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Rivaroxaban
Clinical data
Trade namesXarelto, others
Other namesBAY 59-7939
AHFS/Drugs.comMonograph
MedlinePlusa611049
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80–100%; Cmax = 2–4 hours (10 mg oral)[5]
MetabolismCYP3A4, CYP2J2 and CYP-independent mechanisms[5]
Elimination half-life5–9 hours in healthy subjects aged 20 to 45[5][8]
Excretion⁠2/3⁠ metabolized in liver and ⁠1/3⁠ eliminated unchanged[5]
Identifiers
  • (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)
    phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.210.589 Edit this at Wikidata
Chemical and physical data
FormulaC19H18ClN3O5S
Molar mass435.88 g·mol−1
3D model (JSmol)
  • O=C1COCCN1c2ccc(cc2)N3C[C@@H](OC3=O)CNC(=O)c4ccc(s4)Cl
  • InChI=1S/C19H18ClN3O5S/c20-16-6-5-15(29-16)18(25)21-9-14-10-23(19(26)28-14)13-3-1-12(2-4-13)22-7-8-27-11-17(22)24/h1-6,14H,7-11H2,(H,21,25)/t14-/m0/s1 checkY
  • Key:KGFYHTZWPPHNLQ-AWEZNQCLSA-N checkY
 ☒NcheckY (what is this?)  (verify)

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.[9] 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.[9] It is taken by mouth.[9]

Common side effects include bleeding.[9] Other serious side effects may include spinal hematoma and anaphylaxis.[9] It is unclear if use in pregnancy and breastfeeding is safe.[1] Compared to warfarin it has fewer interactions with other medications.[10] It works by blocking the activity of the clotting protein factor Xa.[9]

Rivaroxaban was patented in 2007 and approved for medical use in the United States in 2011.[11] It is available as a generic medication.[12] It is on the World Health Organization's List of Essential Medicines.[13] In 2023, it was the 88th most commonly prescribed medication in the United States, with more than 7 million prescriptions.[14][15]

Medical uses

[edit]

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.[6]

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.[16][17]

In July 2012, the UK's National Institute for Health and Clinical Excellence recommended rivaroxaban to prevent and treat venous thromboembolism.[18]

Contraindications

[edit]

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.[19][20] Once the surgery is over, it can be recommenced after 1 to 3 days with doctor consultation.[19][20]

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.[6][21] 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.[22] Although this increase was not statistically significant, there was a trend showing increased bleeding in the rivaroxaban with moderate CYP3A4 and P-glycoprotein inhibitors group.[22] Therefore, it is important to monitor for bleeding when concurrently on rivaroxaban and moderate CYP3A4 and P-glycoprotein inhibitors.[22]

Adverse effects

[edit]

The most serious adverse effect is bleeding, including severe internal bleeding.[23][24][25]

As of 2015, post-marketing assessments showed liver toxicity, and further studies are needed to quantify this risk.[26][27] 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).[28]

Reversal agent

[edit]

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.[29][30] Andexanet alfa was approved by the U.S. Food and Drug Administration in May 2018, under the trade name AndexXa.[31][32]

Mechanism of action

[edit]

Rivaroxaban inhibits both free and bound Factor Xa in the prothrombinase complex.[33] It is a selective direct factor Xa inhibitor with an onset of action of 2.5 to 4 hours.[34] 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.[5] It allows predictable anticoagulation and dose adjustments and routine coagulation monitoring;[5] dietary restrictions are not needed.[35]

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.[36]

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).[37] The oral bioavailability is dose-dependent.[6] 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.[38] 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%).[38]

Chemistry

[edit]
Chemical structures of linezolid (top) and rivaroxaban (bottom). The shared structure is shown in blue.

Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same N-phenyl-oxazolidinone core structure.[39] 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.[40] Neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria.[40][41] As for mitochondrial toxicity, in vitro studies published before 2008 found the risk to be low.[39]

History

[edit]

Rivaroxaban was initially developed by Bayer.[42] In the United States, it is marketed by Janssen Pharmaceuticals (a part of Johnson & Johnson).[42] It was the first available direct factor Xa inhibitor which is taken by mouth.[43]

Society and culture

[edit]
Rivaroxaban capsules

Economics

[edit]

Using rivaroxaban rather than warfarin costs 70 times more, according to Express Scripts Holding Co, the largest U.S. pharmacy benefits manager.[35] As of 2016, Bayer claimed that the drug was licensed in 130 countries and that more than 23 million patients had been treated.[44]

[edit]

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.[45]

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.[46][7]

In July 2011, the US 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.[47]

In November 2011, the US FDA approved rivaroxaban for stroke prevention in people with non-valvular atrial fibrillation.[48]

[edit]

In March 2019, over 25,000 lawsuits in the US about rivaroxaban were settled for $775 million. Plaintiffs accused the drugmakers of not warning about the bleeding risks, claiming their injuries could have been prevented had doctors and patients been provided adequate information.[49][50]

Research

[edit]

Researchers at the Duke Clinical Research Institute have been accused of withholding clinical data used to evaluate rivaroxaban.[51] Duke tested rivaroxaban in a clinical trial known as the ROCKET AF trial.[52] The clinical trial, published 2011, found rivaroxaban to be more effective than warfarin in reducing the likelihood of ischemic strokes in participants with atrial fibrillation.[53] 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,[51][52] 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.[54]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Rivaroxaban

View on Grokipedia
from Grokipedia

Rivaroxaban is an oral direct factor Xa inhibitor anticoagulant that selectively targets free and clot-bound factor Xa, as well as factor Xa within the prothrombinase complex, thereby interrupting the coagulation cascade without affecting thrombin directly. It is primarily indicated for the prophylaxis of deep vein thrombosis in patients undergoing hip or knee replacement surgery, the treatment of deep vein thrombosis and pulmonary embolism, and the reduction of risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Unlike vitamin K antagonists such as warfarin, rivaroxaban offers fixed dosing without the need for routine coagulation monitoring, though it carries risks of bleeding that require careful patient selection and management. Discovered and initially developed by HealthCare in collaboration with Janssen Research & Development, rivaroxaban received FDA approval in July 2011 for venous prophylaxis following , with subsequent expansions to broader indications based on pivotal trials. The ROCKET AF trial demonstrated its noninferiority to in preventing or systemic among patients with at moderate-to-high risk, while the EINSTEIN program established efficacy for acute treatment and secondary prevention of venous , often with reduced dosing for extended . Despite its clinical advancements in convenience and efficacy, rivaroxaban has been associated with significant risks, including major hemorrhage, as observed in trials and post-marketing , leading to precautions against use in patients with active or high bleed risk, and prompting multidistrict litigation alleging inadequate warnings—though empirical from randomized studies indicate bleeding rates comparable to or variably higher than depending on dose and population.

Clinical Applications

Indications

Rivaroxaban, marketed as Xarelto, is approved by the U.S. (FDA) for the prophylaxis of deep vein (DVT) in adult patients undergoing elective hip or surgery, based on evidence from the RECORD clinical trials demonstrating superior efficacy over enoxaparin in reducing VTE events without increased bleeding risk. It is also indicated for the treatment of DVT and (PE), following demonstration of noninferiority to in the EINSTEIN trials for initial and long-term treatment, with the convenience of fixed dosing without routine coagulation monitoring. For patients completing at least six months of initial anticoagulant therapy, rivaroxaban is approved to reduce the risk of recurrence of DVT and/or PE in adults at continued risk, supported by the EINSTEIN CHOICE trial showing lower recurrence rates compared to aspirin alone. In patients with nonvalvular , rivaroxaban is indicated to reduce the risk of and systemic embolism, as established by the ROCKET AF trial, which showed noninferiority to for the primary efficacy endpoint with lower rates of . Additionally, in combination with aspirin, it is approved to reduce the risk of major cardiovascular events (including cardiovascular death, , and ) in adults with chronic (CAD) or (PAD), per the COMPASS trial results indicating a 24% versus aspirin alone, despite increased bleeding. For medically ill adults hospitalized for an acute illness and at risk for thromboembolic events, rivaroxaban is indicated for VTE prophylaxis during hospitalization and up to 45 days post-discharge, based on the MARINER trial, which demonstrated a modest reduction in symptomatic VTE without a significant increase in major bleeding when added to standard care. Pediatric indications include treatment of VTE and reduction of recurrence risk in patients aged 0 to less than 18 years after at least 5 to 21 days of initial parenteral therapy, approved in December 2021 following the EINSTEIN-Jr trial showing comparable safety and efficacy to adults. It is also the first direct oral anticoagulant approved for primary VTE prophylaxis in pediatric patients post-Fontan procedure, addressing a gap in congenital heart disease management.

Contraindications and Precautions

Rivaroxaban is contraindicated in patients with active pathological bleeding, as its factor Xa inhibitory action substantially increases the risk of serious or fatal hemorrhage. It is also contraindicated in those with known to rivaroxaban or any component of the formulation, including anaphylactic reactions or . Key precautions involve heightened bleeding risk, which necessitates careful patient selection and monitoring, particularly in scenarios elevating exposure or impairing . Concomitant use with other anticoagulants, antiplatelet agents like aspirin or NSAIDs, or drugs affecting (e.g., SSRIs) is generally avoided due to additive effects on bleeding propensity. Spinal or poses a serious risk during or after neuraxial or spinal puncture; dosing should be delayed post-procedure (e.g., 18-24 hours after traumatic puncture) with close neurological monitoring for symptoms like or weakness. Premature discontinuation heightens thrombotic event risk, such as in patients, warranting bridging with alternative anticoagulation if needed. Renal impairment requires dose adjustment or avoidance: use is contraindicated or avoided in creatinine clearance (CrCl) below 15 mL/min, with caution and potential reduction (e.g., to 15 mg daily for if CrCl 15-50 mL/min) in moderate impairment; acute renal failure during mandates discontinuation and reevaluation. Hepatic impairment similarly demands avoidance in moderate (Child-Pugh B) or severe (Child-Pugh C) cases, or any linked to , due to elevated plasma levels and bleeding potential. Drug interactions amplifying exposure, such as combined P-gp and strong inhibitors (e.g., ), should be avoided, particularly in renally impaired patients. In special populations, elderly patients (≥75 years) exhibit higher bleeding and thrombotic rates without routine dose adjustment, necessitating individualized . Low body weight (<50 kg) correlates with increased exposure and bleeding risk. Pregnancy use is cautioned due to potential maternal hemorrhage and fetal harm observed in animal studies (e.g., reproductive toxicity at exposures exceeding human levels); human data are limited, and it is contraindicated by some authorities, with alternatives preferred. For breastfeeding, rivaroxaban appears in low milk levels (exposing infants to <2% of maternal weight-adjusted dose), but discontinuation of nursing or the drug is recommended pending clinical judgment, as no infant adverse effects are documented but monitoring is advised.

Dosage and Administration

Rivaroxaban is administered orally as film-coated tablets in strengths of 2.5 mg, 10 mg, 15 mg, and 20 mg. Doses of 15 mg and 20 mg should be taken with food to enhance bioavailability, while 10 mg and 2.5 mg doses may be taken with or without food. Tablets must not be split to achieve fractional doses; for patients unable to swallow whole tablets, 15 mg or 20 mg tablets may be crushed and mixed with applesauce immediately before administration, followed promptly by food. For reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation, the recommended dose is 20 mg once daily with the evening meal in patients with creatinine clearance (CrCl) greater than 50 mL/min; reduce to 15 mg once daily with the evening meal for CrCl 15-50 mL/min. Use is not recommended for CrCl less than 15 mL/min. For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), initiate with 15 mg twice daily with food for the first 21 days, followed by 20 mg once daily with food for the remaining duration; for extended treatment to reduce recurrence after at least 6 months of standard anticoagulation, use 10 mg once daily with or without food. Avoid in CrCl less than 30 mL/min for acute treatment. For prophylaxis of DVT in patients undergoing knee replacement surgery, administer 10 mg once daily with or without food, starting 6-10 hours after surgery (provided hemostasis has been established), for 12 days; for hip replacement, extend to 35 days. No dose adjustment is required for renal impairment in this indication if CrCl greater than or equal to 30 mL/min. For reduction of major cardiovascular events in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD), use 2.5 mg twice daily with or without food, in combination with aspirin 75-100 mg once daily. This dose may be considered in select patients with CrCl 15-29 mL/min, but avoid if CrCl less than 15 mL/min or in severe hepatic impairment.
IndicationStandard DoseRenal Adjustment (CrCl)
NVAF Stroke Prevention20 mg OD with food15 mg OD if 15-50 mL/min; avoid <15 mL/min
Acute DVT/PE Treatment15 mg BID x 21 days, then 20 mg OD with foodAvoid <30 mL/min for acute phase
VTE Extended Prevention10 mg ODNo specific adjustment; avoid <30 mL/min if prior acute dose not tolerated
Post-Surgical DVT Prophylaxis10 mg ODNo adjustment ≥30 mL/min
CAD/PAD CV Risk Reduction2.5 mg BID + aspirinUse with caution 15-29 mL/min; avoid <15 mL/min
Periprocedural management requires balancing thrombotic and bleeding risks. Generally, discontinue rivaroxaban at least 24 hours before invasive procedures with low bleeding risk or longer for high-risk procedures, resuming once hemostasis is achieved; for elective surgery, consider switching to parenteral anticoagulant if CrCl less than 30 mL/min. However, for dental procedures such as extractions, which are typically classified as minimal or low bleeding risk, current recommendations generally advise against routine discontinuation for most patients. The American Dental Association states that anticoagulation therapy, including DOACs like rivaroxaban, typically does not need to be altered prior to dental interventions, with local hemostatic measures (e.g., pressure, agents, suturing) sufficient to control bleeding. Some guidelines, such as the 2024 ACC summary, recommend omitting a single dose for minimal bleeding risk procedures. Manufacturer labeling suggests stopping at least 24 hours before if discontinuation is deemed necessary. Decisions should be individualized, considering patient factors (e.g., renal function, procedure complexity), and made in consultation with the prescribing physician. If a dose is missed, administer as soon as possible on the same day, without doubling. No routine coagulation monitoring is required, but assess renal function periodically, especially in elderly patients or those with declining function.

Pharmacology

Mechanism of Action

Rivaroxaban selectively inhibits factor Xa (FXa), a key serine protease in the coagulation cascade that catalyzes the conversion of prothrombin to thrombin. This direct inhibition occurs through reversible binding to the S1 and S4 pockets of FXa, demonstrating greater than 10,000-fold selectivity over other serine proteases such as thrombin. Unlike indirect FXa inhibitors like heparin or fondaparinux, rivaroxaban does not require antithrombin III as a cofactor for its activity. By targeting both free FXa and FXa incorporated into the prothrombinase complex, rivaroxaban blocks the amplification step of thrombin generation, thereby attenuating the formation of fibrin clots and indirectly reducing thrombin-induced platelet aggregation without directly affecting platelet aggregation itself. This mechanism interrupts the common pathway of coagulation downstream of the intrinsic and extrinsic pathways, prolonging clotting times such as prothrombin time (PT) in a concentration-dependent manner. Rivaroxaban also inhibits clot-bound FXa, providing anticoagulant effects even in established thrombi.

Pharmacokinetics and Pharmacodynamics

Rivaroxaban is a selective, direct inhibitor of factor Xa (FXa), a serine protease in the coagulation cascade that mediates the conversion of prothrombin to thrombin. Unlike indirect FXa inhibitors such as fondaparinux, rivaroxaban does not require antithrombin III as a cofactor and potently inhibits both free FXa and clot-bound FXa within the prothrombinase complex, thereby attenuating thrombin generation and subsequent fibrin formation and platelet activation. The pharmacodynamic response is concentration-dependent, manifesting as dose-proportional inhibition of FXa activity and prolongation of clotting times, including prothrombin time (PT; most sensitive), activated partial thromboplastin time (aPTT), and HepTest, with effects correlating linearly with plasma levels via an Emax model for FXa inhibition and direct proportionality for PT extension. Routine monitoring of these parameters is not recommended for dose adjustment due to variability and lack of established therapeutic ranges. Absorption. Rivaroxaban demonstrates rapid oral absorption, with time to maximum plasma concentration (Tmax) of 2–4 hours post-dose. Absolute bioavailability is 80–100% for doses of 10 mg or less, unaffected by food, but drops to ~66% for the 20 mg dose under fasting conditions; concomitant intake with a high-fat meal boosts area under the curve (AUC) by 39% and Cmax by 76%, supporting administration with food for higher doses to optimize exposure. Distribution. Steady-state volume of distribution is approximately 50 L (0.62 L/kg), indicating moderate tissue distribution beyond plasma volume. Plasma protein binding is high at 92–95%, predominantly to , with unbound fractions remaining low across therapeutic concentrations; this binding is nonsaturable and unaffected by conditions like renal impairment. Metabolism. Hepatic metabolism accounts for ~66% of the dose via dual mechanisms: P450-mediated oxidation (primarily /5 at 18% and CYP2J2 at 14%) and CYP-independent pathways such as (14%). The resulting metabolites are largely inactive, with no significant circulating active species; overall, ~51% of the dose appears as inactive metabolites (30% urinary, 21% fecal). Elimination. Clearance occurs via parallel renal and nonrenal routes, with ~36% of unchanged rivaroxaban excreted renally (primarily active tubular secretion via , minor glomerular filtration) and the balance as metabolized drug split evenly between renal (~33%) and hepatobiliary/fecal (~33%) elimination. Terminal elimination is 5–9 hours in healthy adults aged 20–45 years, extending to 11–13 hours in those over 60 years due to reduced clearance; systemic clearance averages 10 L/hour. Renal function influences exposure, with creatinine clearance below 50 mL/min increasing AUC by 50–65% and necessitating dose adjustments in moderate-to-severe impairment.

Chemical Structure and Properties


Rivaroxaban is a chiral small-molecule with the molecular formula C₁₉H₁₈ClN₃O₅S and a molecular weight of 435.9 g/mol. Its systematic IUPAC name is 5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl}thiophene-2-carboxamide, reflecting a thiophene-2-carboxamide core linked via an bond to the of a substituted oxazolidin-2-one ring, which bears a 4-(3-oxomorpholin-4-yl)phenyl at the 3-position. The possesses a single chiral center at the 5-position of the oxazolidinone ring, configured as (5S). Physicochemical properties of rivaroxaban include a of 228–229 °C and poor aqueous , limited to 5–7 mg/L in a pH-independent manner across the range of 1–9. It appears as a to off- crystalline and exhibits slight in organic solvents such as acetone, contributing to its as a (BCS) Class II drug with low but high permeability. These properties influence its formulation requirements for oral bioavailability.

Safety and Risks

Adverse Effects

The most frequent adverse reactions associated with rivaroxaban are complications, which occur due to its inhibition of factor Xa and resultant effects. In the ROCKET AF trial involving patients with nonvalvular , major events occurred in 3.6% of rivaroxaban-treated patients compared to 3.5% on ( [HR] 1.04, 95% CI 0.90-1.20). was notably higher with rivaroxaban at 2.0% versus 1.2% with (HR 1.61, 95% CI 1.30-1.99), while was lower at 0.5% versus 0.7% (HR 0.67, 95% CI 0.47-0.93). Fatal rates were reduced with rivaroxaban (0.2% vs. 0.5%; HR 0.50, 95% CI 0.31-0.79). In trials for deep vein thrombosis (DVT) and (PE) treatment, such as EINSTEIN, major bleeding rates were 1.0% with rivaroxaban versus 1.7% with enoxaparin followed by vitamin K antagonists. Post-surgical DVT prophylaxis trials (RECORD program) showed major bleeding in 0.3% of rivaroxaban patients versus 0.2% with enoxaparin. Bleeding risk increases with concomitant use of antiplatelet agents like aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), with dual therapy elevating major bleeding by approximately 1.5- to 2-fold in cardiovascular outcome trials like (1.6% per year vs. 0.9% with rivaroxaban monotherapy; HR 1.8, 95% CI 1.5-2.3). Non-bleeding adverse effects are generally mild and occur at low frequencies (1-3%) in clinical trials. Common reports include (approximately 2%), (2-3%), (1-7%), and (2-3%), with higher incidences of extremity pain and observed in pediatric populations (up to 10%). Dermatologic reactions such as pruritus or affect 1-2% of patients, and central nervous system effects like or syncope are reported in about 1-2%. , often secondary to , is also noted but not independently frequent. Post-marketing surveillance has identified rare hypersensitivity reactions, including .

Bleeding Risks

Rivaroxaban, as a direct factor Xa inhibitor, elevates the risk of , including serious or fatal events, due to its interference with the coagulation cascade. In the ROCKET AF trial, which compared rivaroxaban to in patients with nonvalvular , the annual rate of major or nonmajor clinically relevant was 14.9% with rivaroxaban versus 14.5% with . Major occurred at rates of approximately 3.6% per year in the rivaroxaban arm, with reduced compared to (0.5% vs. 0.7%) but increased (3.2% vs. 2.2%). Real-world studies report major bleeding incidences ranging from 1.0% to 2.86 per 100 person-years among rivaroxaban users with , with higher rates observed in those with renal dysfunction (e.g., up to 4.63% per year in patients over age 75). Clinically relevant nonmajor bleeding occurs at rates around 4.3%, equivalent to 22.7 events per 100 patient-years. Gastrointestinal bleeding constitutes a significant portion, with rivaroxaban linked to higher overall risk compared to some other direct oral anticoagulants like or in population-based analyses. Key risk factors for major bleeding include advanced age, reduced renal function (e.g., clearance below 50 mL/min), concomitant use of antiplatelet agents like aspirin, prior bleeding history, , and . Doses of 15 mg/day or higher have been associated with elevated risks of intracranial hemorrhage, major bleeding, and fatal bleeding in observational data. Modifiable factors such as uncontrolled or concurrent nonsteroidal drugs further amplify these risks, underscoring the need for individualized assessment prior to initiation.

Management and Reversal

Management of in patients receiving rivaroxaban involves immediate discontinuation of the drug, assessment of severity, and supportive measures such as local , fluid resuscitation, and transfusion of or other blood products as indicated by levels and clinical status. For minor , withholding one or more doses and applying mechanical compression often suffices, with resumption guided by resolution and thrombotic risk. In major or life-threatening hemorrhage, such as intracranial or , urgent reversal of anticoagulation is prioritized alongside addressing the source through , , or . Andexanet alfa, a modified recombinant factor Xa decoy protein, serves as the specific reversal agent for rivaroxaban-induced anticoagulation in adults with active major bleeding. Administered as an intravenous bolus (400-800 mg based on rivaroxaban dose and timing) followed by a 2-hour (4-8 mg/min), it rapidly reduces anti-factor Xa activity by 92% within minutes in rivaroxaban-treated patients, with hemostatic achieved in 80% of cases per the ANNEXA-4 prospective study involving 479 patients (median rivaroxaban level 27 ng/mL). FDA approval occurred in 2018 for rivaroxaban reversal in life-threatening bleeding, though real-world data indicate a 10-15% risk within 30 days post-administration, higher than some alternatives, prompting selective use in high-bleed scenarios. In settings where is unavailable or contraindicated, four-factor (4F-PCC, dosed at 25-50 units/kg based on body weight and inhibitor level) is recommended by guidelines including those from the and American Society of for urgent rivaroxaban reversal. Studies in healthy volunteers demonstrate 4F-PCC normalizes and generation within 30 minutes, with partial to complete reversal of rivaroxaban's effects, outperforming three-factor PCC in some comparisons. Clinical outcomes in cohorts show reduced expansion and mortality rates similar to andexanet, though without direct head-to-head trials; non-specific agents like are less effective and not routinely advised. Activated (50 g) may be considered if ingestion occurred within 2-8 hours, but hemodialysis is ineffective due to rivaroxaban's 92-95% . Post-reversal, anticoagulation restart timing depends on bleeding control and indication, typically delayed 24-72 hours for major events, with bridging to shorter-acting agents if high thrombotic risk persists. Ongoing monitoring includes anti-factor Xa levels if available, though routine tests like PT/INR provide limited guidance due to rivaroxaban's variable effects. Emerging agents like ciraparantag show promise in phase 2 trials for universal DOAC reversal but lack approval as of 2023.

Comparative Analysis

Efficacy and Safety Versus Warfarin

In the ROCKET AF trial, a double-blind randomized controlled trial involving 14,264 patients with nonvalvular atrial fibrillation and a history of stroke, transient ischemic attack, or systemic embolism, rivaroxaban at 20 mg daily (15 mg for creatinine clearance 30-49 mL/min) demonstrated noninferiority to dose-adjusted warfarin (target INR 2.0-3.0) for the primary efficacy endpoint of stroke or systemic embolism, with event rates of 1.7% per year versus 2.2% per year (hazard ratio [HR] 0.79; 95% CI 0.66-0.96; P<0.001 for noninferiority). Rivaroxaban also showed superiority for the principal safety endpoint in the per-protocol analysis, particularly with reduced rates of intracranial hemorrhage (0.5% vs. 0.7% per year; HR 0.67; 95% CI 0.47-0.93; P=0.02) and fatal bleeding (0.2% vs. 0.5% per year; HR 0.50; 95% CI 0.31-0.79; P=0.003). However, rates of major or nonmajor clinically relevant bleeding were similar overall (14.9% vs. 14.5% per year; P=0.76), though rivaroxaban was associated with higher gastrointestinal bleeding in some analyses.
OutcomeRivaroxaban (events/year)Warfarin (events/year)Hazard Ratio (95% CI)
Stroke or systemic embolism1.7%2.2%0.79 (0.66-0.96)
Intracranial hemorrhage0.5%0.7%0.67 (0.47-0.93)
Major bleeding3.6%3.4%1.03 (0.96-1.11)
Subgroup analyses from ROCKET AF confirmed consistent efficacy across age groups, with noninferiority in patients over 75 years (HR 0.80; 95% CI 0.63-1.02) and reduced nonmajor clinically relevant bleeding in older patients. Meta-analyses of direct oral anticoagulants, including rivaroxaban, in atrial fibrillation patients indicate a class effect of lower intracranial hemorrhage risk compared to warfarin (relative risk 0.48; 95% CI 0.39-0.59), though rivaroxaban's gastrointestinal bleeding risk may exceed warfarin's in certain real-world cohorts with comorbidities like diabetes or heart failure. For venous thromboembolism (VTE), the EINSTEIN program evaluated rivaroxaban against enoxaparin followed by warfarin. In the EINSTEIN DVT trial (n=3,449), rivaroxaban was noninferior for recurrent VTE (2.1% vs. 1.8%; HR 1.12; 95% CI 0.75-1.68) with similar major bleeding rates (1.0% vs. 1.7%; HR 0.65; 95% CI 0.38-1.11). The EINSTEIN PE trial (n=4,813) similarly showed noninferiority (2.1% vs. 1.8%; HR 1.12; 95% CI 0.90-1.50) and a trend toward lower bleeding (10.3% vs. 11.4% for clinically relevant bleeding; HR 0.90; 95% CI 0.76-1.07). Pooled EINSTEIN data confirmed comparable efficacy and safety, with rivaroxaban offering the advantage of fixed dosing without routine monitoring, though warfarin required initial parenteral bridging and INR adjustments. Real-world evidence supports these findings, with observational studies reporting rivaroxaban's lower hazard for recurrent VTE (HR 0.81; 95% CI 0.74-0.89) and major bleeding (HR 0.79; 95% CI 0.71-0.88) versus in routine VTE treatment. Nonetheless, in high-risk subgroups such as those with , rivaroxaban showed increased thrombotic events compared to (HR 5.27 for recurrent thrombosis), highlighting context-specific limitations. Overall, rivaroxaban provides noninferior efficacy to across indications with a favorable profile for intracranial bleeding reduction, though bleeding risks warrant individualized assessment based on patient factors like renal function and concomitant medications.

Comparisons to Other Direct Oral Anticoagulants

Rivaroxaban, along with and , belongs to the class of direct factor Xa inhibitors, while is a direct thrombin inhibitor; these differences in mechanism influence their pharmacokinetic profiles and clinical use. In network meta-analyses of patients with , all four DOACs demonstrate comparable efficacy in preventing stroke or systemic embolism, with no significant differences in ischemic event rates. For venous thromboembolism (VTE) treatment and secondary prevention, real-world data indicate similar effectiveness among rivaroxaban, , and , though head-to-head trials are limited and often rely on indirect comparisons. Safety profiles diverge notably in bleeding risk. Apixaban is associated with lower rates of major bleeding and gastrointestinal bleeding compared to (hazard ratio for gastrointestinal bleeding, 0.66; 95% CI, 0.59-0.74), a finding corroborated across multiple observational studies and meta-analyses. Edoxaban shows reduced major bleeding versus (risk ratio, 0.76; 95% CI, 0.65-0.89) in network meta-analyses for stroke prevention. Dabigatran at 150 mg twice daily carries a higher major bleeding risk than apixaban but similar to in some comparisons, though it may confer lower myocardial infarction rates than . In elderly patients with atrial fibrillation, ranking by safety favors apixaban, followed by edoxaban, dabigatran, and . Pharmacokinetic distinctions include rivaroxaban's once-daily dosing (typically 20 mg), which produces greater peak-trough variability and more sustained thrombin generation inhibition compared to apixaban's twice-daily regimen (5 mg), potentially contributing to its higher bleeding associations. Rivaroxaban exhibits moderate renal clearance (about 33%), similar to apixaban but higher than edoxaban in some contexts, influencing dose adjustments in renal impairment; dabigatran relies more heavily on renal excretion (80%). These properties underpin guidelines favoring apixaban for patients at elevated bleeding risk, while rivaroxaban's once-daily convenience supports adherence in lower-risk VTE cases.
DOACDosing Frequency (Standard AF Dose)Relative Major Bleeding Risk vs. RivaroxabanKey Efficacy Note
ApixabanTwice daily (5 mg)LowerComparable stroke prevention
DabigatranTwice daily (150 mg)Similar or higher in some cohortsComparable, potentially lower MI
EdoxabanOnce daily (60 mg)LowerComparable VTE treatment
Overall, while efficacy is broadly equivalent, rivaroxaban's safety profile, particularly bleeding, is less favorable than apixaban's in real-world and meta-analytic evidence, informing individualized selection based on patient factors like age, renal function, and comorbidity burden.

Development and Regulatory History

Discovery and Key Clinical Trials

Rivaroxaban, chemically designated as 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide and originally coded as BAY 59-7939, was discovered through a Bayer HealthCare medicinal chemistry program targeting non-peptidic, direct factor Xa inhibitors in the late 1990s. Researchers optimized structure-activity relationships around a morpholinone-oxazolidinone scaffold to achieve high potency (IC50 of 0.4 nM against factor Xa), selectivity over other serine proteases, and favorable pharmacokinetic properties including rapid absorption and a of 5-9 hours in humans. Preclinical studies in and thrombosis models confirmed dose-dependent efficacy with a wider therapeutic window than or antagonists, as measured by prolongation of without excessive bleeding. The compound's development advanced to clinical phases after demonstrating oral exceeding 80% in animal models and minimal cytochrome P450 interactions, addressing limitations of prior parenteral anticoagulants. Phase I trials in healthy volunteers, initiated around 2001, established predictable , dose-proportional exposure, and inhibition of factor Xa activity by over 90% at therapeutic doses, paving the way for efficacy studies. Key clinical trials focused on nonvalvular (AF) and (VTE) prevention. The ROCKET AF trial (NCT00403767), a double-blind, noninferiority study published in 2011, enrolled 14,264 high-risk AF patients (mean CHADS2 score 3.5) randomized to rivaroxaban 20 mg daily (15 mg for clearance 30-49 mL/min) or dose-adjusted (INR 2.0-3.0). Rivaroxaban met the noninferiority criterion for preventing or systemic (1.7% vs. 2.2% per year in ; hazard ratio 0.79, 95% CI 0.66-0.96), with similar rates of major and nonmajor clinically relevant bleeding (14.9% vs. 14.5%; hazard ratio 1.03, 95% CI 0.96-1.11). The RECORD program comprised four phase III trials (RECORD1-4, 2008-2009 publications) evaluating VTE prophylaxis after major . RECORD1 ( arthroplasty, n=4,541) and RECORD3 ( arthroplasty, n=2,539) showed rivaroxaban 10 mg daily superior to enoxaparin 40 mg subcutaneously ( reductions 49% and 44% for composite VTE endpoint, respectively), while RECORD2 (extended prophylaxis post-, n=2,509) demonstrated 79% superiority for extended regimen versus short-term enoxaparin. RECORD4 (, n=2,531) confirmed superiority ( 0.74). Across trials, over 12,700 patients experienced no significant increase in major bleeding (0.3% vs. 0.2% pooled; 1.35, 95% CI 0.62-2.94). These outcomes supported initial European approval in 2008 for postoperative VTE prevention.

Approvals and Milestones

Rivaroxaban received its initial marketing authorization from the (EMA) on September 30, 2008, for the prevention of venous thromboembolism in adult patients undergoing elective hip or surgery. This approval marked an early milestone for the drug as one of the first direct oral anticoagulants (DOACs) to reach the European market, developed jointly by and Janssen Research & Development. In the United States, the Food and Drug Administration (FDA) granted initial approval on July 1, 2011, for the prophylaxis of deep vein thrombosis (DVT) in patients undergoing knee or hip replacement surgery. Subsequent expansions followed: on November 4, 2011, for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; on November 2, 2012, for the treatment of DVT and pulmonary embolism (PE), and to reduce the risk of recurrent DVT and PE; and in 2016, for extended treatment of DVT and PE at a 10 mg daily dose following initial therapy. Further FDA label expansions included October 11, 2018, approval in combination with aspirin to reduce the risk of major cardiovascular events (such as cardiovascular death, , and ) in patients with chronic (CAD) or (PAD); and December 20, 2021, for treatment and prevention of venous thromboembolism (VTE) in pediatric patients aged 2 years and older, available as tablets or oral suspension, including those post-Fontan procedure. The EMA paralleled many of these, with approvals for in 2012 and CAD/PAD indications in 2018.
DateAgencyKey Indication/Expansion
September 30, 2008EMAVTE prophylaxis after / surgery
July 1, 2011FDADVT prophylaxis after /
November 4, 2011FDA/systemic risk reduction in nonvalvular AF
November 2, 2012FDADVT/PE treatment and recurrence risk reduction
2016FDAExtended 10 mg treatment for DVT/PE
October 11, 2018FDA/EMACV event reduction in CAD/PAD with aspirin
December 20, 2021FDAVTE treatment/prevention in ≥2 years

Societal and Economic Aspects

Market and Economics

Rivaroxaban, commercially known as Xarelto and co-developed by Bayer AG and (a of ), achieved peak global branded sales surpassing $7 billion annually in the early , positioning it as one of Bayer's leading pharmaceutical products. In 2023, Xarelto generated approximately $6.79 billion in worldwide revenue, reflecting its dominance in the direct oral anticoagulant (DOAC) segment for preventing and treating thromboembolic disorders. This figure represented a decline from prior years due to emerging generic pressures but still underscored the drug's entrenched market position amid rising prevalence. Patent expirations have accelerated generic entry, particularly in where the core product lapsed on April 1, 2024, and subsequent formulations faced challenges, including a key European in July 2025 set to end exclusivity by January 2026. In the United States, generics for specific indications began entering in 2025, triggering sharp price erosion—up to 90% reductions in competitive markets—which is projected to diminish branded sales by €1-1.5 billion in 2025 alone. anticipates further contraction, with Xarelto's market value estimated at $3.11 billion in 2025, declining to $1.77 billion by 2032 as generics capture share. The broader rivaroxaban market, encompassing off-patent generics, is valued at approximately $16.3 billion in and forecasted to expand to $22.4 billion by 2030 at a CAGR of 5.5%, fueled by demand in and prophylaxis despite branded erosion. Within the global anticoagulants market ($35.96 billion in ) and DOACs subset (over $43 billion in 2023), rivaroxaban commands a significant portion of the factor Xa inhibitor category, which totaled $22.1 billion in 2023, though it trails (Eliquis) in some regions due to latter's later patent cliff. holds the largest regional share (over 40%), but generic influx is eroding originator pricing and volumes there. Economic analyses highlight cost savings from generics, potentially improving access in lower-income settings while challenging innovator profitability. Rivaroxaban is classified as a prescription-only in jurisdictions where it is approved, requiring a physician's due to its properties and potential for serious bleeding risks. It holds no status under frameworks like the U.S. . Regulatory approvals span over 130 countries, with the granting initial authorization in September 2011 for prevention of venous thromboembolism in adults undergoing elective hip or , followed by expansions for other indications. The U.S. approved it in November 2011 for stroke prevention in patients with non-valvular , with additional approvals for thrombosis treatment and prophylaxis. authorized it in January 2012, while China's approved it in May 2015 for stroke prevention. Generic rivaroxaban became available in select markets starting in 2024, enhancing access amid patent expirations; in , the main patent for the 2.5 mg strength lapsed in 2024, enabling launches such as Sandoz's version in August 2025. The FDA approved the first U.S. generic 2.5 mg tablets on March 4, 2025, for reducing cardiovascular event risks in coronary or patients, with further approvals for other strengths like 1 mg/mL oral suspension in June and September 2025. In the , the EMA authorized generic formulations such as Rivaroxaban Koanaa by September 2025, demonstrating to the originator Xarelto. These developments have lowered costs in competitive markets, though affordability remains influenced by national reimbursement policies and coverage variations.

Litigation and Controversies

In the United States, rivaroxaban (marketed as Xarelto by and ) became the subject of extensive products liability litigation, primarily alleging failure to adequately warn about risks of severe, uncontrollable events, including gastrointestinal hemorrhage and intracranial , which plaintiffs claimed led to permanent or . These suits, consolidated into Multidistrict Litigation (MDL) No. 2592 in the U.S. for the Eastern starting in 2014, involved claims that the manufacturers misrepresented the drug's safety profile relative to , particularly emphasizing no need for routine monitoring while downplaying the absence of a reliable reversal agent at launch (later addressed by in 2018). Over 25,000 cases were filed by patients or estates asserting that alternative anticoagulants or dosing regimens could have prevented harm without sacrificing efficacy. The litigation culminated in a $775 million global settlement in March 2019, resolving approximately 25,000 claims without any admission of liability by or Janssen, with funds distributed to eligible s based on injury severity verified through a court-approved matrix. trials preceded the settlement; for instance, three federal trials in 2017 resulted in defense verdicts, where juries found insufficient evidence of inadequate warnings given the drug's FDA-approved labeling, though s argued post-marketing data revealed higher risks in certain populations like the elderly or renally impaired. A separate state court case in in December 2021 awarded $27.8 million to an couple, including , for alleged failure to warn of internal risks leading to a hemorrhage, marking one of the few victories amid predominantly settled or dismissed claims. Critics of the lawsuits, including some medical commentators, noted that anticoagulation carries inherent risks regardless of agent, and rivaroxaban's overall profile in clinical trials like ROCKET-AF demonstrated noninferiority to for prevention in with comparable major rates, suggesting claims often stemmed from expected adverse events rather than defective design or concealment. Nonetheless, the volume of suits prompted enhanced FDA post-market surveillance and labeling updates on management. As of , the MDL has largely concluded, with remaining severed cases addressed individually and no major new waves of litigation reported, though isolated suits continue alleging links to rare events like vitreous hemorrhage. Separate disputes over rivaroxaban formulations, such as MDL No. 3103, focused on generic entry delays rather than and were resolved through licensing agreements without significant controversy.

Ongoing Research and Developments

Ongoing clinical trials continue to investigate rivaroxaban's role in cardiovascular thrombotic prevention beyond established indications. The LA-HCM study (NCT07202897), initiated to assess rivaroxaban for antithrombotic therapy in patients with in at risk for , remains active as of 2025, aiming to extend anticoagulation benefits to non-AF populations. Similarly, the trial extension and related analyses in post-revascularization, published in 2025, affirm rivaroxaban's consistent superiority in reducing composite cardiovascular outcomes when combined with low-dose aspirin, with net clinical benefit across ranked endpoints. In left ventricular thrombus management, recent randomized trials support rivaroxaban as a viable alternative to . The RIVAWAR trial, an investigator-initiated study completed in 2025, found rivaroxaban noninferior to for resolution at three months post-myocardial infarction, with equivalent safety profiles regarding and risks. An ongoing open-label RCT (NCT04970576) further evaluates rivaroxaban's efficacy in post-MI LV dissolution compared to standard care, with primary outcomes focused on resolution rates. Head-to-head comparisons with other direct oral anticoagulants persist in niche indications. A single-blinded RCT recruiting through September 2026 compares to rivaroxaban in cerebral venous thrombosis, assessing recurrence and bleeding outcomes. Additionally, a landmark VA-FDA collaboration, launching recruitment in spring 2025 across 100 sites, will directly compare rivaroxaban against other blood thinners in real-world veteran populations for efficacy and safety in and . Formulation innovations address pharmacokinetic limitations. A 2024 study developed an immediate-release rivaroxaban variant to eliminate the food effect on , ensuring consistent absorption independent of meals and potentially improving adherence in outpatient settings. Pediatric underscores extended-use , with 2025 data confirming rivaroxaban's effectiveness in preventing venous recurrence in children without increased over prolonged therapy. These efforts reflect broader trends in generation, prioritizing comparisons to antagonists and dose optimizations for diverse patient cohorts.

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