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 a gastric acid secretion inhibitor. The empirical formula of omeprazole is C17H19N3O3S, with a molecular weight of 345.42. 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 the USP Drug Release Test 2 standards and are available for oral administration in dosages of 10 mg, 20 mg, or 40 mg. Each capsule contains enteric-coated granules of omeprazole along with inactive ingredients such as 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 used on the capsules includes 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. 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.

Limitations of Use: 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.

In the case of gastric ulcers, the recommended dosage of omeprazole is 40 mg once daily for a treatment period of 4 to 8 weeks. For 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, a dosage of 20 mg of omeprazole is recommended once daily. For patients with pathological hypersecretory conditions, the dosage of omeprazole may vary, typically starting 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 patients weighing between 10 kg and 20 kg, the recommended dosage is 10 mg once daily.

• For patients weighing 20 kg or more, the recommended 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 risk of severe allergic reactions, including angioedema and anaphylaxis, which have been reported in such cases.

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 if symptoms persist or worsen (5.1).

Long-term therapy with proton pump inhibitors (PPIs) has been associated with the development of atrophic gastritis. This condition may necessitate careful monitoring of gastric health in patients undergoing extended treatment (5.2).

There is an increased risk of osteoporosis-related fractures of the hip, wrist, or spine associated with long-term and multiple daily doses of PPI therapy. Clinicians should assess the fracture risk in patients, particularly those with additional risk factors for osteoporosis (5.3).

The use of 80 mg omeprazole may diminish the anti-platelet activity of clopidogrel due to impaired CYP2C19 function. It is essential to evaluate the potential impact on patients requiring antiplatelet therapy and consider alternative management strategies (5.4).

When prescribing triple therapy for Helicobacter pylori eradication, healthcare providers should be aware of the risks associated with the antibiotics used. Refer to the prescribing information for each antibiotic for specific warnings and precautions (5.5, 5.6).

Hypomagnesemia has been reported rarely in patients receiving prolonged treatment with PPIs. Monitoring of magnesium levels may be warranted in patients on long-term therapy, especially if they exhibit symptoms suggestive of magnesium deficiency (5.7).

Concomitant use of omeprazole with St. John’s Wort or rifampin should be avoided due to the potential for reduced omeprazole concentrations, which may compromise therapeutic efficacy (5.8, 7.3).

In patients undergoing diagnostic investigations for neuroendocrine tumors, it is important to note that increases in intragastric pH may lead to hypergastrinemia and enterochromaffin-like cell hyperplasia, resulting in elevated Chromogranin A levels. These changes can interfere with diagnostic accuracy, necessitating careful interpretation of results (5.9, 12.2).

Side Effects

Most common adverse reactions reported in adult 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 of adults; however, respiratory system events and fever were the most frequently reported reactions in clinical studies involving this age group.

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

In cases of overdosage with omeprazole, reports have included symptoms such as 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 of note include atrophic gastritis, which has been documented with long-term therapy. Long-term and multiple daily dose proton pump inhibitor (PPI) therapy may also be associated with an increased risk of osteoporosis-related fractures of the hip, wrist, or spine. Rare instances of hypomagnesemia have been reported with prolonged PPI treatment.

It is important to note that omeprazole may diminish the anti-platelet activity of clopidogrel due to impaired CYP2C19 function when administered at a dose of 80 mg. Furthermore, concomitant use of omeprazole with St. John’s Wort or rifampin should be avoided due to the potential reduction in omeprazole concentrations.

Lastly, increases in intragastric pH caused by omeprazole may result in hypergastrinemia and enterochromaffin-like cell hyperplasia, which can interfere with diagnostic investigations for neuroendocrine tumors by increasing Chromogranin A levels.

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. Therefore, the combination of these medications should be avoided. In contrast, omeprazole increases plasma levels of saquinavir, necessitating careful monitoring for potential toxicity. A dose reduction of saquinavir may be warranted in such cases.

Omeprazole may also interfere with the bioavailability of drugs that are sensitive to gastric pH changes, including ketoconazole, iron salts, ampicillin esters, and digoxin. Patients receiving both omeprazole and digoxin should be monitored for signs of increased digoxin toxicity.

The systemic exposure of cilostazol and one of its active metabolites is increased when administered with omeprazole. A dose reduction of cilostazol should be considered to mitigate the risk of adverse effects.

Drugs that are metabolized by cytochrome P450, such as diazepam, warfarin, phenytoin, cyclosporine, disulfiram, and various benzodiazepines, may have prolonged elimination when used concurrently with omeprazole. Monitoring is advised to determine the necessity for dose adjustments. In particular, patients on warfarin should be closely monitored for increases in INR and prothrombin time.

Additionally, the use of combined inhibitors of CYP 2C19 and 3A4, such as voriconazole, may elevate omeprazole levels, warranting caution. Omeprazole may also increase serum levels of tacrolimus and methotrexate, necessitating monitoring and potential dose adjustments for these medications.

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 aged 65 years and older in clinical trials conducted in the U.S. and Europe. The results from these studies indicate no significant differences in safety and effectiveness between elderly patients and younger subjects. However, it is important to note that while clinical experience has not identified distinct differences in response between these age groups, the possibility of greater sensitivity in some older individuals cannot be entirely excluded.

Pharmacokinetic studies reveal 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 changes, 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 routine dose modifications are not warranted.

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. 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 was reported at 4.4% (95% CI 3.6 to 5.3), the malformation rate for first trimester exposure specifically 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), effectively ruling out a relative risk greater than 2.5 for all malformations. Rates of preterm delivery and growth retardation did not differ between groups, and the reported rates of major congenital malformations were 4% for the omeprazole group, compared to 2% for controls exposed to non-teratogens and 2.8% in disease-paired controls, with a background incidence of major malformations ranging from 1% to 5%.

Additionally, rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight did not differ between the groups. 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.

Animal studies have shown that omeprazole administered to pregnant rabbits at doses approximately 5.5 to 56 times the human dose resulted in dose-related increases in embryo lethality, fetal resorptions, and pregnancy loss. In rats treated with omeprazole at doses about 5.6 to 56 times the human dose, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring.

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, corresponding 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

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to 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 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 transient, and it is noteworthy that 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 is standard in the management of any overdose.

For the most current information regarding the treatment of any drug overdose, it is advisable to contact the local Poison Control Center.

Animal Studies

In animal studies, single oral doses of omeprazole at 1350 mg/kg in mice, 1339 mg/kg in rats, and 1200 mg/kg in dogs were found to be 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 monitoring and management in cases of suspected overdosage.

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 rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring from parents treated with omeprazole at doses of 13.8 to 138.0 mg/kg/day (about 5.6 to 56 times the human doses on a body surface area basis).

Omeprazole at oral doses up to 138 mg/kg/day in rats (approximately 56 times the human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance.

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0, 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 in female rats, which exhibited higher blood levels of omeprazole. Gastric carcinoids are rarely observed in untreated rats. ECL cell hyperplasia was noted 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 develop carcinoids. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% in treated rats vs 10% in controls). By the second year, the difference between treated and control rats diminished (46% vs 26%), yet hyperplasia remained more prevalent in the treated group. Gastric adenocarcinoma was observed in one rat (2%), but no similar tumors were noted in male or female rats treated for two years. Historically, no similar tumors have been reported in this strain of rat, although 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 doses 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), while no astrocytomas were 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 carcinogenicity study in mice did not demonstrate increased tumor occurrence, although the study was inconclusive. 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, 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.

Postmarketing Experience

Postmarketing experience has identified several adverse events reported voluntarily or through surveillance programs.

Low magnesium levels have been observed in some individuals taking proton pump inhibitors for at least three months, with occurrences typically noted after one year of treatment. Symptoms associated with low magnesium may include seizures, dizziness, abnormal or rapid heartbeat, jitteriness, jerking movements or shaking (tremors), muscle weakness, spasms of the hands and feet, cramps or muscle aches, and spasm of the voice box. Patients are advised to inform their healthcare provider immediately if they experience any of these symptoms.

Additionally, prolonged use of proton pump inhibitors, particularly at multiple daily doses, may be associated with an increased risk of fractures of the hip, wrist, or spine.

The most commonly reported side effects associated with omeprazole delayed-release capsules in both adults and children include headache, abdominal pain, nausea, diarrhea, vomiting, gas, respiratory system events, and fever. Patients are encouraged to report any side effects that are bothersome or persistent to their healthcare provider. It is important to note that these are not all possible side effects, and further inquiries regarding side effects can be directed to a healthcare professional or pharmacist. Side effects may also be reported to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients should be advised to take omeprazole delayed-release capsules at least one hour before a meal to ensure optimal effectiveness. It is important for patients to swallow the capsules whole and not to chew or crush them. For those who experience 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, ensuring that the pellets are swallowed completely. Patients should be informed that the applesauce must not be hot and should be soft enough to swallow without chewing. Additionally, the pellets/applesauce mixture should not be stored for future use.

Patients should be instructed to read the patient information that accompanies omeprazole delayed-release capsules before starting treatment and each time they receive a refill, as there may be new information. They should also be encouraged to ask their doctor any questions they may have regarding the medication.

It is crucial for patients to disclose all medical conditions to their healthcare provider, particularly if they have low magnesium levels, liver problems, or if they are pregnant, planning to become pregnant, breastfeeding, or planning to breastfeed. Patients should inform their doctor about all medications they are taking, including prescription and non-prescription drugs, anti-cancer medications, vitamins, and herbal supplements.

Patients must take omeprazole delayed-release capsules exactly as prescribed and should not alter their dose or discontinue use without consulting their doctor. In the event of a missed dose, patients should take it as soon as they remember, but if it is close to the time for the next dose, they should skip the missed dose and resume their regular schedule without taking a double dose.

Patients should be made aware of the potential symptoms of low magnesium, such as seizures, dizziness, abnormal or rapid heartbeat, jitteriness, jerking movements or shaking, muscle weakness, spasms of the hands and feet, cramps or muscle aches, or spasm of the voice box. They should be instructed to report any such symptoms to their doctor immediately. Furthermore, patients should notify their healthcare provider of any side effects that are bothersome or persistent. Lastly, patients should not take omeprazole delayed-release capsules if they are allergic to any of its ingredients or any other Proton Pump Inhibitor (PPI) medication.

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)