Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01 
Mechanism of action
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.

Pharmacodynamic effects
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the INR is only calibrated and validated for coumarins and cannot be used for any other anticoagulant.
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95 percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for 15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15 to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s.
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e.
at the time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough (16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 to 26 s.
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC (Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3- factor PCC reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the 4-factor PCC (see section 4.9).
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose- dependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban.
There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-factor Xa tests (see section 5.2).

Paediatric population
PT (neoplastin reagent), aPTT, and anti-Xa assay (with a calibrated quantitative test) display a close correlation to plasma concentrations in children. The correlation between anti-Xa to plasma concentrations is linear with a slope close to 1. Individual discrepancies with higher or lower anti-Xa values as compared to the corresponding plasma concentrations may occur. There is no need for routine monitoring of coagulation parameters during clinical treatment with rivaroxaban.
However, if clinically indicated, rivaroxaban concentrations can be measured by calibrated quantitative anti-Factor Xa tests in mcg/L (see table 13 in section 5.2 for ranges of observed rivaroxaban plasma concentrations in children). The lower limit of quantifications must be considered when the anti-Xa test is used to quantify plasma concentrations of rivaroxaban in children. No threshold for efficacy or safety events has been established.

Clinical efficacy and safety
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
In the pivotal double-blind ROCKET AF study, 14,264 patients were assigned either to rivaroxaban 20 mg once daily (15 mg once daily in patients with creatinine clearance 30 - 49 ml/min) or to warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0). The median time on treatment was 19 months and overall treatment duration was up to 41 months.
34.9% of patients were treated with acetylsalicylic acid and 11.4% were treated with class III antiarrhythmic including amiodarone.

Rivaroxaban was non-inferior to warfarin for the primary composite endpoint of stroke and non-CNS systemic embolism. In the per-protocol population on treatment, stroke or systemic embolism occurred in 188 patients on rivaroxaban (1.71% per year) and 241 on warfarin (2.16% per year) (HR 0.79; 95% CI, 0.66 – 0.96; P<0.001 for non-inferiority). Among all randomised patients analysed according to ITT, primary events occurred in 269 on rivaroxaban (2.12% per year) and 306 on warfarin (2.42% per year) (HR 0.88; 95% CI, 0.74 – 1.03; P<0.001 for non-inferiority; P=0.117 for superiority). Results for secondary endpoints as tested in hierarchical order in the ITT analysis are displayed in Table 4.
Among patients in the warfarin group, INR values were within the therapeutic range (2.0 to 3.0) a mean of 55% of the time (median, 58%; interquartile range, 43 to 71). The effect of rivaroxaban did not differ across the level of centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized quartiles (P=0.74 for interaction). Within the highest quartile according to centre, the Hazard Ratio (HR) with rivaroxaban versus warfarin was 0.74 (95% CI, 0.49 - 1.12).
The incidence rates for the principal safety outcome (major and non-major clinically relevant bleeding events) were similar for both treatment groups (see Table 5).

Table 4: Efficacy results from phase III ROCKET AF
ITT analyses of efficacy in patients with non-valvular atrial
Study population fibrillation
Rivaroxaban             Warfarin
20 mg once daily        titrated to a target
(15 mg once daily in    INR of 2.5 patients with           (therapeutic range      HR (95% CI)
Treatment dose              moderate renal          2.0 to 3.0)             p-value, test for impairment)                                     superiority
Event rate (100 pt-     Event rate (100 pt- yr)                     yr)

269                     306                     0.88
Stroke and non-CNS
(2.12)                  (2.42)              (0.74 - 1.03) systemic embolism
0.117

Stroke, non-CNS                      572                     609                     0.94 systemic embolism and               (4.51)                  (4.81)              (0.84 - 1.05) vascular death                                                                      0.265 
Stroke, non-CNS                      659                     709                     0.93 systemic embolism,                  (5.24)                  (5.65)              (0.83 - 1.03) vascular death and                                                                  0.158 myocardial infarction

253                     281                    0.90
Stroke                            (1.99)                  (2.22)              (0.76 - 1.07) 0.221

Non-CNS                             20                      27                     0.74 systemic                          (0.16)                  (0.21)              (0.42 - 1.32) embolism                                                                          0.308 ITT analyses of efficacy in patients with non-valvular atrial
Study population fibrillation
Rivaroxaban            Warfarin
20 mg once daily       titrated to a target
(15 mg once daily in   INR of 2.5 patients with          (therapeutic range        HR (95% CI)
Treatment dose             moderate renal         2.0 to 3.0)               p-value, test for impairment)                                      superiority
Event rate (100 pt-    Event rate (100 pt- yr)                    yr)

130                     142                   0.91
Myocardial infarction               (1.02)                  (1.11)             (0.72 - 1.16) 0.464



Table 5: Safety results from phase III ROCKET AF
Study population          Patients with non-valvular atrial fibrillationa Rivaroxaban              Warfarin
20 mg once daily         titrated to a target
(15 mg once daily in     INR of 2.5 patients with            (therapeutic range          HR (95% CI)
Treatment dose            moderate renal           2.0 to 3.0)                 p-value impairment)
Event rate (100 pt-      Event rate (100 pt- yr)                      yr)

Major and non-major                                                            1.03 1,475                    1,449 clinically relevant                                                            (0.96 - 1.11) (14.91)                  (14.52) bleeding events                                                                0.442 
1.04
395                      386
Major bleeding events                                                         (0.90 - 1.20) (3.60)                   (3.45)
0.576

27                       55                          0.50
Death due to
(0.24)                   (0.48)                      (0.31 - 0.79) bleeding*
0.003

91                       133                         0.69
Critical organ
(0.82)                   (1.18)                      (0.53 - 0.91) bleeding*
0.007
Study population            Patients with non-valvular atrial fibrillationa Rivaroxaban              Warfarin
20 mg once daily         titrated to a target
(15 mg once daily in     INR of 2.5 patients with            (therapeutic range        HR (95% CI)
Treatment dose              moderate renal           2.0 to 3.0)               p-value impairment)
Event rate (100 pt-      Event rate (100 pt- yr)                      yr)

55                       84                        0.67
Intracranial
(0.49)                   (0.74)                    (0.47 - 0.93) haemorrhage*
0.019

305                      254                       1.22
Haemoglobin drop*      (2.77)                   (2.26)                    (1.03 - 1.44) 0.019
Transfusion of 2 or       183                      149                       1.25 more units of packed red                                                       (1.01 - 1.55) (1.65)                   (1.32) blood cells or whole                                                           0.044 blood*
Non-major clinically                                                          1.04 1,185                    1,151 relevant bleeding                                                             (0.96 - 1.13) (11.80)                  (11.37) events                                                                        0.345 
0.85
208                      250
All cause mortality                                                            (0.70 - 1.02) (1.87)                   (2.21)
0.073 a)       Safety population, on treatment
*        Nominally significant

In addition to the phase III ROCKET AF study, a prospective, single-arm, post-authorization, non- interventional, open-label cohort study (XANTUS) with central outcome adjudication including thromboembolic events and major bleeding has been conducted. 6,704 patients with non-valvular atrial fibrillation were enrolled for prevention of stroke and non-central nervous system (CNS) systemic embolism in clinical practice. The mean CHADS2 score was 1.9 and HAS-BLED scores was 2.0 in XANTUS, compared to a mean CHADS2 and HAS-BLED score of 3.5 and 2.8 in ROCKET AF, respectively. Major bleeding occurred in 2.1 per 100 patient years. Fatal haemorrhage was reported in 0.2 per 100 patient years and intracranial haemorrhage in 0.4 per 100 patient years. Stroke or non-CNS systemic embolism was recorded in 0.8 per 100 patient years.
These observations in clinical practice are consistent with the established safety profile in this indication.

In a post-authorisation, non-interventional study, in more than 162,000 patients from four countries, rivaroxaban was prescribed for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. The event rate for ischaemic stroke was 0.70 (95% CI 0.44 - 1.13) per 100 patient-years. Bleeding resulting in hospitalisation occurred at event rates per 100 patient- years of 0.43 (95% CI 0.31 - 0.59) for intracranial bleeding, 1.04 (95% CI 0.65 - 1.66) for gastrointestinal bleeding, 0.41 (95% CI 0.31 - 0.53) for urogenital bleeding and 0.40 (95% CI 0.25 - 0.65) for other bleeding.

Patients undergoing cardioversion
A prospective, randomised, open-label, multicentre, exploratory study with blinded endpoint evaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naive and pre-treated) with non-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose- adjusted VKA (randomised 2:1), for the prevention of cardiovascular events. TEE- guided (1 - 5 days of pre-treatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies were employed. The primary efficacy outcome (all stroke, transient ischaemic attack, non-CNS systemic embolism, myocardial infarction (MI) and cardiovascular death) occurred in 5 (0.5 %) patients in the rivaroxaban group (n = 978) and 5 (1.0 %) patients in the VKA group (n = 492; RR 0.50; 95 % CI 0.15-1.73; modified ITT population). The principal safety outcome (major bleeding) occurred in 6 (0.6 %) and 4 (0.8 %) patients in the rivaroxaban (n = 988) and VKA (n = 499) groups, respectively (RR 0.76; 95 % CI 0.21-2.67; safety population). This exploratory study showed comparable efficacy and safety between rivaroxaban and VKA treatment groups in the setting of cardioversion.

Patients with non-valvular atrial fibrillation who undergo PCI with stent placement A randomised, open-label, multicentre study (PIONEER AF-PCI) was conducted in 2,124 patients with non-valvular atrial fibrillation who underwent PCI with stent placement for primary atherosclerotic disease to compare safety of two rivaroxaban regimens and one VKA regimen.
Patients were randomly assigned in a 1:1:1 fashion for an overall 12-month-therapy. Patients with a history of stroke or TIA were excluded.
Group 1 received rivaroxaban 15 mg once daily (10 mg once daily in patients with creatinine clearance 30 - 49 ml/min) plus P2Y12 inhibitor. Group 2 received rivaroxaban 2.5 mg twice daily plus DAPT (dual antiplatelet therapy i.e. clopidogrel 75 mg [or alternate P2Y12 inhibitor] plus low- dose acetylsalicylic acid [ASA]) for 1, 6 or 12 months followed by rivaroxaban 15 mg (or 10 mg for subjects with creatinine clearance 30 - 49 ml/min) once daily plus low-dose ASA. Group 3 received dose-adjusted VKA plus DAPT for 1, 6 or 12 months followed by dose-adjusted VKA plus low- dose ASA.
The primary safety endpoint, clinically significant bleeding events, occurred in 109 (15.7%), 117 (16.6%), and 167 (24.0%) subjects in group 1, group 2 and group 3, respectively (HR 0.59; 95% CI 0.47-0.76; p<0.001, and HR 0.63; 95% CI 0.50-0.80; p<0.001, respectively). The secondary endpoint (composite of cardiovascular events CV death, MI, or stroke) occurred in 41 (5.9%), 36 (5.1%), and 36 (5.2%) subjects in the group 1, group 2 and group 3, respectively. Each of the rivaroxaban regimens showed a significant reduction in clinically significant bleeding events compared to the VKA regimen in patients with non-valvular atrial fibrillation who underwent a PCI with stent placement.
The primary objective of PIONEER AF-PCI was to assess safety. Data on efficacy (including thromboembolic events) in this population are limited.
Treatment of DVT, PE and prevention of recurrent DVT and PE
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban in the initial and continued treatment of acute DVT and PE and prevention of recurrence.
Over 12,800 patients were studied in four randomised controlled phase III clinical studies (Einstein DVT, Einstein PE , Einstein Extension and Einstein Choice) and additionally a predefined pooled analysis of the Einstein DVT and Einstein PE studies was conducted. The overall combined treatment duration in all studies was up to 21 months.

In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the prevention of recurrent DVT and PE (patients who presented with symptomatic PE were excluded from this study). The treatment duration was for 3, 6 or 12 months depending on the clinical judgement of the investigator.
For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily.
This was followed by 20 mg rivaroxaban once daily.

In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention of recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinical judgement of the investigator.
For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks. This was followed by 20 mg rivaroxaban once daily.

In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted of enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until the PT/INR was in therapeutic range (≥ 2.0). Treatment was continued with a vitamin K antagonist dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0.

In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism depending on the clinical judgment of the investigator. Rivaroxaban 20 mg once daily was compared with placebo.

Einstein DVT, PE and Extension used the same pre-defined primary and secondary efficacy outcomes. The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of recurrent DVT, non-fatal PE and all-cause mortality.
In Einstein Choice, 3,396 patients with confirmed symptomatic DVT and/or PE who completed 6- 12 months of anticoagulant treatment were studied for the prevention of fatal PE or non-fatal symptomatic recurrent DVT or PE. Patients with an indication for continued therapeutic-dosed anticoagulation were excluded from the study. The treatment duration was up to 12 months depending on the individual randomisation date (median : 351 days). Rivaroxaban 20 mg once daily and Rivaroxaban 10 mg once daily were compared with 100 mg acetylsalicylic acid once daily.
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT or fatal or non-fatal PE.

In the Einstein DVT study (see Table 6) rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority);HR: 0.680 (0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) was reported with a HR of 0.67 ((95% CI: 0.47 – 0.95), nominal p value p=0.027) in favour of rivaroxaban. INR values were within the therapeutic range a mean of 60.3% of the time for the mean treatment duration of 189 days, and 55.4%, 60.1%, and 62.8% of the time in the 3-, 6-, and 12-month intended treatment duration groups, respectively.
In the enoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in Target INR Range of 2.0 – 3.0) in the equally sized tertiles and the incidence of the recurrent VTE (P=0.932 for interaction). Within the highest tertile according to centre, the HR with rivaroxaban versus warfarin was 0.69 (95% CI: 0.35 - 1.35).

The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding events) as well as the secondary safety outcome (major bleeding events) were similar for both treatment groups.

Table 6: Efficacy and safety results from phase III Einstein DVT

3,449 patients with symptomatic acute deep vein
Study population thrombosis
Rivaroxaban a)                 Enoxaparin/VKAb
Treatment dose and duration 3, 6 or 12 months                      3, 6 or 12 months N=1,731                        N=1,718
36                             51
Symptomatic recurrent VTE*
(2.1%)                         (3.0%)
20                             18
Symptomatic recurrent PE
(1.2%)                         (1.0%)
14                             28
Symptomatic recurrent DVT
(0.8%)                         (1.6%)
1
Symptomatic PE and DVT                                          0
(0.1%)
Fatal PE/death where PE          4                              6 cannot be ruled out              (0.2%)                         (0.3%) Major or clinically relevant non- 139                              138 major bleeding                      (8.1%)                         (8.1%) 14                             20
Major bleeding events
(0.8%)                         (1.2%) a)      Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily b)      Enoxaparin for at least 5 days, overlapped with and followed by VKA *       p < 0.0001 (non-inferiority to a prespecified HR of 2.0);HR: 0.680 (0.443 - 1.042), p=0.076 (superiority)

In the Einstein PE study (see Table 7) rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority);HR: 1.123 (0.749 – 1.684)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) was reported with a HR of 0.849 ((95% CI: 0.633 - 1.139), nominal p value p= 0.275). INR values were within the therapeutic range a mean of 63% of the time for the mean treatment duration of 215 days, and 57%, 62%, and 65% of the time in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in Target INR Range of 2.0 – 3.0) in the equally sized tertiles and the incidence of the recurrent VTE (p=0.082 for interaction). Within the highest tertile according to centre, the HR with rivaroxaban versus warfarin was 0.642 (95% CI: 0.277 - 1.484).

The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome (major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the enoxaparin/VKA group (2.2% (52/2405)) with a HR 0.493 (95% CI: 0.308 - 0.789).

Table 7: Efficacy and safety results from phase III Einstein PE

Study population                    4,832 patients with an acute symptomatic PE Rivaroxaban a)                  Enoxaparin/VKAb
Treatment dose and duration 3, 6 or 12 months                       3, 6 or 12 months N=2,419                         N=2,413
50                              44
Symptomatic recurrent VTE*
(2.1%)                          (1.8%)
23                              20
Symptomatic recurrent PE
(1.0%)                          (0.8%)
18                              17
Symptomatic recurrent DVT
(0.7%)                          (0.7%)
2
Symptomatic PE and DVT           0
(<0.1%)
Fatal PE/death where PE          11                              7 cannot be ruled out              (0.5%)                          (0.3%) Major or clinically relevant non- 249                               274 major bleeding                      (10.3%)                         (11.4%) 26                              52
Major bleeding events
(1.1%)                          (2.2%) a)      Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily b)      Enoxaparin for at least 5 days, overlapped with and followed by VKA *       p < 0.0026 (non-inferiority to a prespecified HR of 2.0); HR: 1.123 (0.749 – 1.684) 
A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see Table 8).
Table 8: Efficacy and safety results from pooled analysis of phase III Einstein DVT and Einstein PE

Study population                    8,281 patients with an acute symptomatic DVT or PE Rivaroxaban a)                  Enoxaparin/VKAb
Treatment dose and duration 3, 6 or 12 months                       3, 6 or 12 months N=4,150                         N=4,131
86                              95
Symptomatic recurrent VTE*
(2.1%)                          (2.3%)
43                              38
Symptomatic recurrent PE
(1.0%)                          (0.9%)
32                              45
Symptomatic recurrent DVT
(0.8%)                          (1.1%)
1                               2
Symptomatic PE and DVT
(<0.1%)                         (<0.1%)
Fatal PE/death where PE          15                              13 cannot be ruled out              (0.4%)                          (0.3%) Major or clinically relevant non- 388                               412 major bleeding                      (9.4%)                          (10.0%) 40                              72
Major bleeding events
(1.0%)                          (1.7%) a)      Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily b)      Enoxaparin for at least 5 days, overlapped with and followed by VKA *       p < 0.0001 (non-inferiority to a prespecified HR of 1.75); HR: 0.886 (0.661 – 1.186) 
The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the pooled analysis was reported with a HR of 0.771 ((95% CI: 0.614 – 0.967), nominal p value p= 0.0244).

In the Einstein Extension study (see Table 9) rivaroxaban was superior to placebo for the primary and secondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was a non-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once daily compared to placebo. The secondary safety outcome (major or clinically relevant non- major bleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared to placebo.
Table 9: Efficacy and safety results from phase III Einstein Extension 
1,197 patients continued treatment and prevention
Study population of recurrent venous thromboembolism
Rivaroxaban a)                Placebo
Treatment dose and duration 6 or 12 months                      6 or 12 months N=602                         N=594
8                             42
Symptomatic recurrent VTE*
(1.3%)                        (7.1%)
2                             13
Symptomatic recurrent PE
(0.3%)                        (2.2%)
5                             31
Symptomatic recurrent DVT
(0.8%)                        (5.2%)
Fatal PE/death where PE        1                             1 cannot be ruled out            (0.2%)                        (0.2%)
4                             0
Major bleeding events
(0.7%)                        (0.0%)
Clinically relevant non-major     32                            7 bleeding                          (5.4%)                        (1.2%) a)     Rivaroxaban 20 mg once daily
*      p < 0.0001 (superiority), HR: 0.185 (0.087 - 0.393)

In the Einstein Choice study (see Table 10) rivaroxaban 20 mg and 10 mg were both superior to 100 mg acetylsalicylic acid for the primary efficacy outcome. The principal safety outcome (major bleeding events) was similar for patients treated with rivaroxaban 20 mg and 10 mg once daily compared to 100 mg acetylsalicylic acid


Table 10: Efficacy and safety results from phase III Einstein Choice
3,396 patients continued prevention of
Study population recurrent venous thromboembolism
Rivaroxaban 20 mg       Rivaroxaban 10         ASA 100 mg once
Treatment dose                once daily              mg once daily          daily N=1,107                 N=1,127                N=1,131
Treatment duration
353 [190-362] median [interquartile         349 [189-362] days                             350 [186-362] days days range]
Symptomatic recurrent         17                      13                     50 VTE                           (1.5%)*                 (1.2%)**               (4.4%) Symptomatic recurrent      6                       6                      19 PE                         (0.5%)                  (0.5%)                 (1.7%) Symptomatic recurrent      9                       8                      30 DVT                        (0.8%)                  (0.7%)                 (2.7%) Fatal PE/death where       2                       0                      2 PE cannot be ruled out     (0.2%)                  (0.0%)                 (0.2%) Symptomatic recurrent
19                      18                     56
VTE, MI, stroke, or non-
(1.7%)                  (1.6%)                 (5.0%)
CNS systemic embolism
6                       5                      3
Major bleeding events
(0.5%)                  (0.4%)                 (0.3%)
Clinically relevant non-      30                      22                     20 major bleeding                (2.7%)                  (2.0%)                 (1.8%) Symptomatic recurrent
23                   17               53
VTE or major bleeding
(2.1%)+
(1.5%)++
(4.7%)
(net clinical benefit)
* p<0.001(superiority) rivaroxaban 20 mg od vs ASA 100 mg od; HR=0.34 (0.20–0.59) ** p<0.001 (superiority) rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.26 (0.14–0.47) +
Rivaroxaban 20 mg od vs. ASA 100 mg od; HR=0.44 (0.27–0.71), p=0.0009 (nominal) ++
Rivaroxaban 10 mg od vs. ASA 100 mg od; HR=0.32 (0.18–0.55), p<0.0001 (nominal) 
In addition to the phase III EINSTEIN programme, a prospective, non-interventional, open-label cohort study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and death has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long- term safety of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice. Rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 0.5%, respectively. There were differences in patient baseline characteristics including age, cancer and renal impairment. A pre-specified propensity score stratified analysis was used to adjust for measured baseline differences but residual confounding may, in spite of this, influence the results. Adjusted HRs comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-cause mortality were 0.77 (95% CI 0.40 - 1.50), 0.91 (95% CI 0.54 - 1.54) and 0.51 (95% CI 0.24 - 1.07), respectively.
These results in clinical practice are consistent with the established safety profile in this indication.
In a post-authorisation, non-interventional study, in more than 40,000 patients without a history of cancer from four countries, rivaroxaban was prescribed for the treatment or prevention of DVT and PE. The event rates per 100 patient-years for symptomatic/clinically apparent VTE/thromboembolic events leading to hospitalisation ranged from 0.64 (95% CI 0.40 - 0.97) in the UK to 2.30 (95% CI 2.11 - 2.51) for Germany. Bleeding resulting in hospitalisation occurred at event rates per
100 patient-years of 0.31 (95% CI 0.23 - 0.42) for intracranial bleeding, 0.89 (95% CI 0.67 - 1.17) for gastrointestinal bleeding, 0.44 (95% CI 0.26 - 0.74) for urogenital bleeding and 0.41 (95% CI 0.31 - 0.54) for other bleeding.
Paediatric population
Treatment of VTE and prevention of VTE recurrence in paediatric patients A total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in 6 open-label, multicentre paediatric studies. Body weight-adjusted dosing in patients from birth to less than 18 years resulted in rivaroxaban exposure similar to that observed in adult DVT patients treated with rivaroxaban 20 mg once daily as confirmed in the phase III study (see section 5.2).

The EINSTEIN Junior phase III study was a randomised, active-controlled, open-label multicentre clinical study in 500 paediatric patients (aged from birth to < 18 years) with confirmed acute VTE.
There were 276 children aged 12 to < 18 years, 101 children aged 6 to < 12 years, 69 children aged 2 to < 6 years, and 54 children aged < 2 years.

Index VTE was classified as either central venous catheter-related VTE (CVC-VTE; 90/335 patients in the rivaroxaban group, 37/165 patients in the comparator group), cerebral vein and sinus thrombosis (CVST; 74/335 patients in the rivaroxaban group, 43/165 patients in the comparator group), and all others including DVT and PE (non-CVC-VTE; 171/335 patients in the rivaroxaban group, 85/165 patients in the comparator group). The most common presentation of index thrombosis in children aged 12 to < 18 years was non-CVC-VTE in 211 (76.4%); in children aged 6 to < 12 years and aged 2 to < 6 years was CVST in 48 (47.5%) and 35 (50.7%), respectively; and in children aged < 2 years was CVC-VTE in 37 (68.5%). There were no children < 6 months with CVST in the rivaroxaban group. 22 of the patients with CVST had a CNS infection (13 patients in the rivaroxaban group and 9 patients in comparator group).

VTE was provoked by persistent, transient, or both persistent and transient risk factors in 438 (87.6%) children.

Patients received initial treatment with therapeutic doses of UFH, LMWH, or fondaparinux for at least 5 days, and were randomised 2:1 to receive either body weight-adjusted doses of rivaroxaban or comparator group (heparins, VKA) for a main study treatment period of 3 months (1 month for children < 2 years with CVC-VTE). At the end of the main study treatment period, the diagnostic imaging test, which was obtained at baseline, was repeated, if clinically feasible. The study treatment could be stopped at this point, or at the discretion of the Investigator continued for up to 12 months (for children <2 years with CVC-VTE up to 3 months) in total.

The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was the composite of major bleeding and clinically relevant non-major bleeding (CRNMB). All efficacy and safety outcomes were centrally adjudicated by an independent committee blinded for treatment allocation. The efficacy and safety results are shown in Tables 11 and 12 below.
Recurrent VTEs occurred in the rivaroxaban group in 4 of 335 patients and in the comparator group in 5 of 165 patients. The composite of major bleeding and CRNMB was reported in 10 of 329 patients (3%) treated with rivaroxaban and in 3 of 162 patients (1.9%) treated with comparator.
Net clinical benefit (symptomatic recurrent VTE plus major bleeding events) was reported in the rivaroxaban group in 4 of 335 patients and in the comparator group in 7 of 165 patients.
Normalisation of the thrombus burden on repeat imaging occurred in 128 of 335 patients with rivaroxaban treatment and in 43 of 165 patients in the comparator group. These findings were generally similar among age groups. There were 119 (36.2%) children with any treatment-emergent bleeding in the rivaroxaban group and 45 (27.8%) children in the comparator group.


Table 11: Efficacy results at the end of the main treatment period
Event                                                Rivaroxaban            Comparator N=335*                 N=165*
Recurrent VTE (primary efficacy outcome)             4                      5 (1.2%, 95% CI          (3.0%, 95% CI
0.4% – 3.0%)           1.2% - 6.6%)
Composite: Symptomatic recurrent VTE +               5                      6 asymptomatic deterioration on repeat imaging         (1.5%, 95% CI          (3.6%, 95% CI 0.6% – 3.4%)           1.6% – 7.6%)
Composite: Symptomatic recurrent VTE +               21                     19 asymptomatic deterioration + no change on repeat     (6.3%, 95% CI          (11.5%, 95% CI imaging                                              4.0% – 9.2%)           7.3% – 17.4%) Normalisation on repeat imaging                      128                    43 (38.2%, 95% CI         (26.1%, 95% CI
33.0% - 43.5%)         19.8% - 33.0%)
Composite: Symptomatic recurrent VTE + major         4                      7 bleeding (net clinical benefit)                      (1.2%, 95% CI          (4.2%, 95% CI 0.4% - 3.0%)           2.0% - 8.4%)
Fatal or non-fatal pulmonary embolism                 1                     1 (0.3%, 95% CI         (0.6%, 95% CI
0.0% – 1.6%)          0.0% – 3.1%)
*      FAS= full analysis set, all children who were randomised

Table 12: Safety results at the end of the main treatment period
Rivaroxaban         Comparator
N=329*              N=162*
Composite: Major bleeding + CRNMB (primary             10                  3 safety outcome)                                        (3.0%, 95% CI       (1.9%, 95% CI 1.6% - 5.5%)        0.5% - 5.3%)
Major bleeding                                         0                   2 (0.0%, 95% CI       (1.2%, 95% CI
0.0% - 1.1%)        0.2% - 4.3%)
Any treatment-emergent bleedings                       119 (36.2%)         45 (27.8%) *       SAF = safety analysis set, all children who were randomised and received at least 1 dose of study medicinal product
The efficacy and safety profile of rivaroxaban was largely similar between the paediatric VTE population and the DVT/PE adult population, however, the proportion of subjects with any bleeding was higher in the paediatric VTE population as compared to the DVT/PE adult population.

Patients with high risk triple positive antiphospholipid syndrome
In an investigator sponsored, randomized open-label multicenter study with blinded endpoint adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for all 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of 120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. 59 patients were randomized to rivaroxaban 20 mg (15 mg for patients with creatinine clearance (CrCl) <50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 12% of patients randomized to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions).
No events were reported in patients randomized to warfarin. Major bleeding occurred in 4 patients (7%) of the rivaroxaban group and 2 patients (3%) of the warfarin group.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
The following information is based on the data obtained in adults.
Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose.
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg tablet under fasting conditions. When rivaroxaban 20 mg tablets are taken together with food increases in mean AUC by 39% were observed when compared to tablet intake under fasting conditions, indicating almost complete absorption and high oral bioavailability. Rivaroxaban 15 mg and 20 mg are to be taken with food (see section 4.2).
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state. Under fed conditions rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose- proportionality. At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased absorption rate with increased dose.
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to 40%.
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the stomach should be avoided since this can result in reduced absorption and related rivaroxaban exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable to lower rivaroxaban doses.

Paediatric population
Children received rivaroxaban tablet or oral suspension during or closely after feeding or food intake and with a typical serving of liquid to ensure reliable dosing in children. As in adults, rivaroxaban is readily absorbed after oral administration as tablet or granules for oral suspension formulation in children. No difference in the absorption rate nor in the extent of absorption between the tablet and granules for oral suspension formulation was observed. No PK data following intravenous administration to children are available so that the absolute bioavailability of rivaroxaban in children is unknown. A decrease in the relative bioavailability for increasing doses (in mg/kg bodyweight) was found, suggesting absorption limitations for higher doses, even when taken together with food.
Rivaroxaban 20 mg tablets should be taken with feeding or with food (see section 4.2).

Distribution
Plasma protein binding in adults is high at approximately 92 % to 95 %, with serum albumin being the main binding component. The volume of distribution is moderate with Vss being approximately 50 litres.
Paediatric population
No data on rivaroxaban plasma protein binding specific to children is available. No PK data following intravenous administration of rivaroxaban to children is available. Vss estimated via population PK modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and can be described with an allometric function, with an average of 113 L for a subject with a body weight of 82.8 kg.

Biotransformation and elimination
In adults, of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion.
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be classified as a low-clearance substance. After intravenous administration of a 1 mg dose the elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.

Paediatric population
No metabolism data specific to children is available. No PK data following intravenous administration of rivaroxaban to children is available. CL estimated via population PK modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and can be described with an allometric function, with an average of 8 L/h for a subject with body weight of 82.8 kg. The geometric mean values for disposition half-lives (t1/2) estimated via population PK modelling decrease with decreasing age and ranged from 4.2 h in adolescents to approximately 3 h in children aged 2-12 years down to 1.9 and 1.6 h in children aged 0.5-< 2 years and less than 0.5 years, respectively.

Special populations
Gender
In adults, there were no clinically relevant differences in pharmacokinetics and pharmacodynamics between male and female patients. An exploratory analysis did not reveal relevant differences in rivaroxaban exposure between male and female children.

Elderly population
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No dose adjustment is necessary.

Different weight categories
In adults, extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasma concentrations (less than 25 %). No dose adjustment is necessary.
In children, rivaroxaban is dosed based on body weight. An exploratory analysis did not reveal a relevant impact of underweight or obesity on rivaroxaban exposure in children.

Inter-ethnic differences
In adults, no clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics.
An exploratory analysis did not reveal relevant inter-ethnic differences in rivaroxaban exposure among Japanese, Chinese or Asian children outside Japan and China compared to the respective overall paediatric population.

Hepatic impairment
Cirrhotic adult patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT.
Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 4.3).
No clinical data is available in children with hepatic impairment.
Renal impairment
In adults, there was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min), moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no data in patients with creatinine clearance < 15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance < 15 ml/min. Rivaroxaban is to be used with caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).
No clinical data is available in children 1 year or older with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m2).

Pharmacokinetic data in patients
In patients receiving rivaroxaban for treatment of acute DVT 20 mg once daily the geometric mean concentration (90% prediction interval) 2 - 4 h and about 24 h after dose (roughly representing maximum and minimum concentrations during the dose interval) was 215 (22 - 535) and 32 (6 - 239) mcg/l, respectively.
In paediatric patients with acute VTE receiving body weight-adjusted rivaroxaban leading to an exposure similar to that in adult DVT patients receiving a 20 mg once daily dose, the geometric mean concentrations (90% interval) at sampling time intervals roughly representing maximum and minimum concentrations during the dose interval are summarised in Table 13.

Table 13: Summary statistics (geometric mean (90% interval)) of rivaroxaban steady state plasma concentrations (mcg/L) by dosing regimen and age
Time intervals o.d.        N    12 -           N    6-
< 18 years          < 12 years
2.5-4h post 171 241.5           24 229.7
(105-484)           (91.5-777)
20-24h      151 20.6            24 15.9 post             (5.69-66.5)         (3.42-45.5) b.i.d.      N    6-             N    2 -< 6 years N 0.5 -
< 12 years                           < 2 years
2.5-4h post 36 145.4            38 171.8          2 n.c.
(46.0-343)          (70.7-438)
10-16h      33 26.0             37 22.2           3 10.7 post             (7.99-94.9)         (0.25-127)       (n.c.-n.c.) t.i.d.      N    2 -< 6 years N      Birth -      N 0.5 -             N Birth - < 2 years        < 2 years           < 0.5 years
0.5-3h post 5    164.7          25 111.2          13 114.3            12 108.0 (108-283)           (22.9-320)       (22.9-346)          (19.2-320)
7-8h post   5    33.2           23 18.7           12 21.4             11 16.1 (18.7-99.7)            (10.1-36.5)           (10.5-65.6)          (1.03-33.6) o.d. = once daily, b.i.d. = twice daily, t.i.d. three times daily, n.c. = not calculated Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation of statistics (LLOQ = 0.5 mcg/L).


Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, the linear intercept model generally described the data better. Depending on the different PT reagents used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and the slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses in Phase II and III were consistent with the data established in healthy subjects.

Paediatric population
Safety and efficacy have not been established in the indication prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation for children and adolescents up to 18 years.