Omeprazole

Description

The active ingredient in omeprazole delayed-release capsules is a substituted benzimidazole, specifically 5-methoxy-2-[(4-methoxy-3, 5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, which functions as an inhibitor of gastric acid secretion. The empirical formula of omeprazole is C₁₇H₁₉N₃O₃S, and it has a molecular weight of 345.42. The structural formula is provided in the accompanying documentation.

Omeprazole appears as a white to off-white crystalline powder that melts with decomposition at approximately 155°C. It is classified as a weak base, exhibiting solubility characteristics that include being freely soluble in ethanol and methanol, slightly soluble in acetone and isopropanol, and very slightly soluble in water. The stability of omeprazole is pH-dependent; it is rapidly degraded in acidic environments but maintains acceptable stability in alkaline conditions.

Omeprazole delayed-release capsules are formulated to meet the USP Drug Release Test 2 and are intended for oral administration. Each capsule contains either 10 mg, 20 mg, or 40 mg of omeprazole in the form of enteric-coated granules. The inactive ingredients include crospovidone, hypromellose, magnesium stearate, mannitol, meglumine, methacrylic acid copolymer, poloxamer, povidone, and triethyl citrate. The capsule shells are composed of D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, yellow iron oxide, gelatin, silicon dioxide, sodium lauryl sulfate, and titanium dioxide. The imprinting ink contains D&C Yellow No. 10 aluminum lake, FD&C Blue No. 1 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, n-butyl alcohol, pharmaceutical glaze, propylene glycol, SDA-3A alcohol, and synthetic black iron oxide.

Uses and Indications

Omeprazole is indicated for the treatment of duodenal ulcers and gastric ulcers in adults. Additionally, it is indicated for the treatment of gastroesophageal reflux disease (GERD) in both adults and children, as well as for the maintenance of healing of erosive esophagitis in these populations.

The safety and effectiveness of omeprazole in pediatric patients under 1 year of age have not been established.

Dosage and Administration

For the treatment of active duodenal ulcer, the recommended dosage of omeprazole is 20 mg administered once daily for a duration of 4 weeks. In some cases, an additional 4 weeks may be necessary based on the patient's response.

For the eradication of H. pylori to reduce the risk of duodenal ulcer recurrence, two therapeutic regimens are available:

Triple Therapy:

• Omeprazole: 20 mg, administered twice daily for 10 days.

• Amoxicillin: 1000 mg, administered twice daily for 10 days.

• Clarithromycin: 500 mg, administered twice daily for 10 days.

Dual Therapy:

• Omeprazole: 40 mg, administered once daily for 14 days.

• Clarithromycin: 500 mg, administered three times daily for 14 days.

For gastric ulcers, the recommended dosage of omeprazole is 40 mg once daily for a treatment period of 4 to 8 weeks. In cases of gastroesophageal reflux disease (GERD), omeprazole should be administered at a dosage of 20 mg once daily for 4 to 8 weeks.

To maintain healing of erosive esophagitis, the dosage of omeprazole is 20 mg once daily. For patients with pathological hypersecretory conditions, the dosage may vary, with a typical starting dose of omeprazole at 60 mg once daily, adjusted according to individual patient needs.

In pediatric patients aged 2 to 16 years, the dosing for GERD is weight-dependent: for those weighing between 10 kg and 20 kg, the recommended dose is 10 mg once daily; for patients weighing 20 kg or more, the recommended dose is 20 mg once daily.

Contraindications

Use is contraindicated in patients with known hypersensitivity to any component of the formulation or substituted benzimidazoles. This is due to the potential risk of severe allergic reactions, including angioedema and anaphylaxis, which have been reported in such individuals.

Warnings and Precautions

Symptomatic response to treatment does not exclude the possibility of underlying gastric malignancy; therefore, healthcare professionals should remain vigilant for signs of such conditions during therapy (5.1).

Long-term therapy with proton pump inhibitors (PPIs) has been associated with the development of atrophic gastritis, necessitating careful monitoring of patients on extended treatment regimens (5.2). Additionally, there is an increased risk of Clostridium difficile-associated diarrhea in patients receiving PPI therapy, which should be considered when evaluating gastrointestinal symptoms (5.3).

Concomitant use of omeprazole with clopidogrel is contraindicated due to the potential for reduced effectiveness of clopidogrel, which may lead to adverse cardiovascular outcomes (5.4). Furthermore, long-term and multiple daily doses of PPI therapy may elevate the risk of osteoporosis-related fractures, particularly in the hip, wrist, or spine (5.5). Healthcare providers should assess fracture risk in patients requiring prolonged PPI therapy. Rare instances of hypomagnesemia have also been reported with extended PPI use, warranting periodic monitoring of magnesium levels in these patients (5.6).

The concomitant use of omeprazole with St. John’s Wort or rifampin should be avoided, as these agents may significantly reduce omeprazole concentrations, potentially compromising therapeutic efficacy (5.7, 7.3).

In patients undergoing diagnostic investigations for neuroendocrine tumors, it is important to note that increases in intragastric pH due to PPI therapy can lead to hypergastrinemia and enterochromaffin-like cell hyperplasia, which may interfere with the accuracy of Chromogranin A levels and other diagnostic parameters (5.8, 12.2). Regular monitoring and appropriate adjustments in therapy may be necessary to mitigate these risks.

Side Effects

Most common adverse reactions reported in clinical trials, occurring in more than 2% of patients, include headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence.

In pediatric patients aged 2 to 16 years, the safety profile is similar to that observed in adults; however, respiratory system events and fever were the most frequently reported reactions in studies involving this population.

Serious hypersensitivity reactions have been documented, including angioedema and anaphylaxis, in patients with known hypersensitivity to any component of the formulation or substituted benzimidazoles.

Overdosage of omeprazole has been reported in humans, with doses reaching up to 2400 mg. Manifestations of overdosage included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, and dry mouth. These symptoms were transient, and no serious clinical outcomes have been reported when omeprazole was taken alone.

Additional adverse reactions and important considerations include the potential for atrophic gastritis with long-term therapy. Proton pump inhibitor (PPI) therapy may be associated with an increased risk of Clostridium difficile-associated diarrhea. Long-term and multiple daily dose PPI therapy may also be linked to an increased risk of osteoporosis-related fractures of the hip, wrist, or spine. Rarely, hypomagnesemia has been reported with prolonged treatment with PPIs. It is advised to avoid concomitant use of omeprazole with clopidogrel, St John’s Wort, or rifampin due to potential drug interactions.

Drug Interactions

Concomitant use of omeprazole with certain antiretroviral agents is not recommended due to significant interactions. Specifically, omeprazole reduces plasma levels of atazanavir and nelfinavir, which may compromise their efficacy. In contrast, omeprazole increases plasma levels of saquinavir, necessitating monitoring for potential toxicity and consideration of saquinavir dose reduction.

Omeprazole may also interfere with the bioavailability of drugs affected by gastric pH, including ketoconazole, iron salts, erlotinib, ampicillin esters, and digoxin. Patients receiving both omeprazole and digoxin should be monitored for increased digoxin toxicity.

The interaction between omeprazole and clopidogrel is clinically significant, as omeprazole decreases exposure to the active metabolite of clopidogrel, potentially reducing its antiplatelet effect. Additionally, omeprazole increases systemic exposure to cilostazol and one of its active metabolites, which may warrant a dose reduction of cilostazol.

Drugs metabolized by cytochrome P450, such as diazepam, warfarin, phenytoin, cyclosporine, disulfiram, and benzodiazepines, may have prolonged elimination when used with omeprazole. Therefore, monitoring and potential dose adjustments are advised. Patients on warfarin should be closely monitored for increases in INR and prothrombin time.

Furthermore, combined inhibitors of CYP 2C19 and 3A4, such as voriconazole, may elevate omeprazole levels. Omeprazole may also increase serum levels of tacrolimus and methotrexate, necessitating careful monitoring of these medications to avoid toxicity.

Packaging & NDC

The table below lists all NDC Code configurations of Omeprazole, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The use of omeprazole in pediatric patients aged 2 to 16 years for the treatment of gastroesophageal reflux disease (GERD) and the maintenance of healing of erosive esophagitis is supported by extrapolation of results from adequate and well-controlled studies conducted in adults, as well as safety and pharmacokinetic studies performed in this pediatric population.

However, the safety and effectiveness of omeprazole for the treatment of GERD in patients younger than 1 year of age have not been established. Additionally, the safety and effectiveness of omeprazole for other pediatric indications remain unproven.

Geriatric Use

Omeprazole has been administered to over 2,000 elderly individuals (≥ 65 years of age) in clinical trials conducted in the U.S. and Europe, demonstrating no significant differences in safety and effectiveness when compared to younger subjects. While other clinical experiences have not identified notable differences in response between elderly and younger patients, it is important to acknowledge that greater sensitivity in some older individuals cannot be entirely excluded.

Pharmacokinetic studies indicate that the elimination rate of omeprazole is somewhat decreased in the elderly, with an increased bioavailability observed. Specifically, the plasma clearance of omeprazole in elderly patients is approximately 250 mL/min, which is about half that of younger volunteers. Additionally, the plasma half-life of omeprazole in this population averages one hour, which is roughly twice that observed in young healthy volunteers.

Despite these pharmacokinetic variations, no dosage adjustment is necessary for elderly patients. Healthcare providers should remain vigilant in monitoring for any potential increased sensitivity in this population, although current evidence does not necessitate changes in dosing regimens.

Pregnancy

There are no adequate and well-controlled studies with omeprazole in pregnant women; therefore, it is classified as Pregnancy Category C. Available epidemiologic data do not demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester use of omeprazole. However, omeprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human data from four epidemiological studies have compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with those born to women exposed to H2-receptor antagonists or other controls. A population-based retrospective cohort study from the Swedish Medical Birth Registry reported on 955 infants whose mothers used omeprazole during pregnancy, finding that the incidence of malformations, low birth weight, low Apgar scores, or hospitalization was similar to that observed in the general population. Another study covering all live births in Denmark reported that the overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9%, compared to 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. Additionally, a retrospective cohort study involving 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester found an overall malformation rate of 3.6% in offspring born to mothers with omeprazole exposure. A small prospective observational cohort study of 113 women exposed to omeprazole during pregnancy reported a rate of major congenital malformations of 4% in the omeprazole group.

Several studies have indicated no apparent adverse short-term effects on infants when single doses of oral or intravenous omeprazole were administered to over 200 pregnant women as premedication for cesarean section under general anesthesia.

Animal studies have shown that reproductive studies conducted with omeprazole in rats and rabbits did not reveal any evidence of teratogenic potential. However, in rabbits, omeprazole was associated with dose-related increases in embryo lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole.

Lactation

Omeprazole is present in human milk. Following oral administration of 20 mg, omeprazole concentrations were measured in the breast milk of a lactating mother. The peak concentration of omeprazole in breast milk was found to be less than 7% of the peak serum concentration, which corresponds to approximately 0.004 mg of omeprazole in 200 mL of milk.

Caution should be exercised when administering omeprazole to nursing women, as the effects on breastfed infants have not been fully established.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Reports have been documented regarding overdosage with omeprazole in humans, with doses reaching up to 2400 mg, which is approximately 120 times the usual recommended clinical dose. The manifestations of overdosage were variable and included symptoms such as confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, and dry mouth. These symptoms were generally transient, and no serious clinical outcomes have been reported when omeprazole was taken in isolation.

Management of Overdosage

There is currently no specific antidote available for omeprazole overdosage. Given that omeprazole is extensively protein-bound, it is not readily dialyzable. In cases of overdosage, treatment should focus on symptomatic and supportive care. Healthcare professionals should also consider the possibility of multiple drug ingestion, as this may complicate the clinical picture.

For guidance on the management of any drug overdose, including omeprazole, it is advisable to contact the local Poison Control Center for the most current information and recommendations.

Animal Studies

Toxicological studies in animals have indicated that single oral doses of omeprazole at 1350 mg/kg in mice, 1339 mg/kg in rats, and 1200 mg/kg in dogs were lethal. Observed effects in these animals included sedation, ptosis, tremors, convulsions, decreased activity, reduced body temperature, and alterations in respiratory rate, including increased depth of respiration. These findings underscore the importance of careful dosing and monitoring in clinical practice.

Nonclinical Toxicology

No teratogenic effects were observed in studies involving omeprazole. In terms of non-teratogenic effects, administration of omeprazole at oral doses up to 138 mg/kg/day in rats, which is approximately 56 times the human dose on a body surface area basis, did not impact fertility or reproductive performance.

In two separate 24-month carcinogenicity studies conducted in rats, omeprazole was administered at daily doses of 1.7, 3.4, 13.8, 44.0, and 140.8 mg/kg/day, corresponding to about 0.7 to 57 times a human dose of 20 mg/day based on body surface area. These studies revealed a dose-related increase in the incidence of gastric ECL cell carcinoids in both male and female rats, with a notably higher incidence in females, who exhibited elevated blood levels of omeprazole. Gastric carcinoids are rarely observed in untreated rats. Additionally, ECL cell hyperplasia was noted across all treated groups of both sexes. In one study, female rats treated with 13.8 mg/kg/day of omeprazole for one year, followed by an additional year without treatment, did not develop carcinoids. However, a significant increase in treatment-related ECL cell hyperplasia was recorded at the end of the first year (94% in treated rats versus 10% in controls). By the second year, the difference diminished (46% in treated versus 26% in controls), yet hyperplasia remained more prevalent in the treated group. Gastric adenocarcinoma was identified in one rat (2%), but no similar tumors were observed in male or female rats over the two-year period. Historically, this strain of rat has not shown similar tumors, making the interpretation of a single tumor finding challenging.

In a 52-week toxicity study involving Sprague-Dawley rats, brain astrocytomas were detected in a small number of males receiving omeprazole at doses of 0.4, 2, and 16 mg/kg/day, which is approximately 0.2 to 6.5 times the human dose on a body surface area basis. No astrocytomas were found in female rats during this study. Conversely, in a separate two-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were observed in either sex at the high dose of 140.8 mg/kg/day, equating to about 57 times the human dose on a body surface area basis. A 78-week carcinogenicity study in mice did not indicate an increased occurrence of tumors, although the results were inconclusive. Additionally, a 26-week p53 (+/-) transgenic mouse carcinogenicity study yielded negative results.

Omeprazole demonstrated clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, as well as in one of two in vivo mouse micronucleus tests and an in vivo bone marrow cell chromosomal aberration assay. However, it was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay. The significant increase in gastric carcinoid tumors and ECL cell hyperplasia observed in the 24-month carcinogenicity studies in rats was noted in both male and female animals. Carcinoid tumors have also been reported in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with the use of omeprazole delayed-release capsules, reported voluntarily or through surveillance programs.

Chronic inflammation of the stomach lining, known as atrophic gastritis, has been observed in patients using omeprazole for extended periods. This condition may occur with or without symptoms, and patients are advised to inform their healthcare provider if they experience stomach pain, nausea, vomiting, or weight loss.

Additionally, low magnesium levels have been reported in some individuals taking proton pump inhibitors for at least three months, with a higher incidence noted after one year of treatment. Symptoms of low magnesium may not be present, but patients should seek medical attention if they develop seizures, dizziness, abnormal or rapid heartbeat, jitteriness, jerking movements or shaking (tremors), muscle weakness, spasms of the hands and feet, cramps, or muscle aches.

The most common side effects reported in adults and children include headache, stomach pain, nausea, diarrhea, vomiting, and gas. In children aged 2 to 16 years, respiratory system events and fever have also been frequently reported.

Serious allergic reactions have been documented, with symptoms such as rash, facial swelling, throat tightness, and difficulty breathing. Patients experiencing these symptoms should contact their healthcare provider, who may consider discontinuing the medication.

Patients are encouraged to report any side effects to their healthcare provider and may also report them to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients should be advised to take omeprazole delayed-release capsules before eating. It is important to inform them that these capsules should be swallowed whole and not chewed or crushed. For those who have difficulty swallowing capsules, the contents can be mixed with applesauce. Specifically, one tablespoon of applesauce should be placed in an empty bowl, and the capsule should be opened to carefully empty all the pellets onto the applesauce. The mixture should be consumed immediately with a glass of cool water to ensure complete swallowing. It is crucial that the applesauce is not hot and is soft enough to swallow without chewing. Additionally, any remaining pellets/applesauce mixture should not be stored for future use.

Patients should be instructed to report any diarrhea that does not improve, as this may indicate Clostridium difficile associated diarrhea, and to seek immediate medical attention for any cardiovascular or neurological symptoms, such as palpitations, dizziness, seizures, or tetany, which may suggest hypomagnesemia. They should also be encouraged to read the Medication Guide before starting omeprazole delayed-release capsules and with each refill, as there may be new information.

Patients must take omeprazole delayed-release capsules exactly as prescribed, at the lowest effective dose for the shortest duration necessary. It is advisable for them to discuss their risk of bone fracture with their healthcare provider if they are on this medication. They should inform their doctor immediately if they experience any symptoms of low magnesium, including seizures, dizziness, abnormal or rapid heartbeat, jitteriness, tremors, muscle weakness, spasms, cramps, or voice box spasms.

Healthcare providers may monitor magnesium levels before initiating treatment or during prolonged use of omeprazole delayed-release capsules. Patients should also be encouraged to report any bothersome side effects or those that do not resolve.

Storage and Handling

Omeprazole delayed-release capsules are supplied in a tight container to ensure protection from light and moisture. It is essential to store the capsules at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are crucial to maintain the integrity and efficacy of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Omeprazole as submitted by Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)