Cobicistat

Dabigatran

Combination to avoid or use with caution.

No pharmaceutical opinion available for this interaction.

Mechanism

Cobicistat can inhibit the intestinal P-gp and increase the plasma concentration of Dabigatran.

Cobicistat

Pharmacodynamic effects

Recommendations

Avoid association.

Alternative solution(s)

Choose an antiretroviral that does not have this interaction.

Dabigatran

Pharmacodynamic effects

Possible increase of adverse effects.

Recommendations

Choose an alternative.

If this combination cannot be avoided, give only after considering increased risk of bleeding: co-administration with antiplatelet (including aspirin or NSAIDs), age > 75 years, weight < 60kg, impaired renal function, systemic corticosteroids,

history or active gastrointestinal bleeding, recent surgery (eyes, brain), thrombocytopenia (eg chemotherapy), HAS-BLED ≥ 3.

Use this combination with caution.

See comments.

Alternative solution(s)

Prefer warfarin or low molecular weight heparin (LMWH).

Monitor

Tests

Pharmacokinetic parameters
Parameters
Reference number
# patients
HIV
Dose
Frequency
Cmax
AUC
Cobicistat
3341 3341
16 16
- -
150 mg 150 mg
QD QD
   
   
Dabigatran
3341 3341
16 16
- -
150 mg * 150 mg †
x 1 * x 1 †
+ 99% (2x) + 127% (2.3x)
+ 110% (2.1x) + 127% (2.3x)
Comment

Ref #3341 : * Dabigatran given 2 hours before cobicistat.
† Dabigatran given simultaneously with cobicistat.
Unlike ritonavir, cobicistat significantly increased dabigatran concentrations 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.

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, 7 juin 2015.
  • 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.
  • 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.
  • 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.
  • 2949
    Cobicistat (Tybost), European public assessment report (EPAR) Product Information, London, United Kingdom, 4 juin 2015.
  • 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).
  • 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).