Stroke Risk in Patients With Atrial Fibrillation (AF)

CONTRAINDICATIONS

• Active pathological bleeding

• Severe hypersensitivity reaction to XARELTO^® (e.g., anaphylactic reactions)

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 and consider the need for blood replacement. Discontinue XARELTO^® in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

  • 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 other 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. If traumatic puncture occurs, the administration of XARELTO^® is to be delayed 24 hours.

• Use in Patients With Renal Impairment:

  • Nonvalvular Atrial Fibrillation: Avoid the use of XARELTO^® in patients with creatinine clearance (CrCl) <15 mL/min since drug exposure is increased. 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^®.

  • Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO^® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.

  • Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO^® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO^® should discontinue the treatment.

• Use in Patients With Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid 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, since drug exposure and bleeding risk may be increased.

• Use With P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO^® with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan). Avoid concomitant use of XARELTO^® with drugs that are P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort).

• Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO^® should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO^® dosing in pregnancy has not been studied. 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).

DRUG INTERACTIONS

• Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO^® with combined P-gp and strong CYP3A4 inhibitors.

• Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Results from drug interaction studies and population pharmacokinetic (PK) analyses from clinical studies — coadministration of XARELTO^® with a combined P-gp and strong CYP3A4 inducers (eg, rifampin, phenytoin) decreased rivaroxaban exposure by 27%-50%. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy. Avoid concomitant use of XARELTO^® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort).

• Anticoagulants and NSAIDs/Aspirin: Single doses of enoxaparin and XARELTO^® given concomitantly resulted in an additive effect on anti-factor Xa activity. Single doses of warfarin and XARELTO^® resulted in an additive effect on factor Xa inhibition and PT. Concomitant aspirin use has been identified as an independent risk factor for major bleeding in efficacy trials. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO^®. Avoid concurrent use of XARELTO^® with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

• Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Patients with renal impairment receiving full dose XARELTO^® in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (eg, amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected. XARELTO^® should be used in patients with CrCl 15 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.

USE IN SPECIFIC POPULATIONS

• Pregnancy Category C: There are no adequate or well-controlled studies of XARELTO^® in pregnant women, and dosing for pregnant women has not been established. Use XARELTO^® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO^® cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post implantation pregnancy loss occurred in rabbits. XARELTO^® should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus.

• Labor and Delivery: Safety and effectiveness of XARELTO^® during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum exposure of the unbound drug at the human dose of 20 mg/day).

• Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and 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.

• Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use: In the EINSTEIN DVT, PE, and Extension clinical studies, approximately 37% were 65 years and over and about 16% were >75 years. 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.

• Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

• Renal Impairment: In a pharmacokinetic study, comparing healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44% to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed. In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO^® in patients with CrCl <30 mL/min.

• Hepatic Impairment: In a pharmacokinetic study, comparing healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B). The safety and PK of XARELTO^® in patients with hepatic impairment (Child-Pugh C) have not been evaluated. 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. Discontinue XARELTO^® and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. 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.

• Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, 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 non-bleeding adverse events was similar in both treatment groups.

• Treatment of DVT, PE and to Reduce the Risk of Recurrence of DVT and of PE: In the pooled analysis of the EINSTEIN DVT and PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO^® versus enoxaparin/vitamin K antagonist (VKA) incidence rates of 1.7% versus 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO^®-treated patients and 204 days for enoxaparin/VKA-treated patients. In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for XARELTO^® versus 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both XARELTO^® and placebo treatment groups.

• Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO^®.

• 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.

K02X121084
Please see full Prescribing Information, including Boxed WARNINGS.