{{drugbox |
| IUPAC_name = (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)
phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
| image = Rivaroxaban structure.svg
| width = 200
| CAS_number = 366789-02-8
| ATC_prefix = B01
| ATC_suffix = AX06
| ATC_supplemental =
| PubChem = 6433119
| DrugBank =
| C=19 | H=18 | Cl=1 | N=3 | O=5 | S=1
| molecular_weight = 435.882 g/mol
| smiles = O=C1COCCN1c3ccc(cc3)N2CC(OC2=O)CNC(=O)c(cc4)sc4Cl
| bioavailability = 80% to 100%; Cmax = 2 – 4 hours (10 mg oral)
| metabolism = CYP3A4 , CYP2J2 and CYP-independent mechanisms
| elimination_half-life = 10 mg oral 7 – 11 hours
| excretion = 2/3 metabolized in liver and 1/3 eliminated unchanged
| pregnancy_category =
| legal_status = Rx-only
| routes_of_administration = oral
| licence_EU = Xarelto
}}
Rivaroxaban (BAY 59-7939) is an oral anticoagulant invented and manufactured by Bayer; in a number of countries it is marketed as Xarelto. If approved by the United States FDA, it will be marketed by Ortho-McNeil Pharmaceutical. It is the first available orally active direct inhibitor of coagulation Factor Xa. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs three hours after a dose. The effects lasts 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.

Regulatory approval and indications

In September 2008, Health Canada granted marketing authorization for rivaroxaban as one 10 mg tablet taken once daily for the prevention of venous thromboembolism (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.

In September 2008, the European Commission granted marketing authorization of rivaroxaban for the prevention of venous thromboembolism in adult patients undergoing elective hip and knee replacement surgery.

Rivaroxaban is undergoing review by the U.S. Food and Drug Administration (FDA). On March 19, 2009, an advisory panel recommended FDA approval of rivaroxaban 10 mg once daily for use in patients undergoing hip or knee replacement surgery. The advisory panel concluded that the RECORD trials demonstrate that rivaroxaban is non-inferior and possibly superior to subcutaneous enoxaparin 40 mg once daily. However, they also found an increased risk of bleeding with rivaroxaban and did not address the question of long-term (i.e. > 35 days) use. The advisory panel noted that 1 participant out of 6183 randomized to rivaroxaban died of liver toxicity..

Mechanism of action

Rivaroxaban is an oxazolidinone derivative optimized for inhibiting both free Factor Xa and Factor Xa bound in the prothrombinase complex. It is a highly selective direct Factor Xa inhibitor with oral bioavailability and rapid onset of action. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated Factor II), and no effects on platelets have been demonstrated.

Rivaroxaban has predictable pharmacokinetics across a wide spectrum of patients (age, gender, weight, race) and has a flat dose response across an eightfold dose range (5–40 mg). Clinical trial data have shown that it allows predictable anticoagulation with no need for dose adjustments and routine coagulation monitoring. However, these trials have excluded patients with liver disease and end-stage liver disease and use of rivaroxaban may be unsafe in these populations.

Clinical development

It is expected that more than 60,000 patients will be enrolled in the rivaroxaban clinical development program, which evaluates the product in the prevention and treatment of a broad range of blood-clotting disorders.

Four clinical studies have shown that oral rivaroxaban has non-inferior and possibly superior efficacy compared to 40 mg per day of the subcutaneous low molecular weight heparin (LMWH) enoxaparin in preventing VTE in adult patients undergoing total hip or knee replacement surgery. However, the risk of bleeding was greater in patients randomized to rivaroxaban (10 mg/day) rather than enoxaparin (40 mg/day) and one patient (out of > 6000) randomized to rivaroxaban died of liver toxicity. The four studies include RECORD1 and 2 (hip replacement) and RECORD3 and 4 (knee replacement). The RECORD4 study concluded that rivaroxaban was significantly more effective in reducing the occurrence of venous blood clots following knee replacement surgery than enoxaparin.

In addition, rivaroxaban is being studied in phase III clinical trials for stroke prevention in non-valvular atrial fibrillation (AF or afib) (ROCKET-AF), prevention of VTE in hospitalized medically ill patients (MAGELLAN), treatment and secondary prevention of VTE (EINSTEIN), and secondary prevention of major cardiovascular events in patients with acute coronary syndrome (ACS) (ATLAS ACS TIMI 51).

Chemistry

thumb|Chemical structures of [[linezolid (top) and rivaroxaban (bottom). The shared oxazolidinone core is shown in blue.]]

Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same oxazolidinone-derived core structure. Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of mitochondrial toxicity, which is a known complication of long-term linezolid use. Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria. As for mitochondrial toxicity, in vitro studies found the risk to be low, and not likely to be of clinical consequence because rivaroxaban is only meant (and approved) for short-term use.

Related drugs

A number of anticoagulants inhibit the activity of Factor Xa. Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux inhibit the activity of factor Xa indirectly by binding to circulating antithrombin (AT III). These agents must be injected. Warfarin, phenprocoumon, and acenocoumarol are orally active vitamin K antagonists (VKA) which decrease hepatic synthesis of a number of coagulation factors, including Factor X. In recent years, a new series of oral, direct acting inhibitors of Factor Xa have entered clinical development. These include rivaroxaban, apixaban, betrixaban, LY517717, YM150, and DU-176b.