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Rivaroxaban: Drug information

Rivaroxaban: Drug information
(For additional information see "Rivaroxaban: Patient drug information" and see "Rivaroxaban: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Premature discontinuation increases the risk of thrombotic events:

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.

Spinal/Epidural hematomas:

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.

Brand Names: US
  • Xarelto;
  • Xarelto Starter Pack
Brand Names: Canada
  • Xarelto;
  • Xarelto Starter Pack [DSC]
Pharmacologic Category
  • Anticoagulant;
  • Anticoagulant, Factor Xa Inhibitor;
  • Direct Oral Anticoagulant (DOAC)
Dosing: Adult

The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP.

Atrial fibrillation, nonvalvular

Atrial fibrillation, nonvalvular (to prevent stroke and systemic embolism):

Oral: 20 mg once daily with the evening meal.

Postpercutaneous coronary intervention with stent placement and nonvalvular atrial fibrillation (off-label):

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 (ACC [Kumbhani 2021]; Gibson 2016; Khan 2020).

Coronary artery disease

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 (Lip 2020).

Oral: 2.5 mg twice daily; administer in combination with low dose aspirin plus clopidogrel; continue rivaroxaban for ~1 year (Lip 2020; Mega 2012).

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 is not required for another indication (Eikelboom 2017).

Oral: 2.5 mg twice daily; administer in combination with daily low dose aspirin.

Heparin-induced thrombocytopenia

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 (Kunk 2017; Shatzel 2016; Warkentin 2017).

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 (Crowther 2021).

Duration: Not well established:

HIT without thrombosis: Typically, 4 weeks to 3 months (ACCP [Linkins 2012]). Some experts allow for discontinuation of anticoagulation after platelet count recovery, potentially resulting in a shorter duration (ASH [Cuker 2018]).

HIT with thrombosis: Typically, 3 to 6 months (ACCP [Linkins 2012]; ASH [Cuker 2018]).

Peripheral artery disease, stable

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 (Bonaca 2020; Eikelboom 2017; Hess 2020).

Oral: 2.5 mg twice daily; administer in combination with daily low dose aspirin.

Superficial vein thrombosis, acute symptomatic

Superficial vein thrombosis, acute symptomatic (alternative agent) (off-label use):

Note: Consider as an alternative to fondaparinux for use in patients at increased risk for thromboembolism or with recurrent superficial vein thrombosis (ACCP [Stevens 2021]):

Oral: 10 mg once daily for 45 days (Beyer-Westendorf 2017).

Venous thromboembolism

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 (ACCP [Stevens 2021]; ASCO [Key 2020]; Leader 2020; Young 2018).

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) (ACCP [Stevens 2021]).

Unprovoked venous thromboembolism or provoked venous thromboembolism with a persistent risk factor: ≥3 months depending on risk of venous thromboembolism (VTE) recurrence and bleeding (ACCP [Stevens 2021]; ISTH [Baglin 2012]).

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 (Crowther 2017; Lip 2021a):

Oral: 10 mg once daily (Weitz 2017).

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) (Cohen 2013; Spyropoulos 2018; manufacturer's labeling). Some experts prefer LMWH as prophylaxis during acute hospitalization and suggest not routinely extending prophylaxis beyond discharge (Pai 2019). 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 (Cuker 2020).

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) (Pai 2020; Samama 2020).

Oral: 10 mg once daily initiated ≥6 to 10 hours after surgery; continue for the duration of immobilization (Pai 2020; Samama 2020).

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 (ACCP [Falck-Ytter 2012]; Eikelboom 2001); 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) (Pai 2020).

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 (Anderson 2018; Pai 2020).

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: Start rivaroxaban within 2 hours prior to the next scheduled dose of the parenteral agent.

Transitioning from argatroban, bivalirudin, or unfractionated heparin (UFH) continuous infusion to rivaroxaban: Start rivaroxaban when the parenteral anticoagulant infusion is stopped (consult local protocol if aPTT is above the target range) (Bethea 2017; Davis 2017; Tran 2018).

Transitioning from warfarin to rivaroxaban: Discontinue warfarin and initiate rivaroxaban as soon as INR falls to <3 (US labeling) or ≤2.5 (Canadian labeling).

Transitioning from rivaroxaban to another anticoagulant:

Transitioning from rivaroxaban to UFH continuous infusion, LMWH, or fondaparinux: Start the parenteral anticoagulant when the next dose of rivaroxaban was scheduled to be given.

Transitioning from rivaroxaban to warfarin: Rivaroxaban can elevate the INR, complicating interpretation if overlapped with warfarin (Moore 2015). To minimize interference, check INR near the end of rivaroxaban dosing interval. Some experts suggest overlapping rivaroxaban with warfarin for ≥2 days until INR is therapeutic. An alternative is to stop rivaroxaban, start warfarin the same day, and bridge with a parenteral anticoagulant until the desired INR is reached (Leung 2019).

Transitioning between direct oral anticoagulants: Start new direct oral anticoagulants (DOACs) when the next dose of previous DOAC was scheduled to be given (Leung 2019).

Transitioning between anticoagulants in the perioperative setting: See 2017 AHA Scientific Statement, “Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting” and/or 2017 ACC Expert Consensus Decision Pathway, “Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation.”

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason 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) (Janssen Pharmaceuticals Inc, written communication, May 2012). Monitor for worsening renal function. Discontinue in patients who develop acute renal failure.

Atrial fibrillation, nonvalvular (to prevent stroke and systemic embolism):

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 15 to 50 mL/minute: 15 mg once daily with food (AHA/ACC/HRS [January 2014]; AHA/ACC/HRS [January 2019]). Patients with CrCl <30 mL/minute were excluded from clinical trials (Patel 2011).

CrCl <15 mL/minute: Avoid use; apixaban or warfarin is preferred (AHA/ACC/HRS [January 2014]; AHA/ACC/HRS January 2019]). Patients with CrCl <15 mL/minute were excluded from clinical trials (Patel 2011); currently no other clinical data are available to support use in this population (Ha 2019). 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 (Kubitza 2010).

Hemodialysis, intermittent (thrice weekly): Not dialyzable (De Vriese 2015; Dias 2016): Avoid use (Dager 2018). Limited and conflicting data are available (Chan 2015; Coleman 2019).

Peritoneal dialysis: Avoid use (expert opinion).

Postpercutaneous coronary intervention with stent placement and nonvalvular atrial fibrillation (off label):

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 (Gibson 2016). 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 nonvalvular atrial fibrillation.

CrCl <30 mL/minute: Avoid use. These patients were excluded from the clinical trial for this indication (Gibson 2016).

Hemodialysis, intermittent (thrice weekly): Not dialyzable (De Vriese 2015; Dias 2016): Avoid use (Dager 2018).

Peritoneal dialysis: Avoid use (expert opinion).

Coronary artery disease:

Acute coronary syndrome (after stabilization with initial management) (off label):

CrCl ≥ 30 mL/minute: No dosage adjustment necessary (Mega 2012).

CrCl <30 mL/minute: Avoid use; these patients were excluded from the clinical trial for this indication (Mega 2012).

Hemodialysis, intermittent (thrice weekly): Not dialyzable (De Vriese 2015; Dias 2016): Avoid use (Dager 2018).

Peritoneal dialysis: Avoid use (expert opinion).

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 (Eikelboom 2017); currently, no other clinical data are available to support use in this population (Ha 2019). 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 (De Vriese 2015; Dias 2016): Avoid use (Dager 2018).

Peritoneal dialysis: Avoid use (expert opinion).

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 (Bonaca 2020; Eikelboom 2017); currently, no other clinical data are available to support use in this population (Ha 2019). 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 (De Vriese 2015; Dias 2016): Avoid use (Dager 2018).

Peritoneal dialysis: Avoid use (expert opinion).

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 (Beyer-Westendorf 2017); no other clinical data are available to support use in this population (Ha 2019).

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 (Dager 2018). Patients with CrCl <30 mL/minute were excluded from clinical trials (EINSTEIN Investigators 2010; EINSTEIN-PE Investigators 2012); no other clinical data are available to support use in this population (Ha 2019). Manufacturer labeling recommends no dose adjustment in patients with CrCl ≥15 mL/minute but mentions that for CrCl <30 mL/minute, exposure and pharmacodynamic effects are increased compared to patients with normal kidney function. The manufacturer also acknowledges that there are limited clinical data in patients with CrCl 15 to <30 mL/minute.

CrCl <15 mL/minute: Avoid use.

Hemodialysis, intermittent (thrice weekly): Not dialyzable (De Vriese 2015; Dias 2016): Avoid use (Dager 2018).

Peritoneal dialysis: Avoid use (expert opinion).

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 (Dager 2018). Patients with CrCl <30 mL/minute were excluded from clinical trials (Eriksson 2008; Kakkar 2008; Lassen 2008; Samama 2020; Spyropoulos 2018; Turpie 2009; Weitz 2017); no other clinical data are available to support use in this population (Ha 2019). Manufacturer labeling recommends no dose adjustment in patients with CrCl ≥15 mL/minute but mentions that for CrCl <30 mL/minute, exposure and pharmacodynamic effects are increased compared to patients with normal kidney function. The manufacturer also acknowledges that there are limited clinical data in patients with CrCl 15 to <30 mL/minute.

CrCl <15 mL/minute: Avoid use.

Hemodialysis, intermittent (thrice weekly): Not dialyzable (De Vriese 2015; Dias 2016): Avoid use (Dager 2018).

Peritoneal dialysis: Avoid use (expert opinion).

Dosing: Hepatic Impairment: Adult

US labeling:

Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer’s labeling. Limited data indicate pharmacokinetics and pharmacodynamic response were similar to healthy subjects.

Moderate to severe impairment (Child-Pugh class B or C) and any hepatic disease associated with coagulopathy: Avoid use.

Canadian labeling:

Mild hepatic impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer's labeling. Limited data indicate pharmacokinetics and pharmacodynamic response were similar to healthy subjects.

Moderate impairment (Child-Pugh class B): There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Limited data indicate a significant increase in pharmacodynamic response and pharmacokinetics (eg, increased AUC [~2.3-fold for total and ~2.6-fold for unbound] and Cmax [27% for total and 38% for unbound]).

Severe hepatic impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Hepatic impairment (including Child-Pugh class B and C) associated with coagulopathy, and having clinically relevant bleeding risk: Use is contraindicated.

Dosing: Pediatric

(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 (Male 2020; manufacturer's labeling):

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.

Dosing: Kidney Impairment: Pediatric

Infants ≥2.6 kg: Avoid use when serum creatinine is above the 97.5th percentile (no clinical data available):

Reference Values of Serum Creatinine

Age

97.5th Percentile of Creatinine (mg/dL)

97.5th Percentile of Creatinine (µmol/L)

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:

Note: Monitor for worsening renal function. In adults, the manufacturer recommends discontinuing rivaroxaban in patients who develop acute renal failure.

Altered kidney function:

eGFR 50 to 80 mL/minute/1.73 m2: No adjustment needed.

eGFR <50 mL/minute/1.73 m2: Avoid use (limited clinical data available).

Dosing: Hepatic Impairment: Pediatric

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 (Male 2020).

Dosing: Older Adult

Refer to adult dosing.

Dosing: Obesity: Adult

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 (ISTH [Martin 2021]; expert opinion). Refer to adult dosing for indication-specific doses.

Rationale for recommendations:

There are limited data in patients with obesity demonstrating changes in rivaroxaban drug concentrations or anti-factor Xa activity (Arachchillage 2016; ISTH [Martin 2021]; Piran 2018; Sebaaly 2020; Willmann 2018). A pharmacokinetic study in simulated patients with obesity (>150 kg) suggests ~17% decrease in Cmax and ~16% decrease in AUC; however, the decrease in exposure is unlikely to require a change in dosing (Speed 2020). In patients with nonvalvular atrial fibrillation, a post-hoc analysis of a randomized trial and one retrospective cohort study using electronic health record data suggested that dosage adjustment is not necessary in patients with a BMI 30 to 49 kg/m2; when compared to warfarin, there were similar or lower rates of stroke or systemic embolism and bleeding (Balla 2017; Costa 2020; Wang 2020; Zhou 2020). Similarly, in patients with venous thromboembolism, retrospective data suggest no dosage adjustment is necessary for those weighing between 100 and 300 kg; when compared to warfarin, there were similar thrombotic and bleeding events (Arachchillage 2016; Coons 2020; Kushnir 2019; Spyropoulos 2019).

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 (ISTH [Martin 2021]).

Dosage Forms: US

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)

Generic Equivalent Available: US

No

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

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

Tablet Therapy Pack, Oral:

Xarelto Starter Pack: 15 mg (42s) and 20 mg (9s) ([DSC])

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215859s000lbl.pdf#page=77, must be dispensed with this medication.

Administration: Adult

Oral: Administer doses ≥15 mg with food; doses of 2.5 mg and 10 mg may be administered without regard to meals. For nonvalvular atrial fibrillation, administer with the evening meal.

Suspension: Only use oral dosing syringes provided. May be administered via nasogastric/gastric feeding tube; flush feeding tube with water after administration.

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).

For nasogastric/gastric feeding tube administration, the tablets may be crushed and mixed in 50 mL of water; administer the suspension within 4 hours of preparation and follow administration of the 15 mg and 20 mg tablets immediately with enteral feeding (2.5 mg and 10 mg tablets may be administered without regard to food). Avoid administration distal to the stomach; a decrease in the AUC and Cmax (29% and 56%, respectively) was observed when rivaroxaban was delivered to the proximal small intestine; further decreases may be seen with delivery to the distal small intestine or ascending colon.

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.

Administration: Pediatric

Oral: Administer with feeding or food when used to treat venous thromboembolism (VTE). Administer with or without food when used for thromboprophylaxis after Fontan procedure.

Oral suspension: May be administered by mouth or via nasogastric/gastric feeding tube. For nasogastric/gastric feeding tube administration, flush tube with water after administration. If treating or reducing risk of VTE, follow dose immediately by enteral feeding.

Tablets: Swallow tablets whole; do not split tablets. 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.

For nasogastric/gastric feeding tube administration, the tablets may be crushed and mixed in 50 mL of water; administer the suspension within 4 hours of preparation. Avoid administration distal to the stomach; a decrease in the AUC and Cmax was observed when rivaroxaban was delivered to the proximal small intestine; further decreases may be seen with delivery to the distal small intestine or ascending colon.

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.

Use: Labeled Indications

Atrial fibrillation, nonvalvular: Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation.

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.

Use: Off-Label: Adult

Acute coronary syndrome (after stabilization with initial management); Heparin-induced thrombocytopenia (treatment); Superficial vein thrombosis, acute symptomatic; Venous thromboembolism prophylaxis, nonmajor orthopedic surgery of lower limb

Medication Safety Issues
High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

National Patient Safety Goals:

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, renal 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).

Geriatric Patients: High-Risk Medication:

Beers Criteria: Rivaroxaban is identified in the Beers Criteria as a potentially inappropriate medication to be used with caution for the treatment of VTE or atrial fibrillation in patients ≥75 years due to an increased risk of GI bleeding compared to warfarin and to reported rates of other direct oral anticoagulants when used for long-term treatment of VTE or atrial fibrillation (Beers Criteria [AGS 2019]).

Adverse Reactions (Significant): Considerations
Major hemorrhage

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:

General risk factors for bleeding with anticoagulant use:

• Older patients (Ref)

• Race (Ref)

• History of stroke (Ref)

• 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)

• Hypertension (Ref)

• Diabetes (Ref)

• Malignancy (Ref)

• Excessive fall risk (Ref)

Spinal or epidural hematomas

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)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%: Hematologic & oncologic: Hemorrhage (5% to 28%; major hemorrhage: ≤4%) (table 1)

Rivaroxaban: Adverse Reaction: Major Hemorrhage

Drug (Rivaroxaban)

Comparator

Dose

Indication

Number of Patients (Rivaroxaban)

Number of Patients (Comparator)

Comments

4%

4%

15 mg or 20 mg once daily

Nonvalvular atrial fibrillation

7,111

7,125

Comparator: Warfarin

0.2%

0.1%

10 mg once daily

Prophylaxis of deep vein thrombosis following hip surgery

3,281

3,298

Comparator: Enoxaparin

0.6%

0.5%

10 mg once daily

Prophylaxis of deep vein thrombosis following knee replacement surgery

1,206

1,226

Comparator: Enoxaparin

0.7%

0.5%

10 mg once daily

Prophylaxis of venous thromboembolism in acutely ill medical patients

3,218

3,229

Comparator: Enoxaparin/placebo

0.4%

0.3%

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%

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

1% to 10%:

Cardiovascular: Syncope (1%)

Dermatologic: Pruritus (2%), skin blister (1%), 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 (1%), insomnia (2%)

Neuromuscular & skeletal: Back pain (3%), limb pain (2%), muscle spasm (1%)

<1%:

Hematologic & oncologic: Hemophthalmos, surgical bleeding

Nervous system: Intracranial hemorrhage

Postmarketing:

Cardiovascular: Cardiac tamponade (Oladiran 2018), hemopericardium (Basnet 2017), hypersensitivity angiitis (Lee 2019), thrombosis (with premature discontinuation) (Nagasayi 2017; Shaw 2020)

Dermatologic: 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, pulmonary hemorrhage (Ciofoaia 2018; Hammar 2015), retroperitoneal hemorrhage (Börekci 2019), spinal hematoma (rare: <1%) (Goldfine 2018; Madhisetti 2015), splenic rupture (Nagaraja 2018), thrombocytopenia (Mima 2014), vitreous hemorrhage (spontaneous) (Jun 2015)

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), hypersensitivity reaction (Wu 2021)

Immunologic: Drug reaction with eosinophilia and systemic symptoms (Chiasson 2017)

Nervous system: Cerebral hemorrhage (Hagii 2014; Wilson 2016), epidural intracranial hemorrhage (rare: <1%) (Burjorjee 2018; Jaeger 2012)

Respiratory: Bronchiectasis

Contraindications

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

Warnings/Precautions

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 (non-valvular): 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 nonvalvular 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 in patients with moderate to severe hepatic impairment (Child-Pugh classes B and C) or in patients with any hepatic disease associated with coagulopathy.

• Renal impairment: Dose adjustment is necessary for patients with renal impairment, and specific adjustments are indication specific. Discontinue use in patients who develop acute renal 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 [Otto 2021]; AHA/ACC/HRS [January 2014]; AHA/ACC/HRS (January 2019)]; Dangas 2020; Guimarães 2020).

Special populations:

• Elderly: Use with caution in elderly patients. Elderly patients exhibit higher rivaroxaban concentrations compared to younger patients due primarily to reduced clearance. Overall, efficacy of rivaroxaban in elderly patients (≥65 years of age) was similar to that of patients <65 years of age. Both thrombotic and bleeding events were higher in elderly 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:

• Appropriate use: Surgical patients: When temporary interruption is necessary before surgery, the timing of discontinuation depends on renal 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, discontinue therapy ~48 to 72 hours or longer 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. When there is adequate hemostasis after surgery, may reinstitute therapy after 24 hours if there is low risk for bleeding or after 48 to 72 hours if there is high risk for bleeding. Other specific considerations can be found in expert scientific statements and consensus pathways (ACC [Doherty 2017]; 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 renal 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.

Metabolism/Transport Effects

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

Drug Interactions

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

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

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

Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

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

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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Kanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

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 (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

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

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

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

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: Monitor for signs and symptoms of bleeding if these agents are combined. For the treatment of acute ischemic stroke, avoidance with anticoagulants is often recommended, see full Lexicomp or drug interaction monograph for details. Risk C: Monitor therapy

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. Risk X: Avoid combination

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

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

Reproductive Considerations

Clinically significant uterine bleeding requiring surgical intervention may occur during therapy in patients of reproductive potential.

Information related to the use of direct acting oral anticoagulants in pregnancy is 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).

Pregnancy Considerations

Based on ex vivo data, rivaroxaban crosses the placenta (Bapat 2015).

Information related to the use of rivaroxaban during pregnancy (Beyer-Westendorf 2016; Hoeltzenbein 2015; Königsbrügge 2014; Lameijer 2018; Myers 2016) and postpartum (Rudd 2015) is 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; Regitz-Zagrosek [ESC 2018]). Agents other than rivaroxaban are preferred for the treatment of AF or VTE in pregnant patients (Kearon 2016; Lip 2018; Regitz-Zagrosek [ESC 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).

Breastfeeding Considerations

Rivaroxaban is present in breast milk (Wiesen 2016).

The relative infant dose (RID) of rivaroxaban is 3.6% when calculated using the highest breast milk concentration located and compared to the weight-adjusted maternal dose of 30 mg/day.

In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).

The RID of rivaroxaban was calculated using a milk concentration of 86.4 mcg/L, providing an estimated daily infant dose via breast milk of 12.96 mcg/kg/day. This was the highest milk concentration obtained following maternal administration of oral rivaroxaban 15 mg twice daily for 3 days to one woman on postpartum days 7 to 10 (calculation based on actual maternal weight) (Wiesen 2016).

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; Cohen 2016).

Monitoring Parameters

Renal 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 renal 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 2019).

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).

Reference Range

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 2019).

Mechanism of Action

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.

Pharmacokinetics

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]).

Pharmacokinetics: Additional Considerations

Renal function impairment: Rivaroxaban exposure is increased by 44% in patients with mild impairment (CrCl 50 to 79 mL/minute) and by 52% in patients with moderate impairment (CrCl 30 to 49 mL/minute). In patients with moderate renal impairment, a 1.86-fold increase in the AUC for factor Xa inhibition and a 2.16-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-Pugh class B). Increases in pharmacodynamic effects were also observed. No clinical data are available for patients with severe hepatic impairment.

Pediatric: Bodyweight-adjusted dosing regimen matches exposure range in adults <45 years of age treated with rivaroxaban 20 mg once daily (Male 2020).

Geriatric: 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: Healthy Japanese subjects were found to have 20% to 40% higher exposures compared with other ethnicities, including Chinese subjects.

Pricing: US

Suspension (reconstituted) (Xarelto Oral)

1 mg/mL (per mL): $4.00

Tablet Therapy Pack (Xarelto Starter Pack Oral)

15 & 20 mg (per each): $20.67

Tablets (Xarelto Oral)

2.5 mg (per each): $10.33

10 mg (per each): $20.67

15 mg (per each): $20.67

20 mg (per each): $20.67

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.

Brand Names: International
  • Ixarola (IN);
  • Orgoroxaban (EG);
  • Rivarox (BD);
  • RivaXa (BD);
  • Roxarel (BD);
  • Vaxato (EG);
  • Xarelto (AE, AR, AT, AU, BB, BE, BH, BM, BR, BS, BZ, CH, CL, CN, CO, CR, CU, CY, CZ, DE, DK, DO, EC, EE, EG, ES, ET, FI, FR, GB, GR, GT, GY, HK, HN, HR, ID, IE, IL, IN, IS, IT, JM, JO, JP, KR, KW, LB, LT, LU, LV, MT, MY, NI, NL, NO, NZ, PA, PE, PH, PL, PR, PT, QA, RO, RU, SA, SE, SG, SI, SK, SR, SV, TH, TR, TT, TW, UA, UY, VN, ZA, ZW)


For country abbreviations used in Lexicomp (show table)

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