Edoxaban should not be used in patients with CrCl >95 mL/minute. In the ENGAGE AF-TIMI 48 study, nonvalvular atrial fibrillation patients with CrCl >95 mL/minute had an increased rate of ischemic stroke with edoxaban 60 mg once daily compared to patients treated with warfarin. In these patients another anticoagulant should be used.
Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If edoxaban 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.
Epidural or spinal hematomas may occur in patients treated with edoxaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
- use of indwelling epidural catheters
- concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
- a history of traumatic or repeated epidural or spinal punctures
- a history of spinal deformity or spinal surgery
- optimal timing between the administration of edoxaban and neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients who are anticoagulated or are to be anticoagulated.
The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP.
Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism):
Note: In patients with nonvalvular atrial fibrillation (AF) and CrCl >95 mL/minute, the efficacy of edoxaban for prevention of ischemic stroke was decreased. Do not use edoxaban for nonvalvular AF if CrCl is >95 mL/minute (Bohula 2016; US manufacturer's labeling [recommendations may vary in international labeling]). Dosage reductions for renal impairment are listed under "Dosing: Renal Impairment: Adult."
Oral: 60 mg once daily.
Post-percutaneous coronary intervention with stent placement and nonvalvular atrial fibrillation: Oral: 60 mg once daily; administer with an appropriate antithrombotic regimen including clopidogrel (preferred P2Y12 inhibitor in this situation) with or without aspirin, depending on risks for thrombosis and bleeding and time since percutaneous coronary intervention (PCI) (ACC [Kumbhani 2021]; Khan 2020; Vranckx 2019). It is recommended to discontinue aspirin 1 to 4 weeks after PCI and continue edoxaban and clopidogrel (ACC/AHA [Lawton 2022]). Note: In the clinical trial, use of edoxaban plus clopidogrel did not demonstrate a reduced risk of bleeding compared to a regimen including a vitamin K antagonist, aspirin, plus clopidogrel, although efficacy between treatment groups was similar (Vranckx 2019).
Venous thromboembolism:
Deep vein thrombosis and/or pulmonary embolism treatment :
Note: May be used in patients with active cancer (eg, metastatic disease or receiving chemotherapy); however, avoid use in patients with upper GI tract cancers due to increased bleeding risk (ACCP [Stevens 2021]; ASCO [Key 2020]; Raskob 2017). Prior to initiation of edoxaban, assess CrCl using the Cockcroft-Gault equation. Some experts recommend not using edoxaban for venous thromboembolism (VTE) treatment if CrCl is >95 mL/minute, although specific data regarding an increased risk of recurrent VTE are lacking in this population (Hull 2022). Dosage reductions for renal impairment are listed under Dosing: Renal Impairment: Adult.
Oral: After at least 5 days of initial therapy with a parenteral anticoagulant, transition to edoxaban in hemodynamically stable patients:
Patient weight >60 kg: 60 mg once daily.
Patient weight ≤60 kg: 30 mg once daily.
Duration of therapeutic anticoagulation (first episode, general recommendations): Optimal duration of therapy is unknown and is dependent on many factors, such as whether provoking events were present, patient risk factors for recurrence and bleeding, and individual preferences:
Provoked venous thromboembolism: 3 months, provided provoking risk factor is no longer present (ACCP [Stevens 2021]).
Unprovoked venous thromboembolism or provoked venous thromboembolism with a persistent risk factor: ≥3 months depending on risk of VTE recurrence and bleeding (ACCP [Stevens 2021]; ISTH [Baglin 2012]).
Note: All patients receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at periodic intervals.
Transitioning between anticoagulants :
Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail:
Transitioning from another anticoagulant to edoxaban:
Transitioning from low-molecular-weight heparin or fondaparinux (therapeutic dose) to edoxaban:
General transition recommendation: Initiate edoxaban at the time of the next scheduled dose of the parenteral anticoagulant.
Venous thromboembolism initial treatment transition (alternative recommendation): For acute VTE, some experts start edoxaban within 6 to 12 hours after the last dose of a twice-daily LMWH regimen and within 12 to 24 hours after a once-daily regimen (Hull 2022).
Transitioning from unfractionated heparin continuous infusion to edoxaban: Initiate edoxaban when the unfractionated heparin continuous infusion is stopped (consult local protocol if aPTT is above target range) (Hull 2022).
Transitioning from warfarin to edoxaban: Discontinue warfarin and initiate edoxaban as soon as INR falls to ≤2.5 (US labeling).
Transitioning from edoxaban to another anticoagulant:
Transitioning from edoxaban to parenteral anticoagulant: Start the parenteral anticoagulant when the next dose of edoxaban was scheduled to be given.
Transitioning from edoxaban to warfarin:
Oral option: For patients taking edoxaban 60 mg once daily, reduce the dose to 30 mg once daily and begin warfarin concomitantly. For patients taking edoxaban 30 mg once daily, reduce the dose to 15 mg once daily and begin warfarin concomitantly. Measure INR at least weekly and just prior to the daily dose of edoxaban to minimize influence of edoxaban on INR measurements. Discontinue edoxaban once a stable INR ≥2 is achieved; continue warfarin (Leung 2019).
Parenteral option: Discontinue edoxaban and initiate a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose. Discontinue the parenteral anticoagulant once a stable INR ≥2 is achieved; continue warfarin.
Transitioning between direct oral anticoagulants: Start new direct oral anticoagulant (DOAC) when next dose of previous DOAC was scheduled to be given (Leung 2019).
Transitioning between anticoagulants in the perioperative setting : See 2017 AHA scientific statement, "Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting" and/or 2017 ACC expert consensus decision pathway, "Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation.”
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Calculate CrCl using the Cockcroft-Gault equation. In patients who develop acute kidney injury during use, closely monitor or consider switching to an alternative anticoagulant due to an increased risk of bleeding in this population (AHA [Raval 2017]).
Deep vein thrombosis and/or pulmonary embolism, treatment:
Altered kidney function:
CrCl >50 mL/minute: No dosage adjustment necessary. Note: Some experts recommend not using edoxaban for VTE treatment if CrCl is >95 mL/minute although specific data regarding an increased risk of recurrent VTE is lacking in this population (Hull 2018).
CrCl 15 to 50 mL/minute: Oral: 30 mg once daily. Note: Patients with CrCl <30 mL/minute (as determined by Cockcroft-Gault equation) at baseline were excluded from the Hokusai-VTE trial (Hokusai-VTE Investigators 2013) and from the VTE trial in cancer patients (Raskob 2017).
CrCl <15 mL/minute: Use is not recommended.
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable (Parasrampuria 2015): Avoid use (expert opinion).
Peritoneal dialysis: Unlikely to be dialyzed: Avoid use (expert opinion).
Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism):
Altered kidney function:
CrCl >95 mL/minute: Use is not recommended due to increased risk of ischemic stroke compared to warfarin(Bohula 2016; US manufacturer's labeling [recommendations may vary in international labeling]).
CrCl >50 to 95 mL/minute: No dosage adjustment necessary.
CrCl 15 to 50 mL/minute: Oral: 30 mg once daily. Note: Patients with CrCl <30 mL/minute (as determined by Cockcroft-Gault equation) at baseline were excluded from the ENGAGE AF-TIMI 48 trial (Giugliano 2013). However, a post-hoc analysis suggested that for subjects whose CrCl fell below 30 mL/minute during the trial, stroke and major bleeding rates in patients receiving edoxaban 30 mg once daily were similar to those in patients treated with warfarin (FDA 2014). Additionally, a small, retrospective observational study similarly suggested efficacy and safety of edoxaban 30 mg once daily in patients with CrCl between 15 and <30 mL/minute (Fazio 2018).
CrCl <15 mL/minute: Avoid use (AHA/ACC/HRS [January 2019]).
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable (Parasrampuria 2015). Avoid use (AHA/ACC/HRS [January 2019]).
Peritoneal dialysis: Unlikely to be dialyzed: Avoid use (expert opinion).
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate to severe impairment (Child-Pugh class B and C): Use is not recommended.
Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): Note: In patients with nonvalvular atrial fibrillation (AF) and CrCl >95 mL/minute, the efficacy of edoxaban for prevention of ischemic stroke was decreased. Do not use edoxaban for nonvalvular AF if CrCl is >95 mL/minute (Bohula 2016; US manufacturer's labeling [recommendations may vary in international labeling]). Dosage reductions for renal impairment are listed under "Dosing: Renal Impairment: Adult."
Oral: 60 mg once daily.
Dosage adjustment considerations: Note: Limited data exists regarding dosage adjustments; however, some trials have utilized the following adjustments:
Patients ≥65 years of age and at least one of the following characteristics: Weight ≤60 kg, concomitant use of potent P-glycoprotein inhibitors (eg, verapamil, quinidine), CrCl ≤50 mL/minute (patients with CrCl <30 mL/minute were excluded) (Giugliano 2013; Kato 2016):
Oral: 30 mg once daily.
Patients ≥80 years of age who are considered to be inappropriate candidates for oral anticoagulants at the approved doses (eg, low body weight [ie, ≤45 kg] or body weight ≤60 kg plus one of the following: severe kidney impairment [eg, CrCl <30 mL/minute], history of GI bleeding or bleeding from a critical area, continuous use of a nonsteroidal anti-inflammatory drug, or concurrent use of an antiplatelet agent):
Oral: 15 mg once daily may be considered. Note: Dosing is based on a relatively small, randomized, placebo-controlled trial (n = 984) of elderly Japanese patients ≥80 years of age with low body weight (mean weight: 50.6 kg) and reduced renal function (mean CrCl = 36.3 mL/minute). The results of this trial may not be applicable to other populations (Okumura 2020).
Postpercutaneous coronary intervention with stent placement and nonvalvular atrial fibrillation: Refer to adult dosing.
Venous thromboembolism: Refer to adult dosing.
Transitioning between anticoagulants: Refer to adult dosing.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The International Society on Thrombosis and Haemostasis (ISTH) 2016 guideline suggests avoiding the use of edoxaban (and other direct oral anticoagulants [DOACs]) in patients with a BMI >40 kg/m2 or weight >120 kg due to the lack of clinical data in this population. If used in a patient with a BMI >40 kg/m2 or weight >120 kg, ISTH suggests measuring peak and trough levels using an anti-factor Xa assay or mass spectrometry. If drug level is below the expected range, ISTH suggests changing to a vitamin K antagonist rather than adjusting the dose of edoxaban (ISTH [Martin 2016]).
For bariatric and other GI surgery patients, evaluate the risk versus benefit of possible decreased drug absorption. Edoxaban tablets disintegrate in the stomach, which is dependent on an acidic environment. Absorption primarily occurs in the proximal small intestine. Surgeries which raise the pH of the stomach (eg, Roux-en-Y gastric bypass) or decrease small intestine sites may decrease absorption of edoxaban (Hakeam 2017). The available data are conflicting for absorption alterations, derived from small populations, and underrepresent individual DOACs and distinct surgeries (Kröll 2017; Kröll 2018; Lee 2013; Rottenstreich 2018). Since there is no established correlation between target blood levels of DOACs with efficacy, therapeutic drug monitoring is difficult. Consider alternative anticoagulation if there is a need for direct monitoring (Hakeam 2017).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Savaysa: 15 mg, 30 mg, 60 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Lixiana: 15 mg, 30 mg, 60 mg
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Savaysa: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/206316s018MedGuide.pdf
Oral: Administer without regard to food.
Patients unable to swallow whole tablets may crush tablets and mix with applesauce or 60 to 90 mL water; administer immediately. For patients with a gastric tube, mix crushed tablets with 60 to 90 mL water and administer immediately.
Nonvalvular atrial fibrillation: To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF).
Limitations of use: Do not use in nonvalvular AF patients with CrCl >95 mL/minute because of an increased risk of ischemic stroke compared to warfarin (Bohula 2016; US manufacturer's labeling [recommendations may vary in international labeling]).
Venous thromboembolism (deep vein thrombosis and pulmonary embolism): Treatment of deep vein thrombosis and pulmonary embolism following 5 to 10 days of initial therapy with a parenteral anticoagulant.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
The Joint Commission (TJC) requires healthcare organizations that provide anticoagulant therapy to have approved protocols and evidence-based practice guidelines in place to reduce the risk of anticoagulant-associated patient harm. Patients receiving anticoagulants should receive individualized care through a defined process that includes medication selection, dosing (including adjustments for age, renal function, or liver function), drug-drug interactions, drug-food interactions, other applicable risk factors, monitoring, patient and family education, proper administration, reversal of anticoagulation, management of bleeding events, and perioperative management. This does not apply to routine short-term use of anticoagulants for prevention of venous thromboembolism during procedures or hospitalizations (NPSG.03.05.01).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Hematologic and oncologic: Hemorrhage (22% to 26%), major hemorrhage (1% to 13%), minor hemorrhage (7% to 13%)
1% to 10%:
Dermatologic: Dermal hemorrhage (6%), skin rash (4%)
Gastrointestinal: Gastrointestinal hemorrhage (≤4%)
Genitourinary: Gross hematuria (≤2%), urethral bleeding (≤2%), vaginal hemorrhage (9%)
Hematologic and oncologic: Anemia (2%), oral hemorrhage (≤3%), puncture site bleeding (1%)
Hepatic: Abnormal hepatic function tests (5% to 8%)
Respiratory: Epistaxis (5%), pharyngeal bleeding (≤3%)
<1%:
Nervous system: Intracranial hemorrhage
Respiratory: Interstitial pulmonary disease
Frequency not defined:
Cardiovascular: Ischemia (with premature discontinuation)
Hematologic & oncologic: Spinal hematoma (in patients receiving neuraxial anesthesia or undergoing spinal puncture)
Nervous system: Epidural intracranial hemorrhage (in patients receiving neuraxial anesthesia or undergoing spinal puncture)
Postmarketing:
Dermatologic: Urticaria
Gastrointestinal: Abdominal pain
Hematologic & oncologic: Thrombocytopenia
Hypersensitivity: Angioedema, hypersensitivity reaction
Nervous system: Dizziness, headache
Active pathological bleeding
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to edoxaban or any component of the formulation; conditions at increased risk of significant bleeding (recent hemorrhagic or ischemic cerebral infarction); active peptic ulcer disease with recent bleeding; impaired spontaneous or acquired hemostasis; hepatic disease associated with coagulopathy and clinically relevant bleeding risk; concomitant use with any other anticoagulant such as unfractionated heparin (except at doses used to maintain a patent central venous or arterial catheter), low molecular weight heparins (eg, enoxaparin and dalteparin); heparin derivatives (eg, fondaparinux), oral anticoagulants (eg, warfarin, dabigatran, apixaban, rivaroxaban) except when switching therapy to or from edoxaban; pregnant or breastfeeding women.
Concerns related to adverse effects:
• Bleeding: May increase the risk of bleeding, including severe and potentially fatal bleeding. Concomitant use of drugs that affect hemostasis (eg, aspirin, other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, chronic NSAID use, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors) may increase the risk of bleeding. Discontinue therapy with active pathological hemorrhage and promptly evaluate for bleeding source. Hemodialysis does not have a substantial impact on edoxaban clearance and protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant effect of edoxaban. Andexanet alfa should be considered for reversal of edoxaban (ACC [Tomaselli 2020]; Baugh 2019; Cuker 2019). Depending on the bleeding severity, activated oral charcoal should be considered if ingestion occurred within 1 to 2 hours of presentation. The following alternative options may also be considered depending on the clinical scenario: 4-factor unactivated prothrombin concentrate (PCC) (eg, Kcentra) or 4-factor activated prothrombin complex concentrate (aPCC) (eg, FEIBA). Some studies and case reports have shown moderate success in correcting coagulation tests with some of these agents; however, correction of coagulation tests does not imply reversal of the anticoagulation effect of the medication (AHA/ASA [Hemphill 2015]; EHRA [Heidbuchel 2015]; NCS/SCCM [Frontera 2016]).
• Thromboembolic events: [US Boxed Warning]: Premature discontinuation of any oral anticoagulant, including edoxaban, in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If edoxaban is discontinued for reasons other than pathological bleeding or completion of a course of therapy, consider the use of another anticoagulant. In patients with non-valvular atrial fibrillation who had an acute ischemic stroke while receiving a direct oral anticoagulant (DOAC) (eg, edoxaban), guidelines generally support withholding oral anticoagulation until 4 to 14 days after the onset of neurological symptoms (time frame may vary with shorter times for transient ischemic attack or small, nondisabling stroke and longer times for moderate to severe stroke) (AHA/ASA [Kernan 2014]; AHA/ASA [Powers 2018]).
Disease-related concerns:
• Antiphospholipid syndrome: Use not recommended for patients with triple-positive antiphospholipid syndrome (APS). Patients with APS (especially if triple positive for all 3 antiphospholipid antibodies [lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I]) may have increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
• GI/Bariatric surgery: Altered absorption: Evaluate the risk versus benefit of possible decreased drug absorption. Edoxaban tablets disintegrate in the stomach, which is dependent on an acidic environment. Absorption primarily occurs in the proximal small intestine. Surgeries which raise the pH of the stomach (eg, Roux-en-Y gastric bypass) or decrease small intestine sites may decrease absorption of edoxaban (Hakeam 2017).
• Hepatic impairment: Use is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B and C) due to intrinsic coagulation abnormalities.
• Nonvalvular atrial fibrillation: [US Boxed Warning]: Do not administer to nonvalvular atrial fibrillation (NVAF) patients with CrCl >95 mL/minute (calculated using the Cockcroft-Gault formula). In clinical trials, these patients had an increased rate of ischemic stroke with edoxaban 60 mg once daily compared to patients treated with warfarin; use another anticoagulant in these patients (Bohula 2016; US manufacturer's labeling [recommendations may vary in international labeling]).
• Renal impairment: Dose adjustment is necessary in patients with renal impairment. In patients who develop acute kidney injury during use, closely monitor or consider switching to an alternative anticoagulant due to an increased risk of bleeding in this population (AHA [Raval 2017]).
• Valvular disease: Avoid use in patients with surgically implanted mechanical heart valve, transcatheter aortic valve replacement with no other indication for anticoagulation, moderate to severe mitral stenosis, or significant rheumatic heart disease; however, may be used in patients with atrial fibrillation and native aortic valve disease, tricuspid valve disease, mitral regurgitation, or surgical bioprosthetic mitral valve replacement when anticoagulation is required (ACC/AHA [Otto 2021]; AHA/ACC/HRS [January 2014]; AHA/ACC/HRS [January 2019]; Gaasch 2020).
Other warnings/precautions:
• Appropriate use: Surgical patients: When temporary interruption is necessary before surgery, the timing of discontinuation depends on renal function and risk for bleeding complications. In patients with CrCl ≥30 mL/minute, discontinue therapy ~24 to 48 hours before surgery, depending on risk for bleeding. In patients with CrCl <30 mL/minute, discontinue therapy ~48 to 72 hours or longer before surgery, depending on risk for bleeding. Consider discontinuing for a longer period of time in patients undergoing major surgery, spinal puncture, or insertion of a spinal or epidural catheter or port. When there is adequate hemostasis after surgery, may reinstitute therapy after 24 hours if there is low risk for bleeding or after 48 to 72 hours if there is high risk for bleeding. Other specific considerations can be found in expert scientific statements and consensus pathways (ACC [Doherty 2017]; AHA [Raval 2017]).
• Body weight: In patients with venous thromboembolism (DVT and/or PE) and body weight ≤60 kg, dosage reduction is necessary.
• Spinal or epidural hematoma: [US Boxed Warning]: Spinal or epidural hematomas resulting in long-term or permanent paralysis may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal/epidural puncture; the risk is increased by the use of indwelling epidural catheters, concomitant administration of other drugs that affect hemostasis (eg, NSAIDS, platelet inhibitors, other anticoagulants), in patients with a history of traumatic or repeated epidural or spinal punctures, a history of spinal deformity or surgery, or if optimal timing between the administration of edoxaban and neuraxial procedures is not known. Consider the potential benefits and risks prior to neuraxial intervention in patients who are anticoagulated or scheduled to be anticoagulated. Monitor frequently for signs and symptoms of neurologic impairment (eg, numbness/weakness of legs, bowel/bladder dysfunction). If neurologic impairment is noted, urgent treatment is necessary.
- In patients who receive both edoxaban and neuraxial anesthesia, avoid removal of epidural or intrathecal catheter for at least 12 hours following last edoxaban dose; avoid edoxaban administration for at least 2 hours following catheter removal.
Substrate of P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Adagrasib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: Avoid concomitant use of adagrasib and these narrow therapeutic/sensitive substrates of P-gp when possible. If combined, monitor for increased toxicities of these substrates. Risk D: Consider therapy modification
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Risk C: Monitor therapy
Alemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Anticoagulants: Edoxaban may enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Risk X: Avoid combination
Antiplatelet Agents (P2Y12 Inhibitors): May enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider the anticipated risks and benefits of this combination. If combined, increased monitoring for bleeding is recommended. Risk D: Consider therapy modification
Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Aspirin: May enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Aspirin may increase the serum concentration of Edoxaban. Management: Carefully consider the anticipated risks and benefits of this combination. If combined, increased monitoring for bleeding is recommended. Risk D: Consider therapy modification
Azithromycin (Systemic): May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30mg daily when combined with azithromycin. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined. Risk D: Consider therapy modification
Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification
Clarithromycin: May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce edoxaban dose to 30 mg daily when combined with clarithromycin. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined. Risk D: Consider therapy modification
Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy
Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: If coadministration with these narrow therapeutic index/sensitive P-gp substrates is unavoidable, separate erdafitinib administration by at least 6 hours before or after administration of these P-gp substrates. Risk D: Consider therapy modification
Erythromycin (Systemic): May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30 mg daily when combined with erythromycin. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined Risk D: Consider therapy modification
Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Risk C: Monitor therapy
Futibatinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapy
Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Itraconazole: May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30 mg daily when combined with itraconazole. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined Risk D: Consider therapy modification
Kanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Ketoconazole (Systemic): May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30 mg daily when combined with oral ketoconazole. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding). Risk D: Consider therapy modification
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Lenacapavir: May increase the serum concentration of Edoxaban. Risk C: Monitor therapy
Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy
Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Lumacaftor and Ivacaftor: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Risk C: Monitor therapy
Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination
Mitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Nonselective): May enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of edoxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy
Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid combination
Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Oritavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy
Pacritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Edoxaban. Management: Avoid coadministration of edoxaban and P-glycoprotein (P-gp) inducers if possible. If concomitant use is required, be aware the edoxaban efficacy may be decreased. Risk D: Consider therapy modification
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Edoxaban. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy
QuiNIDine: May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30 mg daily when combined with quinidine. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined. Risk D: Consider therapy modification
RifAMPin: May decrease the serum concentration of Edoxaban. Risk X: Avoid combination
Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Sotorasib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: Consider avoiding use of sotorasib and narrow therapeutic index/sensitive P-gp substrates. If combined use is unavoidable, monitor for increased toxicities of the substrate and consider a decrease in the substrate dosage. Risk D: Consider therapy modification
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Taurursodiol: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy
Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: Monitor for signs and symptoms of bleeding if these agents are combined. For the treatment of acute ischemic stroke, avoidance with anticoagulants is often recommended, see full Lexicomp or drug interaction monograph for details. Risk C: Monitor therapy
Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Verapamil: May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30 mg daily when combined with verapamil. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined. Risk D: Consider therapy modification
Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination
Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Information related to the use of direct-acting oral anticoagulants in pregnancy is limited; until safety data are available, adequate contraception is recommended during therapy for patients who may become pregnant. Patients planning to become pregnant should be switched to alternative anticoagulants prior to conception (Cohen 2016).
Information related to the use of edoxaban in pregnancy is limited (Beyer-Westendorf 2020; Lameijer 2018; Sakai 2019). Use of direct-acting oral anticoagulants increases the risk of bleeding in all patients. When used in pregnancy, there is also the potential for fetal bleeding or subclinical placental bleeding, which may increase the risk of miscarriage, preterm delivery, fetal compromise, or stillbirth (Cohen 2016).
Data are insufficient to evaluate the safety of direct-acting oral anticoagulants during pregnancy and use in pregnant patients is not recommended (ACOG 2018; Regitz-Zagrosek [ESC 2018]). Agents other than edoxaban are preferred for the treatment of AF or VTE in pregnant patients (Kearon 2016; Lip 2018; Regitz-Zagrosek [ESC 2018]). Patients should be switched to an alternative anticoagulant if pregnancy occurs during therapy. Fetal monitoring that includes evaluations for fetal bleeding and assessments for risk of preterm delivery are recommended if the direct-acting oral anticoagulant is continued (Cohen 2016).
It is not known if edoxaban is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer. Until safety data are available, direct-acting oral anticoagulants are not recommended for use in patients who are breastfeeding; use of an alternative anticoagulant is preferred (ACOG 2018; Cohen 2016).
CBC, aPTT, PT, serum creatinine, and liver function tests prior to initiation, when clinically indicated, and at least annually (AHA/ACC/HRS [January 2014]; Leung 2019)
Routine coagulation testing is not required or necessary for direct oral anticoagulants (DOACs). There are currently no FDA-approved assays or calibration reagents available.
In clinical situations when assessment of the anticoagulant effect is useful (eg, acute care, periprocedural settings, absorption), evaluating a recent creatinine clearance and time since the last dose was ingested is usually sufficient for guiding clinical decisions. Most commonly used coagulation tests (PT, INR, aPTT) cannot definitively exclude the presence of clinically relevant serum concentrations. A prolonged PT suggests clinically relevant serum concentrations are present, but normal PT and aPTT values using standard reagents cannot rule out the presence of edoxaban. Highly sensitive reagents for PT testing may be able to exclude the presence of edoxaban.
If available, the preferred test to rule out clinically significant serum concentrations and quantify anticoagulant effect is anti-factor Xa activity calibrated specifically for edoxaban (undetectable anti-factor Xa activity likely excludes clinically relevant drug concentrations). An anti-factor Xa assay calibrated for low molecular weight heparin can rule out clinically relevant drug concentrations but is not useful for quantification (ACC [Tomaselli 2020]; AHA [Raval 2017]; Leung 2019).
The International Council for Standardization in Haematology (ICSH) provides examples of edoxaban drug levels for the 60 mg once daily dose, with an expected median peak of ~170 to 234 ng/mL (interquartile range of 125 to 317 ng/mL) and an expected median trough of ~19 to 36 ng/mL (interquartile range of 10 to 62 ng/mL) (Gosselin 2018). These values are intended to be used as guides to provide evidence of drug absorption, not as therapeutic targets (Leung 2019).
Edoxaban, a selective factor Xa inhibitor, inhibits free factor Xa and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of factor Xa in the coagulation cascade reduces thrombin generation and thrombus formation.
Distribution: Vdss: 107 L
Protein binding: ~55%
Metabolism: Minimal via hydrolysis, conjugation and oxidation by CYP3A4; predominant metabolite (M-4) is active (<10% of parent compound)
Bioavailability: 62%
Half-life elimination: 10 to 14 hours
Time to peak: 1 to 2 hours
Excretion: Urine (primarily unchanged); renal clearance: ~50% of total clearance
Renal impairment: Systemic exposure increased by 32% (CrCl >50 to <80 mL/minute), 74% (CrCl 30 to 50 mL/minute), and 72% (CrCl <30 mL/minute), and 93% (peritoneal dialysis).
No renal impairment: Edoxaban blood levels are lower in patients with better renal function, averaging about 30% less in patients with CrCl >80 mL/minute and 40% less in patients with CrCl >95 mL/minute when compared to patients with CrCl >50 to ≤80 mL/minute.
Body weight: Total exposure in patients with low body weight (55 kg) was increased by 13%.
Tablets (Savaysa Oral)
15 mg (per each): $15.56
30 mg (per each): $15.56
60 mg (per each): $15.56
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