rivaroxaban 20 MG Oral Tablet [Xarelto]
Generic Name: RIVAROXABAN
Brand Name: XARELTO
- Substance Name(s):
- RIVAROXABAN
DRUG INTERACTIONS
7 Avoid combined P-gp and strong CYP3A inhibitors and inducers ( 7.2 , 7.3 ) Anticoagulants: Avoid concomitant use ( 7.4 ) 7.1 General Inhibition and Induction Properties Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters.
Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding.
Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.
7.2 Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems Interaction with Combined P-gp and Strong CYP3A Inhibitors Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) ] .
Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology (12.3) ] .
Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ] .
7.3 Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St.
John’s wort) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) ] .
7.4 Anticoagulants and NSAIDs/Aspirin Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology (12.3) ].
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 [see Warnings and Precautions (5.2) ] .
OVERDOSAGE
10 Overdose of XARELTO may lead to hemorrhage.
Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur.
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 dialyzable [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] .
Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products.
An agent to reverse the anti-factor Xa activity of rivaroxaban is available.
DESCRIPTION
11 Rivaroxaban, a factor Xa (FXa) inhibitor, is the active ingredient in XARELTO ® Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.
The molecular formula of rivaroxaban is C 19 H 18 ClN 3 O 5 S and the molecular weight is 435.89.
The structural formula is: Rivaroxaban is a pure ( S )-enantiomer.
It is an odorless, non-hygroscopic, white to yellowish powder.
Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.
Each XARELTO tablet contains 2.5 mg, 10 mg, 15 mg, or 20 mg of rivaroxaban.
The inactive ingredients of XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.
Additionally, the proprietary film coating mixture used for XARELTO 2.5 mg is Opadry ® Light Yellow, containing ferric oxide yellow, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 10 mg tablets is Opadry ® Pink and for XARELTO 15 mg tablets is Opadry ® Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is Opadry ® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.
Chemical Structure
CLINICAL STUDIES
14 14.1 Stroke Prevention in Nonvalvular Atrial Fibrillation The evidence for the efficacy and safety of XARELTO was derived from R ivaroxaban O nce-daily oral direct factor Xa inhibition C ompared with vitamin K antagonist for the prevention of stroke and E mbolism T rial in A trial F ibrillation (ROCKET AF) [NCT00403767], a multi-national, double-blind study comparing XARELTO (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to 50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF).
Patients had to have one or more of the following additional risk factors for stroke: a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or 2 or more of the following risk factors: age ≥75 years, hypertension, heart failure or left ventricular ejection fraction ≤35%, or diabetes mellitus ROCKET AF was a non-inferiority study designed to demonstrate that XARELTO preserved more than 50% of warfarin’s effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation.
A total of 14264 patients were randomized and followed on study treatment for a median of 590 days.
The mean age was 71 years and the mean CHADS 2 score was 3.5.
The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black.
There was a history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening.
Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%.
At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on clopidogrel.
Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%).
Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.
In ROCKET AF, XARELTO was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism [HR (95% CI): 0.88 (0.74, 1.03)], but superiority to warfarin was not demonstrated.
There is insufficient experience to determine how XARELTO and warfarin compare when warfarin therapy is well-controlled.
Table 11 displays the overall results for the primary composite endpoint and its components.
Table 11: Primary Composite Endpoint Results in ROCKET AF Study (Intent-to-Treat Population) XARELTO Warfarin XARELTO vs.
Warfarin Event N=7081 n (%) Event Rate (per 100 Pt-yrs) N=7090 n (%) Event Rate (per 100 Pt-yrs) Hazard Ratio (95% CI) Primary Composite Endpoint The primary endpoint was the time to first occurrence of stroke (any type) or non-CNS systemic embolism.
Data are shown for all randomized patients followed to site notification that the study would end.
269 (3.8) 2.1 306 (4.3) 2.4 0.88 (0.74, 1.03) Stroke 253 (3.6) 2.0 281 (4.0) 2.2 Hemorrhagic Stroke Defined as primary hemorrhagic strokes confirmed by adjudication in all randomized patients followed up to site notification 33 (0.5) 0.3 57 (0.8) 0.4 Ischemic Stroke 206 (2.9) 1.6 208 (2.9) 1.6 Unknown Stroke Type 19 (0.3) 0.2 18 (0.3) 0.1 Non-CNS Systemic Embolism 20 (0.3) 0.2 27 (0.4) 0.2 Figure 5 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.
Figure 5: Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group (Intent-to-Treat Population) Figure 6 shows the risk of stroke or non-CNS systemic embolism across major subgroups.
Figure 6: Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AF Data are shown for all randomized patients followed to site notification that the study would end.
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.
(Intent-to-Treat Population) The efficacy of XARELTO was generally consistent across major subgroups.
The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin.
XARELTO patients were generally switched to warfarin without a period of coadministration of warfarin and XARELTO, so that they were not adequately anticoagulated after stopping XARELTO until attaining a therapeutic INR.
During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking XARELTO vs.
6 in the 4691 patients taking warfarin.
Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation.
The utility of XARELTO for preventing post-cardioversion stroke and systemic embolism is unknown.
Figure 5 Figure 6 14.2 Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism Studies XARELTO for the treatment of DVT and/or PE was studied in EINSTEIN DVT [NCT00440193] and EINSTEIN PE [NCT00439777], multi-national, open-label, non-inferiority studies comparing XARELTO (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by XARELTO 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0–3.0) was reached.
Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies.
The intended treatment duration was 3, 6, or 12 months based on investigator’s assessment prior to randomization.
A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the XARELTO group and 204 days in the enoxaparin/VKA group.
The mean age was approximately 57 years.
The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black.
About 73% and 92% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days.
Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days.
Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups.
Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.
In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline.
Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic conditions (6%), or active cancer (5%).
In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI): 1.12 (0.75, 1.68)].
In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.
Table 12 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.
Table 12: Primary Composite Endpoint Results For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (3, 6 or 12 months) irrespective of the actual treatment duration.
If the same patient had several events, the patient may have been counted for several components.
in EINSTEIN DVT and EINSTEIN PE Studies – Intent-to-Treat Population Event XARELTO 20 mg Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0–3.0)] Enoxaparin/VKA XARELTO vs.
Enoxaparin/VKA Hazard Ratio (95% CI) EINSTEIN DVT Study N=1731 n (%) N=1718 n (%) Primary Composite Endpoint 36 (2.1) 51 (3.0) 0.68 (0.44, 1.04) Death (PE) 1 (<0.1) 0 Death (PE cannot be excluded) 3 (0.2) 6 (0.3) Symptomatic PE and DVT 1 (<0.1) 0 Symptomatic recurrent PE only 20 (1.2) 18 (1.0) Symptomatic recurrent DVT only 14 (0.8) 28 (1.6) EINSTEIN PE Study N=2419 n (%) N=2413 n (%) Primary Composite Endpoint 50 (2.1) 44 (1.8) 1.12 (0.75, 1.68) Death (PE) 3 (0.1) 1 (<0.1) Death (PE cannot be excluded) 8 (0.3) 6 (0.2) Symptomatic PE and DVT 0 2 (<0.1) Symptomatic recurrent PE only 23 (1.0) 20 (0.8) Symptomatic recurrent DVT only 18 (0.7) 17 (0.7) Figures 7 and 8 are plots of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively.
Figure 7: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN DVT Study Figure 8: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study Figure 7 Figure 8 14.3 Reduction in the Risk of Recurrence of DVT and/or PE EINSTEIN CHOICE Study XARELTO for reduction in the risk of recurrence of DVT and of PE was evaluated in the EINSTEIN CHOICE study [NCT02064439], a multi-national, double-blind, superiority study comparing XARELTO (10 or 20 mg once daily with food) to 100 mg acetylsalicylic acid (aspirin) once daily in patients who had completed 6 to 12 months of anticoagulant treatment for DVT and/or PE following the acute event.
The intended treatment duration in the study was up to 12 months.
Patients with an indication for continued therapeutic-dose anticoagulation were excluded.
Because the benefit-risk assessment favored the 10 mg dose versus aspirin compared to the 20 mg dose versus aspirin, only the data concerning the 10 mg dose is discussed below.
A total of 2275 patients were randomized and followed on study treatment for a mean of 290 days for the XARELTO and aspirin treatment groups.
The mean age was approximately 59 years.
The population was 56% male, 70% Caucasian, 14% Asian and 3% Black.
In the EINSTEIN CHOICE study, 51% of patients had DVT only, 33% had PE only, and 16% had PE and DVT combined.
Other risk factors included idiopathic VTE (43%), previous episode of DVT/PE (17%), recent surgery or trauma (12%), prolonged immobilization (10%), use of estrogen containing drugs (5%), known thrombophilic conditions (6%), Factor V Leiden gene mutation (4%), or active cancer (3%).
In the EINSTEIN CHOICE study, XARELTO 10 mg was demonstrated to be superior to aspirin 100 mg for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE.
Table 13 displays the overall results for the primary composite endpoint and its components.
Table 13: Primary Composite Endpoint and its Components Results For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (12 months) irrespective of the actual treatment duration.
The individual component of the primary endpoint represents the first occurrence of the event.
in EINSTEIN CHOICE Study – Full Analysis Set Event XARELTO 10 mg N=1,127 n (%) Acetylsalicylic Acid (Aspirin) 100 mg N=1,131 n (%) XARELTO 10 mg vs.
Aspirin 100 mg Hazard Ratio (95% CI) Primary Composite Endpoint 13 (1.2) 50 (4.4) 0.26 (0.14, 0.47) p<0.0001 Symptomatic recurrent DVT 8 (0.7) 29 (2.6) Symptomatic recurrent PE 5 (0.4) 19 (1.7) Death (PE) 0 1 (<0.1) Death (PE cannot be excluded) 0 1 (<0.1) Figure 9 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.
Figure 9: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Full Analysis Set) – EINSTEIN CHOICE Study Figure 9 14.4 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery XARELTO was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the RE gulation of C oagulation in OR thopedic Surgery to Prevent D VT and PE, Controlled, Double-blind, Randomized Study of BAY 59-7939 in the Extended Prevention of VTE in Patients Undergoing Elective Total Hip or Knee Replacement (RECORD 1, 2, and 3) [NCT00329628, NCT00332020, NCT00361894] studies.
The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively.
In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug.
The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female.
More than 82% of patients were White, 7% were Asian, and less than 2% were Black.
The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis).
In RECORD 1, the mean exposure duration (± SD) to active XARELTO and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively.
In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively.
After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration.
The efficacy data for RECORD 1 and 2 are provided in Table 14.
Table 14: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery – Modified Intent-to-Treat Population RECORD 1 RECORD 2 Treatment Dosage and Duration XARELTO 10 mg once daily Enoxaparin 40 mg once daily RRR Relative Risk Reduction; CI = confidence interval , p-value XARELTO 10 mg once daily Enoxaparin Includes the placebo-controlled period of RECORD 2 40 mg once daily RRR , p-value Number of Patients N=1513 N=1473 N=834 N=835 Total VTE 17 (1.1%) 57 (3.9%) 71% (95% CI: 50, 83), p<0.001 17 (2.0%) 70 (8.4%) 76% (95% CI: 59, 86), p<0.001 Components of Total VTE Proximal DVT 1 (0.1%) 31 (2.1%) 5 (0.6%) 40 (4.8%) Distal DVT 12 (0.8%) 26 (1.8%) 11 (1.3%) 43 (5.2%) Non-fatal PE 3 (0.2%) 1 (0.1%) 1 (0.1%) 4 (0.5%) Death (any cause) 4 (0.3%) 4 (0.3%) 2 (0.2%) 4 (0.5%) Number of Patients N=1600 N=1587 N=928 N=929 Major VTE Proximal DVT, nonfatal PE or VTE-related death 3 (0.2%) 33 (2.1%) 91% (95% CI: 71, 97), p<0.001 6 (0.7%) 45 (4.8%) 87% (95% CI: 69, 94), p<0.001 Number of Patients N=2103 N=2119 N=1178 N=1179 Symptomatic VTE 5 (0.2%) 11 (0.5%) 3 (0.3%) 15 (1.3%) One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared XARELTO 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin.
In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively.
The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years.
Sixty-eight percent (68%) of patients were female.
Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black.
The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis).
The mean exposure duration (± SD) to active XARELTO and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively.
The efficacy data are provided in Table 15.
Table 15: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Knee Replacement Surgery – Modified Intent-to-Treat Population RECORD 3 Treatment Dosage and Duration XARELTO 10 mg once daily Enoxaparin 40 mg once daily RRR Relative Risk Reduction; CI = confidence interval , p-value Number of Patients N=813 N=871 Total VTE 79 (9.7%) 164 (18.8%) 48% (95% CI: 34, 60), p<0.001 Components of events contributing to Total VTE Proximal DVT 9 (1.1%) 19 (2.2%) Distal DVT 74 (9.1%) 154 (17.7%) Non-fatal PE 0 4 (0.5%) Death (any cause) 0 2 (0.2%) Number of Patients N=895 N=917 Major VTE Proximal DVT, nonfatal PE or VTE-related death 9 (1.0%) 23 (2.5%) 60% (95% CI: 14, 81), p = 0.024 Number of Patients N=1206 N=1226 Symptomatic VTE 8 (0.7%) 24 (2.0%) 14.5 Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding The efficacy and safety of XARELTO for prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding was evaluated in the MAGELLAN study ( M ulticenter, r A ndomized, parallel G roup E fficacy and safety study for the prevention of venous thromboembolism in hospitalized medically i LL patients comparing rivaroxab aN with enoxaparin [NCT00571649]).
MAGELLAN was a multicenter, randomized, double-blind, parallel-group efficacy and safety study comparing XARELTO to enoxaparin, in the prevention of VTE in hospitalized acutely ill medical patients during the in-hospital and post-hospital discharge period.
Eligible patients included adults who were at least 40 years of age, hospitalized for an acute medical illness, at risk of VTE due to moderate or severe immobility, and had additional risk factors for VTE.
The population at risk of VTE was required to have one or more of the following VTE risk factors, i.e.
prolonged immobilization, age ≥75 years, history of cancer, history of VTE, history of heart failure, thrombophilia, acute infectious disease contributing to the hospitalization and BMI ≥35 kg/m 2 ).
The causes for hospitalization included heart failure, active cancer, acute ischemic stroke, acute infectious and inflammatory disease and acute respiratory insufficiency.
Patients were randomized to receive either XARELTO 10 mg once daily for 35 ±4 days starting in hospital and continuing post hospital discharge (n=4050) or enoxaparin 40 mg once daily for 10 ±4 days starting in hospital followed by placebo post-discharge (n=4051).
The major efficacy outcome in the MAGELLAN trial was a composite endpoint that included asymptomatic proximal deep venous thrombosis (DVT) in lower extremity, symptomatic proximal or distal DVT in the lower extremity, symptomatic non-fatal pulmonary embolism (PE), and death related to venous thromboembolism (VTE).
A total of 6024 patients were evaluable for the major efficacy outcome analysis (2967 on XARELTO 10 mg once daily and 3057 on enoxaparin/placebo).
The mean age was 68.9 years, with 37.1% of the subject population ≥ 75 years.
VTE risk factors included severe immobilization at study entry (99.9%), D-dimer > 2X ULN (43.7%), history of heart failure (35.6%), BMI ≥ 35 kg/m 2 (15.2%), chronic venous insufficiency (14.9%), acute infectious disease (13.9%), severe varicosis (12.5%), history of cancer (16.2%), history of VTE (4.5%), hormone replacement therapy (1.1%), and thrombophilia (0.3%), recent major surgery (0.8%) and recent serious trauma (0.2%).
The population was 54.7% male, 68.2% White, 20.4% Asian, 1.9% Black and 5.3% Other.
Admitting diagnoses for hospitalization were acute infectious diseases (43.8%) followed by congestive heart failure NYHA class III or IV (33.2%), acute respiratory insufficiency (26.4%), acute ischemic stroke (18.5%) and acute inflammatory diseases (3.4%).
Table 16 shows the overall results from the prespecified, modified intent-to-treat (mITT) analysis for the efficacy outcomes and their components.
This analysis excludes approximately 25% of the patients mainly due to no ultrasonographic assessment (13.5%), inadequate assessment at day 35 (8.1%), or lack of intake of study medication (1.3%).
Table 16: Efficacy Results at Day 35 (modified Intent-to-Treat) and at Day 10 (per protocol) in the MAGELLAN Study mITT: modified intent-to-treat; PP: per protocol; DVT: Deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; CI: Confidence Interval; RR: Relative Risk Events from Day 1 to Day 35, mITT analysis set XARELTO 10 mg N=2967 n (%) Enoxaparin 40 mg/placebo N=3057 n (%) RR (95% CI) Primary Composite Endpoint at Day 35 131 (4.4%) 175 (5.7%) 0.77 (0.62, 0.96) Symptomatic non-fatal PE 10 (0.3) 14 (0.5) Symptomatic DVT in lower extremity 13 (0.4) 15 (0.5) Asymptomatic proximal DVT in lower extremity 103 (3.5) 133 (4.4) VTE related death 19 (0.6) 30 (1.0) Events from Day 1 to Day 10, PP analysis set XARELTO 10 mg N=2938 n (%) Enoxaparin 40 mg N=2993 n (%) RR (95% CI) Primary Composite Endpoint at Day 10 78 (2.7) 82 (2.7) 0.97 (0.71, 1.31) Symptomatic non-fatal PE 6 (0.2) 2 (<0.1) Symptomatic DVT in lower extremity 7 (0.2) 6 (0.2) Asymptomatic proximal DVT in lower extremity 71 (2.4) 71 (2.4) VTE related death 3 (0.1) 6 (0.2) mITT analysis set plus all-cause mortality N=3096 n (%) N=3169 n (%) RR (95% CI) Other Composite Endpoint at Day 35 266 (8.6) 293 (9.2) 0.93 (0.80, 1.09) Symptomatic non-fatal PE 10 (0.3) 14 (0.4) Symptomatic DVT in lower extremity 13 (0.4) 15 (0.5) Asymptomatic proximal DVT in lower extremity 103 (3.3) 133 (4.2) All-cause mortality 159 (5.1) 153 (4.8) Patients with bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months (19.4%) all had an excess of bleeding with XARELTO compared with enoxaparin/placebo.
Therefore, patients meeting these criteria were excluded from the following analyses presented below.
Table 17 provides the efficacy results for the subgroup of patients not at a high risk of bleeding.
Table 17: Efficacy Results at Day 35 (modified Intent-to-Treat) and at Day 10 (per protocol) in patients not at a high risk of bleeding in the MAGELLAN Study Patients at high risk of bleeding (i.e.
bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded.
mITT: modified intent-to-treat; PP: per protocol; DVT: Deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; CI: Confidence Interval; RR: Relative Risk Events from Day 1 to Day 35, mITT analysis set XARELTO 10 mg N=2419 n (%) Enoxaparin 40 mg/placebo N=2506 n (%) RR (95% CI) Primary Composite Endpoint at Day 35 94 (3.9) 143 (5.7) 0.68 (0.53, 0.88) Symptomatic non-fatal PE 7 (0.3) 10 (0.4) Symptomatic DVT in lower extremity 9 (0.4) 10 (0.4) Asymptomatic proximal DVT in lower extremity 73 (3.0) 110 (4.4) VTE related death 15 (0.6) 26 (1.0) Events from Day 1 to Day 10, PP analysis set XARELTO 10 mg N=2385 n (%) Enoxaparin 40 mg N=2433 n (%) RR (95% CI) Primary Composite Endpoint at Day 10 58 (2.4) 72 (3.0) 0.82 (0.58, 1.15) Symptomatic non-fatal PE 5 (0.2) 2 (<0.1) Symptomatic DVT in lower extremity 6 (0.3) 4 (0.2) Asymptomatic proximal DVT in lower extremity 52 (2.2) 62 (2.5) VTE related death 2 (<0.1) 6 (0.2) mITT analysis set plus all-cause mortality N=2504 n (%) N=2583 n (%) RR (95% CI) Other Composite Endpoint at Day 35 184 (7.3) 225 (8.7) 0.84 (0.70, 1.02) Symptomatic non-fatal PE 7 (0.3) 10 (0.4) Symptomatic DVT in lower extremity 9 (0.4) 10 (0.4) Asymptomatic proximal DVT in lower extremity 73 (2.9) 110 (4.3) All-cause mortality 107 (4.3) 112 (4.3) 14.6 Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD The evidence for the efficacy and safety of XARELTO for the reduction in the risk of stroke, myocardial infarction, or cardiovascular death in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) was derived from the double-blind Cardiovascular OutcoMes for People using Anticoagulation StrategieS trial (COMPASS) [NCT10776424].
A total of 27,395 patients were evenly randomized to rivaroxaban 2.5 mg orally twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg orally twice daily alone, or aspirin 100 mg once daily alone.
Because the 5 mg dose alone was not superior to aspirin alone, only the data concerning the 2.5 mg dose plus aspirin are discussed below.
Patients with established CAD or PAD were eligible.
Patients with CAD who were younger than 65 years of age were also required to have documentation of atherosclerosis involving at least two vascular beds or to have at least two additional cardiovascular risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate [eGFR] <60 mL per minute, heart failure, or non-lacunar ischemic stroke ≥1 month earlier).
Patients with PAD were either symptomatic with ankle brachial index <0.90 or had asymptomatic carotid artery stenosis ≥50%, a previous carotid revascularization procedure, or established ischemic disease of one or both lower extremities.
Patients were excluded for use of dual antiplatelet, other non-aspirin antiplatelet, or oral anticoagulant therapies, ischemic, non-lacunar stroke within 1 month, hemorrhagic or lacunar stroke at any time, or eGFR <15 mL/min.
[see Warnings and Precautions (5.2) ] .
The mean age was 68 years and 21% of the subject population were ≥75 years.
Of the included patients, 91% had CAD, 27% had PAD, and 18% had both CAD and PAD.
Of the patients with CAD, 69% had prior MI, 60% had prior percutaneous transluminal coronary angioplasty (PTCA)/atherectomy/ percutaneous coronary intervention (PCI), and 26% had history of coronary artery bypass grafting (CABG) prior to study.
Of the patients with PAD, 49% had intermittent claudication, 27% had peripheral artery bypass surgery or peripheral percutaneous transluminal angioplasty, 26% had asymptomatic carotid artery stenosis > 50%, and 4% had limb or foot amputation for arterial vascular disease.
The mean duration of follow-up was 23 months.
Relative to aspirin alone, XARELTO plus aspirin reduced the rate of the primary composite outcome of stroke, myocardial infarction or cardiovascular death.
The benefit was observed early with a constant treatment effect over the entire treatment period (see Table 18 and Figure 11 ).
A benefit-risk analysis of the data from COMPASS was performed by comparing the number of CV events (CV deaths, myocardial infarctions and non-hemorrhagic strokes) prevented to the number of fatal or life-threatening bleeding events (fatal bleeds + symptomatic non-fatal bleeds into a critical organ) in the XARELTO plus aspirin group versus the aspirin group.
Compared to aspirin alone, during 10,000 patient-years of treatment, XARELTO plus aspirin would be expected to result in 70 fewer CV events and 12 additional life-threatening bleeds, indicating a favorable balance of benefits and risks.
The results in patients with PAD, CAD, and both CAD and PAD were consistent with the overall efficacy and safety results (see Figure 10 ).
Figure 10 shows the risk of primary efficacy outcome across major subgroups.
Figure 10: Risk of Primary Efficacy Outcome by Baseline Characteristics in COMPASS (Intent-to-Treat Population) Table 18: Efficacy results from COMPASS study Study Population Patients with CAD or PAD intention to treat analysis set, primary analyses.
Event XARELTO plus aspirin Treatment schedule: XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily, or aspirin 100 mg once daily.
N=9152 Aspirin alone N=9126 Hazard Ratio (95% CI) vs.
aspirin 100 mg n (%) Event Rate (%/year) n (%) Event Rate (%/year) CHD: coronary heart disease, CI: confidence interval; CV: cardiovascular; MI: myocardial infarction Stroke, MI or CV death 379 (4.1) 2.2 496 (5.4) 2.9 0.76 (0.66, 0.86) – Stroke 83 (0.9) 0.5 142 (1.6) 0.8 0.58 (0.44, 0.76) – MI 178 (1.9) 1.0 205 (2.2) 1.2 0.86 (0.70, 1.05) – CV death 160 (1.7) 0.9 203 (2.2) 1.2 0.78 (0.64, 0.96) Coronary heart disease death, MI, ischemic stroke, acute limb ischemia 329 (3.6) 1.9 450 (4.9) 2.6 0.72 (0.63, 0.83) – Coronary heart disease death Coronary heart disease death: death due to acute MI, sudden cardiac death, or CV procedure.
86 (0.9) 0.5 117 (1.3) 0.
7 0.73 (0.55, 0.96) – Ischemic stroke 64 (0.7) 0.4 125 (1.4) 0.7 0.51 (0.38, 0.69) – Acute limb ischemia Acute limb ischemia is defined as limb-threatening ischemia leading to an acute vascular intervention (i.e., pharmacologic, peripheral arterial surgery/reconstruction, peripheral angioplasty/stent, or amputation).
22 (0.2) 0.1 40 (0.4) 0.2 0.55 (0.32, 0.92) CV death CV death includes CHD death, or death due to other CV causes or unknown death.
, MI, ischemic stroke, acute limb ischemia 389 (4.3) 2.2 516 (5.7) 3.00 0.74 (0.65, 0.85) All-cause mortality 313 (3.4) 1.
8 378 (4.1) 2.2 0.82 (0.71, 0.96) Lower extremity amputations for CV reasons 15 (0.2) <0.1 31 (0.3) 0.2 0.48 (0.26, 0.89) Patients with PAD Acute limb ischemia 19 (0.8) 0.4 34 (1.4) 0.8 0.56 (0.32, 0.99) Figure 11: Time to first occurrence of primary efficacy outcome (stroke, myocardial infarction, cardiovascular death) in COMPASS CI: confidence interval Figure 10 Figure 11
HOW SUPPLIED
16 /STORAGE AND HANDLING XARELTO ® (rivaroxaban) Tablets are available in the strengths and packages listed below: 2.5 mg tablets are round, light yellow, and film-coated with a triangle pointing down above a “2.5” marked on one side and “Xa” on the other side.
The tablets are supplied in the packages listed: NDC 50458-577-60 Bottle containing 60 tablets NDC 50458-577-18 Bottle containing 180 tablets NDC 50458-577-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 10 mg tablets are round, light red, biconvex film-coated tablets marked with a triangle pointing down above a “10” on one side, and “Xa” on the other side.
The tablets are supplied in the packages listed: NDC 50458-580-30 Bottle containing 30 tablets NDC 50458-580-90 Bottle containing 90 tablets NDC 50458-580-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 15 mg tablets are round, red, biconvex film-coated tablets with a triangle pointing down above a “15” marked on one side and “Xa” on the other side.
The tablets are supplied in the packages listed: NDC 50458-578-30 Bottle containing 30 tablets NDC 50458-578-90 Bottle containing 90 tablets NDC 50458-578-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 20 mg tablets are triangle-shaped, dark red film-coated tablets with a triangle pointing down above a “20” marked on one side and “Xa” on the other side.
The tablets are supplied in the packages listed: NDC 50458-579-30 Bottle containing 30 tablets NDC 50458-579-90 Bottle containing 90 tablets NDC 50458-579-89 Bulk bottle containing 1000 tablets NDC 50458-579-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) Starter Pack for treatment of deep vein thrombosis and treatment of pulmonary embolism: NDC 50458-584-51 30-day starter blister pack containing 51 tablets: 42 tablets of 15 mg and 9 tablets of 20 mg Store at 25°C (77°F) or room temperature; excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].
Keep out of the reach of children.
RECENT MAJOR CHANGES
Warnings and Precautions ( 5.8 ) 03/2020
GERIATRIC USE
8.5 Geriatric Use Of the total number of patients in the RECORD 1–3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years.
In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years.
In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years.
In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were >75 years.
In the MAGELLAN study, approximately 67% were 65 years and over and about 37% were >75 years.
In the COMPASS study, approximately 76% were 65 years and over and about 17% 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 [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] .
DOSAGE FORMS AND STRENGTHS
3 2.5 mg tablets: Round, light yellow, and film-coated with a triangle pointing down above a “2.5” marked on one side and “Xa” on the other side 10 mg tablets: Round, light red, biconvex and film-coated with a triangle pointing down above a “10” marked on one side and “Xa” on the other side 15 mg tablets: Round, red, biconvex, and film-coated with a triangle pointing down above a “15” marked on one side and “Xa” on the other side 20 mg tablets: Triangle-shaped, dark red, and film-coated with a triangle pointing down above a “20” marked on one side and “Xa” on the other side Tablets: 2.5 mg, 10 mg, 15 mg, and 20 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action XARELTO is a selective inhibitor of FXa.
It does not require a cofactor (such as Anti-thrombin III) for activity.
Rivaroxaban inhibits free FXa and prothrombinase activity.
Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin.
By inhibiting FXa, rivaroxaban decreases thrombin generation.
INDICATIONS AND USAGE
1 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 ) for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery ( 1.5 ) for prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients ( 1.6 ) to reduce the risk of major cardiovascular events in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD) ( 1.7 ) 1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation XARELTO 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 [see Clinical Studies (14.1) ].
1.2 Treatment of Deep Vein Thrombosis XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
1.3 Treatment of Pulmonary Embolism XARELTO is indicated for the treatment of pulmonary embolism (PE).
1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.
1.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.
1.6 Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding XARELTO 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 [see Warnings and Precautions (5.2) and Clinical Studies (14.5) ].
1.7 Reduction of Risk of Major Cardiovascular Events in Patients with Chronic Coronary Artery Disease (CAD) or Peripheral Artery Disease (PAD) XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular (CV) death, myocardial infarction (MI) and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Risk Summary The limited available data on XARELTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.
Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery.
The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing.
Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman [see Warnings and Precautions (5.2 , 5.7) ] .
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias.
Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia.
Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.
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.
Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see Warnings and Precautions (5.7) ].
The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.
Data Human Data There are no adequate or well-controlled studies of XARELTO 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.
In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.
Animal Data Rivaroxaban crosses the placenta in animals.
Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis.
This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day.
Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis.
This dose corresponds to about 14 times the human exposure of unbound drug.
In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).
BOXED WARNING
WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning.
(A) Premature discontinuation of XARELTO increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events.
To reduce this risk, consider coverage with another anticoagulant if XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy.
( 2.2 , 2.3 , 5.1 , 14.1 ) (B) Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture.
These hematomas may result in long-term or permanent paralysis.
( 5.2 , 5.3 , 6.2 ) Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently.
Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated.
( 5.3 ) A.
Premature discontinuation of XARELTO increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events.
If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.2 , 2.3) , Warnings and Precautions (5.1) , and Clinical Studies (14.1) ] .
B.
Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with XARELTO who 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: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants a history of traumatic or repeated epidural or spinal punctures a history of spinal deformity or spinal surgery optimal timing between the administration of XARELTO and neuraxial procedures is not known [see Warnings and Precautions (5.2 , 5.3) and Adverse Reactions (6.2) ].
Monitor patients frequently for signs and symptoms of neurological impairment.
If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.3) ] .
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.3) ] .
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Risk of bleeding: XARELTO can cause serious and fatal bleeding.
An agent to reverse the activity of rivaroxaban is available.
( 5.2 ) Pregnancy-related hemorrhage: Use XARELTO with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery.
( 5.7 , 8.1 ) Prosthetic heart valves: XARELTO use not recommended ( 5.8 ) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: XARELTO use not recommended.
( 5.10 ) 5.1 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.
If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.2 , 2.3) and Clinical Studies (14.1) ] .
5.2 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.
Concomitant use of other drugs that impair hemostasis increases the risk of bleeding.
These include aspirin, P2Y 12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.4) ] , selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.
Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions (7.2) ] .
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 XARELTO for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e.
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 An agent to reverse the anti-factor Xa activity of rivaroxaban is available.
Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology (12.3) ] .
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.
Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.
5.3 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 ] .
To reduce the potential risk of bleeding associated with the concurrent use of XARELTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO [see Clinical Pharmacology (12.3) ] .
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.
An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 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 XARELTO [see Clinical Pharmacology (12.3) ] .
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.
5.4 Use in Patients with Renal Impairment Nonvalvular Atrial Fibrillation Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly [see Dosage and Administration (2.1) ] .
Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations (8.6) ].
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.
Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations (8.6) ] .
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.
Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations (8.6) ].
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.
Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations (8.6) ].
5.5 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 [see Use in Specific Populations (8.7) ] .
5.6 Use with P-gp and Strong CYP3A Inhibitors or Inducers Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions (7.2) ] .
Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions (7.3) ] .
5.7 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.
Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1) ].
5.8 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.
5.9 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.
5.10 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Instructions for Patient Use Advise patients to take XARELTO only as directed.
Remind patients to not discontinue XARELTO without first talking to their healthcare professional.
Advise patients with atrial fibrillation to take XARELTO once daily with the evening meal.
Advise patients for initial treatment of DVT and/or PE to take XARELTO 15 mg or 20 mg tablets with food at approximately the same time every day [see Dosage and Administration (2.1) ] .
Advise patients who are at a continued risk of recurrent DVT and/or PE after at least 6 months of initial treatment, to take XARELTO 10 mg once daily with or without food [see Dosage and Administration (2.1) ].
Advise patients who cannot swallow the tablet whole to crush XARELTO and combine with a small amount of applesauce followed by food [see Dosage and Administration (2.5) ] .
For patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush the XARELTO tablet and mix it with a small amount of water before administering via the tube [see Dosage and Administration (2.5) ] .
If a dose is missed, advise the patient to take XARELTO as soon as possible on the same day and continue on the following day with their recommended daily dose regimen [see Dosage and Administration (2.4) ] .
Bleeding Risks Advise patients to report any unusual bleeding or bruising to their physician.
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 XARELTO [see Warnings and Precautions (5.2) ] .
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 back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence.
If any of these symptoms occur, advise the patient to contact his or her physician immediately [see Boxed Warning ] .
Invasive or Surgical Procedures Instruct patients to inform their healthcare professional that they are taking XARELTO before any invasive procedure (including dental procedures) is scheduled.
Concomitant Medication and Herbals Advise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential interactions [see Drug Interactions (7) ] .
Pregnancy and Pregnancy-Related Hemorrhage Advise patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with XARELTO [see Use in Specific Populations (8.1) ] .
Advise pregnant women receiving XARELTO to immediately report to their physician any bleeding or symptoms of blood loss [see Warnings and Precautions (5.7) ] .
Lactation Advise patients to discuss with their physician the benefits and risks of XARELTO for the mother and for the child if they are nursing or intend to nurse during anticoagulant treatment [see Use in Specific Populations (8.2) ] .
Females and Males of Reproductive Potential Advise patients who can become pregnant to discuss pregnancy planning with their physician [see Use in Specific Populations (8.3) ] .
DOSAGE AND ADMINISTRATION
2 Nonvalvular Atrial Fibrillation : 15 or 20 mg, once daily with food ( 2.1 ) Treatment of DVT and/or PE : 15 mg orally twice daily with food for the first 21 days followed by 20 mg orally once daily with food for the remaining treatment ( 2.1 ) Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE : 10 mg once daily with or without food, after at least 6 months of standard anticoagulant treatment ( 2.1 ) Prophylaxis of DVT Following Hip or Knee Replacement Surgery : 10 mg orally once daily with or without food ( 2.1 ) Prophylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding: 10 mg once daily, with or without food, in hospital and after hospital discharge for a total recommended duration of 31 to 39 days ( 2.1 ) CAD or PAD: 2.5 mg orally twice daily with or without food, in combination with aspirin (75–100 mg) once daily ( 2.1 ) 2.1 Recommended Dosage Table 1: Recommended Dosage Indication Renal Considerations Calculate CrCl based on actual weight.
See Warnings and Precautions (5.4) and Use in Specific Populations (8.6) Dosage Food/Timing See Clinical Pharmacology (12.3) Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation CrCl >50 mL/min 20 mg once daily Take with evening meal CrCl ≤50 mL/min Patients with CrCl <30 mL/min were not studied, but administration of XARELTO is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Use in Specific Populations (8.6) ] 15 mg once daily Take with evening meal Treatment of DVT and/or PE CrCl ≥15 mL/min 15 mg twice daily ▼ after 21 days, transition to ▼ 20 mg once daily Take with food, at the same time each day CrCl <15 mL/min Avoid Use Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE CrCl ≥15 mL/min 10 mg once daily, after at least 6 months of standard anticoagulant treatment Take with or without food CrCl <15 mL/min Avoid Use Prophylaxis of DVT Following: – Hip Replacement Surgery See Dosage and Administration (2.3) CrCl ≥15 mL/min 10 mg once daily for 35 days, 6–10 hours after surgery once hemostasis has been established Take with or without food CrCl <15 mL/min Avoid Use – Knee Replacement Surgery CrCl ≥15 mL/min 10 mg once daily for 12 days, 6–10 hours after surgery once hemostasis has been established Take with or without food CrCl <15 mL/min Avoid Use Prophylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding CrCl ≥15 mL/min 10 mg once daily, in hospital and after hospital discharge, for a total recommended duration of 31 to 39 days Take with or without food CrCl <15 mL/min Avoid Use Reduction of Risk of Major Cardiovascular Events (CV Death, MI, and Stroke) in Chronic CAD or PAD No dose adjustment needed based on CrCl 2.5 mg twice daily , plus aspirin (75–100 mg) once daily Take with or without food 2.2 Switching to and from XARELTO Switching from Warfarin to XARELTO – When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.
Switching from XARELTO to Warfarin – 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.
Switching from XARELTO to Anticoagulants other than Warfarin – For patients currently taking XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO dose would have been taken [see Drug Interactions (7.4) ] .
Switching from Anticoagulants other than Warfarin to XARELTO – For patients currently receiving an anticoagulant other than warfarin, start XARELTO 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., 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.
2.3 Discontinuation for Surgery and other Interventions If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see Warnings and Precautions (5.2) ] .
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.
XARELTO should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short [see Warnings and Precautions (5.1) ] .
If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.
2.4 Missed Dose For patients receiving 2.5 mg twice daily: if a dose is missed, the patient should take a single 2.5 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.
2.5 Administration Options For 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.
Administration with food is not required for the 2.5 mg or 10 mg tablets [see Clinical Pharmacology (12.3) ] .
Administration 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.
Enteral feeding is not required following administration of the 2.5 mg or 10 mg tablets [see Clinical Pharmacology (12.3) ] .
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.