General Information

Savaysa (edoxaban) is a Factor Xa inhibitor and works as an anticoagulant.

Savaysa is specifically indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Savaysa is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following five to 10 days of initial therapy with a parenteral anticoagulant.

Mechanism of Action

Savaysa (edoxaban) is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Edoxaban inhibits free FXa, and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of FXa in the coagulation cascade reduces thrombin generation and reduces thrombus formation. 

Side Effects

Adverse effects associated with the use of Savaysa may include, but are not limited to, the following:

NVAF:

• bleeding
• anemia

DVT and PE:

• bleeding
• rash
• abnormal liver function tests
• anemia

Dosing/Administration

Savaysa is supplied as a tablet for oral administration. Savaysa can be taken without regard to food. The recommended dose of Savaysa is as follows:

Nonvalvular atrial fibrillation
The recommended dose is 60 mg taken orally once daily Assess creatinine clearance, as calculated using the Cockcroft-Gault equation, before initiating therapy with Savaysa. Do not use Savaysa in patients with CrCL > 95 mL/min due to an increased risk of ischemic stroke compared to warfarin. Reduce Savaysa dose to 30 mg once daily in patients with CrCL 15 to 50 mL/min. 

Deep vein thrombosis and pulmonary embolism
The recommended dose of Savaysa is 60 mg taken orally once daily following 5 to 10 days of initial therapy with a parenteral anticoagulant. The recommended dose of Savaysa is 30 mg once daily in patients with CrCL 15 to 50 mL/min, patients who weigh less than or equal to 60 kg, or patients who are taking certain concomitant P-gp inhibitor medications based on clinical study data in this indication.

For transition to Savaysa from other medications or from other medications to Savaysa, please see the drug label.

Clinical Trial Results

The FDA approval of Savaysa was based on the following studies:

Nonvalvular Atrial Fibrillation

The ENGAGE AF-TIMI 48 study was a multinational, double-blind, non-inferiority study comparing the efficacy and safety of two Savaysa treatment arms (60 mg and 30 mg) to warfarin (titrated to INR 2.0 to 3.0) in reducing the risk of stroke and systemic embolic events in patients with NVAF. A total of 21,105 patients were randomized and followed for a median of 2.8 years and treated for a median of 2.5 years. Patients in the Savaysa treatment arms had their dose halved (60 mg halved to 30 mg or 30 mg halved to 15 mg) if one or more of the following clinical factors were present: CrCL ≤ 50 mL/min, low body weight (≤ 60 kg) or concomitant use of specific P-gp inhibitors (verapamil, quinidine, dronedarone). The primary endpoint of the study was the occurrence of first stroke (either ischemic or hemorrhagic) or of a systemic embolic event (SEE) that occurred during treatment or within 3 days from the last dose taken. Both treatment arms of SAVAYSA were non-inferior to warfarin for the primary efficacy endpoint of stroke or SEE. However, the 30 mg (15 mg dose-reduced) treatment arm was numerically less effective than warfarin for the primary endpoint, and was also markedly inferior in reducing the rate of ischemic stroke. Based on the planned superiority analysis (ITT, which required p < 0.01 for success), statistical superiority of the 60 mg (30 mg dose reduced) treatment arm compared to warfarin was not established in the total study population, but there was a favorable trend. Savaysa demonstrated significantly less major bleeding compared to warfarin.

Deep vein thrombosis and pulmonary embolism
Hokusai VTE was a multinational, double-blind study which compared the efficacy and safety of Savaysa 60 mg orally once daily to warfarin (titrated to INR 2.0 3.0) in 8,292 patients with acute symptomatic venous thromboembolism (VTE) (DVT or PE with or without DVT).  The subjects were randomized to receive Savaysa or warfarin and were followed for a mean treatment duration of 252 days for Savaysa and 250 days for warfarin. In the trial, 3.2 percent of participants taking Savaysa had a symptomatic recurrent VTE compared to 3.5 percent of those taking warfarin.