Esomeprazole Magnesium

Esomeprazole magnesium for delayed-release oral suspension is a proton pump inhibitor (PPI).

Esomeprazole magnesium for delayed-release oral suspension is indicated for the:

• Short-term treatment in the healing of erosive esophagitis (EE) in adults and pediatric patients 12 years to 17 years of age. (
  1.1 Healing of Erosive Esophagitis (EE)

  Adults

  Esomeprazole magnesium for delayed-release oral suspension is indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed EE in adults. For those patients who have not healed after 4 to 8 weeks of treatment, an additional 4- to 8- week course of esomeprazole magnesium for delayed-release oral suspension may be considered.

  Pediatric Patients 12 Years to 17 Years of Age

  Esomeprazole magnesium for delayed-release oral suspension is indicated for the short-term treatment (4 to 8 weeks) for the healing of EE in pediatric patients 12 years to 17 years of age.

  Pediatric Patients 1 Year to 11 Years of Age

  Esomeprazole magnesium for delayed-release oral suspension is indicated for the short-term treatment (8 weeks) for the healing of EE in pediatric patients 1 year to 11 years of age.

  Pediatric Patients 1 Month to Less Than 1 Year of Age

  Esomeprazole magnesium for delayed-release oral suspension is indicated for short-term treatment (up to 6 weeks) of EE due to acid-mediated GERD in pediatric patients 1 month to less than 1 year of age.
  )
• Maintenance of healing of EE in adults. (
  1.2 Maintenance of Healing of EE

  Esomeprazole magnesium for delayed-release oral suspension is indicated for the maintenance of healing of EE in adults. Controlled studies do not extend beyond 6 months.
  )
• Short-term treatment of heartburn and other symptoms associated GERD in adults and pediatric patients 12 years to 17 years of age. (
  1.3 Treatment of Symptomatic GERD

  Adults

  Esomeprazole magnesium for delayed-release oral suspension is indicated for short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults.

  Pediatric Patients 12 Years to 17 Years of Age

  Esomeprazole magnesium for delayed-release oral suspension is indicated for short-term treatment (4 weeks) of heartburn and other symptoms associated with GERD in pediatric patients 12 years to 17 years of age.

  Pediatric Patients 1 Year to 11 Years of Age

  Esomeprazole magnesium for delayed-release oral suspension is indicated for short-term treatment (up to 8 weeks) of heartburn and other symptoms associated with GERD in pediatric patients 1 year to 11 years of age.
  )
• Risk reduction of nonsteroidal anti-inflammatory drugs (NSAID)-associated gastric ulcer in adults at risk for developing gastric ulcers due to age (60 years and older) and/or documented history of gastric ulcers. (
  1.4 Risk Reduction of Nonsteroidal Anti-Inflammatory Drugs (NSAID)-Associated Gastric Ulcer

  Esomeprazole magnesium for delayed-release oral suspension is indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in adult patients at risk for developing gastric ulcers. Patients are considered to be at risk due to their age (60 years and older) and/or documented history of gastric ulcers. Controlled studies do not extend beyond 6 months.
  )
• Helicobacter pylori
  eradication in adult patients to reduce the risk of duodenal ulcer recurrence in combination with amoxicillin and clarithromycin. (
  1.5

  Helicobacter pylori

  Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

  Eradication of

  H. pylori

  has been shown to reduce the risk of duodenal ulcer recurrence.

  Triple Therapy

  Esomeprazole magnesium for delayed-release oral suspension in combination with amoxicillin and clarithromycin is indicated for the treatment of adult patients with

  H. pylori

  infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate

  H. pylori

  .

  In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted

  [see

  Clinical Pharmacology (12.4)

  and

  the prescribing information for clarithromycin

  ]

  .
  )
• Long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome in adults. (
  1.6 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

  Esomeprazole magnesium for delayed-release oral suspension is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome, in adults.
  )

Esomeprazole magnesium for delayed-release oral suspension is indicated for the:

• Short-term treatment in the healing of EE in pediatric patients 1 year to 11 years of age and of EE due to acid-mediated GERD in pediatric patients 1 month to less than 1 year of age. (
  1.1 Healing of Erosive Esophagitis (EE)

  Adults

  Esomeprazole magnesium for delayed-release oral suspension is indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed EE in adults. For those patients who have not healed after 4 to 8 weeks of treatment, an additional 4- to 8- week course of esomeprazole magnesium for delayed-release oral suspension may be considered.

  Pediatric Patients 12 Years to 17 Years of Age

  Esomeprazole magnesium for delayed-release oral suspension is indicated for the short-term treatment (4 to 8 weeks) for the healing of EE in pediatric patients 12 years to 17 years of age.

  Pediatric Patients 1 Year to 11 Years of Age

  Esomeprazole magnesium for delayed-release oral suspension is indicated for the short-term treatment (8 weeks) for the healing of EE in pediatric patients 1 year to 11 years of age.

  Pediatric Patients 1 Month to Less Than 1 Year of Age

  Esomeprazole magnesium for delayed-release oral suspension is indicated for short-term treatment (up to 6 weeks) of EE due to acid-mediated GERD in pediatric patients 1 month to less than 1 year of age.
  )
• Short-term treatment of heartburn and other symptoms associated with GERD in pediatric patients 1 year to 11 years of age. (
  1.3 Treatment of Symptomatic GERD

  Adults

  Esomeprazole magnesium for delayed-release oral suspension is indicated for short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults.

  Pediatric Patients 12 Years to 17 Years of Age

  Esomeprazole magnesium for delayed-release oral suspension is indicated for short-term treatment (4 weeks) of heartburn and other symptoms associated with GERD in pediatric patients 12 years to 17 years of age.

  Pediatric Patients 1 Year to 11 Years of Age

  Esomeprazole magnesium for delayed-release oral suspension is indicated for short-term treatment (up to 8 weeks) of heartburn and other symptoms associated with GERD in pediatric patients 1 year to 11 years of age.
  )

Esomeprazole Magnesium for Delayed-Release Oral Suspension, 10 mg - unit dose packets containing a light yellow, free flow granules consisting of off-white to cream esomeprazole pellets and pale yellow inactive granules.

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

  In adults, symptomatic response to therapy with esomeprazole magnesium for delayed-release oral suspension does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.
  )
• Acute Tubulointerstitial Nephritis
  : Discontinue treatment and evaluate patients. (
  5.2 Acute Tubulointerstitial Nephritis

  Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to 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 magnesium for delayed-release oral suspension and evaluate patients with suspected acute TIN

  [see

  Contraindications

  ]

  .
  )
• Clostridium difficile

  -Associated Diarrhea
  : PPI therapy may be associated with increased risk. (
  5.3

  Clostridium difficile

  -Associated Diarrhea

  Published observational studies suggest that PPI therapy like esomeprazole magnesium for delayed-release oral suspension may be associated with an increased risk of C

  lostridium difficile-

  associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve

  [see

  Adverse Reactions

  ]

  .

  Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

  Clostridium difficile

  -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with esomeprazole magnesium, refer to Warnings and Precautions section of the corresponding prescribing information.
  )
• Bone Fracture
  : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (
  5.4 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

  and

  Adverse Reactions

  ]

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

  Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) 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

  [see Adverse Reactions (

  6.2

  )]

  .

  Discontinue esomeprazole magnesium for delayed-release oral suspension at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
  )
• Cutaneous and Systemic Lupus Erythematosus
  : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue esomeprazole magnesium for delayed-release oral suspension and refer to specialist for evaluation. (
  5.6 Cutaneous and Systemic Lupus Erythematosus

  Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including esomeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.

  The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.

  Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

  Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving esomeprazole magnesium for delayed-release oral suspension, 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 (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.
  )
• Interaction with Clopidogrel
  : Avoid concomitant use of esomeprazole magnesium for delayed-release oral suspension (
  5.7 Interaction with Clopidogrel

  Avoid concomitant use of esomeprazole magnesium 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 esomeprazole magnesium consider alternative anti-platelet therapy

  [see

  Drug Interactions

  ]

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

  Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
  )
• Hypomagnesemia and Mineral Metabolism
  : Reported rarely with prolonged treatment with PPIs. (
  5.9 Hypomagnesemia and Mineral Metabolism

  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. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. 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

  )]

  .

  Consider monitoring magnesium and calcium levels prior to initiation of esomeprazole magnesium for delayed-release oral suspension and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI.
  )
• Interaction with St. John’s Wort or Rifampin
  : Avoid concomitant use of esomeprazole magnesium for delayed-release oral suspension. (
  5.10 Interaction with St. John’s Wort or Rifampin

  Drugs which induce CYP2C19 or CYP3A4 (such as St. John's Wort or rifampin) can substantially decrease esomeprazole concentrations

  [see

  Drug Interactions

  ]

  . Avoid concomitant use of esomeprazole magnesium for delayed-release oral suspension with St. John's Wort or rifampin.
  ,
  7 DRUG INTERACTIONS

  See full prescribing information for a list of clinically important drug interactions. (

  7

  )

  Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with esomeprazole and instructions for preventing or managing them.

  Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

  Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Esomeprazole and Interaction with Diagnostics

  Antiretrovirals
  Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine atazanavir, and nelfinavir) when used concomitantly with esomeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3) ]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole may increase toxicity [see Clinical Pharmacology (12.3) ]. There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole.
  Intervention:	Rilpivirine-containing products: Concomitant use with esomeprazole magnesium is contraindicated [see Contraindications (4) ] . Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with esomeprazole magnesium. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs
  Warfarin
  Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including esomeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
  Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain the target INR range.
  Methotrexate
  Clinical Impact:	Concomitant use of esomeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.12) ].
  Intervention:	A temporary withdrawal of esomeprazole magnesium may be considered in some patients receiving high-dose methotrexate.
  2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol)
  Clopidogrel
  Clinical Impact:	Concomitant use of esomeprazole 40 mg resulted in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3) ] . There are no adequate combination studies of a lower dose of esomeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel .
  Intervention:	Avoid concomitant use with esomeprazole magnesium Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.7) ].
  Citalopram
  Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3) ].
  Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
  Cilostazol
  Clinical Impact:	Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3) ].
  Intervention:	Consider reducing the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
  Digoxin
  Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3) ].
  Intervention:	Monitor digoxin concentrations and adjust the dose, if needed, to maintain therapeutic drug concentrations. See prescribing information for digoxin.
  Combination Therapy with Clarithromycin and Amoxicillin
  Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
  Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
  Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
  Clinical Impact:	Esomeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity
  Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole is an enantiomer, in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving esomeprazole magnesium and MMF. Use esomeprazole magnesium with caution in transplant patients receiving MMF [ see Clinical Pharmacology (12.3) ] . See the prescribing information for other drugs dependent on gastric pH for absorption.
  Tacrolimus
  Clinical Impact:	Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
  Intervention:	Monitor tacrolimus whole blood concentrations and consider reducing the dose, if needed, to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
  Interactions with Investigations of Neuroendocrine Tumors
  Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.11 ), Clinical Pharmacology ].
  Intervention:	Discontinue esomeprazole magnesium at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
  Interaction with Secretin Stimulation Test
  Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
  Intervention:	Discontinue esomeprazole magnesium 4 weeks prior to testing [see Clinical Pharmacology (12.2) ]
  False Positive Urine Tests for THC
  Clinical Impact:	There have been reports of false positive urine screening test for tetrahydrocannabinol (THC) in patients receiving PPIs.
  Intervention:	An alternative confirmatory method should be considered to verify positive results.

  Table 4: Clinically Relevant Interactions Affecting Esomeprazole When Co-Administered with Other Drugs

  CYP2C19 or CYP3A4 Inducers
  Clinical Impact:	Decreased exposure of esomeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3) ] .
  Intervention:	St. John’s Wort, rifampin : Avoid concomitant use with [see Warnings and Precautions (5.10) ] . Ritonavir-containing products: see prescribing information for specific drugs
  Voriconazole
  Clinical Impact:	Increased exposure of esomeprazole [see Clinical Pharmacology (12.3) ] .
  Intervention:	Dose adjustment of esomeprazole magnesium is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dosage adjustment may be considered. See prescribing information for voriconazole.
  )
• Interactions with Diagnostic Investigations for Neuroendocrine Tumors
  : Increased chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors, temporarily stop esomeprazole magnesium for delayed-release oral suspension at least 14 days before assessing CgA levels. (
  5.11 Interactions with Diagnostic Investigations for Neuroendocrine Tumors

  Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary

  [see

  Clinical Pharmacology

  ].
  ,
  12.2 Pharmacodynamics

  Antisecretory Activity

  Adults

  The effect of esomeprazole on intragastric pH was determined in adult patients with symptomatic GERD in two separate studies. In the first study of 36 patients, esomeprazole magnesium 40 mg and 20 mg delayed-release capsules were administered once daily over 5 days as  shown in Table 5:

  Table 5: Effect of Esomeprazole on Intragastric pH on Day 5 (N=36) Following Once Daily Dosing of Esomeprazole Magnesium Delayed-Release Capsules in Adult Patients with Symptomatic GERD

  1.000000000000000e+00Gastric pH was measured over a 24-hour period
  2.000000000000000e+00p< 0.01 esomeprazole magnesium 40 mg vs. esomeprazole magnesium 20 mg
  	Esomeprazole Magnesium Delayed-Release Capsules
  Parameter	40 mg once daily	20 mg once daily
  % Time Gastric pH >41(Hours)	70%2(16.8 h)	53% (12.7 h)
  Coefficient of variation	26%	37%
  Median 24 Hour pH	4.92	4.1
  Coefficient of variation	16%	27%

  In a second study, the effect on intragastric pH of esomeprazole magnesium 40 mg delayed-release capsules administered once daily over a five-day period was similar to the first study, (% time with pH > 4 was 68% or 16.3 hours).

  Pediatrics

  In infants (1 to 11 months old, inclusive) with GERD given esomeprazole magnesium for delayed-release oral suspension 1 mg/kg once daily, the percent time with intragastric pH > 4 increased from 29% at baseline to 69% on Day 7, which is similar to the pharmacodynamic effect in adults.

  Serum Gastrin Effects

  The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials of oral esomeprazole for up to 8 weeks and in over 1,300 patients for up to 12 months. The mean fasting gastrin level increased in a dose-related manner. The increase in serum gastrin concentrations reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.

  Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors.

  [see Warnings and Precautions (5.11)]

  Enterochromaffin-like (ECL) Cell Effects

  Human gastric biopsy specimens have been obtained from more than 3,000 patients (both pediatrics and adults) treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients.

  [

  see Nonclinical Toxicology (13.1)

  ]

  In over 1,000 patients treated with oral esomeprazole (10 mg, 20 mg or 40 mg/day) for up to 12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.

  Endocrine Effects

  Esomeprazole had no effect on thyroid function in adults when given esomeprazole magnesium 20 mg or 40 mg delayed-release capsules once daily for 4 weeks. Other effects of esomeprazole on the endocrine system were assessed in studies of omeprazole. Oral doses of omeprazole 30 mg or 40 mg once daily for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin, or secretin.
  )
• Interaction with Methotrexate
  : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider temporary withdrawal of esomeprazole magnesium for delayed-release oral suspension. (
  5.12 Interaction with Methotrexate

  Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients

  [see

  Drug Interactions

  ]

  .
  ,
  7 DRUG INTERACTIONS

  See full prescribing information for a list of clinically important drug interactions. (

  7

  )

  Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with esomeprazole and instructions for preventing or managing them.

  Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

  Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Esomeprazole and Interaction with Diagnostics

  Antiretrovirals
  Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine atazanavir, and nelfinavir) when used concomitantly with esomeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3) ]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole may increase toxicity [see Clinical Pharmacology (12.3) ]. There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole.
  Intervention:	Rilpivirine-containing products: Concomitant use with esomeprazole magnesium is contraindicated [see Contraindications (4) ] . Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with esomeprazole magnesium. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs
  Warfarin
  Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including esomeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
  Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain the target INR range.
  Methotrexate
  Clinical Impact:	Concomitant use of esomeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.12) ].
  Intervention:	A temporary withdrawal of esomeprazole magnesium may be considered in some patients receiving high-dose methotrexate.
  2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol)
  Clopidogrel
  Clinical Impact:	Concomitant use of esomeprazole 40 mg resulted in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3) ] . There are no adequate combination studies of a lower dose of esomeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel .
  Intervention:	Avoid concomitant use with esomeprazole magnesium Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.7) ].
  Citalopram
  Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3) ].
  Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
  Cilostazol
  Clinical Impact:	Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3) ].
  Intervention:	Consider reducing the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
  Digoxin
  Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3) ].
  Intervention:	Monitor digoxin concentrations and adjust the dose, if needed, to maintain therapeutic drug concentrations. See prescribing information for digoxin.
  Combination Therapy with Clarithromycin and Amoxicillin
  Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
  Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
  Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
  Clinical Impact:	Esomeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity
  Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole is an enantiomer, in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving esomeprazole magnesium and MMF. Use esomeprazole magnesium with caution in transplant patients receiving MMF [ see Clinical Pharmacology (12.3) ] . See the prescribing information for other drugs dependent on gastric pH for absorption.
  Tacrolimus
  Clinical Impact:	Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
  Intervention:	Monitor tacrolimus whole blood concentrations and consider reducing the dose, if needed, to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
  Interactions with Investigations of Neuroendocrine Tumors
  Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.11 ), Clinical Pharmacology ].
  Intervention:	Discontinue esomeprazole magnesium at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
  Interaction with Secretin Stimulation Test
  Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
  Intervention:	Discontinue esomeprazole magnesium 4 weeks prior to testing [see Clinical Pharmacology (12.2) ]
  False Positive Urine Tests for THC
  Clinical Impact:	There have been reports of false positive urine screening test for tetrahydrocannabinol (THC) in patients receiving PPIs.
  Intervention:	An alternative confirmatory method should be considered to verify positive results.

  Table 4: Clinically Relevant Interactions Affecting Esomeprazole When Co-Administered with Other Drugs

  CYP2C19 or CYP3A4 Inducers
  Clinical Impact:	Decreased exposure of esomeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3) ] .
  Intervention:	St. John’s Wort, rifampin : Avoid concomitant use with [see Warnings and Precautions (5.10) ] . Ritonavir-containing products: see prescribing information for specific drugs
  Voriconazole
  Clinical Impact:	Increased exposure of esomeprazole [see Clinical Pharmacology (12.3) ] .
  Intervention:	Dose adjustment of esomeprazole magnesium is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dosage adjustment may be considered. See prescribing information for voriconazole.
  )
• Fundic Gland Polyps
  : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. (
  5.13 Fundic Gland Polyps

  PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.
  )

The following serious adverse reactions are described below and elsewhere in labeling:

• Acute Tubulointerstitial Nephritis
  [see

  Warnings and Precautions (5.2)

  ]
• Clostridium difficile -Associated Diarrhea
  [see

  Warnings and Precautions (5.3)

  ]
• Bone Fracture
  [see

  Warnings and Precautions (5.4)

  ]
• Severe Cutaneous Adverse Reactions
  [

  see Warnings and Precautions (5.5)

  ]
• Cutaneous and Systemic Lupus Erythematosus
  [see

  Warnings and Precautions (5.6)

  ]
• Cyanocobalamin (Vitamin B-12) Deficiency
  [see

  Warnings and Precautions (5

  5.8 Cyanocobalamin (Vitamin B-12) Deficiency

  Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.

  8)

  ]
• Hypomagnesemia and Mineral Metabolism
  [see

  Warnings and Precautions (5.9

  )]
• Fundic Gland Polyps
  [see

  Warnings and Precautions (5.13)

  ]