Questions about Atrial Fibrillation? Get answers from our expert.

Generic Name: Rivaroxaban
Class: Direct Factor Xa Inhibitors
Chemical Name: 5 - Chloro - N - [[(5S) - 2 - oxo - 3 - [4 - (3 - oxo - 4 - morpholinyl)phenyl] - 5 - oxazolidinyl]methyl] - 2 - thiophenecarboxamide
Molecular Formula: C19H18ClN3O5S
CAS Number: 366789-02-8

Warning(s)

  • Risks of Thrombosis Following Discontinuance of Therapy
  • Increased risk of thrombotic events following rivaroxaban discontinuance.1 990 If discontinuance required for reasons other than pathologic bleeding (e.g., prior to surgery), consider use of an alternative anticoagulant.1 (See Risks of Discontinuing Rivaroxaban in Atrial Fibrillation Patients under Cautions.)

  • Spinal/Epidural Hematoma Risk
  • Risk of epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, in patients who are anticoagulated and also receiving neuraxial (spinal/epidural) anesthesia or spinal puncture.1

  • Risk increased by use of indwelling epidural catheters or by concomitant use of drugs affecting hemostasis (e.g., NSAIAs, platelet inhibitors, other anticoagulants).1

  • Risk also increased by history of traumatic or repeated epidural or spinal puncture or history of spinal deformity or spinal surgery.1

  • Monitor frequently for signs and symptoms of neurologic impairment and treat urgently if neurologic compromise noted.1

  • Consider potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for thromboprophylaxis with anticoagulants.1 (See Spinal/Epidural Hematoma under Cautions and also see Interactions.)

REMS:

FDA approved a REMS for rivaroxaban to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of rivaroxaban and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anticoagulant; an oral, direct, activated factor X (Xa) inhibitor.1 2 3 4 5 7 8 9 12 16 17 18 20 32 33

Uses for Xarelto

Embolism Associated with Atrial Fibrillation

Reduction in the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.1 32

Appears to be no less effective than warfarin for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; risk of major bleeding similar with rivaroxaban or warfarin.1 32 However, limited data exist on relative efficacy of rivaroxaban and warfarin when warfarin anticoagulation is well controlled.1 11 32 40

The American College of Chest Physicians (ACCP), ACC, AHA, and other experts recommend antithrombotic therapy (e.g., warfarin, aspirin) in all patients with paroxysmal (intermittent), persistent, or permanent atrial fibrillation, unless such therapy is contraindicated.989 990 999 1007

Choice of antithrombotic therapy is based on patient's risk for stroke; in general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients with moderate to high risk for stroke, while aspirin is recommended in low-risk patients and those with contraindications to oral anticoagulant therapy.988 989 990 999 1007 Patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or TIA, advanced age (e.g., ≥75 years), history of hypertension, diabetes mellitus, or recent exacerbation of congestive heart failure.990 999 1007

Slideshow: Atrial Fibrillation - Stroke Prevention Guidelines & Treatment Options

Rivaroxaban is suggested by some experts as a useful alternative to warfarin in selected patients at moderate to high risk of stroke who are unable to comply with warfarin monitoring requirements or in whom a consistent therapeutic response to warfarin cannot be achieved; warfarin still may be preferred in patients who have well-controlled INRs and are compliant with regular laboratory monitoring.32 37 38 49 69 70 71 73

Relative efficacy and safety of rivaroxaban and other new oral anticoagulants (e.g., apixaban, dabigatran) remain to be fully elucidated.37 38 40 45 49 50 66 67 68 70 989

When selecting an appropriate anticoagulant, consider factors such as patient's risks of stroke and bleeding, compliance, preference, and comorbidities; cost; and availability of agents to reverse anticoagulant effects in case of bleeding complications.37 45 49 50 999 1007

Efficacy of rivaroxaban for prevention of post-cardioversion stroke and systemic embolism in patients with atrial fibrillation not established.1

Thromboprophylaxis in Hip- or Knee-Replacement Surgery

Prevention of postoperative DVT and associated PE in patients undergoing hip- or knee-replacement surgery.1 2 3 4 5 6

More effective than enoxaparin in preventing DVT and associated PE in patients undergoing elective total hip- or knee-replacement surgery; bleeding rates similar with rivaroxaban or enoxaparin.1 2 3 4 5 6 11 12 29 30 37

ACCP and other clinicians consider rivaroxaban an acceptable option for pharmacologic thromboprophylaxis in patients undergoing total hip- or knee-replacement surgery;12 29 37 1003 however, a low molecular weight heparin (LMWH) generally is preferred.1003 Rivaroxaban may be a reasonable choice when an LMWH is not available or cannot be used.1003

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, bleeding risk, logistics, and compliance issues.1003

Treatment and Prevention of Venous Thromboembolism

Initial treatment and secondary prevention of DVT and/or PE.1 59 60 1005

Also used beyond the initial 6 months of treatment to reduce the risk of recurrent venous thromboembolic events.1 59

Appears to be as effective as (noninferior to) standard therapy (sub-Q enoxaparin followed by a vitamin K antagonist [e.g., warfarin]) for initial treatment of DVT and/or PE, and more effective than placebo when used long-term for secondary prevention of recurrent thromboembolism.1 59 60

Recommended by ACCP and other experts as an acceptable option for initial and long-term anticoagulant therapy in patients with acute proximal DVT of the leg and/or PE.63 1005 However, pending additional data and experience with rivaroxaban, warfarin or an LMWH generally suggested over rivaroxaban.1005

Additional studies and experience are needed to evaluate efficacy and safety of rivaroxaban for treatment of cancer-related venous thromboembolism.61 63 1005

Xarelto Dosage and Administration

General

  • Routine monitoring of coagulation tests not required.10 12 14 20 28 46 54 55 56 57

  • May be possible to use PT test to assess rivaroxaban plasma concentration; however, PT test results may vary depending on reagent used and may not reliably predict degree of anticoagulation.11 28 54 55 56 57 58

Administration

Oral Administration

Administer orally.1 Administer 15- or 20-mg tablets with food; 10-mg tablets may be taken with or without food.1

If a dose is missed, take as soon as possible on the same day, then resume regular schedule the following day.1 Patients receiving a dosage of 15 mg twice daily who miss a dose may take two 15-mg tablets at the same time to ensure full intake of the 30-mg daily dosage, then resume the regular twice-daily dosing schedule the following day.1

In patients unable to swallow whole tablets, may crush 15- or 20-mg tablets and mix with applesauce immediately before administration, followed by food.1

NG or Gastric Feeding Tube

Confirm placement of tube, then administer 15- or 20-mg tablets by crushing and suspending drug in 50 mL of water; immediately follow dose with enteral feeding via tube.1 To avoid possibility of reduced absorption, do not administer by a method that could deposit drug distal to the stomach.1

Dosage

Adults

Embolism Associated with Atrial Fibrillation
Oral

Patients with normal renal function (Clcr >50 mL/minute): 20 mg once daily with the evening meal.1

Thromboprophylaxis in Hip- or Knee-Replacement Surgery
Oral

10 mg once daily.1

Administer first dose at least 6–10 hours after surgery, provided hemostasis has been established.1

Duration of therapy: Manufacturer recommends 35 days for patients undergoing hip-replacement surgery, 12 days for patients undergoing knee-replacement surgery.1

ACCP recommends at least 10–14 days, possibly up to 35 days, for patients undergoing major orthopedic surgery (e.g., hip-replacement, knee-replacement surgery).

Treatment and Secondary Prevention of Venous Thromboembolism
Oral

Initial treatment and secondary prevention of DVT and/or PE: 15 mg twice daily for the first 21 days, followed by 20 mg once daily taken at approximately the same time every day.1 62 Initial twice-daily dosing may provide higher trough drug concentrations and improved thrombus regression.60 62 64 65

Continued prophylaxis (after initial 6 months of treatment) to reduce risk of recurrent DVT and/or PE: 20 mg once daily taken at approximately the same time every day.1

Determine optimum duration of anticoagulation based on individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors for thrombosis, presence of cancer, risk of bleeding).1005 In general, ACCP states that anticoagulant therapy should be continued beyond the acute treatment period for at least 3 months, and possibly longer in patients with a high risk of recurrence and low risk of bleeding.1005

Transitioning to and from Rivaroxaban Therapy
Transferring to Rivaroxaban from Warfarin

Discontinue warfarin and initiate rivaroxaban as soon as INR < 3.1

Transferring to Rivaroxaban from Other Anticoagulants

Administer initial dose of rivaroxaban within 2 hours of the next scheduled evening dose of the other anticoagulant (e.g., LMWH, non-warfarin oral anticoagulant) and discontinue other anticoagulant.1

When transferring to rivaroxaban from continuous IV heparin infusion, discontinue heparin infusion and initiate rivaroxaban at same time.1

Transferring from Rivaroxaban to Warfarin

Data from clinical trials not available to guide conversion from rivaroxaban to warfarin.1 A suggested approach is to discontinue rivaroxaban and simultaneously initiate a parenteral anticoagulant and warfarin at the time of the next scheduled dose of rivaroxaban.1 INR measurements may not be useful in determining appropriate dosage of warfarin during conversion.1

Transferring from Rivaroxaban to Other Anticoagulants

When transferring from rivaroxaban to an anticoagulant (oral or parenteral) with a rapid onset of action, discontinue rivaroxaban and administer first dose of the other anticoagulant at the time of the next scheduled dose of rivaroxaban.1

Managing Anticoagulation in Patients Requiring Invasive Procedures

If temporary discontinuance of anticoagulation required prior to surgery or other invasive procedures, discontinue rivaroxaban ≥24 hours prior to procedure.1 In deciding whether a procedure should be delayed, weigh increased risk of bleeding against urgency of intervention.1 Resume therapy after procedure once adequate hemostasis established; if oral anticoagulation not possible, consider use of a parenteral anticoagulant.1 (See Risks of Discontinuing Rivaroxaban in Atrial Fibrillation Patients under Cautions.)

Special Populations

Hepatic Impairment

Avoid use in patients with moderate or severe hepatic impairment or any hepatic disease associated with coagulopathy.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Embolism Associated with Atrial Fibrillation
Oral

Patients with Clcr15–50 mL/minute: Reduce dosage to 15 mg once daily with the evening meal.1 (See Renal Impairment under Cautions.)

Patients with Clcr <15 mL/minute: Avoid use.1

Thromboprophylaxis in Hip- or Knee-Replacement Surgery
Oral

No specific dosage recommendations.1

Avoid use in patients with Clcr <30 mL/minute.1

Treatment and Secondary Prevention of Venous Thromboembolism

Avoid use in patients with Clcr <30 mL/minute.1

Geriatric Patients

No specific dosage recommendations.1

Body Weight

Dosage adjustments not likely to be necessary in patients weighing <50 kg or >120 kg.1 9 21

Pregnant Women

Dosing not established.1

Cautions for Xarelto

Contraindications

  • Active pathologic bleeding.1

  • Severe hypersensitivity reaction to rivaroxaban.1

Warnings/Precautions

Warnings

Risks of Discontinuing Rivaroxaban in Atrial Fibrillation Patients

Increased risk of stroke observed in patients with nonvalvular atrial fibrillation who discontinued rivaroxaban in the absence of adequate alternative anticoagulation in principal efficacy study.1 Such patients were generally switched to warfarin without a period of concurrent warfarin and rivaroxaban until a therapeutic INR was obtained.1

If discontinuance of rivaroxaban required for reasons other than pathologic bleeding, consider use of an alternative anticoagulant.1 (See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration.)

Spinal/Epidural Hematoma

Epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, associated with concomitant use of rivaroxaban and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.1 42 (See Boxed Warning.) Monitor frequently for manifestations of neurologic impairment.1 (See Advice to Patients.)

Do not remove epidural catheters <18 hours after a dose of rivaroxaban, and give next dose ≥6 hours after catheter removal.1 If traumatic puncture occurs, delay rivaroxaban administration for 24 hours.1

Bleeding

Rivaroxaban increases risk of hemorrhage and can cause serious, sometimes fatal bleeding.1 2 12 32 59 60 Weigh risk of bleeding against risk of thrombotic events in patients with increased risk of bleeding (e.g., congenital or acquired bleeding disorders; active ulceration, hemorrhagic stroke, uncontrolled arterial hypertension, diabetic retinopathy; recent brain, spinal, ophthalmic surgery).1 13 Promptly evaluate any manifestations of blood loss during therapy.1 Discontinue if active pathologic hemorrhage occurs.1 (See Contraindications under Cautions.)

Renal impairment and concomitant use of drugs that affect hemostasis (e.g., aspirin, NSAIAs, fibrinolytics, thienopyridines, other antithrombotic agents) or drugs that are combined P-glycoprotein (P-gp) and CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) may increase risk of bleeding.1 5 6 8 30 (See Interactions.)

Use with caution in pregnant women because of risk of pregnancy-related hemorrhage and/or emergent delivery.1 (See Pregnancy.) Closely monitor for bleeding manifestations (e.g., decline in hemoglobin and/or hematocrit, hypotension, fetal distress).1

No specific antidote or reversal agent for rivaroxaban; discontinue drug and initiate appropriate treatment if bleeding associated with overdosage occurs.1 7 49 50 68 Not expected to be dialyzable because of high plasma protein binding.1 May consider use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), anti-inhibitor coagulant complex (activated prothrombin complex concentrate), or factor VIIa (recombinant) for immediate reversal of anticoagulation; however, data from clinical studies are limited.1 43 68 Protamine sulfate and vitamin K not expected to affect anticoagulant activity of rivaroxaban, and no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) or systemic hemostatics (desmopressin, aprotinin).1

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, reported.1 (See Contraindications under Cautions.)

Specific Populations

Pregnancy

Category C.1

No adequate data in pregnant women; pronounced maternal bleeding, post-implantation pregnancy loss, and fetotoxic effects observed in animals.1

Use with caution in pregnant women and only when potential benefits justify potential risks (e.g., hemorrhage, emergent delivery while receiving an anticoagulant that is not readily reversible).1 ACCP recommends avoidance of rivaroxaban in pregnant women.1012 Women of childbearing potential should discuss pregnancy planning with their clinician prior to initiating therapy.1

Lactation

Parent drug and metabolites distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1 ACCP recommends alternative anticoagulants to rivaroxaban in nursing women.1012

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1 2 3 4

Geriatric Use

No substantial differences in efficacy relative to younger adults in clinical studies.1 Although older patients experienced a higher rate of thrombotic and bleeding events, risk-to-benefit profile was favorable in all age groups.1

Hepatic Impairment

Possible increased systemic exposure and pharmacodynamic effects (inhibition of factor Xa activity, PT prolongation) in patients with moderate hepatic impairment (Child-Pugh class B); clinically important effects in patients with mild hepatic impairment not observed.1 9 (See Special Populations, under Pharmacokinetics.) Pharmacokinetic profile not established in patients with severe hepatic impairment (Child-Pugh class C).1 9

Avoid use in patients with moderate or severe hepatic impairment or with any hepatic disease associated with coagulopathy.1

Renal Impairment

Possible increased exposure and increased pharmacodynamic effects with decreasing renal function.1 9 12 18 27 (See Special Populations under Pharmacokinetics.) Discontinue drug if acute renal failure develops.1

Patients receiving thromboprophylaxis for orthopedic surgery: Closely monitor those with moderate renal impairment (Clcr 30 to <50 mL/minute) and promptly evaluate if any manifestations of bleeding occur.1 Do not use in patients with Clcr <30 mL/minute.1

Patients with nonvalvular atrial fibrillation: Assess renal function periodically and adjust dosage accordingly.1 (See Renal Impairment under Dosage and Administration.) More frequent monitoring may be necessary in clinical situations in which renal function may decline.1 Do not use in patients with Clcr <15 mL/minute.1

Patients with venous thromboembolism: Do not use in patients with Clcr <30 mL/minute.1

In patients with renal impairment, concomitant use of drugs that are combined P-gp and weak/moderate CYP3A4 inhibitors may substantially increase rivaroxaban exposure, which may increase risk of bleeding.1 (See Drugs Affecting Both P-glycoprotein and CYP3A4 under Interactions.)

Common Adverse Effects

Bleeding.1 2 12 32 59 60

Interactions for Xarelto

Metabolized by CYP 3A4/5 and 2J2.1 Does not inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A4 nor induce CYP1A2, 2B6, 2C19, and 3A4 in vitro; pharmacokinetic interaction unlikely with drugs metabolized by these enzymes.1 8 9

Substrate of the efflux transporters P-gp and ABCG2 (breast cancer resistance protein [BCRP]); does not appear to inhibit these transporters.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4/5 or 2J2: Potential pharmacokinetic interaction (increased rivaroxaban exposure).1

Inducers of CYP3A4/5 or 2J2: Potential pharmacokinetic interaction (decreased rivaroxaban exposure).1

Drugs Affecting Efflux Transport Systems

Inhibitors of P-gp or ABCG2: Potential pharmacokinetic interaction (increased rivaroxaban exposure).1

Inducers of P-gp or ABCG2: Potential pharmacokinetic interaction (decreased rivaroxaban exposure).1

Drugs Affecting Both P-glycoprotein and CYP3A4

Combined P-gp and CYP3A4 inhibitors: Possible increased rivaroxaban exposure and pharmacodynamic effects, which may increase risk of bleeding.1 Extent of interaction appears to be related to degree of P-gp or CYP3A4 inhibition.1 No special precautions necessary when clinical data suggest that increased exposure is unlikely to affect bleeding.1 Avoid concomitant use of combined P-gp and potent CYP3A4 inhibitors.1

Combined P-gp and potent CYP3A4 inducers: Possible decreased rivaroxaban exposure and pharmacodynamic effects, which may decrease efficacy.1 Avoid concomitant use.1

Simulated pharmacokinetic data suggest that exposure to rivaroxaban may be substantially increased in patients with renal impairment receiving full-dose (20 mg) rivaroxaban in conjunction with a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor.1 11 Increased bleeding risk not observed in a clinical study in patients with renal impairment (Clcr 30–49 mL/minute) who received such a combination.1 However, manufacturer advises use of rivaroxaban concomitantly with a combined P-gp and weak or moderate CYP3A4 inhibitor in patients with Clcr 15–50 mL/minute only if potential benefits justify potential risks.1

Drugs Affecting Hemostasis

Potential increased risk of hemorrhage.1 8 Promptly evaluate any manifestations of bleeding.1

Protein-bound Drugs

Potential interaction with other highly protein-bound drugs.8

Specific Drugs

Drug

Interaction

Comments

Antacids (aluminum- or magnesium-containing)

No effect on rivaroxaban bioavailability or systemic exposure1

Antiarrhythmic agents, class III (amiodarone, dronedarone)

Substantial increases in rivaroxaban exposure may occur in patients with renal impairment1

Use concomitantly in patients with renal impairment only when potential benefits justify risks1

Anticoagulants, other

Potential increased risk of hemorrhage1

Promptly evaluate if bleeding manifestations occur1

Avoid concomitant use in patients receiving rivaroxaban for DVT prophylaxis1

Antifungals, azole (fluconazole, itraconazole, ketoconazole)

Fluconazole: Possible increased AUC and peak plasma concentrations of rivaroxaban1

Itraconazole, ketoconazole: Possible increased rivaroxaban exposure, which may increase risk of bleeding1

Itraconazole, ketoconazole: Avoid concomitant use1

Antiretrovirals, HIV protease inhibitors

Lopinavir/ritonavir, indinavir/ritonavir, ritonavir: Possible increased rivaroxaban exposure, which may increase risk of bleeding1

Avoid concomitant use1

Aspirin

Potential increased risk of hemorrhage1 5 6 8 30

Increased bleeding time, but no effect on aspirin's inhibitory effects on platelet aggregation; no substantial change in pharmacokinetics or pharmacodynamics of rivaroxaban1 8 9 23

Promptly evaluate if bleeding manifestations occur1

Atorvastatin

Pharmacokinetic interaction unlikely1

Calcium-channel blocking agents (diltiazem, felodipine, verapamil)

Substantial increases in rivaroxaban exposure may occur in patients with renal impairment1

Use concomitantly in patients with renal impairment only when potential benefits justify risks1

Carbamazepine

Possible decreased rivaroxaban exposure and pharmacodynamic effects, which may decrease efficacy1

Avoid concomitant use1

Clopidogrel

Increased bleeding time; no change in pharmacokinetics of either drug1

Promptly evaluate if bleeding manifestations occur1

Conivaptan

Possible increased rivaroxaban exposure and pharmacodynamic effects, which may increase risk of bleeding1

Avoid concomitant use1

Digoxin

Pharmacokinetic interaction unlikely1

Enoxaparin

Additive effects on anti-factor Xa activity; pharmacokinetics of rivaroxaban not affected1 9 39

Promptly evaluate if bleeding manifestations occur1

Avoid concurrent use in patients receiving rivaroxaban for DVT prophylaxis1

Fibrinolytics

Potential increased risk of hemorrhage1

Macrolides (azithromycin, clarithromycin, erythromycin)

Clarithromycin, erythromycin: Increased rivaroxaban exposure; however, not expected to increase risk of bleeding1

Azithromycin, erythromycin: Substantial increases in rivaroxaban exposure may occur in patients with renal impairment1 1

No special precautions necessary in patients with normal renal function1

Azithromycin, erythromycin: Use concomitantly in patients with renal impairment only when potential benefits justify risks1

Midazolam

Pharmacokinetic interaction unlikely1

NSAIAs (e.g., naproxen)

Potential increased risk of hemorrhage1 5 6 8 30

Naproxen: Bleeding time increased slightly, but no substantial pharmacokinetic or pharmacodynamic interaction1 8 9 24 39

Promptly evaluate if bleeding manifestations occur1

Omeprazole

Pharmacokinetics of rivaroxaban not affected1 44

Phenytoin

Possible decreased rivaroxaban exposure and pharmacodynamic effects, which may decrease efficacy1

Avoid concomitant use1

Platelet-aggregation inhibitors

Potential increased risk of hemorrhage1

Promptly evaluate if bleeding manifestations occur1

Quinidine

Substantial increases in rivaroxaban exposure may occur in patients with renal impairment1

Use concomitantly in patients with renal impairment only when potential benefits justify risks1

Ranitidine

No effect on rivaroxaban bioavailability or systemic exposure1

Ranolazine

Substantial increases in rivaroxaban exposure may occur in patients with renal impairment1

Use concomitantly in patients with renal impairment only when potential benefits justify risks1

Rifampin

Decreased rivaroxaban exposure and pharmacodynamic effects; possible decreased efficacy1

Avoid concomitant use1

St. John's wort (Hypericum perforatum)

Possible decreased rivaroxaban exposure and pharmacodynamic effects, which may decrease efficacy1

Avoid concomitant use1

Warfarin

Additive effects on factor Xa inhibition and PT prolongation; pharmacokinetics of rivaroxaban not affected1

Promptly evaluate if bleeding manifestations occur1

Avoid concurrent use in patients receiving rivaroxaban for DVT prophylaxis1

Xarelto Pharmacokinetics

Absorption

Bioavailability

Rapidly and well absorbed following oral administration; bioavailability approximately 80–100% (10-mg dose).1 8 9 12 15 16 20

Following oral administration, peak plasma concentrations occur within 2–4 hours.1 8 9 12 15 16 46

Absorption dependent on site of release in the GI tract; exposure reduced when drug released into the proximal small intestine and further reduced when released in distal small intestine or ascending colon.1 (See Oral Administration under Dosage and Administration.)

Not adsorbed to PVC or silicone nasogastric tubing when drug administered as suspension in water.1 (See Oral Administration under Dosage and Administration.)

Food

Food increases peak plasma concentrations and systemic exposure to 20-mg dose; effects of food on 10-mg dose not expected to be clinically important.1 22 39

When administered as crushed tablets (20 mg) in applesauce, mean AUC and peak plasma concentrations comparable to those with whole tablets.1 When administered as crushed tablets in water via nasogastric tube followed by liquid meal, mean AUC with crushed tablets was comparable to that with a whole tablet, but mean peak plasma concentration was 18% lower.1

Distribution

Extent

Parent drug and metabolites distributed into milk in rats; not known whether distributed into human milk.1

Crosses the placenta in animals.1

Plasma Protein Binding

Approximately 92–95% (mainly to albumin).1 9

Elimination

Metabolism

Undergoes oxidative degradation (by CYP3A4/5 and 2J) and hydrolysis.1 26 No major circulating metabolites identified.1 8 26

Elimination Route

Approximately 66% of administered dose eliminated renally (36% unchanged drug) and 28% eliminated in feces (7% unchanged drug).1 8 26

No substantial accumulation with multiple dosing.8 9

Not expected to be removed by dialysis due to high plasma protein binding.1

Half-life

5–9 hours in healthy individuals 20–45 years of age.1 8

Special Populations

Exposure to rivaroxaban increased by 44, 52, or 64% in patients with mild, moderate, or severe renal impairment, respectively, compared with those with normal renal function.1 9 27

Substantial increased exposure in patients with moderate hepatic impairment (Child-Pugh class B).1 9

Systemic exposure in geriatric patients increased by approximately 50% compared with younger individuals, likely due to reduced total body and renal clearance; half-life 11–13 hours.1 9 12

Exposure to rivaroxaban on average 20–40% higher in patients of Japanese ancestry compared with other ethnicities (including Chinese); however, difference reduced after adjustment for body weight.1

Stability

Storage

Oral

Tablet

25°C (may be exposed to 15–30°C).1

Crushed tablets in water or applesauce: Stable for ≤4 hours.1

Actions

  • Selectively blocks active site of factor Xa; inhibits both free and prothrombinase-bound factor Xa.1 8 9 10 12 17

  • Inhibition of coagulation factor Xa prevents conversion of prothrombin to thrombin and subsequent thrombus formation.1 7 8 9 12 15 16 17 23

  • Unlike fondaparinux, unfractionated heparin, and LMWHs, rivaroxaban blocks factor Xa directly and does not require a cofactor (antithrombin III) to exert its anticoagulant activity.1 8 9 15 23

  • Inhibits factor Xa activity, PT, aPTT, and HepTest (an indirect measure of factor Xa activity) in a dose-dependent manner.1 8 12 15 18 20 43

Advice to Patients

  • Importance of taking drug exactly as prescribed and not discontinuing therapy without first consulting a clinician.1 Patients with atrial fibrillation should take rivaroxaban once daily with the evening meal.1

  • Importance of taking any missed dose as soon as possible on the same day and then resuming regular dosing schedule the following day.1 If a patient is taking a dosage of 15 mg twice daily and misses a dose, two 15-mg tablets may be taken at the same time to ensure full intake of the 30-mg daily dosage.1 (See Administration under Dosage and Administration.)

  • Importance of advising patients who cannot swallow tablets whole to crush a 15- or 20-mg tablet and combine with a small amount of applesauce immediately before administration, followed by food.1

  • For patients requiring an NG or gastric feeding tube, the patient or caregiver should be instructed to crush the tablet and mix it with a small amount of water before administration via the tube, followed immediately by enteral feeding.1

  • Importance of advising patients who have had neuraxial anesthesia or spinal puncture to monitor for manifestations of spinal or epidural hematoma (e.g., tingling or numbness in lower limbs, muscle weakness), particularly if they are receiving concomitant NSAIAs or platelet-aggregation inhibitors (e.g., clopidogrel); importance of immediately contacting a clinician if any of these symptoms occur.1

  • Importance of informing patients that they may bruise and/or bleed more easily and that a longer than normal time may be required to stop bleeding when taking rivaroxaban.1 Importance of informing clinicians about any unusual bleeding or bruising during therapy.1

  • Importance of informing clinicians about rivaroxaban therapy before scheduling any invasive procedures, including dental procedures.1

  • Importance of women immediately informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Women of childbearing potential should discuss pregnancy planning with their clinician prior to receiving rivaroxaban.1 Importance of pregnant women immediately reporting any bleeding or symptoms of blood loss to a clinician.1

  • Importance of informing clinicians (e.g., physicians, dentists) of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Rivaroxaban

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg

Xarelto

Janssen

15 mg

Xarelto

Janssen

20 mg

Xarelto

Janssen

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 26, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Janssen. Xarelto (rivaroxaban ) oral tablets prescribing information. Titusville, NJ: 2013 Mar.

2. Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008; 358:2765-75. [PubMed 18579811]

3. Kakkar AK, Brenner B, Dahl OE et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008; 372:31-9. [PubMed 18582928]

4. Lassen MR, Ageno W, Borris LC et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008; 358:2776-86. [PubMed 18579812]

5. Turpie AG, Lassen MR, Davidson BL et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009; 373:1673-80. [PubMed 19411100]

6. Turpie AG, Lassen MR, Eriksson BI et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost. 2011; 105:444-53. [PubMed 21136019]

7. Van Thiel D, Kalodiki E, Wahi R et al. Interpretation of benefit-risk of enoxaparin as comparator in the RECORD program: rivaroxaban oral tablets (10 milligrams) for use in prophylaxis in deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery. Clin Appl Thromb Hemost. 2009 Jul-Aug; 15:389-94.

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