ESOMEPRAZOLE MAGNESIUM (Generic for NEXIUM)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer esomeprazole on an empty stomach, 1 hour before meals.
-May be taken during antacid therapy.
Oral Solid Formulations
Delayed-release capsules
-Administer whole, do not crush or chew the delayed-release, enteric-coated granules within the capsule.
-Alternatively, for patients with difficulty swallowing, the capsule contents can be sprinkled on applesauce. The applesauce should not be hot. Once sprinkled on applesauce, swallow the mixture. Do not chew. Do not store the mixture for future use.
-An in vitro study indicates that the capsule contents are stable for 30 minutes when suspended in yogurt, cultured milk, apple or orange juice, or tap water. When suspending the contents of a capsule in any of these solid foods or liquids, the mixture should be swallowed without chewing; do not mix and store for future use.
-Nasogastric (NG) tube administration: The capsules can be opened and the granules emptied into a 60 mL catheter-tipped syringe and mixed with 50 mL of water. It is important to only use a catheter-tipped syringe when administering through a NG tube. Replace the plunger and shake the syringe vigorously for 15 seconds. Hold the syringe with the tip up and check for granules remaining in the tip. Attach the syringe to the NG tube and deliver the contents of the syringe through the tube into the stomach. After administering the granules, the NG tube should be flushed with additional water. Do not administer the granules if they have dissolved or disintegrated. Administer the contents of the syringe immediately; do not store.

Oral Liquid Formulations
Delayed-release oral suspension granules
-Do not divide the suspension packet to obtain a smaller dosage. Use the appropriate packet size for the dose to be administered.
-Do not crush or chew the granules.

Administration of a 2.5-mg or 5-mg packet
-Empty the contents of the packet into a container with 1 teaspoon (5 mL) of water. Stir and leave 2 to 3 minutes to thicken. Re-stir the mixture before administration; administer within 30 minutes of preparation. Flush any residual drug left in a container with more water and administer immediately.
-Nasogastric (NG) or gastric tube (French size 6 or larger) administration: Add 5 mL of water to a catheter tipped syringe and then add the contents of a 2.5mg or 5mg packet. It is important to only use a catheter-tipped syringe when administering through an NG or gastric tube. Immediately shake the syringe and leave 2 to 3 minutes to thicken. Upon administration, shake the syringe again, and flush the contents through the NG or gastric tube into the stomach; administer within 30 minutes of preparation. Refill the syringe with 5 ml of water, shake to rinse and flush any remaining contents from the NG or gastric tube into the stomach.

Administration of the 10-mg, 20-mg, or 40-mg packet
-Empty into a container with 1 tablespoon (15 mL) of water. Stir and leave 2 to 3 minutes to thicken. Re-stir the mixture before administration; administer within 30 minutes of preparation. Flush any residual drug left in a container with more water and administer immediately.
-Nasogastric (NG) or gastric tube (French size 6 or larger) administration: Add 15 mL of water to a catheter tipped syringe and then add the contents of a 10mg, 20mg, or 40mg packet. It is important to only use a catheter-tipped syringe when administering through an NG or gastric tube. Immediately shake the syringe and leave 2 to 3 minutes to thicken. Upon administration, shake the syringe again, and flush the contents through the NG or gastric tube into the stomach; administer within 30 minutes of preparation. Refill the syringe with 15 mL of water, shake to rinse and flush any remaining contents from the NG or gastric tube into the stomach.



Injectable Administration
-For intravenous administration only; do not give intramuscularly or subcutaneously.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Oral antacids may be used during treatment with intravenous esomeprazole.
Intravenous Administration
Intermittent IV Infusion
-IV infusion administration is recommended for all pediatric patients.
-Reconstitute the contents of 1 vial (either 20 or 40 mg) with 5 mL of 0.9% Sodium Chloride injection, 5% Dextrose, or Lactated Ringer's.
-Before administration, must further dilute the resulting solution in 50 mL of 0.9% Sodium Chloride injection, 5% Dextrose, or Lactated Ringer's.
-The final infusion concentrations are 0.8 mg/mL (40 mg/50 mL) OR 0.4 mg/mL (20 mg/50 mL).
-Withdraw the appropriate volume from the standard infusion preparation to prepare the desired pediatric infusion dose.
-Flush the IV line with either 0.9% Sodium Chloride injection, 5% Dextrose, or Lactated Ringer's both before and after administration.
-Infuse IV over 10 to 30 minutes.
-Do NOT administer concomitantly with any other medications through the same IV site and tubing.
-Storage of infusion solutions: Store at room temperature up to 30 degrees C (86 degrees F). Administer solutions diluted with 0.9% 0.9% Sodium Chloride injection or Lactated Ringer's within 12 hours; administer solutions diluted with 5% Dextrose within 6 hours.

IV Push
-IV push administration is indicated for ADULTS only.
-Reconstitute the contents of one vial (either 20 or 40 mg) with 5 mL with 0.9% Sodium Chloride Injection.
-Flush the IV line with either 0.9% Sodium Chloride injection, 5% Dextrose, or Lactated Ringer's injection both before and after administration.
-Withdraw dose from the vial.
-Administer slowly over no less than 3 minutes.
-Do NOT administer concomitantly with any other medications through the same IV site and tubing.
-Storage of reconstituted injection: Store at room temperature up to 30 degrees C (86 degrees F) for up to 12 hours when diluted with 0.9% Sodium Chloride Injection.

In general, oral esomeprazole has been well-tolerated in clinical trials (n > 10,000; all ages). Greater than 2900 patients have been evaluated in 6-12 month long studies. The types of adverse events are similar with short or long-term use, and have been comparable to placebo rates. Additionally, the safety of esomeprazole has been studied in pediatric patients aged birth to 17 years of age.

Animal and human data have demonstrated a proliferation of enterochromaffin-like cells due to hypergastrinemia, which may be associated with the development of malignant gastric carcinoma during long-term administration of proton pump inhibitors (PPIs). In over 1000 patients treated with esomeprazole for up to 12 months, the prevalence of ECL cell hyperplasia increased with time and dose, but no patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa. In esomeprazole clinical trials, there were dose-related increases in mean fasting gastrin levels which reached plateaus at 2-3 months and returned to baseline 4 weeks after drug discontinuation. According to the manufacturer of esomeprazole, < 1% of patients were reported to have hypergastrinemia or GI dysplasia. Historically, omeprazole has been given for as long as 5 years without concern for the development of gastric neoplasia. The overall risk of carcinoid tumors during therapy with PPIs is low based on cumulative safety experience; monitoring of serum gastrin levels during PPI therapy is generally not necessary.

Following completion of a comprehensive review, the FDA believes that the long-term use of omeprazole or esomeprazole is not likely to be associated with an increased risk of heart problems. Preliminary analysis of two small, long-term clinical studies raised concerns about a possible link between the long-term use of these drugs and cardiovascular events. In both studies, patients with severe gastroesophageal reflux disease (GERD) were randomized to receive drug therapy, with omeprazole or esomeprazole, or surgery to control GERD. Results from the studies appeared to show an increased risk of myocardial infarction, heart failure, and heart-related sudden death in patients who received drug therapy compared to those who received surgery. However, the results of these two studies along with results from other comparative studies of omeprazole, which did not show an increased risk of heart related adverse events, were analyzed by the FDA. The FDA did not find a correlation between the reported cardiovascular events and the use of either drug; thus, the FDA recommends that health care professionals and their patients continue to prescribe and use these two products in accordance with their labeled uses.

The safety profile of esomeprazole in pediatrics is similar to that of adults. In a randomized, open-label, multi-national study to evaluate the pharmacokinetics of repeated IV doses of once-daily esomeprazole, esomeprazole was well tolerated in pediatric patients 1 month to 17 years old, inclusive; no unexpected safety signals were identified. The safety of oral esomeprazole has been evaluated in several pediatric studies with patients ranging from 1 month to 17 years of age. Diarrhea is among the most frequently reported adverse events associated with esomeprazole therapy. In pediatric patients, diarrhea was reported in 2.8% of those 1 to 11 years af age, and in 2% of those 12 years and older. Among patients receiving oral esomeprazole for the treatment of healing of erosive esophagitis, diarrhea was reported in 1% or more of patients; in patients receiving esomeprazole for GERD, the reported rate was 4%. Diarrhea has also been reported in patients receiving esomeprazole injection (3.9%). Esomeprazole use in combination with amoxicillin and clarithromycin was associated with diarrhea (9.2%) of patients treated for H. pylori. Among the most common adverse events, abdominal pain (1% to 3%), nausea (2%), regurgitation (1%), and vomiting have been reported. In a study that included 26 pediatric patients aged birth to 1 month, there were no treatment-related adverse reactions. No new safety concerns were identified in pediatric patients. Overall, the most commonly reported adverse events associated with esomeprazole are mostly gastrointestinal (GI) in nature. Nausea has been reported in 1% or more of adults; the incidence of nausea in patients receiving IV esomeprazole is 6.4%. Abdominal pain has been reported in 1% to 4% of adults taking oral esomeprazole and in 5.8% of patients receiving IV esomeprazole. Other GI-related adverse events reported in patients receiving esomeprazole include flatulence (oral: 1% or more; IV: 10.3%), constipation (oral: 1% or more; IV: 2.5%), and xerostomia (oral: 1% or more; IV: 3.9%). Dyspepsia has also been reported in less than 1% of patients receiving oral esomeprazole and 6.4% of patients receiving IV esomeprazole. In upper GI rebleeding prophylaxis trials in adults, duodenal ulcer hemorrhage was reported in 4.3% of esomeprazole-receiving patients. Less common GI-related adverse events (less than 1% of patients) have included: abdomen enlarged, bowel irregularity, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, frequent stools, gastritis, gastroenteritis, GI bleeding, GI symptoms not otherwise specified, hiccups, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, weight gain, weight loss, and vomiting. During postmarketing surveillance, gastric polyps/fundic gland polyps, pancreatitis, stomatitis, and taste disturbances/dysgeusia were also reported. In patients treated for H. pylori, esomeprazole in combination with amoxicillin and clarithromycin was associated with taste disturbance (6.6%, mostly attributed to the use of clarithromycin) and abdominal pain (3.7%).

Intravenous (IV) esomeprazole has been associated with injection site reaction (1.7%), including mild focal erythema and itching at the IV insertion site. In upper GI rebleeding prophylaxis trials in adults, injection site reactions (4.3%) included erythema, swelling, inflammation, itching, phlebitis, thrombophlebitis and superficial phlebitis; with the exception of injection site reactions, IV administration was associated with a similar safety profile to that of oral administration.

The safety profile of esomeprazole in pediatrics is similar to that of adults. In a randomized, open-label, multi-national study to evaluate the pharmacokinetics of repeated IV doses of once daily esomeprazole, esomeprazole was well tolerated in pediatric patients 1 month to 17 years old, inclusive; no unexpected safety signals were identified. The safety of oral esomeprazole has been evaluated in several pediatric studies with patients ranging from 1 month to 17 years of age. Headache (1.9% to 8%), drowsiness or somnolence (1.9%), and irritability have been reported as the most common central nervous system (CNS) events. In adult trials, headache was reported in 5% to 5.5% of patients receiving oral esomeprazole for the treatment of healing of erosive esophagitis; in patients receiving esomeprazole for GERD, the reported rate was 4%. Headache has also been reported in patients receiving IV esomeprazole (10.9%). Dizziness (2.5%) was also reported in patients receiving IV esomeprazole and in less than 1% of patients receiving oral formulations. Somnolence/drowsiness was reported in less than 1% of adult patients taking esomeprazole. Other less commonly reported (less than 1%) CNS adverse events possibly or probably related to esomeprazole have included: anorexia, apathy, appetite stimulation, blurred vision, confusion, depression, hypertonia, nervousness (anxiety), hypoesthesia, insomnia, migraine, parosmia, paresthesias, sleep disorder, tremor, vertigo, and visual impairment. During postmarketing surveillance, aggression, agitation, depression, hallucinations, and taste disturbances/dysgeusia were also reported. In patients treated for H. pylori, esomeprazole in combination with amoxicillin and clarithromycin was associated with taste disturbance (6.6%, dygeusia was mostly attributed to the use of clarithromycin).

During clinical evaluation, patients receiving IV esomeprazole reported pruritus (1.1%); pruritus has also been reported in less than 1% of patients taking oral esomeprazole. In addition, dermatological reactions occurring in less than 1% of patients judged by investigators during pre-approval trials as possibly or probably related to oral esomeprazole included: acne vulgaris, angioedema, dermatitis, pruritus ani, rash, maculopapular rash, skin inflammation, increased sweating/diaphoresis, and urticaria. During postmarketing surveillance, the following were also reported: alopecia, anaphylactic shock, anaphylactoid reactions, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and toxic epidermal necrolysis (some fatal). Exfoliative dermatitis has been reported with omeprazole, and could potentially occur with esomeprazole based on the similarity in dermatological reactions.

In a study that included 98 pediatric patients (1 to 11 months, inclusive) exposed to esomeprazole for up to 6 weeks, increased ALT (1%) was considered a treatment-related adverse reaction. Overall, elevated hepatic enzymes (ALT, AST, and alkaline phosphatase) and hyperbilirubinemia (less than 1%) have been reported with oral esomeprazole. During postmarketing experience, hepatic failure, hepatitis with or without jaundice, and hepatic encephalopathy were also reported.

In a study that included 98 pediatric patients (1 to 11 months, inclusive) exposed to esomeprazole for up to 6 weeks, tachypnea (1%) was considered a treatment-related adverse reaction. Adverse events reported in less than 1% of patients during clinical evaluation and judged by investigators as possibly or probably related to oral esomeprazole include: arthralgia, arthritis, arthropathy, asthenia, asthma, back pain, chest pain (unspecified), cough, conjunctivitis, muscle cramps, dyspnea, earache, edema, fibromyalgia syndrome, flushing, goiter, hernia, hypertension, hyperuricemia, hyponatremia, peripheral edema, hot flashes, fatigue, fever, flu-like disorder, malaise, otitis media, pain, pharyngitis, polymyalgia rheumatica, rhinitis, rigors, sinus tachycardia, thirst/polydipsia, and tinnitus. Also, sinusitis was reported in both oral esomeprazole trials (less than 1%) as well as in IV esomeprazole trials (1.7%). During postmarketing surveillance, muscular weakness, myalgia, gynecomastia, and bronchospasm were also reported.

In clinical evaluation, a respiratory infection was reported among 1.1% of patients receiving intravenous (IV) esomeprazole. Gastric acid suppression with proton pump inhibitors (PPIs) has been associated with an increased risk of infection in pediatric patients. A prospective, multi-center study in previously healthy infants and young children found an increased risk of pneumonia (OR: 6.39; 95% CI = 1.38 to 29.7) and acute gastroenteritis (OR: 3.58; 95% CI = 1.87 to 6.86) in patients receiving gastric acid inhibitors (n = 91) compared to controls (n = 95). Another study in critically ill pediatric patients (n = 60) did not find an increased incidence of ventilator-associated pneumonia in patients receiving acid-suppression therapy compared to those not receiving treatment. A causal relationship between the use of esomeprazole or other PPIs and pneumonia has not been established. Until more is known about the relationship between acid-suppression and pneumonia, clinicians are encouraged to carefully select patients before empirically initiating acid-suppressive therapy with H2-blockers or PPIs. Increasing evidence in adults suggests a link between acid-suppression therapy and pneumonia (community- and hospital-acquired). Several mechanisms have been proposed to account for this association. One such mechanism states that gastric pH serves as a barrier against pathogenic colonization of the gastrointestinal tract. An increase in gastric pH allows for bacterial and viral invasion, which, in theory, can precipitate respiratory infections. Another proposed mechanism accounts for the role that gastric acid may have on stimulating the cough reflex that allows for the clearing of infectious agents from the respiratory tract. Finally, the fact that acid-suppressive therapy may impair white blood cell function, which in turn may lead to a depressed immune response to an infection, is listed among possible mechanisms.

As with omeprazole, hematologic abnormalities have been reported with oral esomeprazole (less than 1%) including anemia, hypochromic anemia, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, and thrombocytopenia. Other potentially serious, but rare adverse events that have also been reported in spontaneous postmarketing reports include agranulocytosis and pancytopenia; however, causality cannot be assessed. Long-term treatment with acid-suppressing agents can lead to malabsorption of vitamin B12 (cyanocobalamin). Vitamin B12 deficiency has been reported in less than 1% of patients taking esomeprazole. IIn a large case-controlled study, adult patients with and without an incident diagnosis of vitamin B12 deficiency (n = 25,956 and 184,199, respectively) were compared, and a correlation between vitamin B12 deficiency and gastric acid-suppression therapy was found. The use of a proton pump inhibitor or H2-receptor antagonist for more than 2 years was associated with an increased risk for vitamin B12 deficiency. A dose-dependent relationship was evident, as daily doses greater than 1.5 PPI pills/day were more strongly associated with vitamin B12 deficiency compared to daily doses less than 0.75 pills/day. It may be prudent to monitor patients for signs of pernicious anemia. Neurological manifestations of pernicious anemia can occur in the absence of hematologic changes.

Acute tubulo-interstitial nephritis (AIN or 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 non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue esomeprazole and evaluate patients with suspected acute AIN. During clinical trials, other renal and genitourinary (GU) adverse events reported (less than 1%) in patients receiving oral esomeprazole included: abnormal urine, albuminuria (proteinuria), cystitis, dysmenorrhea, dysuria, fungal infection, hematuria, menstrual irregularity, increased urinary frequency, and polyuria. Adverse events reported in less than 1% of patients and judged by investigators as possibly or probably related to esomeprazole included glycosuria.

Cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), and lupus-like symptoms have occurred in patients taking PPIs, including esomeprazole. Both exacerbation and new onset of existing autoimmune disease have been reported, with the majority of PPI-induced lupus erythematosus cases being CLE. Subacute CLE (SCLE) is the most common form of CLE reported in patients treated with PPIs, occurring within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Histological findings were usually observed without organ involvement. SLE is less commonly reported; PPI associated SLE is generally milder than non-drug induced SLE. The onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from infants to the elderly. Most patients presented with rash; however, arthralgia and cytopenia were also reported. Do not administer PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE occur, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks; serological testing (ANA) may be positive, and elevated serological test results may take longer to resolve than clinical manifestations.

Proton pump inhibitors (PPIs) have been associated with a possible increased risk of bone fractures of the hip, wrist, and spine. There have been 6 epidemiological studies that have reported an increased risk of fractures with the use of PPIs; the studies compared claims data of patients treated with PPIs versus individuals who were not using PPIs. Depending on the study, exposure to PPIs ranged between 1 to 12 years. The emergence of fractures varied among studies; 1 study reported an increase in fractures with use of PPIs in the previous year and another study found an increase after 5 to 7 years of PPI use. An increased risk was primarily observed in adult patients 50 years and older, patients taking prescription PPIs for at least 1 year, and patients who had been taking high doses (doses greater than those recommended with OTC use). Alternatively, in another epidemiological study with a similar study design, a relationship between PPI use and fractures was not established; however, the study population did not have major risk factors for fracture at study entry. It should be noted that randomized clinical trials (RCTs) of PPIs have not found an increased risk of fractures of the hip, wrist, or spine; some limitations of these RCTs were the study duration (generally 6 months) and insufficient information on effects of higher than recommended doses. Until more data are available, when prescribing PPIs, consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition. In patients with or at risk for osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation.

Hypomagnesemia, hypocalcemia, and hypokalemia have been reported during postmarketing esomeprazole use. Cases of hypomagnesemia have been reported in association with prolonged (3 months to more than 1 year) proton pump inhibitor (PPI) use. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in patients at risk. Low serum magnesium may lead to serious adverse reactions such as muscle spasm (tetany), seizures, and irregular heartbeat (arrhythmias). Consider monitoring electrolyte concentrations and supplementing electrolytes when needed. Discontinuation of PPI therapy may be necessary.

During postmarketing surveillance of esomeprazole, microscopic colitis has been reported. A link between the onset of microscopic colitis and PPI therapy has been suggested in case reports and case series. Reports and subsequent histological confirmation of both collagenous colitis and lymphocytic colitis, two distinct forms of microscopic colitis, have been observed in patients treated with lansoprazole, another PPI. One case series included 6 patients who developed microscopic colitis after a formulary switch to lansoprazole from omeprazole; upon lansoprazole discontinuation, associated loose stools resolved. The mechanism of this rare adverse reaction is not clear; however, an idiosyncratic immune reaction is suspected. Because small changes in the structures of PPIs may elicit different immunological responses, it is difficult to predict if this adverse effect can be expected with other PPIs. Until more is known about the association between PPIs and microscopic colitis, clinicians should advise patients to report prolonged watery loose stools and should consider PPI discontinuation or substitution in these patients.

C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with esomeprazole. PPI therapy, such as esomeprazole, may be associated with an increased risk of CDAD, especially in hospitalized patients. The use of gastric acid suppressive therapy, such as PPIs, may increase the risk of enteric infection or superinfection by encouraging the growth of gut microflora. If pseudomembranous colitis is suspected or confirmed, institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate. Other infection-related events reported in less than 1% of patients include vaginitis and candidiasis reported as gastrointestinal candidiasis, moniliasis, and genital moniliasis.

Esomeprazole is contraindicated in patients with known hypersensitivity to esomeprazole or other substituted benzimidazoles such as omeprazole or lansoprazole (i.e., known proton pump inhibitors (PPIs) hypersensitivity). There has been evidence of PPI cross-sensitivity in some sensitive individuals in literature reports, and some cases have been serious (e.g., angioedema or anaphylaxis). Serious rash and severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS), erythema multiforme, and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs. Discontinue the PPI at the first signs or symptoms of severe cutaneous adverse reactions or other hypersensitivity and consider further evaluation. Acute tubulo-interstitial nephritis (TIN or AIN) 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 non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). There have been reports of patients who were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue esomeprazole and evaluate patients with suspected acute TIN.

Esomeprazole undergoes extensive hepatic metabolism. No dosage adjustment is recommended in patients with mild to moderate hepatic impairment (Child Pugh Classes A and B). Dosing in adult patients with severe hepatic disease (Child Pugh Class C) should not exceed 20 mg/day; pediatric population recommendations for maximum dosage are not specifically available.

Consider pseudomembranous colitis in patients presenting with diarrhea after PPI use. PPI therapy, such as esomeprazole, may be associated with an increased risk of C. difficile-associated diarrhea (CDAD), especially in hospitalized patients. CDAD may range in severity from mild to life-threatening. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Gastric polyps/fundic gland polyps have been reported during postmarketing surveillance. Patients are usually asymptomatic and fundic gland polyps are identified incidentally on endoscopy. The risk of fundic gland polyps increases with long term proton pump inhibitor (PPI) use, especially beyond one year. Use the shortest duration of PPI therapy appropriate to treat specific condition. Symptomatic response to therapy with esomeprazole does not preclude the presence of gastric cancer or other malignancy.

Chronic use of gastric acid-suppressing agents should be used cautiously and with monitoring in patients who are prone to vitamin B12 deficiency. Daily treatment with a gastric acid-suppressing medication, such as esomeprazole, over a long period of time (e.g., generally 2 to 3 years or more) has been associated with malabsorption of cyanocobalamin in adults. Consider the possibility of cyanocobalamin deficiency if clinical symptoms are observed.

Use esomeprazole with caution in pediatric patients with low bone density. Observational studies have suggested that proton pump inhibitors (PPIs) may be associated with an increased risk for osteoporosis related fractures of the hip, wrist, or spine. In studies, patients at highest risk of fracture were those who received high-dose (defined as multiple daily doses) and long-term PPI therapy (a year or longer). Until more data are available, when prescribing PPIs, consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition. In patients with or at risk for osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation.

Use esomeprazole with caution in patients with a pre-existing risk of hypocalcemia (e.g., hypoparathyroidism), hypokalemia, or hypomagnesemia; consider monitoring magnesium and calcium concentrations prior to initiating therapy and periodically while on treatment in these patients. Supplement with magnesium and/or calcium as needed and consider discontinuing proton pump inhibitor (PPI) therapy if hypomagnesemia or hypocalcemia is refractory to treatment. For patients expected to be on PPI therapy for a prolonged period of time or who take concomitant medications such as digoxin or those that may cause hypomagnesemia (e.g., diuretics), consider monitoring of serum magnesium prior to initiation and periodically during treatment. Daily treatment with a PPI over a long period of time (e.g., 3 months to more than 1 year) may lead to hypomagnesemia; cases have been reported in patients taking esomeprazole. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in patients at risk. In most patients, the treatment of hypomagnesemia required magnesium replacement and PPI discontinuation. Low serum magnesium may lead to serious adverse reactions such as muscle spasm (tetany), seizures, and irregular heartbeat (arrhythmias). Use PPIs with caution and, if possible, avoid long-term (greater than 14 days) use in patients with congenital long QT syndrome, as they may be at higher risk for arrhythmias.

The use of the esomeprazole strontium salt is not recommended in neonates, infants, children, and adolescents due to a lack of adequate safety data. Strontium competes with calcium for intestinal absorption and is incorporated into bone; the clinical consequences of use in pediatric patients has not been determined.

The package labeling for non-prescription (OTC) esomeprazole recommends against self-medication with esomeprazole in patients with the following: trouble swallowing (dysphagia); vomiting with blood or bloody or black stools (GI bleeding); heartburn with lightheadedness, sweating, or dizziness; chest pain or shoulder pain with shortness of breath, sweating, pain spreading to arms, neck or shoulders, or lightheadedness; or frequent chest pain. Also, advise patients to speak with a health care provider prior to using esomeprazole OTC if there is a history of any of the following: heartburn for more than 3 months; frequent wheezing, particularly with heartburn; unexplained weight loss; nausea or vomiting; or abdominal pain. Such symptoms may be signs of a serious condition requiring medical evaluation and perhaps prescription therapy.

Use with caution in patients with a history of systemic lupus erythematosus (SLE) as esomeprazole has been reported to activate or exacerbate SLE.

Administration of esomeprazole may result in laboratory test interference, specifically serum chromogranin A (CgA) tests for neuroendocrine tumors, urine tests for tetrahydrocannabinol (THC), secretin stimulation tests, and diagnostic tests for Helicobacter pylori. Gastric acid suppression may increase serum CgA. Increased CgA concentrations may cause false positive results in diagnostic investigations for neuroendocrine tumors. To prevent this interference, temporarily stop esomeprazole at least 14 days before assessing CgA concentrations and consider repeating the test if initial concentrations are high. If serial tests are performed, ensure the same commercial laboratory is used as reference ranges may vary. Reports have suggested use of proton pump inhibitors (PPIs) may cause false positive urine screening tests for THC. If a PPI-induced false positive urine screen is suspected, confirm the positive results using an alternative testing method. PPIs may also cause a hyper-response in gastrin secretion to the secretin stimulation test, falsely suggesting gastrinoma. Health care providers are advised to temporarily stop esomeprazole at least 14 days prior to performing a secretin stimulation test to allow gastrin concentrations to return to baseline. Preparations that combine PPIs with antimicrobials and bismuth are known to suppress H. pylori; thus, ingestion of these preparations within 4 weeks of performing diagnostic tests for H. pylori may lead to false negative results. At a minimum, instruct the patient to avoid the use of esomeprazole in the 1 to 2 weeks prior to the test and the use of antimicrobials and bismuth preparations in the 4 weeks prior to the test.

Description: Esomeprazole is a proton pump inhibitor (PPI) antiulcer agent and is the S-isomer of omeprazole. In pediatrics, esomeprazole is approved for the healing of erosive esophagitis and for symptomatic gastroesophageal reflux disease (GERD). Although many studies have demonstrated some level of benefit from the use of PPIs in the treatment of GERD or erosive esophagitis when compared to placebo, conflicting evidence on the safety and efficacy of PPIs warrants cautious use of these drugs in pediatric patients, particularly infants. PPIs are not recommended as first-line therapy for symptomatic GERD in otherwise healthy infants (1 to 11 months); nonpharmacologic measures such as diet modification and positioning strategies are recommended first-line and treatment with PPIs should be reserved for use in infants with acid reflux disease diagnosed by endoscopy (e.g., erosive esophagitis). No clear advantage has been demonstrated for the use of one PPI over another in the treatment of GERD. Instead, a key to optimizing effectiveness is tailoring dosage timing; administer traditional delayed-release PPIs 30 to 60 minutes before a meal for maximal pH control. A one-time switch to a different PPI in a refractory patient may be useful. Esomeprazole is used in combination with antibiotics to eradicate Helicobacter pylori (H. pylori) in patients with active or prior duodenal ulcer disease, for risk reduction of NSAID-associated gastric ulcer, and for pathological hypersecretory conditions, including Zollinger-Ellison syndrome; these are potential off-label uses in pediatric patients. Additionally, PPIs are often used for stress ulcer prophylaxis in critically ill patients; however, evidence for benefit is lacking, and use may increase the risk of adverse reactions such as pneumonia and Clostridioides difficile (C. diff) infection. Reserve stress ulcer prophylaxis for patients with risk factors for clinically significant gastrointestinal bleeding (e.g., multiple organ dysfunction, prolonged mechanical ventilation, coagulopathy, persistent shock, concomitant corticosteroid therapy). In a retrospective case-controlled trial in 136 pediatric patients, the use of a PPI was significantly higher in the C. diff positive group compared with the C. diff negative group (OR = 4.5; 95% CI = 1.4 to 14.4). Esomeprazole is FDA-approved for pediatric patients as young as 1 month of age, for both oral and intravenous use.

For the treatment of symptomatic, non-erosive gastroesophageal reflux disease (GERD):
Oral dosage:
Neonates*: Safety and efficacy have not been established; esomeprazole was not superior to placebo in 1 small randomized controlled trial. Doses of 0.5 mg/kg/day PO were used for up to 14 days in a randomized, placebo controlled study of premature and term neonates (n = 52, gestational ages 24 to 40 weeks) with symptoms of gastroesophageal reflux disease (GERD). There were no significant differences in the total number of GERD-related signs and symptoms or the total number of reflux episodes in patients receiving esomeprazole compared to those receiving placebo. Patients receiving esomeprazole did have significantly fewer acidic reflux episodes compared to patients receiving placebo. Esomeprazole was well tolerated.
Infants*: Esomeprazole was not more effective than placebo in a 4-week, placebo-controlled study (data not published). Doses of 0.25 mg/kg/day and 1 mg/kg/day PO were used in a short-term pharmacokinetic study (n = 45). After 1 week of treatment, the 1 mg/kg/day dose provided similar exposure to that seen in adults receiving 20 mg/day PO; this dose also provided the most effective acid suppression. Both doses of esomeprazole were well tolerated. PPIs are not recommended as first-line therapy for symptomatic GERD in otherwise healthy infants (1 to 11 months); non-pharmacologic measures such as diet modification and positioning strategies are preferred. Reserve pharmacologic treatment for use in infants with disease diagnosed by endoscopy (e.g., esophageal erosion).
Children 1 to 11 years: 10 mg PO once daily taken 1 hour before meals, for up to 8 weeks. Alternatively, a dose range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP).
Children and Adolescents 12 to 17 years: 20 mg PO once daily taken 1 hour before meals, for 4 weeks. Alternatively, a dose range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Do not exceed recommended adult doses (20 to 40 mg/day).

For the treatment of diagnostically confirmed erosive esophagitis due to GERD:
-oral dosing for the healing of erosive esophagitis:
Oral dosage:
Neonates*: Safety and efficacy have not been established; esomeprazole was not superior to placebo in one small randomized controlled trial. Doses of 0.5 mg/kg/day PO were used for up to 14 days in a randomized, placebo controlled study of premature and term neonates (n = 52, gestational ages 24 to 40 weeks) with symptoms of gastroesophageal reflux disease (GERD). There were no significant differences in the total number of GERD-related signs and symptoms or the total number of reflux episodes in patients receiving esomeprazole compared to those receiving placebo. Patients receiving esomeprazole did have significantly fewer acidic reflux episodes compared to patients receiving placebo. Esomeprazole was well tolerated.
Infants: Dosing is weight based and administered PO once daily for up to 6 weeks as follows: 2.5 mg for weight 3 to 5 kg; 5 mg for weight 5.1 to 7.5 kg; and 10 mg for weight 7.6 to 12 kg. Doses greater than 1.33 mg/kg/day PO have not been studied. PPI treatment in infants should be reserved for those with disease diagnosed by endoscopy (e.g., esophageal erosion) and nonpharmacologic measures such as diet modification and positioning strategies are recommended.
Children 1 to 11 years: 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Do not exceed recommended adult doses (20 to 40 mg/day). The FDA-approved dosage is weight based and administered PO once daily for 8 weeks as follows: 10 mg for weight less than 20 kg; 10 or 20 mg for weight 20 kg or more.
Children and Adolescents 12 years and older: 20 mg or 40 mg PO once daily for 4 to 8 weeks. Alternatively, a dosage range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Do not exceed recommended adult doses (20 to 40 mg/day).
-for short-term parenteral treatment in pediatric patients unable to take oral therapy:
Intravenous dosage:
Neonates*: Safety and efficacy have not been established; 0.5 mg/kg/dose IV once daily infused over 10 to 30 minutes has been suggested.
Infants: 0.5 mg/kg/dose IV once daily infused over 10 to 30 minutes for up to 10 days. The IV formulation is indicated as an alternative to oral therapy for the short-term treatment of GERD when oral therapy is not possible or appropriate. Switch to oral therapy when feasible.
Children and Adolescents weighing less than 55 kg: 10 mg IV once daily over 10 to 30 minutes for up to 10 days. The IV formulation is indicated as an alternative to oral therapy for the short-term treatment of GERD when oral therapy is not possible or appropriate. Switch to oral therapy when feasible.
Children and Adolescents weighing 55 kg or more: 20 mg IV once daily over 10 to 30 minutes for up to 10 days. The IV formulation is indicated as an alternative to oral therapy for the short-term treatment of GERD when oral therapy is not possible or appropriate. Switch to oral therapy when feasible.

For Helicobacter pylori (H. pylori) eradication*:
-in combination with amoxicillin and clarithromycin:
Oral dosage (esomeprazole magnesium capsules or suspension):
Children weighing 15 to 24 kg: 20 mg PO twice daily in combination with amoxicillin and clarithromycin for 14 days. Triple therapy with standard-dose amoxicillin, clarithromycin, and a proton pump inhibitor is the first-line treatment option for patients infected with fully susceptible H. pylori strains or strains susceptible to clarithromycin but resistant to metronidazole. In cases of penicillin allergy, use metronidazole in place of amoxicillin for patients infected with fully susceptible strains.
Children and Adolescents weighing 25 to 34 kg: 30 mg PO twice daily in combination with amoxicillin and clarithromycin for 14 days. Triple therapy with standard-dose amoxicillin, clarithromycin, and a proton pump inhibitor is the first-line treatment option for patients infected with fully susceptible H. pylori strains or strains susceptible to clarithromycin but resistant to metronidazole. In cases of penicillin allergy, use metronidazole in place of amoxicillin for patients infected with fully susceptible strains.
Children and Adolescents weighing 35 kg or more: 40 mg PO twice daily in combination with amoxicillin and clarithromycin for 14 days. Triple therapy with standard-dose amoxicillin, clarithromycin, and a proton pump inhibitor is the first-line treatment option for patients infected with fully susceptible H. pylori strains or strains susceptible to clarithromycin but resistant to metronidazole. In cases of penicillin allergy, use metronidazole in place of amoxicillin for patients infected with fully susceptible strains.
-in combination with amoxicillin and metronidazole:
Oral dosage (esomeprazole magnesium capsules or suspension):
Children weighing 15 to 24 kg: 20 mg PO twice daily in combination with amoxicillin and metronidazole for 14 days. Triple therapy with standard-dose amoxicillin, metronidazole, and a proton pump inhibitor (PPI) is a first-line treatment option for patients infected with H. pylori strains with known susceptibility to metronidazole and resistance to clarithromycin. Triple therapy with high-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.
Children and Adolescents weighing 25 to 34 kg: 30 mg PO twice daily in combination with amoxicillin and metronidazole for 14 days. Triple therapy with standard-dose amoxicillin, metronidazole, and a proton pump inhibitor (PPI) is a first-line treatment option for patients infected with H. pylori strains with known susceptibility to metronidazole and resistance to clarithromycin. Triple therapy with high-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.
Children and Adolescents weighing 35 kg or more: 40 mg PO twice daily in combination with amoxicillin and metronidazole for 14 days. Triple therapy with standard-dose amoxicillin, metronidazole, and a proton pump inhibitor (PPI) is a first-line treatment option for patients infected with H. pylori strains with known susceptibility to metronidazole and resistance to clarithromycin. Triple therapy with high-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.
-as part of a sequential therapy regimen:
Oral dosage (esomeprazole magnesium capsules or suspension):
Children weighing 15 to 24 kg: 20 mg PO twice daily for 10 days. Use in combination with amoxicillin for days 1 through 5, and then clarithromycin and metronidazole for days 6 through 10. Sequential therapy is a first-line treatment option for patients infected with fully susceptible H. pylori strains. Sequential therapy is not recommended if susceptibility testing is unavailable.
Children and Adolescents weighing 25 to 34 kg: 30 mg PO twice daily for 10 days. Use in combination with amoxicillin for days 1 through 5, and then clarithromycin and metronidazole for days 6 through 10. Sequential therapy is a first-line treatment option for patients infected with fully susceptible H. pylori strains. Sequential therapy is not recommended if susceptibility testing is unavailable.
Children and Adolescents weighing 35 kg or more: 40 mg PO twice daily for 10 days. Use in combination with amoxicillin for days 1 through 5, and then clarithromycin and metronidazole for days 6 through 10. Sequential therapy is a first-line treatment option for patients infected with fully susceptible H. pylori strains. Sequential therapy is not recommended if susceptibility testing is unavailable.
-as part of a quadruple therapy regimen:
Oral dosage (esomeprazole magnesium capsules or suspension):
Children weighing 15 to 24 kg: 20 mg PO twice daily in combination with amoxicillin, metronidazole, and clarithromycin for 14 days. Concomitant quadruple therapy with amoxicillin, metronidazole, clarithromycin, and a proton pump inhibitor is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.
Children and Adolescents weighing 25 to 34 kg: 30 mg PO twice daily in combination with amoxicillin, metronidazole, and clarithromycin for 14 days. Concomitant quadruple therapy with amoxicillin, metronidazole, clarithromycin, and a proton pump inhibitor is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.
Children and Adolescents weighing 35 kg or more: 40 mg PO twice daily in combination with amoxicillin, metronidazole, and clarithromycin for 14 days. Concomitant quadruple therapy with amoxicillin, metronidazole, clarithromycin, and a proton pump inhibitor is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.

For the treatment of gastric acid hypersecretion associated with cysteamine therapy for nephropathic cystinosis*:
Oral dosage:
Children 2 to 10 years*: Initial doses of 1.1 mg/kg/day PO divided twice daily were used in a small, prospective, open-label study of 12 children aged 2 to 10 years receiving cysteamine therapy. Doses were adjusted during the study based on upper GI symptoms. The mean final dose of esomeprazole was 1.7 mg/kg/day PO (range: 0.7 to 2.75 mg/kg/day PO; Max: 40 mg/day). The authors report a significant decrease in basal gastric acid output and significant improvement in symptom scores.

For stress gastritis prophylaxis* in patients unable to take oral therapy:
Intravenous dosage:
Neonates: 0.5 mg/kg/dose IV once daily.
Infants 1 to 11 months: 0.5 mg/kg/dose IV once daily.
Children and Adolescents weighing less than 55 kg: 10 mg IV once daily over 15 to 30 minutes.
Children and Adolescents weighing 55 kg or more: 20 mg IV once daily over 15 to 30 minutes.

For the treatment of eosinophilic esophagitis*:
Oral dosage (esomeprazole magnesium):
Children and Adolescents: 1 mg/kg/dose (Max: 40 mg/dose) PO twice daily for 8 to 12 weeks, then reduce dose to the lowest dose that maintains remission.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, 0.5 mg/kg/day PO/IV has been used off-label.
-Infants
In general for infants, maximum doses are 1.33 mg/kg/day PO and 0.5 mg/kg/day IV.
weight 3 to 5 kg: 2.5 mg/day PO; 0.5 mg/kg/day IV.
weight 5.1 to 7.5 kg: 5 mg/day PO; 0.5 mg/kg/day IV.
weight 7.6 to 12 kg: 10 mg/day PO; 0.5 mg/kg/day IV.
-Children
1 to 11 years and weight less than 20 kg: 10 mg/day PO is the FDA-approved maximum; however, up to 3.3 mg/kg/day PO (Max: 40 mg/day) has been used off-label; 10 mg/day IV.
1 to 11 years and weight 20 to 54 kg: 20 mg/day PO is the FDA-approved maximum; however, up to 3.3 mg/kg/day PO (Max: 80 mg/day) has been used off-label; 10 mg/day IV.
1 to 11 years and weight 55 kg or more: 20 mg/day PO is the FDA-approved maximum; however, up to 3.3 mg/kg/day PO (Max: 80 mg/day) has been used off-label; 20 mg/day IV.
12 years and weight less than 55 kg: 40 mg/day PO is the FDA-approved maximum; however, up to 80 mg/day PO has been used off-label; 10 mg/day IV.
12 years and weight 55 kg or more: 40 mg/day PO is the FDA-approved maximum; however, up to 80 mg/day PO has been used off-label; 20 mg/day IV.
-Adolescents
weight less than 55 kg: 40 mg/day PO is the FDA-approved maximum; however, up to 80 mg/day PO has been used off-label; 10 mg/day IV.
weight 55 kg or more: 40 mg/day PO is the FDA-approved maximum; however, up to 80 mg/day PO has been used off-label; 20 mg/day IV.

Patients with Hepatic Impairment Dosing
No dosage adjustment is recommended for mild to moderate hepatic impairment (Child Pugh Class A or B).In adult patients with severe hepatic insufficiency (Child Pugh Class C), do not exceed 20 mg/day; specific maximum dose recommendations are not available for pediatric patients.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Intermittent hemodialysis
No dosage adjustment is necessary. Due to high protein binding, esomeprazole is not expected to be removed by hemodialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Esomeprazole is a substituted benzimidazole proton-pump inhibitor (PPI) that suppresses gastric acid secretion by inhibiting the gastric (H+, K+)-ATPase enzyme pump. Following activation in an acidic pH, esomeprazole binds irreversibly to the (H+, K+)-ATPase pump on the secretory surface of the parietal cell membrane. Subsequently, the secretion of hydrogen ions into the gastric lumen is inhibited. Gastric acid pump inhibitors block the final step of gastric acid production, and inhibit both basal and stimulus-induced acid secretion. Delayed-release adult doses of 20 mg and 40 mg maintained intragastric pH greater than 4.0 for 12.7 hours and 16.8 hours, respectively.

Significant in vitro activity against Helicobacter pylori (H. Pylori) has been demonstrated for esomeprazole. Esomeprazole monotherapy increases the clearance rate of H. pylori; however, eradication does not occur without appropriate antimicrobial therapy.

Pharmacokinetics: someprazole is administered orally and intravenously. It is 97% bound to plasma proteins. Metabolism occurs extensively in the liver to inactive metabolites via CYP2C19 and to a lesser extent by CYP3A4. The metabolites lack antisecretory activity. Esomeprazole is a time-dependent inhibitor of CYP2C19, resulting in autoinhibition and nonlinear pharmacokinetics. The systemic exposure (AUC) increases in a more than dose proportional manner after multiple oral doses of esomeprazole. Compared to the first dose, the systemic exposure (Cmax and AUC) at steady state following once daily dosing increased by 43% and 90%, respectively, compared to after the first dose for the 20 mg dose and increased by 95% and 159%, respectively, for the 40 mg dose. The plasma elimination half-life is approximately 1.5 hours. Less than 1% of parent drug is excreted in the urine with the remainder excreted as inactive metabolites in both the urine and feces.

Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2C19, CYP3A4
Esomeprazole is metabolized by CYP2C19 and CYP3A4, and it inhibits the CYP2C19 isoenzyme. Combined inhibitors of CYP2C19 and 3A4 may raise esomeprazole exposure, while inducers of CYP2C19 or CYP3A4 may reduce esomeprazole levels and drug efficacy. Esomeprazole is a time-dependent inhibitor of CYP2C19 and can increase the systemic exposure of co-administered drugs that are CYP2C19 substrates. In addition, administration of esomeprazole increases intragastric pH and can alter the systemic exposure of certain drugs that exhibit pH-dependent solubility. In vitro and in vivo drug interaction studies note that esomeprazole is not likely to inhibit CYP3A4, CYP1A2, CYP2A6, CYP2C9, CYP2D6, or CYP2E1.


-Route-Specific Pharmacokinetics
Oral Route
Esomeprazole dissolves rapidly in an acidic environment and therefore is formulated as a capsule containing enteric-coated pellets. Esomeprazole has a greater bioavailability compared to omeprazole. Multiple dosing at 40 mg/day results in 90% bioavailability versus 64% after a single 40 mg dose. The maximum concentration (Cmax) is reached within 1 to 3.5 hours. The AUC of esomeprazole (the S-isomer) is 80% higher than with omeprazole (both S- and R-isomer) due to decreased clearance and first-pass elimination of the S-isomer. Clinically this allows more esomeprazole to reach the site of action and may contribute to higher efficacy rates. Compared to the first dose, the systemic exposure (Cmax and AUC0 to 24h) at steady state following once a day dosing increased by 43% and 90%, respectively, compared to after the first dose for the 20 mg dose and increased by 95% and 159%, respectively, for the 40 mg dose. The AUC of a single 40 mg dose of esomeprazole is decreased by 33% to 53% after food intake compared to fasting conditions.

Intravenous Route
The pharmacokinetics of intravenous esomeprazole were determined in healthy adult subjects following once daily administration of 20 mg and 40 mg by constant rate of infusion over 30 minutes for 5 days. The pharmacokinetic profile for the 20 mg and 40 mg dose is as follows: AUC (5.11 and 16.21 micromoles x hour/L, respectively) and Cmax (3.86 and 7.51 micromoles/L, respectively).


-Special Populations
Pediatrics
Neonates and Infants
Pharmacokinetic simulation analysis of esomeprazole showed that steady-state plasma exposure after 2.5 mg/dose PO (infant weight 3 to 5 kg), 5 mg/dose PO (infant weight 5.1 to 7.5 kg), and 10 mg/dose PO (infant weight 7.6 to 12 kg), respectively, would be similar to that seen after 10 mg/dose PO in 1 to 11-year-olds and 20 mg/dose PO in 12 to 18-year-olds. After repeated doses of 1 mg/kg/day PO in infants 1 to 11 months of age (n = 8), the mean half-life was 0.93 hours. Following administration of oral and intravenous esomeprazole in neonates, the geometric mean for the apparent clearance (Cl/F) was 0.55 L /hour/kg and 0.17 L/hour/kg, respectively. The apparent clearance (CL/F) increases with age in pediatric patients with GERD from 1 month to 2 years of age.

Children
A small pharmacokinetic study of esomeprazole involving 31 children ages 1 to 11 years found dose- and age-dependent properties in this population. Doses of 5 mg/day and 10 mg/day PO 11-year-old in patients aged 1 to 5 years and 10 mg/day and 20 mg/day PO were examined in patients aged 6 to 11 years. When normalized for body weight children 5-year-old years of age and younger demonstrated a significantly higher clearance than the older children. The study suggests that 10 mg/day PO in children ages 1 to 11 years of age results in similar exposure compared to a 20 mg/day PO in adults. Mean daily doses were 0.71 mg/kg in the 1 to 5-year-old group and 0.34 mg/kg in the 6 to 11-year-old group. For both age groups and all doses, the mean Cmax was reached in less than 2 hours, and the elimination half-life was less than 1 hour.

Adolescents
Pharmacokinetic parameters of esomeprazole in adolescents from 12 to 17 years of age were similar to those observed in adult patients with symptomatic GERD.

Hepatic Impairment
Data in adult patients with hepatic cirrhosis showed that the mean AUC of esomeprazole was 76% higher, and the half-life was 29% longer compared with GERD patients with no hepatic dysfunction. However, cirrhotic patients with mild to moderate liver dysfunction exhibited similar pharmacokinetic parameters to otherwise healthy GERD patients. Cirrhotic patients with severe hepatic insufficiency exhibited AUCs 2 to 3 times higher than those with normal liver function. In adult patients with severe hepatic insufficiency (Child-Pugh Class C), do not exceed 20 mg/day; specific maximum dose recommendations are not available for pediatric patients.

Renal Impairment
Pharmacokinetic parameters of esomeprazole are not altered in renal insufficiency and the drug is not expected to be removed by hemodialysis due to high protein binding.

Other
CYP2C19 Poor Metabolizers
CYP2C19, a polymorphic enzyme, is involved in the metabolism of esomeprazole. The CYP2C19*1 allele is fully functional while the CYP2C19*2 and *3 alleles are nonfunctional. There are other alleles associated with no or reduced enzymatic function. Patients carrying 2 fully functional alleles are extensive metabolizers and those carrying 2 loss-of-function alleles are poor metabolizers. In extensive metabolizers, esomeprazole is primarily metabolized by CYP2C19. The systemic exposure to esomeprazole varies with a patient's metabolism status, with poor metabolizers having the greatest exposure and extensive metabolizers having the least exposure. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers. Systemic esomeprazole exposures were modestly higher (approximately 17%) in CYP2C19 intermediate metabolizers (IM; n=6) compared to extensive metabolizers (EM; n=17) of CYP2C19. Similar pharmacokinetic differences were noted across these genotypes in a study of Chinese healthy subjects that included 7 EMs and 11 IMs. There is very limited pharmacokinetic information for poor metabolizers (PM) from these studies. At steady state following once daily administration of esomeprazole 40 mg given intravenously, the ratio of AUC in Poor Metabolizers to AUC in the rest of the population (EMs) is approximately 1.5. This change in exposure is not considered clinically meaningful.