7.1 Interference With Antiretroviral Therapy 

Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended. Coadministration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Coadministration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction.

Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19.

Reduced concentrations of atazanavir and nelfinavir

For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended.

Increased concentrations of saquinavir

For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in Cmax by 75%, and in Cmin by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily coadministered days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with esomeprazole magnesium. Dose reduction of saquinavir should be considered from the safety perspective for individual patients.

There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.

7.2 Drugs for Which Gastric pH Can Affect Bioavailability

Due to its effects on gastric acid secretion, esomeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Esomeprazole is an enantiomer of omeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Coadministration of digoxin with esomeprazole magnesium is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with esomeprazole magnesium.

Coadministration of omeprazole 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)].

7.3 Effects on Hepatic Metabolism/Cytochrome P-450 Pathways

Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1, and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin, or amoxicillin.

However, postmarketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme. Coadministration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam.

Clopidogrel

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of esomeprazole 40 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of esomeprazole magnesium with clopidogrel. When using esomeprazole magnesium, consider use of alternative anti-platelet therapy [see Pharmacokinetics (12.3)].

Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69% respectively. Coadministration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered.

Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required. However, in patients with Zollinger-Ellison’s Syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered.

Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampin) may lead to decreased esomeprazole serum levels. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St. John’s Wort an inducer of CYP3A4. In a cross-over study in 12 healthy male subjects, St. John’s Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with esomeprazole magnesium.

7.4 Interactions With Investigations of Neuroendocrine Tumors

Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors [see Warnings and Precautions (5.10) and Clinical Pharmacology (12.2)].

7.5 Tacrolimus

Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus.

7.6 Combination Therapy With Clarithromycin

Coadministration of esomeprazole, clarithromycin, and amoxicillin has resulted in increases in the plasma levels of esomeprazole and 14-hydroxyclarithromycin [see Clinical Pharmacology (12.4)].

Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [see Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for coadministration with certain drugs [see Contraindications in prescribing information for clarithromycin].

7.7 Methotrexate

Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].