Omeprazole

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Omeprazole

Dosage Form: Delayed release capsules

Omeprazole Description

The active ingredient in Omeprazole Delayed-Release Capsules is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C17H19N3O3S, with a molecular weight of 345.42. The structural formula is:

Omeprazole is a white to off-white crystalline powder which melts with decomposition at about 155° C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of Omeprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions.

Each delayed-release capsule, for oral administration, contains either 10 mg or 20 mg of Omeprazole in the form of enteric-coated microtablets. In addition, each capsule contains the following inactive ingredients: crospovidone, glyceryl behenate, hypromellose, lactose monohydrate, methacrylic acid copolymer dispersion, silicon dioxide, talc, titanium dioxide and triethyl citrate. The capsule shells have the following inactive ingredients: gelatin, titanium dioxide, sodium lauryl sulfate, synthetic black iron oxide, shellac glaze, and other inactive ingredients. In addition, the 20 mg capsule shells also contain yellow iron oxide.

This product meets USP Dissolution Test 2.

Omeprazole - Clinical Pharmacology

Pharmacokinetics and Metabolism: Omeprazole

Omeprazole Delayed-Release Capsules contain an enteric-coated microtablet formulation of Omeprazole (because Omeprazole is acid-labile), so that absorption of Omeprazole begins only after the microtablets leave the stomach. Absorption is rapid, with peak plasma levels of Omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of Omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared to intravenous administration) is about 30-40% at doses of 20-40 mg, due in large part to presystemic metabolism. In healthy subjects, the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500-600 mL/min. Protein binding is approximately 95%.

The bioavailability of Omeprazole increases slightly upon repeated administration of Omeprazole Delayed-Release Capsules.

Following single dose oral administration of a buffered solution of Omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyOmeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of Omeprazole. Three metabolites have been identified in plasma — the sulfide and sulfone derivatives of Omeprazole, and hydroxyOmeprazole. These metabolites have very little or no antisecretory activity.

In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared to an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared to the half-life in normals of 0.5-1 hour. Plasma clearance averaged 70 mL/min, compared to a value of 500-600 mL/min in normal subjects.

In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and
62 mL/min/1.73 m2, the disposition of Omeprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of Omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance.

The elimination rate of Omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of Omeprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of Omeprazole and no unchanged drug was detected. The plasma clearance of Omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers.

In pharmacokinetic studies of single 20 mg Omeprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared to Caucasians.

Dose adjustment, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired and Asian subjects should be considered.

Omeprazole Delayed-Release Capsule 40 mg was bioequivalent when administered with and without applesauce. However, Omeprazole Delayed-Release Capsule 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for Omeprazole Delayed-Release Capsule 20 mg. The clinical relevance of this finding is unknown.

The pharmacokinetics of Omeprazole have been investigated in pediatric patients of different ages.

Pharmacokinetic Parameters of Omeprazole Following Single and Repeated Oral Administration in Pediatric Populations Compared to Adults
*
Data from single and repeated dose studies
Data from a single and repeated dose study
Doses of 10, 20 and 40 mg Omeprazole
plasma concentration adjusted to an oral dose of 1 mg/kg.
Single or Children* Children* Adults
Repeated < 20 kg > 20 kg (mean 76 kg)
Oral Dosing 2-5 years 6-16 years 23-29 years
/Parameter 10 mg 20 mg (n=12)
Single Dosing
Cmax 288 (n=10) 495 (n=49) 668
(ng/mL)
AUC 511 (n=7) 1140 (n=32) 1220
(ng•h/mL)
Repeated Dosing
Cmax 539 (n=4) 851 (n=32) 1458
(ng/mL)
AUC 1179 (n=2) 2276 (n=23) 3352
(ng•h/mL)

Following comparable mg/kg doses of Omeprazole, younger children (2-5 years) have lower AUCs than children 6-16 years or adults; AUCs of the latter two groups did not differ. (See Dosage and Administration - Pediatric Patients.)

Pharmacokinetics: Combination Therapy with Antimicrobials

Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of Omeprazole were increased (Cmax, AUC0-24, and T1/2 increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin. The observed increases in Omeprazole plasma concentration were associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when Omeprazole was administered alone and 5.7 when co-administered with clarithromycin.

The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of Omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with Omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of Omeprazole.

Clarithromycin Tissue Concentrations 2 hours after Dose*
*
Mean ± SD (µg/g)

Tissue

Clarithromycin
Clarithromycin +
Omeprazole
Antrum 10.48 ± 2.01 (n = 5) 19.96 ± 4.71 (n = 5)
Fundus 20.81 ± 7.64 (n = 5) 24.25 ± 6.37 (n = 5)
Mucus 4.15 ± 7.74 (n = 4) 39.29 ± 32.79 (n = 4)

For information on clarithromycin pharmacokinetics and microbiology, consult the clarithromycin package insert, CLINICAL PHARMACOLOGY section.

The pharmacokinetics of Omeprazole, clarithromycin, and amoxicillin have not been adequately studied when all three drugs are administered concomitantly.

For information on amoxicillin pharmacokinetics and microbiology, see the amoxicillin package insert, ACTIONS, PHARMACOLOGY and MICROBIOLOGY sections.

Pharmacodynamics

Mechanism of Action

Omeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic properties, but that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, Omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, Omeprazole can be found within the gastric mucosa for a day or more.

Antisecretory Activity

After oral administration, the onset of the antisecretory effect of Omeprazole occurs within one hour, with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H+/K+ ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of Omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days.

Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of Omeprazole in normal volunteers and patients are shown below. The “max” value represents determinations at a time of maximum effect (2-6 hours after dosing), while “min” values are those 24 hours after the last dose of Omeprazole.

Range of Mean Values from Multiple Studies of the Mean Antisecretory Effects of Omeprazole After Multiple Daily Dosing
*
Single Studies
Parameter

Omeprazole

20 mg

Omeprazole

40 mg
% Decrease in
Basal Acid Output
Max
78*
Min
58-80
Max
94*
Min
80-93
% Decrease in
Peak Acid Output

79*

50-59

88*

62-68
% Decrease in
24-hr. Intragastric
Acidity

80-97


92-94

Single daily oral doses of Omeprazole ranging from a dose of 10 mg to 40 mg have produced 100% inhibition of 24-hour intragastric acidity in some patients.

Enterochromaffin-like (ECL) Cell Effects

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 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 3000 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. (See also CLINICAL PHARMACOLOGY, Pathological Hypersecretory Conditions.) However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of Omeprazole on the development of any premalignant or malignant conditions.

Serum Gastrin Effects

In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of Omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H2-receptor antagonists, the median increases produced by 20 mg doses of Omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy.

Other Effects

Systemic effects of Omeprazole in the CNS, cardiovascular and respiratory systems have not been found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin.

No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of Omeprazole 90 mg. In healthy subjects, a single I.V. dose of Omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans.

However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased.

As do other agents that elevate intragastric pH, Omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment.

The course of Barrett’s esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of Omeprazole 40 mg b.i.d. for 12 months followed by 20 mg b.i.d. for 12 months or ranitidine 300 mg b.i.d. for 24 months. No clinically significant impact on Barrett’s mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during anti-secretory therapy, complete elimination of Barrett’s mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett’s mucosa and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter (see also CLINICAL PHARMACOLOGY, Enterochromaffin-like (ECL) Cell Effects ).

Clinical Studies

Duodenal Ulcer Disease

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 20 mg once a day than with placebo (p ≤ 0.01).

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

Omeprazole

20 mg a.m.

Placebo

a.m.
(n=99) (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 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received Omeprazole 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 20 mg once a day than with ranitidine 150 mg b.i.d. (p <0.01).

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

Omeprazole

20 mg a.m.

Ranitidine

150 mg b.i.d.
(n=145) (n=148)
Week 2 42 34
Week 4 *82 63

Healing occurred significantly faster in patients treated with Omeprazole 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 were compared to 150 mg b.i.d. of ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of Omeprazole were statistically superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of Omeprazole, 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 Ranitidine
20 mg 40 mg 150 mg b.i.d.
(n=34)  (n=36) (n=35)
Week 2 *83 *83 53
Week 4 *97 *100 82
Week 8 100 100 94

H. pylori Eradication in Patients with Duodenal Ulcer Disease

Triple Therapy (Omeprazole/clarithromycin/amoxicillin)

Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared Omeprazole plus clarithromycin plus amoxicillin to clarithromycin plus amoxicillin. Two studies (126 and 127) were conducted in patients with an active duodenal ulcer, and the other study (M96-446) was conducted in patients with a history of a duodenal ulcer in the past
5 years but without an ulcer present at the time of enrollment. The dose regimen in the studies was Omeprazole 20 mg b.i.d. plus clarithromycin 500 mg b.i.d. plus amoxicillin 1 g b.i.d. for
10 days; or clarithromycin 500 mg b.i.d. plus amoxicillin 1 g b.i.d. for 10 days. In studies 126 and 127, patients who took the Omeprazole regimen also received an additional 18 days of Omeprazole 20 mg q.d. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (studies 126 and 127 only). H. pylori status was determined by CLOtest®, histology and culture in all three studies. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and none was positive.

The combination of Omeprazole plus clarithromycin plus amoxicillin was effective in eradicating H. pylori.

Per-Protocol and Intent-to-Treat H. pylori Eradication Rates % of Patients Cured [95% Confidence Interval]
*
Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 126 and 127; history of ulcer within 5 years, study M96-446) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest®, histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer.
Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.
(p <0.05) versus clarithromycin plus amoxicillin.

Omeprazole +Clarithromycin

+Amoxicillin
Clarithromycin +Amoxicillin
Per-Protocol * Intent-to-Treat Per-Protocol * Intent-to-Treat
Study 126

77 [64, 86]

(n=64)

69 [57, 79]

(n = 80)

43 [31, 56]

(n = 67)

37 [27, 48]

(n = 84)
Study 127

78 [67, 88]

(n = 65)

73 [61, 82]

(n = 77)

41 [29, 54]

(n = 68)

36 [26, 47]

(n = 83)
Study M96-446

90 [80, 96]

(n = 69)

83 [74, 91]

(n = 84)

33 [24, 44]

(n = 93)

32 [23, 42]

(n = 99)

Dual Therapy (Omeprazole/clarithromycin)

Four randomized, double-blind, multicenter studies (M93-067, M93-100, M92-812b, and M93-058) evaluated Omeprazole 40 mg q.d. plus clarithromycin 500 mg t.i.d. for 14 days, followed by Omeprazole 20 mg q.d. (M93-067, M93-100, M93-058) or by Omeprazole 40 mg q.d. (M92-812b) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Studies M93-067 and M93-100 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in Study M93-067 and 228 patients in Study M93-100. These studies compared the combination regimen to Omeprazole and clarithromycin monotherapies. Studies M92-812b and M93-058 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in study M92-812b and 208 patients in Study M93-058. These studies compared the combination regimen to Omeprazole monotherapy. The results for the efficacy analyses for these studies are described below. H. pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated of H. pylori. In the per-protocol analysis, the following patients were excluded: dropouts, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori eradication because they were found to have an ulcer at the end of treatment.

The combination of Omeprazole and clarithromycin was effective in eradicating H. pylori.

H. pylori Eradication Rates (Per-Protocol Analysis at 4 to 6 Weeks) % of Patients Cured [95% Confidence Interval]
*
Statistically significantly higher than clarithromycin monotherapy (p <0.05)
Statistically significantly higher than Omeprazole monotherapy (p <0.05)
Omeprazole + Clarithromycin Omeprazole Clarithromycin
U.S. Studies
Study M93-067 74 [60, 85]* 0 [0, 7] 31 [18, 47]
(n = 53) (n = 54) (n = 42)
Study M93-100 64 [51, 76]* 0 [0, 6] 39 [24, 55]
(n = 61) (n = 59) (n = 44)
Non U.S. Studies
Study M92-812b 83 [71, 92] 1 [0, 7] N/A
(n = 60) (n = 74)
Study M93-058 74 [64, 83] 1 [0, 6] N/A
(n = 86) (n = 90)

Ulcer healing was not significantly different when clarithromycin was added to Omeprazole therapy compared to Omeprazole therapy alone.

The combination of Omeprazole and clarithromycin was effective in eradicating H. pylori and reduced duodenal ulcer recurrence.

Duodenal Ulcer Recurrence Rates by H. pylori Eradication Status % of Patients with Ulcer Recurrence
*
H. pylori eradication status assessed at same timepoint as ulcer recurrence
Combined results for Omeprazole + clarithromycin, Omeprazole, and clarithromycin treatment arms
(p ≤ 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori eradicated
§
Combined results for Omeprazole + clarithromycin and Omeprazole treatment arms

H. pylori

eradicated*

H. pylori not

eradicated*
U.S. Studies
6 months post-treatment
Study M93-067 35 60
(n = 49) (n = 88)
Study M93-100 8 60
(n = 53) (n = 106)
Non U.S. Studies §
6 months post-treatment
Study M92-812b 5 46
(n = 43) (n = 78)
Study M93-058 6 43
(n = 53) (n = 107)
12 months post-treatment
Study M92-812b 5 68
(n = 39) (n = 71)

Gastric Ulcer

In a U.S., multicenter, double-blind study of Omeprazole 40 mg once a day, 20 mg once a day, and placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results were obtained.

Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated)
*
(p <0.01) Omeprazole 40 mg or 20 mg versus placebo
(p <0.05) Omeprazole 40 mg versus 20 mg

Omeprazole

20 mg q.d.

Omeprazole

40 mg q.d.
Placebo
(n=202) (n=214) (n=104)
Week 4 47.5* 55.6* 30.8
Week 8 74.8* 82.7* 48.1

For the stratified groups of patients with ulcer size less than or equal to 1 cm, no difference in healing rates between 40 mg and 20 mg was detected at either 4 or 8 weeks. For patients with ulcer size greater than 1 cm, 40 mg was significantly more effective than 20 mg at 8 weeks.

In a foreign, multinational, double-blind study of 602 patients with endoscopically diagnosed gastric ulcer, Omeprazole 40 mg once a day, 20 mg once a day, and ranitidine 150 mg twice a day were evaluated.

Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated)
*
(p <0.01) Omeprazole 40 mg versus ranitidine
(p <0.01) Omeprazole 40 mg versus 20 mg

Omeprazole

20 mg q.d.

Omeprazole

40 mg q.d.

Ranitidine

150 mg b.i.d.
(n=200) (n=187) (n=199)
Week 4 63.5 78.1* 56.3
Week 8 81.5 91.4* 78.4

Gastroesophageal Reflux Disease (GERD)

Symptomatic GERD

A placebo-controlled study was conducted in Scandinavia to compare the efficacy of Omeprazole
20 mg or 10 mg once daily for up to 4 weeks in the treatment of heartburn and other symptoms in GERD patients without erosive esophagitis. Results are shown below.

% Successful Symptomatic Outcome*
*
 Defined as complete resolution of heartburn
(p <0.005) versus 10 mg
 (p <0.005) versus placebo

Omeprazole

20 mg a.m.

Omeprazole

10 mg a.m.

Placebo

a.m.
All patients 46, 31 13
(n=205) (n=199) (n=105)
Patients with 56, 36 14
confirmed GERD (n=115) (n=109) (n=59)

Erosive Esophagitis

In a U.S., multicenter, double-blind, placebo-controlled study of 20 mg or 40 mg of Omeprazole in patients with symptoms of GERD and endoscopically diagnosed erosive esophagitis of grade 2 or above, the percentage healing rates (per protocol) were as follows:

*
(p <0.01) Omeprazole versus placebo
20 mg Omeprazole 40 mg Omeprazole Placebo
Week (n=83) (n=87) (n=43)
4 39* 45* 7
8 74* 75* 14

In this study, the 40 mg dose was not superior to the 20 mg dose of Omeprazole in the percentage healing rate. Other controlled clinical trials have also shown that Omeprazole is effective in severe GERD. In comparisons with histamine H2-receptor antagonists in patients with erosive esophagitis, grade 2 or above, Omeprazole in a dose of 20 mg was significantly more effective than the active controls. Complete daytime and nighttime heartburn relief occurred significantly faster (p <0.01) in patients treated with Omeprazole than in those taking placebo or histamine H2-receptor antagonists.

In this and five other controlled GERD studies, significantly more patients taking 20 mg Omeprazole (84%) reported complete relief of GERD symptoms than patients receiving placebo (12%).

Long Term Maintenance Treatment of Erosive Esophagitis

In a U.S., double-blind, randomized, multicenter, placebo-controlled study, two dose regimens of Omeprazole were studied in patients with endoscopically confirmed healed esophagitis. Results to determine maintenance of healing of erosive esophagitis are shown below.

Life Table Analysis
*
(p <0.01) Omeprazole 20 mg q.d. versus Omeprazole 20 mg 3 consecutive days per week or placebo.

Omeprazole

20 mg q.d.

Omeprazole

20 mg 3 days

per week
Placebo
(n=138) (n=137) (n=131)
Percent in endoscopic
remission at 6 months *70 34 11

In an international, multicenter, double-blind study, Omeprazole 20 mg daily and 10 mg daily were compared to ranitidine 150 mg twice daily in patients with endoscopically confirmed healed esophagitis. The table below provides the results of this study for maintenance of healing of erosive esophagitis.

Life Table Analysis
*
(p =0.01) Omeprazole 20 mg q.d. versus Omeprazole 10 mg q.d. or ranitidine.
(p =0.03) Omeprazole 10 mg q.d. versus ranitidine.

Omeprazole

20 mg q.d.

Omeprazole

10 mg q.d.

Ranitidine

150 mg b.i.d.
(n=131) (n=133) (n=128)
Percent in endoscopic
remission at 12 months *77 58 46

In patients who initially had grades 3 or 4 erosive esophagitis, for maintenance after healing, 20 mg daily of Omeprazole was effective, while 10 mg did not demonstrate effectiveness.

Pathological Hypersecretory Conditions

In open studies of 136 patients with pathological hypersecretory conditions, such as Zollinger-Ellison (ZE) syndrome with or without multiple endocrine adenomas, Omeprazole significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg every other day to 360 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery, and below 5 mEq/hr in patients with prior gastric surgery.

Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients (see DOSAGE AND ADMINISTRATION). Omeprazole was well tolerated at these high dose levels for prolonged periods (>5 years in some patients). In most ZE patients, serum gastrin levels were not modified by Omeprazole. However, in some patients, serum gastrin increased to levels greater than those present prior to initiation of Omeprazole therapy. At least 11 patients with ZE syndrome on long-term treatment with Omeprazole developed gastric carcinoids. These findings are believed to be a manifestation of the underlying condition, which is known to be associated with such tumors, rather than the result of the administration of Omeprazole. (See ADVERSE REACTIONS.)

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 as described in the INDICATIONS AND USAGE section.

Helicobacter
Helicobacter pylori

Pretreatment Resistance

Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the Omeprazole/clarithromycin dual therapy studies (M93-067, M93-100) and 9.3% (41/439) in Omeprazole/clarithromycin/amoxicillin triple therapy studies (126, 127, M96-446).

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 (126, 127, M96-446). 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®.

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 q.d./clarithromycin 500 mg t.i.d. for 14 days followed by Omeprazole 20 mg q.d. for another 14 days) (Studies M93-067, M93-100)
Susceptible 108 72 1 26 9
Intermediate 1 1
Resistant 4 4
Triple Therapy - (Omeprazole 20 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 10 days - Studies 126, 127, M96-446; followed by Omeprazole 20 mg q.d. for another 18 days - Studies 126, 127)
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.

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