INTERACTIONS Anticoagulants, Antiplatelets, Thrombolytics, and Selective Serotonin Reuptake Inhibitors (SSRIs)/Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): Avoid concomitant use due to increased risk of bleeding. ( 7.1 ) Rifampin: Avoid concomitant use ( 7.2 )
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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> . Long-term concomitant treatment with SAVAYSA and other anticoagulants is not recommended because of increased risk of bleeding <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> . Short term co-administration may be needed for patients transitioning to or from SAVAYSA <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span>. 7.2 P-gp Inducers Avoid the concomitant use of SAVAYSA with rifampin <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 7.3 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ]</span> . Treatment of Deep Vein Thrombosis and Pulmonary Embolism <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span>
SAVAYSA is contraindicated in patients with: Active pathological bleeding [see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ] . Active pathological bleeding ( 4 )
AND PRECAUTIONS Bleeding: Serious and potentially fatal bleeding. Promptly evaluate signs and symptoms of blood loss ( 5.3 )
Mechanical Heart
Valves or Moderate to Severe Mitral Stenosis: Use is not recommended ( 5.5 )
Increased
Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: SAVAYSA use not recommended. ( 5.6 )
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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) and Clinical Studies (14.1) ]</span> .
5.2 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) and Clinical Studies (14.1) ]</span> .
5.3 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) <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . 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.
5.4 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.
5.5 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> .
5.6 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.