Class: Direct factor Xa inhibitor
- Tablets, oral 10 mg
- Tablets, oral 15 mg
- Tablets, oral 20 mg
Selectively blocks the active site of factor Xa.
Absorption is dependent on the site of drug release in the GI tract; AUC and C max are decreased 29% and 56%, respectively, when released in the proximal small intestine. Absolute bioavailability is approximately 80% to 100% for the 10 mg dose and is not affected by food. Absolute bioavailability for the 20 mg dose is 66% in the fasted state; administration with food increases the bioavailability. T max is 2 to 4 h.
Plasma protein binding is approximately 92% to 95% (primarily albumin). The Vd is approximately 50 L.
Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites.
Approximately 51% of an orally administered dose was recovered as metabolites in urine (30%) and feces (21%). Following oral administration of a dose, 66% of the radioactive dose was recovered in urine (36% as unchanged drug) and 28% was recovered in feces (7% as unchanged drug). Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration. Systemic Cl is approximately 10 L/h. The terminal elimination half-life is 5 to 9 h.
Special PopulationsRenal Function Impairment
Rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.Hepatic Function Impairment
Significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh class B). Increases in pharmacodynamic effects were also observed. No clinical data are available for patients with severe hepatic impairment.Elderly
Elderly patients exhibit higher plasma concentrations than younger patients, with mean AUC values being approximately 50% higher, mainly because of reduced (apparent) total body and renal Cl. The terminal elimination half-life is 11 to 13 h in elderly patients.Gender
Gender did not influence the pharmacokinetics or pharmacodynamics of rivaroxaban.Race
Healthy Japanese subjects were found to have 20% to 40% higher exposures compared with other ethnicities, including Chinese subjects.Body weight
Body weight did not influence exposure.
Indications and Usage
For the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery; to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
Hypersensitivity to rivaroxaban; active pathological bleeding.
Dosage and AdministrationDeep Vein Thrombosis Prophylaxis
PO 10 mg once daily. Initial dose should be taken at least 6 to 10 h after surgery once hemostasis has been established. Usual duration of therapy is 35 days following hip replacement surgery or 12 days following knee replacement surgery.Nonvalvular Atrial Fibrillation
PO 20 mg once daily with the evening meal.Conversion
When switching patients from warfarin, discontinue warfarin and start rivaroxaban as soon as the INR is below 3. When switching patients to warfarin, one approach is to discontinue rivaroxaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban should be taken. Because rivaroxaban affects the INR, INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. For patients receiving anticoagulants other than warfarin, start rivaroxaban 0 to 2 h prior to the next scheduled evening administration of the drug and omit administration of the other anticoagulant. For unfractionated heparin administered by continuous infusion, stop the infusion and start rivaroxaban at the same time. To transition from rivaroxaban to an anticoagulant with a rapid onset, discontinue rivaroxaban and give the first dose of the other anticoagulant at the time that the next dose of rivaroxaban would have been taken.Renal Function Impairment
Deep vein thrombosis prophylaxis Adults
PO For CrCl 30 to 50 mL/min, observe closely and promptly evaluate any signs or symptoms of blood loss. Avoid use in patients with CrCl less than 30 mL/min.Nonvalvular atrial fibrillation Adults
PO For CrCl 15 to 50 mL/min, 15 mg once daily with the evening meal. Avoid use in patients with CrCl less than 15 mL/min.
- For prophylaxis of DVT, rivaroxaban may be taken with or without food. For nonvalvular atrial fibrillation, administer with evening meal.
- If a dose is not taken at the scheduled time, it should be taken as soon as possible on the same day.
- If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, stop rivaroxaban at least 24 h before the procedure. Restart rivaroxaban after the surgical or other procedure as soon as adequate hemostasis has been established. If oral medication cannot be taken after surgical intervention, consider administering a parenteral anticoagulant.
- An epidural catheter should not be removed earlier than 18 h after the last administration of rivaroxaban. The next rivaroxaban dose is not to be administered earlier than 6 h after the removal of the catheter. If traumatic puncture occurs, the administration of rivaroxaban is to be delayed for 24 h.
Store between 59° and 86°F.
Drug InteractionsAspirin, clopidogrel, desirudin, drugs that are both strong CYP3A4 inhibitors and P-glycoprotein inhibitors (eg, conivaptan, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, voriconazole), heparins (eg, enoxaparin), NSAIDs (eg, naproxen), ticlopidine, tissue plasminogen activators (eg, alteplase), warfarin
The risk of bleeding may be increased when rivaroxaban is given concomitantly with these agents. If coadministration cannot be avoided, closely monitor patients and promptly evaluate any signs or symptoms of blood loss.Drugs that are both strong CYP3A4 inducers and P-glycoprotein inducers (eg, carbamazepine, phenytoin, rifampin, St. John's wort)
Rivaroxaban efficacy may be decreased. If coadministration cannot be avoided, consider increasing the rivaroxaban dose.Food
Coadministration of rivaroxaban 20 mg with food increases rivaroxaban bioavailability. Rivaroxaban 15 and 20 mg should be taken with the evening meal.
Syncope (1%); cerebral hemorrhage, epidural hematoma, hemiparesis, subdural hematoma (postmarketing).
Pruritus (2%); blister (1%); Steven-Johnson syndrome (postmarketing).
Any bleeding event (6%); agranulocytosis, retroperitoneal hemorrhage (postmarketing).
Cholestasis, cytolytic hepatitis, jaundice (postmarketing).
Anaphylactic reaction, anaphylactic shock, hypersensitivity (postmarketing).
Pain in extremity (2%); muscle spasm (1%).
Wound secretion (3%).
WarningsDiscontinuation in patients with nonvalvular atrial fibrillation
Discontinuing rivaroxaban places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.Spinal/Epidural hematoma
Epidural or spinal hematomas may occur in patients who are treated with rivaroxaban and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include the following: use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as NSAIDs, platelet inhibitors, and other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; and a history of spinal deformity or spinal surgery.
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients who are anticoagulated or are to be anticoagulated for thromboprophylaxis.
Promptly monitor and evaluate patients for signs and symptoms of blood loss (eg, drop in hemoglobin and/or hematocrit, hypotension). Monitor patients frequently for signs and symptoms of neurological impairment. Periodically assess renal function as clinically indicated.
Category C . Dosing for pregnant women has not been established. There is the potential for pregnancy-related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible.
Safety and efficacy have not been established.
Both thrombotic and bleeding event rates were higher in older patients, but the risk-benefit profile was favorable in all age groups.
Anaphylaxis has been reported.
Avoid use in patients with CrCl less than 30 mL/min (DVT prophylaxis) or CrCl less than 15 mL/min (nonvalvular atrial fibrillation). Observe closely and promptly evaluate any signs or symptoms of blood loss in patients being treated with rivaroxaban for DVT prophylaxis with moderate renal impairment (CrCl 30 to less than 50 mL/min). Adjust the dose of rivaroxaban in patients with nonvalvular atrial fibrillation and CrCl 15 to 50 mL/min. Patients who develop acute renal failure while on treatment should discontinue the treatment.
Avoid use in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment or with any hepatic disease associated with coagulopathy.
Increased risk of bleeding; serious and fatal bleeding may occur.
- Remind patients not to discontinue rivaroxaban prematurely without first talking to their health care provider.
- Advise patients with atrial fibrillation to take rivaroxaban once daily with the evening meal.
- If a dose is missed, advise patients to take rivaroxaban as soon as possible and continue on the following day with their once-daily dose regimen.
- If patients have had neuraxial anesthesia or spinal puncture and particularly if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs), and muscular weakness. If any of these symptoms occur, advise patients to contact their health care provider immediately.
- Advise patients to report any unusual bleeding or bruising to their health care provider. Inform patients that it might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily when they are treated with rivaroxaban.
- Advise patients to inform their health care providers and dentists if they are taking, or planning to take, any prescription, OTC, or herbal products, so potential interactions can be evaluated.
- Advise patients to inform their health care provider immediately if they become pregnant or intend to become pregnant during treatment with rivaroxaban. Advise pregnant women receiving rivaroxaban to immediately report to their health care provider any bleeding or symptoms of blood loss.
- Advise patients to discuss with their health care provider if they are breast-feeding or intend to breast-feed during anticoagulant treatment.
- Advise female patients of childbearing potential requiring anticoagulation to discuss pregnancy planning with their health care provider.
Copyright © 2009 Wolters Kluwer Health.
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