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ICYMI: New Updates to Antiretroviral Drug Interactions with Direct Oral Anticoagulants

By: 

  • Elizabeth Sherman, PharmD, AAHIVP
    South Florida, Southeast AIDS Education and Training Center
    College of Pharmacy, Nova Southeastern University

  • Molly Macek, PharmD Candidate
    College of Pharmacy, Nova Southeastern University

  • Andrea Levin, PharmD, BCACP
    South Florida, Southeast AIDS Education and Training Center
    College of Pharmacy, Nova Southeastern University

    Antiretroviral therapy (ART), especially HIV protease inhibitors and pharmacokinetic enhancers (i.e. ritonavir and cobicistat), can have significant drug-drug interactions with anticoagulant drugs. Health care providers should carefully consider potential drug-drug interactions before initiating or changing ART or treating comorbid conditions such as stroke or venous thromboembolism (VTE). The DHHS adult HIV guidelines were recently updated on October 25, 2018. In case you missed it (ICYMI), in the previous 2016 version of the guidelines, most direct oral anticoagulants (DOACs) were recommended to be avoided with many ARTs and the only recommended anticoagulant for use with HIV protease inhibitors was warfarin. However, in the most recent 2018 guideline update, the DHHS now recommends that certain DOACs can be safely combined with ART. ICYMI, a summary of the old 2016 and new 2018 DHHS HIV guideline recommendations on drug interactions between ART and DOACs is reviewed in Table 1. Dosing guidance and comparisons of all currently available DOACs is displayed in Table 2.

    Since 2010, the United States Food and Drug Administration has approved several DOACs. Unlike warfarin that requires blood monitoring, the DOACs do not, making their use more convenient. DOACs include both rapid and short acting agents with good overall safety profiles and relatively low bleeding risks. Available medications in this class include apixaban (Eliquis®), rivaroxaban (Xarelto®), dabigatran (Pradaxa®), edoxaban (Savaysa®), and betrixaban (BevyxXa®).

    DOACs are a good choice for VTE prevention and treatment and stroke prevention in appropriately selected patients. These agents have shown to be highly effective, require less monitoring, and may reduce the risk of brain bleed (vs. warfarin). Although DOACs do not require routine laboratory monitoring and are not affected by dietary considerations, they tend to be more expensive than warfarin and are shorter acting, making it important for patients to remain adherent.

    Table 1. Difference in DHHS Guideline Recommendations Regarding Drug Interactions between Protease Inhibitors/Boosted Integrase Strand Transfer Inhibitor and Anticoagulants from the 2016 Guidelines vs the Updated 2018 Guidelines
    Anticoagulant
    Drug    		 ART Effect on
    Concomitant Drug
    Concentrations    		 2016 Dosing Recommendations
    and Clinical Comments    		 2018 Dosing Recommendations and Clinical Comments
    Apixaban
    (Eliquis®)    		 PI/c, PI/r ↑ apixaban expected Avoid concomitant use

    Coadministration is not recommended in patients who require apixaban 2.5 mg twice daily.

    In patients who require apixaban 5 mg or 10 mg twice daily, reduce apixaban dose by 50%.
    EVG/c
    Betrixaban
    (BevyxXa®)    		 ATV/c, ATV/r,
    LPV/r    		 ↑ betrixaban expected N/A- Betrixaban was FDA approved July
    2017    		 Administer an initial single dose of betrixaban 80 mg followed by betrixaban 40
    mg once daily.
    EVG/c
    DRV/c, DRV/r ←→ betrixaban expected No dose adjustment necessary
    Dabigatran
    (Pradaxa®)    		 ATV/c, ATV/r,
    LPV/r    		 ↑ dabigatran expected
    With COBI 150 mg alone:
    Dabigatran AUC ↑110% to
    127%

    No dosage adjustment if CrCl > 50 mL/min.

    Avoid coadministration if CrCl < 50 mL/min.

    		 Dabigatran dosing recommendation depends on indication and renal function.
    Refer to dabigatran dosing instructions for concomitant use with P-gp inhibitors
    EVG/c in dabigatran prescribing information.
    EVG/c
    DRV/c, DRV/r ←→ dabigatran expected No dosage adjustment necessary
    Edoxaban
    (Savaysa®)    		 ATV/c, ATV/r,
    LPV/r    		 ↑ edoxaban expected Avoid concomitant use

    Stroke Prevention in nonvalvular atrial fibrillation indication:

    • No dose adjustment necessary

    Deep venous thrombosis and pulmonary embolism indication:

    • Administer edoxaban 30 mg once daily
    EVG/c
    DRV/c, DRV/r ←→ edoxaban expected No dosage adjustment necessary
    Rivaroxaban
    (Xarelto®)    		 PI/c, PI/r ↑ rivaroxaban Avoid concomitant use Coadministration is not recommended
    EVG/c
    Warfarin PI/c No data No data Monitor INR closely when stopping or starting PI/c and adjust warfarin doseaccordingly. If switching between RTV and COBI, the effect of COBI on warfarinis not expected to be equivalent to RTV’s effect on warfarin.
    PI/r ↓ warfarin possible Monitor INR closely when stopping or starting PI/r and adjust warfarin
    accordingly
    EVG/c ↑ ↓ warfarin possible Monitor INR and adjust warfarin
    accordingly    		 Monitor INR and adjust warfarin accordingly

    Table 2. Dosing Comparison of Direct Oral Anticoagulants (DOACs)
    Anticoagulant Non-valvular Atrial
    Fibrillation – Stroke
    Prophylaxis    		 VTE Treatment VTE Prophylaxis Clinical Comments from DOAC Prescribing Information
    Apixaban
    (Eliquis®)    		 5 mg BID; reduce dose to
    2.5 mg BID if 2 or more of
    the following:
    – ≥80 yrs old
    – ≤ 60 kg
    – SCr ≥ 1.5 mg/dL

    10 mg BID for one week,
    then 5 mg BID

    Consider reducing dose to
    2.5 mg BID after 6 months of
    treatment

    No dose adjustment based
    on renal function

    		 2.5 mg BID

    Strong dual CYP3A4 and P-glycoprotein inhibitors (eg, ketoconazole,
    itraconazole, ritonavir)
    Recommended apixaban doses >2.5 mg twice daily: Reduce
    apixaban dose by 50%
    Recommended apixaban dose of 2.5 mg twice daily: Avoid
    concomitant use.

    Strong dual CYP3A4 and P-glycoprotein inducers (eg, rifampin,
    carbamazepine, phenytoin, St John’s wort): Avoid concomitant use.
    Betrixaban
    (BevyxXa®)    		 Not an FDA approved
    indication    		 Not an FDA approved
    indication    		 160 mg as a single
    dose on day 1,
    followed by 80 mg
    once daily,
    CrCl 15-30 mL/min: 80
    mg as a single dose,
    then 40 mg daily    		 Reduce betrixaban dose (initial and maintenance) by 50% for
    patients receiving or starting P-glycoprotein inhibitors (eg,
    amiodarone, azithromycin, clarithromycin, ketoconazole, verapamil).
    If patient also has severe renal impairment, avoid use of betrixaban.
    Dabigatran
    (Pradaxa®)    		 150 mg BID Parenteral anticoagulation
    for 5-10 days; then
    dabigatran 150 mg BID    		 110 mg for the first
    day, then 220 mg daily

    Non-valvular AFib
    Any P-gp inducer (eg rifampin): avoid concurrent use
    Any P-gp inhibitor (eg amiodarone, clarithromycin, dronedarone,
    ketoconazole, verapamil and others) with CrCl <30 ml/min: Avoid
    concurrent use
    CrCl 15-30 mL/min: 75 mg BID (renal dose adjustment was not
    extensively studied)
    CrCl< 15 mL/min: use is not recommended

    VTE Treatment/Prophylaxis
    Any P-gp inducer (eg rifampin): avoid concurrent use
    Any P-gp inhibitor (eg amiodarone, clarithromycin, dronedarone,
    ketoconazole, verapamil and others) with CrCl <50 ml/min: Avoid
    concurrent use
    Edoxaban
    (Savaysa®)    		 60 mg daily Parenteral anticoagulation
    for 5-10 days; then
    Pt wt > 60 kg: 60 mg daily
    Pt wt <60 kg: 30 mg daily    		 Not an FDA approved
    indication

    Non-valular AFib
    P-gp inhibitors: No dose adjustment necessary
    P-gp inducers: Avoid concurrent use
    CrCl>95 mL/min: efficacy is decreased, use not recommended
    CrCl 15-50 mL/min: 30 mg daily
    CrCl< 15 mL/min: use is not recommended

    VTE Treatment
    P-gp inhibitors (eg verapamil, quinidine, azithromycin,
    clarithromycin): 30 mg daily
    P-gp inducers (eg rifampin): Avoid concurrent use
    CrCl 15-50 mL/min: 30 mg daily
    CrCl< 15 mL/min: use is not recommended
    Rivaroxaban
    (Xarelto®)    		 20 mg once daily with
    evening meal
    CrCl 15-50 mL/min: 15 mg
    daily    		 15 mg BID with food for 3
    weeks; then 20 mg once
    daily with food
    CrCl< 30 mL/min: Avoid use    		 10 mg once daily with
    or without food
    CrCl< 30 mL/min:
    Avoid use

    Strong dual CYP3A4 and P-glycoprotein inhibitors (eg, ketoconazole,
    itraconazole, ritonavir): Avoid concomitant use

    Strong dual CYP3A4 and P-glycoprotein inducers (eg, rifampin, carbamazepine, phenytoin, St John’s wort): Avoid concomitant use.

    References:

    1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Section accessed [Nov. 15, 2018] [L-6-7, Table 19a]
    2. Burn, John et al. “Correction: Direct Oral Anticoagulants versus Warfarin: Is New Always Better than the Old?” Open Heart, vol. 5, no. 1, 2018,
      doi:10.1136/openhrt-2017-000712corr1.
    3. Lip, Gregory et al. Antithrombotic Therapy for Atrial Fibrillation CHEST Guideline and Expert Panel Report , Volume 154, Issue 5, 1121-1201, 2018
    4. C Kearon et al. “Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149:315
    5. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; June 2018.
    6. Bevyxxa (betrixaban) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals Inc; June 2017
    7. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc; August 2018.
    8. Pradaxa (dabigatran) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; March 2018.
    9. Savaysa (edoxaban) [prescribing information]. Parsippany, NJ: Daiichi Sankyo; November 2017.