https://interactions.guidetherapeutiquevih.com/en/interaction-details?id=13341

Darunavir / cobicistat

Dabigatran

Dose adjustment and closer monitoring are required.

Available pharmaceutical opinion

Document made available to the pharmacist to communicate a drug interaction to the doctor.

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Mechanism

Darunavir / cobicistat can inhibit the intestinal P-gp and increase the plasma concentration of Dabigatran.

Darunavir / cobicistat

Pharmacodynamic effects

–

Recommendations

–

Alternative solution(s)

Choose an antiretroviral that does not have this interaction.

Dabigatran

Pharmacodynamic effects

Possible increased anticoagulant effect and associated risk of bleeding.

Recommendations

Use this combination with caution.

A dose reduction to 110 mg BID should be considered.

Monitor for adverse effects.

A dose reduction to 75 mg BID should be considered in patients with moderate renal impairment.

See comments.

Alternative solution(s)

Prefer warfarin or low molecular weight heparin (LMWH).

Monitor

Adverse effects of dabigatran: Bleeding (suspect bleeding if there is a drop in hemoglobin and/or hematocrit or hypotension), anemia, hematoma, hematuria, epistaxis, gastrointestinal disorders (abdominal pain, diarrhea, dyspepsia and nausea), gastrointestinal and urinary hemorrhage.

Tests

–

Pharmacokinetic parameters

–

Comment

Ref #2368 : Some studies have shown a significant increase in dabigatran bioavailability when administered with P-gp inhibitors (ketoconazole and glecaprévir/pibrentasvir). The product monograph recommends caution when co-administering certain P-gp inhibitors, including but not limited to cyclosporine, itraconazole, nelfinavir, posaconazole, ritonavir, saquinavir, tacrolimus and tipranavir as they may increase systemic exposure to dabigatran.

Ref #3341 : Unlike ritonavir, cobicistat significantly increased dabigatran concentrations (2-2.3-fold) weither being administered simultaneously or 2 hours after dabigatran. The anticoagulant effect was also increased, with a 46-51% increase in thrombin time (TT) at 24 hours and a 30-33% increase in TT-AUC. Researchers conclude that dabigatran should be co-administered with cobicistat with caution by decreasing dabigratran dosing or by spacing administration with cobicistat by ≥4 hours, in addition with close monitoring of its anticoagulant effect.
See dabigatran + cobicistat.

The product monograph recommended dose adjustments when used for prevention of venous thrombophlebitis after surgery:
A. With potent P-gp inhibitors (as ketoconazole): Avoid administration.
B. With P-gp inhibitors (amiodarone, quinidine, verapamil*): Consider dose reduction. See product monograph for indications.
C. With P-gp inhibitors (amiodarone, quinidine, vérapamil*) and moderate renal impairment (ClCre 30-50 ml/min) : Consider a greater dose reduction. See product monograph for indications.
D. With other P-gp inhibitors (cyclosporine, itraconazole, posaconazole, nelfinavir, ritonavir, saquinavir) : Exercer un suivi plus étroit.
* For verapamil, it is also recommended to avoid concurrent administration. Give dabigatran 2 hours before verapamil.

Reference
  • 2638
    Dabigatran (Pradaxa), Boehringer Ingelheim, Ontario, Canada, 23 mars 2020.
  • 3341
    Kumar P, Gordon LA, Brooks KM, George JM, Kellogg A et al. Differential influence of the antiretroviral pharmacokinetic enhancers ritonavir and cobicistat on intestinal P-glycoprotein transport and the pharmacokinetic/pharmacodynamic disposition of dabigatran. Antimicrob Agents Chemother. 2017 Oct 24; 61(11).
  • 3658
    Lingineni K, Farhan N, Kim S, Cristofoletti R, Gordon LA, et al. Quantitative benefit-risk assessment of P-gp mediated drug-drug interactions (DDIs) of dabigatran co-administered with pharmacokinetic enhancers in patients with renal impairment. Clin Pharmacol Ther, 2021; 109 (1): 193-200.
  • 3071
    Darunavir/cobicistat (Prezcobix), Janssen, Ontario, Canada, 7 avril 2017.
  • 2971
    Egan G, Hughes CA, Ackman ML. Drug interactions between antiplatelet or novel anticoagulant medications and antiretroviral medications. Ann Pharmacother. 2014 Jun; 48 (6): 734-40.
  • 2693
    Horn JR, Hansten PD. Dabigatran : a new oral anticoagulant. Pharmacy times 2010; 12(10): 59.
  • 2694
    Pradax (dabigatran). Pharmacist’s Letter/Prescriber’s Letter 2011; 27(1): 270119.
  • 2973
    INESSS : Anticoagulothérapie par le dabigatran. Décembre 2011. http://www.inesss.qc.ca/fileadmin/doc/INESSS/Outils/Pradax/Pradaxa_FINAL_201205_FR.pdf
  • 2998
    Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC et al. Updated European Heart Rythm association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace, 2015 Oct; 17(10): 1467-507.
  • 2999
    Wigle P, Hein B, Bloomfield HE et al. Update guidelines on outpatient anticoagulantion. American Family Physician 2013; 87(8); 557-566.
  • 3004
    Ageno W, Gallus AS, Wittkowsky A et al. Oral anticoagulant therapy guidelines. CHEST 2012; 141(2): E44S-E88S.
  • 3399
    Kakadiva PP, Higginson RT and Fulco PP. Ritonavir-Boosted Protease Inhibitors but Not Cobicistat Appear Safe in HIV-Positive Patients Ingesting Dabigatran. Antimicrob agents Chemother 2018 Jan 25; 62(2).
  • 3437
    Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (Symtuza), Janssen Inc, Ontario, Canada, 3 octobre 2018.
  • 3528
    Wiggins BS, Dixon DL Neyens RR, Page RL et al. Select Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic of the Week. J Am Coll Cardiol. 2020 Mar 24; 75 (11): 1341-50.