Prilosec: Package Insert and Label Information (Page 5 of 8)

12.4 Microbiology

Omeprazole and clarithromycin dual therapy and omeprazole, clarithromycin and amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections [see Indications and Usage (1.2), Clinical Studies (14.2)].

Helicobacter pylori

Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology1 , and minimum inhibitory concentrations (MICs) were determined.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.

Pretreatment Resistance

Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3% (41/439) in omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2 and 3).

Amoxicillin pretreatment susceptible isolates (≤ 0.25 µg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 µg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin and amoxicillin study arm. One patient had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 µg/mL by Etest®.

Table 8: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes
*
Includes only patients with pretreatment clarithromycin susceptibility test results.
Susceptible (S) MIC ≤ 0.25 μg/mL, Intermediate (I) MIC 0.5-1.0 μg/mL, Resistant (R) MIC ≥ 2 μg/mL.

Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes *

Clarithromycin Pretreatment Results

Clarithromycin Post-treatment Results

H. pylori negative – eradicated

H. pylori positive – not eradicated

Post-treatment susceptibility results

S

I

R

No MIC

Dual Therapy – (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed by omeprazole 20 mg once daily for another 14 days) (Studies 4, 5)

Susceptible

108

72

1

26

9

Intermediate

1

1

Resistant

4

4

Triple Therapy – (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice daily for 10 days – Studies 1, 2, 3; followed by omeprazole 20 mg once daily for another 18 days – Studies 1, 2)

Susceptible

171

153

7

3

8

Intermediate

Resistant

14

4

1

6

3

Patients not eradicated of H. pylori following omeprazole/clarithromycin/amoxicillin triple therapy or omeprazole/clarithromycin dual therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy, omeprazole/clarithromycin/amoxicillin triple therapy, or other regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the triple therapy clinical trials, 84.9% (157/185) of the patients in the omeprazole/clarithromycin/amoxicillin treatment group who had pretreatment amoxicillin susceptible MICs (≤ 0.25 µg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs.

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, in hospitalized patients, possibly also Clostridium difficile.

12.5 Pharmacogenomics

CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole. The CYP2C19*1 allele is fully functional while the CYP2C19*2 and *3 alleles are nonfunctional. There are other alleles associated with no or reduced enzymatic function. Patients carrying two fully functional alleles are extensive metabolizers and those carrying two loss-of-function alleles are poor metabolizers. In extensive metabolizers, omeprazole is primarily metabolized by CYP2C19. The systemic exposure to omeprazole varies with a patient’s metabolism status: poor metabolizers > intermediate metabolizers > extensive metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers.

In a pharmacokinetic study of single 20 mg omeprazole dose, the AUC of omeprazole in Asian subjects was approximately four-fold of that in Caucasians [see Dosage and Administration (2.1), Use in Specific Populations (8.7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.4 to 34 times a human dose of 40 mg/day, as 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 a human dose of 40 mg/day, based on body surface area) for one year, and 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 one 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 two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.9 times the human dose of 40 mg/day, based on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay.

Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times an oral human dose of 40 mg on a body surface area basis) was found to have no effect on fertility and reproductive performance.

In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [see Warnings and Precautions (5)]. 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.

14 CLINICAL STUDIES

14.1 Active Duodenal Ulcer

In a multicenter, double-blind, placebo-controlled study of 147 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 2 and 4 weeks was significantly higher with omeprazole magnesium delayed-release capsules 20 mg once daily than with placebo (p ≤ 0.01).

Treatment of Active Duodenal Ulcer % of Patients Healed
*
(p≤0.01)

omeprazole magnesium delayed-release capsules

20 mg a.m.

(n=99)

Placebo

a.m.

(n=48)

Week 2

41*

13

Week 4

75*

27

Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated with omeprazole magnesium delayed-release capsules 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received omeprazole magnesium delayed-release capsules had complete relief of daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01).

In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 4 weeks was significantly higher with omeprazole magnesium delayed-release capsules 20 mg once daily than with ranitidine 150 mg b.i.d. (p < 0.01).

Treatment of Active Duodenal Ulcer % of Patients Healed
*
(p < 0.01)

omeprazole magnesium delayed-release capsules

20 mg a.m.

(n = 145)

Ranitidine

150 mg twice daily

(n = 148)

Week 2

42

34

Week 4

82*

63

Healing occurred significantly faster in patients treated with omeprazole magnesium delayed-release capsules than in those treated with ranitidine 150 mg b.i.d. (p < 0.01).

In a foreign multinational, randomized, double-blind study of 105 patients with endoscopically documented duodenal ulcer, 20 mg and 40 mg of omeprazole magnesium delayed-release capsules were compared with 150 mg b.i.d. of ranitidine at 2, 4, and 8 weeks. At 2 and 4 weeks, both doses of PRILOSEC were statistically superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of omeprazole magnesium delayed-release capsules, and at 8 weeks there was no significant difference between any of the active drugs.

Treatment of Active Duodenal Ulcer % of Patients Healed
*
(p ≤ 0.01)

omeprazole magnesium delayed-release capsules

Ranitidine

20 mg

(n = 34)

40 mg

(n = 36)

150 mg twice daily

(n = 35)

Week 2

83*

83*

53

Week 4

97*

100*

82

Week 8

100

100

94

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