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Active pathological bleeding
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Severe hypersensitivity reaction to ZORALTO (eg, anaphylactic reactions)
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Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including ZORALTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ZORALTO to warfarin in clinical trials in atrial fibrillation patients. If ZORALTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
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Risk of Bleeding: ZORALTO increases the risk of bleeding and can cause serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue in patients with active pathological hemorrhage.
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An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable.
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Concomitant use of other drugs that impair hemostasis increases risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). |
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Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding: Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of ZORALTO for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage; active cancer (ie, undergoing acute, in-hospital cancer treatment); active gastroduodenal ulcer or history of bleeding in the three months prior to treatment; or dual antiplatelet therapy. ZORALTO is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.
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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. To reduce the potential risk of bleeding associated with concurrent use of ZORALTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of ZORALTO. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of ZORALTO is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (ie, 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of ZORALTO. The next dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of ZORALTO for 24 hours. Monitor frequently to detect signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), or bowel and/or bladder dysfunction. Instruct patients to immediately report any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
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Use in Patients with Renal Impairment:
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Nonvalvular Atrial Fibrillation: Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation in patients who develop acute renal failure while on ZORALTO. Clinical efficacy and safety studies with ZORALTO did not enroll patients with CrCl <30 mL/min or end-stage renal disease (ESRD) on dialysis.
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Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of ZORALTO in these patients. Discontinue ZORALTO in patients who develop acute renal failure while on treatment.
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Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of ZORALTO in these patients. Discontinue ZORALTO in patients who develop acute renal failure while on treatment.
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Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of ZORALTO in these patients. Discontinue ZORALTO in patients who develop acute renal failure while on treatment.
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Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD: For patients with CrCl <15 mL/min, no data are available, and limited data are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, a dose of 2.5 mg ZORALTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min), whose efficacy and safety outcomes were similar to those with preserved renal function. Clinical efficacy and safety studies with ZORALTO did not enroll patients with end-stage renal disease (ESRD) on dialysis.
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Use in Patients with Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid use 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.
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Use with P-gp and Strong CYP3A Inhibitors or Inducers: Avoid concomitant use of ZORALTO with known combined P-gp and strong CYP3A inhibitors or inducers.
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Risk of Pregnancy-Related Hemorrhage: In pregnant women, ZORALTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. ZORALTO dosing in pregnancy has not been studied. The anticoagulant effect of ZORALTO cannot be monitored with standard laboratory testing. Promptly evaluate signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
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Patients with Prosthetic Heart Valves:
Use of ZORALTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR), based on the results of the GALILEO study, which reported higher rates of death and bleeding in patients randomized to ZORALTO compared to those randomized to an antiplatelet regimen. Safety and efficacy of ZORALTO have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of ZORALTO is not recommended in patients with prosthetic heart valves.
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Acute PE in Hemodynamically Unstable Patients/Patients Who Require Thrombolysis or Pulmonary Embolectomy: Initiation of ZORALTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
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Increased Risk of Thrombosis in Patients with Antiphospholipid Syndrome: Direct-acting oral anticoagulants (DOACs), including ZORALTO, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
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Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase risk of bleeding.
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Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase risk of thromboembolic events.
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ZORALTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (eg, erythromycin) unless the potential benefit justifies the potential risk.
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Coadministration of enoxaparin, warfarin, aspirin, clopidogrel, and chronic NSAID use may increase risk of bleeding.
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Avoid concurrent use of ZORALTO with other anticoagulants due to increased bleeding risk, unless benefit outweighs risk. Promptly evaluate signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.
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USE IN SPECIFIC POPULATIONS
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Pregnancy: The limited available data on ZORALTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use ZORALTO with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery. The anticoagulant effect of ZORALTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of ZORALTO for the mother and possible risks to the fetus when prescribing to a pregnant woman.
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Fetal/Neonatal adverse reactions: Based on
the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any
site in the fetus and/or neonate.
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Labor or delivery: The risk of bleeding should be balanced with the risk of thrombotic events when considering use in this setting.
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There are no adequate or well-controlled studies of ZORALTO in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage.
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Lactation: Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for ZORALTO and any potential adverse effects on the breastfed infant from ZORALTO or from the underlying maternal condition.
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Females and Males of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.
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Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
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Overdose of ZORALTO may lead to hemorrhage. Discontinue ZORALTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.
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ADVERSE REACTIONS IN CLINICAL STUDIES
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Most common adverse reactions with ZORALTO were bleeding complications.
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ZORALTO is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE-related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE, and not at high risk of bleeding.
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DOAC = direct oral anticoagulant; VTE = venous thromboembolism.
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XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany.
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