Santarus Inc

MAGNESIUM HYDROXIDE AND OMEPRAZOLE AND SODIUM BICARBONATE

magnesium hydroxide; omeprazole; sodium bicarbonate

LOE Approaching

ORAL · TABLET

CLINICAL PHARMACOLOGY Omeprazole is acid labile and thus rapidly degraded by gastric acid. ZEGERID with Magnesium Hydroxide is an immediate-release chewable tablet formulation that contains an antacid component (sodium bicarbonate plus magnesium hydroxide) which raises the gastric pH and thus protects omeprazole from acid degradation. Pharmacokinetics: Absorption When ZEGERID with Magnesium Hydroxide chewable tablets are administered on an empty stomach at least 1 hour prior to a meal, the absorption of omeprazole is rapid, with a mean peak plasma level (%CV) of omeprazole being 1763 ng/mL (25%) and time to peak of approximately 30 minutes (range 10-90 min) after a single-dose or repeated-dose administration. Following single or repeated once daily dosing, peak plasma concentrations of omeprazole from ZEGERID are approximately proportional from 20 to 40 mg doses of omeprazole, but a greater than linear mean AUC (three-fold increase) is observed when doubling the dose to 40 mg. The bioavailability of omeprazole from ZEGERID increases upon repeated administration. When ZEGERID with Magnesium Hydroxide chewable tablets are administered 1 hour after a meal, the AUC is reduced by approximately 22% relative to administration 1 hour prior to a meal. Distribution Omeprazole is bound to plasma proteins. Protein binding is approximately 95%. Metabolism Following single dose oral administration of omeprazole, the majority of the dose (about 77%) is eliminated in urine as at least six metabolites. Two metabolites have been 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. Excretion Following single dose oral administration of omeprazole, little if any, unchanged drug is excreted in urine. The mean plasma omeprazole half-life in healthy subjects is approximately 1 hour (range 0.4 to 3.1 hours) and the total body clearance is 500-600 mL/min. Special Populations Geriatric 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 subjects, versus 58% in young subjects 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 subjects) and its plasma half-life averaged one hour, similar to that of young healthy subjects. Pediatric The pharmacokinetics of ZEGERID with Magnesium Hydroxide have not been studied in patients < 18 years of age. Gender There are no known differences in the absorption or excretion of omeprazole between males and females. Hepatic Insufficiency In patients with chronic hepatic disease, the bioavailability of omeprazole from a buffered solution increased to approximately 100% compared to an I.V. dose, reflecting decreased first-pass effect, and the mean plasma half-life of the drug increased to nearly 3 hours compared to the mean half-life of 1 hour in normal subjects. Plasma clearance averaged 70 mL/min, compared to a value of 500-600 mL/min in normal subjects. Renal Insufficiency In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m, the disposition of omeprazole from a buffered solution was very similar to that in healthy subjects, 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. ZEGERID chewable tablets contain magnesium hydroxide (292 mg of Mg++); therefore, magnesium levels should be closely monitored when using this product in patients with renal failure. Asians 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. Drug-Drug Interactions When omeprazole 40 mg was given once daily in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects, the steady-state plasma concentrations of omeprazole were increased by the concomitant administration of clarithromycin [Cmax, AUC(0-24) and T½ increased 30%, 89%, and 34%, respectively]. Pharmacodynamics: Mechanism of Action Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not ex

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