Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Bayer AG, 51368 Leverkusen, Germany
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors
ATC code: B01AF01
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.
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).
The rivaroxaban clinical programme was designed to demonstrate the efficacy of Xarelto 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: Xarelto 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 Xarelto 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, Xarelto 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 Xarelto than in patients who received placebo (see Table 6). However the incidence rates were balanced between Xarelto 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 syndromea | |
|---|---|---|
| Treatment dose | Xarelto 2.5 mg, twice daily, N=5,114. n () Hazard Ratio (HR) (95 CI) p-valueb | Placebo N=5,113 n (%) |
| Cardiovascular death, MI or stroke | 313 (6.1%) 0.84 (0.72, 0.97) p=0.020* | 376 (7.4%) |
| All-cause death, MI or stroke | 320 (6.3%) 0.83 (0.72, 0.97) p=0.016* | 386 (7.5%) |
| Cardiovascular death | 94 (1.8%) 0.66 (0.51, 0.86) p=0.002** | 143 (2.8%) |
| All-cause death | 103 (2.0%) 0.68 (0.53, 0.87) p=0.002** | 153 (3.0%) |
| MI | 205 (4.0%) 0.90 (0.75, 1.09) p=0.270 | 229 (4.5%) |
| Stroke | 46 (0.9%) 1.13 (0.74, 1.73) p=0.562 | 41 (0.8%) |
| Stent thrombosis | 61 (1.2%) 0.70 (0.51, 0.97) p=0.033** | 87 (1.7%) |
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 PCIa | |
|---|---|---|
| Treatment dose | Xarelto 2.5 mg, twice daily, N=3114 n () HR (95 CI) p-valueb | Placebo N=3096 n (%) |
| Cardiovascular death, MI or stroke | 153 (4.9%) 0.94 (0.75, 1.17) p=0.572 | 165 (5.3%) |
| Cardiovascular death | 24 (0.8%) 0.54 (0.33, 0.89) p=0.013** | 45 (1.5%) |
| All-cause death | 31 (1.0%) 0.64 (0.41, 1.01) p=0.053 | 49 (1.6%) |
| MI | 115 (3.7%) 1.03 (0.79, 1.33) p=0.829 | 113 (3.6%) |
| Stroke | 27 (0.9%) 1.30 (0.74, 2.31) p=0.360 | 21 (0.7%) |
| Stent thrombosis | 47 (1.5%) 0.66 (0.46, 0.95) p=0.026** | 71 (2.3%) |
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 syndromea | |
|---|---|---|
| Treatment dose | Xarelto 2.5 mg, twice daily, N=5,115 n () HR (95 CI) p-valueb | Placebo N=5,125 n (%) |
| Non-CABG TIMI major bleeding event | 65 (1.3%) 3.46 (2.08, 5.77) p=<0.001* | 19 (0.4%) |
| Fatal bleeding event | 6 (0.1%) 0.67 (0.24, 1.89) p=0.450 | 9 (0.2%) |
| Symptomatic intracranial haemorrhage | 14 (0.3%) 2.83 (1.02, 7.86) p=0.037 | 5 (0.1%) |
| Hypotension requiring treatment with intravenous inotropic agents | 3 (0.1%) | 3 (0.1%) |
| Surgical intervention for ongoing bleeding | 7 (0.1%) | 9 (0.2%) |
| Transfusion of 4 or more units of blood over a 48 hour period | 19 (0.4%) | 6 (0.1%) |
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):
The phase III COMPASS study (27,395 patients, 78.0% male, 22.0% female) demonstrated the efficacy and safety of Xarelto 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.
CAD patients had multivessel CAD and/or prior MI. For patients <65 years of age atherosclerosis involving at least two vascular beds or at least two additional cardiovascular risk factors 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.
Xarelto 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 Xarelto 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%).
Table 7. Efficacy results from phase III COMPASS:
| Study Population | Patients with CAD/PADa | |||||
|---|---|---|---|---|---|---|
| Treatment Dosage | Xarelto 2.5 mg bid in combination with ASA 100 mg od N=9152 | ASA 100 mg od N=9126 | ||||
| Patients with events | KM % | Patients with events | KM % | HR (95% CI) | p-valueb | |
| Stroke, MI or CV death | 379 (4.1%) | 5.20% | 496 (5.4%) | 7.17% | 0.76 (0.66;0.86) | p=0.00004* |
| Stroke | 83 (0.9%) | 1.17% | 142 (1.6%) | 2.23% | 0.58 (0.44;0.76) | p=0.00006 |
| MI | 178 (1.9%) | 2.46% | 205 (2.2%) | 2.94% | 0.86 (0.70;1.05) | p=0.14458 |
| CV death | 160 (1.7%) | 2.19% | 203 (2.2%) | 2.88% | 0.78 (0.64;0.96) | p=0.02053 |
| All-cause mortality | 313 (3.4%) | 4.50% | 378 (4.1%) | 5.57% | 0.82 (0.71;0.96) | |
| Acute limb ischaemia | 22 (0.2%) | 0.27% | 40 (0.4%) | 0.60% | 0.55 (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 | Xarelto 2.5 mg bid in combination with ASA 100 mg od, N=9152 n (Cum. risk %) | ASA 100 mg od N=9126 n (Cum.risk %) | Hazard Ratio (95% CI) p-value^b^ |
| 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 critical organ (non-fatal) | 63 (0.9%) | 49 (0.7%) | 1.28 (0.88;1.86) p=0.19679 |
| Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) | 10 (0.1%) | 8 (0.1%) | 1.24 (0.49;3.14) p=0.65119 |
| Bleeding leading to hospitalisation (non-fatal, not in critical organ, not requiring reoperation) | 208 (2.9%) | 109 (1.6%) | 1.91 (1.51;2.41) p<0.00001 |
| - 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 |
| 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:
The European Medicines Agency has deferred the obligation to submit the results of studies with Xarelto in one or more subsets of the paediatric population in the treatment of thromboembolic events. The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see section 4.2 for information on paediatric use).
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.
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.
Of the administered rivaroxaban dose, approximately ⅔ undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the faecal route. The final ⅓ 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.
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between male and female patients.
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.
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.
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics.
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. Xarelto 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).
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. Xarelto is to be used with caution in patients with creatinine clearance 15-29 ml/min (see section 4.4).
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.
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 E max 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 mcgl). The results of the PK/PD analyses in Phase II and III were consistent with the data established in healthy subjects.
Safety and efficacy have not been established for children and adolescents up to 18 years.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile toxicity.
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant exposure levels.
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, hepatic multiple light coloured spots) and an increased incidence of common malformations as well as placental changes were observed at clinically relevant plasma concentrations. In the pre- and post- natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.
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