Important Safety Information

CONTRAINDICATIONS

• Active pathological bleeding

• Severe hypersensitivity reaction to XARELTO^®

WARNINGS AND PRECAUTIONS

• Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO^®, in the absence of adequate alternative anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO^® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO^® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

• Risk of Bleeding: XARELTO^® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO^® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO^® in patients with active pathological hemorrhage.

  • A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

  • Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

  • Concomitant use of drugs that are combined P‑gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

• Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

  An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO^®. The next XARELTO^® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO^® for 24 hours if traumatic puncture occurs.

• Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO^® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C

• Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO^® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO^® should not receive XARELTO^®.

DOSING AND ADMINISTRATION

• For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO^® is 20 mg taken orally once daily with the evening meal. For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal.

• Missed Dose: If a dose of XARELTO^® is not taken at the scheduled time, administer the dose as soon as possible on the same day.

• Instructions for Patient Use

  • Remind patients to not discontinue XARELTO^® without first talking to their healthcare professional to minimize the risk of post-discontinuation thrombotic events.

  • Advise patients with atrial fibrillation to take XARELTO^® once daily with the evening meal.

DRUG INTERACTIONS

• Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO^® with combined P‑gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

• Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO^® with drugs that are combined P‑gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

• NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO^®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

• Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.

• Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P‑gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk (eg, amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, azithromycin, chloramphenicol, and cimetidine).

USE IN SPECIFIC POPULATIONS

• Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO^®, taking into account the importance of the drug to the mother.

• Geriatric Use: In clinical trials the efficacy of XARELTO^® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

• Renal Impairment

  • Patients with renal impairment taking P‑gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.

  • For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO^® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO^® in patients who develop acute renal failure while on XARELTO^®.

• Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO^® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE

• Overdose of XARELTO^® may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO^® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO^® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES

• Hemorrhage: The most common adverse reactions with XARELTO^® were bleeding complications.

• The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO^® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO^®- versus warfarin-treated patients, respectively, major bleeding events were 5.6% versus 5.4%.

• Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO^®
  10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Please see full Prescribing Information, including Boxed WARNINGS.

Indication

XARELTO^® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO^® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

02X11219R1
Revised 11/17/11