Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 26/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- Neratinib Lorlatinib containing coformulations Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- ivacaftor Tamoxifen* Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole Verapamil (isavuconazonium sulfate) Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 27/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. [1,2] These classifications are based upon US FDA guidance. classification system resulting in some agents being classified differently. Other sources may use a different Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 28/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 29/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]). Dose of apixaban was adjusted to 2.5 mg twice daily for patients with two or more of: age 80 years, body weight 60 kg, or renal insufficiency (serum creatinine level 1.5 mg/dL [133 micromol/L]). For patients in either dose group, the dose of edoxaban was reduced by 50% if any of the following characteristics were present: estimated creatinine clearance 30 to 50 mL/minute, body weight 60 kg, or concomitant use of verapamil, quinidine, or dronedarone. For the individual trials, the annual event rate (expressed as %/year) is presented for each outcome. For the meta-analysis, the table provides the absolute event rates (%) during the total study duration, which varied between studies (median follow-up 1.8 to 2.8 years). Major bleeding was variably defined. In RE-LY, it was defined as a reduction in hemoglobin of at least 2 g/dL [20 g/L], transfusion of 2 units of blood, or symptomatic bleeding in a critical area or organ. In ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48, it was defined as fatal bleeding, bleeding at a critical site, or overt bleeding plus fall in hemoglobin of at least 2 g/dL [20 g/L] or transfusion of 2 units of blood. For ROCKET-AF, the results for hemorrhagic stroke and for bleeding are based on an as-treated safety population. These combined results include data for dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily. Data from: 1. Connolly SJ, Ezekowitz MD, Eikelbloom YS, et al. Dabigatran versus warfarin in patients with atrial brillation; N Engl J Med 2009; 361:1139. 2. Patel MR, Maha ey KE, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial brillation; N Engl J Med 2011; 365:883. 3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial brillation; N Engl J Med 2011; 365:981. 4. Giugliano RP, Ru CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial brillation. N Engl J Med 2013; 369:2093. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 30/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 5. Ru CT, Giugliano RP, Braunwald E, et al. Comparison of the e cacy and safety of new oral anticoagulants with warfarin in patients with atrial brillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. Graphic 131871 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 31/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Optimal INR to minimize both bleeding and thromboembo lism in patients with atrial fibrillation (A) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 8 INR categories using INR 2.0 to 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. (B) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 6 INR categories using INR 2.0 to https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 32/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. AF: atrial fibrillation; INR: international normalized ratio; OR: odds ratio; TE: thromboembolism; ICH: intracranial hemorrhage; CI: confidence interval. Reproduced with permission from: Singer DE, Chang Y, Fang MC, et al. Should patient characteristics in uence target anticoagulation intensity for stroke prevention in nonvalvular atrial brillation? The ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. Copyright 2009 Lippincott Williams & Wilkins. Graphic 65373 Version 13.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 33/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Switching between oral anticoagulants Switching from a DOAC to warfarin Dabigatran Overlap warfarin with dabigatran for 3 days (normal renal function); 2 days (CrCl 30 to 50 mL/min); or 1 day (CrCl 15 to 30 mL/min); note that dabigatran can contribute to INR elevation. or- Overlap warfarin with dabigatran until the INR is therapeutic on warfarin (ASH).* Apixaban If continuous anticoagulation is needed, discontinue apixaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). Note that apixaban can contribute to INR elevation. or- Overlap warfarin with apixaban until the INR is therapeutic on warfarin, testing right before the next apixaban dose to minimize the effect of apixaban on INR elevation (ASH).* Edoxaban Reduce dose by half (eg, from 60 to 30 mg daily or from 30 to 15 mg daily) and begin warfarin concurrently (PI). Discontinue edoxaban when the INR is 2; note that edoxaban can contribute to INR elevation. or- Discontinue edoxaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). or- Overlap warfarin with edoxaban until the INR is therapeutic on warfarin, testing right before the next edoxaban dose to minimize the effect of edoxaban on INR elevation (ASH).* Rivaroxaban Discontinue rivaroxaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). Note that rivaroxaban can contribute to INR elevation. or- Overlap warfarin with rivaroxaban until the INR is therapeutic on warfarin, testing right before the next rivaroxaban dose to minimize the effect of rivaroxaban on INR elevation (ASH).* Switching from warfarin to a DOAC Dabigatran Stop warfarin, monitor the PT/INR, and start dabigatran when the INR https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 34/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate is <2 (PI). Apixaban Stop warfarin, monitor the PT/INR, and start apixaban when the INR is <2 (PI). Edoxaban Stop warfarin, monitor the PT/INR, and start edoxaban when the INR is 2.5 (PI). Rivaroxaban Stop warfarin, monitor the PT/INR, and start rivaroxaban when the INR is <3 (PI). Switching from one DOAC to a different DOAC Any DOAC Start the second DOAC when the next dose of the first DOAC would have been due; do not overlap. This table presents a reasonable approach to switching between oral anticoagulants. It does not substitute for clinical judgment regarding individual patient risks of thrombosis and bleeding. Individuals switching from a DOAC to warfarin are more likely to require continuous anticoagulation if they have had a recent thromboembolic event or if they are at especially high risk of thromboembolism. Refer to UpToDate topics on specific indications, perioperative management, and the use of DOACs and warfarin for further details. DOAC: direct oral anticoagulant; CrCl: creatinine clearance; INR: international normalized ratio; ASH: American Society of Hematology clinical practice guideline; PI: package insert; PT: prothrombin time. Two to three days of overlap after the INR becomes therapeutic may be needed in individuals with higher thrombosis risk, because the PT/INR will enter the therapeutic range before full anticoagulation occurs. In individuals overlapping warfarin and a DOAC, the DOAC may contribute to INR elevation. Prepared with information from: 1. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv 2018; 2:3257. 2. PRADAXA (dabigatran etexilate mesylate) capsules. US FDA approval 2010. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022512s035lbl.pdf (Accessed on April 25, 2019). 3. ELIQUIS (apixaban) tablets. US FDA approval 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202155s020lbl.pdf (Accessed on April 25, 2019). 4. SAVAYSA (edoxaban) tablets. US FDA approval 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/206316s012lbl.pdf (Accessed on April 25, 2019). 5. XARELTO (rivaroxaban) tablets. US FDA approval 2011. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022406s030s032lbledt.pdf (Accessed on April 25, 2019). Graphic 120639 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 35/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Staging of patients who meet the definition of CKD GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). GFR: glomerular filtration rate. Reprinted by permission from: Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int 2013; 3(Suppl):5. Copyright 2013. http://www.nature.com/ki/index.html. Graphic 59716 Version 7.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 36/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Daniel E Singer, MD Grant/Research/Clinical Trial Support: Bristol-Myers Squibb [Screening for atrial fibrillation]. Consultant/Advisory Boards: Bristol-Myers Squibb [Atrial fibrillation and stroke]; Fitbit [Screening for atrial fibrillation]; Medtronic [Atrial fibrillation and stroke]. All of the relevant financial relationships listed have been mitigated. Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 37/37