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Drug-Drug Interactions with Direct Oral Anticoagulants: Practical Recommendations for Clinicians

  • Jean Terrier
    Correspondence
    Requests for reprints should be addressed to Jean Terrier, MD, PharmD, PhD, Hopitaux Universitaries de Geneve, Internal Medicine, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.
    Affiliations
    Division of General Internal Medicine, Geneva University Hospitals, Geneva, Switzerland

    Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Clinical Pharmacology and Toxicology Division, Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine Department, Geneva University Hospitals, Geneva, Switzerland
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  • Frédéric Gaspar
    Affiliations
    Center for Research and Innovation in Clinical Pharmaceutical Sciences, University Hospital and University of Lausanne, Lausanne, Switzerland

    School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland

    Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Switzerland
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  • Pierre Fontana
    Affiliations
    Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Division of Angiology and Hemostasis, Geneva University Hospitals, Geneva, Switzerland
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  • Youssef Daali
    Affiliations
    Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Clinical Pharmacology and Toxicology Division, Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine Department, Geneva University Hospitals, Geneva, Switzerland
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  • Jean-Luc Reny
    Affiliations
    Division of General Internal Medicine, Geneva University Hospitals, Geneva, Switzerland

    Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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  • Chantal Csajka
    Affiliations
    Center for Research and Innovation in Clinical Pharmaceutical Sciences, University Hospital and University of Lausanne, Lausanne, Switzerland

    School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland

    Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Switzerland
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  • Caroline F. Samer
    Affiliations
    Clinical Pharmacology and Toxicology Division, Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine Department, Geneva University Hospitals, Geneva, Switzerland
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      Introduction

      Current guidelines from the European Society of Cardiology and American Heart Association widely recommend direct oral anticoagulants (DOACs) instead of vitamin K antagonists (VKAs) in the vast majority of patients with nonvalvular atrial fibrillation.

      European Society of Cardiology. Guidelines for management of atrial fibrillation. Available at: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Atrial-Fibrillation-Management. Accessed April 6, 2021.

      ,
      • January CT
      • Wann LS
      • Calkins H
      • et al.
      2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons.
      In theory, DOACs do not require routine monitoring because of their stable pharmacological profiles compared with VKAs.
      • Drouet L
      • Bal Dit Sollier C
      • Steiner T
      • Purrucker J
      Measuring non-vitamin K antagonist oral anticoagulant levels: when is it appropriate and which methods should be used?.
      However, when they are used in real-world conditions and outside the stringent framework of clinical trials, substantial interindividual variations in dose-concentration response are observed, leading to consider dose adjustment outside the standard risk groups.
      • Chen A
      • Stecker E
      • Warden BA
      Direct oral anticoagulant use: a practical guide to common clinical challenges.
      Of note, drug-drug interactions are barely mentioned in the dose adjustment guidelines and product information can be contradictory.

      European Medicine Agency. Dabigatran, rivaroxaban, apixaban and edoxaban product information. Available at: https://www.ema.europa.eu/en/glossary/product-information. Accessed April 6, 2021.

      ,

      US Food and Drug Administration. Dabigatran, rivaroxaban, apixaban and edoxaban product information. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed April 6, 2021.

      This represents a significant issue for clinicians because it is well-established that patients with atrial fibrillation receive numerous medications and that polymedication increases the bleeding risk.
      • Piccini JP
      • Hellkamp AS
      • Washam JB
      • et al.
      Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation.
      A growing number of case reports have also highlighted a direct role of drug-drug interactions in bleeding or thrombotic events involving DOACs.
      • Li A
      • Li MK
      • Crowther M
      • Vazquez SR
      Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: a systematic review.
      ,
      • Pfeilschifter W
      • Luger S
      • Brunkhorst R
      • Lindhoff-Last E
      • Foerch C
      The gap between trial data and clinical practice – an analysis of case reports on bleeding complications occurring under dabigatran and rivaroxaban anticoagulation.
      Several large registry-based retrospective studies have also suggested an increased risk of bleeding when DOACs are coadministered with P-glycoprotein (Pgp) or cytochrome P450 (CYP) 3A4/5 inhibitors.
      • Chang S-H
      • Chou I-J
      • Yeh Y-H
      • et al.
      Association between use of non-vitamin k oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation.
      • Lee JY
      • Oh I-Y
      • Lee J-H
      • et al.
      The increased risk of bleeding due to drug-drug interactions in patients administered direct oral anticoagulants.
      • Hanigan S
      • Das J
      • Pogue K
      • Barnes GD
      • Dorsch MP
      The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding.
      A multidisciplinary team (composed of clinical pharmacologists, pharmacists, internal medicine physicians, and hemostasis physicians) proposes practical recommendations for pharmacokinetic drug-drug interactions based on the best available clinical and pharmacological evidence that can be implemented easily at the patient's bedside (Table 1). Each time a problematic scenario is met we suggest: 1) stopping or finding an alternative to the perpetrator (eg, the drug responsible for the drug-drug interaction), and 2) consider the use of VKAs if the first step cannot be achieved. We admit that VKAs have potential drug-drug interactions too but offer the possibility of monitoring with the international normalized ratio, which alleviates this issue.

      US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed April 6, 2021.

      Table 1Practical Recommendations for Drug-Drug Interactions Management with DOACs
      DabigatranRivaroxabanApixabanEdoxaban
      Strong Pgp inhibitor onlyAssociation not recommended (unless proven otherwise
      If in vivo human studies show evidence of a ≤2 times increase in area under the curve (AUC) exposure for inhibitors or ≥20% decrease in exposure for inducers.
      )

      -> consider VKA as a first-line treatment or if possible change the perpetrator to a noninteracting molecule
      Strong CYP3A/5 inhibitor only or combined Pgp/CYP3A4/5 inhibitorOKAssociation not recommended (unless proven otherwise
      If in vivo human studies show evidence of a ≤2 times increase in area under the curve (AUC) exposure for inhibitors or ≥20% decrease in exposure for inducers.
      )

      -> consider VKA as a first-line treatment or if possible change the perpetrator to a noninteracting molecule
      OK
      Moderate to Weak Pgp inhibitor onlyUse with caution

      Weigh risk-to-benefit ratio or consider VKA as a first-line treatment if ≥2 risk factors
      Risk factors: renal failure (CL <50 mL/min according to Cockroft-Gault equation), weight <60 kg, advanced age (>80 years), additional Pgp or CYP3A4/5 inhibitor. Classification of inhibitors/inducers according to the Food & Drug Administration.13
      or if CL<30 mL/min
      Moderate to Weak CYP3A4/5 inhibitor onlyOKUse with caution

      Weigh risk-to-benefit or consider VKA as a first-line treatment if ≥2 risk factors
      Risk factors: renal failure (CL <50 mL/min according to Cockroft-Gault equation), weight <60 kg, advanced age (>80 years), additional Pgp or CYP3A4/5 inhibitor. Classification of inhibitors/inducers according to the Food & Drug Administration.13
      or if CL<30 mL/min
      OK
      CYP3A4/5 or combined Pgp/CYP3A4/5 inducerAssociation not recommended (unless proven otherwise
      If in vivo human studies show evidence of a ≤2 times increase in area under the curve (AUC) exposure for inhibitors or ≥20% decrease in exposure for inducers.
      )

      -> consider VKA as a first-line treatment or if possible change the perpetrator to a noninteracting molecule
      CL = clearance; DOACs = direct oral anticoagulants; VKA = vitamin K antagonists.
      low asterisk If in vivo human studies show evidence of a ≤2 times increase in area under the curve (AUC) exposure for inhibitors or ≥20% decrease in exposure for inducers.
      Risk factors: renal failure (CL <50 mL/min according to Cockroft-Gault equation), weight <60 kg, advanced age (>80 years), additional Pgp or CYP3A4/5 inhibitor.Classification of inhibitors/inducers according to the Food & Drug Administration.

      US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed April 6, 2021.

      Strong Pgp or CYP 3A4/5 Inhibitors

      There is currently sufficient evidence showing an association between exposure to DOACs and major bleeding.
      • Ieuter RC
      Pharmacokinetic drug-drug interactions with warfarin.
      Dabigatran median trough concentration in patients with major bleeding was 55% higher than in those without major bleeding (116 vs 75.3 ng/mL).
      • Eikelboom JW
      • Quinlan DJ
      • Hirsh J
      • Connolly SJ
      • Weitz JI
      Laboratory monitoring of non-vitamin k antagonist oral anticoagulant use in patients with atrial fibrillation: a review.
      A doubling of apixaban area under the curve (AUC) resulted in a near doubling of the risk of major bleeding (2% to 4% a year).
      • Reilly PA
      • Lehr T
      • Haertter S
      • et al.
      The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).
      According to in vivo studies in healthy volunteers, the strong CYP3A4/5 and Pgp/CYP3A4/5 inhibitors are the most likely to increase the DOACs AUC by a factor of 2 and put the patient at high risk for bleeding.

      Center for Drug Evaluation and Research. Eliquis®. Clinical pharmacology/biopharmaceutics review. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000ClinPharmR.pdf. Accessed April 6, 2021.

      ,
      • Herink MC
      • Zhuo YF
      • Williams CD
      • DeLoughery TG
      Clinical management of pharmacokinetic drug interactions with direct oral anticoagulants (DOACs).
      Consequently, in presence of strong CYP3A4/5 inhibitors, edoxaban, dabigatran, or VKAs should be specifically preferred to apixaban and rivaroxaban, which are more significantly eliminated by CYP3A4/5. Because all DOACs are substrates for Pgp, strong Pgp/CYP 3A4/5 inhibitors should be considered at risk for all DOACS. The reader will easily find the potency of the most prescribed inhibitory and inducing drugs on the US Food and Drug Administration website.
      • Foerster KI
      • Hermann S
      • Mikus G
      • Haefeli WE
      Drug–drug interactions with direct oral anticoagulants.
      We also provide a nonexhaustive list of moderate to strong inhibitors and inducers in Tables 2 and 3.
      Table 2Examples of Pgp, CYP3A4/5, and Combined Pgp/CYP3A4/5 Inhibitors (Nonexhaustive List)

      US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed April 6, 2021.

      StrongModerate to weak
      Pgp or combined CYP3A4/5/Pgp inhibitorsketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin, dronedarone, cobicistat, posaconazole, voriconazoleamiodarone, diltiazem, quinidine, verapamil, cyclosporine, ticagrelor
      CYP3A4/5 inhibitorsboceprevir, grapefruit juicefluconazole
      Table 3Examples of Moderate to Strong Pgp/CYP3A4/5 Inducers (Nonexhaustive List)

      US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed April 6, 2021.

      apalutamide

      bosentan

      carbamazepine

      dexamethasone

      enzalutamide

      efavirenz

      mitotane

      phenobarbital

      phenytoin

      primidone

      rifampin (rifampicin)

      St. John's wort

      Moderate to Weak Pgp and CYP 3A4/5 Inhibitors

      In the presence of moderate to weak inhibitors of Pgp or CYP 3A4/5, or if in vivo human data show an increase in DOACs AUC of less than 2-fold in the presence of a given inhibitor, the use of DOACs appears safe in absence of other risk factors.
      The accumulated evidence shows that the presence of several risk factors (such as drug-drug interactions and renal failure) add up to significantly increase exposure to DOAC and, thus, the risk of bleeding.
      • Corsini A
      • Ferri N
      • Proietti M
      • Boriani G
      Edoxaban and the issue of drug-drug interactions: from pharmacology to clinical practice.
      • Greenblatt DJ
      • Patel M
      • Harmatz JS
      • Nicholson WT
      • Rubino CM
      • Chow CR
      Impaired rivaroxaban clearance in mild renal insufficiency with verapamil coadministration: potential implications for bleeding risk and dose selection.
      • Ismail M
      • Lee VH
      • Chow CR
      • Rubino CM
      Minimal physiologically based pharmacokinetic and drug-drug-disease interaction model of rivaroxaban and verapamil in healthy and renally impaired subjects.
      In the presence of a moderate to weak Pgp or CYP 3A4/5 inhibitor, we therefore recommend weighing the risks and benefits of using a DOAC compared with a VKA or stopping the perpetrator in the presence of 2 or more of the following additional risk factors: renal failure (clearance <50 mL/min according to Cockroft-Gault equation), weight <60 kg, advanced age (>80 years), or an additional concomitant Pgp inhibitor (or CYP3A4/5 inhibitor for apixaban and rivaroxaban). Indeed, all of these factors have been shown to increase the AUC of DOACs.
      • Byon W
      • Garonzik S
      • Boyd RA
      • Frost CE
      Apixaban: a clinical pharmacokinetic and pharmacodynamic review.
      ,
      • Mueck W
      • Lensing AWA
      • Agnelli G
      • Décousus H
      • Prandoni P
      • Misselwitz F
      Rivaroxaban.
      For patients with severe renal impairment (CL<30 mL/min), we suggest avoiding DOAC in the presence of a Pgp or CYP 3A4/5 inhibitor. Mild to moderate hepatic impairment (Child-Pugh A or B) does not appear to be a risk factor, except for rivaroxaban.
      • Graff J
      • Harder S
      Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment.

      Pgp or CYP3A4/5 Inducers

      Although the association between DOAC exposure and ischemic events seems less obvious according to the few data available,
      • Ieuter RC
      Pharmacokinetic drug-drug interactions with warfarin.
      the use of Pgp/CYP3A4/5 inducers with DOACs should be avoided because their efficacy in ischemic events may be affected. In addition, case reports in patients treated with inducers such as rifampicin or phenobarbital have shown the occurrence of ischemic events.

      Altena R, Roon E van, Folkeringa R, Wit H de, Hoogendoorn M. Clinical challenges related to novel oral anticoagulants: drug-drug interactions and monitoring. 1. 2014;99(2):e26-e27. doi: 10.3324/haematol.2013.097287.

      ,
      • King PK
      • Stump TA
      • Walkama AM
      • Ash BM
      • Bowling SM
      Management of phenobarbital and apixaban interaction in recurrent cardioembolic stroke.
      Because the therapeutic range is not known for DOACs, it seems reasonable to avoid moderate to strong Pgp/CYP3A4/5 inducers concomitantly with DOACs.

      Conclusion

      DOACs have the potential for drug interactions. We propose recommendations that pragmatically aim to clearly define the situations that require the clinician's attention. These guidelines provide the clinician the opportunity to discuss with the patient the benefits and risks of using a DOAC or VKA in situations where drug interactions are an issue. We also recommend discussing the appropriateness of stopping the inhibitor/inducer in specific settings.
      DOACs remain an important advance in the management of patients requiring anticoagulation because of the overall decrease in major bleeding compared with VKAs and the absence of monitoring. However, prospective studies on the subject or studies that better define the therapeutic range of DOACs should address this issue in future.

      References

      1. European Society of Cardiology. Guidelines for management of atrial fibrillation. Available at: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Atrial-Fibrillation-Management. Accessed April 6, 2021.

        • January CT
        • Wann LS
        • Calkins H
        • et al.
        2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons.
        Circulation. 2019; 140: e125-e151https://doi.org/10.1161/CIR.0000000000000665
        • Drouet L
        • Bal Dit Sollier C
        • Steiner T
        • Purrucker J
        Measuring non-vitamin K antagonist oral anticoagulant levels: when is it appropriate and which methods should be used?.
        Int J Stroke. 2016; 11: 748-758https://doi.org/10.1177/1747493016659671
        • Chen A
        • Stecker E
        • Warden BA
        Direct oral anticoagulant use: a practical guide to common clinical challenges.
        J Am Heart Assoc. 2020; 9e017559https://doi.org/10.1161/JAHA.120.017559
      2. European Medicine Agency. Dabigatran, rivaroxaban, apixaban and edoxaban product information. Available at: https://www.ema.europa.eu/en/glossary/product-information. Accessed April 6, 2021.

      3. US Food and Drug Administration. Dabigatran, rivaroxaban, apixaban and edoxaban product information. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed April 6, 2021.

        • Piccini JP
        • Hellkamp AS
        • Washam JB
        • et al.
        Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation.
        Circulation. 2016; 133: 352-360https://doi.org/10.1161/CIRCULATIONAHA.115.018544
        • Li A
        • Li MK
        • Crowther M
        • Vazquez SR
        Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: a systematic review.
        Thromb Res. 2020; 194: 240-245https://doi.org/10.1016/j.thromres.2020.08.016
        • Pfeilschifter W
        • Luger S
        • Brunkhorst R
        • Lindhoff-Last E
        • Foerch C
        The gap between trial data and clinical practice – an analysis of case reports on bleeding complications occurring under dabigatran and rivaroxaban anticoagulation.
        Cerebrovasc Dis. 2013; 36: 115-119https://doi.org/10.1159/000352062
        • Chang S-H
        • Chou I-J
        • Yeh Y-H
        • et al.
        Association between use of non-vitamin k oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation.
        JAMA. 2017; 318: 1250-1259https://doi.org/10.1001/jama.2017.13883
        • Lee JY
        • Oh I-Y
        • Lee J-H
        • et al.
        The increased risk of bleeding due to drug-drug interactions in patients administered direct oral anticoagulants.
        Thromb Res. 2020; 195: 243-249https://doi.org/10.1016/j.thromres.2020.07.054
        • Hanigan S
        • Das J
        • Pogue K
        • Barnes GD
        • Dorsch MP
        The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding.
        J Thromb Thrombolysis. 2020; 49: 636-643https://doi.org/10.1007/s11239-020-02037-3
      4. US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed April 6, 2021.

        • Ieuter RC
        Pharmacokinetic drug-drug interactions with warfarin.
        Oral Anticoagulation Therapy: Cases and Clinical Correlation. 2017; : 221-227https://doi.org/10.1007/978-3-319-54643-8_32
        • Eikelboom JW
        • Quinlan DJ
        • Hirsh J
        • Connolly SJ
        • Weitz JI
        Laboratory monitoring of non-vitamin k antagonist oral anticoagulant use in patients with atrial fibrillation: a review.
        JAMA Cardiol. 2017; 2: 566-574https://doi.org/10.1001/jamacardio.2017.0364
        • Reilly PA
        • Lehr T
        • Haertter S
        • et al.
        The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).
        J Am Coll Cardiol. 2014; 63: 321-328https://doi.org/10.1016/j.jacc.2013.07.104
      5. Center for Drug Evaluation and Research. Eliquis®. Clinical pharmacology/biopharmaceutics review. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000ClinPharmR.pdf. Accessed April 6, 2021.

        • Herink MC
        • Zhuo YF
        • Williams CD
        • DeLoughery TG
        Clinical management of pharmacokinetic drug interactions with direct oral anticoagulants (DOACs).
        Drugs. 2019; 79: 1625-1634https://doi.org/10.1007/s40265-019-01183-0
        • Foerster KI
        • Hermann S
        • Mikus G
        • Haefeli WE
        Drug–drug interactions with direct oral anticoagulants.
        Clin Pharmacokinet. 2020; 59: 967-980https://doi.org/10.1007/s40262-020-00879-x
        • Corsini A
        • Ferri N
        • Proietti M
        • Boriani G
        Edoxaban and the issue of drug-drug interactions: from pharmacology to clinical practice.
        Drugs. 2020; 80: 1065-1083https://doi.org/10.1007/s40265-020-01328-6
        • Greenblatt DJ
        • Patel M
        • Harmatz JS
        • Nicholson WT
        • Rubino CM
        • Chow CR
        Impaired rivaroxaban clearance in mild renal insufficiency with verapamil coadministration: potential implications for bleeding risk and dose selection.
        J Clin Pharmacol. 2018; 58: 533-540https://doi.org/10.1002/jcph.1040
        • Ismail M
        • Lee VH
        • Chow CR
        • Rubino CM
        Minimal physiologically based pharmacokinetic and drug-drug-disease interaction model of rivaroxaban and verapamil in healthy and renally impaired subjects.
        J Clin Pharmacol. 2018; 58: 541-548https://doi.org/10.1002/jcph.1044
        • Byon W
        • Garonzik S
        • Boyd RA
        • Frost CE
        Apixaban: a clinical pharmacokinetic and pharmacodynamic review.
        Clin Pharmacokinet. 2019; 58: 1265-1279https://doi.org/10.1007/s40262-019-00775-z
        • Mueck W
        • Lensing AWA
        • Agnelli G
        • Décousus H
        • Prandoni P
        • Misselwitz F
        Rivaroxaban.
        Clin Pharmacokinet. 2011; 50: 675-686https://doi.org/10.2165/11595320-000000000-00000
        • Graff J
        • Harder S
        Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment.
        Clin Pharmacokinet. 2013; 52: 243-254https://doi.org/10.1007/s40262-013-0034-0
      6. Altena R, Roon E van, Folkeringa R, Wit H de, Hoogendoorn M. Clinical challenges related to novel oral anticoagulants: drug-drug interactions and monitoring. 1. 2014;99(2):e26-e27. doi: 10.3324/haematol.2013.097287.

        • King PK
        • Stump TA
        • Walkama AM
        • Ash BM
        • Bowling SM
        Management of phenobarbital and apixaban interaction in recurrent cardioembolic stroke.
        Ann Pharmacother. 2018; 52: 605-606https://doi.org/10.1177/1060028018759938