Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication (blood thinner) used to treat and reduce the risk of blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is taken by mouth. Common side effects include bleeding. Other serious side effects may include spinal hematoma and anaphylaxis. It is unclear if use in pregnancy and breastfeeding is safe. Compared to warfarin it has fewer interactions with other medications. It works by blocking the activity of the clotting protein factor Xa. Rivaroxaban was patented in 2007 and approved for medical use in the United States in 2011. It is available as a generic medication. It is on the World Health Organization's List of Essential Medicines. In 2023, it was the 88th most commonly prescribed medication in the United States, with more than 7 million prescriptions.
Medical uses Rivaroxaban is indicated to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation; for the treatment of deep vein thrombosis; for the treatment of pulmonary embolism; for the reduction in the risk of recurrence of deep vein thrombosis or pulmonary embolism; for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in people undergoing knee or hip replacement surgery; for the prophylaxis of venous thromboembolism in acutely ill medical patients; to reduce the risk of major cardiovascular events in people with coronary artery disease; to reduce the risk of major thrombotic vascular events in people with peripheral artery disease, including people after recent lower extremity revascularization due to symptomatic peripheral artery disease; for the treatment of venous thromboembolism and reduction in the risk of recurrent venous thromboembolism in children from birth to less than 18 years of age; for thromboprophylaxis in children aged two years of age and older with congenital heart disease after the Fontan procedure. In those with non-valvular atrial fibrillation, rivaroxaban appears to be as effective as warfarin in preventing strokes and embolic events in patients who are classified as moderate-to-high risk, as defined by a score of a number of specific medical conditions. In July 2012, the UK's National Institute for Health and Clinical Excellence recommended rivaroxaban to prevent and treat venous thromboembolism.
Contraindications When undergoing surgeries, due to the concern over managing bleeding, rivaroxaban can be discontinued 24 hours prior to low-bleeding risk surgery and 48-72 hours prior to high-bleeding risk surgeries. Once the surgery is over, it can be recommenced after 1 to 3 days with doctor consultation. Dosing recommendations do not recommend administering rivaroxaban with drugs known to be strong combined CYP3A4/P-glycoprotein inhibitors because this results in significantly higher plasma concentrations of rivaroxaban. A small retrospective cohort study reported that the use of moderate CYP3A4 and P-glycoprotein inhibitors such as amiodarone or verapamil, increased the risk of bleeding when administered with rivaroxaban. Although this increase was not statistically significant with verapamil, A later study found that amiodarone, which inhibits three cytochrome P450 enzymes, i.e., CYP2C9 and P-glycoprotein as well as CYP3A4, that metabolize rivaroxaban caused a highly significant increase in the blood levels of rivaroxaban and thereby excessive but not life-threatening bleeding in patients with atrial fibrillation. Therefore, it is important to monitor for bleeding when concurrently on rivaroxaban and inhibitors of CYP2C9, P-glycoprotein, CYP3A4,
Adverse effects The most serious adverse effect is bleeding, including severe internal bleeding. As of 2015, post-marketing assessments showed liver toxicity, and further studies are needed to quantify this risk. In 2015, rivaroxaban accounted for the highest number of reported cases of serious injury among regularly monitored medications to the FDA's Adverse Events Reporting System (AERS).
Reversal agent In October 2014, Portola Pharmaceuticals completed Phase I and II clinical trials for andexanet alfa as an antidote for Factor Xa inhibitors with few adverse effects, and started Phase III trials. Andexanet alfa was approved by the U.S. Food and Drug Administration in May 2018, under the trade name AndexXa.
Mechanism of action Rivaroxaban inhibits both free and bound Factor Xa in the prothrombinase complex. It is a selective direct factor Xa inhibitor with an onset of action of 2.5 to 4 hours. 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. It allows predictable anticoagulation and dose adjustments and routine coagulation monitoring; dietary restrictions are not needed. Unfractionated heparin, low molecular weight heparin, and fondaparinux also inhibit the activity of factor Xa, indirectly, by binding to circulating antithrombin (AT III) and must be injected, whereas the orally active warfarin, phenprocoumon, and acenocoumarol are vitamin K antagonists, decreasing a number of coagulation factors, including factor X. Rivaroxaban has predictable pharmacokinetics across a wide spectrum of people (age, gender, weight, race) and has a flat dose response across an eightfold dose range (5–40 mg). The oral bioavailability is dose-dependent. Doses of rivaroxaban under 10 mg can be taken with or without food, as it displayed high bioavailability independent of whether food was consumed or not. If rivaroxaban is given at oral doses of 15 mg or 20 mg, it needs to be taken with food to aid in drug absorption and achieve appropriate bioavailability (≥ 80%).
Chemistry
Rivaroxaban bears a strong structural similarity to the antibiotic linezolid: both drugs share the same N-phenyl-2-oxazolidinone 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. Neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria. As for mitochondrial toxicity, in vitro studies published before 2008 found the risk to be low.
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