Omeprazole/Bicarbonate (Page 5 of 10)

8.4 Pediatric Use

Safety and effectiveness of omeprazole and sodium bicarbonate have not been established in pediatric patients less than 18 years of age.

Juvenile Animal Data

In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg on a body surface area basis. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth. [See Nonclinical Toxicology (13.2).]

8.5 Geriatric Use

Omeprazole was administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Pharmacokinetic studies with buffered omeprazole have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects). The plasma half-life averaged one hour, about twice that in nonelderly, healthy subjects taking omeprazole and sodium bicarbonate. However, no dosage adjustment is necessary in the elderly. [See Clinical Pharmacology (12.3).]

8.6 Hepatic Impairment

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3).]

8.7 Renal Impairment

No dose reduction is necessary. [See Clinical Pharmacology (12.3).]

8.8 Asian Population

Recommend dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3).]

10 OVERDOSAGE

Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience [See Adverse Reactions (6)]. Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.

As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose, a certified Regional Poison Control Center should be contacted. Telephone numbers are listed in the Physicians’ Desk Reference (PDR) or local telephone book.

Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were lethal to mice, rats, and dogs, respectively. Animals given these doses showed sedation, ptosis, tremors, convulsions, and decreased activity, body temperature, and respiratory rate and increased depth of respiration.

In addition, a sodium bicarbonate overdose may cause hypocalcemia, hypokalemia, hypernatremia, and seizures.

11 DESCRIPTION

Omeprazole and sodium bicarbonate is a combination of omeprazole, a proton-pump inhibitor, and sodium bicarbonate, an antacid. Omeprazole is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3,5dimethyl-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:

Chemical Structure

Omeprazole, USP is a white or almost white powder which melts with decomposition at about 155°C. Soluble in dichloromethane, practically insoluble 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.

Omeprazole and sodium bicarbonate is supplied as immediate-release capsules. Each capsule contains either 40 mg or 20 mg of omeprazole and 1100 mg of sodium bicarbonate with the following excipients: croscarmellose sodium and sodium stearyl fumarate. The capsules consist of gelatin and titanium dioxide. In addition the 20 mg/1100 mg capsule shell contains sodium lauryl sulfate and the 40 mg/1100 mg capsule shell contains FD&C Blue 1. The capsules are printed with edible ink containing black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, propylene glycol, potassium hydroxide, shellac and strong ammonia solution.

12 CLINICAL PHARMACOLOGY

12.1 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.

Omeprazole is acid labile and thus rapidly degraded by gastric acid. Omeprazole and sodium bicarbonate capsules are immediate-release formulations that contain sodium bicarbonate which raises the gastric pH and thus protects omeprazole from acid degradation.

12.2 Pharmacodynamics

Antisecretory Activity

Results from a PK/PD study of the antisecretory effect of repeated once-daily dosing of 40 mg and 20 mg of omeprazole and sodium bicarbonate oral suspension in healthy subjects are shown in Table 5 below.

Table 5: Effect of Omeprazole and Sodium Bicarbonate Oral Suspension on Intragastric pH, Day 7
Parameter Omeprazole/Sodium Bicarbonate
40 mg/1680 mg (n = 24) 20 mg/1680 mg (n = 28)
Note: Values represent medians. All parameters were measured over a 24-hour period.
*
p < 0.05 20 mg vs. 40 mg

% Decrease from Baseline for Integrated Gastric Acidity (mmol∙hr/L)

84%

82%

Coefficient of variation

20%

24%

% Time Gastric pH > 4*(Hours)*

77(18.6 h)

51(12.2 h)

Coefficient of variation

27%

43%

Median pH

5.2

4.2

Coefficient of variation

17%

37%

Results from a separate PK/PD study of antisecretory effect on repeated once daily dosing of 40 mg/1100 mg and 20 mg/1100 mg of omeprazole and sodium bicarbonate capsules in healthy subjects show similar effects in general on the above three PD parameters as those for omeprazole and sodium bicarbonate 40 mg/1680 mg and 20 mg/1680 mg oral suspension, respectively.

The antisecretory effect lasts 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.

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 Nonclinical Toxicology (13.1)]. 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.

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.

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 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.

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