NEXIUM (Page 5 of 13)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of esomeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system:

Blood and Lymphatic: agranulocytosis, pancytopenia;

Eye: blurred vision;

Gastrointestinal: pancreatitis; stomatitis; microscopic colitis; fundic gland polyps;

Hepatobiliary: hepatic failure, hepatitis with or without jaundice;

Immune System: anaphylactic reaction/shock; systemic lupus erythematosus;

Infections and Infestations: GI candidiasis; Clostridium difficile- associated diarrhea;

Metabolism and nutritional disorders: hypomagnesemia (may lead to hypocalcemia and/or hypokalemia) [see Warnings and Precautions (5.9)] ;

Musculoskeletal and Connective Tissue: muscular weakness, myalgia, bone fracture;

Nervous System: hepatic encephalopathy, taste disturbance;

Psychiatric: aggression, agitation, depression, hallucination;

Renal and Urinary: interstitial nephritis;

Reproductive System and Breast: gynecomastia, erectile dysfunction;

Respiratory, Thoracic, and Mediastinal: bronchospasm;

Skin and Subcutaneous Tissue: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), cutaneous lupus erythematosus.

Adverse reactions associated with omeprazole may also be expected to occur with esomeprazole. See the full prescribing information for omeprazole for complete safety information.


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


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.


Rilpivirine-containing products: Concomitant use with NEXIUM is contraindicated [see Contraindications (4)].

Atazanavir: See prescribing information for atazanavir for dosing information.

Nelfinavir: Avoid concomitant use with NEXIUM. 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


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.


Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain the target INR range.


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)].


A temporary withdrawal of NEXIUM may be considered in some patients receiving high-dose methotrexate.

2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol)


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.


Avoid concomitant use with NEXIUM Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.7)].


Clinical Impact:

Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].


Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.


Clinical Impact:

Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].


Consider reducing the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.


Clinical Impact:

Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].


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.


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


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 NEXIUM and MMF. Use NEXIUM 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.


Clinical Impact:

Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.


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 (12.2)].


Discontinue NEXIUM 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.


Discontinue NEXIUM 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.


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)].


St. John’s Wort, rifampin: Avoid concomitant use with [see Warnings and Precautions (5.10)].

Ritonavir-containing products: see prescribing information for specific drugs


Clinical Impact:

Increased exposure of esomeprazole [see Clinical Pharmacology (12.3)].


Dose adjustment of NEXIUM 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.

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