Prescription Required
Manufacturer
JANSSEN PHARM.
SKU
50458058030

brand xarelto 10 mg tablet

Brand
$14.59 / Tablet
First Order Ships Free Free 1-5 Day Shipping
+ -
In Stock
Total Price:

Uses

Embolism Associated with Atrial Fibrillation

Rivaroxaban is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Current evidence suggests that rivaroxaban is no less effective than warfarin for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and does not increase the risk of major bleeding relative to warfarin. However, there are limited data on the relative efficacy of rivaroxaban and warfarin for the reduction of stroke and systemic embolism when warfarin anticoagulation is well controlled. Efficacy of rivaroxaban for the prevention of postcardioversion stroke and systemic embolism in patients with atrial fibrillation has not been established. Efficacy and safety of the drug in patients with prosthetic heart valves also have not been established.(See Patients with Prosthetic Heart Valves under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

The American College of Chest Physicians (ACCP), the American College of Cardiology (ACC), the American Heart Association (AHA), the American Stroke Association (ASA), and other experts currently recommend that antithrombotic therapy be administered 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 such therapy is contraindicated. Recommendations regarding choice of antithrombotic therapy are based on the patient's risk for stroke and bleeding. In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients with atrial fibrillation who have a 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. Although many risk stratification methods have been used, patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or transient ischemic attack (TIA), advanced age (e.g., 75 years or older), history of hypertension, diabetes mellitus, or congestive heart failure. In addition, population-based studies suggest that female sex is an important risk factor for stroke in patients with atrial fibrillation, particularly in patients 75 years of age or older, and AHA and ASA recommend the use of risk stratification tools that account for age- and sex-specific differences in stroke risk. One such tool is the CHA2DS2-VASc score, an extension of the CHADS2 system (which considers the risk factors congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and prior stroke/TIA) that adds extra points for female sex (1 point); previous myocardial infarction, peripheral arterial disease, or aortic plaque (1 point); and age 65-74 years (1 point) or 75 years or older (2 points).

The risk of thromboembolism in patients with atrial flutter is not as well established as it is in those with atrial fibrillation. In addition, many patients with atrial flutter have alternating periods of atrial fibrillation. Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.

Although warfarin traditionally has been used for oral anticoagulation in patients with atrial fibrillation at increased risk of stroke, some experts suggest that non-vitamin K antagonist oral anticoagulants such as rivaroxaban may provide certain advantages over warfarin (e.g., rapid onset of action, predictable anticoagulant effect, no requirement for coagulation monitoring, less potential for drug-drug and drug-food interactions) and may be considered as alternative therapy in selected patients. Rivaroxaban may be particularly useful in 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 (e.g., because of drug or food interactions), while warfarin may continue to be preferred in patients who have well-controlled international normalized ratios (INRs) (e.g., INR in the therapeutic range more than 70% of the time) and are compliant with regular laboratory monitoring. However, because of the lack of direct, comparative studies, the relative efficacy and safety of rivaroxaban and other non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran, edoxaban) used for the prevention of stroke in patients with nonvalvular atrial fibrillation remain to be fully elucidated. Some evidence from indirect comparisons suggests that there may be important differences (e.g., bleeding risk) between these agents; however, results of such analyses should be interpreted with caution because of possible confounding factors (e.g., differences in study design and methods, patient populations, and anticoagulation control). AHA and ASA state that while clinical trials of non-vitamin K antagonist oral anticoagulants were not designed to determine differences in efficacy compared with warfarin in men versus women, apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in women with paroxysmal or permanent atrial fibrillation and prespecified risk factors (according to CHA2DS2-VASc) who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (creatinine clearance less than 15 mL/minute), lower body weight (less than 50 kg), or advanced liver disease (impaired baseline clotting function). When selecting an appropriate anticoagulant in patients with atrial fibrillation, the relative risks versus benefits should be considered for individual patients based on factors such as the absolute and relative risks of stroke and bleeding; patient compliance, preference, tolerance, and comorbidities; cost; availability of agents to reverse anticoagulant effects in case of bleeding complications; and other clinical factors such as renal function, availability of facilities to monitor INR; and degree of current INR control in patients already receiving warfarin.

Efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation were evaluated in a randomized, double-blind, noninferiority study (ROCKET AF) in approximately 14,000 adults with nonvalvular atrial fibrillation who were considered to be at moderate to high risk of stroke (defined as having a history of stroke, TIA, non-CNS systemic embolism, or at least 2 of the following additional risk factors: age 75 years or older, hypertension, heart failure or left ventricular ejection fraction of 35% or less, or diabetes mellitus). The study population consisted principally of Caucasian men with a mean age of 71 years and a mean Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke (doubled) (i.e., CHADS2) score of 3.5; approximately 55% of patients had a history of stroke, TIA, or non-CNS systemic embolism. Patients received either rivaroxaban (20 mg once daily for those with a creatinine clearance of at least 50 mL/minute or 15 mg once daily for those with a creatinine clearance of 30-49 mL/minute) or adjusted-dose warfarin (titrated to an international normalized ratio [INR] of 2-3) for a median duration of 590 days; median follow-up was 707 days.

The primary composite end point of the study was the incidence of stroke (hemorrhagic or ischemic) and non-CNS systemic embolism. The primary efficacy analysis was performed in the per-protocol (as-treated) population, which included all patients who received at least one dose of a study drug, did not have a major protocol violation, and were followed for events while receiving a study drug or within 2 days after discontinuance of the drug. Outcome analyses also were performed in the intent-to-treat (per-randomization) population, which included all patients who underwent randomization and were followed for events during treatment or following premature discontinuance, and the safety population, which included all patients who received at least one dose of a study drug and were followed for events while they were receiving study drug or within 2 days after discontinuation, regardless of protocol adherence. Testing for superiority was performed if noninferiority was achieved.

Rivaroxaban was noninferior to warfarin for the primary composite outcome of time to first occurrence of stroke or non-CNS systemic embolism; noninferiority was demonstrated in both the per-protocol and intent-to-treat populations. Efficacy of rivaroxaban was consistent across a variety of patient subgroups, including in those with renal insufficiency, different CHADS2 scores, prior warfarin use, and history of stroke. Superiority of rivaroxaban over warfarin was not demonstrated in the intent-to-treat population in this study; the rate of stroke or non-CNS systemic embolism with rivaroxaban therapy was no different than that observed with warfarin therapy (annualized event rate of 2.1 and 2.4% of patients, respectively). However, superiority of rivaroxaban over warfarin was shown in the as-treated safety population. This difference in the results of superiority testing may be explained by the inclusion of embolic events in patients who discontinued drug treatment prematurely as well as those occurring during study drug treatment in the intent-to-treat population, while analysis of the per-protocol population only included events that occurred during drug treatment and for 2 days after drug discontinuance. In addition, a requirement for anticoagulation following study drug discontinuance was not specified in the ROCKET AF protocol; however, patients in the warfarin group generally continued to receive warfarin after the treatment portion of the study, while those who had received rivaroxaban during the treatment portion were switched to warfarin without a period of overlap and therefore were not adequately anticoagulated until a therapeutic INR with warfarin was obtained. During the 28 days following the end of the study, a higher incidence of stroke was observed in patients who had received rivaroxaban compared with those who had received warfarin.(See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Warnings/Precautions: Warnings, in Cautions.) There was no statistically significant difference in the risk of major and nonmajor clinically important bleeding between the treatment groups, although intracranial and fatal bleeding occurred less frequently in patients receiving rivaroxaban.

Patients who received warfarin in the ROCKET AF study had INRs within the therapeutic range of 2-3 only 55% of the time on average, which is lower than that reported with warfarin anticoagulation in other trials of non-vitamin K antagonist oral anticoagulants (e.g., dabigatran, apixaban) in patients with atrial fibrillation (e.g., 62-64%). It has been suggested that this difference may be explained in part by the inclusion of a higher-risk patient population in the ROCKET AF trial or to geographic variations among the study sites with respect to warfarin anticoagulation management skills. Therefore, data currently are insufficient to establish the relative efficacy of rivaroxaban and warfarin for the reduction of stroke and systemic embolism when warfarin therapy is well controlled.

Deep-Vein Thrombosis and Pulmonary Embolism

Prophylaxis

Major Orthopedic Surgery

Rivaroxaban is used for the prevention of postoperative deep-vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing total hip- or knee-replacement surgery.

ACCP recommends routine thromboprophylaxis in all patients undergoing major orthopedic surgery, including total hip- or knee-replacement surgery, because of the high risk of postoperative venous thromboembolism. According to ACCP, thromboprophylaxis with an appropriate antithrombotic agent or an intermittent pneumatic compression device should be continued for at least 10-14 days and possibly for up to 35 days after surgery. ACCP and other clinicians consider rivaroxaban to be an acceptable option for pharmacologic thromboprophylaxis in patients undergoing total hip- or knee-replacement surgery, although ACCP suggests that a low molecular weight heparin generally is preferred because of its relative efficacy and safety and extensive clinical experience. Rivaroxaban may be a reasonable choice in situations in which a low molecular weight heparin is not available or cannot be used (e.g., in patients with heparin-induced thrombocytopenia or in those who refuse or are uncooperative with subcutaneous injections). ACCP states that when selecting an appropriate thromboprophylaxis regimen, factors such as relative efficacy and bleeding risk as well as logistics and compliance issues should be considered. For additional details on prevention of venous thromboembolism in patients undergoing major orthopedic surgery, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.

Efficacy and safety of rivaroxaban for the prevention of postoperative venous thromboembolism after major orthopedic surgery are based principally on the results of 4 randomized, double-blind, double-dummy trials known as the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep-vein Thrombosis and Pulmonary Embolism) trials. In these trials, rivaroxaban was more effective than subcutaneous enoxaparin in preventing venous thromboembolism in patients undergoing elective total hip-replacement (RECORD 1 and 2) or total knee-replacement (RECORD 3 and 4) surgery and was associated with similar rates of bleeding. The primary efficacy and safety end points in all 4 trials were identical; however, there were differences with respect to dosage and duration of enoxaparin therapy. Patients received oral rivaroxaban (10 mg once daily initiated at least 6-8 hours after surgery) or subcutaneous enoxaparin sodium (40 mg once daily initiated 12 hours before surgery and resumed 6-8 hours after wound closure in RECORD 1, 2, and 3, or 30 mg twice daily initiated 12 hours before surgery and resumed 12-24 hours after wound closure in RECORD 4). Treatment generally was continued for 31-39 days in the hip-replacement trials and for 10-14 days in the knee-replacement trials. However, in RECORD 2, the duration of active drug treatments was different; rivaroxaban was administered for 31-39 (mean 33.5) days (with placebo injection for 10-14 days) while enoxaparin was administered for 10-14 (mean 12.4) days (with placebo tablets for 31-39 days).

In all 4 RECORD trials, the incidence of the composite primary outcome of DVT (symptomatic or venographic), nonfatal PE, and all-cause mortality was substantially lower in patients receiving rivaroxaban than in those receiving enoxaparin. Treatment with rivaroxaban resulted in relative risk reductions for venous thromboembolism of 70 and 79%, respectively, in patients undergoing hip replacement in RECORD 1 and 2, and relative risk reductions of 49 and 31%, respectively, in patients undergoing knee replacement in RECORD 3 and 4. Rivaroxaban was generally well tolerated across all trials and rates of major bleeding or any bleeding event were generally similar between treatment groups.

Some clinicians have suggested that the observed differences in outcome between the rivaroxaban and enoxaparin groups in the RECORD trials were influenced by differences in dosage and/or duration of enoxaparin therapy. In RECORD 1-3, an enoxaparin sodium dosage of 40 mg once daily was used, while the preferred dosage for thromboprophylaxis after hip-replacement surgery and the only recommended dosage for knee-replacement surgery in the US is 30 mg every 12 hours (i.e., twice daily), which was used only in the RECORD 4 trial. In addition, enoxaparin was given for an average of approximately 2 weeks versus approximately 5 weeks for rivaroxaban in the RECORD 2 trial. It has been suggested that use of a potentially suboptimal enoxaparin sodium dosage of 40 mg daily in RECORD 1-3 and an unequal (shorter) duration of enoxaparin therapy in RECORD 2 may have contributed to the increased risk of the primary efficacy end point with enoxaparin in these trials. In addition, in RECORD 3, which employed the 40-mg once-daily dosage of enoxaparin sodium in patients undergoing total knee replacement, there was an absolute risk difference of 9.2% favoring rivaroxaban for the primary end point (any DVT, nonfatal PE, and all-cause mortality in the modified intent-to-treat population), while in RECORD 4, which employed the US FDA-labeled enoxaparin sodium dosage of 30 mg every 12 hours for the same indication, the absolute risk difference favoring rivaroxaban for the same primary end point was only 3.2%. In an attempt to account for differences in study design among the RECORD trials, an analysis of pooled data that used only the period of active treatment common to all 4 trials (the 12 +/- 2 days in which enoxaparin was administered) as the primary efficacy end point was performed; results of this analysis supported those of the individual trials with regard to the greater efficacy of rivaroxaban versus enoxaparin for reduction of total venous thromboembolism.

In the RECORD trials, use of a definition of major bleeding that did not include surgical site bleeding unless it necessitated reoperation or resulted in death may have resulted in a more conservative estimate of bleeding risk in these trials than in other comparative studies of other non-vitamin K antagonist oral anticoagulants and enoxaparin. Differences in the timing of initiation of rivaroxaban and enoxaparin therapy (preoperatively in RECORD 1-3; 6-8 hours postoperatively for rivaroxaban versus 12-24 hours postoperatively for enoxaparin in RECORD 4) potentially could have affected relative bleeding risk. The overall incidence of major bleeding in the RECORD trials was low (less than 1%), and these trials were not designed with enough statistical power to demonstrate differences in the end point of major bleeding. However, there was a trend toward increased bleeding events (numerically more frequent) with rivaroxaban in the RECORD trials. In a pooled analysis of data from all 4 trials, a small but statistically significant increase in the end point of major plus clinically relevant nonmajor bleeding was demonstrated for rivaroxaban versus enoxaparin in the total treatment duration pool; however, analysis of the active treatment pool at day 12+/-2 (i.e., the enoxaparin-controlled period common to all 4 RECORD studies) did not reveal a statistically significant difference in bleeding between the 2 groups.

The manufacturer states that rivaroxaban is not recommended as initial therapy (as an alternative to heparin) in patients with PE who have hemodynamic instability or who may receive thrombolytic therapy or undergo pulmonary embolectomy.(See Patients with Pulmonary Embolism under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Treatment and Secondary Prevention

Rivaroxaban is used for the initial treatment of acute DVT and/or PE. The drug also is used beyond the initial 6 months of treatment to reduce the risk of recurrent venous thromboembolic events (secondary prevention) in patients with DVT and/or PE.

Rivaroxaban is 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. In such patients, ACCP recommends that anticoagulant therapy be continued beyond the acute treatment period for at least 3 months, and possibly longer depending on the individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors, presence of cancer, patient's risk of bleeding). Although rivaroxaban may offer some advantages over existing anticoagulant drugs for the treatment of venous thromboembolism (e.g., oral administration, no requirement for routine coagulation monitoring, minimal drug and food interactions), ACCP generally suggests the use of warfarin or a low molecular weight heparin rather than rivaroxaban for long-term anticoagulant therapy pending additional data and experience with rivaroxaban. The relative efficacy and safety of rivaroxaban versus other non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran) for the treatment of venous thromboembolism remains to be established in controlled, comparative trials. For additional information on treatment of venous thromboembolism, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.

In 2 randomized, open-label, noninferiority studies (EINSTEIN DVT and EINSTEIN PE) designed to evaluate efficacy and safety of rivaroxaban for the initial treatment and secondary prevention of venous thromboembolism, treatment with rivaroxaban was noninferior to therapy with enoxaparin and a vitamin K antagonist in preventing recurrent thromboembolic events. Patients in the studies were given either rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) or a standard anticoagulant regimen consisting of enoxaparin sodium (1 mg/kg subcutaneously twice daily for at least 5 days), followed by a vitamin K antagonist (warfarin or acenocoumarol adjusted to maintain an INR of 2-3). The average duration of therapy in both treatment groups was approximately 200 days. The primary efficacy outcome in these studies was a composite of symptomatic recurrent DVT or nonfatal or fatal PE. The primary efficacy outcome (based on the intent-to-treat population) occurred in 2.1 or 3% of patients receiving rivaroxaban or standard therapy, respectively, in the EINSTEIN DVT study, and in 2.1 or 1.8% of patients receiving rivaroxaban or standard therapy, respectively, in the EINSTEIN PE study. The incidence of major and clinically relevant nonmajor bleeding was similar between the treatment groups.

In a double-blind, placebo-controlled extension study (EINSTEIN EXT) in patients who had already completed a course of anticoagulant therapy with rivaroxaban or a vitamin K antagonist, continued treatment with rivaroxaban was substantially more effective than placebo in reducing the rate of recurrent DVT, nonfatal PE, or fatal PE. Patients in the extension study received rivaroxaban 20 mg daily or placebo for an additional 6 or 12 months (average duration of 190 days). Recurrent thromboembolism occurred in 1.3% of patients receiving rivaroxaban compared with 7.1% of those receiving placebo. Major bleeding occurred in 0.7% of patients in the rivaroxaban group and in none of the patients in the placebo group.

Additional studies and experience are needed to evaluate the efficacy and safety of rivaroxaban for the treatment of cancer-related venous thromboembolism; relatively few patients with cancer were included in the principal efficacy studies evaluating rivaroxaban for the treatment and secondary prevention of venous thromboembolism.

Dosage and Administration

General

Routine coagulation monitoring (e.g., prothrombin time [PT], activated partial thromboplastin time [aPTT], international normalized ratio [INR]) is not necessary during rivaroxaban therapy because of the drug's predictable pharmacokinetic and pharmacodynamic effects. However, in certain situations, such as in the case of overdosage or in patients with hemorrhagic or thromboembolic complications, it may be useful to assess the degree of anticoagulation. It has been suggested that the PT test may be used to assess rivaroxaban plasma concentrations since the drug prolongs PT in a concentration-dependent manner; however, PT test results may vary depending on the type of reagent and may not be a reliable indicator of the degree of anticoagulation with rivaroxaban. The INR is calibrated specifically for vitamin K antagonists (e.g., warfarin) and should not be used to monitor the effects of rivaroxaban.

Administration

Rivaroxaban is administered orally. The manufacturer states that the 15- and 20-mg tablets should be taken with food; the 10-mg tablet may be administered with or without food. If a dose of rivaroxaban is missed, the missed dose should be taken immediately. If a dose is missed in patients receiving a dosage of 15 mg twice daily, two 15-mg tablets may be taken at the same time to ensure full intake of the 30-mg daily dose; the regular twice-daily dosing schedule should then be resumed the following day.(See Advice to Patients.)

In patients who are unable to swallow whole tablets, rivaroxaban 15- or 20-mg tablets may be crushed and mixed with applesauce immediately before administration. When given orally as a crushed tablet, the dose of rivaroxaban should be followed immediately by food. In patients requiring a nasogastric or gastric feeding tube, after confirming placement of the tube, rivaroxaban 15- or 20-mg tablets should be administered by crushing and suspending the drug in 50 mL of water; enteral feeding via the tube should immediately follow administration of the drug.

Because of the possibility of reduced absorption and thereby reduced drug exposure, rivaroxaban should not be administered by a method that could deposit the drug distal to the stomach.(See Description.)

Dosage

Embolism Associated with Atrial Fibrillation

For reduction of the risk of stroke and systemic embolism in adults with nonvalvular atrial fibrillation, the recommended dosage of rivaroxaban in patients without renal impairment (creatinine clearance exceeding 50 mL/minute) is 20 mg once daily with the evening meal.

Deep-Vein Thrombosis and Pulmonary Embolism

Thromboprophylaxis in Hip- or Knee-Replacement Surgery

For prophylaxis of deep-vein thrombosis (DVT) and associated pulmonary embolism (PE) in adults who have undergone hip- or knee-replacement surgery, the recommended dosage of rivaroxaban is 10 mg once daily. The initial dose should be administered at least 6-10 hours after surgery, provided hemostasis has been established. The recommended duration of rivaroxaban therapy is 35 days for patients undergoing hip-replacement surgery and 12 days for patients undergoing knee-replacement surgery.

Treatment and Secondary Prevention

The recommended dosage of rivaroxaban for the treatment of acute DVT and/or PE is 15 mg orally twice daily for the first 21 days, followed by 20 mg once daily taken at approximately the same time every day. The initial twice-daily dosing regimen provides higher trough drug concentrations and may be associated with improved thrombus regression compared with a once-daily regimen.

To reduce the risk of recurrent venous thromboembolism after an initial 6 months of rivaroxaban treatment (secondary prevention), the recommended dosage of rivaroxaban is 20 mg once daily taken at approximately the same time every day.

The optimum duration of anticoagulant therapy should be determined by the individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors for thrombosis, presence of cancer, risk of bleeding). In general, the American College of Chest Physicians (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.

Transitioning to and from Rivaroxaban Therapy

When switching from warfarin to rivaroxaban therapy, the manufacturer states that warfarin should be discontinued and rivaroxaban initiated as soon as the INR is less than 3 to avoid periods of inadequate anticoagulation. When transitioning to rivaroxaban from therapy with other anticoagulants (e.g., low molecular weight heparin, oral anticoagulant other than warfarin), the initial dose of rivaroxaban should be administered within 2 hours of the next scheduled evening dose of the other anticoagulant, and the other anticoagulant should be discontinued. When transitioning to rivaroxaban from heparin given by continuous IV infusion, the heparin infusion should be discontinued and rivaroxaban initiated at the same time.

The manufacturer states that data from clinical trials currently are not available to guide conversion from rivaroxaban to warfarin therapy. A suggested approach is to discontinue rivaroxaban and simultaneously initiate a parenteral anticoagulant and warfarin at the time the next scheduled dose of rivaroxaban would have been administered. Because rivaroxaban may affect INR, INR measurements may not be useful in determining an appropriate dose of warfarin during conversion. When converting from rivaroxaban to an oral or parenteral anticoagulant with a rapid onset of action, rivaroxaban should be discontinued and the first dose of the other anticoagulant should be administered at the time of the next scheduled dose of rivaroxaban.

Managing Anticoagulation in Patients Requiring Invasive Procedures

If temporary discontinuance of anticoagulation is necessary prior to surgery or other invasive procedures to reduce the risk of bleeding, the manufacturer recommends that rivaroxaban be discontinued at least 24 hours prior to the procedure. In deciding whether a procedure should be delayed until 24 hours after the last dose of rivaroxaban, the increased risk of bleeding should be weighed against the urgency of the intervention. If rivaroxaban is discontinued prior to surgery or other invasive procedure, the drug should be resumed postoperatively as soon as adequate hemostasis has been established; if oral anticoagulation is not possible, use of a parenteral anticoagulant should be considered.(See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Warnings/Precautions: Warnings, in Cautions.)

Special Populations

Hepatic Impairment

Use of rivaroxaban should be avoided in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment or with any hepatic disease associated with coagulopathy; systemic exposure and risk of bleeding may be increased in such patients.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

Embolism Associated with Atrial Fibrillation

For patients with a creatinine clearance of 15-50 mL/minute, the recommended dosage of rivaroxaban is 15 mg once daily with the evening meal. The drug should not be used in patients with a creatinine clearance of less than 15 mL/minute. Renal function should be periodically assessed as clinically indicated (i.e., more frequently in situations where renal function may decline) and therapy adjusted accordingly. Rivaroxaban should be discontinued if acute renal failure develops.

In the ROCKET AF trial, serum concentrations of rivaroxaban and clinical outcomes were similar in patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute) receiving rivaroxaban 15 mg once daily compared with those with normal renal function receiving rivaroxaban 20 mg once daily. Although patients with creatinine clearance of 15-30 mL/minute were not studied, the manufacturer states that a rivaroxaban dosage of 15 mg once daily in such patients is expected to result in serum concentrations similar to those observed in patients with normal renal function.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Thromboprophylaxis in Hip- or Knee-Replacement Surgery

Use of rivaroxaban should be avoided in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) undergoing hip- or knee-replacement surgery because of an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population; the manufacturer makes no specific dosage recommendations for patients with mild or moderate renal impairment (creatinine clearance of 30-50 mL/minute). Such patients should be observed closely and promptly evaluated if any signs or symptoms of blood loss occur. Rivaroxaban should be discontinued if acute renal failure develops.

Treatment and Secondary Prevention of Venous Thromboembolism

Rivaroxaban should not be used for the treatment or secondary prevention of venous thromboembolism or for long-term thromboembolic risk reduction in patients with creatinine clearance less than 30 mL/minute because of an expected increase in rivaroxaban exposure and pharmacodynamic effects in such patients.

Body Weight

Dosage adjustments based on weight are not likely to be necessary. Extremes in body weight in patients weighing less than 50 kg or more than 120 kg did not influence rivaroxaban exposure.

Pregnant Women

An appropriate dosage of rivaroxaban in pregnant women has not been established.

Cautions

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, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events (e.g., stroke). An increased incidence of stroke was observed during the transition from rivaroxaban to warfarin in clinical trials (e.g., ROCKET AF) in patients with atrial fibrillation. In the ROCKET AF trial, rivaroxaban-treated patients generally were switched to warfarin without a period of concurrent administration of warfarin and rivaroxaban, so that they were not adequately anticoagulated until attaining a therapeutic international normalized ratio (INR). If discontinuance of rivaroxaban is required for reasons other than pathologic bleeding or completion of a course of therapy, anticoagulant coverage with an alternative anticoagulant should be considered. When transitioning patients from one anticoagulant therapy to another, it is important to ensure continuous anticoagulation while minimizing the risk of bleeding. Particular caution is advised when switching patients from a factor Xa inhibitor to warfarin therapy because of the slow onset of action of warfarin.(See Transitioning to and from Rivaroxaban Therapy under Dosage and Administration: Dosage.)

Spinal/Epidural Hematoma

Patients receiving anticoagulants are at risk of developing an epidural or spinal hematoma when concomitant neuraxial (epidural/spinal) anesthesia or spinal puncture is employed; such complications can result in long-term or permanent paralysis. Epidural and subdural hematomas have been reported during postmarketing experience in patients receiving rivaroxaban. The risk of these adverse events is increased by use of indwelling epidural catheters or by concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory agents (NSAIAs), platelet-aggregation inhibitors, or other anticoagulants. Risk also may be increased in patients with a history of traumatic or repeated epidural or spinal punctures, spinal deformity, or spinal surgery.

To reduce the risk of bleeding with concurrent use of rivaroxaban and neuraxial anesthesia or spinal puncture procedures, clinicians should carefully consider the pharmacokinetic profile of the anticoagulant. Insertion or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is minimal. Although the optimal timing between the administration of rivaroxaban and neuraxial procedures is not known, the following recommendations should be considered. At least 18 hours should elapse following administration of a rivaroxaban dose prior to removal of an epidural catheter, and at least 6 hours should elapse following removal of the catheter before the next dose is administered. If traumatic puncture occurs, administration of rivaroxaban should be delayed for 24 hours.

Patients receiving rivaroxaban in the setting of epidural or spinal anesthesia or lumbar puncture should be monitored frequently for manifestations of neurologic impairment (e.g., midline back pain; numbness, tingling, or weakness in lower limbs; bowel or bladder dysfunction). If spinal hematoma is suspected, urgent diagnosis and treatment are necessary; spinal cord decompression should be considered even though it may not prevent or reverse neurologic sequelae. Clinicians should consider the potential benefits versus risks of neuraxial intervention in patients who are currently receiving or will receive anticoagulant prophylaxis.

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, have been reported during postmarketing experience in patients receiving rivaroxaban to reduce the risk of deep-vein thrombosis (DVT).(See Cautions: Contraindications.)

Other Warnings and Precautions

Bleeding

Rivaroxaban increases the risk of hemorrhage and can cause serious or fatal bleeding. Bleeding complications were the most common adverse effects of rivaroxaban reported in clinical trials. In the ROCKET AF trial in patients with nonvalvular atrial fibrillation, bleeding that required permanent drug discontinuance occurred in 4.3% of patients receiving rivaroxaban and 3.1% of those receiving warfarin. The rate of major bleeding (defined as clinically overt bleeding that resulted in death, involved a critical site [i.e., intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal], was associated with a fall in hemoglobin of at least 2 g/dL or required transfusion of at least 2 units of whole blood or packed red blood cells, or resulted in permanent disability) was similar between the rivaroxaban and warfarin treatment groups in the ROCKET AF trial (5.6 and 5.4%, respectively); however, decreases in hemoglobin concentration of at least 2 g/dL, bleeding requiring transfusion, and major bleeding from a GI site were more common in patients receiving rivaroxaban. In the RECORD trials in patients undergoing orthopedic surgery, major bleeding (defined as fatal bleeding, bleeding into a critical organ, bleeding requiring reoperation, or extra-surgical site bleeding that was clinically overt and was associated with a fall in hemoglobin of at least 2 g/dL or that required transfusion of at least 2 units of whole blood or packed red blood cells) was reported in 0.3% of patients who received rivaroxaban 10 mg once daily and 0.2% of those who received enoxaparin. Although bleeding rates were comparable between rivaroxaban and enoxaparin in these trials, comparison of bleeding rates in the RECORD trials with those of other trials involving non-vitamin K antagonist oral anticoagulants and enoxaparin may be confounded by the use of different definitions for major bleeding. In the EINSTEIN DVT and EINSTEIN PE studies evaluating rivaroxaban for the treatment of venous thromboembolism, rates of major bleeding and clinically relevant nonmajor bleeding were similar between patients receiving rivaroxaban and those receiving enoxaparin plus a vitamin K antagonist; in the EINSTEIN EXT study in which rivaroxaban was compared with placebo, there was a slight increase in major and clinically relevant nonmajor bleeding with rivaroxaban therapy.

When deciding whether to use rivaroxaban in patients with an increased risk of bleeding (e.g., congenital or acquired bleeding disorders; active ulceration, hemorrhagic stroke, uncontrolled arterial hypertension, diabetic retinopathy; recent brain, spinal, or ophthalmic surgery), clinicians should weigh the risk of bleeding against the risk of thrombotic events. Patients with any manifestations of blood loss during rivaroxaban therapy should be promptly evaluated. Rivaroxaban should be discontinued if active pathologic hemorrhage occurs.(See Cautions: Contraindications.) However, minor or ''nuisance'' bleeding is a common occurrence in patients receiving any anticoagulant and should not readily lead to treatment discontinuance.(See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Warnings/Precautions: Warnings, in Cautions.)

Risk of bleeding may be increased in patients with renal impairment and in those receiving concomitant therapy with drugs that affect hemostasis (e.g., aspirin, NSAIAs, fibrinolytics, thienopyridines, other antithrombotic agents) or drugs that are inhibitors of both P-glycoprotein and cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., ketoconazole, ritonavir). Patients with renal impairment taking P-glycoprotein inhibitors and weak to moderate CYP3A4 inhibitors may have substantial increases in exposure to rivaroxaban, which may increase bleeding risk. (See Drug Interactions and also see Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Because of the risk of pregnancy-related hemorrhage and/or emergent delivery, rivaroxaban should be used with caution in pregnant women.(See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.) Pregnant women who receive rivaroxaban should be promptly evaluated if any manifestations of blood loss occur, such as a decline in hemoglobin and/or hematocrit, hypotension, or fetal distress.

There is no specific antidote or reversal agent for rivaroxaban; the manufacturer states that the drug should be discontinued and appropriate treatment initiated if bleeding associated with overdosage occurs. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Procoagulant reversal agents such as prothrombin complex concentrate (PCC), anti-inhibitor coagulant complex (also known as activated prothrombin complex concentrate), or factor VIIa (recombinant) may be considered for immediate reversal of the anticoagulant effect of rivaroxaban; however, data from clinical studies are limited. In a randomized, double-blind, placebo-controlled study in 12 healthy men receiving rivaroxaban 20 mg twice daily, administration of a single dose of a 4-factor PCC (50 units/kg by IV infusion) immediately and completely reversed the anticoagulant effects of rivaroxaban as assessed by the prothrombin time and endogenous thrombin potential (ETP). Because the study was conducted in healthy individuals, caution should be used in extrapolating these findings to clinical practice. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban, and there is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) or systemic hemostatics (desmopressin, aprotinin [no longer commercially available in the US]) in patients receiving rivaroxaban.

Patients with Prosthetic Heart Valves

Safety and efficacy of rivaroxaban have not been established in patients with prosthetic heart valves, and the manufacturer states that the drug is not recommended in such patients.

Patients with Pulmonary Embolism

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

Specific Populations

Pregnancy

Category C.

There are no adequate or well-controlled studies of rivaroxaban in pregnant women. In animal reproduction studies, pronounced maternal bleeding, postimplantation pregnancy loss, and fetotoxic effects have been observed. Because of the risks associated with rivaroxaban during pregnancy (e.g., hemorrhage, emergent delivery while receiving an anticoagulant that is not readily reversible), the manufacturer states that the drug should be used with caution in pregnant women and only if the potential benefits justify the potential risks to the mother and fetus. The American College of Chest Physicians (ACCP) recommends that rivaroxaban be avoided in pregnant women. Women of childbearing potential should discuss pregnancy planning with their clinician prior to initiating rivaroxaban therapy. Rivaroxaban dosing in pregnancy has not been studied.

Lactation

Rivaroxaban and/or its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into milk in humans. Because of the potential for serious adverse reactions to rivaroxaban in nursing infants, the manufacturer states that a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. ACCP recommends that anticoagulants other than rivaroxaban be used in nursing women.

Pediatric Use

Safety and efficacy have not been established in pediatric patients younger than 18 years of age.

Geriatric Use

No substantial differences in efficacy were observed in geriatric patients 65 years of age or older relative to younger adults in clinical trials. Although thrombotic and bleeding events occurred at a higher rate in older patients, the risk-to-benefit profile was favorable in all age groups.

Hepatic Impairment

Results of a pharmacokinetic study indicate that rivaroxaban exposure (area under the plasma concentration-time curve [AUC] and peak plasma concentrations) and pharmacodynamic effects (inhibition of factor Xa activity and prolongation of prothrombin time [PT]) are increased in patients with moderate hepatic impairment (Child-Pugh class B). Clinically important changes in pharmacokinetics or pharmacodynamics of rivaroxaban were not observed in patients with mild hepatic impairment (Child-Pugh class A). The safety and pharmacokinetics of rivaroxaban in patients with severe hepatic impairment (Child-Pugh class C) have not been established. Patients with substantial liver disease (hepatitis or cirrhosis) were excluded from the major efficacy trials of rivaroxaban.

Rivaroxaban should not be used in patients with moderate or severe hepatic impairment or with any hepatic disease associated with coagulopathy.

Renal Impairment

Clearance of rivaroxaban is decreased in patients with renal impairment, resulting in increased systemic exposure and pharmacodynamic effects. Rivaroxaban should be discontinued in patients who develop acute renal failure.

In a study in individuals with various degrees of renal function, rivaroxaban AUC was increased by 44, 52, or 64% in those with mild (creatinine clearance of 50-79 mL/minute), moderate (creatinine clearance of 30-49 mL/minute), or severe (creatinine clearance of 15-29 mL/minute) renal impairment, respectively, compared with individuals with normal renal function (creatinine clearance of at least 80 mL/minute). Increased pharmacodynamic effects (PT prolongation, factor Xa inhibition) also were observed with decreasing renal function.

In patients with nonvalvular atrial fibrillation, renal function should be assessed periodically and dosage of rivaroxaban adjusted accordingly. More frequent monitoring may be necessary in situations in which renal function may be expected to decline. Patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute) who received a reduced dosage of rivaroxaban (15 mg once daily) had clinical outcomes similar to those in patients with normal renal function who received a dosage of 20 mg once daily. Rivaroxaban should be avoided in patients with nonvalvular atrial fibrillation who have a creatinine clearance of less than 15 mL/minute.(See Embolism Associated with Atrial Fibrillation under Special Populations: Renal Impairment, in Dosage and Administration.)

In an analysis of pooled data from RECORD trials 1-3, bleeding risk was not increased in patients with creatinine clearance of 30-50 mL/minute, but a possible increase in total venous thromboembolism was observed in this population. Patients with creatinine clearance of 30-50 mL/minute receiving rivaroxaban therapy for prophylaxis of DVT following hip- or knee-replacement surgery should be observed closely and promptly evaluated if any manifestations of bleeding occur. Rivaroxaban should not be used in such patients with creatinine clearance of less than 30 mL/minute because of a risk of increased exposure to the drug, which may increase risk of bleeding.

Patients with creatinine clearance less than 30 mL/minute were excluded from the EINSTEIN studies evaluating the use of rivaroxaban for treatment of venous thromboembolism; the manufacturer states that rivaroxaban should not be used in such patients because of an expected increase in drug exposure and pharmacodynamic effects.

Patients with renal impairment receiving concomitant therapy with drugs that are combined P-glycoprotein and moderate CYP3A4 inhibitors may experience a substantial increase in rivaroxaban exposure, which may increase risk of bleeding.(See Drug Interactions: Drugs Affecting P-glycoprotein Transport and CYP3A4.)

Common Adverse Effects

Bleeding was the most common adverse effect reported in clinical trials of rivaroxaban, occurring in more than 5% of patients receiving the drug.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Rivaroxaban is metabolized by cytochrome P-450 (CYP) isoenzymes 3A4/5 and 2J2; inhibitors or inducers of these enzymes may potentially alter rivaroxaban exposure.(See Drug Interactions: Drugs Affecting P-glycoprotein Transport and CYP3A4.)

In vitro studies indicate that rivaroxaban does not inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A4 nor induce CYP1A2, 2B6, 2C19, and 3A4; therefore, drug interactions involving these pathways are unlikely.

Drugs Affecting Efflux Transport Systems

Rivaroxaban is a substrate of the efflux transporter P-glycoprotein; inhibitors or inducers of this transport protein may potentially alter rivaroxaban exposure.(See Drug Interactions: Drugs Affecting P-glycoprotein Transport and CYP3A4.) In vitro data indicate a low inhibitory potential of rivaroxaban for this transport protein.

Rivaroxaban is a substrate of the efflux transporter ABCG2 (breast cancer resistance protein [BCRP]); inhibitors or inducers of this transport protein may potentially alter rivaroxaban exposure. In vitro data indicate a low inhibitory potential of rivaroxaban for this transporter.

Drugs Affecting P-glycoprotein Transport and CYP3A4

Concomitant use of rivaroxaban with drugs that inhibit both P-glycoprotein and CYP3A4 (e.g, clarithromycin, erythromycin, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, conivaptan) increases exposure to and pharmacodynamic effects (e.g., factor Xa inhibition, prolongation of prothrombin time [PT]) of rivaroxaban. A substantial increase in rivaroxaban exposure may increase risk of bleeding; however, the extent of this interaction appears to be related to the degree of P-glycoprotein or CYP3A4 inhibition, and in some cases the increased exposure may not have a substantial effect on bleeding. The manufacturer states that concomitant use of rivaroxaban and combined P-glycoprotein and potent CYP3A4 inhibitors such as ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, and conivaptan should be avoided. When clinical data suggest that increased rivaroxaban exposure is unlikely to affect bleeding, such as in the case of concomitant clarithromycin or erythromycin in patients receiving prophylaxis for deep-vein thrombosis (DVT), no special precautions are necessary for concomitant use with drugs that are combined P-glycoprotein and CYP3A4 inhibitors.

Combined P-glycoprotein and potent CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [Hypericum perforatum]) may decrease exposure to rivaroxaban, resulting in possible reduced efficacy; such concomitant use should be avoided.

Results from a pharmacokinetic trial with erythromycin 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-glycoprotein and moderate CYP3A4 inhibitor (e.g., diltiazem, verapamil, dronedarone, erythromycin). While increases in rivaroxaban exposure can be expected under such conditions, analysis of data from the ROCKET AF trial showed no increased risk of bleeding in patients with moderate renal impairment (creatinine clearance of 30-49 mL/minute) who received rivaroxaban in conjunction with combined P-glycoprotein and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, erythromycin). The manufacturer states that rivaroxaban should not be used in patients with creatinine clearances of 15-80 mL/minute who are receiving concomitant therapy with a combined P-glycoprotein and moderate CYP3A4 inhibitor unless the potential benefits justify the potential risks.

Drugs Affecting Gastric Acidity

Concomitant administration of a single 30-mg dose of rivaroxaban with ranitidine (150 mg twice daily) or an antacid containing aluminum hydroxide and magnesium hydroxide (10 mL) did not affect bioavailability of or exposure to rivaroxaban. Concomitant administration of a single 20-mg dose of rivaroxaban and omeprazole (40 mg once daily for 5 days) also did not affect the pharmacokinetics of rivaroxaban.

Drugs Affecting Hemostasis

Concomitant use of rivaroxaban and drugs that affect hemostasis (e.g., aspirin, platelet-aggregation inhibitors, other antithrombotic agents, fibrinolytics, nonsteroidal anti-inflammatory agents [NSAIAs]) increases risk of bleeding.

Anticoagulants

Because of an increased risk of bleeding, use of other anticoagulants should be avoided in patients receiving rivaroxaban unless the benefits outweigh the risks.(See Bleeding under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Concomitant administration of a single 40-mg dose of enoxaparin sodium with rivaroxaban 10 mg resulted in an additive effect on antifactor Xa activity; enoxaparin did not affect the pharmacokinetics of rivaroxaban. Administration of a single 15-mg dose of warfarin sodium with rivaroxaban 5 mg resulted in additive effects on factor Xa inhibition and prothrombin time; warfarin did not affect the pharmacokinetics of rivaroxaban.

Nonsteroidal Anti-inflammatory Agents

Patients receiving concomitant therapy with rivaroxaban and NSAIAs, including aspirin, should be promptly evaluated if any manifestations of blood loss occur.

In a single-dose drug interaction study in healthy men, concomitant administration of rivaroxaban 15 mg and naproxen (500 mg daily for 2 days) did not result in any substantial pharmacokinetic or pharmacodynamic interaction; although bleeding time was slightly increased, this was not considered clinically important.

In a single-dose study in healthy men, concurrent administration of aspirin and rivaroxaban 15 mg resulted in a slightly increased bleeding time compared with administration of aspirin alone, but did not affect the inhibitory effects of aspirin on platelet aggregation. No substantial change in pharmacokinetics or pharmacodynamics of rivaroxaban was observed. In the ROCKET AF trial, concomitant use of aspirin was identified as an independent risk factor for major bleeding.

Platelet-aggregation Inhibitors

Patients receiving concomitant therapy with rivaroxaban and clopidogrel or other platelet-aggregation inhibitors (see Nonsteroidal Anti-inflammatory Agents under Drug Interactions: Drugs Affecting Hemostasis) should be promptly evaluated if any manifestations of blood loss occur. In 2 drug interaction studies in which healthy individuals received clopidogrel (300-mg loading dose followed by 75 mg daily) and a single 15-mg dose of rivaroxaban concomitantly, bleeding time was increased to 45 minutes (approximately twice the maximum increase observed with either drug alone) in approximately 30-45% of these individuals; no change in pharmacokinetics of either drug was observed.

Atorvastatin

A substantial pharmacokinetic interaction was not observed with concomitant administration of rivaroxaban (20 mg) and atorvastatin (20 mg once daily) in a study in healthy individuals. However, in the RECORD trials, the incidence of major or nonmajor clinically relevant bleeding was increased in patients receiving the combination of rivaroxaban and a statin compared with those receiving enoxaparin and a statin (23 or 18%, respectively).

Azole Antifungals

Concomitant administration of rivaroxaban and ketoconazole (a combined P-glycoprotein and potent CYP3A4 inhibitor) increased steady-state exposure (area under the plasma concentration-time curve [AUC]) and peak plasma concentrations of rivaroxaban by 160 and 70%, respectively; similar increases in pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) also were observed. Concomitant use of ketoconazole should be avoided in patients receiving rivaroxaban. Because of the potential for substantially increased rivaroxaban exposure which may increase risk of bleeding, concomitant use of rivaroxaban and itraconazole (a combined P-glycoprotein and potent CYP3A4 inhibitor) also should be avoided.

Concomitant administration of a single dose of rivaroxaban and fluconazole (a moderate CYP3A4 inhibitor) increased AUC and peak plasma concentrations of rivaroxaban by 40 and 30%, respectively.

Digoxin

A substantial pharmacokinetic interaction was not observed with concomitant administration of rivaroxaban (20 mg) and digoxin (0.375 mg once daily) in healthy individuals.

HIV Protease Inhibitors

AUC and peak plasma concentrations of rivaroxaban were increased substantially (by 150 and 60%, respectively) when administered concurrently with ritonavir; similar increases in pharmacodynamic effects also were observed.

Because of the potential for substantially increased rivaroxaban exposure which may increase risk of bleeding, concomitant use of rivaroxaban with ritonavir, lopinavir/ritonavir, or indinavir should be avoided.

Macrolide Antibiotics

Concomitant administration of a single dose of rivaroxaban with clarithromycin increased AUC and peak plasma concentrations of rivaroxaban by 50 and 40%, respectively. Both single-dose AUC and peak plasma concentrations of rivaroxaban were increased by 30% when administered concomitantly with erythromycin. In both cases, the increased exposure is not expected to increase risk of bleeding; therefore, the manufacturer states that no special precautions are necessary with concomitant administration of clarithromycin or erythromycin and rivaroxaban.

Midazolam

A substantial pharmacokinetic interaction was not observed with concomitant administration of rivaroxaban (20 mg) and midazolam (single dose of 7.5 mg) in healthy individuals.

Protein-bound Drugs

Interactions between rivaroxaban and other highly protein-bound drugs such as phenytoin or aspirin are likely.

Rifampin

Concomitant administration of rifampin (a combined P-glycoprotein and potent CYP3A4 inducer) titrated up to a dosage of 600 mg once daily and a single 20-mg dose of rivaroxaban (with food) decreased AUC and peak plasma concentrations of rivaroxaban by 50 and 22%, respectively; similar decreases in pharmacodynamic effects also were observed. Because of the potential for reduced efficacy of rivaroxaban, concomitant use of rifampin should be avoided.

Write Your Own Review
You're reviewing:XARELTO 10 MG TABLET
Your Rating

How to save on your prescriptions!