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)methyl sulfinyl]-1H-benzimidazole, which functions as an inhibitor of gastric acid secretion. The empirical formula of omeprazole is C17H19N3O3S, with a molecular weight of 345.42 g/mol. It appears as a white to off-white crystalline powder that decomposes at approximately 155°C.

Omeprazole 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. Its stability is pH-dependent, with rapid degradation occurring in acidic environments, while it maintains acceptable stability under alkaline conditions.

Omeprazole Delayed-Release Capsules are formulated to meet USP Dissolution Test 2 and are available for oral administration in strengths of 10 mg, 20 mg, or 40 mg, presented as enteric-coated granules. The inactive ingredients in the capsules include magnesium hydroxide, mannitol, methacrylic acid copolymer dispersion, povidone, and triethyl citrate. The capsule shells contain D&C Red No. 28, D&C Red No. 33, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, gelatin, iron oxide red, and titanium dioxide, with some ingredients being present in one or more of these components. The imprinting ink used on the capsules consists of ammonium hydroxide, black iron oxide, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, potassium hydroxide, propylene glycol, and shellac.

Uses and Indications

This drug is indicated for the treatment of active duodenal ulcers in adults. It is also indicated for the eradication of Helicobacter pylori to reduce the risk of duodenal ulcer recurrence in adults. Additionally, this drug is used for the treatment of active benign gastric ulcers in adults.

In pediatric populations, this drug is indicated for the treatment of symptomatic gastroesophageal reflux disease (GERD) in patients aged 1 year and older, as well as for the treatment of erosive esophagitis (EE) due to acid-mediated GERD in patients aged 1 month and older. Furthermore, it is indicated for the maintenance of healing of EE due to acid-mediated GERD in patients aged 1 year and older.

This drug is also indicated for the treatment of pathologic hypersecretory conditions in adults. There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

For the treatment of active duodenal ulcer, the recommended dosage is 20 mg administered orally once daily for a duration of 4 weeks. In some cases, an additional 4 weeks of treatment 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 orally twice daily for 10 days.

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

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

Dual Therapy:

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

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

For the treatment of active benign gastric ulcer, the recommended dosage is 40 mg administered orally once daily for a period of 4 to 8 weeks.

In cases of symptomatic gastroesophageal reflux disease (GERD), the dosage is 20 mg administered orally once daily for up to 4 weeks. For erosive esophagitis (EE) due to acid-mediated GERD, the initial dosage is 20 mg once daily for 4 to 8 weeks. If there is no response, an additional 4 weeks of treatment may be warranted. In instances of recurrence, further courses of 4 to 8 weeks may be considered.

For the maintenance of healing of EE due to acid-mediated GERD, a dosage of 20 mg administered orally once daily is recommended.

In patients with pathological hypersecretory conditions, the starting dose is 60 mg administered orally once daily. This dosage may vary based on individual patient needs and should be adjusted as clinically indicated.

All dosages are intended for oral administration.

Contraindications

Use of this product is contraindicated in patients with known hypersensitivity to substituted benzimidazoles or any component of the formulation. Additionally, it should not be administered to patients receiving rilpivirine-containing products due to potential drug interactions. When used in combination with clarithromycin and amoxicillin, please refer to the Contraindications section of their respective prescribing information for further guidance.

Warnings and Precautions

In adults, it is important to note that a symptomatic response to treatment does not exclude the possibility of gastric malignancy. Therefore, healthcare professionals should consider additional follow-up and diagnostic testing to rule out this condition.

Acute tubulointerstitial nephritis has been reported in patients receiving treatment. If this condition is suspected, it is crucial to discontinue the medication and evaluate the patient accordingly.

There is an association between proton pump inhibitor (PPI) therapy and an increased risk of Clostridium difficile-associated diarrhea. Clinicians should be vigilant for signs of this infection in patients undergoing PPI treatment.

Long-term use of PPIs, particularly at multiple daily doses, may increase the risk of osteoporosis-related fractures, specifically of the hip, wrist, or spine. It is advisable to assess the need for ongoing therapy in patients at risk for bone fractures.

Severe cutaneous adverse reactions may occur; therefore, treatment should be discontinued at the first signs or symptoms of such reactions or any other indications of hypersensitivity. Further evaluation by a specialist may be warranted.

Patients may experience new onset or exacerbation of cutaneous and systemic lupus erythematosus. In such cases, discontinuation of omeprazole is recommended, and referral to a specialist for evaluation should be considered.

Concomitant use of omeprazole with clopidogrel is contraindicated due to potential interactions that may diminish the effectiveness of clopidogrel.

Long-term daily use of PPIs, particularly beyond three years, may lead to malabsorption or deficiency of cyanocobalamin (Vitamin B-12). Monitoring of vitamin B-12 levels in patients on prolonged therapy is advisable.

Hypomagnesemia and disturbances in mineral metabolism have been reported, albeit rarely, with prolonged PPI treatment. Clinicians should monitor magnesium levels in patients receiving long-term therapy.

The concomitant use of omeprazole with St. John’s Wort or rifampin should be avoided due to potential interactions that may affect the efficacy of omeprazole.

In patients undergoing diagnostic investigations for neuroendocrine tumors, it is important to note that increased levels of Chromogranin A (CgA) may interfere with test results. Omeprazole should be temporarily discontinued at least 14 days prior to assessing CgA levels.

Caution is advised when using omeprazole in conjunction with methotrexate, as this combination may elevate and prolong serum concentrations of methotrexate and its metabolites, potentially leading to toxicity. In cases of high-dose methotrexate administration, a temporary withdrawal of omeprazole should be considered.

Finally, the risk of developing fundic gland polyps increases with long-term use of PPIs, particularly beyond one year. It is recommended to use the shortest duration of therapy necessary to manage the patient's condition.

Side Effects

Most common adverse reactions reported in adults, with an incidence of 2% or greater, include headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence. In pediatric patients aged 1 to 16 years, the safety profile is similar to that of adults; however, respiratory system events and fever were the most frequently reported reactions in pediatric studies.

Serious adverse reactions warranting attention include gastric malignancy, where a symptomatic response does not exclude the possibility of underlying gastric malignancy, necessitating further follow-up and diagnostic testing. Acute tubulointerstitial nephritis has been observed, and treatment should be discontinued and patients evaluated if this occurs. There is an increased risk of Clostridium difficile-associated diarrhea associated with PPI therapy. Long-term and multiple daily doses of PPIs may also be linked to an increased risk of osteoporosis-related fractures of the hip, wrist, or spine.

Severe cutaneous adverse reactions have been reported; treatment should be discontinued at the first signs or symptoms of such reactions or other signs of hypersensitivity, with further evaluation considered. Additionally, new onset or exacerbation of cutaneous and systemic lupus erythematosus has been noted, necessitating discontinuation of omeprazole and referral to a specialist for evaluation.

Interactions with other medications are significant; concomitant use of omeprazole with clopidogrel, St. John’s Wort, or rifampin should be avoided. Long-term daily use of omeprazole (beyond three years) may lead to malabsorption or deficiency of cyanocobalamin (Vitamin B-12). Rare cases of hypomagnesemia and mineral metabolism disturbances have been reported with prolonged PPI treatment. Furthermore, increased levels of Chromogranin A (CgA) may interfere with diagnostic investigations for neuroendocrine tumors, and omeprazole should be temporarily stopped at least 14 days prior to assessing CgA levels. Caution is advised when using omeprazole with methotrexate, as it may elevate and prolong serum concentrations of methotrexate and its metabolites, potentially leading to toxicity; a temporary withdrawal of omeprazole should be considered during high-dose methotrexate administration. The risk of fundic gland polyps increases with long-term use, particularly beyond one year, thus the shortest duration of therapy is recommended.

In cases of overdosage, reports indicate variable manifestations including confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, and dry mouth. Symptoms were transient, and no serious clinical outcomes have been reported when omeprazole was taken alone.

Drug Interactions

Clinically important drug interactions should be reviewed in the full prescribing information. It is essential for healthcare professionals to consider the potential for both pharmacodynamic and pharmacokinetic interactions when prescribing medications.

Pharmacodynamic interactions may occur when drugs with similar effects are used concurrently, potentially leading to enhanced therapeutic effects or increased risk of adverse reactions. Monitoring for increased effects or side effects is advised in such cases.

Pharmacokinetic interactions can arise from alterations in drug absorption, distribution, metabolism, or excretion. These interactions may necessitate dosage adjustments or increased monitoring of drug levels to ensure therapeutic efficacy while minimizing toxicity.

Healthcare providers are encouraged to consult the complete prescribing information for a comprehensive list of drug interactions and specific recommendations regarding dosage adjustments and monitoring protocols.

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 safety and effectiveness of omeprazole have been established in pediatric patients aged 1 to 16 years for the treatment of symptomatic gastroesophageal reflux disease (GERD), the treatment of erosive esophagitis (EE) due to acid-mediated GERD, and the maintenance of healing of EE due to acid-mediated GERD. In infants aged 1 month to less than 1 year, omeprazole is indicated for the treatment of EE due to acid-mediated GERD.

Adverse reactions have been reported in the pediatric population, with respiratory system events frequently noted across the entire age range of 1 month to 16 years. Specific age-related adverse reactions include otitis media, which was commonly reported in infants aged 1 month to less than 1 year, fever in children aged 1 to less than 2 years, and accidental injuries in those aged 2 to 16 years.

It is important to note that the safety and effectiveness of omeprazole have not been established in patients under 1 year of age for the treatment of symptomatic GERD or for the maintenance of healing of EE due to acid-mediated GERD. Additionally, omeprazole is not indicated for pediatric patients for the treatment of active duodenal ulcers, H. pylori eradication to reduce the risk of duodenal ulcer recurrence, treatment of active benign gastric ulcers, or pathological hypersecretory conditions. Furthermore, omeprazole is contraindicated in patients less than 1 month of age for any indication.

Geriatric Use

Omeprazole has been administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials conducted in the U.S. and Europe. The results indicated no significant differences in safety and effectiveness between elderly patients and younger subjects. While other clinical experiences have not identified notable differences in response between these age groups, it is important to acknowledge that greater sensitivity in some older individuals cannot be entirely excluded.

Pharmacokinetic studies have demonstrated 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 when prescribing omeprazole. Healthcare providers should remain vigilant and monitor for any potential increased sensitivity in this population, although the overall safety profile appears consistent with that of younger patients.

Pregnancy

There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data do not demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with the use of omeprazole during the first trimester. In a population-based retrospective cohort study from the Swedish Medical Birth Registry, the rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9%, which is comparable to the 2.6% observed in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole was 3.6%, compared to 5.5% for H2-blockers and 4.1% for unexposed mothers. The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls.

Reproduction studies in rats and rabbits have shown dose-dependent embryo-lethality at omeprazole doses approximately 3.4 to 34 times the oral human dose of 40 mg, based on body surface area for a 60 kg person. However, teratogenicity was not observed in animal reproduction studies with the administration of oral esomeprazole, an enantiomer of omeprazole, during organogenesis at doses about 68 times and 42 times, respectively, the oral human dose of 40 mg. Changes in bone morphology were noted in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times the oral human dose of 40 mg. When maternal administration was limited to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown; however, all pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 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. Given the available data, healthcare professionals should weigh the potential benefits against the risks when considering omeprazole for pregnant patients.

Lactation

There are no adequate and well-controlled studies with omeprazole in nursing mothers. Reproductive studies conducted with omeprazole in rats during the lactation period have shown dose-related embryo/fetal toxicity and postnatal developmental toxicity. Additionally, effects on maternal bone were observed in pregnant and lactating rats when esomeprazole magnesium was administered. However, when maternal administration of esomeprazole was limited to gestation only, there were no observed effects on bone physeal morphology in the offspring at any age. Given the lack of data in human subjects and the potential risks observed in animal studies, caution is advised when considering the use of omeprazole in lactating mothers.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular assessment of renal function may be warranted to ensure safe and effective use of the medication in patients with reduced kidney function.

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 indicated for individuals with compromised liver function. It is recommended that healthcare providers exercise caution and consider the overall clinical context when prescribing this medication to patients with hepatic impairment.

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 have been variable, but commonly reported symptoms include confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, and dry mouth. These adverse reactions are consistent with those observed in normal clinical experience.

It is important to note that the symptoms associated with omeprazole overdosage are typically transient, and no serious clinical outcomes have been reported when omeprazole is taken in isolation. Currently, there is no specific antidote available for omeprazole overdosage. Given that omeprazole is extensively protein-bound, it is not readily dialyzable.

In the event of an overdosage, treatment should focus on symptomatic and supportive care. Healthcare professionals are advised to contact the Poison Control Center at 1-800-222-1222 for the most current information regarding the management of poisoning or overdosage.

Nonclinical Toxicology

In two 24-month carcinogenicity studies conducted in rats, omeprazole was administered at daily doses of 1.7, 3.4, 13.8, 44, and 140.8 mg/kg/day, corresponding to approximately 0.4 to 34 times the human dose of 40 mg/day based on body surface area. The 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 observed in female rats, which exhibited elevated blood levels of omeprazole. Gastric carcinoids are infrequently observed in untreated rats. Additionally, ECL cell hyperplasia was noted in all treated groups across both sexes. In one study, female rats treated with 13.8 mg/kg/day for one year and subsequently observed for an additional year without the drug 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 between treated and control rats diminished (46% versus 26%), yet the treated group still exhibited a higher prevalence of hyperplasia. Gastric adenocarcinoma was identified in one rat (2%), with no similar tumors reported in male or female rats over the two-year period. Historically, this strain of rat has not shown similar tumors, although the interpretation of a single tumor finding is challenging.

In a 52-week toxicity study involving Sprague-Dawley rats, brain astrocytomas were observed in a small number of male rats receiving omeprazole at doses of 0.4, 2, and 16 mg/kg/day (approximately 0.1 to 3.9 times the human dose of 40 mg/day based on body surface area). No astrocytomas were detected in female rats during this study. Conversely, in a separate 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in either sex at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis). A 78-week carcinogenicity study in mice did not demonstrate an increased occurrence of tumors, although the results were inconclusive. Additionally, a 26-week p53 (+/-) transgenic mouse carcinogenicity study yielded negative results.

Omeprazole exhibited positive 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, omeprazole 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.

In terms of reproductive toxicity, omeprazole administered at oral doses up to 138 mg/kg/day in rats (approximately 34 times the oral human dose of 40 mg based on body surface area) did not affect fertility or reproductive performance. Furthermore, the 24-month carcinogenicity studies in rats indicated a significant dose-related increase in gastric carcinoid tumors and ECL cell hyperplasia in both male and female animals. It is noteworthy that 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

No specific postmarketing experience details are available in the provided text. As such, there are no reported adverse events or case reports to summarize.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, which includes the Medication Guide and Instructions for Use. This information is essential for understanding the proper use of the medication, potential side effects, and any necessary precautions. Emphasizing the importance of this material can help ensure that patients are well-informed and can engage in their treatment plan effectively.

Storage and Handling

Omeprazole delayed-release capsules are supplied in a tight container that is designed to protect the contents from light and moisture. It is essential to store the capsules at a temperature range of 20°C to 25°C (68°F to 77°F). Temporary excursions outside this range are permissible, provided they do not exceed 15°C to 30°C (59°F to 86°F), in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

Serum chromogranin A (CgA) levels may increase due to drug-induced reductions in gastric acidity, potentially leading to false positive results in neuroendocrine tumor diagnostics. Clinicians are advised to discontinue omeprazole treatment at least 14 days prior to CgA level assessment and to consider retesting if initial levels are elevated. For serial testing, it is important to utilize the same commercial laboratory, as reference ranges may differ.

Patients should be counseled to use the lowest effective dose of proton pump inhibitors (PPIs) for the shortest duration necessary. If symptoms indicative of cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) arise, omeprazole should be discontinued, and the patient referred for specialist evaluation, with most patients showing improvement within 4 to 12 weeks post-discontinuation. For those on prolonged PPI therapy or concomitant medications that may induce hypomagnesemia, such as diuretics, monitoring of magnesium levels is recommended prior to and during treatment. Postmarketing reports have indicated severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), as well as cases of hypomagnesemia and fundic gland polyps associated with PPI use.

FDA Insert (PDF)

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

View full prescribing information (PDF)