Darunavir / ritonavir

Rivaroxaban

Contraindicated.

No pharmaceutical opinion available for this interaction.

Mechanism

Darunavir / ritonavir may inhibit CYP3A4 and transporters P-gp and BCRP and therefore decrease hepatic metabolism and renal excretion Rivaroxaban.

Darunavir / ritonavir

Pharmacodynamic effects

Recommendations

Alternative solution(s)

Rivaroxaban

Pharmacodynamic effects

Increased risk of severe bleeding including hemorrhage.

Recommendations

Choose an alternative.

Rivaroxaban monograph contraindicates concomitant administration with a strong CYP3A4 and P-gp inhibitors like ketocanazole, ritonavir, itraconazole and posaconazole.

Alternative solution(s)

Prefer warfarin or potentially dabigatran or low molecular weight heparin (LMWH).

Monitor

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).

Tests

Pharmacokinetic parameters

Comment

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.

Reference
  • 2605
    Rivaroxaban (Xarelto), Bayer Inc, Ontario, Canada, 13 septembre 2018.
  • 2614
    Wolfgang M, Kubitza D and Becka M. Co-administration of rivaroxaban with drugs that share its elimination patways : pharmacokinetic effects in healthy subjects. The Journal of clinical pharmacology 2013.
  • 2695
    New drug : Xarelto (rivaroxaban). Pharmacist’s Letter/Prescriber’s Letter 2008; 24 (11): 241117.
  • 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.
  • 2993
    Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways : pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013 Sep; 76 (3): 455-66.
  • 2994
    Haas S, Bode C, Norrving B, Turpie AG. Practical guidance for using rivaroxaban in patients with atrial fibrillation: balancing benefit and risk. Vasc Health Risk Manag. 2014 Mar 10; 10: 101-14.
  • 2995
    Guyatt GH, Akl EA et al. American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb; 141 (2 suppl): 7S-47S.
  • 2996
    Turpie AG. Rivaroxaban as an oral anticoagulant for stroke prevention in atrial fibrillation. The Clin Risk Manag. 2014 Mar 22: 10: 197-205.
  • 2997
    Bleeding with dabigatran, rivaroxaban, apixaban. No antidote, and little clinical experience. Prescrire Int. 2013 Jun; 22 (139): 155-9.
  • 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.
  • 3130
    Lakatos B, Stoeckle M, Elzi L, et al. Gastrointestinal bleeding associated with rivaroxaban administration in a treated patient infected with human immunodeficiency virus. Swiss medical weekly 2014; 144: w13906.
  • 3168
    Mueck W, Stampfuss J, Kubitza D et Becka M. Clinical Pharmacokinetic and Pharmacodynamic Profile of Rivaroxaban. Clin Pharmacokinet (2014) 53: 1–16.