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

Drug Saf - Case Rep (2015) 2:11 DOI 10.1007/s40800-015-0014-4 CASE REPORT Postoperative Bleeding After Administration of a Single Dose of Rivaroxaban to a Patient Receiving Antiretroviral Therapy Carmela E. Corallo1 • Louise Grannell1 • Huyen Tran2 Published online: 1 August 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com 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 & Carmela E. Corallo 1 Department of Pharmacy, Alfred Health, Alfred Hospital, 55 Commercial Road, Melbourne, VIC 3004, Australia 2 Haemostasis/Thrombosis Unit, Haemophilia Centre, Alfred Health, Melbourne, VIC, Australia 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. Key Points Drug interactions with rivaroxaban are a potential cause for serious adverse effects. An interaction between a single dose of rivaroxaban and protease inhibitors may result in bleeding. Extensive evaluation of the interaction profile is essential prior to adding rivaroxaban to antiretroviral therapy. Introduction A recent study by McDonald et al. showed that a large proportion of spontaneous reports of adverse events with rivaroxaban were associated with concomitant medicines, which may have increased the risk [1]. The authors concluded that there is a need for ongoing postmarketing surveillance of rivaroxaban, together with an increased awareness of the potential for drug interactions as a cause 11 Page 2 of 4 for serious adverse events. However, there was no mention of reports of interactions with antiretroviral agents (ARVs). We would like to describe a case report that illustrates the rapid effect of an interaction between the target-specific oral anticoagulant (TSOAC) rivaroxaban and ARVs. Case Report A 62-year-old male orthopedic surgical patient receiving long-term ARVs was commenced on enoxaparin 40 mg subcutaneously daily for venous thromboembolism (VTE) prophylaxis 3 weeks preoperatively. Preadmission medications that were continued postoperatively included the ARVs, etravirine 200 mg twice daily, ritonavir 100 mg twice daily, darunavir 600 mg twice daily, raltegravir 400 mg twice daily and emtricitabine/tenofovir 300/200 mg daily; mirtazapine 45 mg at night, aspirin 100 mg in the morning, esomeprazole 20 mg daily, valaciclovir 500 mg daily, and oxycodone sustained-release 60 mg twice daily. New medications that were commenced postoperatively included intravenous prophylactic antibiotics, meropenem 1000 mg three times daily and linezolid 600 mg twice daily for 1 week, and a single dose of antifungal therapy, oral fluconazole 400 mg. Pain was managed with pregabalin 75 mg twice daily, ketamine intravenous infusion up to 16 mg/h and morphine patient-controlled analgesia. Postoperatively, enoxaparin was replaced with rivaroxaban 10 mg daily. Twenty-four hours after concomitant administration of rivaroxaban with ARVs, the patient experienced profound hypotension and bleeding at the surgical site. At the time of bleeding, laboratory results showed a prolonged prothrombin time (PT) of 24.3 (10.6–15.3) s and a significantly elevated rivaroxaban trough level of 75 ng/mL (median plasma concentration 24 h after a 10 mg dose has been reported to be 9 ng/mL) [2]. Renal function was normal. Rivaroxaban was ceased and the patient was managed with fluid resuscitation, packed red blood cells, fresh frozen plasma and human prothrombin complex (ProthrombinexVFÒ). No further bleeding occurred and 24 h later PT had normalized and the rivaroxaban level had decreased to 11 ng/mL. Enoxaparin for VTE prophylaxis was commenced 1 week later. Discussion 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 [3]. The PI darunavir, a moderate CYP3A4 inhibitor, should also be avoided in patients receiving rivaroxaban [4, 5]. C. E. Corallo et al. This recommendation is based on in vitro data and a pharmacokinetic study in healthy volunteers of rivaroxaban coadministered with drugs that share its metabolic pathway, e.g. ritonavir, midazolam [6]. Our patient was taking six ARVs, including the two PIs ritonavir and darunavir, and one non-nucleoside reverse-transcriptase inhibitor (NNRTI), etravirine (a moderate CYP3A4 inducer) [4]. No clinically significant interactions were expected to occur with the other ARVs, i.e. the integrase inhibitor, raltegravir and the nucleoside reverse-transcriptase inhibitors (NRTIs) emtricitabine/tenofovir [5]. After oral administration of a CYP3A4 inhibitor such as ritonavir, there is a rapid increase in the substrate plasma level, which is reversible, typically within 2–3 days of stopping the inhibitor [7]. Ritonavir is used as a pharmacokinetic booster and is included in most PI-based regimens at the lower dose of 100 mg twice daily compared with the 600 mg twice-daily regimen when used for its antiviral activity [4]. In this setting, ritonavir is a pharmacologic enhancer because it inhibits the metabolism of (...truncated)