Rivaroxaban, sold under the brand name Xarelto, among others, is an anticoagulant medication (blood thinner), which is taken by mouth. It is commonly used to prevent blood clots. It was initially developed by Bayer. In the United States, it is marketed by Janssen Pharmaceutica. It is the first available active direct factor Xa inhibitor which is taken by mouth. The maximum inhibition of factor Xa occurs four hours after a dose. The effects last approximately 8-12 hours, but factor Xa activity does not return to normal within 24 hours, so once-daily dosing is possible.
Rivaroxaban was patented in the United States in 2007, approved for medical use in 2011, and begins to lose its patent coverage in 2020.
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Medical uses
In those with non-valvular atrial fibrillation it appears to be as effective as warfarin in preventing nonhemorrhagic strokes and embolic events. Rivaroxaban is associated with lower rates of serious and fatal bleeding events than warfarin though rivaroxaban is associated with higher rates of bleeding in the gastrointestinal tract.
In July 2012, the UK´s National Institute for Health and Clinical Excellence recommended rivaroxaban to prevent and treat venous thromboembolism.
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Adverse effects
The most serious adverse effect is bleeding, including severe internal bleeding. Rivaroxaban is associated with lower rates of serious and fatal bleeding events than warfarin but is associated with higher rates of bleeding in the gastrointestinal tract. There is currently no antidote for rivaroxaban (unlike warfarin, the action of which can be reversed with vitamin K or prothrombin complex concentrate), meaning that serious bleeding may be difficult to manage.
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 expected to be approved in 2016.As of 2017, the compound has yet to be approved by the U.S. Food and Drug Administration.
As of 2015, post-marketing assessments showed liver toxicity, and further studies are needed to quantify the risk. The drug is contraindicated in people with significant liver disease and end-stage kidney disease, in whom the drug was not trialed.
Rivaroxaban has a boxed warning to make clear that people using the drug should not discontinue it before talking with their health care professional, because it can increase the risk of stroke.
In 2015, rivaroxaban accounted for the highest number of reported cases of serious injury among regularly monitored drugs to the FDA's Adverse Events Reporting System (AERS).
Mechanism of action
Rivaroxaban inhibits 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. It allows predictable anticoagulation and dose adjustments and routine coagulation monitoring as well as dietary restrictions are not needed.
Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux also inhibit the activity of factor Xa but indirectly by binding to circulating antithrombin (AT III) and must be injected. Whereas, the orally active warfarin, phenprocoumon, and acenocoumarol are vitamin K antagonists (VKA) decrease a number of coagulation factors, including Factor X.
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).
Chemistry
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 published before 2008 found the risk to be low.
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Economics
Using rivaroxaban rather than warfarin costs 70 times more, according to Express Scripts Holding Co, the largest U.S. pharmacy benefits manager. As of 2016, Bayer claimed that the drug was licensed in 130 countries and that more than 23 million patients had been treated.
Approval
In September 2008, Health Canada granted marketing authorization for rivaroxaban to prevent venous thromboembolism (VTE) in people who have undergone elective total hip replacement or total knee replacement surgery.
In the same month, the European Commission also granted marketing authorization of rivaroxaban to prevent venous thromboembolism in adults undergoing elective hip and knee replacement.
On July 1, 2011, the U.S. Food and Drug Administration (FDA) approved rivaroxaban for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adults undergoing hip and knee replacement surgery.
On November 4, 2011, the U.S. FDA approved rivaroxaban for stroke prevention in people with non-valvular atrial fibrillation.
Research
Researchers at the Duke Clinical Research Institute have been accused of withholding clinical data used to evaluate rivaroxaban. Duke tested rivaroxaban in a clinical trial known as the ROCKET AF trial. The clinical trial, published 2011 in the New England Journal of Medicine and headed by Robert Califf, then Commissioner of the FDA) found rivaroxaban to be more effective than warfarin in reducing the likelihood of ischemic strokes in patients with atrial fibrillation. The validity of the study was called into question in 2014 when pharmaceutical sponsors Bayer and Johnson & Johnson revealed that the INRatio blood monitoring devices used were not functioning properly, A subsequent analysis by the Duke team published in February 2016 found that this had no significant effect on efficacy and safety in the trial.
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