Edoxaban

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Savaysa: 15 mg, 30 mg, 60 mg

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 107 L

Metabolism

Minimal via hydrolysis, conjugation and oxidation by CYP3A4; predominant metabolite (M-4) is active (<10% of parent compound)

Excretion

Urine (primarily unchanged); renal clearance: ~50% of total clearance.

Time to Peak

1 to 2 hours

Half-Life Elimination

10 to 14 hours

Protein Binding

~55%

Use in Specific Populations

Special Populations: Renal Function 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 a CrCl >50 to ≤80 mL/minute.

Special Populations Note

Body weight: Total exposure in patients with low body weight (55 kg) was increased by 13%.

Use: Labeled Indications

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.

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.

Contraindications

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.

Dosage and Administration

Dosing: Adult

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism):

Note: Prior to initiation of edoxaban, assess kidney function using the Cockcroft-Gault equation. 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. Dosage reductions for renal impairment are listed under Dosing: Renal Impairment: Adult.

Oral: 60 mg once daily.

Venous thromboembolism:

Deep vein thrombosis and/or pulmonary embolism, treatment: Oral:

Note: In patients with GI cancer, low molecular weight heparin (LMWH) is preferred (ASCO [Key 2019]; Bauer 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 2018). Dosage reductions for renal impairment are listed under Dosing: Renal Impairment: Adult.

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 [Kearon 2016]).

Unprovoked pulmonary embolism or deep vein thrombosis (proximal or isolated distal): ≥3 months depending on risk of VTE recurrence and bleeding (ACCP [Kearon 2012]; ACCP [Kearon 2016]; 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 2018).

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 2018).

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."

Dosage adjustment of edoxaban with concomitant medications:

Deep vein thrombosis and/or pulmonary embolism, treatment:

P-gp inhibitors (eg, verapamil, quinidine, azithromycin, clarithromycin, erythromycin, oral itraconazole, oral ketoconazole): Oral: 30 mg once daily.

P-gp inducers (eg, rifampin): Avoid concurrent use.

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism):

P-gp inhibitors: No dosage adjustments recommended.

P-gp inducers (eg, rifampin): Avoid concurrent use.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Obesity

The International Society on Thrombosis and Haemostasis (ISTH) 2016 guideline suggests avoiding the use of edoxaban (and other direct oral anticoagulants) 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 antifactor 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]).

Administration

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.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

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. 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. Exceptions: Acenocoumarol; Warfarin. 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. 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. Avoid combination

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. Consider therapy modification

Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Edoxaban. Management: Combined use of carbamazepine and edoxaban should generally be avoided. Consider therapy modification

Cobicistat: May increase the serum concentration of Edoxaban. Monitor therapy

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. 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. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. 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. 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. Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds). Consider therapy modification

Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Inotersen: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Avoid combination

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. 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. Consider therapy modification

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. 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. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. 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. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Edoxaban. Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

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. Monitor therapy

RifAMPin: May decrease the serum concentration of Edoxaban. 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. Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

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. Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Adverse Reactions

>10%:

Hematologic and oncologic: Hemorrhage (22% to 26%), minor hemorrhage (7% to 13%), major hemorrhage (1% to 13%)

1% to 10%:

Dermatologic: Dermal hemorrhage (6%), skin rash (4%)

Gastrointestinal: Gastrointestinal hemorrhage (≤4%)

Genitourinary: Vaginal hemorrhage (9%), gross hematuria (≤2%), urethral bleeding (≤2%)

Hematologic and oncologic: Oral hemorrhage (≤3%), anemia (2%), puncture site bleeding (1%)

Hepatic: Abnormal hepatic function tests (5% to 8%)

Respiratory: Epistaxis (5%), pharyngeal bleeding (≤3%)

<1%: Interstitial pulmonary disease, intracranial hemorrhage

Frequency not defined:

Cardiovascular: Ischemia (with premature discontinuation)

Central nervous system: Epidural intracranial hemorrhage (in patients receiving neuraxial anesthesia or undergoing spinal puncture)

Hematologic & oncologic: Spinal hematoma (in patients receiving neuraxial anesthesia or undergoing spinal puncture)

Postmarketing: Angioedema, hypersensitivity reaction, thrombocytopenia, urticaria

Warnings/Precautions

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. No specific antidote for edoxaban reversal exists. 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. 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 specific 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:

• Bariatric surgery:

– Altered absorption: Evaluate the risk versus benefit of possible decreased drug absorption against the consideration of alternative anticoagulants; efficacy may be decreased after gastric bypass or sleeve gastrectomy. Apixaban’s absorption appears to occur primarily in the small intestine. Peak apixaban concentrations and total AUC are reduced by 60% when released in the distal small intestine and further reduced to 90% and 84%, respectively, when released in the ascending colon (Frost 2013).

– Rivaroxaban: Peak concentrations and AUC were reduced by 56% and 29%, respectively, when released into the proximal small intestine and further reduced in the distal small intestine or colon (manufacturer labeling 2019). Patients with significantly altered GI tracts are represented by small series and case reports (Hakeam 2017). The available data are conflicting for absorption alterations, derived from small populations, and underrepresent individual direct oral anticoagulants and surgeries (Kroll 2017; Kroll 2018; Lee 2013; Rottenstreich 2018).

• 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.
• Renal impairment: In patients with CrCl of 15 to 50 mL/minute (calculated using the Cockcroft-Gault formula), dosage reduction is necessary. Use is not recommended in patients with CrCl <15 mL/minute (limited clinical data). Use with caution in patients on hemodialysis; limited information is available. 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: Use is not recommended in patients with prosthetic heart valves or significant rheumatic heart disease. Avoid use of DOACs in patients with mechanical valves or with moderate to severe mitral stenosis (AHA/ACC/HRS [January 2019]). However, a DOAC may be used in patients with AF and native aortic valve disease, tricuspid valve disease, or mitral regurgitation when anticoagulation is required (AHA/ACC/HRS [January 2014, 2019]; AHA/ACC [Nishimura 2017]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• 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.

Monitoring Parameters

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 antifactor Xa activity calibrated specifically for edoxaban (undetectable anti-Xa activity likely excludes clinically relevant drug concentrations). An antifactor Xa assay calibrated for low molecular weight heparin can rule out clinically relevant drug concentrations, but is not useful for quantification (ACC [Tomaselli 2017]; AHA [Raval 2017]; Leung 2019).

Pregnancy

Pregnancy Considerations

Information related to the use of edoxaban in pregnancy is limited (Beyer-Westendorf 2016; 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 (Bates 2012) and use in pregnant females is not recommended (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).

Until safety data are available, adequate contraception is recommended during therapy for females of childbearing potential. Females planning a pregnancy should be switched to alternative anticoagulants prior to conception (Cohen 2016).

Patient Education

What is this drug used for?

• It is used to treat blood clots.
• It is used to prevent strokes.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes.
• Pale skin
• Severe headache
• Loss of strength and energy
• Back pain
• Numbness or tingling
• Muscle weakness
• Paralysis
• Leaking of urine
• Leaking of stool
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.