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Atazanavir / ritonavir may inhibit CYP3A4 and transporters P-gp and BCRP and therefore decrease hepatic metabolism and renal excretion Rivaroxaban.
3A4, P-gp/3A4 > 2D6, P-gp
Ritonavir: 1A2, 2C9, 2C19, UGT, 2B6, 3A4 (auto-induction)
3A4, UGT1A1, P-gp E et 2C8/3A4 > 2D6 > 2A6, 2E1, P-gp, MRP2
3A4/3A5, 2J2 and P-gp (intestinal); BCRP and P-gp (renal secretion)
Increased risk of severe bleeding including hemorrhage.
Choose an alternative.
Rivaroxaban monograph contraindicates concomitant administration with a strong CYP3A4 and P-gp inhibitors like ketocanazole, ritonavir, itraconazole and posaconazole.
Prefer warfarin or potentially dabigatran or low molecular weight heparin (LMWH).
Effectiveness and safety (signs and symptoms of bleeding : anemia, hematoma, hematuria, epistaxis, gastrointestinal disorders, urinary and digestive haemorrhage) and, particularly in patients with bleeding risk factors (old person, low body weight, impaired kidney function).
See ritonavir and rivaroxaban.
Ref #2993 : It has been shown that co-administration of rivaroxaban with ketoconazole (another potent 3A4 and P-gp inhibitor) increased rivaroxaban AUC and Cmax by 2.6-fold and 1.7-fold respectively. Also, another study showed similar results with the administration of ritonavir 600 mg BID, which caused an increase in rivaroxaban AUC by 2.5-fold (153%) and Cmax by 1.6-fold (55%).
All studies with rivaroxaban in combination with strong CYP3A4, CYP2J2 and/or P-gp/BCRP (kidney) inhibitors :
1. Ketoconazole 200 mg QD + rivaroxaban 10 mg : ↑ 53% Cmax, ↑ 82% AUC; ↓ 45% rivaroxaban clearance Cl/f.
2. Ketoconazole 400 mg QD + rivaroxaban 10 mg : ↑ 72% Cmax, ↑ 158% AUC; ↓ 61% rivaroxaban clearance Cl/f and ↓ 44% renal clearance.
3. Ritonavir 600 mg BID + rivaroxaban 10 mg : ↑ 55% Cmax, ↑ 158% AUC; ↓ 60% rivaroxaban clearance Cl/f and ↓ 82% renal clearance.
4. Clarithromycin 500 mg BID + rivaroxaban 10 mg : ↑ 40% Cmax, ↑ 54% AUC; ↓ 35% rivaroxaban clearance Cl/f and ↓ 10% renal clearance.
5. Erythromycin 500 mg TID + rivaroxaban 10 mg : ↑ 38% Cmax, ↑ 34% AUC; ↓ 25% rivaroxaban clearance Cl/f and ↓ 7% renal clearance.
6. Fluconazole 400 mg QD + rivaroxaban 10 mg : ↑ 28% Cmax, ↑ 42% AUC; ↓ 29% rivaroxaban clearance Cl/f and ↓ 22% renal clearance.
Ref #3130 : Case report in patient on salvage regimen including darunavir/ritonavir 600 mg/100 mg BID, lamivudine 150 mg BID, tenofovir 300 mg QD, etravirine 200 mg BID and raltegravir 400 mg BID. Rivaroxaban was measured after two weeks of treatment because of the expected interaction and then the plasma plasma level was 253 µg/l; of note, the median peak concentration (Cmax) value of rivaroxaban predicted from population pharmacokinetic analyses is 125 µg/l for 10 mg QD. The dose of rivaroxaban was therefore reduced from 10 mg QD (postoperative leg fracture) to 5 mg QD. During a trip to Mexico, the patient experienced bloody diarrhea possibly related to the increase of adverse effects of rivaroxaban. Salmonellosis, Shigellosis and Campylobacter jejuni infections were excluded. Furthermore, the patient did not present any other gastrointestinal symptoms before the bleeding and had no history of colorectal disease. Thus, the exclusion of other possible causes, the chronology of events, the documented elevated plasma level of rivaroxaban and the resolution of the symptoms shortly after the interruption of the anticoagulant are highly suggestive of a drug-drug interaction between rivaroxaban and darunavir/ritonavir, which led to increased exposure to the anticoagulant and gastrointestinal bleeding. The other symptoms (fever, dizziness and diarrhea) likely resulted from associated traveller’s diarrhea. Since the treatment for the prevention of venous thromboembolism was almost completed, no other anticoagulant was further prescribed.
Rivaroxaban monograph contraindicates concomitant administration with a strong CYP3A4 and/or P-gp inhibitor like ketocanazole and ritonavir.
Moreover, we do not have a specific marker for monitoring the safety of rivaroxaban nor antidote for bleeding.