indication

Rivaroxaban is indicated for the prevention of venous thromboembolic events (VTE) in patients who have undergone total hips replacements and total knee replacement surgery. Due to a lack of safety studies, it is not recommended for use in those under 18 years old. Its use is also not recommended in those with severe renal impairment (<30mL/min).

pharmacology

Rivaroxaban is an anticoagulant which binds directly to factor Xa. Thereafter, it effectively blocks the amplification of the coagulation cascade, preventing the formation of thrombus. Rivaroxaban is a unqiue anticoagulant for two reasons. First of all, it is does not involve antithrombin III (ATIII) to exert its anticoagulant effects. Secondly, it is an oral agent whereas the widely used unfractionated heparin and low molecular weight heparins are for parenteral use only. Although the activated partial thromboplastin time (aPTT) and HepTest (a test developed to assay low molecular weight heparins) are prolonged in a dose-dependant manner, neither test is recommended for the assessment of the pharmacodynamic effects of rivaroxaban. Anti-Xa activity and inhibition of anti-Xa activity monitoring is also not recommended despite being influenced by rivaroxaban.

mechanism of action

Rivaroxaban competitively inhibits free and clot bound factor Xa. Factor Xa is needed to activate prothrombin (factor II) to thrombin (factor IIa). Thrombin is a serine protease that is required to activate fibrinogen to fibrin, which is the loose meshwork that completes the clotting process. Since one molecule of factor Xa can generate more than 1000 molecules of thrombin, selective inhibitors of factor Xa are profoundly useful in terminating the amplification of thrombin generation. The action of rivaroxaban is irreversible.

toxicity

Excessive bleeding. Overdosages should be treated using activated charcoal and supportive measures such as mechanical compression and hemodynamic support. If bleeding is not controlled, the following procoagulants can be administered: activated prothrombin complex concentrate, prothrombin complex concentrate and recombinant factor VIIa. There is also a higher chance of post procedural hemorrhage compared to enoxaparin (1.55% vs. 1.39% respectively).

biotransformation

Approximately 2/3 of the dose is metabolized. It is metabolized by CYP3A4, CYP2J2 and CYP-independant mechanisms

absorption

Following oral administration, the absolute bioavailability is about 100%

half life

The terminal half life is 5-9 hours in young individuals and 11-13 hours in the elderly.

route of elimination

About 1/3 of the administered dose is excreted unchanged via the kidneys, 1/3 is metabolized to inactive metabolites and then excreted by the kidneys and 1/3 is metabolized to inactive metabolites and excreted fecally.

drug interactions

Bivalirudin: Anticoagulants may enhance the anticoagulant effect of rivaroxaban. Avoid concurrent use of rivaroxaban with other anticoagulants whenever possible, other than during transition periods, due to the possible increased for bleeding.

Clopidogrel: Antiplatelet agents such as clopidogrel may enhance the anticoagulant effect of rivaroxaban. Avoid concurrent use of clopidogrel with rivaroxaban unless the anticipated benefits outweigh the risks of bleeding. Canadian rivaroxaban labeling recommends avoiding concurrent use with any antiplatelet agent, while the U.S. rivaroxaban labeling recommends caution and increased monitoring if used with any other antiplatelet agent. Any combined use should only be undertaken with increased monitoring for evidence of bleeding.

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rivaroxaban. Consider avoiding use of rivaroxaban with any strong CYP3A4 inhibitors as many such agents are inhibitors of both CYP3A4 and P-glycoprotein. Use of rivaroxaban concomitantly with drugs that are strong inhibitors of both CYP3A4 and P-glycoprotein is specifically contraindicated.

Dabigatran etexilate: Using additional anticoagulants such as dabigatran can increase the anticoagulant effect of rivaroxaban. Avoid concurrent use of rivaroxaban with other anticoagulants whenever possible, other than during transition periods, due to the possible increased for bleeding.

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Itraconazole: Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 and P-glycoproteins are contraindicated.

Ketoconazole: Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 and P-glycoproteins are contraindicated.

Posaconazole: Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 and P-glycoproteins are contraindicated.

Ritonavir: Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 like ritonavir and P-glycoproteins are contraindicated.

Tamoxifen: Tamoxifen may increase serum concentrations of Rivaroxaban increasing the risk of bleeding. Concomitant therapy should be avoided.

Telithromycin: Telithromycin may reduce clearance of Rivaroxaban. Concomitant therapy is contraindicated.

Treprostinil: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Rivaroxaban. Monitor for increased bleeding during concomitant thearpy.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of rivaroxaban by decreasing its metabolism. Increased bleed risks may occur. Consider alternate therapy.