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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
Brands: Xarelto

Medically reviewed by Drugs.com on Oct 4, 2021. Written by ASHP.

Warning

    Risk of Thrombosis Following Premature Discontinuance of Anticoagulation
  • Premature discontinuance of any oral anticoagulant, including rivaroxaban, increases risk of thrombotic events.

    If discontinuance is required for reasons other than pathologic bleeding or completion of a course of therapy, consider coverage with an alternative anticoagulant. (See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Cautions.)

    Spinal/Epidural Hematoma
  • 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.

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

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

  • Optimal timing between administration of rivaroxaban and neuraxial procedures not known.

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

  • Consider potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for anticoagulant therapy. (See Spinal/Epidural Hematoma under Cautions.)

Introduction

Anticoagulant; an oral, direct, activated factor X (Xa) inhibitor.

Uses for Rivaroxaban

Embolism Associated with Atrial Fibrillation

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

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. However, limited data exist on relative efficacy of rivaroxaban and warfarin when warfarin anticoagulation is well controlled.

The American College of Chest Physicians (ACCP), American Stroke Association (ASA), ACC, AHA, and other experts currently recommend that antithrombotic therapy be given to all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless contraindicated.

Antithrombotic therapy in patients with atrial flutter generally managed in the same manner as in patients with atrial fibrillation.

Choice of antithrombotic therapy is based on patient's risk for stroke and bleeding. In general, oral anticoagulant therapy is recommended in patients with moderate to high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke. 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 congestive heart failure. In addition, female sex is considered an important risk factor for stroke in patients with atrial fibrillation, particularly in patients ≥75 years of age.

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.

Relative efficacy and safety of rivaroxaban and other non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran) has not been fully elucidated.

AHA and ASA state that apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in selected women with paroxysmal or permanent atrial fibrillation and certain risk factors who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (Clcr<15 mL/minute), lower body weight (<50 kg), or advanced liver disease (impaired baseline clotting function).

When selecting an appropriate anticoagulant, consider factors such as individual patient's risks of stroke and bleeding; patient compliance, preference, and comorbidities; cost; availability of agents to reverse anticoagulant effects in case of bleeding complications; availability of facilities to monitor INR; and degree of current INR control in patients already taking warfarin.

Efficacy of rivaroxaban for prevention of postcardioversion stroke and systemic embolism in patients with atrial fibrillation not established. Efficacy and safety also not established in patients with prosthetic heart valves. (See Patients with Prosthetic Heart Valves under Cautions.)

Thromboprophylaxis in Hip- or Knee-Replacement Surgery

Prevention of postoperative DVT and associated PE in patients undergoing hip- or knee-replacement surgery.

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.

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

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

Treatment and Secondary Prevention of Venous Thromboembolism

Initial treatment and secondary prevention of DVT and/or PE.

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

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.

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.

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

CAD or Peripheral Artery Disease (PAD)

Used in conjunction with aspirin to reduce the risk of major cardiovascular events (e.g., cardiovascular death, MI, stroke) in patients with CAD or PAD.

Data indicate that rivaroxaban in conjunction with low-dose aspirin is more effective than low-dose aspirin alone in improving cardiovascular outcomes; however, risk of major bleeding is increased with such concomitant therapy.

Rivaroxaban Dosage and Administration

General

  • Routine monitoring of coagulation tests not required.

  • 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.

Administration

Oral Administration

Administer orally. Administer 15- or 20-mg tablets with food; 2.5- or 10-mg tablets may be taken with or without food.

In patients unable to swallow whole tablets, may crush tablets and mix with applesauce immediately before administration. Follow administration of 15- or 20-mg tablets with food. (See Storage under Stability.)

NG or Gastric Feeding Tube

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

Missed Doses

For dosage of 2.5 mg twice daily: If a dose is missed, take a single 2.5-mg dose as recommended at the next scheduled time.

For dosage of 10, 15, or 20 mg once daily: Take the missed dose as soon as possible on the same day, then resume regular schedule the following day. Do not double the dose within the same day to make up for a missed dose.

For dosage of 15 mg twice daily: If a dose is missed, take a dose immediately upon remembering; if necessary, 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.

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.

Thromboprophylaxis in Hip- or Knee-Replacement Surgery
Oral

10 mg once daily.

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

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

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. Initial twice-daily dosing may provide higher trough drug concentrations and improved thrombus regression.

Continued prophylaxis (after initial 6 months of anticoagulant treatment) to reduce risk of recurrent DVT and/or PE: 10 mg once daily.

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). 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.

CAD or PAD
Oral

Risk reduction of major cardiovascular events: 2.5 mg twice daily, administered in conjunction with aspirin 75–100 mg once daily.

Transitioning to and from Rivaroxaban Therapy
Transferring to Rivaroxaban from Warfarin

Discontinue warfarin and initiate rivaroxaban as soon as INR < 3.

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.

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

Transferring from Rivaroxaban to Warfarin

Data from clinical trials not available to guide conversion from rivaroxaban to warfarin. 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. INR measurements may not be useful in determining appropriate dosage of warfarin during conversion.

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.

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. In deciding whether a procedure should be delayed, weigh increased risk of bleeding against urgency of intervention. Resume therapy after procedure once adequate hemostasis established; if oral anticoagulation not possible, consider use of a parenteral anticoagulant. (See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Cautions.)

Special Populations

Hepatic Impairment

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

Renal Impairment

Embolism Associated with Atrial Fibrillation
Oral

Consider dosage adjustment or discontinuance of rivaroxaban in patients who develop acute renal failure.

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

Thromboprophylaxis in Hip- or Knee-Replacement Surgery
Oral

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

Treatment and Secondary Prevention of Venous Thromboembolism
Oral

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

Discontinue in patients who develop acute renal failure.

CAD or PAD
Oral

Manufacturer states no dosage adjustment needed based on Clcr. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.

Body Weight

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

Pregnant Women

Dosing not established.

Cautions for Rivaroxaban

Contraindications

  • Active pathologic bleeding.

  • Severe hypersensitivity reaction to rivaroxaban.

Warnings/Precautions

Warnings

Risk of Thrombosis Following Premature Discontinuance of Anticoagulation

Premature discontinuance of any oral anticoagulant, including rivaroxaban, increases risk of thrombotic events (e.g., stroke) in the absence of adequate alternative anticoagulation. (See Boxed Warning.) An increased risk of stroke was observed during transition from rivaroxaban to warfarin therapy in clinical trials in patients with atrial fibrillation. Such patients generally had been switched to warfarin without a period of concurrent warfarin and rivaroxaban therapy and thus were not adequately anticoagulated after stopping rivaroxaban until a therapeutic INR with warfarin had been obtained.

If discontinuance of rivaroxaban required for reasons other than pathologic bleeding (e.g., prior to surgery or other invasive procedures) or completion of a course of therapy, consider coverage with an alternative anticoagulant. Important to ensure continuous anticoagulation during transition to alternative anticoagulant while minimizing risk of bleeding. Particular caution advised when switching from a factor Xa inhibitor to warfarin therapy because of warfarin's slow onset of action. (See Dosage under Dosage and Administration.)

Advise patients regarding importance of adhering to therapeutic regimen and on steps to take if doses are missed. (See Advice to Patients.)

Spinal/Epidural Hematoma

Epidural or spinal hematoma reported with concurrent use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures. Such hematomas have resulted in neurologic injury, including long-term or permanent paralysis. (See Boxed Warning.)

To reduce risk of bleeding with concurrent use of rivaroxaban and neuraxial anesthesia or spinal puncture, carefully consider the pharmacokinetic profile of the anticoagulant in relation to the timing of such procedures.

Do not remove indwelling epidural or intrathecal catheters before ≥2 half-lives have elapsed (i.e., 18 hours in patients 20–45 years of age; 26 hours in patients 60–76 years of age) after a dose of rivaroxaban, and administer next dose ≥6 hours after catheter removal; optimal timing between administration of rivaroxaban and neuraxial procedures to reach sufficiently low anticoagulant effect not known. If traumatic puncture occurs, delay rivaroxaban administration for 24 hours.

Frequently monitor for signs of neurologic impairment (e.g., midline back pain; numbness, tingling, or weakness in lower limbs; bowel or bladder dysfunction). If spinal hematoma suspected, diagnose and treat immediately; consider spinal cord decompression even though such treatment may not prevent or reverse neurologic sequelae. Carefully consider potential benefits versus risks of neuraxial intervention in patients who are currently receiving or will receive anticoagulant prophylaxis.

Sensitivity Reactions

Hypersensitivity Reactions

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

Other Warnings and Precautions

Bleeding

Rivaroxaban increases risk of hemorrhage and can cause serious, sometimes fatal bleeding. Weigh risk of bleeding against risk of thrombotic events in patients with increased risk of bleeding. Promptly evaluate any manifestations of blood loss during therapy. Discontinue if active pathologic hemorrhage occurs. (See Contraindications under Cautions.) However, should not readily discontinue anticoagulation for commonly occurring minor or “nuisance” bleeding. (See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Cautions.)

Renal impairment and concomitant use of drugs that affect hemostasis (e.g., aspirin or other NSAIAs, fibrinolytics, SNRIs, SSRIs, 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. (See Interactions.)

Factor Xa (recombinant), inactivated-zhzo (also known as andexanet alfa), a recombinant modified human factor Xa protein, is a specific reversal agent for the anticoagulant effects of rivaroxaban. Safety of factor Xa (recombinant), inactivated-zhzo not established in patients who have experienced a thromboembolic event or disseminated intravascular coagulation (DIC) within 2 weeks prior to the life-threatening bleeding event requiring treatment with the drug or in those who have received prothrombin complex concentrates (PCC), recombinant factor VIIa, or whole blood products ≤7 days prior to the bleeding event.

Discontinue rivaroxaban and initiate appropriate treatment if bleeding associated with overdosage occurs. Not expected to be dialyzable because of high plasma protein binding.

May consider use of procoagulant reversal agents such as 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.

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 [no longer commercially available in the US]).

Patients with Prosthetic Heart Valves

Efficacy and safety not established; manufacturer states that use not recommended.

Patients with Pulmonary Embolism

Manufacturer states that rivaroxaban is not recommended as initial therapy (as alternative to heparin) in patients with PE who have hemodynamic instability or who may receive thrombolytic therapy or undergo pulmonary embolectomy.

Specific Populations

Pregnancy

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

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). Closely monitor for bleeding manifestations (e.g., decline in hemoglobin and/or hematocrit, hypotension, fetal distress). ACCP recommends avoidance of rivaroxaban in pregnant women. Women of childbearing potential should discuss pregnancy planning with their clinician prior to initiating therapy.

Lactation

Distributed into human milk. Effects of rivaroxaban on the breastfed infant or on milk production unknown. Consider benefits of breast-feeding and the clinical need for rivaroxaban in the woman along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition. ACCP recommends alternative anticoagulants to rivaroxaban in nursing women.

Pediatric Use

Safety and efficacy not established in patients <18 years of age.

Geriatric Use

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

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. (See Special Populations, under Pharmacokinetics.) Pharmacokinetic profile not established in patients with severe hepatic impairment (Child-Pugh class C).

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

Renal Impairment

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

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. Do not use in patients with Clcr <30 mL/minute.

Patients with nonvalvular atrial fibrillation: Assess renal function periodically and adjust dosage accordingly. (See Renal Impairment under Dosage and Administration.) More frequent monitoring may be necessary in clinical situations in which renal function may decline.

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

Cardiovascular risk reduction in patients with CAD or PAD: Rivaroxaban dosage of 2.5 mg twice daily in patients with Clcr ≤30 mL/minute expected to result in rivaroxaban exposure similar to that observed in patients with moderate renal impairment, whose efficacy and safety outcomes were similar to those with preserved renal function. (See Renal Impairment under Dosage and Administration.)

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. (See Drugs Affecting Both P-gp and CYP3A4 under Interactions.)

Common Adverse Effects

Bleeding.

Interactions for Rivaroxaban

Metabolized by CYP 3A4/5 and 2J2. 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.

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

Drugs Affecting Hepatic Microsomal Enzymes

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

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

Drugs Affecting Efflux Transport Systems

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

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

Drugs Affecting Both P-gp and CYP3A4

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

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

Results of pharmacokinetic trial 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 moderate CYP3A4 inhibitor. Increased bleeding risk not observed in a clinical study in patients with renal impairment (Clcr 30–49 mL/minute) who received such a combination. However, manufacturer advises against concomitant use of rivaroxaban and a combined P-gp and moderate CYP3A4 inhibitor in patients with Clcr 15–80 mL/minute unless potential benefits justify potential risks.

Drugs Affecting Hemostasis

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

Protein-bound Drugs

Potential interaction with other highly protein-bound drugs.

Specific Drugs

Drug

Interaction

Comments

Antacids (aluminum- or magnesium-containing)

No effect on rivaroxaban bioavailability or systemic exposure

Antiarrhythmic agents, class III (amiodarone, dronedarone)

Amiodarone: No increased risk of bleeding observed in patients with Clcr 30–49 mL/minute

Dronedarone: Substantial increases in rivaroxaban exposure may occur in patients with renal impairment

Anticoagulants, other

Potential increased risk of hemorrhage

Promptly evaluate if bleeding manifestations occur

Antidepressants (SNRIs, SSRIs)

May impair hemostasis and may further increase bleeding risk

Promptly evaluate if bleeding manifestations occur

Antifungals, azole (fluconazole, itraconazole, ketoconazole)

Fluconazole: Possible increased AUC and peak plasma concentrations of rivaroxaban

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

Itraconazole, ketoconazole: Avoid concomitant use

Antiretrovirals, HIV protease inhibitors

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

Avoid concomitant use

Aspirin

Potential increased risk of hemorrhage

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

Promptly evaluate if bleeding manifestations occur

Atorvastatin

Pharmacokinetic interaction unlikely

Calcium-channel blocking agents (diltiazem, verapamil)

Concomitant use of verapamil or diltiazem not associated with increased risk of stroke or non-CNS embolism; increased risk of major bleeding and intracranial hemorrhage observed in ROCKET AF

In a case-cohort analysis, coadministration of rivaroxaban with diltiazem did not result in an increased rate of bleeding

Carbamazepine

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

Avoid concomitant use

Clopidogrel

Increased bleeding time; no change in pharmacokinetics of either drug

Promptly evaluate if bleeding manifestations occur

Conivaptan

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

Avoid concomitant use

Digoxin

Pharmacokinetic interaction unlikely

Enoxaparin

Additive effects on anti-factor Xa activity; pharmacokinetics of rivaroxaban not affected

Promptly evaluate if bleeding manifestations occur

Avoid concomitant use unless benefit outweighs risk

Macrolides (clarithromycin, erythromycin)

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

Erythromycin: Substantial increases in rivaroxaban exposure may occur in patients with renal impairment

No special precautions necessary in patients with normal renal function

Erythromycin: Use concomitantly in patients with renal impairment only when potential benefits justify risks

Midazolam

Pharmacokinetic interaction unlikely

NSAIAs (e.g., naproxen)

Potential increased risk of hemorrhage

Naproxen: Bleeding time increased slightly, but no substantial pharmacokinetic or pharmacodynamic interaction

Promptly evaluate if bleeding manifestations occur

Omeprazole

Pharmacokinetics of rivaroxaban not affected

Phenytoin

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

Avoid concomitant use

Platelet-aggregation inhibitors

Potential increased risk of hemorrhage

Promptly evaluate if bleeding manifestations occur

Ranitidine

No effect on rivaroxaban bioavailability or systemic exposure

Rifampin

Decreased rivaroxaban exposure and pharmacodynamic effects; possible decreased efficacy

Avoid concomitant use

St. John's wort (Hypericum perforatum)

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

Avoid concomitant use

Thrombolytic agents

Potential increased risk of hemorrhage

Warfarin

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

Promptly evaluate if bleeding manifestations occur

Avoid concomitant use unless benefit outweighs risk

Rivaroxaban Pharmacokinetics

Absorption

Bioavailability

Rapidly and well absorbed following oral administration; bioavailability approximately 80–100% (2.5- and 10-mg doses) and 66% (20-mg dose).

Following oral administration, peak plasma concentrations occur within 2–4 hours.

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. (See Administration under Dosage and Administration.)

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

Food

Food increases peak plasma concentrations and systemic exposure to 20-mg dose; effects of food on 2.5- or 10-mg dose not expected to be clinically important.

When administered as crushed tablets (20 mg) in applesauce, mean AUC and peak plasma concentrations comparable to those with whole tablets. 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.

Distribution

Extent

Distributed into human milk.

Crosses the placenta in animals.

Plasma Protein Binding

Approximately 92–95% (mainly to albumin).

Elimination

Metabolism

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

Elimination Route

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

No substantial accumulation with multiple dosing.

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

Half-life

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

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.

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

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.

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.

Stability

Storage

Oral

Tablet

25°C (may be exposed to 15–30°C).

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

Actions

  • Selectively blocks active site of factor Xa; inhibits both free and prothrombinase-bound factor Xa.

  • Inhibition of coagulation factor Xa prevents conversion of prothrombin to thrombin and subsequent thrombus formation.

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

  • Inhibits factor Xa activity, PT, aPTT, and HepTest (an indirect measure of factor Xa activity) in a dose-dependent manner.

Advice to Patients

  • Importance of taking drug exactly as prescribed and not discontinuing therapy without first consulting a clinician. Patients with atrial fibrillation should take rivaroxaban once daily with the evening meal. Patients should be advised to take the 15- or 20-mg tablets with food at approximately the same time every day.

  • Importance of taking any missed dose as soon as possible on the same day and then resuming regular dosing schedule the following day. 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. (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.

  • 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.

  • In patients who are at a continued risk of recurrent DVT and/or PE after ≥6 months of initial anticoagulant treatment, importance of advising such patients to take rivaroxaban 10 mg once daily with or without food.

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

  • 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. Importance of informing clinicians about any unusual bleeding or bruising during therapy.

  • Importance of patients informing clinicians (e.g., physicians, dentists) about rivaroxaban therapy before scheduling any surgery or invasive procedures, including dental procedures.

  • Importance of not administering rivaroxaban to patients with prosthetic heart valves.

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

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements.

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

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Rivaroxaban

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2.5 mg

Xarelto

Janssen

10 mg

Xarelto

Janssen

15 mg

Xarelto

Janssen

20 mg

Xarelto

Janssen

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 14, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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