Sign Out
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability.
PHARMACOLOGY: Pharmacodynamics: 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.
Treatment and prevention of recurrent DVT and PE: Clinical efficacy and safety: The Xarelto clinical program was designed to demonstrate the efficacy of 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 3). 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 Xarelto was administered twice daily. This was followed by 20 mg of 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. 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). Xarelto 20 mg once daily and 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 1) 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 2) 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 3).
In the EINSTEIN Extension study (see Table 4 ) 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 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 Xarelto 20 mg once daily compared to placebo.
In the EINSTEIN CHOICE study 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 Xarelto 20 mg or 10 mg vs. 100 mg acetylsalicylic acid. The principal safety outcome (major bleeding events) was similar for patients treated with 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 Xarelto 20 mg or 10 mg vs. 100 mg acetylsalicylic acid. Outcomes were consistent across the patients with provoked and unprovoked VTE (see Table 5).
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 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 Xarelto 10 mg once daily vs 100 mg acetylsalicylic acid once daily were reported. (See Tables 1, 2, 3, 4 and 5.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
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.
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 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 20 mg (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 Bioavailability: 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 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or Cmax at the 10 mg dose. Xarelto 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 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. Xarelto 15 mg and 20 mg should be taken with food (see 'Dosage & Administration').
Under fed condition Xarelto 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality.
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to 40%.
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.
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.
Continue with Google