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|Omeprazole |
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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 PharmacologyPharmacokinetics and Metabolism: OmeprazoleOmeprazole 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 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.
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 AntimicrobialsOmeprazole 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.
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. PharmacodynamicsMechanism of ActionOmeprazole 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 ActivityAfter 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.
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 EffectsIn 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 EffectsIn 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 EffectsSystemic 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 StudiesDuodenal Ulcer DiseaseActive Duodenal Ulcer
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 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).
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.
H. pylori Eradication in Patients with Duodenal Ulcer DiseaseTriple 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 The combination of Omeprazole plus clarithromycin plus amoxicillin was effective in eradicating H. pylori.
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.
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.
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.
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.
Symptomatic GERDA placebo-controlled study was conducted in Scandinavia to compare the efficacy of Omeprazole
Erosive EsophagitisIn 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:
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 EsophagitisIn 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.
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.
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 ConditionsIn 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.) MicrobiologyOmeprazole 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
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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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