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 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
ACS

The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for the prevention of cardiovascular (CV) death, myocardial infarction (MI) or stroke in subjects with a recent ACS (ST-elevation myocardial infarction [STEMI], non- ST-elevation myocardial infarction [NSTEMI] or unstable angina [UA]). In the pivotal double-blind ATLAS ACS 2 TIMI 51 study, 15,526 patients were randomly assigned in a 1:1:1 fashion to one of three treatment groups: rivaroxaban 2.5 mg orally twice daily, 5 mg orally twice daily or to placebo twice daily co- administered with ASA alone or with ASA plus a thienopyridine (clopidogrel or ticlopidine). Patients with an ACS under the age of 55 had to have either diabetes mellitus or a previous MI. The median time on treatment was 13 months and overall treatment duration was up to almost 3 years. 93.2 % of patients received ASA concomitantly plus thienopyridine treatment and 6.8 % ASA only. Among patients receiving dual anti-platelets therapy 98.8% received clopidogrel, 0.9 % received ticlopidine and 0.3 % received prasugrel. Patients received the first dose of rivaroxaban at a minimum of 24 hours and up to 7 days (mean 4.7 days) after admission to the hospital, but as soon as possible after stabilisation of the ACS event, including revascularisation procedures and when parenteral anticoagulation therapy would normally be discontinued.


Both the 2.5 mg twice daily and the 5 mg twice daily regimens of rivaroxaban were effective in further reducing the incidence of CV events on a background of standard antiplatelet care. The 2.5 mg twice daily regimen reduced mortality, and there is evidence that the lower dose had lower bleeding risks, therefore rivaroxaban 2.5 mg twice daily co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine is recommended for the prevention of atherothrombotic events in adult patients after an ACS with elevated cardiac biomarkers.

Relative to placebo, rivaroxaban significantly reduced the primary composite endpoint of CV death, MI or stroke. The benefit was driven by a reduction in CV death and MI and appeared early with a constant treatment effect over the entire treatment period (see Table 4 and Figure 1). Also the first secondary endpoint (all cause death, MI or stroke) was reduced significantly. An additional retrospective analysis showed a nominally significant reduction in the incidence rates of stent thrombosis compared with placebo (see Table 4). The incidence rates for the principal safety outcome (non- coronary artery bypass graft (CABG) TIMI major bleeding events) were higher in patients treated with rivaroxaban than in patients who received placebo (see Table 6). However the incidence rates were balanced between rivaroxaban and placebo for the components of fatal bleeding events, hypotension requiring treatment with intravenous inotropic agents and surgical intervention for ongoing bleeding.

In Table 5 the efficacy results of patients undergoing percutaneous coronary intervention (PCI) are presented. The safety results in this subgroup of patients undergoing PCI were comparable to the overall safety results.

Patients with elevated biomarkers (troponin or CK-MB) and without a prior stroke/TIA constituted 80 % of the study population. The results of this patient population were also consistent with the overall efficacy and safety results.


Table 4: Efficacy results from phase III ATLAS ACS 2 TIMI 51
Study population                        Patients with a recent acute coronary syndrome a)   P 


Treatment dose                           Xarelto 2.5 mg, twice daily, N=5,114          Placebo n (%)                          N=5,113
Hazard Ratio (HR) (95% CI) p-                 n (%) value b)P



Cardiovascular death, MI or stroke
313 (6.1%)                     376 (7.4%)
0.84 (0.72, 0.97) p = 0.020*
All-cause death, MI or stroke
320 (6.3%)                     386 (7.5%)
0.83 (0.72, 0.97) p = 0.016*
Cardiovascular death
94 (1.8%)                     143 (2.8%)
0.66 (0.51, 0.86) p = 0.002**
All-cause death
103 (2.0%)                     153 (3.0%)
0.68 (0.53, 0.87) p = 0.002**
MI
205 (4.0%)                     229 (4.5%)
0.90 (0.75, 1.09) p = 0.270
Stroke
46 (0.9%)                      41 (0.8%)
1.13 (0.74, 1.73) p = 0.562
Stent thrombosis
61 (1.2%)                      87 (1.7%)
0.70 (0.51, 0.97) p = 0.033**
a)   modified intent to treat analysis set (intent to treat total analysis set for stent thrombosis) b)   vs. placebo; Log-Rank p-value
*    statistically superior
**   nominally significant



Table 5: Efficacy results from phase III ATLAS ACS 2 TIMI 51 in patients undergoing PCI Study population                          Patients with recent acute coronary syndrome undergoing PCI a)  P



Treatment dose                               Rivaroxaban 2.5 mg, twice daily,                Placebo N=3114                               N=3096 n (%)                                n (%)
HR (95% CI) p-value b)     P



Cardiovascular death, MI or stroke
153 (4.9%)                       165 (5.3%)
0.94 (0.75, 1.17) p = 0.572
Cardiovascular death
24 (0.8%)                         45 (1.5%)
0.54 (0.33, 0.89) p = 0.013**
All-cause death
31 (1.0%)                        49 (1.6%)
0.64 (0.41, 1.01) p = 0.053
MI
115 (3.7%)                       113 (3.6%)
1.03 (0.79, 1.33) p = 0.829
Stroke
27 (0.9%)                        21 (0.7%)
1.30 (0.74, 2.31) p = 0.360
Stent thrombosis
47 (1.5%)                         71 (2.3%)
0.66 (0.46, 0.95) p = 0.026** a) modified intent to treat analysis set (intent to treat total analysis set for stent thrombosis) b) vs. placebo; Log-Rank p-value
** nominally significant
Table 6: Safety results from phase III ATLAS ACS 2 TIMI 51
Study population                          Patients with recent acute coronary syndrome a)       P 


Treatment Dose                            Rivaroxaban 2.5 mg, twice daily,      Placebo N=5,115                               N=5,125 n (%)                                 n(%)
HR (95% CI) p-value b)   P



Non-CABG TIMI major bleeding
65 (1.3%)                                  19 (0.4%) event
3.46 (2.08, 5.77) p = < 0.001*
Fatal bleeding event
6 (0.1%)                                   9 (0.2%)
0.67 (0.24, 1.89) p = 0.450
Symptomatic intracranial
14 (0.3%)                                  5 (0.1%) haemorrhage
2.83 (1.02, 7.86) p = 0.037
Hypotension requiring treatment with
3 (0.1%)                                   3 (0.1%) intravenous inotropic agents
Surgical intervention for ongoing
7 (0.1%)                                   9 (0.2%) bleeding
Transfusion of 4 or more units of
19 (0.4%)                                  6 (0.1%) blood over a 48 hour period



a)     safety population, on treatment b) vs. placebo; Log-Rank p-value
* statistically significant

Figure 1: Time to first occurrence of primary efficacy endpoint (CV death, MI or stroke) 

15
XARELTO 2.5 mg twice daily
Cumulative Event Rate (%)


14       Placebo

13

12
11

10

9
8

7

6
5

4

3
2                                                                      Hazard Ratio: 0.84 1
95% CI: (0.72, 0.97)
P-value=0.020*
0

0           90        180        270    360        450     540     630       720         810 
No. of Patients at Risk                                                             Relative Days from the Randomization XARELTO                              5114        4431      3943       3199   2609       2005    1425    878       415         89 Placebo                              5113        4437      3974       3253   2664       2059    1460    878       421         87 


CAD/PAD
The phase III COMPASS study (27,395 patients, 78.0% male, 22.0% female) demonstrated the efficacy and safety of rivaroxaban for the prevention of a composite of CV death, MI, stroke in patients with CAD or symptomatic PAD at high risk of ischaemic events. Patients were followed for a median of 23 months and maximum of 3.9 years.

Subjects without a continuous need for treatment with a proton pump inhibitor were randomized to pantoprazole or placebo. All patients were then randomized 1:1:1 to rivaroxaban 2.5 mg twice daily/ASA 100 mg once daily, to rivaroxaban 5 mg twice daily, or ASA 100 mg once daily alone, and their matching placebos.

High risk patients are defined by COMPASS inclusion criteria

CAD patients had multivessel CAD and/or prior MI. Patients included in COMPASS were ≥65 years of age, or if < 65 years of age atherosclerosis or revascularization involving at least two vascular beds or at least two additional cardiovascular risk factors (smoking, diabetes mellitus, renal dysfunction with estimated glomerular filtration rate <60 ml/min, heart failure, non-lacunar ischemic stroke ≥1 month ago) were required.

PAD patients had previous interventions such as bypass surgery or percutaneous transluminal angioplasty or limb or foot amputation for arterial vascular disease or intermittent claudication with ankle/arm blood pressure ratio < 0.90 and/ or significant peripheral artery stenosis or previous carotid revascularization or asymptomatic carotid artery stenosis ≥ 50%.

Exclusion criteria included the need for dual antiplatelet or other non-ASA antiplatelet or oral anticoagulant therapy and patients with high bleeding risk, or heart failure with ejection fraction 
< 30% or New York Heart Association class III or IV, or any ischaemic, non-lacunar stroke within 1 month or any history of haemorrhagic or lacunar stroke.

Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily was superior to ASA 100 mg, in the reduction of the primary composite outcome of CV death, MI, stroke (see Table 7 and Figure 2).

There was a significant increase of the primary safety outcome (modified ISTH major bleeding events) in patients treated with Xarelto 2.5 mg twice daily in combination with ASA 100 mg once daily compared to patients who received ASA 100 mg (see Table 8).
For the primary efficacy outcome, the observed benefit of rivaroxaban 2.5 mg twice daily plus ASA 100 mg once daily compared with ASA 100 mg once daily was HR=0.89 (95% CI 0.7-1.1) in patients ≥75 years (incidence: 6.3% vs 7.0%) and HR=0.70 (95% CI 0.6-0.8) in patients <75 years (3.6% vs 5.0%). For modified ISTH major bleeding, the observed risk increase was HR=2.12 (95% CI 1.5-3.0) in patients ≥75 years (5.2% vs 2.5%) and HR=1.53 (95% CI 1.2-1.9) in patients <75 years (2.6% vs 1.7%).
The use of pantoprazole 40 mg once daily in addition to antithrombotic study medication in patients with no clinical need for a proton pump inhibitor showed no benefit in the prevention of upper gastrointestinal events (i.e. composite of upper gastrointestinal bleeding, upper gastrointestinal ulceration, or upper gastrointestinal obstruction or perforation); the incidence rate of upper gastrointestinal events was 0.39/100 patient-years in the pantoprazole 40 mg once daily group and 0.44/100 patient-years in the placebo once daily group.

Table 7: Efficacy results from phase III COMPASS
Study              Patients with CAD/PAD a)
Population
Treatment          Rivaroxaban 2.5 mg       ASA 100 mg od
Dosage             bid in combination with
ASA 100 mg od
N=9152                   N=9126
Patients with KM %       Patients    KM %             HR            p-value b) events                   with events                  (95% CI)


Stroke, MI or                                                            0.76 379 (4.1%)      5.20%      496 (5.4%)     7.17%                    p = 0.00004* CV death                                                                 (0.66;0.86) 0.58
-   Stroke        83 (0.9%)       1.17%      142 (1.6%)     2.23%                    p = 0.00006 (0.44;0.76)
0.86
-   MI            178 (1.9%)      2.46%      205 (2.2%)     2.94%                    p = 0.14458 (0.70;1.05)
0.78
-   CV death      160 (1.7%)      2.19%      203 (2.2%)     2.88%                    p = 0.02053 (0.64;0.96)

All-cause                                                                 0.82 313 (3.4%)        4.50%      378 (4.1%) 5.57% mortality                                                                 (0.71;0.96) Acute limb                                                                0.55 22 (0.2%)         0.27%      40 (0.4%)  0.60% ischaemia                                                                 (0.32;0.92) a)     intention to treat analysis set, primary analyses b)     vs. ASA 100 mg; Log-Rank p-value
*      The reduction in the primary efficacy outcome was statistically superior.
bid: twice daily; CI: confidence interval; KM %: Kaplan-Meier estimates of cumulative incidence risk calculated at 900 days; CV: cardiovascular; MI: myocardial infarction; od: once daily 


Table 8: Safety results from phase III COMPASS
Study population                                     Patients with CAD/PAD a) Treatment Dose                       Rivaroxaban 2.5 mg ASA 100 mg od          Hazard Ratio bid in combination                          (95 % CI) with ASA 100 mg od, N=9152              N=9126          p-value b) n (Cum. risk %)       n (Cum.risk %)
Modified ISTH major bleeding              288 (3.9%)           170 (2.5%)     1.70 (1.40;2.05) p < 0.00001
- Fatal bleeding event                  15 (0.2%)            10 (0.2%)      1.49 (0.67;3.33) p = 0.32164
- Symptomatic bleeding in               63 (0.9%)            49 (0.7%)      1.28 (0.88;1.86) critical organ (non-fatal)                                                  p = 0.19679 - Bleeding into the surgical site        10 (0.1%)            8 (0.1%)      1.24 (0.49;3.14) requiring reoperation (non- fatal, not in critical organ)                                               p = 0.65119 - Bleeding leading to                   208 (2.9%)           109 (1.6%)     1.91 (1.51;2.41) hospitalisation (non-fatal, not                                             p < 0.00001 in critical organ, not requiring reoperation)
- With overnight stay               172 (2.3%)            90 (1.3%)     1.91 (1.48;2.46) p < 0.00001
- Without overnight stay             36 (0.5%)            21 (0.3%)     1.70 (0.99;2.92) p = 0.04983
Major gastrointestinal bleeding           140 (2.0%)           65 (1.1%)      2.15 (1.60;2.89) p < 0.00001



Study population                                       Patients with CAD/PAD a) Treatment Dose                         Rivaroxaban 2.5 mg ASA 100 mg od             Hazard Ratio bid in combination                            (95 % CI) with ASA 100 mg od, N=9152            N=9126              p-value b) n (Cum. risk %)      n (Cum.risk %)
Major intracranial bleeding                  28 (0.4%)           24 (0.3%)         1.16 (0.67;2.00) p = 0.59858 a) intention-to-treat analysis set, primary analyses b) vs. ASA 100 mg; Log-Rank p-value bid: twice daily; CI: confidence interval; Cum. Risk: Cumulative incidence risk (Kaplan-Meier estimates) at 30 months; ISTH: International Society on Thrombosis and Haemostasis; od: once daily

Figure 2: Time to first occurrence of primary efficacy outcome (stroke, myocardial infarction, cardiovascular death) in COMPASS



Kaplan-Meier Estimates (%) at 30 months:
Xarelto 2.5mg bid + ASA 100mg od: 5.2 (4.7 - 5.8)
ASA 100mg od: 7.2 (6.5 - 7.9)


 bid: twice daily; od: once daily; CI: confidence interval
CAD with heart failure
The COMMANDER HF study included 5,022 patients with heart failure and significant coronary artery disease (CAD) following a hospitalization of decompensated heart failure (HF) which were randomly assigned into one of the two treatment groups: rivaroxaban 2.5 mg twice daily (N=2,507) or matching placebo (N=2,515), respectively. The overall median study treatment duration was 504 days.
Patients must have had symptomatic HF for at least 3 months and left ventricular ejection fraction (LVEF) of ≤40% within one year of enrollment. At baseline, the median ejection fraction was 34% (IQR: 28%-38%) and 53% of subjects were NYHA Class III or IV.
The primary efficacy analysis (i.e. composite of all-cause mortality, MI, or stroke) showed no statistically significant difference between the rivaroxaban 2.5 mg twice daily group and the placebo group with a HR=0.94 (95% CI 0.84 - 1.05), p=0.270. For all-cause mortality, there was no difference between rivaroxaban and placebo in the number of events (event rate per 100 patient-years; 11.41 vs.
11.63, HR: 0.98; 95% CI: 0.87 to 1.10; p=0.743). The event rates for MI per 100 patient-years (rivaroxaban vs placebo) were 2.08 vs 2.52 (HR 0.83; 95% CI: 0.63 to 1.08; p=0.165) and for stroke the event rates per 100 patient-years were 1.08 vs 1.62 (HR: 0.66; 95% CI: 0.47 to 0.95; p=0.023). The principal safety outcome (i.e. composite of fatal bleeding or bleeding into a critical space with a potential for permanent disability), occurred in 18 (0.7%) patients in the rivaroxaban 2.5 mg twice daily treatment group and in 23 (0.9%) patients in the placebo group, respectively (HR=0.80; 95% CI 0.43 - 1.49; p=0.484). There was a statistically significant increase in ISTH major bleeding in the rivaroxaban group compared with placebo (event rate per 100 patient-years: 2.04 vs 1.21, HR 1.68; 95% CI: 1.18 to 2.39; p=0.003).
In patients with mild and moderate heart failure the treatment effects for the COMPASS study subgroup were similar to those of the entire study population (see section CAD/PAD).
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 %.
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 2.5 mg twice daily for the prevention of atherothrombotic events in patients with ACS the geometric mean concentration (90 % prediction interval) 2 - 4 h and about 12 h after dose (roughly representing maximum and minimum concentrations during the dose interval) was 47 (13 - 123) and 9.2 (4.4 - 18) 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.

Paediatric population
Safety and efficacy have not been established in the indications ACS and CAD/PAD for children and adolescents up to 18 years.