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Pharmacology: Pharmacodynamics: Mechanism of Action: Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability.
Activation of factor X to factor Xa (FXa) via the intrinsic and extrinsic pathway plays a central role in the cascade of blood coagulation. FXa directly converts prothrombin to thrombin through the prothrombinase complex, and ultimately, this reaction leads to fibrin clot formation and activation of platelets by thrombin.
One molecule of FXa is able to generate more than 1000 molecules of thrombin due to the amplification nature of the coagulation cascade. In addition, the reaction rate of prothrombinase-bound FXa increases 300,000-fold compared to that of free FXa and causes an explosive burst of thrombin generation. Selective inhibitors of FXa can terminate the amplified burst of thrombin generation. Consequently, several specific and global clotting tests are affected by rivaroxaban. Dose dependent inhibition of factor Xa activity was observed in humans.
Pharmacodynamics 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 (International Normalized Ratio) is only calibrated and validated for coumarins and cannot be used for any other anticoagulant.
2.5 and 10 mg: In patients undergoing major orthopedic 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 sec.
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 Overdosage).
15 and 20 mg: In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrent DVT and PE, the 5/95 percentiles for PT (Neoplastin) 2-4 hours after tablet intake (i.e. at the time of maximum effect) ranged from 17 sec to 32 sec for 15 mg twice daily or 15 sec to 30 sec for 20 mg once daily, respectively.
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) ranged from 14 sec to 40 sec in patients treated with 20 mg once daily and from 10 sec to 50 sec in patients with moderate renal impairment treated with 15 mg once daily.
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. Anti-factor Xa activity is also influenced by rivaroxaban; however, no standard for calibration is available.
There is no need for monitoring of coagulation parameters during routine clinical treatment with Rivaroxaban (Xarelto).
Clinical efficacy and safety: 2.5 mg: The rivaroxaban clinical program was designed to demonstrate the efficacy of Rivaroxaban (Xarelto) for the prevention of cardiovascular (CV) death, MI, or stroke in subjects with a recent ACS (ST-elevation myocardial infarction [STEMI], non-ST-elevation myocardial infarction [NSTEMI] or unstable angina [UA]). Few patients with a prior stroke or TIA were included. The limited data in patients with a prior stroke or TIA do not support that 2.5 mg Rivaroxaban (Xarelto) BID in combination with ASA or ASA in addition to clopidogrel/ticlopidine provides adequate efficacy in these patients. In the pivotal double-blind ATLAS ACS 2 TIMI 51 trial, 15,526 patients were randomly assigned in a 1:1:1 fashion to one of 3 treatment groups: Rivaroxaban (Xarelto) 2.5 mg orally twice daily, 5 mg orally twice daily or to placebo twice daily. The median time on treatment was 13 months and overall treatment duration was up to almost 3 years.
93.2% of patients received concomitantly ASA plus thienopyridine treatment and 6.8% ASA only.
Among patients receiving dual anti-platelet therapy 98.8% received clopidogrel, 0.9 % received ticlopidine and 0.3 % received prasugrel.
Relative to placebo, Rivaroxaban (Xarelto) significantly reduced the primary composite endpoint of CV death, MI, or stroke. In addition the secondary endpoint 1 (all cause death, MI, or stroke; ) was also reduced significantly (see Table 1).
Subjects with a history of CHF derived substantial benefit from rivaroxaban treatment (see Table 1). An additional analysis showed differences in the incidence rates of stent thrombosis compared with placebo in the 2.5 mg bid (HR: 0.70, 95% CI: 0.51, 0.97) and 5 mg bid (HR: 0.70, 95% CI: 0.51, 0.98) groups (see Table 1). The incidence rates for the principal safety outcome (non-CABG TIMI major bleeding events) were higher in patients treated with Rivaroxaban (Xarelto) than in patients who received placebo (see Table 2), as were the incidence rates of life-threatening bleeding events, but were balanced between Rivaroxaban (Xarelto) and placebo for the components of fatal bleeding events, hypotension requiring treatment with intravenous inotropic agents and surgical intervention for ongoing bleeding.
Patients received the first dose of Rivaroxaban (Xarelto) at a minimum of 24 hours and up to 7 days (mean 4.7 days) after admission to hospital and as soon as possible after stabilization, of the index ACS event, including revascularization 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 should be used for the prevention of CV events in patients after an ACS in combination with ASA alone or with ASA plus a thienopyridine. (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageCAD or PAD (2.5 mg only): The Rivaroxaban (Xarelto) clinical program was designed to demonstrate the efficacy and safety of Rivaroxaban (Xarelto) for the prevention of stroke, myocardial infarction, or cardiovascular death in patients with CAD or PAD. In the pivotal phase III double-blind COMPASS trial, 27,395 patients were randomly assigned to one of three antithrombotic treatment groups: Rivaroxaban (Xarelto) 2.5 mg twice daily in combination with ASA 100 mg once daily, Rivaroxaban (Xarelto) 5 mg twice daily or to ASA 100 mg once daily in a 1:1:1 fashion. Patients with established CAD or PAD were eligible. Patients with CAD who were younger than 65 years of age were also required to have documentation of atherosclerosis involving at least two vascular beds or to have at least two additional cardiovascular risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate [eGFR] <60 ml per minute, heart failure, or non-lacunar ischemic stroke ≥1 month earlier). Certain patients were excluded, such as those patients in need of dual antiplatelet, other non-ASA antiplatelet, or oral anticoagulant therapies, as well as patients with a history of ischemic, non-lacunar stroke within 1 month, any history of hemorrhagic or lacunar stroke, or patients with eGFR < 15 ml/min.
The mean duration of follow-up was 23 months and the maximum follow-up was 3.9 years. The mean age was 68 years and 21% of the subject population were ≥75 years. Of the patients included, 91% had CAD, 27% had PAD, and 18% had both CAD and PAD. Of the patients with CAD, 69% had prior myocardial infarction, 60% had prior percutaneous transluminal coronary angioplasty (PTCA)/atherectomy/percutaneous coronary intervention (PCI), and 26% had a history of coronary artery bypass grafting (CABG) prior to study. Of the patients with PAD, 49% had intermittent claudication, 27% had peripheral artery bypass surgery or peripheral percutaneous transluminal angioplasty (PTA), 26% had asymptomatic carotid artery stenosis >50%, and 5% had limb or foot amputation for arterial vascular disease.
Relative to ASA 100 mg, Rivaroxaban (Xarelto) 2.5 mg twice daily in combination with ASA 100 mg once daily was superior in the reduction of the primary composite outcome of stroke, myocardial infarction or cardiovascular death. The benefit was observed early with a constant treatment effect over the entire treatment period (see Table 3 and figure). The composite secondary outcomes (composites of coronary heart disease death, or cardiovascular death, with myocardial infarction, ischemic stroke, and acute limb ischemia) as well as all-cause mortality were reduced (see Table 3). Acute limb ischemic events were reduced (hazard ratio [HR] 0.55; 95% confidence interval [CI] 0.32-0.92). Amputations for cardiovascular reasons were also reduced (HR 0.48; 95% CI 0.26-0.89). The composite outcome of stroke, myocardial infarction and all-cause mortality was also reduced (HR 0.79; 95% CI 0.70-0.88; p=0.00005, post-hoc analysis). There was a significant 1.7-fold increase of the primary safety outcome (modified International Society on Thrombosis and Haemostasis [ISTH] major bleeding events) in patients treated with Rivaroxaban (Xarelto) 2.5 mg twice daily in combination with ASA 100 mg once daily compared to patients who received ASA 100 mg (see Table 5). However the incidence rates for fatal bleeding events, non-fatal symptomatic bleeding into a critical organ as well as intracranial bleeding events did not differ significantly. The prespecified composite outcome for net clinical benefit (cardiovascular death, myocardial infarction, stroke, fatal or symptomatic critical-organ bleeding events) was reduced (see Table 3). The results in patients with PAD, CAD, and both CAD and PAD were consistent with the overall efficacy and safety results (Table 4).
In the 3.8% of patients with a history of ischemic, non-lacunar stroke (median time since stroke: 5 years), the reduction of stroke, myocardial infarction, cardiovascular death, and the increase of major bleeding (net clinical benefit HR 0.64; 95%CI 0.4-1.0) were consistent with the overall population (see Precautions).
Relative to ASA 100 mg, Rivaroxaban (Xarelto) 5 mg twice daily alone did not significantly reduce the primary composite efficacy outcome of stroke, myocardial infarction or cardiovascular death (HR 0.90; 95% CI 0.79-1.03; p = 0.11490). The incidence rates for the primary safety outcome (modified ISTH major bleeding events) were significantly increased in patients treated with Rivaroxaban (Xarelto) 5 mg twice daily compared with patients who received ASA 100 mg once daily (HR 1.51; 95% CI 1.25-1.84; p = 0.00003). (See Tables 3, 4, 5 and figure.)
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Click on icon to see table/diagram/imageTreatment and prevention of recurrent DVT and PE (10, 15 and 20 mg only): The Rivaroxaban (Xarelto) clinical program was designed to demonstrate the efficacy of Rivaroxaban (Xarelto) in the initial and continued treatment of acute DVT and PE and prevention of recurrent DVT and PE.
Over 12,800 patients were studied in four randomized controlled phase III clinical studies (EINSTEIN DVT, EINSTEIN PE, EINSTEIN Extension and EINSTEIN CHOICE) and additionally a predefined analysis of the pooled Einstein DVT and Einstein PE studies was conducted (see Table 8).
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. The treatment duration was up to 12 months depending on the clinical judgment of the investigator.
For the initial 3 week treatment of acute DVT 15 mg of Rivaroxaban (Xarelto) was administered twice daily. This was followed by 20 mg of Rivaroxaban (Xarelto) 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 up to 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 up to 12 months depending on the clinical judgment of the investigator. Rivaroxaban (Xarelto) 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 randomization date (median: 351 days). Rivaroxaban (Xarelto) 20 mg once daily and Rivaroxaban (Xarelto) 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. The secondary efficacy outcome was the composite of the primary efficacy outcome, MI, ischemic stroke, or non-CNS systemic embolism.
In the EINSTEIN DVT study (see Table 6) Rivaroxaban (Xarelto) was demonstrated to be non-inferior to enoxaparin/VKA for the primary outcome.
The prespecified NCB (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.
The incidence rates for the principal 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.
In the EINSTEIN PE study (see Table 7) Rivaroxaban (Xarelto) was demonstrated to be non-inferior to enoxaparin/VKA for the primary outcome (p=0.0026 (test for non-inferiority); hazard ratio: 1.12 (0.75 1.68)).
The prespecified NCB (primary efficacy outcome plus major bleeding events) was reported with a HR of 0.85 ((95% CI= 0.63 - 1.14), nominal p value p=0.275).
A prespecified pooled analysis of the outcome of the EINSTEIN DVT and PE studies was conducted (see Table 8).
In the EINSTEIN Extension study (see Table 9) Rivaroxaban (Xarelto) was superior to placebo for the primary and secondary efficacy outcomes. For the principal safety outcome (major bleeding events) there was a non-significant numerically higher incidence rate for patients treated with Rivaroxaban (Xarelto) 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 (Xarelto) 20 mg once daily compared to placebo.
In the EINSTEIN CHOICE study Rivaroxaban (Xarelto) 20 mg and 10 mg were both superior to 100 mg acetylsalicylic acid for the primary efficacy outcome. The secondary efficacy outcome was significantly reduced when comparing Rivaroxaban (Xarelto) 20 mg or 10 mg vs. 100 mg acetylsalicylic acid. The principal safety outcome (major bleeding events) was similar for patients treated with Rivaroxaban (Xarelto) 20 mg and 10 mg once daily compared to 100 mg acetylsalicylic acid. The secondary safety outcome (non-major bleeding associated with treatment cessation of more than 14 days) was similar when comparing Rivaroxaban (Xarelto) 20 mg or 10 mg vs. 100 mg acetylsalicylic acid. Outcomes were consistent across the patients with provoked and unprovoked VTE (see Table 10).
In a prespecified net clinical benefit analysis (NCB) (primary efficacy outcome plus major bleeding events) of EINSTEIN CHOICE, a HR of 0.44 (95% CI 0.27 - 0.71, p=0.0009) for Rivaroxaban (Xarelto) 20 mg once daily vs 100 mg acetylsalicylic acid once daily and a HR of 0.32 (95% CI 0.18 - 0.55, p<0.0001) for Rivaroxaban (Xarelto) 10 mg once daily vs 100 mg acetylsalicylic acid once daily were reported. (See Tables 6, 7, 8, 9 and 10.)
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Click on icon to see table/diagram/imageIn addition to the phase III EINSTEIN program, 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 under real-world conditions. Rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 0.5%, respectively. Hazard ratios comparing rivaroxaban and standard-of-care were adjusted to account for differences in patient baseline characteristics. Adjusted hazard ratios 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.
Rivaroxaban showed similar safety and efficacy compared to standard anticoagulation.
These results in patients who were observed in routine clinical practice are consistent with those observed in the EINSTEIN DVT study.
VTE prevention (10 mg only): Prevention of venous thromboembolic events (VTE) in patients undergoing major orthopedic surgery of the lower limbs.
The rivaroxaban clinical program was designed to demonstrate the efficacy of Rivaroxaban (Xarelto) for the prevention of venous thromboembolic events (VTE), i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing major orthopedic surgery of the lower limbs. Over 9,500 patients (7,050 in total hip replacement surgery - 2,531 in total knee replacement surgery) were studied in controlled randomized double-blind phase III clinical studies, the RECORD-program.
Rivaroxaban (Xarelto) 10 mg once daily started not earlier than 6 hours postoperatively was compared with enoxaparin 40 mg once daily started 12 hours preoperatively.
In three phase III studies (see Table 11) rivaroxaban significantly reduced the rate of total VTE (any venographically detected or symptomatic DVT, non-fatal PE or 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 (Xarelto) treated patients compared to patients treated with enoxaparin.
The main safety endpoint, major bleeding, showed comparable rates for patients treated with Rivaroxaban (Xarelto) 10 mg compared to enoxaparin 40 mg. (See Table 11.)
Click on icon to see table/diagram/imageThe analysis of the pooled results of the phase III trials corroborated the data obtained in the individual studies regarding reduction of total VTE, major VTE and symptomatic VTE with Rivaroxaban (Xarelto) 10 mg once daily compared to enoxaparin 40 mg once daily.
In addition to the phase III RECORD program, a post-authorization, non-interventional, open-label cohort study (XAMOS) has been conducted in 17,413 patients undergoing major orthopedic surgery of the hip or knee, to compare rivaroxaban with other standard-of-care pharmacological thromboprophylaxis in 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). This non-interventional study confirmed the efficacy and safety results seen in the RECORD program.
SPAF (15 and 20 mg only): The Rivaroxaban (Xarelto) clinical program was designed to demonstrate the efficacy of Rivaroxaban (Xarelto) for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF).
In the pivotal double-blind ROCKET AF study, 14,264 patients were assigned either to Rivaroxaban (Xarelto) 20 mg orally once daily (15 mg orally once daily in patients with moderate (CrC: <50-30 mL/min) renal impairment) 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 on ASA treatment and 11.4% were on class III antiarrythmics including amiodarone.
Relative to warfarin, Rivaroxaban (Xarelto) significantly reduced the primary composite endpoint of stroke and non-CNS systemic embolism. In addition major secondary endpoints (composite of stroke, non-CNS systemic embolism and vascular death and composite of stroke, non-CNS systemic embolism, MI and vascular death) were also reduced significantly (see Table 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 13). (See Tables 12 and 13.)
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Click on icon to see table/diagram/imageIn 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 thromoboembolic events and major bleeding has been conducted. 6,785 patients with non-valvular atrial fibrillation were enrolled for prevention of stroke and non-central nervous system (CNS) systemic embolism under real-world conditions. The mean CHADS2 score was 2.0 compared to a mean CHADS2 score of 3.5 in ROCKET AF. 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 from routine clinical practice are consistent with the results observed in the ROCKET AF study.
SPAF: Cardioversion: A prospective, randomized, open-label, multicenter, exploratory study with blinded endpoint evaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naïve and pre-treated) with non-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted VKA (randomized 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 ischemic attack, non-CNS systemic embolism, 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 VKAs treatment groups in the setting of cardioversion.
SPAF: Patients who undergo PCI with stent placement: A randomized, open-label, multicenter study (PIONEER AF-PCI) was conducted in 2124 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.
Group 1 received rivaroxaban 15 mg once daily (10 mg once daily in patients with CrCl: 30 to <50 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 CrCl: 30 to <50 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.
Special patient populations: Ethnic differences: (see Pharmacokinetics as follows).
Geriatric patients: see Pharmacokinetics as follows.
Gender: see Pharmacokinetics as follows.
Body weight: see Pharmacokinetics as follows.
Hepatic impairment: see Pharmacokinetics as follows.
Renal impairment: see Pharmacokinetics as follows.
Effect on QTc: No QTc prolonging effects were observed in healthy men and women older than 50 years.
Patients with prosthetic heart valves having recently undergone TAVR: In the randomised, open label, active-controlled, event-driven multicenter phase III GALILEO study 1644 patients were randomized to either a rivaroxaban-based strategy or an antiplatelet-based strategy 26 / Xarelto (SPAF, DVT, PE) / 10, 15, 20 mg film-coated tablets / 1-7 days after a successful transcatheter aortic valve replacement. Patients with previous atrial fibrillation or with an ongoing indication for oral anticoagulation were excluded.
The main objective was to assess the efficacy and safety of a rivaroxaban-based treatment strategy (10 mg rivaroxaban od plus 75-100 mg acetylsalicylic acid (ASA) od for 90 days followed by rivaroxaban 10 mg od) compared to standard of care (clopidogrel 75 mg od plus 75-100 mg ASA od for 90 days followed by ASA od). The study was terminated early due to an imbalance in death and thromboembolic events.
In the intention-to-treat (ITT) analysis the primary efficacy endpoint, i.e. death and thromboembolic events, occurred in 105 patients (9.8 per 100 patient years) in the rivaroxaban arm and in 78 patients (7.21 per 100 patient years) in the antiplatelet arm; the HR was 1.35 (95% CI: 1.01; 1.81). In the on-treatment analysis the primary efficacy outcome occurred in 68 patients (8.11 per 100 patient years) in the rivaroxaban arm compared to 63 (6.6 per 100 patient years) in the antiplatelet arm; the HR was 1.21 (95% CI: 0.86; 1.70).
In the ITT analysis the primary safety endpoint, i.e. composite of life-threatening, disabling or major bleeding, occurred in 46 patients (4.29 per 100 patient years) in the rivaroxaban arm compared to 31 (2.83 per 100 patient years) in the antiplatelet arm; the HR was 1.50 (95% CI 0.95; 2.37).
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 trial was terminated prematurely after the enrollment of 120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. Fifty-nine patients were randomized to rivaroxaban 20mg (15 mg for patients with creatinine clearance <50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 12% of patients randomized to rivaroxaban(4 ischaemic stroke and 3 myocardial infarction). 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.
Pharmacokinetics: Absorption and Biovailability: 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 10 mg dose. Rivaroxaban (Xarelto) 2.5 mg tablets and 10 mg tablets can be taken with or without food (see Dosage & Administration).
Due to reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg tablet under fasting conditions. When Rivaroxaban (Xarelto) 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 (Xarelto) 15 mg and 20 mg should be taken with food (see Dosage & Administration).
Under fed condition Rivaroxaban (Xarelto) 10 mg, 15 mg and 20 mg demonstrated dose-proportionality.
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 drug release in the GI 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 drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce, 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 L.
Metabolism and Elimination: Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half then eliminated renally and the other half eliminated by the fecal route. The other 1/3 of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion.
Rivaroxaban is metabolized via CYP 3A4, CYP 2J2 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 low-clearance drug. Elimination of rivaroxaban from plasma occurred 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.
Geriatric 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 (see Dosage & Administration).
Gender: There were no clinically relevant differences in pharmacokinetics between male and female patients (see Dosage & Administration).
Body weight: Extremes in body weight (<50 kg vs >120 kg) had only a small influence on rivaroxaban plasma concentrations (less than 25%) (see Dosage & Administration).
Children and adolescents: Safety and efficacy have not been established for children and adolescents below 18 years. (see Dosage & Administration).
Ethnic differences: No clinically relevant interethnic differences among Caucasia, African-American, Hispanic, Japanese or Chinese patients were observed regarding pharmacokinetics and pharmacodynamics (see Dosage & Administration).
Hepatic impairment: The effect of hepatic impairment on rivaroxaban pharmacokinetics has been studied in subjects categorized according to the Child Pugh classification, a standard procedure in clinical development. The Child Pugh classification's original purpose is to assess the prognosis of chronic liver disease, mainly cirrhosis. In patients for whom anticoagulation is intended, the critical aspect of liver impairment is the reduced synthesis of normal coagulation factors in the liver. Since this aspect is captured by only one of the five clinical/biochemical measurements composing the Child Pugh classification system, the bleeding risk in patients may not clearly correlate with this classification scheme. The decision to treat patients with an anticoagulant should therefore be made independently of the Child Pugh classification.
Rivaroxaban (Xarelto) is contraindicated in patients with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk.
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. No relevant difference in pharmacodynamic properties was observed between these groups.
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, due to significantly impaired drug clearance which indicates significant liver disease. Unbound AUC was increased 2.6-fold. There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased by a factor of 2.6 as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 2.1. The global clotting test PT assesses the extrinsic pathway that comprises of the coagulation factors VII, X, V, II and I which are synthesized in the liver. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT.
No data are available for Child Pugh C patients (see Dosage & Administration and Contraindications).
Renal impairment: There was an increase in rivaroxaban exposure being inversely correlated to the decrease in renal function, as assessed via creatinine clearance measurements.
In individuals with mild (CrC: ≤80-50 mL/min), moderate (CrC: <50-30 mL/min) or severe (CrC: <30-15 mL/min) renal impairment, rivaroxaban plasma concentrations (AUC) were 1.4, 1.5 and 1.6-fold increased respectively as compared to healthy volunteers (see Dosage & Administration and Precautions).
Corresponding increases in pharmacodynamic effects were more pronounced (see Dosage & Administration and Precautions).
In individuals with mild, moderate or 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 CrC <15 mL/min.
Use is not recommended in patients with creatinine clearance <15 mL/min. Rivaroxaban (Xarelto) is to be used with caution in patients with severe renal impairment creatinine clearance 15-30 mL/min (see Dosage & Administration and Precautions).
Due to the underlying disease patients with severe renal impairment are at an increased risk of both bleeding and thrombosis.
Concomitant administration of strong CYP 3A4 inducers: In a phase I trial, co-administration of Rivaroxaban (Xarelto) with the strong CYP 3A4 and P-gp inducer rifampicin led to an approximate 50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects (see Interactions). In a phase IIa trial, the PK/PD of an adapted rivaroxaban dosing regimen (30 mg twice daily in the first 3 weeks of treatment, followed by 20 mg twice daily) has been studied in 19 patients treated for DVT or PE and who concomitantly were medicated with a strong CYP 3A4 and P-gp inducer (rifampicin or phenytoin). The adapted dosing regimen in these patients led to a similar exposure and pharmacodynamics when compared to patients treated for DVT (15 mg twice daily in the first 3 weeks of treatment, followed by 20 mg once daily) without the concomitant administration of a strong CYP 3A4 inducer.
Toxicology: Preclinical safety data: The non-clinical safety evaluation in the data from conventional and appropriate studies of safety pharmacology, single and repeat-dose toxicity, genotoxicity, phototoxicity, and carcinogenicity and toxicity to reproduction reveal no special hazard for humans.
No organ-specific toxicity of rivaroxaban was observed up to the highest doses tested.
Safety Pharmacology: Cardiovascular, respiratory, and CNS functions were not affected. No pro-arrhythmogenic potential was observed.
No clinically relevant effects on gastro-intestinal motility, liver function, renal function, and blood glucose levels were observed.
Acute and repeat-dose toxicity: Rivaroxaban showed low acute toxicity in rats and mice.
Rivaroxaban was tested in repeat dose studies up to 6 months in rats and up to 12 months in dogs. Based on the pharmacological mode of action a NOEL could not be established due to effects on clotting time. All adverse findings except for a slight body weight gain reduction in rats and dogs could be related to an exaggerated pharmacological effect of the compound. In dogs at very high exposures severe spontaneous bleedings were observed. The NOAELs after chronic exposure are 12.5 mg/kg in rats and 5 mg/kg in dogs.
Carcinogenicity: Rivaroxaban was tested up to 60 mg/kg/day reaching exposure levels similar to humans (mice) or up to 3.6-fold higher (rats) than in humans.
Rivaroxaban showed no carcinogenic potential in rats and mice.
Reproductive toxicology: Rivaroxaban was tested in developmental toxicity studies at exposure levels of up to 14-fold (rat) and up to 33-fold (rabbit) above the therapeutic exposure in humans. The toxicological profile is mainly characterized by maternal toxicity due to exaggerated pharmacodynamic effects.
Up to the highest dose tested no primary teratogenic potential was identified (see Use in Pregnancy & Lactation).
[14C] rivaroxaban-related radioactivity penetrated the placental barrier in rats. In none of the fetal organs and tissues the exposure in terms of maximum concentrations or AUC exceeded the maternal blood exposure. The average exposure in the fetuses based on AUC (0-24) reached about 20% of the exposure in maternal blood. The mammary glands had an approximately blood-equivalent AUC which indicates secretion of radioactivity into milk (see Use in Pregnancy & Lactation).
Rivaroxaban did not show an effect on male or female fertility up to 200 mg/kg (see Use in Pregnancy & Lactation).
Lactation: [14C] rivaroxaban was administered orally to lactating Wistar rats (day 8 to 10 post partum) as a single oral dose of 3 mg/kg body weight.
[14C] rivaroxaban-related radioactivity was secreted into the milk of lactating rats only to a low extent in relation to the administered dose: The estimated amount of radioactivity excreted with milk was 2.12% of the maternal dose within 32 hours after administration (see see Use in Pregnancy & Lactation).
Genotoxicity: No genotoxicity was observed in a test for gene mutation in bacteria (Ames-Test), an in vitro test for chromosomal aberrations or in the in vivo micronucleus test.
