Esomeprazole sodium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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Overview
Esomeprazole sodium is a Proton Pump Inhibitor that is FDA approved for the treatment of Gastroesophageal Reflux Disease (GERD) with Erosive Esophagitis, Risk Reduction of Rebleeding of Gastric or Duodenal Ulcers following Therapeutic Endoscopy in Adults. Common adverse reactions include Injection site reaction, Abdominal pain, Constipation, Diarrhea, Flatulence, Indigestion, Nausea, Xerostomia, Dizziness, Headache.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
General Information
- NEXIUM I.V. for Injection should not be administered concomitantly with any other medications through the same intravenous site and/or tubing. The intravenous line should always be flushed with either 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP both prior to and after administration of NEXIUM I.V. for Injection.
The admixture should be stored at room temperature up to 30°C (86°F) and should be administered within the designated time period as listed in Table 1 below. No refrigeration is required.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
As soon as oral therapy is possible or appropriate, intravenous therapy with NEXIUM I.V. for Injection should be discontinued and the therapy should be continued orally.
GERD with Erosive Esophagitis
- Dosing information
- Recommended adult dosage: 20 mg or 40 mg IV injection qd (no less than 3 minutes) or IV infusion (10 minutes to 30 minutes). Safety and efficacy of NEXIUM I.V. for Injection as a treatment of GERD patients with erosive esophagitis for more than 10 days have not been demonstrated.
- Dosage adjustment is not required in patients with mild to moderate liver impairment (child Pugh Classes A and B). For patients with severe liver impairment (child Pugh Class C),
- Maximum dosage: 20 mg IV qd
Risk Reduction of Rebleeding of Gastric or Duodenal Ulcers following Therapeutic Endoscopy in Adults
- Dosing information
- 80 mg administered as an intravenous infusion over 30 minutes followed by a continuous infusion of 8 mg/h for a total treatment duration of 72 hours (i.e., includes initial 30-minute dose plus 71.5 hours of continuous infusion).
- Intravenous therapy is aimed solely at the acute initial management of bleeding gastric or duodenal ulcers and does not constitute full treatment. Intravenous therapy should be followed by oral acid-suppressive therapy.
- For patients with liver impairment
- No dosage adjustment of the initial esomeprazole 80 mg infusion is necessary.
- For patients with mild to moderate liver impairment (Child Pugh Classes A and B), a maximum continuous infusion of esomeprazole 6 mg/h should not be exceeded.
- For patients with severe liver impairment (Child Pugh Class C), a maximum continuous infusion of 4 mg/h should not be exceeded
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Esomeprazole sodium in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Esomeprazole sodium in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
GERD with Erosive Esophagitis
- Dose should be infused over 10 minutes to 30 minutes.
- 1 year to 17 years:
- Body weight less than 55 kg: 10 mg
- Body weight 55 kg or greater: 20 mg
- 1 month to less than 1 year of age: 0.5 mg/kg
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Esomeprazole sodium in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Esomeprazole sodium in pediatric patients.
Contraindications
Patients with known hypersensitivity to any component of the formulation or to substituted benzimidazoles (angioedema and anaphylaxis have occurred).
Warnings
Risk of Concomitant Gastric Malignancy
Symptomatic response to therapy with NEXIUM does not preclude the presence of gastric malignancy.
Atrophic Gastritis
Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which esomeprazole is an enantiomer.
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 [see Adverse Reactions (6.2)]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Interaction with clopidogrel
Avoid concomitant use of NEXIUM I.V. 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 I.V. consider alternative anti-platelet therapy [see Drug Interactions (7), Pharmacokinetics (12.3)].
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 [see Dosage and Administration (2) and Adverse Reactions (6.2)].
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. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)].
Concomitant use of NEXIUM 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 [see Drug Interactions (7)]. Avoid concomitant use of NEXIUM with St. John’s Wort or rifampin.
Interactions with 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 [see Clinical Pharmacology (12.2)].
Concomitant use of NEXIUM 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 [see Drug Interactions (7.3)].
Adverse Reactions
Clinical Trials Experience
Clinical Trials Experience with Intravenous NEXIUM
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults The safety of intravenous esomeprazole is based on results from clinical trials conducted in four different populations including patients having symptomatic GERD with or without a history of erosive esophagitis (n=199), patients with erosive esophagitis (n=160), healthy subjects (n=204) and patients with bleeding gastric or duodenal ulcers (n=375).
Symptomatic GERD and Erosive Esophagitis Trials
The data described below reflect exposure to NEXIUM I.V. for Injection in 359 patients. NEXIUM I.V. for Injection was studied only in actively-controlled trials. The population was 18 to 77 years of age; 45% Male, 52% Caucasian, 17% Black, 3% Asian, 28% Other, and had either erosive reflux esophagitis (44%) or GERD (56%). Most patients received doses of either 20 or 40 mg either as an infusion or an injection. Adverse reactions occurring in ≥1% of patients treated with intravenous esomeprazole (n=359) in clinical trials are listed below:
Intravenous treatment with esomeprazole 20 and 40 mg administered as an injection or as an infusion was found to have a safety profile similar to that of oral administration of esomeprazole.
Pediatric
A randomized, open-label, multi-national study to evaluate the pharmacokinetics of repeated intravenous doses of once daily esomeprazole in pediatric patients 1 month to 17 years old, inclusive was performed. The safety results are consistent with the known safety profile of esomeprazole and no unexpected safety signals were identified [see Clinical Pharmacology (12.3)].
Risk Reduction of Rebleeding of Gastric or Duodenal Ulcers in Adults
The data described below reflect exposure to NEXIUM I.V. for Injection in 375 patients. NEXIUM I.V. for Injection was studied in a placebo-controlled trial. Patients were randomized to receive NEXIUM I.V. for Injection (n=375) or placebo (n=389). The population was 18 to 98 years old; 68% Male, 87% Caucasian, 1% Black, 7% Asian, 4% other, who presented with endoscopically confirmed gastric or duodenal ulcer bleeding. Following endoscopic hemostasis, patients received either 80 mg esomeprazole as an intravenous infusion over 30 minutes followed by a continuous infusion of 8 mg per hour or placebo for a total treatment duration of 72 hours. After the initial 72-hour period, all patients received oral proton pump inhibitor (PPI) for 27 days.
With the exception of injection site reactions described above, intravenous treatment with esomeprazole administered as an injection or as an infusion was found to have a safety profile similar to that of oral administration of esomeprazole.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of NEXIUM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Postmarketing Reports - There have been spontaneous reports of adverse events with postmarketing use of esomeprazole. These reports occurred rarely and are listed below by body system:
Blood And Lymphatic System Disorders: agranulocytosis, pancytopenia; Eye Disorders: blurred vision; Gastrointestinal Disorders: pancreatitis; stomatitis; microscopic colitis; Hepatobiliary Disorders: hepatic failure, hepatitis with or without jaundice; Immune System Disorders: anaphylactic reaction/shock; Infections and Infestations: GI candidiasis; Metabolism and nutritional disorders: hypomagnesemia with or without hypocalcemia and/or hypokalemia; Musculoskeletal And Connective Tissue Disorders: muscular weakness, myalgia, bone fracture; Nervous System Disorders: hepatic encephalopathy, taste disturbance; Psychiatric Disorders: aggression, agitation, depression, hallucination; Renal and Urinary Disorders: interstitial nephritis; Reproductive System and Breast Disorders: gynecomastia; Respiratory, Thoracic and Mediastinal Disorders: bronchospasm; Skin and Subcutaneous Tissue Disorders: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN, some fatal).
Other adverse events not observed with NEXIUM, but occurring with omeprazole can be found in the omeprazole package insert, ADVERSE REACTIONS section.
Drug Interactions
Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin. Post-marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme. Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam. Increased plasma levels of diazepam were observed 12 hours after dosing and onwards. However, at that time, the plasma levels of diazepam were below the therapeutic interval, and thus this interaction is unlikely to be of clinical relevance. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of esomeprazole 40 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of NEXIUM I.V. with clopidogrel. When using NEXIUM I.V., consider use of alternative anti-platelet therapy. Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26%, respectively. Cmax and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69%, respectively. Co-administration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore, a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required for the recommended doses. However, in patients who may require higher doses, dose adjustment may be considered. Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased esomeprazole serum levels. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St. John’s Wort, an inducer of CYP3A4. In a cross-over study in 12 healthy male subjects, St. John’s Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with NEXIUM. Co-administration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of esomeprazole. Concomitant use of atazanavir and proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect. Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75%, respectively, for nelfinavir and M8. Following multiple doses of atazanavir (400 mg daily) and omeprazole (40 mg daily, 2 hr before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported with an increase in AUC by 82%, in Cmax by 75% and in Cmin by 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole. Studies evaluating concomitant administration of esomeprazole and either naproxen (non-selective NSAID) or rofecoxib (COX-2 selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of esomeprazole or these NSAIDs. Esomeprazole inhibits gastric acid secretion. Therefore, esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, and erlotinib can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Esomeprazole is an enantiomer of omeprazole. Coadministration of digoxin with esomeprazole is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with esomeprazole.
Interactions with Investigations of Neuroendocrine Tumors
Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors [see Warnings and Precautions (5.8) andClinical Pharmacology (12.2)].
Tacrolimus
Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus.
Methotrexate
Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted
Use in Specific Populations
Pregnancy
Risk Summary
There are no adequate and well-controlled studies with NEXIUM 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. Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 57 times and 35 times, respectively, an oral human dose of 40 mg. However, 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 33.6 times an oral human dose of 40 mg (see Animal Data). Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, NEXIUM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Human Data
Esomeprazole is the S-isomer of omeprazole. Four epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2 receptor antagonists or other controls. A population based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. 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 number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996-2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H2 blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. 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.
Animal Data
Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 57 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 35 times the human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium.
A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 57 times an oral human dose of 40 mg on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 33 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 16.8 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis).
Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 57 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis).
A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Esomeprazole sodium in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Esomeprazole sodium during labor and delivery.
Nursing Mothers
Esomeprazole is likely present in human milk. Esomeprazole is the S-isomer of omeprazole and limited data indicate that maternal doses of omeprazole 20 mg daily produce low levels in human milk. Caution should be exercised when NEXIUM I.V. is administered to a nursing woman.
Pediatric Use
The safety and effectiveness of NEXIUM I.V. for Injection have been established in pediatric patients 1 month to 17 years of age for short-term treatment of GERD with Erosive Esophagitis [see Clinical Pharmacology, Pharmacokinetics (12.3)]. However, effectiveness has not been established in patients less than 1 month of age.
1 month to 17 years of age
Use of NEXIUM I.V. for Injection in pediatric patients 1 month to 17 years of age for short-term treatment of GERD with Erosive Esophagitis is supported by: a) results observed from a pharmacokinetic (PK) study on NEXIUM I.V. for Injection performed in pediatric patients, b) predictions from a population PK model comparing I.V. PK data between adult and pediatric patients, and c) relationship between exposure and pharmacodynamic results obtained from adult I.V. and pediatric oral data and d) PK results already included in the current approved labeling and from adequate and well-controlled studies that supported the approval of NEXIUM I.V. for Injection for adults.
Neonates 0 to 1 month of age
Following administration of NEXIUM I.V. in neonates the geometric mean (range) for CL was 0.17 L/h/kg (0.04 L/h/kg- 0.32 L/h/kg). The safety and effectiveness of NEXIUM I.V. in neonates have not been established.
Juvenile Animal Data
In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 57 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology (13.2)].
Geriatic Use
Of the total number of patients who received oral NEXIUM in clinical trials, 1,459 were 65 to 74 years of age and 354 patients were ≥ 75 years of age. No overall differences in safety and efficacy were observed between the elderly and younger individuals, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Gender
There is no FDA guidance on the use of Esomeprazole sodium with respect to specific gender populations.
Race
There is no FDA guidance on the use of Esomeprazole sodium with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Esomeprazole sodium in patients with renal impairment.
Hepatic Impairment
For adult patients with GERD, no dosage adjustment is necessary in patients with mild to moderate hepatic insufficiency (Child Pugh Classes A and B). For patients with severe hepatic insufficiency (Child Pugh Class C) a dose of 20 mg once daily should not be exceeded . For adult patients with bleeding gastric or duodenal ulcers and liver impairment, no dosage adjustment of the initial esomeprazole 80 mg infusion is necessary. For adult patients with mild to moderate liver impairment (Child Pugh Classes A and B), a maximum continuous infusion of esomeprazole 6 mg/h should not be exceeded. For adult patients with severe liver impairment (Child Pugh Class C), a maximum continuous infusion of 4 mg/h should not be exceeded.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Esomeprazole sodium in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Esomeprazole sodium in patients who are immunocompromised.
Administration and Monitoring
Administration
General Information
- The reconstituted solution of Nexium I.V. should be stored at room temperature up to 30°C (86°F) and administered within 12 hours after reconstitution. (Administer within 6 hours if 5% Dextrose Injection is used after reconstitution). No refrigeration is required
- Preparation Instructions for Adult Patients
- Intravenous Injection (20 mg or 40 mg vial) over no less than 3 minutes
- The freeze-dried powder should be reconstituted with 5 mL of 0.9% Sodium Chloride Injection, USP.
- Withdraw 5 mL of the reconstituted solution and administer as an intravenous injection over no less than 3 minutes.
- Preparation Instructions for Pediatric Patients
- Intravenous Infusion (20 mg or 40 mg) over 10 minutes to 30 minutes
- A solution for intravenous infusion is prepared by first reconstituting the contents of one vial* with 5 mL of 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP and further diluting the resulting solution to a final volume of 50 mL. The resultant concentration after diluting to a final volume of 50 mL is 0.8 mg/mL (for 40 mg vial) and 0.4 mg/mL (for 20 mg vial). The solution (admixture) should be administered as an intravenous infusion over a period of 10 minutes to 30 minutes.
- For patients 1 month to less than 1 year of age, first calculate the dose (0.5 mg/kg) to determine the vial size needed.
- Risk Reduction of Rebleeding of Gastric or Duodenal Ulcers in Adults
- Preparation Instructions for Loading dose (80 mg) to be given over 30 minutes
- The loading dose of 80 mg is prepared by reconstituting two 40 mg vials. Reconstitute each 40 mg vial with 5 mL of 0.9% Sodium Chloride Injection, USP. The contents of the two vials should be further diluted in 100 mL 0.9% * Sodium Chloride Injection, USP for intravenous use. Administer over 30 minutes.
- Preparation Instructions for Continuous Infusion to be given at 8 mg/hour for 71.5 hours
- The continuous infusion is prepared by using two 40 mg vials. Reconstitute each 40 mg vial with 5 mL each of 0.9% Sodium Chloride Injection, USP. The contents of the two vials should be further diluted in 100 mL 0.9%
- Sodium Chloride Injection, USP for intravenous use. Administer at a rate of 8 mg/hour for 71.5 hours.
Monitoring
There is limited information about the drug monitoring.
IV Compatibility
There is limited information about the IV Compatibility.
Overdosage
The minimum lethal dose of esomeprazole sodium in rats after bolus administration was 310 mg/kg (about 62 times the human dose on a body surface area basis). The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia and intermittent clonic convulsions. The symptoms described in connection with deliberate NEXIUM overdose (limited experience of doses in excess of 240 mg/day) are transient. Single oral doses of 80 mg and intravenous doses of 308 mg of esomeprazole over 24 hours were uneventful. Reports of overdosage with omeprazole in humans may also be relevant. Doses ranged up to 2,400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience (see omeprazole package insert - ADVERSE REACTIONS). 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. As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose, a certified Regional Poison Control Center should be contacted. Telephone numbers are listed in the Physicians’ Desk Reference (PDR) or local telephone book.
Pharmacology
There is limited information regarding Esomeprazole sodium Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Esomeprazole sodium Mechanism of Action in the drug label.
Structure
There is limited information regarding Esomeprazole sodium Structure in the drug label.
Pharmacodynamics
There is limited information regarding Esomeprazole sodium Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Esomeprazole sodium Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Esomeprazole sodium Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Esomeprazole sodium Clinical Studies in the drug label.
How Supplied
There is limited information regarding Esomeprazole sodium How Supplied in the drug label.
Storage
There is limited information regarding Esomeprazole sodium Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Esomeprazole sodium Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Esomeprazole sodium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Esomeprazole sodium Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Esomeprazole sodium Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.