Omeprazole

Description

Omeprazole delayed-release capsules contain the active ingredient omeprazole, a substituted benzimidazole with the chemical structure 5-methoxy-2-[(4-methoxy-3, 5-dimethyl-2-pyridinyl)methylsulfinyl]1H-benzimidazole, which functions as a gastric acid secretion inhibitor. The molecular formula of omeprazole is C17H19N3O3S, and it has a molecular weight of 345.42.

Omeprazole appears as a white to off-white crystalline powder that decomposes 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, with rapid degradation occurring in acidic environments, while it maintains acceptable stability under alkaline conditions.

The drug is formulated as delayed-release capsules for oral administration, available in strengths of 10 mg, 20 mg, and 40 mg. Each capsule contains enteric-coated granules of omeprazole, USP, along with inactive ingredients such as ammonium hydroxide, dibutyl sebacate, ethylcellulose, fumed silica, hypromellose, methacrylic acid, oleic acid, sugar spheres, talc, titanium dioxide, and triethyl citrate. The gelatin capsule shells are composed of D&C Yellow No. 10, FD&C Green No. 3, gelatin, silicon dioxide, sodium lauryl sulfate, and titanium dioxide, with the 40 mg capsule shell additionally containing FD&C Blue No. 1. The imprinting ink used is a white formulation containing ammonium hydroxide, pharmaceutical glaze, simethicone, and titanium dioxide. Omeprazole delayed-release capsules, at all strengths, comply with the USP Drug Release Test 2.

Uses and Indications

Omeprazole is indicated for the treatment of duodenal ulcers and gastric ulcers in adults. It is also 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.

The safety and effectiveness of omeprazole in pediatric patients under 1 year of age have not been established. There are no teratogenic effects associated with the use of omeprazole.

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.

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

• Clarithromycin: 500 mg, administered twice daily.

Dual Therapy:

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

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

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

To maintain the healing of erosive esophagitis, omeprazole should be administered at a dosage of 20 mg once daily. In cases of pathological hypersecretory conditions, the dosage may vary with individual patient needs, typically starting at 60 mg once daily.

For pediatric patients aged 2 to 16 years with GERD and for the maintenance of healing of erosive esophagitis, the following dosages are recommended:

• For patients weighing less than 20 kg, the dosage is 10 mg once daily.

• For patients weighing 20 kg or more, the dosage is 20 mg once daily.

Contraindications

Use of this product is contraindicated in individuals with known hypersensitivity to any component of the formulation or to substituted benzimidazoles. This is due to the potential for serious allergic reactions, including angioedema and anaphylaxis.

Warnings and Precautions

Symptomatic response to treatment does not exclude the possibility of underlying gastric malignancy. Healthcare professionals should remain vigilant and consider further diagnostic evaluation in patients presenting with symptoms suggestive of gastric conditions, even if symptomatic relief is achieved.

Long-term therapy may lead to the development of atrophic gastritis. Clinicians should monitor patients receiving extended treatment for signs and symptoms indicative of this condition, as it may have implications for gastric health.

When administering triple therapy for the eradication of Helicobacter pylori, it is essential to be aware of the associated risks linked to the individual antibiotics used in the regimen. Healthcare providers should consult the prescribing information for each antibiotic to understand the specific warnings and precautions, ensuring safe and effective treatment for patients.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. The 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 2 to 16 years, the safety profile is similar to that observed in adults; however, respiratory system events and fever were noted as the most frequently reported reactions in clinical studies involving this population.

Serious hypersensitivity reactions have been documented, including angioedema and anaphylaxis, which require immediate medical attention.

In cases of overdosage, patients may present with symptoms such as confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, and dry mouth. These reactions may overlap with those typically observed during normal clinical use.

Long-term therapy has been associated with atrophic gastritis, and it is important to note that a symptomatic response does not exclude the possibility of gastric malignancy.

Drug Interactions

Concomitant use of omeprazole with certain medications may lead to significant drug interactions, necessitating careful monitoring and potential dosage adjustments.

Pharmacodynamic Interactions

Omeprazole may interfere with the bioavailability of drugs that are affected by gastric pH, including ketoconazole, iron salts, ampicillin esters, and digoxin. Clinicians should consider alternative therapies or monitor the effectiveness of these medications when used concurrently with omeprazole.

Pharmacokinetic Interactions

Antiretrovirals:

• Atazanavir and Nelfinavir: Omeprazole reduces plasma levels of both atazanavir and nelfinavir. The concomitant use of these medications with omeprazole is not recommended.

• Saquinavir: Omeprazole increases plasma levels of saquinavir. Monitoring for toxicity is advised, and a dose reduction of saquinavir may be necessary.

Cilostazol:Omeprazole increases the systemic exposure of cilostazol and one of its active metabolites. A dose reduction of cilostazol should be considered.

Cytochrome P450 Metabolized Drugs:Omeprazole can prolong the elimination of drugs metabolized by cytochrome P450, such as diazepam, warfarin, phenytoin, cyclosporine, disulfiram, and benzodiazepines. Monitoring is recommended to assess the need for dose adjustments, particularly in patients taking warfarin, who may require increased monitoring of INR and prothrombin time.

Tacrolimus:Omeprazole may increase serum levels of tacrolimus, necessitating monitoring of tacrolimus levels and potential dose adjustments.

Other Interactions:The use of combined inhibitors of CYP 2C19 and 3A4, such as voriconazole, may elevate omeprazole levels, warranting careful monitoring of omeprazole concentrations and clinical effects.

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) is supported by extrapolation from adequate and well-controlled studies conducted in adults, along with safety and pharmacokinetic studies performed specifically in pediatric and adolescent populations. 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 seen in young healthy volunteers.

Despite these pharmacokinetic variations, no dosage adjustment is necessary for elderly patients. However, healthcare providers should remain vigilant and consider the potential for increased sensitivity in some geriatric patients when prescribing omeprazole. Regular monitoring and assessment of therapeutic response may be warranted to ensure optimal treatment outcomes in this population.

Pregnancy

Pregnancy Category C. Reproductive studies in rats and rabbits, as well as multiple cohort studies involving pregnant women, have not demonstrated an increased risk of congenital anomalies or adverse pregnancy outcomes associated with omeprazole use during the first trimester. However, there are no adequate and well-controlled studies on the use of omeprazole in pregnant women, and because animal reproduction studies are not always predictive of human response, this medication should be used during pregnancy only if clearly needed.

The majority of reported experiences with omeprazole during human pregnancy involve first trimester exposure, with the duration of use often unspecified (e.g., intermittent vs. chronic). An expert review by the Teratogen Information System (TERIS) concluded that therapeutic doses of omeprazole during pregnancy are unlikely to pose a substantial teratogenic risk, although the quantity and quality of data were assessed as fair. In utero exposure to omeprazole has not been associated with an increased risk of malformations (odds ratio 0.82, 95% CI 0.50 to 1.34), low birth weight, or low Apgar scores.

While the overall malformation rate in the omeprazole group was reported at 4.4% (95% CI 3.6 to 5.3), the rate for first trimester exposure was 3.6% (95% CI 1.5 to 8.1). The relative risk of malformations associated with first trimester exposure compared to non-exposed women was 0.9 (95% CI 0.3 to 2.2). Rates of preterm delivery, growth retardation, spontaneous and elective abortions, gestational age at delivery, and mean birth weight did not differ significantly between groups.

Notably, 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 sections under general anesthesia. However, reproductive studies in animals have shown that omeprazole can produce dose-related increases in embryo-lethality, fetal resorptions, and pregnancy loss in pregnant rabbits at doses approximately 5.5 to 56 times the human dose. In rats, doses in the same range resulted in embryo/fetal toxicity and postnatal developmental toxicity in offspring.

Given these findings, healthcare professionals should carefully consider the risks and benefits of omeprazole use in pregnant patients, particularly during the first trimester.

Lactation

Omeprazole concentrations have been measured in the breast milk of a lactating mother following oral administration of 20 mg. 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.

Due to the excretion of omeprazole in human milk and the potential for serious adverse reactions in breastfed infants, as well as the potential for tumorigenicity demonstrated in rat carcinogenicity studies, healthcare professionals should consider the risks and benefits when advising lactating mothers. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of omeprazole to the mother’s health.

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 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 adverse reactions are similar to those observed in normal clinical experience.

It is noteworthy that the symptoms associated with omeprazole overdosage were transient, and no serious clinical outcomes have been reported when omeprazole was 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 be symptomatic and supportive. Healthcare professionals should also consider the possibility of multiple drug ingestion, as is standard in the management of any overdose. For up-to-date information on the treatment of any drug overdose, it is advisable to contact a Poison Control Center at 1-800-222-1222.

Animal studies have indicated that single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were lethal to mice, rats, and dogs, respectively. The observed effects in these animals included sedation, ptosis, tremors, convulsions, decreased activity, reduced body temperature, and respiratory rate, along with increased depth of respiration.

Nonclinical Toxicology

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (approximately 56 times the human dose on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (also about 56 times the human dose on a body surface area basis) did not reveal any evidence of teratogenic potential. However, in rabbits, omeprazole administered at doses ranging from 6.9 to 69.1 mg/kg/day (approximately 5.5 to 56 times the human dose on a body surface area basis) resulted in dose-related increases in embryo lethality, fetal resorptions, and pregnancy disruptions.

In non-teratogenic effects, rats exhibited dose-related embryo/fetal toxicity and postnatal developmental toxicity in offspring from parents treated with omeprazole at doses of 13.8 to 138 mg/kg/day (about 5.6 to 56 times the human doses on a body surface area basis). Notably, omeprazole at oral doses up to 138 mg/kg/day in rats (approximately 56 times the human dose on a body surface area basis) did not affect fertility or reproductive performance.

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44, and 140.8 mg/kg/day (about 0.7 to 57 times a human dose of 20 mg/day, as expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats, with a markedly higher incidence observed in female rats, which had higher blood levels of omeprazole. Gastric carcinoids are rarely seen in untreated rats. ECL cell hyperplasia was present in all treated groups of both sexes. In one study, female rats treated with 13.8 mg omeprazole/kg/day (approximately 6 times a human dose of 20 mg/day, based on body surface area) for one year and subsequently followed for an additional year without the drug did not show carcinoids. An increased incidence of treatment-related ECL cell hyperplasia was noted at the end of one year (94% in treated vs. 10% in controls). By the second year, the difference between treated and control rats was smaller (46% vs. 26%) but still indicated more hyperplasia in the treated group. Gastric adenocarcinoma was observed in one rat (2%), with no similar tumors noted in male or female rats treated for two years. Historically, no similar tumors have been reported in this strain of rat, but the interpretation of a single tumor finding is challenging. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were identified in a small number of males receiving omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (approximately 0.2 to 6.5 times the human dose on a body surface area basis), with no astrocytomas observed in female rats. In a 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 57 times the human dose on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not demonstrate increased tumor occurrence, although the study was inconclusive. Additionally, a 26-week p53 (+/-) transgenic mouse carcinogenicity study yielded negative results.

Omeprazole was found to be positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Conversely, 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 the 24-month carcinogenicity studies in rats, a significant dose-related increase in gastric carcinoid tumors and ECL cell hyperplasia was observed 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 reactions associated with the use of the product. These include Clostridium difficile-associated diarrhea, acute interstitial nephritis, hypomagnesemia, bone fractures, cutaneous and systemic lupus erythematosus, acute kidney injury, liver enzyme elevations, anaphylactic reactions, angioedema, and serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Additionally, gastrointestinal infections, pneumonia, and fundic gland polyps have been reported.

Other rare adverse reactions have also been documented, including but not limited to thrombocytopenia, agranulocytosis, hepatitis, pancreatitis, interstitial nephritis, hypersensitivity reactions, cardiovascular events, respiratory events, neurological events, musculoskeletal events, endocrine events, metabolic events, hematologic events, psychiatric events, vision disorders, hearing disorders, skin disorders, renal disorders, reproductive disorders, and other unspecified events. These events were reported voluntarily or through surveillance programs and do not imply a causal relationship.

Patient Counseling

Healthcare providers should advise patients that omeprazole delayed-release capsules are to be taken before meals to ensure optimal effectiveness. It is important to inform patients that these capsules must be swallowed whole and should not be chewed or crushed, as this may affect the medication's action.

For patients who experience difficulty swallowing capsules, healthcare providers can recommend an alternative method of administration. Patients may open the capsule and mix the contents with one tablespoon of applesauce. Providers should instruct patients to place the applesauce in an empty bowl, carefully empty the pellets from the capsule onto the applesauce, and mix them together. This mixture should be swallowed immediately with a glass of cool water to ensure that all pellets are ingested.

Healthcare providers should emphasize that the applesauce used should not be hot and must be soft enough to swallow without chewing. Additionally, it is crucial to inform patients that the pellets/applesauce mixture should not be stored for future use, as this may compromise the medication's effectiveness.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. It is essential to protect the product from light and moisture to maintain its integrity and efficacy. Proper storage conditions must be adhered to in order to ensure optimal performance.

Additional Clinical Information

Laboratory tests for susceptibility testing of Helicobacter pylori utilize agar dilution minimum inhibitory concentrations (MICs). An inoculum of 1 to 3 microliters, equivalent to a No. 2 McFarland standard (1 x 10^7 to 1 x 10^8 CFU/mL), is applied to Mueller-Hinton agar plates containing 5% aged defibrinated sheep blood. These plates are incubated at 35°C in a microaerobic environment for three days, after which the MICs are determined. The interpretation criteria for clarithromycin and amoxicillin MIC values are as follows: for clarithromycin, ≤0.25 mcg/mL indicates susceptibility, 0.5 mcg/mL is intermediate, and >1 mcg/mL indicates resistance; for amoxicillin, ≤0.25 mcg/mL indicates susceptibility.

For treatment regimens, dual therapy consists of omeprazole 40 mg once daily and clarithromycin 500 mg three times daily for 14 days, followed by omeprazole 20 mg once daily for an additional 14 days. Triple therapy includes omeprazole 20 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily for 10 days, followed by omeprazole 20 mg once daily for another 18 days. Clinicians should counsel patients that those not successfully eradicating H. pylori after these therapies may harbor clarithromycin-resistant strains. Therefore, clarithromycin susceptibility testing is recommended, and patients with resistant strains should avoid regimens that include clarithromycin as the sole antimicrobial agent.

FDA Insert (PDF)

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

View full prescribing information (PDF)