Pharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk management

Figures & data

Table 1 Drug–drug interactions associated with omeprazole and clinical risk management

Drug–drug interactions	Mechanism for drug–drug interactions	Clinical risk management
Precipitant drugs
Diazepam	Omeprazole impairs CYP2C19-mediated demethylation of diazepam.	1. Avoid such combination use in case of diazepam toxicity. 2. Pantoprazole and lansoprazole are alternative proton pump inhibitors. Oxazepam and lorazepam are alternatives to use together with omeprazole.
Carbamazepine	Omeprazole competitively inhibits CYP3A4-mediated carbamazepine metabolism.	1. Therapeutic drug monitoring should be carried out when carbamazepine is coadministered with omeprazole. 2. Select pantoprazole as an alternative proton pump inhibitor.
Clozapine	Omeprazole induces CYP1A2-mediated clozapine metabolism.	1. Close monitoring of plasma clozapine levels is recommended. 2. Select pantoprazole as an alternative proton pump inhibitor.
Indinavir, nelfinavir, atazanavir, and rilpivirine	Omeprazole decreases the solubility and absorption of indinavir, nelfinavir, atazanavir, and rilpivirine by increasing gastric pH. in addition, omeprazole competitively inhibits CYP2C19-mediated formation of nelfinavir’s pharmacologically active metabolite.	1. indinavir: concomitant 200 mg ritonavir therapy may overcome the significant omeprazole–indinavir DDI. Cimetidine is an alternative to omeprazole. 2. Nelfinavir: combination use of nelfinavir and proton pump inhibitor may be acceptable for indications where the proton pump inhibitor is required for fewer than 30 days. 3. Atazanavir: increasing the atazanavir/ritonavir dose to 400/100 mg can attenuate the effect of omeprazole and warrant enough antiviral effect against wild-type HIV. Another option is to select alternative strategies for anti-HIV treatment that have a minimal risk of DDI with omeprazole. 4. Rilpivirine: famotidine may be an alternative to omeprazole if spaced appropriately (ie, famotidine is administered 12 hours before or 4 hours after rilpivirine).
MTX	Omeprazole blocks the active tubular secretion of MTX by the inhibition of renal elimination of hydrogen ion, as well as MTX efflux via the breast cancer-resistance protein in kidney-proximal tubules.	1. Close therapeutic drug monitoring should be performed for patients receiving high-dose MTX therapy so as to decide whether to initiate the calcium folinate rescue therapy. 2. A histamine 2 antagonist is recommended to substitute for a proton pump inhibitor, as concurrent therapy does not result in MTX toxicity.
Tacrolimus	Omeprazole competitively inhibits a CYP3A4-mediated tacrolimus metabolism, especially in poor metabolizers for CYP2C19.	1. Close therapeutic drug monitoring of tacrolimus should be carried out when starting or switching a proton pump inhibitor. 2. Rabeprazole and pantoprazole are alternatives to omeprazole.
MMF	Proton pump inhibitors reduce absorption of MMF by elevating gastric pH and decreasing dissolution of MMF.	1. Pay more attention to monitoring mycophenolic acid levels in the presence of omeprazole, especially in the first week posttransplantation. 2. Adopt a new strategy; that is, intensified dosing of MMF (1.5 g twice daily on days 1–5, then 1.0 g twice daily) instead of standard dosing (1.0 g twice daily). 3. Enteric-coated mycophenolate sodium may be an alternative to MMF.
Clopidogrel	Proton pump inhibitors competitively impair the metabolic activation of clopidogrel via CYP2C19 inhibition.	1. Pantoprazole and rabeprazole are alternatives to omeprazole. 2. PA32540 (a single-tablet formulation of 325 mg aspirin and 40 mg immediate-release omeprazole) and clopidogrel spaced 10 hours apart is a good strategy in comparison with synchronous administration of aspirin, clopidogrel, and omeprazole.
Digoxin	Omeprazole induces the gastric permeability to digoxin and impairs the clearance by P-glycoprotein inhibition.	1. Pantoprazole is an alternative to omeprazole when combination use of proton pump inhibitor and digoxin is needed. 2. Monitor the serum concentrations and toxicity symptoms of digoxin in the presence of omeprazole, and adjust the dose of digoxin as needed.
Itraconazole, posaconazole	Omeprazole reduces the pH-dependent absorption of itraconazole and posaconazole by suppressing gastric secretion.	1. Avoid using proton pump inhibitors for patients receiving itraconazole or posaconazole. 2. Monitor serum levels of posaconazole or switch to an alternative antifungal therapy if combination with omeprazole cannot be avoided. Histamine 2 antagonists have less interaction with posaconazole than proton pump inhibitors. 3. Coadministration of an acidic solution (eg, a cola beverage) can counteract the adverse effect of gastric acid suppressants on the bioavailability of itraconazole.
Oral iron supplementation	Omeprazole decreases the absorption of oral iron supplementation.	Iron-deficient patients taking proton pump inhibitors may have to be treated with high-dose iron therapy for a longer duration or with intravenous iron therapy.
Object drug
Efavirenz, herbal medicines (St John’s wort, Ginkgo biloba, yin zhi huang)	Efavirenz, St John’s wort, and Yin zhi huang induce CYP2C19 and CYP3A activity and enormously accelerate omeprazole elimination. Ginkgo biloba can induce CYP2C19-mediated hydroxylation of omeprazole.	It seems inappropriate to prescribe omeprazole for patients receiving efavirenz, St John’s wort, Ginkgo biloba, or yin zhi huang. Rabeprazole is an alternative proton pump inhibitor to omeprazole.

Abbreviations: CYP, cytochrome P450; DDI, drug–drug interaction; HIV, human immunodeficiency syndrome; MTX, methotrexate; MMF, mycophenolate mofetil.