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Ritonavir can inhibit the CYP 3A4 and P-gp and increase the plasma concentration of Apixaban.
3A4 and 2D6 (major), 1A2 and 2B6 (minor), 5 metabolites, one of which has a weak concentration of an active metabolite (M-2), transporters: MRP1, MRP2, P-gp
2B6, 2C8, 2C9, 1A2, 2C19 (moderate) UGT (moderate)
3A4 (potent) and 2D6 (moderate), transporters: BCRP, OATP1A2, OATP1B1, OATP1B3, MRP1, MRP2, OCT1, OCT2, P-gp
3A4 (major), 1A2 and 2J2 (minor), 2C8, 2C9, 2C19 (very minor), transporters: P-gp, BCRP
Increased risk of severe bleeding including hemorrhage.
The canadian monograph contraindicates this combination.
For patients receiving a 5 or 10 mg BID dose of apixaban, the US Product Monograph suggests a 50% dose reduction when given with potent CYP3A4 or P-gp inhibitors.
This combination, however, should be avoided in patients already taking apixaban 2.5 mg BID or with two or more risk factors for bleeding (elderly ≥ 80 years, low weight ≤ 60 kg, serum creatinine ≥ 133 μmol/L).
Monitor the clinical efficacy and appearance of adverse effects.
Prefer warfarin or potentially dabigatran or low molecular weight heparin (LMWH).
Adverse effects of apixaban : nausea, symptoms of bleeding and anemia. We should also follow CBC closely to detect thrombocytopenia and anemia that may result from apixaban administration.
Ref #2690 : A pharmacokinetic study with a strong CYP3A4 inhibitor, ketoconazole, has shown an increase in apixaban AUC and Cmax of 2-fold and 1.6-fold, respectively. With diltiazem, a moderate CYP3A4 inhibitor, an increase was observed in apixaban AUC and Cmax of 1.3-fold and 1.4-fold, respectively.
Currently available data are not sufficient to define a clear recommendation. In addition, we do not have a specific marker to monitor the efficacy of apixaban or antidote.
Thus, the apixaban monograph considers as contraindicated concomitant administration of this drug with agents that inhibit both CYP3A4 and P-gp. Warfarin can be used as an alternative (see warfarin and PI/r).
However, if the association can be avoided, the American monograph recommends lowering the dose to 2.5 mg BID if the patient has no risk factors for bleeding. The association, however, should be avoided in patients already taking apixaban 2.5 mg bid or with two or more risk factors for bleeding (elderly ≥ 80 years, low weight ≤ 60 kg, serum creatinine ≥ 133 μmol/L).