PRODUCT LABELING

Switching to and from XARELTO

Switching from Warfarin to XARELTO - When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is below 3.0 in adults and below 2.5 in pediatric patients to avoid periods of inadequate anticoagulation.¹

Switching from Anticoagulants Other than Warfarin to XARELTO - For adult and pediatric patients currently receiving an anticoagulant other than warfarin, start XARELTO 0 to 2 hours prior to the next scheduled administration of the drug (e.g., low molecular weight heparin or nonwarfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO at the same time.¹

CLINICAL STUDIES

The selection of the dosing regimen in the EINSTEIN-DVT and EINSTEIN-PE trials^{2, 3} (XARELTO 15 mg twice daily for 3 weeks, followed by 20 mg once daily), and the dosing regimen in the EINSTEIN-Extension trial² (XARELTO 20 mg once daily) were based primarily on the results of the dose-ranging venous thromboembolism (VTE) Treatment phase II trials: the ODIXa-DVT study⁴ and the EINSTEIN-DVT Dose-Ranging study.⁵

Both dose-ranging VTE Treatment phase II 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.

Patients in the EINSTEIN–DVT and EINSTEIN–PE trials were permitted to receive therapeutic doses of low molecular weight heparin, fondaparinux, or unfractionated heparin for up to 48 hours, or a single pre-randomization dose of a vitamin K antagonist (VKA). Patients were assigned to receive XARELTO 15 mg twice daily for 21 days, followed by 20 mg once daily, or subcutaneous (SC) enoxaparin 1.0 mg/kg twice daily followed by dose-adjusted oral VKA started within 48 hours after randomization.^{2, 3}

ODIXa-DVT study

• 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 at three weeks for each of four 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 VKA) for treatment of acute proximal deep vein thrombosis (DVT).⁴
• The primary efficacy endpoint (thrombus score improvement by at least four 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.⁴
• 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.⁴
• Pharmacokinetic 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 pulmonary embolism (PE).⁴

EINSTEIN-DVT Dose-Ranging study

• The EINSTEIN-DVT Dose-Ranging study was a phase II 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-international units (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.⁵
• 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.⁵
• The primary safety outcome (composite of major bleeding and clinically relevant non-major bleeding up until two 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.⁵

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 27 December 2024.