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. The structural formula is provided in the accompanying documentation.

Omeprazole appears as a white to off-white powder that melts between 150°C and 160°C with decomposition. It is soluble in dichloromethane and is sparingly soluble in methanol and alcohol. The formulation of omeprazole delayed-release capsules complies with the USP Drug Release Test 2.

These capsules are designed for oral administration and are available in strengths of 10 mg, 20 mg, or 40 mg of omeprazole, presented as enteric-coated granules. 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) and for the maintenance of healing of erosive esophagitis in both adults and children.

The safety and effectiveness of omeprazole in pediatric patients under 1 year of age have not been established. There are no teratogenic or nonteratogenic 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:

1. Triple Therapy:

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

   • Amoxicillin: 1000 mg, administered twice daily.

   • Clarithromycin: 500 mg, administered twice daily.

2. 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), the dosage is 20 mg once daily for 4 to 8 weeks.

To maintain healing of erosive esophagitis, omeprazole should be administered at a dosage of 20 mg once daily. For patients with pathological hypersecretory conditions, the dosage of omeprazole is 60 mg once daily, although this may vary based on individual patient needs.

For pediatric patients aged 2 to 16 years with GERD, the dosing is weight-dependent:

• For those weighing between 10 kg and 20 kg, the recommended dosage is 10 mg once daily.

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

Specific dosing for the healing of erosive esophagitis in pediatric patients has not been provided.

Contraindications

Use is contraindicated in patients with known hypersensitivity to any component of the formulation or substituted benzimidazoles. This contraindication is based on the potential for serious 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 malignancy in patients presenting with gastrointestinal symptoms (5.1).

Long-term therapy with proton pump inhibitors (PPIs) has been associated with the development of atrophic gastritis, a condition that may have implications for gastric health (5.2). Additionally, acute interstitial nephritis has been reported in patients receiving PPI therapy, necessitating careful monitoring of renal function (5.3).

Healthcare providers should be aware that prolonged daily use of PPIs, particularly beyond three years, may lead to malabsorption or deficiency of cyanocobalamin (vitamin B-12), warranting periodic assessment of vitamin B-12 levels in long-term users (5.4). Furthermore, there is an increased risk of Clostridium difficile-associated diarrhea in patients undergoing PPI therapy, which should be considered when evaluating gastrointestinal symptoms (5.5).

Concomitant use of omeprazole with clopidogrel is contraindicated due to the potential for reduced effectiveness of clopidogrel, which may compromise cardiovascular outcomes (5.6). Long-term and high-dose PPI therapy has also been linked to an elevated risk of osteoporosis-related fractures, particularly of the hip, wrist, or spine, highlighting the need for bone health monitoring in susceptible populations (5.7).

Rare cases of hypomagnesemia have been reported with extended PPI treatment, and healthcare professionals should consider monitoring magnesium levels in patients on prolonged therapy (5.8). Additionally, the concomitant use of omeprazole with St. John’s Wort or rifampin should be avoided, as these agents may significantly reduce omeprazole concentrations, potentially diminishing its therapeutic effect (5.9, 7.3).

Lastly, it is important to note that increases in intragastric pH due to PPI therapy may lead to hypergastrinemia and enterochromaffin-like cell hyperplasia, which can interfere with diagnostic investigations for neuroendocrine tumors by elevating Chromogranin A levels (5.10). Regular monitoring and appropriate diagnostic considerations are essential in managing patients receiving PPI therapy.

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.

Additional adverse reactions and important considerations include the potential for symptomatic responses that do not exclude the presence of gastric malignancy. Long-term therapy has been associated with atrophic gastritis. Acute interstitial nephritis has been observed in patients receiving proton pump inhibitors (PPIs). Furthermore, daily long-term use of PPIs, particularly beyond three years, may lead to malabsorption or deficiency of cyanocobalamin (vitamin B-12).

There is also an increased risk of Clostridium difficile-associated diarrhea associated with PPI therapy. Long-term and multiple daily dose PPI therapy may elevate the risk of osteoporosis-related fractures of the hip, wrist, or spine. Rarely, hypomagnesemia has been reported with prolonged treatment.

Patients with known hypersensitivity to any component of the formulation or substituted benzimidazoles may experience serious reactions, including angioedema and anaphylaxis.

In cases of overdosage, reports indicate a range of manifestations, including 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.

Drug Interactions

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

Pharmacodynamic Interactions

• Clopidogrel: Omeprazole decreases the exposure to the active metabolite of clopidogrel, which may reduce its antiplatelet effect. Monitoring of clinical response is advised.

• Cilostazol: The systemic exposure of cilostazol and one of its active metabolites is increased by omeprazole. A dose reduction of cilostazol should be considered.

Pharmacokinetic Interactions

• Atazanavir and Nelfinavir: Omeprazole reduces plasma levels of atazanavir and nelfinavir. Concomitant use is not recommended.

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

• Drugs Affected by Gastric pH: Omeprazole may interfere with the bioavailability of drugs such as ketoconazole, iron salts, erlotinib, ampicillin esters, digoxin, and mycophenolate mofetil. Patients receiving omeprazole and digoxin should be monitored for increased digoxin toxicity.

• Cytochrome P450 Metabolized Drugs: Omeprazole can prolong the elimination of drugs metabolized by cytochrome P450, including diazepam, warfarin, phenytoin, cyclosporine, disulfiram, and benzodiazepines. Monitoring is recommended to determine the need for dose adjustments.

• Warfarin: Patients treated with proton pump inhibitors, including omeprazole, may require monitoring for increases in INR and prothrombin time.

• Voriconazole: As a combined inhibitor of CYP2C19 and 3A4, voriconazole may raise omeprazole levels, necessitating monitoring.

• Tacrolimus: Omeprazole may increase serum levels of tacrolimus, warranting careful monitoring of tacrolimus levels.

• Methotrexate: Omeprazole may increase serum levels of methotrexate, which may require monitoring and potential dose adjustments.

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

Omeprazole is indicated for use in pediatric and adolescent patients aged 2 to 16 years for the treatment of gastroesophageal reflux disease (GERD) and for the maintenance of healing of erosive esophagitis. This indication is supported by the extrapolation of results from adequate and well-controlled studies conducted in adults, along with safety and pharmacokinetic studies specifically performed 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

Clinical trials involving over 2000 elderly individuals (≥ 65 years of age) have demonstrated that omeprazole is safe and effective, with no significant differences in safety and effectiveness observed 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 some older individuals may exhibit greater sensitivity to the medication.

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

Despite these pharmacokinetic differences, no dosage adjustment is necessary for elderly patients when prescribing omeprazole. However, healthcare providers should remain vigilant and monitor for any potential increased sensitivity in this population.

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 first trimester omeprazole use. Omeprazole is classified as a Pregnancy Category C medication, indicating that risk cannot be ruled out.

Animal reproduction studies have shown no teratogenicity with oral esomeprazole magnesium in rats and rabbits at doses approximately 68 times and 42 times, respectively, the human dose of 40 mg based on body surface area. However, changes in bone morphology were observed in offspring of rats dosed during most of pregnancy and lactation at doses equal to or greater than approximately 34 times the human dose. Due to these findings, omeprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human data from several studies indicate that the overall rates of congenital abnormalities among infants born to women who used omeprazole during pregnancy are comparable to those of control groups. A population-based retrospective cohort study from the Swedish Medical Birth Registry reported that the incidence of malformations, low birth weight, low Apgar scores, and hospitalization among infants exposed to omeprazole in utero was similar to that of the general population. However, a slight increase in the number of infants born with ventricular septal defects and stillbirths was noted in the omeprazole-exposed group.

In a Danish cohort study involving 1,800 live births, 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 proton pump inhibitors. Another retrospective cohort study reported a malformation rate of 3.6% in offspring of mothers exposed to omeprazole in the first trimester, which is lower than the rates observed for H2-blockers and unexposed mothers.

A small prospective observational cohort study involving 113 women exposed to omeprazole during pregnancy (89% in the first trimester) reported a rate of major congenital malformations of 4%, which is comparable to rates in control groups. Additionally, several studies have indicated no apparent adverse short-term effects on infants when omeprazole was administered as premedication for cesarean sections.

In summary, while animal studies have shown potential risks at high doses, human data suggest that first trimester exposure to omeprazole does not significantly increase the risk of major congenital malformations. Healthcare providers should weigh the potential benefits against the risks when considering omeprazole for pregnant patients.

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 omeprazole is administered to a nursing woman, considering the potential exposure to breastfed infants.

Renal Impairment

Patients with renal impairment should be monitored closely for potential adverse effects when taking proton pump inhibitors (PPIs). Acute interstitial nephritis has been observed in this population, necessitating vigilance for signs and symptoms of renal dysfunction. Additionally, hypomagnesemia has been reported rarely with prolonged treatment with PPIs, which may require periodic assessment of magnesium levels in patients with reduced kidney function. Dosing adjustments may be necessary based on the severity of renal impairment, and healthcare professionals should exercise caution when prescribing PPIs to these patients.

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 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 use of the medication.

It is noteworthy 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 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 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 respiratory rate, along with an increased depth of respiration.

Nonclinical Toxicology

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (approximately 34 times the human dose of 40 mg/day on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (also about 34 times the human dose on a body surface area basis) did not reveal any evidence of teratogenic potential. However, in rabbits, doses ranging from 6.9 to 69.1 mg/kg/day (approximately 3.4 to 34 times the human dose) 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 mg/kg/day (about 3.4 to 34 times the human dose).

Omeprazole administered at oral doses up to 138 mg/kg/day in rats (approximately 34 times the human dose) 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, and 140.8 mg/kg/day (about 0.4 to 34 times the human dose) 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/kg/day for one year and 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 vs. 10% in controls). By the second year, the difference between treated and control rats was smaller (46% vs. 26%), but hyperplasia remained more prevalent 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, this strain of rat has not shown similar tumors, making the interpretation of a single tumor finding 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 0.1 to 3.9 times the human dose). No astrocytomas were observed in female rats in this study. 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 34 times the human dose). A 78-week mouse carcinogenicity study did not demonstrate increased tumor occurrence, although the study was inconclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was also not positive.

Omeprazole was 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.

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.

Vitamin B-12 deficiency has also been reported, as omeprazole reduces stomach acid, which is necessary for the proper absorption of vitamin B-12. Patients who have been on omeprazole for more than three years should discuss the potential for deficiency with their doctor.

Low magnesium levels have been noted in some individuals taking proton pump inhibitors, including omeprazole, for at least three months, typically manifesting after one year of treatment. Symptoms of low magnesium may include seizures, dizziness, abnormal or rapid heartbeat, jitteriness, tremors, muscle weakness, spasms of the hands and feet, cramps, and spasm of the voice box. Patients experiencing these symptoms should seek medical attention promptly.

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, additional common side effects include respiratory system events and fever.

Serious allergic reactions have been reported, with symptoms such as rash, facial swelling, throat tightness, and difficulty breathing. Patients are encouraged to contact their healthcare provider if they experience any of these symptoms.

For medical advice regarding side effects, patients should consult their doctor. Side effects can also be reported 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 of the pellets. It is essential 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 persistent diarrhea, 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 should contact their healthcare provider promptly if they experience watery stools, stomach pain, and fever that does not resolve. It is advisable for patients to discuss their risk of bone fractures with their doctor if they are taking omeprazole delayed-release capsules. Furthermore, those who have been on this medication for an extended period (more than three years) should talk to their doctor about the potential for vitamin B-12 deficiency.

Patients should be vigilant for symptoms of low magnesium, including seizures, dizziness, abnormal or rapid heartbeat, jitteriness, jerking movements or shaking (tremors), muscle weakness, spasms of the hands and feet, cramps or muscle aches, or spasm of the voice box, and report these symptoms to their doctor immediately. Healthcare providers may check magnesium levels before initiating treatment or during prolonged use of omeprazole delayed-release capsules.

Lastly, patients should be informed to notify their healthcare provider if they experience any signs of serious allergic reactions, such as rash, facial swelling, throat tightness, or difficulty breathing.

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 Midwest Drug Distribution, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)