Omeprazole

Uses and Indications

Omeprazole is indicated for the treatment of various gastrointestinal conditions in adults and pediatric patients. The specific indications include:

Adult Indications

• Treatment of active duodenal ulcer.

• Eradication of Helicobacter pylori to reduce the risk of duodenal ulcer recurrence.

• Treatment of active benign gastric ulcer.

• Treatment of symptomatic gastroesophageal reflux disease (GERD).

• Treatment of erosive esophagitis (EE) due to acid-mediated GERD.

• Maintenance of healing of erosive esophagitis due to acid-mediated GERD.

• Treatment of pathologic hypersecretory conditions, including Zollinger-Ellison syndrome.

Pediatric Indications

• Treatment of symptomatic gastroesophageal reflux disease (GERD) in patients 1 year of age and older.

• Treatment of erosive esophagitis (EE) due to acid-mediated GERD in patients 1 month of age and older.

• Maintenance of healing of erosive esophagitis due to acid-mediated GERD in patients 1 year of age and older.

Limitations of Use

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

Omeprazole is available in capsule and delayed-release forms.

Dosage and Administration

Omeprazole is administered orally in the form of delayed-release capsules. The recommended dosages and administration guidelines are as follows:

Treatment of Active Duodenal Ulcer: The standard dosage is 20 mg once daily for 4 weeks. Some patients may require an additional 4 weeks of treatment.

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence:

• Triple Therapy: Administer 20 mg of Omeprazole, Amoxicillin 1000 mg, and Clarithromycin 500 mg, with each drug taken twice daily for 10 days.

• Dual Therapy: Administer 40 mg of Omeprazole once daily for 14 days, along with Clarithromycin 500 mg taken three times daily for 14 days.

Active Benign Gastric Ulcer: The recommended dosage is 40 mg once daily for a duration of 4 to 8 weeks.

Symptomatic GERD: The dosage is 20 mg once daily for up to 4 weeks.

Erosive Esophagitis (EE) due to Acid-Mediated GERD: The recommended dosage is 20 mg once daily for 4 to 8 weeks. An additional 4 weeks of treatment may be considered if there is no response, and if recurrence occurs, additional courses of 4 to 8 weeks may be warranted.

Maintenance of Healing of EE due to Acid-Mediated GERD: The dosage is 20 mg once daily. For patients with hepatic impairment (Child-Pugh Class A, B, or C) and Asian patients, the dosage may be reduced to 10 mg once daily.

Pathological Hypersecretory Conditions: The starting dose is 60 mg once daily, which may vary based on individual patient needs.

Pediatric Patients (2 to 16 years of age):

• For GERD and maintenance of healing of erosive esophagitis:

  • Weight < 20 kg: 10 mg once daily.

  • Weight ≥ 20 kg: 20 mg once daily.

All dosages are to be administered orally, and the frequency of administration varies by indication, typically ranging from once daily to multiple times daily as specified in combination therapies.

Contraindications

Patients with known hypersensitivity to substituted benzimidazoles or any component of the formulation are contraindicated from using this medication. Additionally, the use of this medication is not recommended in patients receiving rilpivirine-containing products.

When administered in combination with omeprazole, healthcare providers should refer to the Contraindications section of the prescribing information for clarithromycin and amoxicillin.

Warnings and Precautions

Gastric Malignancy In adults, symptomatic response does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing.

Acute Tubulointerstitial Nephritis Discontinue treatment and evaluate patients. Acute interstitial nephritis has been observed in patients taking PPIs.

Clostridium difficile-Associated Diarrhea PPI therapy may be associated with an increased risk of Clostridium difficile-associated diarrhea.

Bone Fracture Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine.

Severe Cutaneous Adverse Reactions Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

Cutaneous and Systemic Lupus Erythematosus New onset or exacerbation of existing disease may occur; discontinue omeprazole and refer to a specialist for evaluation.

Interaction with Clopidogrel Avoid concomitant use of omeprazole with clopidogrel due to diminished anti-platelet activity.

Cyanocobalamin (Vitamin B-12) Deficiency Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin.

Hypomagnesemia and Mineral Metabolism Reported rarely with prolonged treatment with PPIs.

Interaction with St. John's Wort or Rifampin Avoid concomitant use of omeprazole with St. John's Wort or rifampin due to the potential reduction in omeprazole concentrations.

Interactions with Diagnostic Investigations for Neuroendocrine Tumors Increased Chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors; temporarily stop omeprazole at least 14 days before assessing CgA levels.

Interaction with Methotrexate Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high-dose methotrexate administration, consider a temporary withdrawal of omeprazole.

Fundic Gland Polyps Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy.

Side Effects

Most common adverse reactions reported in adults (incidence ≥2%) include:

• Headache

• Abdominal pain

• Nausea

• Diarrhea

• Vomiting

• Flatulence

In pediatric patients (ages 2 to 16 years), the safety profile is similar to that in adults, with respiratory system events and fever being the most frequently reported reactions.

Serious Adverse Reactions

• Gastric Malignancy: In adults, symptomatic response does not preclude the presence of gastric malignancy. Additional follow-up and diagnostic testing should be considered.

• Acute Tubulointerstitial Nephritis: Discontinue treatment and evaluate patients if this condition is suspected.

• Clostridium difficile-Associated Diarrhea: PPI therapy may be associated with an increased risk of this infection.

• Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine.

• Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

• Cutaneous and Systemic Lupus Erythematosus: New onset or exacerbation of existing disease; discontinue omeprazole and refer to a specialist for evaluation.

Additional Adverse Reactions or Important Notes

• Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin.

• Hypomagnesemia: Reported rarely with prolonged treatment with PPIs.

• Interactions with Clopidogrel: Avoid concomitant use of omeprazole due to potential interactions.

• Interactions with St. John’s Wort or Rifampin: Avoid concomitant use of omeprazole.

• Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Increased Chromogranin A (CgA) levels may interfere with diagnostic investigations; temporarily stop omeprazole at least 14 days before assessing CgA levels.

• Interaction with Methotrexate: Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider a temporary withdrawal of omeprazole.

• Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy.

Overdosage

Reports of overdosage with omeprazole in humans have included manifestations such as:

• Confusion

• Drowsiness

• Blurred vision

• Tachycardia

• Nausea

• Vomiting

• Diaphoresis

• Flushing

• Headache

• Dry mouth

Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone.

Drug Interactions

Omeprazole, available in capsule and delayed-release forms, has several clinically significant drug interactions that can affect its efficacy and safety profile.

Pharmacokinetic Interactions

1. Drugs Affected by Gastric pH: Omeprazole may interfere with the absorption of drugs whose bioavailability is influenced by gastric pH, such as ketoconazole, ampicillin esters, iron salts, erlotinib, and digoxin. Patients taking omeprazole alongside digoxin should be monitored for potential increases in digoxin toxicity.

2. 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, particularly for patients on warfarin, who may require monitoring of INR and prothrombin time.

3. Specific Drug Interactions:

   • Clopidogrel: Omeprazole decreases exposure to the active metabolite of clopidogrel, potentially reducing its effectiveness.

   • Cilostazol: Omeprazole increases systemic exposure of cilostazol and one of its active metabolites, warranting consideration for dose reduction.

   • Tacrolimus: Omeprazole may increase serum levels of tacrolimus, necessitating monitoring for toxicity.

   • Methotrexate: Omeprazole may also increase serum levels of methotrexate.

Pharmacodynamic Interactions

1. Atazanavir and Nelfinavir: Omeprazole reduces plasma levels of both atazanavir and nelfinavir, and concomitant use is not recommended due to the risk of reduced efficacy.

2. Saquinavir: Omeprazole increases plasma levels of saquinavir, which may lead to toxicity; therefore, monitoring for adverse effects and considering a dose reduction of saquinavir is advised.

3. Voriconazole: This combined inhibitor of CYP2C19 and 3A4 may raise omeprazole levels, which could enhance its effects and side effects.

In summary, careful consideration and monitoring are essential when prescribing omeprazole alongside other medications, particularly those that are affected by gastric pH or metabolized by cytochrome P450 enzymes. For a comprehensive list of clinically important drug interactions, refer to the full prescribing information.

Pediatric Use

The safety and effectiveness of omeprazole have been established in pediatric patients aged 2 to 16 years for the treatment of symptomatic gastroesophageal reflux disease (GERD), treatment of erosive esophagitis (EE) due to acid-mediated GERD, and maintenance of healing of EE due to acid-mediated GERD. This use is supported by extrapolation from adequate and well-controlled studies in adults, as well as uncontrolled safety, efficacy, and pharmacokinetic studies performed in pediatric and adolescent patients.

In pediatric patients aged 1 month to less than 1 year, omeprazole has been shown to be effective for the treatment of EE due to acid-mediated GERD. However, the safety and effectiveness of omeprazole have not been established in patients less than 1 month of age for any indication.

Adverse reactions reported in the pediatric population (1 month to 16 years) include respiratory system effects, with frequent reports of otitis media in the 1 month to less than 1 year age group and fever in the 1 to less than 2 year age group. Accidental injuries were frequently reported in patients aged 2 to 16 years.

The safety and effectiveness of omeprazole have not been established for the following indications in pediatric patients:

• Treatment of symptomatic GERD in patients less than 1 year of age

• Maintenance of healing of EE due to acid-mediated GERD in patients less than 1 year of age

• Treatment of active duodenal ulcer

• H. pylori eradication to reduce the risk of duodenal ulcer recurrence

• Treatment of active benign gastric ulcer

• Pathological hypersecretory conditions

Healthcare professionals should exercise caution when prescribing omeprazole to pediatric patients, particularly those under 1 year of age.

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. The data indicate no significant differences in safety and effectiveness between elderly patients and younger subjects. However, clinical experience suggests that greater sensitivity may be observed in some older individuals, although this has not been definitively established.

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

Despite these pharmacokinetic changes, no dosage adjustment is necessary for elderly patients when prescribing omeprazole. Regular monitoring may be warranted to ensure optimal therapeutic outcomes, particularly in those who may exhibit increased sensitivity to the medication.

Pregnancy

There are no adequate and well-controlled studies with omeprazole in pregnant patients. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Reproductive studies in rats and rabbits have shown dose-dependent embryo-lethality at doses approximately 3.4 to 34 times an oral human dose of 40 mg, based on a body surface area for a 60 kg person. Teratogenicity was not observed in animal reproduction studies with the administration of oral esomeprazole (an enantiomer of omeprazole) magnesium during organogenesis at doses about 68 times and 42 times, respectively, an oral human dose of 40 mg.

Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg. However, when maternal administration was confined 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. All pregnancies have a background risk of birth defect, 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. A population-based retrospective cohort study from the Swedish Medical Birth Registry reported that the number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population.

The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9%, compared to 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported an overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole of 3.6%, compared to 5.5% for H2-blockers and 4.1% for unexposed mothers. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy, reporting a rate of major congenital malformations of 4% in the omeprazole group.

In summary, while omeprazole is classified as Pregnancy Category C, indicating that risk cannot be ruled out, the available data suggest that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk. This medication should be used during pregnancy only if clearly needed.

Lactation

Omeprazole is excreted in human milk, with limited data suggesting its presence. Concentrations measured in breast milk following oral administration of 20 mg showed that the peak concentration was less than 7% of the peak serum concentration, corresponding to approximately 0.004 mg of omeprazole in 200 mL of milk.

There are no adequate and well-controlled studies assessing the effects of omeprazole on breastfed infants or on milk production. The potential for serious adverse reactions in nursing infants, as well as concerns regarding tumorigenicity observed in animal studies, necessitates careful consideration. Healthcare providers should weigh the developmental and health benefits of breastfeeding against the mother's clinical need for omeprazole and any potential risks to the breastfed infant.

Given the lack of clinical data, a decision should be made regarding whether to discontinue nursing or to discontinue the drug, taking into account the importance of the medication to the mother. Caution is advised when administering omeprazole to lactating mothers.

Renal Impairment

Patients with renal impairment may not require specific dosage adjustments or special monitoring when using omeprazole, as the available data does not provide any guidelines or recommendations regarding its use in this population.

However, it is important to note that acute interstitial nephritis has been observed in patients taking proton pump inhibitors (PPIs), including omeprazole. Additionally, rare cases of hypomagnesemia have been reported with prolonged treatment with PPIs.

Given these considerations, healthcare providers should remain vigilant and monitor renal function and magnesium levels in patients with existing kidney issues or those on long-term therapy with omeprazole.

Hepatic Impairment

In patients with hepatic impairment, exposure to omeprazole is substantially increased compared to healthy subjects. For those classified under Child-Pugh Class A, B, or C, a dosage reduction is recommended. Specifically, for the maintenance of healing of erosive esophagitis (EE), the dosage of omeprazole delayed-release capsules should be adjusted to 10 mg once daily.

No additional specific information regarding further dosage adjustments, special monitoring, or precautions for patients with liver problems is provided in the available data. Regular monitoring of liver function may be prudent in this patient population, although specific parameters are not detailed in the text.

Overdosage

Reports of overdosage with omeprazole in humans have indicated doses as high as 2400 mg, which is 120 times the usual recommended clinical dose. Manifestations of omeprazole overdosage can vary but commonly include confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, and dry mouth. Symptoms are typically transient, and no serious clinical outcomes have been reported when omeprazole is taken alone.

There is no specific antidote for omeprazole overdosage; therefore, treatment should be symptomatic and supportive. It is important to note that omeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, the possibility of multiple drug ingestion should be considered.

For management of any overdose, including omeprazole, it is recommended to contact a Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage. Additionally, single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg have been lethal to mice, rats, and dogs, respectively, with observed effects in these animals including sedation, ptosis, tremors, convulsions, decreased activity, lowered body temperature, and altered respiratory rates.

Nonclinical Toxicology

Teratogenic Effects

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 (approximately 56 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. However, in rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (approximately 5.5 to 56 times the human dose on a body surface area basis) produced dose-related increases in embryo lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at doses ranging from 13.8 to 138.0 mg/kg/day (approximately 5.6 to 56 times the human doses on a body surface area basis).

Non-Teratogenic Effects

Omeprazole at oral doses up to 138 mg/kg/day in rats (approximately 34 times an oral human dose of 40 mg on a body surface area basis) was found to have no effect on fertility and reproductive performance.

Nonclinical Toxicology

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 (approximately 0.4 to 34 times a human dose of 40 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; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. Additionally, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (approximately 3.4 times a human dose of 40 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs. 10% controls). By the second year, the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was observed in male or female rats treated for two years. For this strain of rat, no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret.

In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels 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 a body surface area basis). 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 males or females at the high dose of 140.8 mg/kg/day (approximately 34 times the human dose of 40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was 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. 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 summary, in 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals. Carcinoid tumors have also been noted in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.

Storage and Handling

Omeprazole is supplied in the form of delayed-release capsules. These capsules must be stored in a tight container that is protected from light and moisture.

The recommended storage temperature for omeprazole delayed-release capsules is between 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Excursions in temperature are permitted between 15° to 30°C (59° to 86°F).

For dispensing, it is essential to use a tight and light-resistant container as specified in USP. Proper storage conditions are crucial to maintain the integrity and efficacy of the product.