Esomeprazole

7 DRUG INTERACTIONS 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 ( 12.2 )]. 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 delayed-release capsules 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. See full prescribing information for a list of clinically important drug interactions. (7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Indicated for: - Short-term treatment and healing of "erosive esophagitis (EE) in adults and pediatric patients 12 years to 17 years," with maintenance of healing in adults - Short-term treatment of heartburn and other symptoms associated with GERD - Reduction of risk of NSAID-associated gastric ulcer in at-risk patients - H. pylori eradication (combined with amoxicillin and clarithromycin) - Long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

Directions • adults 18 years of age and older • this product is to be used once a day (every 24 hours), every day for 14 days • may take 1 to 4 days for full effect 14-Day Course of Treatment • swallow 1 capsule with a glass of water before eating in the morning • take every day for 14 days • do not take more than 1 capsule a day • swallow whole. Do not crush or chew capsules. • do not use for more than 14 days unless directed by your doctor Repeated 14-Day Courses (if needed) • you may repeat a 14-day course every 4 months • do not take for more than 14 days or more often than every 4 months unless directed by a doctor • children under 18 years of age: ask a doctor before use. Heartburn in children may sometimes be caused by a serious condition.

Most common adverse reactions (≥1% in adults) are "headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth"; in pediatric patients, "headache, diarrhea, abdominal pain, nausea, and somnolence" (≥2%). Serious postmarketing reactions include anaphylactic shock, hepatic failure, Stevens-Johnson syndrome/toxic epidermal necrolysis, hypomagnesemia, and interstitial nephritis.