Edoxaban, a factor Xa inhibitor, is supplied as edoxaban tosylate monohydrate. The chemical name is N- (5-Chloropyridin-2-yl)- N'- [(1 S ,2 R ,4 S )-4-( N,N- dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl] oxamide mono (4-methylbenzenesulfonate) monohydrate. Edoxaban tosylate monohydrate has the empirical formula C 24 H 30 ClN 7 O 4 S∙C 7 H 8 O 3 S∙H 2 O representing a molecular weight of 738.27. The chemical structure of edoxaban tosylate monohydrate is: It is a white to pale yellowish-white crystalline powder. The solubility of edoxaban tosylate (pKa 6.7) decreases with increasing pH. It is slightly soluble in water, pH 3 to 5 buffer, very slightly soluble at pH 6 to 7; and practically insoluble at pH 8 to 9. SAVAYSA is available for oral administration as a 60 mg, 30 mg, or 15 mg round shaped, film-coated tablet, debossed with product identification markings. Each 60 mg tablet contains 80.82 mg edoxaban tosylate monohydrate equivalent to 60 mg of edoxaban. Each 30 mg tablet contains 40.41 mg edoxaban tosylate monohydrate equivalent to 30 mg of edoxaban. Each 15 mg tablet contains 20.20 mg edoxaban tosylate monohydrate equivalent to 15 mg of edoxaban. The inactive ingredients are: mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium stearate, talc, and carnauba wax. The color coatings contain hypromellose, titanium dioxide, talc, polyethylene glycol 8000, iron oxide yellow (60 mg tablets and 15 mg tablets), and iron oxide red (30 mg tablets and 15 mg tablets). Chemical Structure

SAVAYSA is a factor Xa inhibitor indicated: To reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF) Limitation of Use for NVAF SAVAYSA should not be used in patients with creatinine clearance (CrCL) > 95 mL/min because of increased risk of ischemic stroke compared to warfarin at the highest dose studied (60 mg) SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant 1.1 Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation SAVAYSA is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). Limitation of Use for NVAF SAVAYSA should not be used in patients with CrCL > 95 mL/min because of an increased risk of ischemic stroke compared to warfarin

Treatment of Deep Vein Thrombosis and Pulmonary Embolism SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.

60 mg, yellow round shaped, film-coated tablets, debossed with DSC L60 on one side 30 mg, pink round shaped, film-coated tablets, debossed with DSC L30 on one side 15 mg, orange round shaped, film-coated tablets, debossed with DSC L15 on one side Tablets: 60 mg, 30 mg, and 15 mg

Treatment of NVAF: Assess CrCL before initiating therapy The recommended dose is 60 mg once daily in patients with CrCL >50 to ≤ 95 mL/min. Do not use SAVAYSA in patients with CrCL > 95 mL/min Reduce dose to 30 mg once daily in patients with creatinine clearance 15 to 50 mL/min Treatment of DVT and PE: The recommended dose is 60 mg once daily Reduce dose to 30 mg once daily for patients with CrCL 15 to 50 mL/min or body weight less than or equal to 60 kg or who use certain P-gp inhibitors 2.1 Nonvalvular Atrial Fibrillation The recommended dose of SAVAYSA is 60 mg taken orally once daily . Assess creatinine clearance, as calculated using the Cockcroft-Gault equation Cockcroft-Gault CrCL = (140-age) × (weight in kg) × (0.85 if female) / (72 × creatinine in mg/dL). , before initiating therapy with SAVAYSA. Do not use SAVAYSA in patients with CrCL > 95 mL/min. Reduce SAVAYSA dose to 30 mg once daily in patients with CrCL 15 to 50 mL/min

Treatment of 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 . Reduce SAVAYSA dose to 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

Administration Information If a dose of SAVAYSA is missed, the dose should be taken as soon as possible on the same day. Dosing should resume the next day according to the normal dosing schedule. The dose should not be doubled to make up for a missed dose. SAVAYSA can be taken without regard to food

Transition to or from SAVAYSA Transition to SAVAYSA From To Recommendation Warfarin or other Vitamin K Antagonists SAVAYSA Discontinue warfarin and start SAVAYSA when the INR is ≤ 2.5 Oral anticoagulants other than warfarin or other Vitamin K Antagonists SAVAYSA Discontinue current oral anticoagulant and start SAVAYSA at the time of the next scheduled dose of the other oral anticoagulant Low Molecular Weight Heparin (LMWH) SAVAYSA Discontinue LMWH and start SAVAYSA at the time of the next scheduled administration of LMWH Unfractionated heparin SAVAYSA Discontinue the infusion and start SAVAYSA 4 hours later Transition from SAVAYSA From To Recommendation Abbreviations: INR=International Normalized Ratio SAVAYSA Warfarin Oral option : For patients taking 60 mg of SAVAYSA, reduce the dose to 30 mg and begin warfarin concomitantly. For patients receiving 30 mg of SAVAYSA, reduce the dose to 15 mg and begin warfarin concomitantly. INR must be measured at least weekly and just prior to the daily dose of SAVAYSA to minimize the influence of SAVAYSA on INR measurements. Once a stable INR ≥ 2.0 is achieved, SAVAYSA should be discontinued and the warfarin continued SAVAYSA Warfarin Parenteral option : Discontinue SAVAYSA and administer a parenteral anticoagulant and warfarin at the time of the next scheduled SAVAYSA dose. Once a stable INR ≥ 2.0 is achieved the parenteral anticoagulant should be discontinued and the warfarin continued SAVAYSA Non-Vitamin-K-Dependent Oral anticoagulants Discontinue SAVAYSA and start the other oral anticoagulant at the time of the next dose of SAVAYSA SAVAYSA Parenteral anticoagulants Discontinue SAVAYSA and start the parenteral anticoagulant at the time of the next dose of SAVAYSA 2.5 Discontinuation for Surgery and Other Interventions Discontinue SAVAYSA at least 24 hours before invasive or surgical procedures because of the risk of bleeding . If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention . SAVAYSA can be restarted after the surgical or other procedure as soon as adequate hemostasis has been established noting that the time to onset of pharmacodynamic effect is 1-2 hours . Administer a parenteral anticoagulant and then switch to oral SAVAYSA, if oral medication cannot be taken during or after surgical intervention

Administration Options For patients who are unable to swallow whole tablets, SAVAYSA tablets may be crushed and mixed with 2 to 3 ounces of water and immediately administered by mouth or through a gastric tube. The crushed tablets may also be mixed into applesauce and immediately administered orally .

Bleeding: Serious and potentially fatal bleeding. Promptly evaluate signs and symptoms of blood loss Mechanical Heart Valves or Moderate to Severe Mitral Stenosis: Use is not recommended Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: SAVAYSA use not recommended. 5.1 Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with CrCL > 95 mL/min SAVAYSA should not be used in patients with CrCL > 95 mL/min. In the randomized ENGAGE AF-TIMI 48 study, NVAF patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with SAVAYSA 60 mg daily compared to patients treated with warfarin. In these patients another anticoagulant should be used

Increased Risk of Stroke with Discontinuation of SAVAYSA in Patients with Nonvalvular Atrial Fibrillation Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If SAVAYSA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described in the transition guidance

Risk of Bleeding SAVAYSA increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue SAVAYSA in patients with active pathological bleeding. Concomitant use of drugs affecting hemostasis may increase the risk of bleeding. These include aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) . Reversal of Anticoagulant Effect There is no established way to reverse the anticoagulant effects of SAVAYSA, which can be expected to persist for approximately 24 hours after the last dose. The anticoagulant effect of SAVAYSA cannot be reliably monitored with standard laboratory testing. A specific reversal agent for edoxaban is not available. Hemodialysis does not significantly contribute to edoxaban clearance . Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of SAVAYSA. The use of prothrombin complex concentrates (PCC), or other procoagulant reversal agents such as activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical outcome studies . When PCCs are used, monitoring for anticoagulation effect of edoxaban using clotting test (PT, INR, or aPTT) or anti-FXa activity is not useful and is not recommended

Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 12 hours after the last administration of SAVAYSA. The next dose of SAVAYSA should not be administered earlier than 2 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis

Patients with Mechanical Heart Valves or Moderate to Severe Mitral Stenosis The safety and efficacy of SAVAYSA has not been studied in patients with mechanical heart valves or moderate to severe mitral stenosis. The use of SAVAYSA is not recommended in these patients

Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including SAVAYSA, are not recommended for use in patients with triple positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Anticoagulants, Antiplatelets, Thrombolytics, and Selective Serotonin Reuptake Inhibitors (SSRIs)/Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): Avoid concomitant use due to increased risk of bleeding. Rifampin: Avoid concomitant use 7.1 Anticoagulants, Antiplatelets, Thrombolytics, and SSRIs/SNRIs Co-administration of anticoagulants, antiplatelet drugs, thrombolytics and SSRIs or SNRIs may increase the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with anticoagulants, aspirin, other platelet aggregation inhibitors, and/or NSAIDs . Long-term concomitant treatment with SAVAYSA and other anticoagulants is not recommended because of increased risk of bleeding . Short term co-administration may be needed for patients transitioning to or from SAVAYSA . In clinical studies with SAVAYSA concomitant use of aspirin (low dose ≤ 100 mg/day) or thienopyridines, and NSAIDs was permitted and resulted in increased rates of Clinically Relevant Bleeding. Carefully monitor for bleeding in patients who require chronic treatment with low dose aspirin and/or NSAIDs . As with other anticoagulants the possibility may exist that patients are at an increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets

P-gp Inducers Avoid the concomitant use of SAVAYSA with rifampin

P-gp Inhibitors Treatment of NVAF Based on clinical experience from the ENGAGE AF-TIMI 48 study, dose reduction in patients concomitantly receiving P-gp inhibitors resulted in edoxaban blood levels that were lower than in patients who were given the full dose. Consequently, no dose reduction is recommended for concomitant P-gp inhibitor use . Treatment of Deep Vein Thrombosis and Pulmonary Embolism