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Xarelto is a brand name for Rivaroxaban. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE XARELTO is a factor Xa inhibitor indicated: to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation ( 1.1 ) for treatment of deep vein thrombosis (DVT) ( 1.2 ) for treatment of pulmonary embolism (PE) ( 1.3 ) for reduction in the risk of recurrence of DVT or PE ( 1.4 )…
Verbatim from this product's FDA label. Tap a section to expand.
6) ] . 3) ] . 6) ] . 4) ] . 5 mg twice daily , plus aspirin (75–100 mg) once daily. When starting therapy after a successful lower extremity revascularization procedure, initiate once hemostasis has been established. 2 Recommended Dosage in Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients Table 2: Recommended Dosage in Pediatric Patients Birth to Less than 18 Years for Treatment of and Reduction in Risk of Recurrent VTE Initiate XARELTO treatment following at least 5 days of initial parenteral anticoagulation therapy.
6 kg at the time of dosing. Dosage Form Body Weight 1 mg XARELTO = 1 mL Suspension Dosage Total Daily Dose All doses should be taken with feeding or with food since exposures match that of 20 mg daily dose in adults. 9 kg 15 mg 15 mg ≥50 kg 20 mg 20 mg Dosing of XARELTO was not studied and therefore dosing cannot be reliably determined in the following patient populations.
6 kg. To increase absorption, all doses should be taken with feeding or with food. Monitor the child's weight and review the dose regularly, especially for children below 12 kg. This is to ensure a therapeutic dose is maintained.
All pediatric patients (except <2 years old with catheter-related thrombosis):
Therapy with XARELTO should be continued for at least 3 months in children with thrombosis. Treatment can be extended up to 12 months when clinically necessary. The benefit of continued therapy beyond 3 months should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential risk of bleeding.
Pediatric patients <2 years old with catheter-related thrombosis:
Therapy with XARELTO should be continued for at least 1 month in children less than 2 years old with catheter-related thrombosis. Treatment can be extended up to 3 months when clinically necessary. The benefit of continued therapy beyond 1 month should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential risk of bleeding.
Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure Table 3: Recommended Dosage for Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease Dosage Form Body Weight 1 mg XARELTO = 1 mL Suspension Dosage Total Daily Dose All doses can be taken with or without food since exposures match that of 10 mg daily dose in adults.
1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. gov/medwatch. 1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
During clinical development for the approved indications, 34,947 adult patients were exposed to XARELTO. 2) ] . 3% for XARELTO vs. 1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.
Table 5 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.
Table 5:
Bleeding Events in ROCKET AF Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment.
- On Treatment Plus 2 Days Parameter XARELTO N=7111 n (%/year) Warfarin N=7125 n (%/year) XARELTO vs.
Warfarin HR (95% CI) Abbreviations:
HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. Major Bleeding Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.
20) Intracranial Hemorrhage (ICH) Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. 93) Hemorrhagic Stroke Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days.
1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including 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. 1) ] . 2 Risk of Bleeding XARELTO increases the risk of bleeding, including in any organ, 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. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding.
4) ] , selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. 2) ] . , undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy.
XARELTO is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding. Reversal of Anticoagulant Effect A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available.
3) ] . Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies.
2) ] Active pathological bleeding ( 4 ) Severe hypersensitivity reaction to XARELTO ( 4 )
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Once a Day Once a day: approximately 24 hours apart; 2 times a day: approximately 12 hours apart. 5 mg Oral Suspension or Tablets ≥50 kg 10 mg 10 mg Administration in Pediatric Patients Food Effect: For the treatment of VTE in children, the dose should be taken with food to increase absorption.
For thromboprophylaxis after Fontan procedure, the dose can be taken with or without food.
Vomit or Spit up:
If the patient vomits or spits up the dose within 30 minutes after receiving the dose, a new dose should be given. However, if the patient vomits more than 30 minutes after the dose is taken, the dose should not be re-administered and the next dose should be taken as scheduled.
If the patient vomits or spits up the dose repeatedly, the caregiver should contact the child's doctor right away.
Tablets:
XARELTO tablet must not be split in an attempt to provide a fraction of a tablet dose. For children unable to swallow 10, 15, or 20 mg whole tablets, XARELTO oral suspension should be used. 4) ] . 73 m 2 ): No dose adjustment is required.
73 m 2 ): avoid use, as limited clinical data are available. 413 × height in cm)/serum creatinine in mg/dL, if serum creatinine (SCr) is measured by an enzymatic creatinine method that has been calibrated to be traceable to isotope dilution mass spectrometry (IDMS).
70 in boys > 13 and < 18 years Patients Less than 1 Year of Age Determine renal function using serum creatinine. 5 th percentile, as no clinical data are available. 5 in pediatric patients to avoid periods of inadequate anticoagulation.
Switching from XARELTO to Warfarin – Adults:
No clinical trial data are available to guide converting patients from XARELTO to warfarin. XARELTO affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin.
One approach is to discontinue XARELTO and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO would have been taken.
Pediatric Patients:
To ensure adequate anticoagulation during the transition from XARELTO to warfarin, continue XARELTO for at least 2 days after the first dose of warfarin. After 2 days of co-administration, an INR should be obtained prior to the next scheduled dose of XARELTO.
0. Once XARELTO is discontinued, INR testing may be done reliably 24 hours after the last dose. 4) ] . , low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO at the same time.
2) ] . In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention. 1) ] . If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.
5 mg XARELTO dose as recommended at the next scheduled time.
For patients receiving 15 mg twice daily:
The patient should take XARELTO immediately to ensure intake of 30 mg XARELTO per day. Two 15 mg tablets may be taken at once.
For patients receiving 20 mg, 15 mg or 10 mg once daily:
The patient should take the missed XARELTO dose immediately. The dose should not be doubled within the same day to make up for a missed dose. Pediatric Patients If XARELTO is taken once a day, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day.
If this is not possible, the patient should skip the dose and continue with the next dose as prescribed. The patient should not take two doses to make up for a missed dose. If XARELTO is taken two times a day, the patient should take the missed morning dose as soon as possible once it is noticed.
A missed morning dose may be taken together with the evening dose. A missed evening dose can only be taken in the same evening. If XARELTO is taken three times a day, if a dose is missed, the patient should skip the missed dose and go back to the regular dosing schedule at the usual time without compensating for the missed dose.
On the following day, the patient should continue with their regular regimen. 6 Administration Options For adult patients who are unable to swallow whole tablets, XARELTO tablets (all strengths) may be crushed and mixed with applesauce immediately prior to use and administered orally.
After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should be immediately followed by food. 3) ] . Administration of XARELTO tablets via nasogastric (NG) tube or gastric feeding tube: After confirming gastric placement of the tube, XARELTO tablets (all strengths) may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube.
Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of XARELTO distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding.
3) ] . Crushed XARELTO tablets (all strengths) are stable in water and in applesauce for up to 4 hours. An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed XARELTO tablet to PVC or silicone nasogastric (NG) tubing.
Administration of XARELTO suspension via NG tube or gastric feeding tube :
XARELTO oral suspension may be given through NG or gastric feeding tube. After the administration, flush the feeding tube with water. For the treatment or reduction in risk of recurrent VTE in pediatric patients, the dose should then be immediately followed by enteral feeding to increase absorption.
For the thromboprophylaxis in pediatric patients with congenital heart disease who have undergone the Fontan procedure, the dose does not require to be followed by enteral feeding. An in vitro compatibility study indicated that XARELTO suspension can be used with PVC, polyurethane or silicone NG tubing.
7 Preparation Instructions for Pharmacy of XARELTO for Oral Suspension Do not add flavor as product is already flavored (sweet and creamy).
Reconstitute before dispensing:
Tap the bottle until all granules flow freely. Add 150 mL of purified water for reconstitution. Shake for 60 seconds. Check that all granules are wetted and the suspension is uniform. Push the adaptor into bottleneck and recap bottle. The suspension must be used within 60 days.
Write the "Discard after" date on the bottle and carton.
Dispensing Instructions:
Dispense in the original bottle. Dispense the bottle upright with the syringes provided in the original carton. Store reconstituted suspension at room temperature between 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F).
Do not freeze. It is recommended the pharmacist counsel the caregiver on proper use. Alert the patient or caregiver to read the Medication Guide and Instructions for Use.
34) Gastrointestinal (GI) Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. 99) Fatal Bleeding Fatal bleeding is adjudicated death with the primary cause of death from bleeding. 82) Figure 1 shows the risk of major bleeding events across major subgroups.
Note:
The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors.
Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
Figure 1:
Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) EINSTEIN DVT and EINSTEIN PE Studies In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs.
7% vs. 5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients. Table 6 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.
Table 6:
Bleeding Events Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. 0) Reduction in the Risk of Recurrence of DVT and/or PE EINSTEIN CHOICE Study In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg.
The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients. Table 7 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.
Table 7:
Bleeding Events Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. in EINSTEIN CHOICE Parameter XARELTO Treatment schedule: XARELTO 10 mg once daily or aspirin 100 mg once daily.
1) Non-fatal non-critical organ bleeding Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells. 1) Clinically relevant non-major (CRNM) bleeding Bleeding which was clinically overt, did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.
2) In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups. 7% with XARELTO. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 8.
Table 8:
Bleeding Events Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication.
Patients may have more than one event. 9) Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding In the MAGELLAN study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events.
Cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. , undergoing acute, in-hospital cancer treatment), dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months all had an excess of bleeding with XARELTO compared with enoxaparin/placebo and are excluded from all MAGELLAN data presented in Table 9.
5% for XARELTO vs. 4% for enoxaparin/placebo. Table 9 shows the number of patients experiencing various types of bleeding events in the MAGELLAN study. e. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded.
Study–Safety Analysis Set - On Treatment Plus 2 Days MAGELLAN Study Patients received either XARELTO or placebo once daily for 35 ±4 days starting in hospital and continuing post hospital discharge or received enoxaparin or placebo once daily for 10 ±4 days in the hospital.
XARELTO 10 mg N=3218 n (%) Enoxaparin 40 mg /placebo N=3229 n (%) Major bleeding Defined as clinically overt bleeding associated with a drop in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.
Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. 1) Fatal bleeding Fatal bleeding is adjudicated death with the primary cause of death from bleeding.
5 mg twice daily vs. 2% for placebo on background therapy for all patients with aspirin 100 mg once daily. The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar. Table 10 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.
Table 10:
Major Bleeding Events in COMPASS - On Treatment Plus 2 Days Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment in the safety analysis set in COMPASS patients.
5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily. N=9134 n (%/year) Placebo N=9107 n (%/year) XARELTO vs.
Placebo HR (95 % CI) CI: confidence interval; HR: hazard ratio; ISTH:
International Society on Thrombosis and Hemostasis Modified ISTH Major Bleeding Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization.
5 mg twice daily vs. 1% vs. 7% vs. 3%, respectively. Table 11 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal.
Table 11:
Major Bleeding Events Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. 5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily.
N=3256 Placebo N=3248 XARELTO vs. 2) Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 12. 1) Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1–3 studies are shown in Table 13.
9) Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients The safety assessment is based on data from the EINSTEIN Junior Phase 3 study in 491 patients from birth to less than 18 years of age.
Patients were randomized 2:1 to receive body weight-adjusted doses of XARELTO or comparator (unfractionated heparin, low molecular weight heparin, fondaparinux or VKA). 9%) patients in the comparator group. Table 14 shows the number of patients experiencing bleeding events in the EINSTEIN Junior study.
In female patients who had experienced menarche, ages 12 to <18 years of age, menorrhagia occurred in 23 (27%) female patients in the XARELTO group and 5 (10%) female patients in the comparator group.
Table 14:
Bleeding Events in EINSTEIN Junior Study – Safety Analysis Set - Main Treatment Period These events occurred after randomization until 3 months of treatment (1 month for patients <2 years with central venous catheter-related VTE (CVC-VTE).
Patients may have more than one event. Parameter XARELTO Treatment schedule: body weight-adjusted doses of XARELTO; randomized 2:1 (XARELTO: Comparator). N=329 n (%) Comparator Group Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA.
N=162 n (%) Major bleeding Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.
2) Clinically relevant non-major bleeding Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.
8) Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 15. 5 for XARELTO versus comparator. 3) Fatigue The following terms were combined: fatigue, asthenia. 6% in the XARELTO group vs 8% in the comparator group).
Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease (CHD) after the Fontan Procedure The data below are based on Part B of the UNIVERSE study which was designed to evaluate the safety and efficacy of XARELTO for thromboprophylaxis in 98 children with CHD after the Fontan procedure who took at least one dose of study drug.
Patients in Part B were randomized 2:1 to receive either body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg). 6%) patient in the XARELTO group and no patients in the aspirin group. Table 16 shows the number of patients experiencing bleeding events in the UNIVERSE study.
Table 16:
Bleeding Events in UNIVERSE Study - Safety Analysis Set - On Treatment Plus 2 Days Parameter XARELTO Treatment schedule: body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg); randomized 2:1 (XARELTO: Aspirin). N=64 n (%) Aspirin N=34 n (%) Major Bleeding Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.
6) 0 Clinically relevant non-major (CRNM) bleeding Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.
2) Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 17. 5 for XARELTO versus aspirin. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of XARELTO.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury) Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: hemiparesis Renal disorders: Anticoagulant-related nephropathy Respiratory, thoracic and mediastinal disorders: Eosinophilic pneumonia Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) Injury, poisoning and procedural complications: Atraumatic splenic rupture
Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended. 3 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 [see Boxed Warning ] .
3) ] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
3) ] . The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for 24 hours. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction.
Instruct patients to immediately report if they experience 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.
1) ] . 6) ]. 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 XARELTO in these patients.
6) ] . 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 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 XARELTO in these patients. 6) ]. 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 XARELTO in these patients.
6) ]. 73 m 2 ); therefore, avoid the use of XARELTO in these patients. 6) ] . 5 Use in Patients with Hepatic Impairment No clinical data are available for adult patients with severe hepatic impairment. 7) ] . No clinical data are available in pediatric patients with hepatic impairment.
2) ] . 3) ] . 7 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.
1) ] . 8 Patients with Prosthetic Heart Valves On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen.
The safety and efficacy of XARELTO have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO is not recommended in patients with prosthetic heart valves. 9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy Initiation of XARELTO 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.
10 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including XARELTO, 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.