Zegerid with Magnesium Hydroxide: Package Insert and Label Information

ZEGERID WITH MAGNESIUM HYDROXIDE- omeprazole, sodium bicarbonate and magnesium hydroxide tablet, chewable
Santarus, Inc.

Rx Only

Chewable Tablets

DESCRIPTION

ZEGERID® with Magnesium Hydroxide (omeprazole/sodium bicarbonate/magnesium hydroxide) is a combination of omeprazole, a proton-pump inhibitor, and sodium bicarbonate plus magnesium hydroxide, both of which are antacids. Omeprazole is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H -benzimidazole, a racemic mixture of two enantiomers that inhibits gastric acid secretion. Its empirical formula is C17 H19 N3 O3 S, with a molecular weight of 345.42. The structural formula is:

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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.

ZEGERID with Magnesium Hydroxide is available in two strengths, 40 mg and 20 mg of omeprazole, and is formulated as an immediate-release chewable tablet. Each chewable tablet contains either 40 mg or 20 mg of omeprazole and 600 mg of sodium bicarbonate plus 700 mg of magnesium hydroxide with the following inactive ingredients: hydroxypropyl cellulose, croscarmellose sodium, xylitol, sucralose, flavoring, magnesium stearate, and FD&C Red #40 Aluminum Lake.

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 m2 , 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 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

Results from PK/PD studies of the antisecretory effect of repeated once-daily dosing of 40 mg and 20 mg of ZEGERID with Magnesium Hydroxide chewable tablets in healthy subjects are shown in Table 1 below.

Table 1: Effect of ZEGERID® with Magnesium Hydroxide Chewable Tablets on Intragastric pH on Day 7
Omeprazole/Sodium Bicarbonate/Magnesium Hydroxide
Parameter 40 mg/600 mg/700 mg(n = 35) 20 mg/600 mg/700 mg(n = 29)

Note: Values are medians. All parameters were measured over a 24-hour period.

% Decrease from Baseline for Integrated Gastric Acidity (mmol*hr/L) 73% 72%
Coefficient of variation 19% 28%
% Time Gastric pH > 4(Hours) 62%(14.9 h) 57%(13.8 h)
Coefficient of variation 30% 32%
Median pH 5.1 4.8
Coefficient of variation 24% 29%

The antisecretory effect of omeprazole thus lasts far longer than would be expected from the very short (1 hour) plasma half-life, apparently due to irreversible binding to the parietal H+/K+ ATPase enzyme.

Repeated single daily oral doses of ZEGERID have produced nearly 100% inhibition of 24-hour integrated gastric acidity in some subjects.

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. 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 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 (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). (See Table 2.)

Table 2: Treatment of Active Duodenal Ulcer; % of Patients Healed
Omeprazole 20 mg a.m. (n = 99) Placebo a.m. (n = 48)

* (p ≤ 0.01)

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). (See Table 3.)

Table 3: Treatment of Active Duodenal Ulcer; % of Patients Healed
Omeprazole 20 mg a.m. (n = 145) Ranitidine 150 mg b.i.d. (n = 148)

* (p < 0.01)

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, 40 mg and 20 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. (See Table 4.)

Table 4: Treatment of Active Duodenal Ulcer; % of Patients Healed
Omeprazole 40 mg (n = 36) Omeprazole 20 mg (n = 34) Ranitidine 150 mg b.i.d. (n = 35)

*(p ≤ 0.01)

Week 2 83* 83* 53
Week 4 100* 97* 82
Week 8 100 100 94
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