Version October 2024
Premature discontinuation of any oral anticoagulant, including rivaroxaban, increases the risk of thrombotic events. If anticoagulation with rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
Epidural or spinal hematomas have occurred in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; or a history of spinal deformity or spinal surgery. The optimal timing between the administration of rivaroxaban and neuraxial procedures is not known.
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients who are anticoagulated or are to be anticoagulated for thromboprophylaxis.
The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP and Kelly Rudd, PharmD, BCPS, CACP, FCCP.
Atrial fibrillation/flutter (atrial flutter is an off-label use):
Note: Used to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation or atrial flutter and no history of moderate to severe mitral stenosis or mechanical valve replacement (Ref).
Oral: 20 mg once daily with the evening meal.
Postpercutaneous coronary intervention with stent placement and atrial fibrillation/flutter:
Oral: 15 mg once daily with food; administer with an appropriate antithrombotic regimen including clopidogrel (preferred P2Y12 inhibitor in this situation) with or without aspirin, depending on risk for thrombosis and bleeding, and time since percutaneous coronary intervention (PCI) (Ref). It is recommended to discontinue aspirin 1 to 4 weeks after PCI and continue rivaroxaban and clopidogrel (Ref).
Coronary artery disease:
Acute coronary syndrome (after stabilization with initial management) (off label):
Note: As add-on to clopidogrel (not prasugrel or ticagrelor) and aspirin therapy in patients who are not at high risk of bleeding and do not require chronic therapeutic anticoagulation for another indication; patient preference should also be taken into consideration given the higher risk of bleeding when adding rivaroxaban to dual antiplatelet therapy (Ref).
Oral: 2.5 mg twice daily; administer in combination with low dose aspirin plus clopidogrel; continue rivaroxaban for ~1 year (Ref).
Coronary artery disease, stable:
Note: May consider for use in patients who are at high risk of cardiovascular events and low risk of bleeding if therapeutic anticoagulation or dual antiplatelet therapy are not required for another indication (Ref).
Oral: 2.5 mg twice daily; administer in combination with daily low dose aspirin.
Heparin-induced thrombocytopenia (off-label use):
Note: For treatment of acute heparin-induced thrombocytopenia (HIT), either as initial therapy in selected hemodynamically stable patients or after initial therapy with a parenteral non-heparin anticoagulant (Ref). Some experts recommend avoiding use of direct oral anticoagulants (DOACs) as initial therapy in the setting of life-threatening or limb-threatening thrombosis or in other clinically unstable patients (Ref).
HIT with or without thrombosis:
Oral: 15 mg twice daily with food for 21 days or until platelet count recovery, whichever is longer, followed by 20 mg once daily with food.
Note: If initially treated with a parenteral non-heparin anticoagulant, can transition to 20 mg once daily after platelet count recovery. However, if the parenteral non-heparin anticoagulant is administered for <21 days, transition to 15 mg twice daily; then, after a total of 21 days with non-heparin anticoagulation, reduce to 20 mg once daily (Ref).
Duration: Not well established:
HIT without thrombosis: Typically, 4 weeks to 3 months (Ref). Alternatively, may discontinue anticoagulation after platelet count recovery, potentially resulting in a shorter duration (Ref).
HIT with thrombosis: Typically, 3 to 6 months (Ref).
Left ventricular thrombus, treatment or prophylaxis (off-label use):
Treatment:
Post myocardial infarction:
Note: When an antiplatelet agent is used in combination with an anticoagulant, selection and duration of antiplatelet therapy for myocardial infarction (MI) may vary; consider risks of bleeding and thrombotic events when choosing antithrombotic therapy combinations (Ref).
Oral: 20 mg once daily for ~3 months in patients with acute MI or ≥3 to 6 months in patients with distant MI (Ref). Duration may vary based on follow-up imaging (eg, assessment of thrombus resolution and left ventricular [LV] function) and shared decision making; indefinite therapy may be considered if LV function does not improve (eg, reduced systolic function, persistent apical akinesis or dyskinesis) or in patients with other ongoing thrombotic risk factors (Ref).
Nonischemic dilated cardiomyopathy: Oral: 20 mg once daily for ≥3 to 6 months; duration may vary based on follow-up imaging (eg, assessment of thrombus resolution and LV function) and shared decision making; indefinite therapy may be considered even after thrombus resolution if LV function does not improve (eg, reduced systolic function, persistent apical akinesis or dyskinesis) or in patients with other ongoing thrombotic risk factors (Ref).
Prophylaxis for high-risk patients post myocardial infarction:
Note: May be used for high-risk patients (eg, ejection fraction <40% and/or anteroapical wall motion abnormality) to prevent LV thrombus. When an antiplatelet agent is used in combination with an anticoagulant, selection and duration of antiplatelet therapy for MI may vary; consider risks of bleeding and thrombotic events when choosing antithrombotic therapy combinations (Ref).
Oral: 20 mg once daily for 1 to 3 months; duration may vary based on follow-up imaging (eg, assessment of LV function) and shared decision making (Ref).
Peripheral artery disease, stable:
Note: May consider for use in patients who are at low risk of bleeding and at high risk of major thrombotic vascular events, including after recent lower extremity revascularization. When starting after lower extremity revascularization, initiate when hemostasis is achieved. Do not use if dual antiplatelet therapy is planned or therapeutic anticoagulation is required for another indication (Ref).
Oral: 2.5 mg twice daily; administer in combination with daily low dose aspirin.
Venous thromboembolism:
Deep vein thrombosis and/or pulmonary embolism treatment:
Note: May be used in patients with active cancer (eg, metastatic disease, receiving chemotherapy); however, avoid use in patients with upper GI tract cancers due to increased bleeding risk (Ref).
Oral: 15 mg twice daily with food for 21 days followed by 20 mg once daily with food.
Duration of therapeutic anticoagulation (first episode, general recommendations): Optimal duration of therapy is unknown and is dependent on many factors, such as whether provoking events were present, patient risk factors for recurrence and bleeding, and individual preferences:
Provoked venous thromboembolism: 3 months (provided the provoking risk factor is no longer present) (Ref).
Unprovoked venous thromboembolism or provoked venous thromboembolism with a persistent risk factor: ≥3 months depending on risk of venous thromboembolism (VTE) recurrence and bleeding (Ref).
Note: All patients receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at periodic intervals.
Indefinite anticoagulation (reduced intensity dosing for prophylaxis against venous thromboembolism recurrence):
Note: For patients at elevated risk of recurrent VTE following ≥6 months of therapeutic anticoagulation. This reduced-intensity regimen is not recommended if indefinite full anticoagulation is indicated (Ref):
Oral: 10 mg once daily (Ref).
Venous thromboembolism prophylaxis:
Acutely ill medical patients:
Oral: 10 mg once daily for a total duration of 31 to 39 days (including hospitalization and postdischarge) (Ref). Some experts prefer LMWH as prophylaxis during acute hospitalization and suggest not routinely extending prophylaxis beyond discharge (Ref). However, in high-risk coronavirus disease 2019 (COVID-19) patients who are discharged from the hospital, some experts would consider extended prophylaxis for a total of 31 to 39 days (Ref).
Nonmajor orthopedic surgery of lower limb (alternative therapy) (off-label use):
Note: Early ambulation alone is preferred when feasible, but pharmacologic prophylaxis may be considered for patients with higher than usual risk (eg, history of venous thromboembolism, limited mobility, or undergoing high risk surgery such as Achilles tendon repair, femoral fracture, tibial plateau fracture, or ligament repair of the knee) (Ref).
Oral: 10 mg once daily initiated ≥6 to 10 hours after surgery; continue for the duration of immobilization (Ref).
Total hip arthroplasty or total knee arthroplasty :
Oral: 10 mg once daily initiated ≥6 to 10 hours after surgery or when hemostasis established.
Duration: Optimal duration of prophylaxis is unknown but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days (Ref); some experts suggest a duration in the lower end of the range (10 to 14 days) for total knee arthroplasty (TKA) or higher end of range (30 days) for total hip arthroplasty (THA) (Ref).
Note: In carefully selected patients at low risk of VTE who are undergoing elective, unilateral THA or TKA, an alternative approach to prophylaxis is to give rivaroxaban 10 mg once daily for 5 days then switch to aspirin for an additional 30 days for THA or 9 days for TKA (Ref).
Transitioning between anticoagulants:
Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail:
Transitioning from another anticoagulant to rivaroxaban:
Transitioning from low-molecular-weight heparin or fondaparinux (therapeutic dose) to rivaroxaban: Discontinue the parenteral anticoagulant and initiate rivaroxaban within 2 hours prior to when the next scheduled dose of the parenteral anticoagulant was scheduled to be administered (Ref).
Transitioning from unfractionated heparin continuous infusion to rivaroxaban: Start rivaroxaban when the unfractionated heparin infusion is stopped (consult local protocol if aPTT is above the target range) (Ref).
Transitioning from warfarin to rivaroxaban: Discontinue warfarin and initiate rivaroxaban when INR is <3 (US labeling) or ≤2.5 (Canadian labeling).
Transitioning from rivaroxaban to another anticoagulant:
Transitioning from rivaroxaban to a parenteral anticoagulant: Start the parenteral anticoagulant when the next dose of rivaroxaban was scheduled to be administered (Ref).
Transitioning from rivaroxaban to warfarin:
Note: Rivaroxaban can elevate the INR, complicating interpretation if overlapped with warfarin. To minimize interference, check INR near the end of rivaroxaban dosing interval (Ref).
Some experts suggest overlapping rivaroxaban with warfarin until INR is within the therapeutic range (Ref). An alternative is to stop rivaroxaban, then start warfarin the same day and bridge with a parenteral anticoagulant until INR is within the therapeutic range (Ref).
Transitioning between direct oral anticoagulants: Start new DOAC when the next dose of previous DOAC was scheduled to be administered (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Clinical trials evaluating safety and efficacy utilized the Cockcroft-Gault formula with the use of actual body weight (weight range of patients enrolled in clinical trials: 33 to 209 kg) (Ref). Monitor for worsening kidney function. Discontinue in patients who develop acute kidney failure.
Atrial fibrillation/flutter (atrial flutter is an off-label use):
CrCl >50 mL/minute: No dosage adjustment necessary.
CrCl 15 to 50 mL/minute: 15 mg once daily with the evening meal (Ref). Patients with CrCl <30 mL/minute were excluded from clinical trials (Ref).
CrCl <15 mL/minute: Avoid use; apixaban or warfarin is preferred. Patients with CrCl <15 mL/minute were excluded from clinical trials (Ref); currently no other clinical data are available to support use in this population (Ref). The US manufacturer's labeling recommends 15 mg once daily in this population based on a single-dose (10 mg) pharmacokinetic study that did not evaluate clinical outcomes (Ref).
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref): Avoid use (Ref). Limited and conflicting data are available (Ref).
Peritoneal dialysis: Avoid use (Ref).
Postpercutaneous coronary intervention with stent placement and atrial fibrillation/flutter:
CrCl >50 mL/minute: No dosage adjustment necessary.
CrCl 30 to 50 mL/minute: 10 mg once daily with food in combination with clopidogrel (preferred P2Y12 inhibitor) is suggested based on trial design of PIONEER AF-PCI (Ref). Note: In the PIONEER AF-PCI study, a relatively small number of patients required this dose reduction. Upon completion of this rivaroxaban and clopidogrel regimen, patient should be transitioned to the recommended rivaroxaban dosing for atrial fibrillation.
CrCl <30 mL/minute: Avoid use. These patients were excluded from the clinical trial for this indication (Ref).
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref): Avoid use (Ref).
Peritoneal dialysis: Avoid use (Ref).
Coronary artery disease:
Acute coronary syndrome (after stabilization with initial management) (off label):
CrCl ≥ 30 mL/minute: No dosage adjustment necessary (Ref).
CrCl <30 mL/minute: Avoid use; these patients were excluded from the clinical trial for this indication (Ref).
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref): Avoid use (Ref).
Peritoneal dialysis: Avoid use (Ref).
Coronary artery disease, stable:
CrCl ≥15 mL/minute: No dosage adjustment necessary; use with caution in severe impairment.
CrCl <15 mL/minute: Avoid use; patients with eGFR <15 mL/minute were excluded from the clinical trial for this indication (Ref); currently, no other clinical data are available to support use in this population (Ref). The manufacturer provides conflicting recommendations in US and Canadian labeling. The US manufacturer's labeling does not recommend a dose adjustment in this population; however, this is based on a single-dose (10 mg) pharmacokinetic study that did not evaluate clinical outcomes. In contrast, the Canadian labeling recommends to avoid use.
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref): Avoid use (Ref).
Peritoneal dialysis: Avoid use (Ref).
Left ventricular thrombus (off-label use):
Specific data in patients with kidney impairment are lacking; as most studies utilized dosing that is consistent with the atrial fibrillation indication, it may be reasonable to apply the same dosage adjustments (Ref).
Peripheral artery disease, stable:
CrCl ≥15 mL/minute: No dosage adjustment necessary; use with caution in severe impairment.
CrCl <15 mL/minute: Avoid use; patients with eGFR <15 mL/minute were excluded from the clinical trial for this indication (Ref); currently, no other clinical data are available to support use in this population (Ref). The manufacturer provides conflicting recommendations in US and Canadian labeling. The US manufacturer's labeling does not recommend a dose adjustment in this population; however, this is based on a single-dose (10 mg) pharmacokinetic study that did not evaluate clinical outcomes. In contrast, the Canadian labeling recommends to avoid use.
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref): Avoid use (Ref).
Peritoneal dialysis: Avoid use (Ref).
Superficial vein thrombosis, acute symptomatic (off-label use):
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: Avoid use; Patients with CrCl <30 mL/minute were excluded from clinical trials (Ref); no other clinical data are available to support use in this population (Ref).
Venous thromboembolism:
Deep vein thrombosis and/or pulmonary embolism treatment OR heparin-induced thrombocytopenia:
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl 15 to <30 mL/minute: Avoid use (Ref). Patients with CrCl <30 mL/minute were excluded from clinical trials (Ref); very limited clinical data are available to support use in this population (Ref). Manufacturer labeling recommends no dosage adjustment in patients with CrCl ≥15 mL/minute but acknowledges the limited clinical data, increased exposure, and increased pharmacodynamic effects compared to patients with normal kidney function.
CrCl <15 mL/minute: Avoid use.
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref): Avoid use (Ref).
Peritoneal dialysis: Avoid use (Ref).
Indefinite anticoagulation (reduced intensity dosing against venous thromboembolism recurrence) OR venous thromboembolism prophylaxis for acutely ill medical patients, nonmajor orthopedic surgery of lower limb, total hip arthroplasty or total knee arthroplasty:
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl 15 to <30 mL/minute: Avoid use (Ref). Patients with CrCl <30 mL/minute were excluded from clinical trials (Ref); very little clinical data are available to support use in this population (Ref). Manufacturer labeling recommends no dosage adjustment in patients with CrCl ≥15 mL/minute but acknowledges the limited clinical data, increased exposure, and increased pharmacodynamic effects compared to patients with normal kidney function.
CrCl <15 mL/minute: Avoid use.
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref): Avoid use (Ref).
Peritoneal dialysis: Avoid use (Ref).
The hepatic dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Matt Harris, PharmD, MHS, BCPS, Jeong Park, PharmD, MS, BCTXP, FCCP, FAST, Arun Jesudian, MD, Sasan Sakiani, MD.
Note: Clinical trials used to support the FDA-approved indications excluded patients with more severe hepatic impairment, and therefore, the manufacturer’s labeling recommends against use in patients with moderate to severe (Child-Turcotte-Pugh class B to C) hepatic impairment or with any hepatic disease associated with coagulopathy. Evidence to support use in liver insufficiency comes from postmarketing, primarily single-center, observational studies. Rivaroxaban is primarily metabolized in the liver (~65%). In a single-dose rivaroxaban pharmacokinetic study, total body clearance and renal clearance are reduced in Child-Turcotte-Pugh class B, leading to an increased AUC with no significant difference in Child-Turcotte-Pugh class A compared to healthy subjects (Ref). Rivaroxaban is also highly albumin bound, and patients with low serum albumin levels have a higher free fraction of drug, which may increase risk of bleeding (Ref). No pharmacokinetic data are available in severe hepatic impairment (Child-Turcotte-Pugh class C).
In patients with a higher bleeding risk, a direct oral anticoagulant, such as apixaban or dabigatran, with an approved antidote and/or more favorable pharmacokinetic profile should be considered (Ref).
Hepatic impairment prior to treatment initiation:
|
Indication |
Child-Turcotte-Pugh class A |
Child-Turcotte-Pugh class B |
Child-Turcotte-Pugh class C |
|---|---|---|---|
|
a In general, use not recommended in patients with platelet count <50,000/mm3, high-risk esophageal varices, or severe kidney impairment (ACG [Simonetto 2020]; Biolato 2022; Vandenberk 2023). | |||
|
b Majority of data is based on studies in patients with portal vein thrombosis. | |||
|
c Vandenberk 2023; Violi 2020. | |||
|
d Vandenberk 2023. | |||
|
e Expert opinion. | |||
|
f Urban 2019; expert opinion. | |||
|
g Bosch 2017; Eikelboom 2017; Mega 2012. | |||
|
h Bonaca 2020; Eikelboom 2017. | |||
|
i Beyer-Westendorf 2017. | |||
|
j Ballestri 2020; Biolato 2022; Potpara 2015. | |||
|
k Biolato 2022. | |||
|
l Ai 2020; Agnelli 2007; Hanafy 2019; Hum 2017; Jarboe 2022; Ilcewicz 2021; Intagliata 2016; Naymagon 2021; expert opinion. | |||
|
m Biolato 2022; Lamarche 2021. | |||
|
n Cohen 2013; Kakkar 2008; Lassen 2008; expert opinion. | |||
|
Atrial fibrillation/flutter | |||
|
Atrial fibrillation/flutter (atrial flutter is an off-label use) |
No dosage adjustment necessary.c |
Use not recommended; use of other direct oral anticoagulant agents with a more favorable pharmacokinetic profile are generally preferred (eg, apixaban, dabigatran).d Additionally, use of rivaroxaban is not recommended if platelet count <50,000/mm3 and/or serum albumin <3 g/dL.e |
Use not recommended.e |
|
Post-percutaneous coronary intervention with stent placement and atrial fibrillation/flutter |
No dosage adjustment necessary.e |
Use not recommended; in general, patients with known hepatic disease considered severe or associated with coagulopathy were excluded from percutaneous coronary intervention clinical trials.f | |
|
Coronary artery disease, stable | |||
|
Coronary artery disease (stable or acute coronary syndrome after stabilization with initial management) |
No dosage adjustment necessary.e |
Use not recommended; patients with known hepatic disease considered severe or associated with coagulopathy were excluded from coronary artery disease clinical trials.g | |
|
Heparin-induced thrombocytopenia | |||
|
Heparin-induced thrombocytopenia with and without thrombosis |
No dosage adjustment necessary.e |
Use not recommended.e | |
|
Peripheral artery disease, stable | |||
|
Peripheral artery disease, stable |
Use not recommended; patients with known hepatic disease associated with coagulopathy were excluded from peripheral artery disease clinical trials.h | ||
|
Superficial vein thrombosis, acute symptomatic | |||
|
Superficial vein thrombosis, acute symptomatic |
Use not recommended; patients with significant liver disease were excluded from superficial vein thrombosis clinical trials.i | ||
|
Venous thromboembolism | |||
|
Deep vein thrombosis and/or pulmonary embolism treatmentb
|
No dosage adjustment necessary.j |
Use of other direct oral anticoagulant agents with a more favorable pharmacokinetic profile in hepatic impairment are generally preferred (eg, apixaban, dabigatran).k If use of rivaroxaban deemed necessary, there are no specific dosage adjustments recommended (dose must be individualized); doses utilized in clinical trials varied considerably; use with extreme caution.l |
Use not recommended.m |
|
Indefinite anticoagulation (reduced intensity dosing for prophylaxis against venous thromboembolism recurrence) |
No dosage adjustment necessary.e |
Use not recommended.e | |
|
Venous thromboembolism prophylaxis, short-term use (eg, acutely ill medical patients, hip/knee arthroplasty) |
Use not recommended; patients with hepatic impairment were excluded from venous thromboembolism prophylaxis clinical trials.n | ||
Dosage adjustment in patients with chronic, worsening hepatic function during treatment (eg, progression from Child-Turcotte-Pugh class A to B):
Progression to Child-Turcotte-Pugh class A: No dosage adjustment necessary (Ref).
Progression to Child-Turcotte-Pugh class B and C: Use not recommended (Ref).
Acute hepatoxicity during treatment:
Acute worsening of hepatic function (eg, requiring hospitalization): Discontinue rivaroxaban in patients with platelet count <50,000/mm3, high-risk esophageal varices, or severe kidney impairment (Ref) or in patients that progress from Child-Turcotte-Pugh class B to C (Ref).
The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.
Class 1, 2, or 3 obesity (BMI ≥ 30 kg/m2): No dosage adjustment necessary (Ref). Refer to adult dosing for indication-specific doses.
Rationale for recommendations:
Pharmacokinetic studies have demonstrated variability in rivaroxaban drug concentrations or anti-factor Xa activity with some studies reporting reduced exposure in obese patients (Ref); however, retrospective studies have not reported adverse clinical outcomes despite possible pharmacokinetic alterations (Ref). Furthermore, systematic reviews and a retrospective study have demonstrated either similar or better outcomes when compared with warfarin (Ref). There are limited data specific to patients with more extreme forms of obesity (eg, BMI ≥50 kg/m2). One retrospective review of patients with atrial fibrillation and BMI ≥50 kg/m2 revealed similar rates of stroke and major bleeding compared to nonobese controls (Ref).
The International Society on Thrombosis and Haemostasis suggests not to regularly monitor peak and trough drug-specific concentrations due to insufficient data to impact clinical decisions (Ref). Others have suggested drug-specific concentrations could be considered in select populations (eg, very high BMI), recognizing the poor correlation to clinical efficacy and safety (Ref).
Refer to adult dosing. Avoid for the long-term treatment of VTE or atrial fibrillation; safer alternatives are preferred. Use may be reasonable in certain situations (eg, when once-daily dosing is necessary for medication adherence) (Ref).
(For additional information see "Rivaroxaban: Pediatric drug information")
Thromboprophylaxis after Fontan procedure:
Children ≥2 years and Adolescents:
Oral suspension:
7 to 7.9 kg: Oral: 1.1 mg/dose every 12 hours.
8 to 9.9 kg: Oral: 1.6 mg/dose every 12 hours.
10 to 11.9 kg: Oral: 1.7 mg/dose every 12 hours.
12 to 19.9 kg: Oral: 2 mg/dose every 12 hours.
20 to 29.9 kg: Oral: 2.5 mg/dose every 12 hours.
30 to 49.9 kg: Oral: 7.5 mg/dose every 24 hours.
≥50 kg: Oral: 10 mg/dose every 24 hours.
Oral tablet: Note: Rivaroxaban 2.5 mg tablets are not recommended for use in pediatric patients; safety, efficacy, and pharmacokinetic/pharmacodynamic data are lacking for this dosage form.
≥50 kg: Oral: 10 mg/dose every 24 hours.
Venous thromboembolism (VTE): Note: Dosing based on the EINSTEIN-Jr phase 3 study (Ref):
Treatment (after stabilization with ≥5 days of initial parenteral treatment):
Note: Begin treatment after at least 10 days of oral feeding. Recommended duration of treatment is 3 months (up to 12 months when clinically appropriate) unless <2 years of age with catheter-related VTE where recommended duration of treatment is 1 month (up to 3 months when clinically appropriate):
Infants, Children, and Adolescents:
Oral suspension:
2.6 to 2.9 kg: Oral: 0.8 mg/dose every 8 hours.
3 to 3.9 kg: Oral: 0.9 mg/dose every 8 hours.
4 to 4.9 kg: Oral: 1.4 mg/dose every 8 hours.
5 to 6.9 kg: Oral: 1.6 mg/dose every 8 hours.
7 to 7.9 kg: Oral: 1.8 mg/dose every 8 hours.
8 to 8.9 kg: Oral: 2.4 mg/dose every 8 hours.
9 to 9.9 kg: Oral: 2.8 mg/dose every 8 hours.
10 to 11.9 kg: Oral: 3 mg/dose every 8 hours.
12 to 29.9 kg: Oral: 5 mg/dose every 12 hours.
30 to 49.9 kg: Oral: 15 mg/dose every 24 hours.
≥50 kg: Oral: 20 mg/dose every 24 hours.
Oral tablet: Note: Rivaroxaban 2.5 mg tablets are not recommended for use in pediatric patients; safety, efficacy, and pharmacokinetic/pharmacodynamic data are lacking for this dosage form.
30 to 49.9 kg: Oral: 15 mg/dose every 24 hours.
≥50 kg: Oral: 20 mg/dose every 24 hours.
Prophylaxis against recurrence (after stabilization with ≥5 days of initial parenteral treatment) :
Note: Begin treatment after at least 10 days of oral feeding:
Infants, Children, and Adolescents:
Oral suspension:
2.6 to 2.9 kg: Oral: 0.8 mg/dose every 8 hours.
3 to 3.9 kg: Oral: 0.9 mg/dose every 8 hours.
4 to 4.9 kg: Oral: 1.4 mg/dose every 8 hours.
5 to 6.9 kg: Oral: 1.6 mg/dose every 8 hours.
7 to 7.9 kg: Oral: 1.8 mg/dose every 8 hours.
8 to 8.9 kg: Oral: 2.4 mg/dose every 8 hours.
9 to 9.9 kg: Oral: 2.8 mg/dose every 8 hours.
10 to 11.9 kg: Oral: 3 mg/dose every 8 hours.
12 to 29.9 kg: Oral: 5 mg/dose every 12 hours.
30 to 49.9 kg: Oral: 15 mg/dose every 24 hours.
≥50 kg: Oral: 20 mg/dose every 24 hours.
Oral tablet: Note: Rivaroxaban 2.5 mg tablets are not recommended for use in pediatric patients; safety, efficacy, and pharmacokinetic/pharmacodynamic data are lacking for this dosage form.
30 to 49.9 kg: Oral: 15 mg/dose every 24 hours.
≥50 kg: Oral: 20 mg/dose every 24 hours.
Transitioning between anticoagulants:
Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail:
Transitioning from another anticoagulant to rivaroxaban:
Transitioning from unfractionated heparin (UFH) by continuous infusion to rivaroxaban: Discontinue infusion and start rivaroxaban at the same time.
Transitioning from warfarin to rivaroxaban: Discontinue warfarin and initiate rivaroxaban as soon as INR falls to <2.5.
Transitioning from anticoagulant other than warfarin to rivaroxaban (eg, low molecular weight heparin [LMWH], non-warfarin oral anticoagulant): Start rivaroxaban within 2 hours prior to the next scheduled dose of the anticoagulant agent. Discontinue the other anticoagulant.
Transitioning from rivaroxaban to another anticoagulant:
Transitioning from rivaroxaban to anticoagulant with rapid onset (oral or parenteral): Start anticoagulant when the next dose of rivaroxaban was scheduled to be given.
Transitioning from rivaroxaban to warfarin: Initiate warfarin and continue rivaroxaban for ≥2 days after first dose warfarin. After 2 days of coadministration, check an INR prior to the next scheduled dose of rivaroxaban. Continue coadministration of warfarin and rivaroxaban until INR ≥2. Note: In adults, rivaroxaban has been shown to elevate the INR and can complicate interpretation when overlapped with warfarin; perform INR monitoring when rivaroxaban is at its trough concentration (Moore 2015). INR monitoring is reliable 24 hours after last dose of rivaroxaban.
Transitioning between anticoagulants in the perioperative setting: Discontinue rivaroxaban ≥24 hours before procedure. Decision to delay surgery or procedure until 24 hours after last dose of rivaroxaban should be based upon increased risk of bleeding and urgency of surgery/procedure. Rivaroxaban should be restarted as soon as adequate hemostasis is established following surgery/procedure. Consider a parenteral anticoagulant if oral administration is not possible.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function:
Infants ≥2.6 kg: Note: Due to limited clinical data, avoid use when serum creatinine is above the 97.5th percentile (manufacturer's labeling).
|
Agea |
97.5th Percentile of Creatinine (mg/dL) |
97.5th Percentile of Creatinine (µmol/L) |
|---|---|---|
|
a Values are derived from term infants (>37 weeks) without kidney impairment. | ||
|
2 weeks |
0.52 mg/dL |
46 µmol/L |
|
3 weeks |
0.46 mg/dL |
41 µmol/L |
|
4 weeks |
0.42 mg/dL |
37 µmol/L |
|
2 months |
0.37 mg/dL |
33 µmol/L |
|
3 to 9 months |
0.34 mg/dL |
30 µmol/L |
|
10 to 12 months |
0.36 mg/dL |
32 µmol/L |
Children and Adolescents (eGFR should be calculated using the Modified Schwartz equation when isotope dilution mass spectrometry (IDMS) calibrated method is used for SCr measurement):
eGFR 50 to 80 mL/minute/1.73 m2: No dosage adjustment necessary (Willmann 2021; manufacturer's labeling).
eGFR <50 mL/minute/1.73 m2: Avoid use (very limited data available in this population) (manufacturer's labeling).
Hemodialysis, intermittent: Not dialyzable (<5%) based on adult studies (Dias 2016).
Infants, Children, and Adolescents: Use not recommended based on adult recommendations; data for use in pediatric patients is lacking (Dager 2018).
There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling (no clinical data). Avoid use in patients with hepatic disease associated with either coagulopathy leading to a clinically relevant bleeding risk or alanine aminotransferase >5 x ULN or total bilirubin >2 x ULN with direct bilirubin >20% of the total; these patients were excluded from the pediatric clinical trial (Ref).
Rivaroxaban may increase the risk of hemorrhage, including severe and potentially fatal major hemorrhage as defined by the International Society on Thrombosis and Hemostasis (Ref).
Onset: Varied; for anticoagulants in general, risk may be highest within 3 months of initiation (Ref).
Risk factors:
Drug-specific:
• Low serum albumin levels (Ref)
General (any anticoagulant):
• History of GI bleeding (Ref)
• History of prior bleeding event (Ref)
• Hemostatic abnormalities (Ref)
• Kidney or hepatic impairment (Ref)
• Coadministration of drugs that affect hemostasis or interact to increase exposure (Ref)
• Alcohol use (Ref)
• Older patients (Ref)
• Nonwhite race (Ref)
• History of stroke (Ref)
• Hypertension (Ref)
• Diabetes (Ref)
• Malignancy (Ref)
• Excessive fall risk (Ref)
Spinal hematoma or epidural intracranial hemorrhage may occur in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture (Ref); may result in long-term or permanent paralysis. Spontaneous spinal or epidural hematomas (SEH) have also been reported (Ref).
Mechanism: SEH due to neuraxial anesthesia or spinal puncture is related to trauma in the presence of impaired hemostasis with rivaroxaban. Spontaneous SEH may be due to sudden increases in thoracic and/or abdominal pressure (Ref).
Onset: SEH in patients treated with rivaroxaban who received neuraxial anesthesia or spinal puncture: Rapid; manifested within 48 hours following the procedure (Ref). Spontaneous SEH: Varied; case reports have occurred from 5 days to 3 years after rivaroxaban initiation (Ref).
Risk factors:
• Use of indwelling epidural catheters
• Concomitant administration of other drugs that affect hemostasis (eg, aspirin, nonsteroidal anti-inflammatory drugs, platelet inhibitors, other anticoagulants)
• History of traumatic or repeated epidural or spinal punctures
• History of spinal deformity or surgery
• If optimal timing between administration of rivaroxaban and neuraxial procedures is unknown
• Older patients (Ref)
• Females (Ref)
• Hemostatic abnormalities (Ref)
• Epidural rather than spinal anesthesia (Ref)
• Challenging neuraxial procedures (Ref)
• Risk factors for spontaneous SEH: Stretch exercises, Valsalva maneuvers, defecation, hypertension, structural extradural anomalies, and rupture of fragile epidural veins by an adjacent herniated disk (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults unless otherwise specified.
>10%:
Endocrine & metabolic: Heavy menstrual bleeding (adolescents: 27%)
Gastrointestinal: Gastroenteritis (pediatric patients: 13%), vomiting (pediatric patients: 11% to 14%)
Hematologic & oncologic: Hemorrhage (pediatric patients and adults: 5% to 36%; major hemorrhage: ≤4%) (table 1)
|
Drug (Rivaroxaban) |
Comparator |
Population |
Dose |
Indication |
Number of Patients (Rivaroxaban) |
Number of Patients (Comparator) |
Comments |
|---|---|---|---|---|---|---|---|
|
2% |
0% |
Pediatric patients |
Body weight-adjusted doses |
Thromboprophylaxis in patients with congenital heart disease after the Fontan procedure |
64 |
34 |
Comparator: Aspirin |
|
0% |
1% |
Pediatric patients |
Body weight-adjusted doses |
Treatment of venous thromboembolism and reduction in risk of recurrent venous thromboembolism |
329 |
162 |
Comparator: Unfractionated heparin, low molecular weight heparin, fondaparinux, or vitamin K antagonist |
|
4% |
4% |
Adults |
15 mg or 20 mg once daily |
Nonvalvular atrial fibrillation |
7,111 |
7,125 |
Comparator: Warfarin |
|
0.2% |
0.1% |
Adults |
10 mg once daily |
Prophylaxis of deep vein thrombosis following hip replacement surgery |
3,281 |
3,298 |
Comparator: Enoxaparin |
|
0.6% |
0.5% |
Adults |
10 mg once daily |
Prophylaxis of deep vein thrombosis following knee replacement surgery |
1,206 |
1,226 |
Comparator: Enoxaparin |
|
0.7% |
0.5% |
Adults |
10 mg once daily |
Prophylaxis of venous thromboembolism in acutely ill medical patients |
3,218 |
3,229 |
Comparator: Enoxaparin/placebo |
|
0.4% |
0.3% |
Adults |
10 mg once daily |
Reduction in the risk of recurrence of deep vein thrombosis and/or pulmonary embolism |
1,127 |
1,131 |
Comparator: Acetylsalicylic acid |
|
1% |
2% |
Adults |
15 mg twice daily for 3 weeks followed by 20 mg once daily |
Treatment of deep vein thrombosis and/or pulmonary embolism |
4,130 |
4,116 |
Comparator: Enoxaparin/vitamin K antagonist |
Respiratory: Cough (pediatric patients: 16%)
1% to 10%:
Cardiovascular: Syncope (1%)
Dermatologic: Pruritus (2%), skin blister (1%), skin rash (pediatric patients: 9%), wound secretion (3%)
Gastrointestinal: Abdominal pain (3%), gastrointestinal hemorrhage (2%)
Hepatic: Increased serum transaminases (>3 x ULN: 2%) (Watkins 2011)
Nervous system: Anxiety (1%), depression (1%), dizziness (2%), fatigue (pediatric patients: 7%; adults: 1%), insomnia (2%)
Neuromuscular & skeletal: Back pain (3%), limb pain (pediatric patients and adults: 2% to 7%), muscle spasm (1%)
<1%:
Hematologic & oncologic: Hemophthalmos, surgical bleeding
Nervous system: Hemorrhagic stroke, intracranial hemorrhage
Postmarketing:
Cardiovascular: Cardiac tamponade (Oladiran 2018), hemopericardium (Basnet 2017), thrombosis (with premature discontinuation) (Nagasayi 2017; Shaw 2020)
Dermatologic: Alopecia (Watras 2016), bullous pemphigoid (Ferreira 2018), Stevens-Johnson syndrome
Endocrine & metabolic: Adrenal hemorrhage (bilateral) (Alidoost 2019)
Gastrointestinal: Cholestasis (Aslan 2016)
Genitourinary: Abnormal uterine bleeding (Jacobson-Kelly 2020)
Hematologic & oncologic: Agranulocytosis, retroperitoneal hemorrhage (Börekci 2019), splenic rupture (Nagaraja 2018), thrombocytopenia (Mima 2014)
Hepatic: Hepatic failure (Baig 2015), hepatic injury (Glenn 2017; Licata 2018), hepatitis (Russmann 2014), jaundice (Glenn 2017)
Hypersensitivity: Anaphylactic shock, anaphylaxis (Khan 2021), angioedema (Patil 2019), drug reaction with eosinophilia and systemic symptoms (Chiasson 2017), hypersensitivity angiitis (Lee 2019), hypersensitivity reaction (Wu 2021)
Nervous system: Cerebral hemorrhage (Hagii 2014; Wilson 2016), epidural intracranial hemorrhage (Burjorjee 2018; Jaeger 2012), hemiparesis, spinal hematoma (Goldfine 2018; Madhisetti 2015)
Ophthalmic: Vitreous hemorrhage (spontaneous) (Jun 2015)
Renal: Renal disease
Respiratory: Bronchiectasis, eosinophilic pneumonitis, pulmonary hemorrhage (Ciofoaia 2018; Hammar 2015)
Severe hypersensitivity to rivaroxaban or any component of the formulation; active pathological bleeding
Canadian labeling: Additional contraindications (not in US labeling): Hepatic disease (including Child-Pugh classes B and C) associated with coagulopathy and clinically relevant bleeding risk; lesions or conditions at increased risk of clinically significant bleeding (eg, hemorrhagic or ischemic cerebral infarction, spontaneous or acquired impairment of hemostasis, active peptic ulcer disease with recent bleeding); concomitant systemic treatment with strong CYP3A4 and P-glycoprotein (P-gp) inhibitors (eg, cobicistat, ketoconazole, itraconazole, posaconazole, ritonavir); concomitant use with any other anticoagulant including unfractionated heparin (except at doses used to maintain central venous or arterial catheter patency), low molecular weight heparins (eg, enoxaparin, dalteparin) or heparin derivatives (eg, fondaparinux); concomitant use with warfarin, dabigatran, edoxaban, or apixaban except when switching therapy to or from rivaroxaban; pregnancy; lactation
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Disease-related concerns:
• Antiphospholipid syndrome: Use not recommended in patients with triple-positive antiphospholipid syndrome; safety and efficacy have not been established. Patients positive for all 3 antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I) may have increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
• Atrial fibrillation: An increased rate of stroke was observed during the transition from rivaroxaban to warfarin in clinical trials in atrial fibrillation (AF) patients. In a post-hoc analysis of the ROCKET AF trial, patients who temporarily (>3 days) or permanently discontinued anticoagulation, the risk of stroke or non-CNS embolism was similar with rivaroxaban as compared to warfarin (Patel 2013). In patients with AF who had an acute ischemic stroke while receiving a direct-acting oral anticoagulant (DOAC) (eg, rivaroxaban), guidelines generally support withholding oral anticoagulation until 4 to 14 days after the onset of neurological symptoms (time frame may vary with shorter times for transient ischemic attack or small, nondisabling stroke and longer times for moderate to severe stroke) (AHA/ASA [Kernan 2014]; AHA/ASA [Powers 2018]).
• GI/Bariatric surgery:
– Altered absorption: Evaluate the risk versus benefit of possible decreased drug absorption. Rivaroxaban is significantly absorbed through the stomach. Procedures that reduce the absorptive surface area of the stomach or accelerate gastric emptying (eg, sleeve gastrectomy) may decrease bioavailability of rivaroxaban. A small study evaluating pre- and post-gastric restriction surgery showed a significant reduction in peak rivaroxaban levels (Rottenstreich 2018). Peak concentrations and AUC were reduced by 56% and 29%, respectively, when released into the proximal small intestine and further reduced in the distal small intestine or colon (manufacturer labeling 2019). The available data are conflicting for absorption alterations, derived from small populations, and underrepresent individual DOACs and distinct surgeries (Kröll 2017; Kröll 2018; Lee 2013; Rottenstreich 2018).
• Hepatic impairment: Avoid use or use with caution in patients with existing hepatic impairment or with any hepatic disease associated with coagulopathy prior to initiation of rivaroxaban therapy. Management of patients established on rivaroxaban who experience acute or chronic worsening of hepatic function may vary depending on degree of dysfunction (eg, class A vs class C) and/or presence of risk factors (eg, low platelet count, esophageal varices).
• Kidney impairment: Dose adjustment is necessary for patients with kidney impairment, and specific adjustments are indication specific. Discontinue use in patients who develop acute kidney failure.
• Valvular disease: Avoid use in patients with surgically implanted mechanical heart valve, transcatheter aortic valve replacement with no other indication for anticoagulation, moderate to severe mitral stenosis, or significant rheumatic heart disease. However, may be used in patients with atrial fibrillation and native aortic valve disease, tricuspid valve disease, mitral regurgitation, or surgical bioprosthetic mitral valve replacement when anticoagulation is required (ACC/AHA [Joglar 2024]; ACC/AHA [Otto 2021]; Dangas 2020; Guimarães 2020).
Special populations:
• Older adult: Use with caution in older adult patients. Older patients exhibit higher rivaroxaban concentrations compared to younger patients due primarily to reduced clearance. Overall, efficacy of rivaroxaban in older patients (≥65 years of age) was similar to that of patients <65 years of age. Both thrombotic and bleeding events were higher in older patients; however, the risk to benefit profile was favorable among all age groups.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Oral suspension contains sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982); some data suggest that benzoate displaces bilirubin from protein-binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
• Lactose intolerance: May contain lactose; use is not recommended in patients with lactose or galactose intolerance (eg, congenital lactase deficiency, glucose-galactose malabsorption).
Other warnings/precautions:
• Elective surgery/procedure: When temporary interruption is necessary before surgery or a procedure, the timing of discontinuation depends on kidney function and risk for bleeding complications. In patients with CrCl ≥30 mL/minute, discontinue therapy ~24 to 48 hours before surgery, depending on risk for bleeding. In patients with CrCl <30 mL/minute, may consider discontinuing therapy ~48 to 72 hours before surgery, depending on risk for bleeding. Consider discontinuing for a longer period of time in patients undergoing major surgery, spinal puncture, or insertion of a spinal or epidural catheter or port. After discontinuation, bridging with low molecular weight heparin or heparin perioperatively is not necessary and may increase risk of bleeding. When there is adequate hemostasis after surgery, may reinstitute therapy after ≥24 hours depending on risk for bleeding. Specific considerations can be found in expert scientific statements and consensus pathways (ACC [Doherty 2017]; ACC/AHA [Joglar 2024]; ACCP [Douketis 2022]; AHA [Raval 2017]).
• Spinal or epidural hematoma: Neuraxial intervention is best performed when the anticoagulant effect of rivaroxaban is low. Guidelines recommend discontinuation of rivaroxaban 72 hours prior to neuraxial intervention; if <72 hours, consider checking anti-factor Xa level (Horlocker 2018). For unanticipated neuraxial intervention, guidelines recommend waiting at least 22 to 26 hours following the last rivaroxaban dose when using prophylactic dosing (eg, 10 mg once daily) before neuraxial puncture and/or catheter manipulation/withdrawal (Horlocker 2018). When higher doses are used (eg, >10 mg once daily) and/or in patients with CrCl <50 mL/minute, waiting 44 to 65 hours following the last rivaroxaban dose is recommended (Horlocker 2018; Rosencher 2013). Avoid rivaroxaban administration for at least 6 hours following neuraxial puncture or neuraxial catheter withdrawal; if traumatic puncture occurs, avoid rivaroxaban administration for at least 24 hours. In addition to these and other clinical variables, consider kidney function and the age of the patient (elderly patients exhibit a prolonged rivaroxaban half-life [11 to 13 hours]) (Kubitza 2010; Rosencher 2013). The Canadian labeling recommends avoiding doses >10 mg in patients with a postoperative indwelling epidural catheter.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension Reconstituted, Oral:
Xarelto: 1 mg/mL (155 mL) [contains sodium benzoate; sweet flavor]
Tablet, Oral:
Xarelto: 2.5 mg, 10 mg, 15 mg, 20 mg
Tablet Therapy Pack, Oral:
Xarelto Starter Pack: 15 mg (42s) and 20 mg (9s) (51 ea)
No
Suspension (reconstituted) (Xarelto Oral)
1 mg/mL (per mL): $4.41
Tablet Therapy Pack (Xarelto Starter Pack Oral)
15 & 20 mg (per each): $22.78
Tablets (Xarelto Oral)
2.5 mg (per each): $11.39
10 mg (per each): $22.78
15 mg (per each): $22.78
20 mg (per each): $22.78
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension Reconstituted, Oral:
Xarelto: 1 mg/mL (100 mL, 250 mL) [contains sodium benzoate]
Tablet, Oral:
Xarelto: 2.5 mg, 10 mg, 15 mg, 20 mg
Generic: 2.5 mg, 10 mg, 15 mg, 20 mg
Oral: Administer doses ≥15 mg with food; doses of 2.5 mg and 10 mg may be administered without regard to meals. For atrial fibrillation, administer with the evening meal.
Suspension: Only use oral dosing syringes provided.
Tablets: For patients who cannot swallow whole tablets, the tablets may be crushed and mixed with applesauce immediately prior to use; immediately follow administration of the 15 mg and 20 mg tablets with food (2.5 mg and 10 mg tablets may be administered without regard to food).
Enteral feeding tube:
The following recommendations are based upon the best available evidence and clinical expertise. Senior editorial team: Joseph I. Boullata, PharmD, RPh, CNS-S, FASPEN, FACN; Peggi A. Guenter PhD, RN, FASPEN; Kathleen Gura, PharmD, BCNSP, FASHP, FASPEN, FPPA, FMSHP; Mark G. Klang MS, RPh, BCNSP, PhD, FASPEN; Linda Lord, NP, ACNP-BC, CNSC, FASPEN.
Note: Avoid post-pyloric (eg, jejunal) administration; absorption is dependent upon site of drug release and is significantly decreased with this route. Consider an alternative anticoagulant if post-pyloric administration is necessary (Ref).
Oral suspension:
Gastric (eg, NG, G-tube) tubes: Shake bottle slowly (to avoid foaming) for 10 seconds prior to drawing up dose. Draw up suspension into enteral dosing syringe and administer via feeding tube (Ref).
General guidance: Hold enteral nutrition during drug administration (Ref). Flush feeding tube with an appropriate volume (eg, 15 mL) of purified water before administration (Ref). Following administration, rinse container used for preparation with purified water; draw up rinse and administer contents to ensure delivery of entire dose (Ref). Flush feeding tube with an appropriate volume (eg, 15 mL) of purified water and restart enteral nutrition (Ref).
Oral tablets:
Gastric (eg, NG, G-tube) tubes (≥12 French): Crush and suspend tablet in 50 mL purified water; draw up mixture into enteral dosing syringe and administer via feeding tube. Administer within 4 hours of mixing (Ref).
General guidance: Hold enteral nutrition during drug administration (Ref). Flush feeding tube with an appropriate volume (eg, 15 mL) of purified water before administration (Ref). Following administration, rinse container used for preparation with purified water; draw up rinse and administer contents to ensure delivery of entire dose (Ref). Flush feeding tube with an appropriate volume (eg, 15 mL) of purified water and restart enteral nutrition (Ref). Note: To ensure adequate bioavailability of crushed 15 and 20 mg tablets, administer just prior to a scheduled intermittent enteral feed, or for continuous enteral feeds restart immediately after final purified water flush; this is not required for other tablet strengths (Ref).
Note: Recommendations may not account for differences in inactive ingredients, osmolality, or other formulation properties among manufacturers.
Missed doses: Patients receiving 15 mg twice daily dosing who miss a dose should take a dose immediately to ensure 30 mg of rivaroxaban is administered per day (two 15 mg tablets may be taken together); resume therapy the following day as previously taken. Patients receiving 2.5 mg twice daily who miss a dose should take a single 2.5 mg dose at the next scheduled time; then resume therapy as usual. Patients receiving once-daily dosing who miss a dose should take a dose as soon as possible on the same day; resume therapy the following day as previously taken.
The following feeding tube recommendations are based upon the best available evidence and clinical expertise. Senior editor panel: Joseph I. Boullata, PharmD, RPh, CNS-S, FASPEN, FACN; Peggi A. Guenter, PhD, RN, FASPEN; Kathleen Gura, PharmD, BCNSP, FASHP, FASPEN, FPPA, FMSHP; Mark G. Klang, MS, RPh, BCNSP, PhD, FASPEN; Linda Lord, NP, ACNP-BC, CNSC, FASPEN.
Note: Recommendations may not account for differences in inactive ingredients, osmolality, or other formulation properties that may vary among products from different manufacturers.
Oral: Administer with feeding or food when used to treat or reduce the risk of venous thromboembolism (VTE). Administer with or without food when used for thromboprophylaxis after Fontan procedure.
Oral suspension: Shake bottle slowly for 10 seconds prior to each dose; do not shake too fast to avoid foaming. An oral dosing syringe is provided with each bottle; do not use a household teaspoon (overdosage may occur).
Administration via feeding tube: Note: Avoid post-pyloric (eg, jejunal) administration; absorption is dependent upon site of drug release and is significantly decreased with this route; consider an alternative anticoagulant if post-pyloric administration is necessary (Ref).
Gastric (eg, NG, G-tube) tubes: Shake bottle slowly (to avoid foaming) for 10 seconds prior to drawing up dose. Draw up suspension into enteral dosing syringe and administer via feeding tube (Ref).
General guidance: Hold enteral nutrition during rivaroxaban administration (Ref). Flush feeding tube with the lowest volume of purified water necessary to clear the tube prior to administration based on size of patient and/or feeding tube (eg, neonates: 1 to 3 mL; infants and children: 2 to 5 mL; adolescents: 15 mL); refer to institutional policies and procedures (Ref). Following administration, flush feeding tube with an appropriate volume of purified water. Note: To ensure adequate bioavailability when used to treat or reduce the risk of venous thromboembolism, administer rivaroxaban just prior to a scheduled intermittent enteral feed, or restart immediately after final flush for continuous enteral feeds; this may not be necessary for thromboprophylaxis after Fontan procedure (Ref).
Tablets: Do not split tablets to provide a lower dose. Note: Rivaroxaban 2.5 mg tablets are not recommended for use in pediatric patients; safety, efficacy, and pharmacokinetic/pharmacodynamic data are lacking for this dosage form. For pediatric patients who cannot swallow the 10 mg, 15 mg, or 20 mg tablet whole, transition to oral suspension. In adults unable to swallow tablets whole, crushing tablets and mixing with applesauce immediately prior to use is recommended; administer within 4 hours of preparation.
Administration via feeding tube: Note: Avoid post-pyloric (eg, jejunal) administration; absorption is dependent upon site of drug release and is significantly decreased with this route; consider an alternative anticoagulant if post-pyloric administration is necessary (Ref).
Gastric (eg, NG, G-tube) tubes (≥12 French) : Crush and suspend tablet in 50 mL purified water; draw up mixture into enteral dosing syringe and administer via feeding tube. Administer within 4 hours of mixing (Ref).
General guidance: Hold enteral nutrition during rivaroxaban administration (Ref). Flush feeding tube with the lowest volume of purified water necessary to clear the tube prior to administration based on size of patient and/or feeding tube (eg, neonates: 1 to 3 mL; infants and children: 2 to 5 mL; adolescents: 15 mL); refer to institutional policies and procedures (Ref). Following administration, rinse container used for preparation with purified water; draw up rinse and administer contents to ensure delivery of entire dose (Ref). Flush feeding tube with an appropriate volume of purified water and restart enteral nutrition (Ref). Note: To ensure adequate bioavailability when used to treat or reduce the risk of venous thromboembolism, administer rivaroxaban just prior to a scheduled intermittent enteral feed, or restart immediately after final flush for continuous enteral feeds; this may not be necessary for thromboprophylaxis after Fontan procedure (Ref).
Missed doses:
Once-daily dosing: Administer missed dose as soon as possible on the same day. If it is not possible to administer on the same day, skip dose and take next scheduled dose.
Twice-daily dosing:
Missed morning dose: Administer missed morning dose as soon as possible; may take missed dose with evening dose.
Missed evening dose: Administer missed evening dose as soon as possible in the same evening. If it is not possible to take in the same evening, skip dose and take next scheduled dose in the morning. Note: A missed evening dose can only be taken in the same evening.
Three-times-a-day dosing: Skip missed dose and take next scheduled dose.
Vomit or spit up: Administer another dose if vomiting or spit up occurs within 30 minutes of receiving dose. If vomiting occurs >30 minutes after dose is administered, do not repeat; administer next scheduled dose.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022406s039,202439s038lbl.pdf#page=77, must be dispensed with this medication.
Atrial fibrillation: Prevention of stroke and systemic embolism in adult patients with atrial fibrillation and no history of moderate to severe mitral stenosis.
Coronary artery disease, stable: Reduction of risk of major cardiovascular events in adult patients with coronary artery disease.
Indefinite anticoagulation (reduced intensity dosing against venous thromboembolism recurrence): Reduction in the risk of recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adult patients at continued risk of DVT and PE following ≥6 months of initial full therapeutic anticoagulant treatment for DVT and/or PE.
Peripheral artery disease, stable: Reduction of risk of major thrombotic vascular events in adult patients with peripheral artery disease, including after recent lower extremity revascularization.
Thromboprophylaxis (pediatric patients with congenital heart disease after the Fontan procedure): Thromboprophylaxis in pediatric patients ≥2 years of age with congenital heart disease who have undergone the Fontan procedure.
Venous thromboembolism (deep vein thrombosis or pulmonary embolism): Treatment of DVT or PE.
Venous thromboembolism and reduction of risk of recurrent venous thromboembolism (pediatric patients): Treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in pediatric patients <18 years of age after ≥5 days of initial parenteral anticoagulant treatment.
Venous thromboembolism prophylaxis in acutely ill medical patients: Prophylaxis of VTE and VTE-related death during hospitalization and posthospital discharge in adults admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding.
Venous thromboembolism prophylaxis in total hip or knee arthroplasty: Postoperative thromboprophylaxis of DVT, which may lead to PE in adult patients undergoing total hip arthroplasty or total knee arthroplasty.
Canadian labeling: Additional formulation-specific indications:
Tablet (15 mg): Treatment of VTE and prevention of VTE recurrence in children and adolescents <18 years of age and weighing 30 to 50 kg after at least 5 days of initial parenteral anticoagulation treatment.
Tablet (20 mg): Treatment of VTE and prevention of VTE recurrence in children and adolescents <18 years of age and weighing >50 kg after at least 5 days of initial parenteral anticoagulation treatment.
Acute coronary syndrome (after stabilization with initial management); Atrial flutter; Heparin-induced thrombocytopenia (treatment); Left ventricular thrombus, treatment or prophylaxis; Superficial vein thrombosis, acute symptomatic; Venous thromboembolism prophylaxis, nonmajor orthopedic surgery of lower limb
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (direct oral anticoagulants) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
The Joint Commission (TJC) requires healthcare organizations that provide anticoagulant therapy to have approved protocols and evidence-based practice guidelines in place to reduce the risk of anticoagulant-associated patient harm. Patients receiving anticoagulants should receive individualized care through a defined process that includes medication selection, dosing (including adjustments for age, kidney function, or liver function), drug-drug interactions, drug-food interactions, other applicable risk factors, monitoring, patient and family education, proper administration, reversal of anticoagulation, management of bleeding events, and perioperative management. This does not apply to routine short-term use of anticoagulants for prevention of venous thromboembolism during procedures or hospitalizations (NPSG.03.05.01).
Beers Criteria: Rivaroxaban is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) for long-term treatment of VTE or atrial fibrillation due to an increased risk of major bleeding and GI bleeding compared to safer alternatives for anticoagulation. Use may be reasonable in certain situations (eg, when once-daily dosing is necessary for medication adherence) (Beers Criteria [AGS 2023]).
Substrate of BCRP/ABCG2, CYP2J2 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Abciximab: May enhance the anticoagulant effect of Direct Oral Anticoagulants (DOACs). Risk X: Avoid combination
Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy
Alemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Alteplase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Amiodarone: May increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Anacaulase: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Anagrelide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Anticoagulants: May enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Antiplatelet Agents (P2Y12 Inhibitors): May enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk D: Consider therapy modification
Apalutamide: May decrease the serum concentration of Rivaroxaban. Risk X: Avoid combination
Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Aspirin: May enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Risk D: Consider therapy modification
Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
BuPROPion: May enhance the anticoagulant effect of Direct Oral Anticoagulants (DOACs). Risk C: Monitor therapy
Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification
Clarithromycin: May increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Rivaroxaban. Management: Consider alternatives to use of rivaroxaban with strong CYP3A4 inducers. Use of a strong CYP3A4 inducer with rivaroxaban should be strictly avoided in any patient who is using an agent (either the CYP3A4 inducer or a third drug) that induces P-gp. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Rivaroxaban. This warning is more specifically for drugs that are inhibitors of both CYP3A4 and P-glycoprotein. For erythromycin, refer to more specific erythromycin-rivaroxaban monograph recommendations. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Rivaroxaban. For clarithromycin, refer to more specific clarithromycin-rivaroxaban monograph recommendations. Risk C: Monitor therapy
Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Defibrotide: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy
Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Risk X: Avoid combination
Enzalutamide: May decrease the serum concentration of Rivaroxaban. Management: Consider alternatives to this combination when possible. Rivaroxaban serum concentrations and efficacy may be reduced. Risk D: Consider therapy modification
Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of Rivaroxaban. Management: Consider alternatives to this combination when possible. Rivaroxaban dose adjustments may be required when used with systemic fusidic acid. Patients using this combination should be monitored extra closely. Risk D: Consider therapy modification
Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapy
Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Inducers of CYP3A4 (Moderate) and P-glycoprotein: May decrease the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Inducers of CYP3A4 (Strong) and P-glycoprotein: May decrease the serum concentration of Rivaroxaban. Risk X: Avoid combination
Inhibitors of CYP3A4 (Moderate) and P-glycoprotein: May increase the serum concentration of Rivaroxaban. Management: No action is needed in patients with normal renal function. Do not use this combination in patients with estimated creatinine clearance 15 to 80 mL/min unless prospective benefits outweigh the risks. Risk D: Consider therapy modification
Inhibitors of CYP3A4 (Strong) and P-glycoprotein: May increase the serum concentration of Rivaroxaban. Risk X: Avoid combination
Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Kanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Lecanemab: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor therapy
Lenacapavir: May increase the serum concentration of Rivaroxaban. Management: No action is needed in patients with normal renal function. Do not use this combination in patients with estimated creatinine clearance 15 to 80 mL/min unless prospective benefits outweigh the risks. Risk D: Consider therapy modification
LevETIRAcetam: May decrease the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy
Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination
Nevirapine: May decrease the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Nonselective): May enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of rivaroxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents (Ophthalmic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy
Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid combination
Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Oritavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy
OXcarbazepine: May decrease the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Pirtobrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy
Protein C Concentrate (Human): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Reteplase: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
St John's Wort: May decrease the serum concentration of Rivaroxaban. Risk X: Avoid combination
Streptokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy
Tenecteplase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Urokinase: May enhance the anticoagulant effect of Anticoagulants. Management: Consider avoiding this combination due to an increased risk of hemorrhage. If anticoagulants are coadministered with urokinase, monitor patients closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Valproate Products: May diminish the therapeutic effect of Rivaroxaban. Risk C: Monitor therapy
Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Volanesorsen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination
Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Pregnancy planning is recommended for patients who could become pregnant and require use of direct acting oral anticoagulants (DOACs). Outcome data related to the use of DOACs in pregnancy are limited; until safety data are available, adequate contraception is recommended during therapy for patients who may become pregnant. Patients planning to become pregnant should be switched to alternative anticoagulants prior to conception (Cohen 2016) or immediately once pregnancy is confirmed (Beyer-Westendorf 2021).
Heavy menstrual bleeding may occur in patients taking DOACs. Evaluate menstrual bleeding patterns prior to therapy in patients with underlying hemorrhagic conditions. Evaluate changes in uterine bleeding. Surgical interventions may be required in patients with abnormal uterine bleeding (Beyer-Westendorf 2021).
Based on ex vivo data, rivaroxaban crosses the placenta (Bapat 2015).
Outcome data related to the use of rivaroxaban during pregnancy (Areia 2022; Beyer-Westendorf 2016; Lameijer 2018; Sessa 2019) and postpartum (Rudd 2015) are limited. Use of direct acting oral anticoagulants increases the risk of bleeding in all patients. When used in pregnancy, there is also the potential for fetal bleeding or subclinical placental bleeding which may increase the risk of miscarriage, preterm delivery, fetal compromise, or stillbirth (Cohen 2016).
Data are insufficient to evaluate the safety of direct acting oral anticoagulants during pregnancy and use in pregnant patients is not recommended (ACOG 2018; ESC [Regitz-Zagrosek 2018]). Patients should be switched to an alternative anticoagulant if pregnancy occurs during therapy. Fetal monitoring that includes evaluations for fetal bleeding and assessments for risk of preterm delivery are recommended if the direct acting oral anticoagulant is continued (Cohen 2016).
Data collection to monitor pregnancy and infant outcomes following exposure to direct acting oral anticoagulants during pregnancy is ongoing. Health care providers may enroll patients in the International Registry of Pregnancy During DOAC Use (https://redcap.isth.org/surveys/?s=P99ARFCM3J) (Othman 2019).
Rivaroxaban is present in breast milk.
Data related to the presence of rivaroxaban in breast milk are available from case reports (Daei 2021).
• Breast milk was sampled following maternal administration of oral rivaroxaban 15 mg twice daily to one woman on postpartum days 7 to 10. Sampling occurred prior to and 3, 6, and 10 hours after the morning dose. Rivaroxaban breast milk concentrations ranged from 11.7 mcg/L to 86.4 mcg/L. The average concentrations of rivaroxaban were 38.4 mcg/L (breast milk) and 94.9 mcg/L (maternal plasma). Authors of the study calculated the relative infant dose (RID) of rivaroxaban to be 1.3% of the weight adjusted maternal dose, providing an estimated infant dose via breast milk of 0.0024 mg/kg over 10 hours (Wiesen 2016).
• Rivaroxaban breast milk concentrations were evaluated in two lactating patients administered a single dose of rivaroxaban 20 mg at 8 months postpartum. Sampling was done prior to and at intervals up to 24 hours after the dose. The average concentrations of rivaroxaban over the 24-hour period were 28.91 mcg/L (breast milk) and 107.06 mcg/L (maternal serum). Authors of the study calculated the relative infant dose (RID) of rivaroxaban to be 1.63% of the weight adjusted maternal dose (based on an average maternal weight of 75 kg), providing an estimated infant dose via breast milk of 0.0043 mg/kg/day (Zhao 2020).
• The presence of rivaroxaban in breast milk was evaluated in two lactating patients following long term dosing. The first patient started treatment at 3 months postpartum and the second patient started rivaroxaban at 4 weeks postpartum. Both patients were treated with rivaroxaban 15 mg twice daily for 21 days, then 20 mg once daily for 6 months. Sampling occurred prior to and at intervals up to 24 hours and were obtained 10 days after initiating the 15 mg dose and 7 days after initiating the 20 mg dose. Both patients pumped breast milk during the study period to maintain milk supply, however neither patient breastfed their infants. Maximum concentrations of rivaroxaban in breast milk were 300 mcg/L (1 hour after the 15 mg dose) and 260 mcg/L (2 hours after the 20 mg dose). For the 15 mg twice daily dose, authors of the study calculated the RID of rivaroxaban to be 5% of the weight adjusted maternal dose, providing an estimated infant dose via breast milk of 0.01 mg/kg every 12 hours. Following the 20 mg once daily dose, the RID of rivaroxaban was calculated to be 4% of the weight adjusted maternal dose, providing an estimated infant dose via breast milk of 0.01 mg/kg/day (Muysson 2020).
• Data are available from a patient treated with rivaroxaban 15 mg once daily, 5 days postpartum. Breast milk was sampled 3 months after dosing, prior to and for up to 20 hours after the dose. The maximum rivaroxaban breast milk concentration was 53.9 mcg/L occurring 6 hours after the dose. The half-life of rivaroxaban in breast milk was 4.7 hours. Authors of the study calculated the RID of rivaroxaban to be 1.79% of the weight adjusted maternal dose, providing an estimated infant dose via breast milk of 0.0034 mg/kg/day. Adverse events were not observed in the partially breastfed infant, evaluated at 1 and 3 months of age (Saito 2019).
• In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Until safety data are available, direct acting oral anticoagulants are not recommended for use in patients who are breastfeeding; use of an alternative anticoagulant is preferred (ACOG 2018; ASH [Bates 2018]; Cohen 2016).
Kidney function and CBC prior to initiation, when clinically indicated, and at least annually in all patients (AHA [Raval 2017]); hepatic function; signs and symptoms of bleeding (eg, weakness, dizziness, unexplained edema; especially in patients with kidney impairment); unexplained decrease in hemoglobin or BP warrants prompt clinical evaluation for bleeding.
Routine coagulation testing is not required or necessary for direct oral anticoagulants (DOACs). There are currently no FDA-approved assays or calibration reagents available.
In clinical situations when assessment of the anticoagulant effect is useful (eg, acute care, periprocedural settings, absorption), evaluating a recent creatinine clearance and time since the last dose was ingested is usually sufficient for guiding clinical decisions. Most commonly used coagulation tests (PT, INR, aPTT) cannot definitively exclude the presence of clinically relevant serum concentrations. A prolonged PT suggests clinically relevant serum concentrations are present, but normal PT and aPTT values using standard reagents cannot rule out the presence of rivaroxaban. Highly sensitive reagents for PT testing may be able to exclude the presence of rivaroxaban.
If available, the preferred test to rule out clinically significant serum concentrations and quantify anticoagulant effect is anti-factor Xa activity calibrated specifically for rivaroxaban (undetectable anti-factor Xa activity likely excludes clinically relevant drug concentrations). An anti-factor Xa assay calibrated for low molecular weight heparin can rule out clinically relevant drug concentrations, but is not useful for quantification (ACC [Tomaselli 2020]; AHA [Raval 2017]; Leung 2023).
In patients receiving rivaroxaban therapy during neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture, monitor frequently for signs and symptoms of neurologic impairment (eg, midline back pain, numbness/weakness of legs, bowel/bladder dysfunction).
Adult: The International Council for Standardization in Haematology provides examples of rivaroxaban drug levels for the 20 mg once-daily dose, with an expected mean peak of ~249 to 270 ng/mL (5th to 95th percentile of 184 to 419 ng/mL) and an expected mean trough of ~26 to 44 ng/mL (5th to 95th percentile, 6 to 137 ng/mL) (Gosselin 2018). These values are intended to be used as guides to provide evidence of drug absorption, not as therapeutic targets (Leung 2023).
Inhibits platelet activation and fibrin clot formation via direct, selective and reversible inhibition of factor Xa (FXa) in both the intrinsic and extrinsic coagulation pathways. FXa, as part of the prothrombinase complex consisting also of factor Va, calcium ions, factor II and phospholipid, catalyzes the conversion of prothrombin to thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin.
Absorption: Rapid; Note: Absorption dependent upon site of drug release; AUC was decreased by 29% and Cmax reduced by 56% when released in proximal small intestine, it is reduced further when released in distal small intestine or ascending colon.
Distribution: Vdss: ~50 L.
Protein binding: ~92% to 95% (primarily to albumin).
Metabolism: Hepatic via CYP3A4/5 and CYP2J2.
Bioavailability: Absolute bioavailability: 2.5 mg and 10 mg dose: ~80% to 100%; 20 mg dose: ~66% (fasting; increased with food).
Half-life elimination:
Pediatric (Young 2020; manufacturer's labeling):
Infants <6 months: 1.6 hours.
Infants ≥6 months and Children <2 years: 1.9 hours.
Children ≥2 years: 3 hours.
Adolescents: 4.2 hours.
Adult: Terminal: 5 to 9 hours; Elderly: 11 to 13 hours.
Time to peak, plasma:
Neonates, Infants, Children, and Adolescents: Median: 1.5 to 2.2 hours.
Adults: 2 to 4 hours.
Excretion: Urine (66% primarily via active tubular secretion [~36% as unchanged drug; 30% as inactive metabolites]); feces (28% [7% as unchanged drug; 21% as inactive metabolites]).
Altered kidney function: Rivaroxaban exposure is increased by a mean 44% in patients with mild impairment (CrCl 50 to 79 mL/minute), 52% in patients with moderate impairment (CrCl 30 to 49 mL/minute), and 64% in patients with severe impairment (CrCl <30 mL/minute). In patients with moderate kidney impairment, a 1.86-fold increase in the AUC for factor Xa inhibition and a 2.16-fold increase in PT prolongation was observed compared to patients with normal kidney function. In patients with severe kidney impairment, a 2-fold increase in the AUC for factor Xa inhibition and a 2.44-fold increase in PT prolongation was observed (Kubitza 2010).
Hepatic function impairment: Significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Turcotte-Pugh class B). Increases in pharmacodynamic effects were also observed. In a single-dose rivaroxaban pharmacokinetic study, total body clearance and renal clearance are reduced in Child-Turcotte-Pugh class B, leading to an increased AUC with no significant difference in Child-Turcotte-Pugh class A compared to healthy subjects (Kubitza 2013). No clinical data are available for patients with severe hepatic impairment (Child-Turcotte-Pugh class C).
Pediatric: Bodyweight-adjusted dosing regimen matches exposure range in adults <45 years of age treated with rivaroxaban 20 mg once daily (Male 2020).
Older adult: Elderly patients exhibit higher plasma concentrations than younger patients, with mean AUC values being ~50% higher, mainly because of reduced (apparent) total body and renal clearance.
Race/ethnicity: Healthy Japanese subjects were found to have 20% to 40% higher exposures compared with other ethnicities, including Chinese subjects.
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