Postoperative Bleeding After Administration of a Single Dose of Rivaroxaban to a Patient Receiving Antiretroviral Therapy

Abstract

A 62-year-old man was admitted to hospital for elective revision of a left total hip arthroplasty. His history was significant for human immunodeficiency virus (HIV) infection for which he was taking the following antiretroviral agents (ARVs): etravirine, ritonavir, darunavir, raltegravir and tenofovir/emtricitabine. Rivaroxaban 10 mg daily was commenced on the second postoperative day for venous thromboembolism (VTE) prophylaxis. Approximately 24 h later, the patient developed hypotension and anaemia, accompanied by thigh swelling due to bleeding at the surgical site. Fluid resuscitation was commenced with red cell transfusion. The prothrombin time (PT) was prolonged at 24.3 (10.6–15.3) s, and a rivaroxaban level taken 24 h after administration was 75 ng/mL. Rivaroxaban was ceased, the PT normalised within 24 h of stopping the drug, and the patient made an uneventful recovery. None of the other coadministered drugs are known to interact with rivaroxaban, or are likely to, based on their metabolic pathways. Rivaroxaban, a substrate for cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), is contraindicated in patients concomitantly treated with strong inhibitors of both these systems, e.g. protease inhibitors (PIs) such as ritonavir (based on in vitro data and a pharmacokinetic study in healthy volunteers). No published data are available on the PI darunavir, a moderate inhibitor; however, concomitant use with rivaroxaban should also be avoided. A prolonged PT and a rivaroxaban trough level greater than eight times that predicted from pharmacokinetic modelling suggests that bleeding was due to increased exposure to rivaroxaban, probably due to an interaction with ritonavir and darunavir. This is supported by a Drug Interaction Probability Scale (DIPS) score of 8. An interaction between a single dose of rivaroxaban and ARVs may be clinically significant; therefore, the patient’s medication history should be extensively evaluated to identify any potential interactions.

The challenge of HIV treatment in an era of polypharmacy

“…Boosted ARVs cause clinically significant DDIs with direct‐acting anticoagulants due to inhibition of CYPs and/or transporters. Data on management of DDIs are limited Apixaban, rivaroxaban: avoid Dabigatran: coadministration is possible with PI boosted with ritonavir* but is not possible with cobicistat boosting. (*a dose adjustment of dabigatran might be needed in patients with mild or moderate renal insufficiency) Edoxaban: consider a dose reduction from 60 to 30 mg …”

Extensive Bruising and Elevated Rivaroxaban Plasma Concentration in a Patient Receiving Cobicistat-Boosted Elvitegravir

“…Drug interactions between rivaroxaban and antiretrovirals have been reviewed and have resulted in serious adverse events. 1,3,4 There have been no published data on the extent of a drug interaction between cobicistat and rivaroxaban. Based on its inhibitory effects, cobicistat would be predicted to significantly increase rivaroxaban's exposure; however, prescribing information for EVG/c/FTC/TDF and other resources do not warn of this interaction.…”

Ritonavir- or cobicistat-boosted antiretroviral therapy and direct oral anticoagulants: A case for apixaban

“…Two early case reports highlight a cautionary tale of bleeding following the administration of rivaroxaban with ART. [7][8] Rivaroxaban is metabolized through a variety of pathways, including CYP3A4, rendering it susceptible to interactions with antiretroviral agents, such as ritonavir. In addition, P-glycoprotein (Pgp) is involved in rivaroxaban's renal elimination further complicating co-administration.…”