Co‐administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects

Mueck, Wolfgang; Kubitza, Dagmar; Becka, Michael

doi:10.1111/bcp.12075

Cited by 317 publications

(405 citation statements)

References 32 publications

(52 reference statements)

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“…Drugs that exhibit strong effects on these proteins therefore have the potential to influence the pharmacokinetics, and thus the safety and efficacy profile, of rivaroxaban 7, 8. Consequently, strong inhibitors of both CYP3A4 and P‐gp are not recommended for systemic concomitant use with rivaroxaban 9.…”

Section: Introductionmentioning

confidence: 99%

Rivaroxaban compared with standard thromboprophylaxis after major orthopaedic surgery: co‐medication interactions

Kreutz

Haas

Holberg

et al. 2016

Brit J Clinical Pharma

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AimThe aim of the present study was to analyse concomitant drug use and its association with outcome in patients (N = 17 701) receiving rivaroxaban or standard of care (SOC) for the prevention of venous thromboembolism after major orthopaedic surgery in the non‐interventional, phase IV XAMOS (Xarelto® in the prophylaxis of post‐surgical venous thromboembolism after elective major orthopaedic surgery of hip or knee) study.MethodsConcomitant drug use was at the discretion of the treating physician. Prespecified co‐medications of interest were cytochrome P450 (CYP) 3A4/P‐glycoprotein inhibitors/inducers, platelet aggregation inhibitors (PAIs) and nonsteroidal anti‐inflammatory drugs (NSAIDs). Crude event incidences were compared between rivaroxaban and SOC groups.ResultsCYP3A4/P‐glycoprotein inhibitor/inducer use was infrequent, in contrast to PAI (~7%) and NSAID (~52%) use. Rivaroxaban was associated with a lower incidence of overall symptomatic thromboembolic events compared with SOC, regardless of co‐medication use. In both treatment groups, PAI users, with higher age and prevalence of cardiovascular co‐morbidities, had similar higher (>7‐fold) incidences of symptomatic arterial but not venous thromboembolic events compared with non‐users. NSAID use had no influence on thromboembolic events. However, odds ratios (ORs) for major bleeding events (European Medicines Agency definition) were higher in NSAID users compared with non‐users in rivaroxaban [OR = 1.50; 95% confidence interval (CI) 1.06, 2.13] and SOC (OR = 1.70; CI 1.16, 2.49) groups. In PAI users, ORs for major bleeding events were no different from those of non‐users in both the rivaroxaban (OR = 1.49; CI 0.84, 2.65) and SOC (OR = 1.46; CI 0.82, 2.62) groups.ConclusionsUse of NSAIDs in XAMOS was frequent and associated with a higher frequency of bleeding events in patients receiving rivaroxaban or SOC, although the benefit–risk profile of rivaroxaban compared with SOC was maintained.

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Section: Introductionmentioning

confidence: 99%

Rivaroxaban compared with standard thromboprophylaxis after major orthopaedic surgery: co‐medication interactions

Kreutz

Haas

Holberg

et al. 2016

Brit J Clinical Pharma

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“…Common to all NOACs is the potential for increased plasma levels when taken in combination with drugs that compete for the P-gp transporter, such as the frequently used antiarrhythmics verapamil, amiodarone and quinidine; dose reduction may be required, in particular with dabigatran or edoxaban. 12 Increased rivaroxaban levels may result from CYP3A4 inhibition, 59 whereas the CYP3A4 pathway makes minimal contribution towards edoxaban clearance and is not involved at all in the clearance of dabigatran. The diverse nature of non-renal clearance of apixaban reduces the impact of any CYP3A4 interactions, 60 such that use of apixaban should be avoided only when drugs that strongly inhibit both CYP3A4 and P-gp are used, such as the HIV protease inhibitors and azole antifungals.…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

Drug therapy in anticoagulation: which drug for which patient?

Millar

Laffan

2017

Clinical Medicine

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Four non-vitamin K oral anticoagulants (NOACs) are now licensed and available in the UK, offering unprecedented choices in anticoagulant therapy for clinicians and patients. NOACs have many clear benefi ts over warfarin, the most striking being the reduction in intracranial haemorrhage. However, a number of uncertainties remain: their effi cacy in certain situations, utility of drug assays, signifi cance of drug interactions and management of bleeding. In the absence of any direct comparative trials, it is not clear that any of the NOACs is signifi cantly better than the others in any of the licensed indications. The differential activities, pharmacokinetics, metabolism, excretion and side effects of the agents should be considered when selecting the most appropriate anticoagulant. In this article, we discuss how, with careful selection for the relevant indication, NOACs can simplify therapy while improving outcomes. We aim to provide clinicians with the information needed to select the most suitable anticoagulant drug for an individual patient in a given situation. KEYWORDS : Anticoagulant therapy , non-vitamin K oral anticoagulants , NOACs IntroductionThe non-vitamin K oral anticoagulants (NOACs) 1 are now established in UK practice and new members continue to arrive. Within their licensed indications they have clear benefits over warfarin, but a number of uncertainties remain: efficacy in some specific situations, the utility of drug assays, significance of drug interactions and the management of bleeding all suffer from a paucity of data.This article provides an update on developments since the 2014 review in this journal.2 Our aim is to provide the information needed to select the most suitable anticoagulant drug for an individual patient in a given situation. ABSTRACTDrug therapy in anticoagulation: which drug for which patient? Properties of NOACsFour NOACs are now licensed and available in the UK: the direct factor Xa (FXa) inhibitors apixaban, edoxaban and rivaroxaban, and the direct thrombin inhibitor dabigatran. The key to best choice of agent lies in their individual pharmacokinetic profiles, metabolism and routes of excretion.

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“…Cytochrome P450 CYP3A4 involved in hepatic clearance of rivaroxaban and apixaban -plasma levels may be affected by CYP3A4 inducers of inhibitors [19].…”

Section: Odi Drug Interactionsmentioning

confidence: 99%

Oral Direct Anticoagulants in Thrombosis Management in Anti-Phospholipid Syndrome: Unanswered Questions

G¹

2015

J Hematol Thrombo Dis

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Anti-phospholipid syndrome comprises a broad spectrum of manifestations with thrombotic events as a serious issue. The current mainstay of treatment for thrombotic anti-phospholipid syndrome is heparin followed by long-term anticoagulation with vitamin K antagonists. Vitamin K antagonists' management in this group of patients is frequently cumbersome, requires close monitoring and may affect patient's quality of life. There is also a high recurrence rate in high risk patients. The introduction of the oral direct inhibitors of coagulation for the management for thromboembolism is currently established for several indications.These agents are fixed dose with predictable anticoagulant effect and do not interact with dietary constituents and have few drug interactions. They have a rapid onset of action and don't routinely require monitoring. The shortcomings of vitamin K antagonists and the advantages of the oral direct inhibitors encouraged their trial in antiphospholipid syndrome. Case series of their use paved the road for designing clinical trials aiming to study their potential role in this important group of patients.In this article, we reviewed the literature regarding the current state of oral direct anticoagulants in thrombosis management in general, cited the case series results and presented the ongoing clinical trials that are currently underway. We also raise some practical points relevant to their application in specific situations. It is premature to pass comments on their applicability, but the seriousness of the issue

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Co‐administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects

Cited by 317 publications

References 32 publications

Rivaroxaban compared with standard thromboprophylaxis after major orthopaedic surgery: co‐medication interactions

Rivaroxaban compared with standard thromboprophylaxis after major orthopaedic surgery: co‐medication interactions

Drug therapy in anticoagulation: which drug for which patient?

Oral Direct Anticoagulants in Thrombosis Management in Anti-Phospholipid Syndrome: Unanswered Questions

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