Elvitegravir / 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

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

Elvitegravir / Cobicistat

Pharmacodynamic effects

Recommendations

If possible, consider an alternative.

Alternative solution(s)

Depending on previous virological failures and genotype reports, doravirine or rilpivirine, or even dolutegravir, raltegravir or bictegravir.

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 for further details.

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.

Comment
Reference
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    Dabigatran (Pradaxa), Boehringer Ingelheim, Ontario, Canada, 23 mars 2020.
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