Summary

• The selection of the 10 mg once daily dose for XARELTO in the RECORD studies^1-4 was based primarily on pharmacokinetic (PK)/pharmacodynamic (PD) data in healthy volunteers⁵ and the results of phase 2 dose-ranging studies in orthopedic surgery patients.^6-9
• The selection of the 20 mg once daily dose for XARELTO in the ROCKET AF study¹⁰ was based primarily on the results of the dose-ranging venous thromboembolism (VTE) treatment phase 2 trials.^11,12
• The selection of the dosing regimen in the EINSTEIN-DVT and EINSTEIN-PE trials^13,14 (XARELTO 15 mg twice daily for 3 weeks, followed by 20 mg once daily), and dosing regimen in the EINSTEIN-Extension trial¹³ (XARELTO 20 mg once daily) were based primarily on the results of the dose-ranging VTE treatment phase 2 trials.^11,12
• The selection of the dosing regimen in the COMPASS¹⁵ trial (XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily, or XARELTO 5 mg twice daily alone, or aspirin 100 mg once daily alone) was based primarily on the results of the ATLAS ACS 2 TIMI-51 study¹⁶ in patients post-acute coronary syndrome (ACS) event.
• The selection of the dosing regimen in MAGELLAN (XARELTO 10 mg daily vs enoxaparin 40 mg daily) was based primarily on the results of phase 2 and 3 studies of XARELTO in hip and knee replacement surgery patients. In these surgical patients, XARELTO 10 mg had comparable safety and efficacy to enoxaparin 40 mg.¹⁷
• In the EINSTEIN-Junior (Jr) study, XARELTO was administered once daily as a body weight-adjusted 20 mg-equivalent dose in patients with a body weight of ≥30 kg, twice daily in patients with a body weight of 12 to <30 kg, or thrice daily in patients with a body weight of <12 kg.¹⁸
  • The treatment regimens were based on the results of a phase 1 and 2 study in which children of all ages were administered XARELTO to target an exposure like that observed in young adults with VTE treated with XARELTO 20 mg once daily, and comprehensive PK modeling predictions.
• In the UNIVERSE study, XARELTO 1 mg/mL oral suspension was administered twice daily by body weight (equivalent to 10 mg once daily dose in adults) in children with single-ventricle physiology who had undergone the Fontan procedure.¹⁹
  • The dose of XARELTO was selected by a physiologically based pharmacokinetic (PBPK) model from the EINSTEIN-Jr study and was adjusted for the pediatric postFontan population.
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^20-24

CLINICAL STUDIES

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

The phase 3 RECORD (REgulation of Coagulation in ORthopaedic surgery to prevent Deep-vein thrombosis and pulmonary embolism) clinical trial program was composed of 4 randomized studies that compared efficacy and safety of oral XARELTO 10 mg once daily and subcutaneous (SC) enoxaparin 40 mg once daily (RECORD1-3) or 30 mg twice daily (RECORD4) for prevention of VTE in patients undergoing elective total hip or knee replacement surgery.^1-4

The selection of the 10-mg once daily dose for XARELTO in the RECORD studies was based primarily on PK/PD data in healthy volunteers⁵ and the results of the phase 2 dose-ranging studies in orthopedic surgery patients^6-9 summarized below.

ODIXa-HIP

As part of the phase 2 ODIXa (Oral, DIrect factor Xa inhibitor) clinical trial program, 3 randomized studies^6-8 assessed oral XARELTO (started 6 to 8 hours after surgery) relative to SC enoxaparin (started the evening before surgery and second dose at least 6 to 8 hours after surgery) for VTE prevention in patients undergoing total hip replacement (THR) surgery.

• Study endpoints were the same in all 3 trials.
• The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT; proximal and/or distal), nonfatal, symptomatic, objectively confirmed pulmonary embolism (PE), and all-cause mortality.
• The primary safety endpoint was major postoperative bleeding (fatal bleeding, bleeding into a critical organ, overt bleeding warranting treatment cessation, bleeding leading to reoperation, or clinically overt bleeding associated with a fall in hemoglobin ≥2 g/dL or leading to transfusion of ≥2 units of blood) occurring after the first postoperative dose of study drug and no later than 2 days after the last dose.

ODIXa-HIP1

ODIXa-HIP1, a phase 2a, randomized, open-label dose-escalation study (N=641), assessed the efficacy and safety of oral XARELTO 2.5, 5, 10, 20, or 30 mg twice daily or 30 mg once daily with a meal compared to enoxaparin 40 mg SC once daily in the evening.⁶

• The primary efficacy endpoint occurred in 22.2%, 23.8%, 20.0%, 10.2%, 17.4%, and 15.1% of the respective XARELTO dose groups and in 16.8% of those receiving enoxaparin.
• The dose-response relationship for XARELTO relative to the primary efficacy endpoint was not statistically significant (P=0.0504). However, the occurrence of major VTE decreased dose dependently with XARELTO (P=0.0108).
• Major postoperative bleeding (the primary safety endpoint) occurred in 0%-10.8% of patients receiving XARELTO and in 0% of those receiving enoxaparin; the occurrence of bleeding increased dose dependently with XARELTO (P=0.0008).
• This study demonstrated proof-of-principle for XARELTO for VTE prevention after THR.

ODIXa-HIP2

ODIXa-HIP2, a phase 2b double-blind, twice-daily, dose-ranging study (N=722), assessed the efficacy and safety of oral XARELTO 2.5, 5, 10, 20, or 30 mg twice daily with food compared to enoxaparin 40 mg SC once daily every evening.⁷

• The primary efficacy endpoint occurred in 15%, 14%, 12%, 18%, and 7% of the respective XARELTO dose groups and in 17% of those receiving enoxaparin. All XARELTO doses had similar efficacy to enoxaparin, and there was no significant trend in dose-response relationship for XARELTO.
• Major postoperative bleeding (the primary safety endpoint) occurred in 0.8% to 5.4% of patients receiving XARELTO and in 1.5% of those receiving enoxaparin. The occurrence of major bleeding increased dose dependently with XARELTO (P=0.045).
• Rates with XARELTO 5, 10, and 20 mg (total daily dose) were similar to those with enoxaparin.
• The efficacy and safety of XARELTO at total daily doses of 5 to 20 mg were similar to enoxaparin for VTE prevention in THR patients and warranted further investigation.

ODIXa-OD-HIP

ODIXa-OD-HIP, a phase 2b randomized, double-blind, once daily, dose-ranging study (N=873), assessed the efficacy and safety of oral XARELTO 5, 10, 20, 30, or 40 mg once daily or enoxaparin 40 mg SC once daily every evening.⁸

• The primary efficacy endpoint occurred in 14.9%, 10.6%, 8.5%, 13.5%, and 6.4% of the respective XARELTO dose groups and in 25.2% of those receiving enoxaparin.
• The efficacy of XARELTO compared favorably with enoxaparin across the dose range, with lower incidences in all XARELTO groups. No significant dose-response relationship was found for XARELTO relative to this endpoint (P=0.0852). However, the occurrence of major VTE (secondary endpoint of proximal DVT, PE, and VTE-related death) showed a significant trend in dose-response relationship (P=0.0072).
• The primary safety endpoint (major postoperative bleeding) occurred in 2.3%, 0.7%, 4.3%, 4.9%, and 5.1% of the respective XARELTO dose groups and in 1.9% of those receiving enoxaparin. The dose-response relationship for XARELTO relative to the primary safety endpoint was significant (P=0.0391).
• Based on these results, 10 mg once daily was selected as the optimal dose to be investigated in phase 3 studies.

ODIXa-KNEE

As part of the phase 2 ODIXa (Oral, DIrect factor Xa inhibitor) clinical trial program, the randomized, double-blind ODIXa-KNEE dose-finding study (N=613) assessed the efficacy and safety of oral XARELTO relative to SC enoxaparin for VTE prevention in patients undergoing elective knee replacement surgery.⁹

• Oral XARELTO 2.5, 5, 10, 20, or 30 mg twice daily with food was started 6 to 8 hours after surgery.
• The primary efficacy endpoint was a composite of any DVT (proximal and/or distal), nonfatal, symptomatic, objectively confirmed PE, and all-cause mortality during treatment.
• The primary safety endpoint was major bleeding occurring after the first postoperative dose of study drug and no later than 2 days after the last dose.
• Among 366 evaluable patients, the primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1% and 25.4% of the respective XARELTO dose groups (with no significant dose trend, P=0.29) and in 44.3% of patients receiving enoxaparin.
• Incidence of the primary efficacy endpoint was lower with XARELTO 10 mg twice daily (absolute reduction: 21.0%; 95% confidence interval [CI]: 5.1-36.8) and with XARELTO 30 mg twice daily (absolute reduction: 18.9%; 95% CI: 2.8-35.0) compared to that of enoxaparin.
• The primary safety endpoint occurred in 1.0%, 0%, 1.9%, 3.1%, and 7.5% of the respective XARELTO dose groups (with a significant dose trend, P=0.0007) and in 1.9% of patients receiving enoxaparin. The incidence of this endpoint was similar to enoxaparin for all XARELTO doses.
• These dose regimens showed potential efficacy and acceptable safety, similar to enoxaparin, for VTE prevention in patients undergoing elective THR. The optimal dose range of oral XARELTO for additional phase 3 studies were 2.5-10 mg twice daily.

Stroke Prevention in Nonvalvular Atrial Fibrillation

The ROCKET AF (Rivaroxaban, Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial was a phase 3 study to evaluate the efficacy and safety of oral fixed-dose XARELTO 20 mg once daily (15 mg for patients with creatine clearance [CrCl] of 30 to 49 mL/min) and dose-adjusted warfarin (target international normalized ratio: 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) at moderate to high risk for stroke.¹⁰

The selection of the 20 mg once daily dose for XARELTO in the ROCKET AF study was based primarily on the results of the dose-ranging VTE treatment phase 2 trials summarized below. These studies demonstrated once daily and twice daily doses from 20 mg per day to 60 mg per day were comparable based on efficacy and safety results. As a result of this data, the lowest dose of 20 mg per day was chosen for further assessment. Based on a PK modeling study, 15 mg once daily was chosen to be used in patients with moderate renal impairment (CrCl of 30 to 49 mL/min).²⁵

ODIXa-DVT

The ODIXa-DVT study¹¹ was a phase 2 dose-finding study (N=613) to compare safety and efficacy between double blinded doses of XARELTO 10 mg, 20 mg, or 30 mg twice daily OR 40 mg once daily, with food and open-label standard anticoagulation (SC enoxaparin 1 mg/kg twice daily [for at least 5 days] followed by a vitamin K antagonist [VKA]) for treatment of acute proximal DVT. Treatment was continued for 12 weeks.

• The primary efficacy endpoint (thrombus score improvement by at least 4 points without VTE recurrence or VTE-related death) occurred in 53%, 59.2%, 56.9%, and 43.8% of the respective XARELTO dose groups and in 45.9% of the enoxaparin/VKA group.
• Major bleeding rates were 1.7%, 1.7%, 3.3%, and 1.7% in the respective XARELTO dose groups and 0% in the enoxaparin/VKA group.
• Rates of any bleeding were 5.0%, 9.4%, 10.7%, and 11.6% in the respective XARELTO dose groups and 6.3% in the enoxaparin/VKA group.

EINSTEIN-DVT Dose-Ranging

The EINSTEIN-DVT Dose-Ranging study¹² was a phase 2 dose-ranging study that compared double blinded oral XARELTO 20, 30, or 40 mg once daily versus open-label parenteral unfractionated heparin (started with 5000-IU bolus and 1250-IU/hour infusion) or low molecular weight heparin (SC tinzaparin 175 IU/kg once daily or SC enoxaparin 1.5 mg/kg once daily or 1 mg/kg twice daily) followed by an oral VKA for treatment of symptomatic acute DVT. Treatment was continued for 12 weeks.

• The primary efficacy endpoint (composite of symptomatic recurrent DVT, symptomatic fatal or nonfatal PE, and asymptomatic deterioration in the thrombotic burden as assessed by comparison of ultrasound or perfusion lung scan at day 84 with baseline) occurred in 6.1%, 5.4%, and 6.6% of the respective XARELTO dose groups and 9.9% in the heparin/VKA group.
• The primary safety outcome (composite of major bleeding and clinically relevant nonmajor bleeding up until 2 days after the end of the treatment) occurred in 5.9%, 6.0%, and 2.2% of the respective XARELTO dose groups and 8.8% in the heparin/VKA group.

Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE

EINSTEIN-DVT

The EINSTEIN-DVT study was a phase 3, randomized, open-label, event-driven, noninferiority trial that compared oral XARELTO alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with SC enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral VKA (warfarin or acenocoumarol) in patients with confirmed symptomatic DVT without symptomatic PE.¹³

EINSTEIN-PE

The EINSTEIN-PE study was a phase 3, randomized, open-label, event-driven, noninferiority study evaluating the efficacy and safety of oral XARELTO (15 mg twice daily for 3 weeks followed by 20 mg once daily) versus SC enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral VKA in patients with acute symptomatic PE with or without DVT.¹⁴

EINSTEIN-Extension

The EINSTEIN-Extension study was a phase 3, randomized, double-blind, event-driven superiority study comparing XARELTO 20 mg once daily to placebo in patients with confirmed symptomatic PE or DVT who have been treated for 6 to 12 months with XARELTO or VKA.¹³

The selection of the dosing regimen in the EINSTEIN-DVT and EINSTEIN-PE trials (XARELTO 15 mg twice daily for 3 weeks, followed by 20 mg once daily), and dosing regimen in the EINSTEIN-Extension trial (XARELTO 20 mg once daily) were based primarily on the results of the dose-ranging VTE treatment phase 2 trials summarized above (see section ROCKET AF).

The initial twice daily dosing regimen used in the EINSTEIN-DVT and EINSTEIN-PE trials was based on the ODIXa-DVT study, which evaluated improvement in thrombotic burden (assessed by repeat venous ultrasonography) at 3 weeks for each of the 4 treatment arms (XARELTO 10 mg, 20 mg, or 30 mg twice daily or 40 mg once daily). This study found numerically greater, but not statistically significant improvement in the twice daily treatment arms compared to the once daily treatment arm. PK modeling demonstrated that higher trough concentrations are observed with a twice daily XARELTO dosing regimen in comparison with a once daily dosing regimen and may provide an intensified anticoagulant effect during initial treatment in patients with a DVT or PE.^11,14,26

Both dose-ranging VTE treatment phase 2 trials suggest the optimal dosing regimen consists of a twice daily administration of 15 mg for the initial 3-week treatment phase followed by once daily administration of 20 mg for the subsequent treatment period in the EINSTEIN program.^14,26

Prevention of Recurrent Cardiovascular Events in Stable Atherosclerotic Vascular Disease

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial was a phase 3, event-driven, double-blind, randomized, controlled study designed to evaluate whether treatment with XARELTO and aspirin versus aspirin alone or XARELTO alone versus aspirin alone is more effective for prevention of recurrent cardiovascular (CV) events in patients with stable atherosclerotic vascular disease.¹⁵

Dosing regimens of XARELTO should be optimized for each indication, and depend on the particular disease pathology, as well as the overall combination of antithrombotic drugs used for treatment.²⁴

The dual pathway of thrombus formation in ACS, involving platelets and fibrin, suggested a potential role for a factor Xa inhibitor to reduce the risk of recurrent CV events in patients with stable atherosclerotic vascular disease in the COMPASS trial.^24,27

Therefore, the combination treatment strategy used in the COMPASS trial was a dual pathway approach that included the anticoagulant XARELTO with the antiplatelet aspirin, thereby inhibiting both thrombin and platelets.

• Dosing interventions were as follows:
  • XARELTO 2.5 mg twice daily + aspirin 100 mg once daily
  • XARELTO 5 mg twice daily + placebo once daily
  • Placebo twice daily + aspirin 100 mg once daily

Findings from previous XARELTO studies were the basis for the COMPASS trial dosing regimen. The ATLAS ACS TIMI 46, ATLAS ACS 2 TIMI 51, and Gemini-ACS-1 trials^16,28,29 tested varying doses of XARELTO taken in combination with aspirin or dual antiplatelet therapy in patients with ACS, and provided efficacy and safety information, to warrant further research of XARELTO 2.5 mg twice daily plus low-dose ASA for the prevention of secondary CV events.

• ATLAS ACS TIMI 46²⁸ was a phase 2, dose-escalation study which investigated XARELTO 5, 10, and 20 mg once daily or the same total daily dose twice daily in combination with aspirin or aspirin plus a thienopyridine. The lowest 2 doses (5 and 10 mg total daily dose) were selected based on already noted efficacy and an observed dose-dependent increase in bleeding across all doses.²⁴
• Full anticoagulant doses of XARELTO can be taken once daily, but once daily doses below 10 mg total daily doses suggested insufficient trough levels.²⁴ Based on PK and PD profiles, the 2.5 mg twice daily and 5 mg twice daily doses were selected for further investigation in the ATLAS ACS 2 TIMI 51 phase 3 trial.²⁸
• The XARELTO 2.5 mg twice daily dose taken in combination with low-dose aspirin was the most appropriate strategy for secondary CV protection in patients with stable atherosclerotic disease as proven by the COMPASS study and previous ACS studies.^15,16,24,30

ATLAS ACS 2 TIMI-51

ATLAS ACS 2 TIMI-51 study was a phase 3, randomized, placebo-controlled, event-driven study (N=15,526) to determine whether XARELTO (2.5 mg or 5 mg twice daily), when added to standard care (including low-dose aspirin once daily [75-100 mg]), is safe and reduces the risk of the composite of CV death, myocardial infarction (MI), or stroke in patients with a recent ACS.¹⁶

• XARELTO 2.5 mg and 5 mg twice daily reduced the primary efficacy endpoint (composite of CV death, MI, or stroke) as compared with placebo (9.1% vs. 10.7%, hazard ratio [HR], 0.84, 95% CI 0.72-0.97, P=0.02; 8.8% vs. 10.7%, HR, 0.85, 95% CI 0.730.98, P=0.03)
• XARELTO 2.5 mg and 5 mg twice daily significantly increased the primary safety endpoint (Thrombolysis in Myocardial Infarction [TIMI] major bleeding not related to coronary artery bypass graft [CABG]) as compared to placebo (1.8% and 2.4% vs. 0.6%, respectively, P<0.001 for both).

MAGELLAN

The MAGELLAN study was a phase 3, international, randomized, blinded, double-dummy, active-comparator, controlled study designed to evaluate the efficacy and safety of once-daily, oral XARELTO compared to standard-duration, once-daily, SC enoxaparin (followed by placebo), and to evaluate the role of extended-duration XARELTO (up to 39 days) for the prevention of VTE in acutely ill medical patients who required hospitalization.³¹

• Efficacy and safety of XARELTO 10 mg daily vs enoxaparin 40 mg daily were demonstrated in phase 2 and 3 studies in hip and knee replacement surgery patients. In these surgical patients, XARELTO 10 mg had comparable safety and efficacy to enoxaparin 40 mg.¹⁷

XARELTO in Pediatric Population

EINSTEIN-Jr

The EINSTEIN-Jr study was a randomized, open-label, multicenter study that compared the efficacy and safety of a body weight-adjusted 20 mgequivalent dose of XARELTO with standard anticoagulants for treatment of VTE in pediatric patients aged ≤17 years.¹⁸

• XARELTO treatment regimens were based on the results of a phase 1 and 2 study in which children of all ages were administered XARELTO to target an exposure similar to that observed in young adults with VTE treated with XARELTO 20 mg once daily.
• In children weighing ≥20 kg, observed exposures were within the adult reference range. However, in children weighing <20 kg, exposures were too low and XARELTO treatment regimens in these children were adjusted based on PK modelling studies.
• Blood samples for PK analysis were collected using a sparse sampling approach to confirm that the revised body weight-adjusted XARELTO regimens attained adult exposures. Additionally, values of the derived PK parameters were related to recurrent VTE, repeat imaging results, bleeding events, and adverse events.
• XARELTO was administered as a body weight-adjusted 20 mg-equivalent dose once daily in patients with a body weight of ≥30 kg, twice daily in patients with a body weight of 12 to <30 kg, or thrice daily in patients with a body weight of <12 kg as either immediate-release film-coated tablets (strengths of 5, 10, 15, or 20 mg) or an oral suspension (1 mg/mL). See Table: XARELTO Doses Evaluated in the Einstein-Jr Study
  • The lower range of adult exposure was targeted in children weighing <12 kg to avoid excessive concentrations at the end of the dosing interval.
• Xarelto exposures were found to be within the adult reference range.
• Exposure-response evaluations did not reveal any clustering for any of the PK parameters with efficacy, bleeding, or adverse event outcomes.

UNIVERSE

The UNIVERSE study was a phase 3, multicenter, 2-part, open-label, active-controlled study that evaluated the PK and PK/PD profile, safety, and efficacy of XARELTO in pediatric patients aged 2-8 years with single-ventricle physiology who had undergone the Fontan procedure within 4 months prior to enrollment.¹⁹

• XARELTO 0.1% (1 mg/mL) oral suspension was administered twice daily by body weight (equivalent to 10 mg once daily dose in adults). See table: XARELTO Body Weight-adjusted Dosing in the UNIVERSE Study
• The dose of XARELTO was selected by a PBPK model from the EINSTEIN-Jr program and was adjusted for the pediatric post-Fontan population and directly evaluated in the UNIVERSE study.
  • The model suggested a body weight-based dosing regimen in pediatric patients after the Fontan procedure that was expected to produce XARELTO exposures similar to the adult reference range (10-mg dose). This dose was then incorporated and tested in the UNIVERSE study.
• The twice-daily dosing regimen was selected since it was intended to match the 10-mg daily dosing in adults.
  • In the pediatric population, XARELTO concentrations had a narrower concentration range (ie, lower maximum plasma drug concentration at steady state [C_max,ss] and higher concentration at the end of the dosing interval at steady state [C_trough,ss]) than adult reference ranges based on a once daily regimen.
    • Results demonstrated an overall similarity in XARELTO exposures between the pediatric population and adult reference range.

LITERATURE SEARCH

A literature search of MEDLINE^® EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 13 December 2023.