NEXIUM® (esomeprazole magnesium) delayed-release capsules
The active ingredient in NEXIUM® (esomeprazole magnesium) delayed-release capsules for oral administration and NEXIUM (esomeprazole magnesium) for delayed-release oral suspension is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium trihydrate, a PPI. Esomeprazole is the Sisomer of omeprazole, which is a mixture of the S- and R- isomers. (Initial U.S. approval of esomeprazole magnesium: 2001). Its molecular formula is (C17H18N3O3S)2Mg x 3 H2O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis.
Indications and usage
NEXIUM is a proton pump inhibitor (PPI). NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the:
- Short-term treatment in the healing of erosive esophagitis (EE) in adults and pediatric patients 12 years to 17 years of age.
- Maintenance of healing of EE in adults.
- Short-term treatment of heartburn and other symptoms associated GERD in adults and pediatric patients 12 years to 17 years of age.
- Risk reduction of nonsteroidal anti-inflammatory drugs (NSAID)-associated gastric ulcer in adults at risk for developing gastric ulcers due to age (60 years and older) and/or documented history of gastric ulcers.
- Helicobacter pylori eradication in adult patients to reduce the risk of duodenal ulcer recurrence in combination with amoxicillin and clarithromycin.
- Long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome in adults.
NEXIUM for delayed-release oral suspension is indicated for the:
- Short-term treatment in the healing of EE in pediatric patients 1 year to 11 years of age and of EE due to acid-mediated GERD in pediatric patients 1 month to less than 1 year of age.
- Short-term treatment of heartburn and other symptoms associated with GERD in pediatric patients 1 year to 11 years of age.
Mechanism of Action
Esomeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, esomeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.
Dosage and administration
|Adult Indication||Recommended Dosage of NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension||Treatment Duration|
|Healing of EE||20 mg or 40 mg1 once daily||4 to 8 weeks2|
|Maintenance of Healing of EE||20 mg once daily||Controlled studies do not extend beyond 6 months|
|Treatment of Symptomatic GERD||20 mg once daily||4 weeks; if symptoms do not resolve completely, consider an additional 4 weeks|
|Risk Reduction of NSAID-Associated Gastric Ulcer||20 mg or 40 mg1 once daily||Controlled studies do not extend beyond 6 months|
|H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (Triple Therapy)||NEXIUM 40 mg once daily1 Amoxicillin 1000 mg twice daily3 Clarithromycin 500 mg twice daily3 Starting dosage is 40 mg twice daily4 ; individualize the regimen to patient needs.||10 days 10 days 10 days|
|Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome||Dosages of up to 240 mg/day have been administered||As long as clinically indicated|
- A maximum dosage of 20 mg once daily is recommended for patients with severe liver impairment (Child-Pugh Class C).
- Most patients are healed within 4 to 8 weeks. For patients who do not heal after 4 to 8 weeks, an additional 4 to 8 weeks of treatment may be required to achieve healing.
- Refer to the amoxicillin and clarithromycin prescribing information for dosage adjustments in elderly and renally-impaired patients.
- A starting dosage of 20 mg twice daily is recommended for patients with severe liver impairment (Child-Pugh Class C)
Recommended Dosage in Pediatric Patients by Indication
Healing of EE:
|12 years to 17 years||NEXIUM delayed-release capsules or NEXIUM for delayed-release oral suspension: 20 mg or 40 mg once daily||4 to 8 Weeks|
|1 year to 11 years1||NEXIUM for delayed-release oral suspension: Less than 20 kg10 mg once daily|
20 kg and greater 10 mg or 20 mg once daily
Treatment of EE due to Acid-Mediated GERD
|1 month to less than 1 year2||NEXIUM for delayed-release oral suspension: 3 kg to 5 kg 2.5 mg once daily|
Greater than 5 kg to 7.5 kg 5 mg once daily
Greater than 7.5 kg to 12 kg 10 mg once daily
|Up to 6 weeks|
Treatment of Symptomatic GERD
|12 years to 17 years||NEXIUM delayed-release capsules or NEXIUM for delayed-release oral suspension: 20 mg once daily||4 weeks|
|1 year to 11 years||NEXIUM for delayed-release oral suspension: 10 mg once daily1||Up to 8 weeks|
- Dosages over 1 mg/kg/day have not been studied
- Dosages over 1.33 mg/kg/day have not been studied
NEXIUM is contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria.
For information about contraindications of amoxicillin and clarithromycin, indicated in combination with NEXIUM for H. pylori eradication to reduce the risk of duodenal ulcer recurrence, refer to the Contraindications section of the respective prescribing information.
Proton pump inhibitors (PPIs), including NEXIUM, are contraindicated in patients receiving rilpivirinecontaining products
Warnings and precautions
Presence of Gastric Malignancy: In adults, symptomatic response to therapy with NEXIUM does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.
Acute Tubulointerstitial Nephritis: Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to nonspecific symptoms of decreased renal function (e.g., malaise, nausea, anorexia).
Clostridium difficile-Associated Diarrhea: Published observational studies suggest that PPI therapy like NEXIUM may be associated with an increased risk of Clostridium difficile-associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve
Bone Fracture: Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines
Cutaneous and Systemic Lupus Erythematosus: Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including esomeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.
The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.
Interaction with Clopidogrel: Avoid concomitant use of NEXIUM with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel. When using NEXIUM consider alternative anti-platelet therapy
Cyanocobalamin (Vitamin B-12) Deficiency: Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
Hypomagnesemia: Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
Interaction with St. John’s Wort or Rifampin: Drugs which induce CYP2C19 or CYP3A4 (such as St. John’s Wort or rifampin) can substantially decrease esomeprazole concentrations. Avoid concomitant use of NEXIUM with St. John’s Wort or rifampin.
Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary
Interaction with Methotrexate: Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients
Fundic Gland Polyps: PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.
Antiretrovirals: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
- Decreased exposure of some antiretroviral drugs (e.g., rilpivirine atazanavir, and nelfinavir) when used concomitantly with esomeprazole may reduce antiviral effect and promote the development of drug resistance
- Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole may increase toxicity.
- There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole.
Warfarin: Increased INR and prothrombin time in patients receiving PPIs, including esomeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain the target INR range.
Methotrexate: Concomitant use of esomeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted
Clopidogrel: Concomitant use of esomeprazole 40 mg resulted in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant use with NEXIUM Consider use of alternative anti-platelet therapy
Citalopram: Increased exposure of citalopram leading to an increased risk of QT prolongation. Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol: Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol). Consider reducing the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Digoxin: Potential for increased exposure of digoxin. Monitor digoxin concentrations and adjust the dose, if needed, to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Use in specific populations
Pregnancy: There are no adequate and well-controlled studies with esomeprazole in pregnant women. Esomeprazole is the S-isomer of omeprazole. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use.
Lactation: Esomeprazole is the S-isomer of omeprazole and limited data suggest that omeprazole may be present in human milk. There are no clinical data on the effects of esomeprazole on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NEXIUM and any potential adverse effects on the breastfed infant from NEXIUM or from the underlying maternal condition.
Hepatic Impairment: In patients with severe hepatic impairment (Child-Pugh Class C) exposure to esomeprazole substantially increased compared to healthy subjects. Dosage modification of NEXIUM is recommended for patients with severe hepatic impairment for the healing of EE, risk reduction of NSAID-associated gastric ulcer, H. pylori eradication to reduce the risk of duodenal ulcer recurrence, and pathological hypersecretory conditions including Zollinger-Ellison Syndrome
In patients with mild to moderate liver impairment (Child-Pugh Classes A and B), no dosage adjustment is necessary.
Manifestations in patients exposed to omeprazole, the racemic mixture, at doses up to 2,400 mg (120 times the usual recommended clinical dose) include confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen at recommended dosages. See the full prescribing information for omeprazole for complete safety information. No specific antidote for esomeprazole is known. Since esomeprazole is extensively protein bound, it is not expected to be removed by dialysis. In the event of overdosage, treatment should be symptomatic and supportive.