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 undergoing major orthopaedic surgery, the 5/95 percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) ranged from 13 to 25 s (baseline values before surgery 12 to 15 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 thomboplastin 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).

Clinical efficacy and safety
Prevention of VTE in adult patients undergoing elective hip or knee replacement surgery The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for the prevention of VTE, i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing major orthopaedic surgery of the lower limbs. Over 9,500 patients (7,050 in total hip replacement surgery and 2,531 in total knee replacement surgery) were studied in controlled randomised double-blind phase III clinical studies, the RECORD-programme.

Rivaroxaban 10 mg once daily (od) started no sooner than 6 hours post-operatively was compared with enoxaparin 40 mg once daily started 12 hours pre-operatively.
In all three phase III studies (see table 4), rivaroxaban significantly reduced the rate of total VTE (any venographically detected or symptomatic DVT, non- fatal PE and death) and major VTE (proximal DVT, non- fatal PE and VTE-related death), the pre-specified primary and major secondary efficacy endpoints. Furthermore, in all three studies the rate of symptomatic VTE (symptomatic DVT, non-fatal PE, VTE-related death) was lower in rivaroxaban treated patients compared to patients treated with enoxaparin.
The main safety endpoint, major bleeding, showed comparable rates for patients treated with rivaroxaban 10 mg compared to enoxaparin 40 mg.

Table 4 : Efficacy and safety results from phase III clinical studies RECORD 1                      RECORD 2                             RECORD 3 Study     4,541 patients undergoing 2,509 patients undergoing total          2,531 patients undergoing total populati total hip replacement          hip replacement surgery              knee replacement surgery on        surgery
Treatme   Rivarox Enoxapari        p     Rivaroxaban Enoxapari         p      Rivaroxaban Enoxapari       p nt dose     aban         n                10 mg od          n                  10 mg od         n and       10 mg     40 mg od             35 ± 4 days    40 mg od              12 ± 2 days 40 mg od duration     od     35 ± 4 day                         12 ± 2 day                          12 ± 2 day after     35 ± 4         s                                  s                                   s surgery    days
Total           18 58 (3.7 %) < 0.0        17 (2.0 %) 81 (9.3 %) < 0.0         79 (9.6 %)          166 < 0.00 VTE       (1.1 %)                   01                                  01                    (18.9 %) 1 Major            4 33 (2.0 %) < 0.0         6 (0.6 %) 49 (5.1 %) < 0.0          9 (1.0 %)   24 (2.6 %) 0.01 VTE       (0.2 %)                   01                                  01 Sympto-          6 11 (0.7 %)               3 (0.4 %) 15 (1.7 %)                8 (1.0 %)   24 (2.7 %) matic VTE (0.4 %)
Major            6   2 (0.1 %)              1 (0.1 %)    1 (0.1 %)              7 (0.6 %)    6 (0.5 %) bleeding  (0.3 %) s

The analysis of the pooled results of the phase III studies corroborated the data obtained in the individual studies regarding reduction of total VTE, major VTE and symptomatic VTE with rivaroxaban 10 mg once daily compared to enoxaparin 40 mg once daily.

In addition to the phase III RECORD programme, a post-authorization, non-interventional, open-label cohort study (XAMOS) has been conducted in 17,413 patients undergoing major orthopaedic surgery of the hip or knee, to compare rivaroxaban with other pharmacological thromboprophylaxis (standard-of-care) under real-life setting. Symptomatic VTE occurred in 57 (0.6%) patients in the rivaroxaban group (n=8,778) and 88 (1.0%) of patients in the standard-of-care group (n=8,635; HR 0.63; 95% CI 0.43-0.91); safety population). Major bleeding occurred in 35 (0.4%) and 29 (0.3%) of patients in the rivaroxaban and standard-of- care groups (HR 1.10; 95% CI 0.67-1.80). Thus, the results were consistent with the results of the pivotal randomised studies.

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 5) rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); Hazard Ratio (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 5: Efficacy and safety results from phase III Einstein DVT
3,449 patients with symptomatic acute deep vein
Study population thrombosis
Xareltoa)                      Enoxaparin/VKAb)
Treatment dose and
3, 6 or 12 months              3, 6 or 12 months duration
N=1,731                        N=1,718
36                             51
Symptomatic recurrent VTE* (2.1%)                               (3.0%) Symptomatic recurrent         20                             18
PE                               (1.2%)                         (1.0%) Symptomatic recurrent         14                             28
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     139                            138 non-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 6) 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 6: 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
3, 6 or 12 months              3, 6 or 12 months duration
N=2,419                        N=2,413
50                             44
Symptomatic recurrent VTE* (2.1%)                               (1.8%) Symptomatic recurrent         23                             20
PE                               (1.0%)                         (0.8%) Symptomatic recurrent         18                             17
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     249                            274 non-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 7).

Table 7: 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
3, 6 or 12 months             3, 6 or 12 months duration
N=4,150                       N=4,131
86                            95
Symptomatic recurrent VTE* (2.1%)                              (2.3%) Symptomatic recurrent         43                            38
PE                               (1.0%)                        (0.9%) Symptomatic recurrent         32                            45
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     388                           412 non-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 8) 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 8: 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
6 or 12 months              6 or 12 months duration
N=602                       N=594
8                           42
Symptomatic recurrent VTE* (1.3%)                            (7.1%)
2                           13
Symptomatic recurrent PE
(0.3%)                      (2.2%)
Symptomatic recurrent         5                           31
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 (Table 9) 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 9: Efficacy and safety results from phase III Einstein Choice
3,396 patients continued prevention of
Study population recurrent venous thromboembolism



Rivaroxaban 20           Rivaroxaban 10          ASA 100 mg
Treatment dose                 mg once daily            mg once daily           once daily N=1,107                  N=1,127                 N=1,131
Treatment duration
353 [190-362]           350 [186-362] median [interquartile          349 [189-362] days days                    days range]
Symptomatic recurrent          17                       13                      50 VTE                            (1.5%)*                  (1.2%)**                (4.4%) Symptomatic                6                        6                       19 recurrent PE               (0.5%)                   (0.5%)                  (1.7%) Symptomatic                9                        8                       30 recurrent DVT              (0.8%)                   (0.7%)                  (2.7%) Fatal PE/death where
2                                                2
PE cannot be ruled                                  0
(0.2%)                                           (0.2%) out
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.

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
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. Rivaroxaban 2.5 mg and 10 mg tablets can be taken with or without food. Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily. At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased absorption rate with increased dose. This is more marked in fasting state than in fed state. Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV %) ranging from 30 % to 40 %, apart from on the day of surgery and the following day when variability in exposure is high (70 %).
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.

Distribution
Plasma protein binding in humans 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.

Biotransformation and elimination
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.

Special populations
Gender
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between male and female patients.

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
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.

Inter-ethnic differences
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics.

Hepatic impairment
Cirrhotic 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).

Renal impairment
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).


Pharmacokinetic data in patients
In patients receiving rivaroxaban for prevention of VTE 10 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 101 (7 - 273) and 14 (4 - 51) mcg/l, respectively.

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. In patients, baseline factor Xa and PT were influenced by the surgery resulting in a difference in the concentration-PT slope between the day post-surgery and steady state.

Paediatric population
Safety and efficacy have not been established in the indication primary prevention of VTE for children and adolescents up to 18 years.