"The U.S. Food and Drug Administration today approved the first generic versions of Aciphex (rabeprazole sodium) delayed-release tablets, used to treat gastroesophageal reflux disease (GERD) in adults and adolescents (ages 12 and up).
Mechanism Of Action
Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, 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.
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.
Table 1 : Range of Mean Values from Multiple Studies
of the Mean Antisecretory Effects of Omeprazole After Multiple Daily Dosing
|Parameter||Omeprazole 20 mg||Omeprazole 40 mg|
|% Decrease in Basal Acid Output||78*||58-80||94*||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.
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.
Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.
Enterochromaffin-like (ECL) Cell Effects
Human gastric biopsy specimens have been obtained from more than 3000 patients (both children and adults) 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. 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.
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 PRILOSEC 40 mg twice daily for 12 months followed by 20 mg twice daily for 12 months or ranitidine 300 mg twice daily for 24 months. No clinically significant impact on Barrett's mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during antisecretory 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.
PRILOSEC Delayed-Release Capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules 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 with 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.
Based on a relative bioavailability study, the AUC and Cmax of PRILOSEC (omeprazole magnesium) for Delayed-Release Oral Suspension were 87% and 88% of those for PRILOSEC Delayed-Release Capsules, respectively.
The bioavailability of omeprazole increases slightly upon repeated administration of PRILOSEC Delayed-Release Capsules.
PRILOSEC Delayed-Release Capsule 40 mg was bioequivalent when administered with and without applesauce. However, PRILOSEC 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 PRILOSEC Delayed-Release Capsule 20 mg. The clinical relevance of this finding is unknown.
Protein binding is approximately 95%.
Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system.
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.
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 C max 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 C min 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.
Table 2 : Clarithromycin Tissue Concentrations 2 hours
|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)|
|1Mean ± SD (μg/g)|
Concomitant Use with Clopidogrel
In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together.
Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period.
In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction.
Concomitant Use with Mycophenolate Mofetil
Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA.
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.
The pharmacokinetics of omeprazole have been investigated in pediatric patients 2 to 16 years of age:
Table 3 : Pharmacokinetic Parameters of Omeprazole
Following Single and Repeated Oral Administration in Pediatric Populations
Compared with Adults
|Single or Repeated Oral Dosing/Parameter||Children† ≤ 20 kg 2-5 years10 mg||Children† > 20 kg 6-16 years 20 mg||Adults‡ (mean76 kg) 23-29 years
|Note: * = plasma concentration
adjusted to an oral dose of 1 mg/kg.
†Data from single and repeated dose studies
‡Data from a single and repeated dose study Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules
Following comparable mg/kg doses of omeprazole, younger children (2 to 5 years of age) have lower AUCs than children 6 to 16 years of age or adults; AUCs of the latter two groups did not differ [see DOSAGE AND ADMINISTRATION].
In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared with an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in normals of 0.5-1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500-600 mL/min in normal subjects. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired should be considered.
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. No dose reduction is necessary in patients with renal impairment.
In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared with Caucasians. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for Asian subjects should be considered.
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 (1.1).
Helicobacter pylori-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 4 : Clarithromycin Susceptibility Test Results
and Clinical/Bacteriological Outcomes
|Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomesa|
|Clarithromycin Pretreatment Results||Clarithromycin Post-treatment Results|
|H. pylori negative -eradicated||H. pylori positive – not eradicated|
|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)|
|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)|
|aIncludes only patients with pretreatment clarithromycin
susceptibility test results
bSusceptible (S) MIC ≤ 0.25 μg/mL, Intermediate (I) MIC 0.5 – 1.0 μg/mL, Resistant (R) MIC ≥ 2 μg/mL
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.
Animal Toxicology And/Or Pharmacology
Reproductive Toxicology Studies
Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 34 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times the human dose of 40 mg/day on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 3.4 to 34 times the human dose of 40 mg/day on a body surface area basis) [see Pregnancy, Animal Data].
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.
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 PRILOSEC 20 mg once daily than with placebo (p ≤ 0.01).
Treatment of Active Duodenal
Ulcer % of Patients Healed
PRILOSEC 20 mg a.m.
(n = 48)
|*(p ≤ 0.01)|
Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated with PRILOSEC 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received PRILOSEC 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 PRILOSEC 20 mg once daily than with ranitidine 150 mg b.i.d. (p < 0.01).
Treatment of Active Duodenal
Ulcer % of Patients Healed
|PRILOSEC 20 mg a.m.
(n = 145)
|Ranitidine 150 mg twice daily
(n = 148)
|*(p < 0.01)|
Healing occurred significantly faster in patients treated with PRILOSEC 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 PRILOSEC 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 PRILOSEC, and at 8 weeks there was no significant difference between any of the active drugs.
Treatment of Active Duodenal
Ulcer % of Patients Healed
|PRILOSEC||Ranitidine 150 mg twice daily
(n = 35)
(n = 34)
(n = 36)
|*(p ≤ 0.01)|
H. pylori Eradication in Patients with Duodenal Ulcer Disease
Triple Therapy (PRILOSEC/clarithromycin/amoxicillin)— Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared PRILOSEC plus clarithromycin plus amoxicillin with clarithromycin plus amoxicillin. Two studies (1 and 2) were conducted in patients with an active duodenal ulcer, and the other study (3) 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 PRILOSEC 20 mg twice daily plus clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days. In studies 1 and 2, patients who took the omeprazole regimen also received an additional 18 days of PRILOSEC 20 mg once daily. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (studies 1 and 2 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.
Table 5 : Per-Protocol and
Intent-to-Treat H. pylori Eradication Rates % of Patients Cured [95%
|PRILOSEC +clarithromycin +amoxicillin||Clarithromycin +amoxicillin|
|Per-Protocol †||Intent-to-Treat‡||Per-Protocol †||Intent-to-Treat‡|
|Study 1||*77 [64, 86]||*69 [57, 79]||43 [31, 56]||37 [27, 48]|
|(n = 64)||(n = 80)||(n = 67)||(n = 84)|
|Study 2||*78 [67, 88]||*73 [61, 82]||41 [29, 54]||36 [26, 47]|
|(n = 65)||(n = 77)||(n = 68)||(n = 83)|
|Study 3||*90 [80, 96]||*83 [74, 91]||33 [24, 44]||32 [23, 42]|
|(n = 69)||(n = 84)||(n = 93)||(n = 99)|
|† Patients were included in the
analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 1
and 2; history of ulcer within 5 years, study 3) 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.
Dual Therapy (PRILOSEC/clarithromycin)
Four randomized, double-blind, multi-center studies (4, 5, 6, and 7) evaluated PRILOSEC 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days, followed by PRILOSEC 20 mg once daily, (Studies 4, 5, and 7) or by PRILOSEC 40 mg once daily (Study 6) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Studies 4 and 5 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 4 and 228 patients in Study 5. These studies compared the combination regimen to PRILOSEC and clarithromycin monotherapies. Studies 6 and 7 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in Study 6 and 208 patients in Study 7. These studies compared the combination regimen with 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.
Table 6 : H. pylori Eradication Rates
(Per-Protocol Analysis at 4 to 6 Weeks) % of Patients Cured [95% Confidence
|PRILOSEC + Clarithromycin||PRILOSEC||Clarithromycin|
|Study 4||74 [60, 85] †‡||0 [0, 7]||31 [18, 47]|
|(n = 53)||(n = 54)||(n = 42)|
|Study 5||64 [51, 76] †‡||0 [0, 6]||39 [24, 55]|
|(n = 61)||(n = 59)||(n = 44)|
|Non U.S. Studies|
|Study 6||83 [71, 92] ‡||1 [0, 7]||N/A|
|(n = 60)||(n = 74)|
|Study 7||74 [64, 83]‡||1 [0, 6]||N/A|
|(n = 86)||(n = 90)|
higher than clarithromycin monotherapy (p < 0.05)
‡Statistically significantly higher than omeprazole monotherapy (p < 0.05)
Ulcer healing was not significantly different when clarithromycin was added to omeprazole therapy compared with omeprazole therapy alone.
The combination of omeprazole and clarithromycin was effective in eradicating H. pylori and reduced duodenal ulcer recurrence.
Table 7 : Duodenal Ulcer Recurrence Rates by H.
pylori Eradication Status % of Patients with Ulcer Recurrence
|H. pylori eradicated#||H. pylori not eradicated#|
|U.S. Studies †|
|6 months post-treatment Study 4||*35||60|
|(n = 49)||(n = 88)|
|(n = 53)||(n = 106)|
|Non U.S. Studies‡|
|6 months post-treatment Study 6||*5||46|
|(n = 43)||(n = 78)|
|(n = 53)||(n = 107)|
|12 months post-treatment Study 6||*5||68|
|(n = 39)||(n = 71)|
|#H. pylori eradication
status assessed at same time point as ulcer recurrence
†Combined results for PRILOSEC + clarithromycin, PRILOSEC, and clarithromycin treatment arms
‡Combined results for PRILOSEC + clarithromycin and PRILOSEC treatment arms
*(p ≤ 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori eradicated
In a U.S. multicenter, double-blind, study of omeprazole 40 mg once daily, 20 mg once daily, 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)
|PRILOSEC 20 mg once daily
(n = 202)
|PRILOSEC 40 mg once daily
(n = 214)
(n = 104)
|Week 4||47 5**||55.6**||30.8|
|**(p < 0.01) PRILOSEC 40 mg
or 20 mg versus placebo
+(p < 0.05) PRILOSEC 40 mg versus 20 mg
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 daily, 20 mg once daily, and ranitidine 150 mg twice a day were evaluated.
Treatment of Gastric Ulcer %
of Patients Healed (All Patients Treated)
|PRILOSEC 20 mg once daily
(n = 200)
|PRILOSEC 40 mg once daily
(n = 187)
|Ranitidine 150 mg twice daily
(n = 199)
|** (p < 0.01) PRILOSEC 40 mg
++ (p < 0.01) PRILOSEC 40 mg versus 20 mg
Gastroesophageal Reflux Disease (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
|PRILOSEC 20 mg a.m.||PRILOSEC 10 mg a.m.||Placebo a.m.|
|All patients||46*,† (n = 205)||31† (n = 199)||13 (n = 105)|
|Patients with confirmed GERD||56*,† (n = 115)||36† (n = 109)||14 (n = 59)|
|aDefined as complete resolution of heartburn
*(p < 0.005) versus 10 mg
†(p < 0.005) versus placebo
In a U.S. multicenter double-blind placebo controlled study of 20 mg or 40 mg of PRILOSEC Delayed-Release Capsules 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:
|Week||20 mg PRILOSEC
(n = 83)
|40 mg PRILOSEC
(n = 87)
(n = 43)
|** (p < 0.01) PRILOSEC versus placebo.|
In this study, the 40 mg dose was not superior to the 20 mg dose of PRILOSEC in the percentage healing rate. Other controlled clinical trials have also shown that PRILOSEC is effective in severe GERD. In comparisons with histamine H2-receptor antagonists in patients with erosive esophagitis, grade 2 or above, PRILOSEC 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 PRILOSEC 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 Of Healing of Erosive Esophagitis
In a U.S. double-blind, randomized, multicenter, placebo controlled study, two dose regimens of PRILOSEC were studied in patients with endoscopically confirmed healed esophagitis. Results to determine maintenance of healing of erosive esophagitis are shown below.
Life Table Analysis
|PRILOSEC 20 mg once daily
(n = 138)
|PRILOSEC 20 mg 3 days per week
(n = 137)
(n = 131)
|Percent in endoscopic remission at 6 months||*||34||11|
|*(p < 0.01) PRILOSEC 20 mg once daily versus PRILOSEC 20 mg 3 consecutive days per week or placebo.|
In an international multicenter double-blind study, PRILOSEC 20 mg daily and 10 mg daily were compared with 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
|PRILOSEC 20 mg once daily
(n = 131)
|PRILOSEC 10 mg once daily
(n = 133)
|Ranitidine 150 mg twice daily
(n = 128)
|Percent in endoscopic remission at 12 months||*77||‡58||46|
|* (p = 0.01) PRILOSEC 20 mg once daily versus PRILOSEC 10
mg once daily or Ranitidine.
‡ (p = 0.03) PRILOSEC 10 mg once daily versus Ranitidine.
In patients who initially had grades 3 or 4 erosive esophagitis, for maintenance after healing 20 mg daily of PRILOSEC 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, PRILOSEC Delayed-Release Capsules 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]. PRILOSEC 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 PRILOSEC. 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 PRILOSEC 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 PRILOSEC [see ADVERSE REACTIONS].
The effectiveness of PRILOSEC for the treatment of nonerosive GERD in pediatric patients 1 to 16 years of age is based in part on data obtained from 125 pediatric patients in two uncontrolled Phase III studies [see Use in Specific Populations].
The first study enrolled 12 pediatric patients 1 to 2 years of age with a history of clinically diagnosed GERD. Patients were administered a single dose of omeprazole (0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg) for 8 weeks as an open capsule in 8.4% sodium bicarbonate solution. Seventy-five percent (9/12) of the patients had vomiting/regurgitation episodes decreased from baseline by at least 50%.
The second study enrolled 113 pediatric patients 2 to 16 years of age with a history of symptoms suggestive of nonerosive GERD. Patients were administered a single dose of omeprazole (10 mg or 20 mg, based on body weight) for 4 weeks either as an intact capsule or as an open capsule in applesauce. Successful response was defined as no moderate or severe episodes of either pain-related symptoms or vomiting/regurgitation during the last 4 days of treatment. Results showed success rates of 60% (9/15; 10 mg omeprazole) and 59% (58/98; 20 mg omeprazole), respectively.
Healing of Erosive Esophagitis
In an uncontrolled, open-label dose-titration study, healing of erosive esophagitis in pediatric patients 1 to 16 years of age required doses that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7 mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than 6% of a 24-hour study). After titration, patients remained on treatment for 3 months. Forty-four percent of the patients were healed on a dose of 0.7 mg/kg body weight; most of the remaining patients were healed with 1.4 mg/kg after an additional 3 months' treatment. Erosive esophagitis was healed in 51 of 57 (90%) children who completed the first course of treatment in the healing phase of the study. In addition, after 3 months of treatment, 33% of the children had no overall symptoms, 57% had mild reflux symptoms, and 40% had less frequent regurgitation/vomiting.
Maintenance of Healing of Erosive Esophagitis
In an uncontrolled, open-label study of maintenance of healing of erosive esophagitis in 46 pediatric patients, 54% of patients required half the healing dose. The remaining patients increased the healing dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire maintenance period, or returned to half the dose before completion. Of the 46 patients who entered the maintenance phase, 19 (41%) had no relapse. In addition, maintenance therapy in erosive esophagitis patients resulted in 63% of patients having no overall symptoms.
1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol, 20, No. 2, NCCLS, Wayne, PA, January 2000.
Last reviewed on RxList: 1/12/2015
This monograph has been modified to include the generic and brand name in many instances.
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