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Combined strong inhibitors of CYP3A4 and P-gp (eg, boceprevir • , clarithromycin, cobicistat containing coformulations, conivaptan • , delavirdine • , all HIV protease inhibitors Δ [eg, ritonavir], imatinib • , itraconazole, ketoconazole, nefazodone • , posaconazole • , telaprevir, telithromycin • , voriconazole • ) Increased apixaban concentration (significant effect) Avoid co-administration of strong inhibitors of both CYP3A4 and P-gp. Apixaban dose reduction is an option, according to US licensing information, for patients with AF requiring co-administration of strong dual inhibitors, provided not more than one of following factors: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. This dose adjustment has not been tested in clinical trials. The efficacy of routine coagulation testing to evaluate the degree of anticoagulation with apixaban is limited and is discussed in the text.

US: Avoid coadministration or reduce apixaban dose to 2.5 mg twice daily for nonvalvular AF. In patients already taking 2.5 mg twice daily due to any two of the following: SCr >1.5 mg/dL, age ≥80 years, or weight ≤60 kg, avoid coadministration.

EMA, UK: Coadministration with strong inhibitors of both CYP3A4 and P-gp is not recommended. Combined inhibitors of P-gp and/or moderate inhibitors of CYP3A4 (eg, amiodarone, azithromycin, chloramphenicol, cimetidine, erythromycin, cyclosporine, diltiazem, dronedarone, felodipine, fluconazole • , grapefruit and grapefruit juice ◊ , lapatinib, lomitapide, mifepristone, naproxen • , nicardipine, quinidine, ranolazine, tamoxifen, verapamil) Increased apixaban concentration (moderate effect in patients with normal renal function; potentially significant effect in patients having severe renal insufficiency) Use with caution; if co-administration is necessary, no specific dose adjustment is recommended. Avoid co-administration in patients with renal insufficiency (CrCl 15 to 50 mL/minute), age ≥80 years, or low body weight <60 kg.

Strong inducers of CYP3A4 (eg, aminoglutethimide, barbiturates, bosentan, efavirenz, etravirine, fosphenytoin, nafcillin, nevirapine, oxcarbazepine, pentobarbital, phenobarbital, phenytoin, primidone, rifabutin, rifapentine) Decreased apixaban concentration (significant effect) Avoid concurrent use with agents known to strongly induce CYP3A4 and/or P-gp. Effect on apixaban concentration may persist for several weeks following discontinuation of a strong inducer of P-gp and/or 3A4.

EMA, UK: Strong inducers of both CYP3A4 and P-gp led to approximately 50 percent decrease in apixaban concentrations. No dose adjustment required. Use caution. Interaction data and recommendations refer to systemic drug forms. Specific drug interactions and management suggestions may be determined by using Lexi-Interact, the drug interactions program included with UpToDate. AF: atrial fibrillation; CYP3A4: cytochrome P-450 3A4; P-gp: P-glycoprotein efflux transporters; VTE: venous thromboembolism; CrCl: creatinine clearance; US: United States Prescribing Information; CAN: Canadian Product Monograph; EMA: European Medicines Agency Summary of Product Characteristics; UK: United Kingdom Summary of Product Characteristics. * Drug interactions, management recommendations, and contraindicated drug combinations listed in licensed product information vary by country. Consult official product information for details before using this agent. • Limited or conflicting data concerning relevance of P-gp inhibition. Δ Atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. ◊ Avoidance of grapefruit and grapefruit juice in large quantities advised due to lack of predictability of its effect. § Rifampicin is international nonproprietary (generic) name. Data from: Eliquis (apixaban) US prescribing information (December, 2012). Available at: file://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf . (Accessed January 7, 2013.) Eliquis Canada Product Monograph (revision November 27, 2012). Available at: file://webprod5.hc-sc.gc.ca/dpd-bdpp/info.do?code=88264&lang=eng. (Accessed January 7, 2013.) Eliquis Summary of Product Characteristics European Medicines Agency version December 20, 2012. Available at: file://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf . (Accessed January 7, 2013.) Eliquis film coated tablets United Kingdom Summary of Product Characteristics version December 3, 2012. Available at: file://www.medicines.org.uk/EMC/medicine/27220/SPC/Eliquis+5+mg+film-coated+tablets/ . (Accessed January 7, 2013.) Lexicomp online Lexi-Interact Copyright © 1978-2013 by Lexicomp, Inc. All rights reserved. Hansten PD, Horn JR. Top 100 drug interactions: Guide to patient management, 13th ed, H&H Publications 2013.

Eliquis film coated tablets United Kingdom Summary of Product Characteristics version December 3, 2012. Available at: file://www.medicines.org.uk/EMC/medicine/27220/SPC/Eliquis+5+mg+film-coated+tablets/ . (Accessed January 7, 2013.) Lexicomp online Lexi-Interact Copyright © 1978-2013 by Lexicomp, Inc. All rights reserved. Hansten PD, Horn JR. Top 100 drug interactions: Guide to patient management, 13th ed, H&H Publications 2013. Poulsen BK, Grove EL, Husted SE. New oral anticoagulants. Drugs 2012; 72:1739.