Duodenal Ulcer
Omeprazole and sodium bicarbonate is indicated for short-term treatment of active duodenal ulcer. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. [See Clinical Studies (14.1)]
Gastric Ulcer
Omeprazole and sodium bicarbonate is indicated for short-term treatment (4 to 8 weeks) of active benign gastric ulcer. (See Clinical Studies (14.2)]
Treatment of Gastroesophageal Reflux Disease (GERD)
Symptomatic GERD
Omeprazole and sodium bicarbonate is indicated for the treatment of heartburn and other symptoms associated with GERD. [See Clinical Studies (14.3)]
Erosive Esophagitis
Omeprazole and sodium bicarbonate is indicated for the short-term treatment (4 to 8 weeks) of erosive esophagitis which has been diagnosed by endoscopy.
The efficacy of omeprazole and sodium bicarbonate used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, it may be helpful to give up to an additional 4 weeks of treatment. If there is recurrence of erosive esophagitis or GERD symptoms (e.g., heartburn), additional 4 to 8 week courses of omeprazole and sodium bicarbonate may be considered. [See Clinical Studies (14.3)]
Maintenance of Healing of Erosive Esophagitis
Omeprazole and Sodium Bicarbonate Capsules is indicated to maintain healing of erosive esophagitis. Controlled studies do not extend beyond 12 months . [See Clinical Studies (14.4)]
Omeprazole and Sodium Bicarbonate Capsule Dosage and Administration
Omeprazole and sodium bicarbonate is available as a capsule in 20 mg and 40 mg strengths of omeprazole for adult use. Directions for use for each indication are summarized in Table 1. All recommended doses throughout the labeling are based upon omeprazole.
Since both the 20 mg and 40 mg capsules contain the same amount of sodium bicarbonate (1100 mg), two capsules of 20 mg are not equivalent to one capsule of omeprazole and sodium bicarbonate 40 mg; therefore, two 20 mg capsules of omeprazole and sodium bicarbonate should not be substituted for one capsule of omeprazole and sodium bicarbonate 40 mg.
Omeprazole and sodium bicarbonate should be taken on an empty stomach at least one hour before a meal.
Special Populations
Hepatic Insufficiency
Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3)]
Administration of Capsules
Omeprazole and Sodium Bicarbonate Capsules should be swallowed intact with water. DO NOT USE OTHER LIQUIDS. DO NOT OPEN CAPSULE AND SPRINKLE CONTENTS INTO FOOD.
Avoid concomitant use of clopidogrel and omeprazole. Coadministration of clopidogrel with 80mg omeprazole, a proton pump inhibitor that is an inhibitor if CYP2C19, reduces the pharmacological activity of clopidogrel if given concomitantly or if given 12 hours apart [see WARNINGS AND PRECAUTIONS (5.6) and Drug Interactions (7) ].
Dosage Forms and Strengths
Contraindications
Omeprazole and sodium bicarbonate is contraindicated in patients with known hypersensitivity to any components of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria.
Warnings and Precautions
Concomitant Gastric Malignancy
Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy.
Atrophic gastritis
Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole.
Buffer Content
Each Omeprazole and Sodium Bicarbonate Capsule contains 1100 mg (13 mEq) of sodium bicarbonate. The total content of sodium in each capsule is 304 mg.
The sodium content of omeprazole and sodium bicarbonate products should be taken into consideration when administering to patients on a sodium restricted diet.
Because omeprazole and sodium bicarbonate products contain sodium bicarbonate, they should be used with caution in patients with Bartter’s syndrome, hypokalemia, hypocalcemia, and problems with acid-base balance. Long-term administration of bicarbonate with calcium or milk can cause milk-alkali syndrome.
Chronic use of sodium bicarbonate may lead to systemic alkalosis and increased sodium intake can produce edema and weight increase.
Bone Fracture
Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines. [See DOSAGE AND ADMINISTRATION ( 2) and ADVERSE REACTIONS (6.2)]
Diminished Anti-platelet Activity of clopidogrel due to Impaired CYP2C19 Function of Omeprazole
Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that interfere with CYP2C19 activity. Avoid concomitant use of clopidogrel and omeprazole. Coadministration of clopidogrel with 80mg omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of clopidogrel if given concomitantly or if given 12 hours apart [ see Drug Interactions (7) ].
Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia recquired magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPI’s with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [See ADVERSE REACTIONS (6.2) ].
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In the U.S. clinical trial population of 465 patients, the adverse reactions summarized in Table 2 were reported to occur in 1% or more of patients on therapy with omeprazole. Numbers in parentheses indicate percentages of the adverse reactions considered by investigators as possibly, probably or definitely related to the drug.
| Omeprazole (n = 465) | Placebo (n = 64) | Ranitidine (n = 195) | |
| Headache | 6.9 (2.4) | 6.3 | 7.7 (2.6) |
| Diarrhea | 3.0 (1.9) | 3.1 (1.6) | 2.1 (0.5) |
| Abdominal Pain | 2.4 (0.4) | 3.1 | 2.1 |
| Nausea | 2.2 (0.9) | 3.1 | 4.1 (0.5) |
| URI | 1.9 | 1.6 | 2.6 |
| Dizziness | 1.5 (0.6) | 0.0 | 2.6 (1.0) |
| Vomiting | 1.5 (0.4) | 4.7 | 1.5 (0.5) |
| Rash | 1.5 (1.1) | 0.0 | 0.0 |
| Constipation | 1.1 (0.9) | 0.0 | 0.0 |
| Cough | 1.1 | 0.0 | 1.5 |
| Asthenia | 1.1 (0.2) | 1.6 (1.6) | 1.5 (1.0) |
| Back Pain | 1.1 | 0.0 | 0.5 |
Table 3 summarizes the adverse reactions that occurred in 1% or more of omeprazole-treated patients from international double-blind, and open-label clinical trials in which 2,631 patients and subjects received omeprazole.
| Omeprazole (n = 2631) | Placebo (n = 120) | |
| Body as a Whole, site unspecified | ||
| Abdominal pain Asthenia | 5.2 1.3 | 3.3 0.8 |
| Digestive System | ||
| Constipation Diarrhea Flatulence Nausea Vomiting Acid regurgitation | 1.5 3.7 2.7 4.0 3.2 1.9 | 0.8 2.5 5.8 6.7 10.0 3.3 |
| Nervous System/Psychiatric | ||
| Headache | 2.9 | 2.5 |
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of omeprazole. Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria (see also Skin below), fever, pain, fatigue, malaise.
Chest pain or angina, tachycardia, bradycardia, palpitation, elevated blood pressure, and peripheral edema.
Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.
Mild and, rarely, marked elevations of liver function tests [ALT (SGPT), AST (SGOT), γ-glutamyl transpeptidase, alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has occurred, including hepatocellular, cholestatic, or mixed hepatitis, liver necrosis (some fatal), hepatic failure (some fatal), and hepatic encephalopathy.
Hyponatremia, hypoglycemia, hypomagnesemia and weight gain.
Muscle cramps, myalgia, muscle weakness, joint pain, and leg pain.
Psychic disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream abnormalities; vertigo; paresthesia; and hemifacial dysesthesia.
Severe generalized skin reactions including toxic epidermal necrolysis (TEN; some fatal), Stevens-Johnson syndrome, and erythema multiforme (some severe); purpura and/or petechiae (some with rechallenge); skin inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis.
Blurred vision, ocular irritation, dry eye syndrome, optic atrophy, anterior ischemic optic neuropathy, optic neuritis and double vision.
Interstitial nephritis (some with positive rechallenge), urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, and gynecomastia.
Rare instances of pancytopenia, agranulocytosis (some fatal), thrombocytopenia, neutropenia, leukopenia, anemia, leucocytosis, and hemolytic anemia have been reported.
The incidence of clinical adverse experiences in patients greater than 65 years of age was similar to that in patients 65 years of age or less.
Additional adverse reactions that could be caused by sodium bicarbonate include metabolic alkalosis, seizures, and tetany.
Drug Interactions
Drugs for which gastric pH can affect bioavailability
Because of its inhibition of gastric acid secretion, it is theoretically possible that omeprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (e.g., ketoconazole, ampicillin esters, iron salts and digoxin). In the clinical efficacy trials, antacids were used concomitantly with the administration of omeprazole.
Drugs metabolized by cytochrome P450 (CYP)
Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by oxidation in the liver. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time.
Although in normal subjects no interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome P-450 system (e.g., cyclosporine, disulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with omeprazole and sodium bicarbonate.
Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of omeprazole is not normally required. When voriconazole (400 mg every 12 hours for one day, then 200 mg for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, it significantly increased the steady-state C max of AUC0-24 of omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole was given without voriconazole.
Antiretroviral Agents
Concomitant administration of atazanavir and proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reducing its therapeutic effect.
Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily), and omeprazole (40 mg, daily), AUC was decreased by 36% and 92%, C max by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported with an increase in AUC by 82%, in Cmax by 75% and in Cmin by 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.
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 (C max, 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-hydroxyclarithromycin 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-hydroxyclarithromycin, 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.
| 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) |
Clopidogrel
Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of omeprazole 80mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see WARNING AND PRECAUTIONS (5.6)].
In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300mg loading dose followed by 75mg per day) alone and with omeprazole (80mg 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.
The active metabolite of clopidogrel selectively and irreversibly inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor, thereby inhibiting platelet aggregation. The mean inhibition of platelet aggregation at 5 mcM ADP was diminished by 39% (Day 1) and 21% (Day 5) when clopidogrel and omeprazole were administered together.
In another study, 72 healthy subjects were given the same doses of clopidogrel and 80mg 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 [see WARNINGS AND PRECAUTIONS (5.6)].
There are no adequate combination studies of a lower dose of omeprazole or higher dose of clopidogrel in comparison with the approved doses of clopidogrel.
Tacrolimus
Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies on the use of omeprazole in pregnant women. The vast majority of reported experience with omeprazole during human pregnancy is first trimester exposure and the duration of use is rarely specified, eg, intermittent vs. chronic. An expert review of published data on experiences with omeprazole use during pregnancy by TERIS – the Teratogen Information System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as fair). 1
Three epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy to the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. A population-based prospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. 2 In utero exposure to omeprazole was not associated with increased risk of any malformation (odds ratio 0.82, 95% CI 0.50-1.34), low birth weight or low Apgar score. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole exposed infants than the expected number in the normal population. The author concluded that both effects may be random.
A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole). 3 The overall malformation rate was 4.4% (95% CI 3.6-5.3) and the malformation rate for first trimester exposure to omeprazole was 3.6% (95% CI 1.5-8.1). The relative risk of malformations associated with first trimester exposure to omeprazole compared with nonexposed women was 0.9 (95% CI 0.3-2.2). The study could effectively rule out a relative risk greater than 2.5 for all malformations. Rates of preterm delivery or growth retardation did not differ between the groups.
A controlled prospective observational study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures) 4. The reported rates of major congenital malformations was 4% for the omeprazole group, 2% for controls exposed to nonteratogens, and 2.8% in disease-paired controls (background incidence of major malformations 1-5%). Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight did not differ between the groups. The sample size in this study has 80% power to detect a 5-fold increase in the rate of major malformation.
Several studies have reported no apparent adverse short term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia.
Reproduction studies conducted with omeprazole in rats at oral doses up to 28 times the human dose of 40 mg/day (based on body surface area) and in rabbits at doses up to 28 times the human dose (based on body surface area) did not show any evidence of terogenicity. In pregnant rabbits, omeprazole at doses about 2.8 to 28 times the human dose of 40mg/day, (based on body surface area) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy loss. In rats treated with omeprazole at doses about 2.8 to 28 times the human dose (based on body surface area), dose-related embryo/fetal toxicity and postnatal developmental toxicity occurred in offspring. [See Animal Toxicology and/or Pharmacology (13.2)].
There are no adequate and well-controlled studies in pregnant women. Because animal studies and studies in humans cannot rule out the possibility of harm, omeprazole and sodium bicarbonate should be used during pregnancy only if the potential benefit to pregnant women justifies the potential risk to the fetus.
Nursing Mothers
Omeprazole concentrations have been measured in breast milk of a woman following oral administration of 20 mg. The peak concentration of omeprazole in breast milk was less than 7% of the peak serum concentration. The concentration will correspond to 0.004 mg of omeprazole in 200 mL of milk. Because omeprazole is excreted in human milk, because of the potential for serious adverse reactions in nursing infants from omeprazole, and because of the potential for tumorigenicity shown for omeprazole in rat carcinogenicity studies, a decision should be taken to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In addition, sodium bicarbonate should be used with caution in nursing mothers.
Pediatric Use
Safety and effectiveness of omeprazole and sodium bicarbonate have not been established in pediatric patients less than 18 years of age.
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 the same as that in nonelderly, healthy subjects taking omeprazole and sodium bicarbonate. However, no dosage adjustment is necessary in the elderly. (See CLINICAL PHARMACOLOGY (12.3)]
Hepatic Impairment
Consider dose reduction, particularly for maintenance of healing erosive esophagitis. [See Clinical Pharmacology (12.3)]
Renal Impairment
No dose reduction is necessary. [See Clinical Pharmacology (12.3)]
Asian Population
Recommended dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3)]
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.
Omeprazole and Sodium Bicarbonate Capsule 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-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H-benzimidazole, a racemic mixture of two enantiomers that inhibits gastric acid secretion. Its structural formula is C17H19N3O3S, with a molecular weight of 345.42. The structural formula is:
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.
Omeprazole and sodium bicarbonate is supplied as 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 magnesium stearate. The capsules consist of black iron oxide, D&C Yellow #10, FD&C Blue #1, FD&C Red #3, FD&C Red #40, gelatin and titanium dioxide. In addition the ink consists of D&C Yellow #10 aluminum lake, iron oxide black, n-butyl alcohol, propylene glycol, FD&C Blue #2 aluminum lake, FD&C Red #40 aluminum lake, FD&C Blue #1 aluminum lake and shellac glaze~45% (20% esterfied) in ethanol.
Omeprazole and Sodium Bicarbonate Capsule - Clinical Pharmacology
Mechanism of Action Section
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 muscosa for a day or more.
Omeprazole is acid labile and thus rapidly degraded by gastric acid. Omeprazole and Sodium Bicarbonate Capsule is an immediate-release formulation that contains sodium bicarbonate which raises the gastric pH and thus protects from acid degradation.
Pharmacodynamics
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 in healthy subjects are shown in Table 5 below.
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.
In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily dosing 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.
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 gm b.i.d. for 12 months followed by 20 mg b.i.d. for 12 mo
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