age of 55.5 years) with pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome, esomeprazole magnesium significantly inhibited gastric acid secretion. Initial dose was 44.6 mg of esomeprazole magnesium (equivalent to 40 mg of esomeprazole) twice daily in 19/21 patients and 89.2 mg of esomeprazole magnesium (equivalent to 80 mg of esomeprazole) twice daily in 2/21 patients. Total daily esomeprazole magnesium doses ranging from 89.2 mg to 267.6 mg (equivalent to 240 mg of esomeprazole) for 12 months maintained gastric acid output below the target levels of 10 mEq/h in patients without prior gastric acid-reducing surgery and below 5 mEq/hr in patients with prior gastric acid-reducing surgery. At the Month 12 final visit, 18/20 (90%) patients had Basal Acid Output (BAO) under satisfactory control (median BAO = 0.17 mmol/hr). Of the 18 patients evaluated with a starting dose of 40 mg twice daily, 13 (72%) had their BAO controlled with the original dosing regimen at the final visit. See Table 10.

table10
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