Edoxaban (Monograph)

Brand name: Savaysa
Drug class: Direct Factor Xa Inhibitors
Chemical name: N1-(5-Chloro-2-pyridinyl)-N2-[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[[(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridin-2-yl)carbonyl]amino]cyclohexyl]-ethanediamide 4-methylbenzenesulfonate (1:1)
Molecular formula: C₂₄H₃₀ClN₇O₄S•C₇H₈O₃S
CAS number: 480449-71-6

Medically reviewed by Drugs.com on Sep 24, 2024. Written by ASHP.

Introduction

Anticoagulant; an oral, direct, activated factor X (Xa) inhibitor.^{1 2 9 16 23}

Uses for Edoxaban

Embolism Associated with Atrial Fibrillation

Reduction in the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.^{1 2 9}

Do not use in patients with Cl_cr >95 mL/minute because of possible reduced efficacy.^{1 9} (See Boxed Warning.)

Direct oral anticoagulants (DOACs; apixaban, dabigatran, edoxaban, rivaroxaban) are noninferior or superior to warfarin in reducing thromboembolic risk in patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of moderate-to-severe mitral stenosis or a mechanical heart valve), and associated with reduced risk of bleeding.^{1 2 7 9 82 87}

The American College of Chest Physicians (ACCP), American Stroke Association (ASA), American College of Cardiology (ACC), American Heart Association (AHA), and other experts recommend antithrombotic therapy in all patients with nonvalvular atrial fibrillation who are considered to be at increased risk of stroke, unless contraindicated.^{80 81 82 87 989 1007}

Current guidelines recommend use of the CHA₂DS₂-VASc risk stratification tool to assess a patient’s risk of stroke and need for anticoagulant therapy.^{82 989 1007} Established clinical risk factors for stroke include prior ischemic stroke or TIA, advanced age (e.g., ≥65 years), hypertension, diabetes mellitus, vascular disease, and CHF; in addition, female sex is a stroke risk modifier.^{80 82 989 1007 1017} The presence of stroke or TIA places a patient in the high-risk category regardless of other risk factors.⁸²

Experts state that antithrombotic therapy generally is not necessary in low-risk patients (CHA₂DS₂-VASc score of 0 in males or 1 in females), but should be considered in all higher-risk patients.^{87 989 1007 1017}

In patients with nonvalvular atrial fibrillation who are eligible for oral anticoagulant therapy, DOACs are recommended over warfarin based on improved safety and similar or improved efficacy.^{82 87 989 1007}

Substantially greater benefit of DOACs versus warfarin observed when INR is in therapeutic range <66% of the time.⁸² If warfarin is used, patients should be optimally managed with well-controlled INRs; in patients unable to achieve optimal warfarin management, DOACs are preferred.^{82 87 989 1007}

Relative efficacy and safety of the DOACs remain to be fully elucidated.^{9 15 84 85 87}

When selecting an appropriate anticoagulant, consider factors such as the absolute and relative risks of stroke and bleeding; costs; patient compliance, preference, tolerance, and comorbidities; and other clinical factors such as renal function and degree of INR control (if the patient has been taking warfarin).^{80 81 82 83 84 989 1007}

Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.^{80 82 1007}

DOACs including edoxaban also have been used for therapeutic anticoagulation prior to and after cardioversion in patients with atrial fibrillation of >48 hours' duration or of unknown duration; DOACs are recommended as an alternative to warfarin in this setting.^{87 1007}

Safety and efficacy of edoxaban not established in patients with mechanical heart valves or moderate to severe mitral stenosis; use not recommended in such patients.^{1 9}

Treatment of Venous Thromboembolism

Treatment of venous thromboembolism (VTE; DVT and/or PE), following initial treatment with a parenteral anticoagulant for 5–10 days.^{1 9 16}

Noninferior to warfarin in reducing the risk of recurrent VTE; associated with substantially reduced rates of clinically important bleeding.^{1 16}

DOACs (e.g., apixaban, dabigatran, edoxaban, rivaroxaban) are among several anticoagulants that can be used for treatment of VTE.^{1005 1104} When selecting an appropriate anticoagulant, consider convenience of administration, cost, patient preference, presence of renal impairment, and cancer or other comorbid conditions, as well as relative efficacy and safety.¹¹⁰⁴

ACCP suggests use of DOACs over warfarin for treatment of VTE in patients without cancer.¹¹⁰⁴ In patients with cancer and established VTE, low molecular weight heparins (LMWHs) or DOACs are generally suggested over warfarin for long-term anticoagulation.^{1102 1103 1104} DOACs generally should not be used in settings with increased risk of bleeding, morbid obesity (body weight >120 kg or BMI >40 mg/m²), drug-drug interactions, or GI complications affecting oral therapy (e.g., poor absorption, nausea and vomiting) because of lack of safety data.^{1102 1104}

Continue anticoagulant therapy for at least 3 months, and possibly longer depending on individual clinical situation.^{1005 1104} In patients with cancer, anticoagulation therapy is recommended for at least 6 months; treatment beyond 6 months may be considered for selected patients.¹¹⁰³

Edoxaban Dosage and Administration

General

Pretreatment Screening

• Prior to initiating therapy, assess renal function.¹ Calculate Cl_cr using the Cockcroft-Gault method; dosage recommendations are based on estimated Cl_cr.¹ Do not use in patients with Cl_cr >95 mL/minute.¹

Patient Monitoring

• Routine coagulation monitoring not required.^{1 20 21} Coagulation tests such as aPTT, PT, and INR generally not useful because of variable and inconsistent results.^{1 20 21 23 28}

Administration

Oral Administration

Administer orally without regard to food.¹

In patients unable to swallow whole tablets, crush and mix with 2–3 ounces of water and administer immediately by mouth or through a gastric tube.¹ Alternatively, mix crushed tablets into applesauce and administer immediately by mouth.¹

If a dose is missed, take as soon as possible on the same day, then resume regular schedule the following day.¹ Do not double dose to make up for missed dose.¹

Dosage

Available as edoxaban tosylate monohydrate; dosage expressed in terms of edoxaban.¹

Adults

Embolism Associated with Atrial Fibrillation

Oral

Patients with Cl_cr of 51–95 mL/minute: 60 mg once daily.¹

Patients with Cl_cr of 15–50 mL/minute: 30 mg once daily.¹ (See Renal Impairment under Dosage and Administration.)

Patients with Cl_cr >95 mL/minute: Do not use.¹ (See Boxed Warning.)

Treatment of DVT and/or PE

Oral

60 mg once daily following 5–10 days of therapy with a parenteral anticoagulant.¹

Reduce to 30 mg once daily in patients with Cl_cr of 15–50 mL/minute, body weight ≤60 kg, and/or in those receiving concomitant therapy with certain P-glycoprotein inhibitors (verapamil, quinidine, or short-term treatment with azithromycin, clarithromycin, erythromycin, oral ketoconazole, or oral itraconazole).¹

Determine optimum duration of anticoagulation based on individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors for thrombosis, presence of cancer, risk of bleeding).¹⁰⁰⁵ In general, ACCP states that anticoagulant therapy for venous thromboembolism should be continued beyond the acute treatment period for at least 3 months, and possibly longer in patients with a high risk of recurrence and low risk of bleeding.¹⁰⁰⁵

Transitioning from Other Anticoagulants

Oral

Transitioning from warfarin to edoxaban: Discontinue warfarin and initiate edoxaban as soon as INR ≤2.5.¹

Transitioning from other oral anticoagulants to edoxaban: Discontinue current anticoagulant and initiate edoxaban at the time of the next scheduled dose of the other anticoagulant.¹

Transitioning from LMWH to edoxaban: Discontinue LMWH and initiate edoxaban at the time of the next scheduled LMWH dose.^{1 29}

Transitioning from heparin IV infusion to edoxaban: Discontinue heparin infusion and initiate edoxaban 4 hours later.¹

Transitioning to Other Anticoagulants

Oral

Transitioning from edoxaban to warfarin therapy (parenteral method): Discontinue edoxaban and initiate a parenteral anticoagulant and warfarin simultaneously at the time of next scheduled dose of edoxaban; discontinue parenteral anticoagulant once a stable INR ≥2 is reached.¹

Transitioning from edoxaban to warfarin therapy (oral method): Decrease current dosage of edoxaban by 50% (60 to 30 mg or 30 to 15 mg) and initiate warfarin simultaneously.¹ Administer 2 drugs concomitantly until a stable INR ≥2 is achieved; once this occurs, discontinue edoxaban and continue warfarin.¹ Monitor INR at least once a week; perform test just prior to the daily dose of edoxaban to minimize effect of the drug on the INR.¹

Transitioning from edoxaban to other anticoagulants, including parenteral anticoagulants and non-vitamin K-antagonist oral anticoagulants: Discontinue edoxaban and initiate other anticoagulant at the time of next scheduled dose of edoxaban.¹

Managing Anticoagulation in Patients Requiring Invasive Procedures

Temporarily discontinue edoxaban at least 24 hours prior to surgery or other invasive procedure.¹ If surgery cannot be delayed, weigh potential increased risk of bleeding against urgency of intervention.¹

May resume therapy postoperatively as soon as adequate hemostasis established; consider onset of the drug's pharmacodynamic effects (1–2 hours) when deciding when to restart therapy.^{1 83} If oral or enteral administration is not possible, administer a parenteral anticoagulant until edoxaban therapy can be resumed.¹ (See Risk of Thrombosis Following Premature Discontinuance of Therapy under Cautions.)

Special Populations

Hepatic Impairment

Oral

No dosage adjustment necessary in patients with mild (Child-Pugh class A) hepatic impairment.¹ Use not recommended in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Oral

Reduce dosage to 30 mg once daily in patients with a Cl_cr of 15–50 mL/minute.^{1 24} Not recommended in patients with a Cl_cr <15 mL/minute.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.¹

Body Weight

Patients with atrial fibrillation: Manufacturer makes no dosage adjustment recommendations based on weight.¹

Patients with VTE: Reduce dosage to 30 mg once daily in patients weighing ≤60 kg.¹

Cautions for Edoxaban

Contraindications

• Active pathologic bleeding.¹

Warnings/Precautions

Warnings

Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Clcr >95 mL/minute

Strong relationship between plasma concentrations of edoxaban and effectiveness observed.¹ Because renal function can affect plasma concentrations, patients with good renal function may have reduced response to edoxaban due to lower plasma concentrations.¹ (See Boxed Warning.)

In principal efficacy trial in patients with nonvalvular atrial fibrillation (ENGAGE AF-TIMI 48), ischemic stroke occurred more frequently in patients with Cl_cr >95 mL/minute who received edoxaban 60 mg daily versus warfarin.¹

Do not use in nonvalvular atrial fibrillation patients with Cl_cr >95 mL/minute; use alternative anticoagulant agents in such patients.¹

Risk of Thrombosis Following Premature Discontinuance of Therapy

Premature discontinuance in the absence of adequate alternative anticoagulation may increase risk of thromboembolic events.^{1 5 11} (See Boxed Warning.)

When transitioning patients from one anticoagulant therapy to another, ensure continuous anticoagulation while minimizing risk of bleeding.⁸³ Particular caution advised when switching patients from a factor Xa inhibitor to warfarin therapy because of the slow onset of action of warfarin.⁸³ (See Dosage under Dosage and Administration.)

If discontinuance required for reasons other than pathologic bleeding or completion of a course of therapy, consider coverage with an alternative anticoagulant.¹ (See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration.)

Advise patients regarding importance of adhering to therapeutic regimen and on steps to take if doses are missed.¹ (See Advice to Patients.)

Spinal/Epidural Hematoma

Epidural or spinal hematoma reported with concurrent use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.¹ Such hematomas have resulted in neurologic injury, including long-term or permanent paralysis.¹ (See Boxed Warning.)

Delay removal of indwelling epidural or intrathecal catheters for ≥12 hours after a dose of edoxaban and wait ≥2 hours after catheter removal before administering next dose.¹

Frequently monitor for signs of neurologic impairment (e.g., numbness or weakness in lower limbs, bowel or bladder dysfunction).¹ If neurologic compromise noted, diagnose and treat immediately.¹ Carefully consider potential benefits versus risks of neuraxial intervention in patients who are currently receiving or will receive anticoagulants.¹

Other Warnings and Precautions

Bleeding

Risk of serious, potentially fatal, bleeding.^{1 2 16 83} Promptly evaluate if any manifestations of blood loss occur during therapy.¹

Discontinue if active pathological bleeding occurs.¹ (See Contraindications under Cautions.)

Risk of bleeding may be increased in patients with renal impairment, low body weight (e.g., ≤60 kg), or those receiving concomitant drugs that affect hemostasis (e.g., aspirin or other antiplatelet drugs, other anticoagulants, chronic use of NSAIAs, SSRIs, SNRIs).^{1 10 32 33} (See Interactions.)

Temporarily interrupt therapy prior to surgery or other invasive procedure to minimize risk of bleeding.¹ (See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration.)

No specific reversal agent for edoxaban; anticoagulant effects expected to persist for approximately 24 hours after the drug is discontinued.^{1 35} Although not FDA-labeled for reversal of edoxaban, coagulation factor Xa (recombinant) inactivated-zhzo (also referred to as andexanet alfa) has been used in a high dose (800 mg administered IV at a rate of 30 mg/minute followed by a continuous infusion of 8 mg/minute for up to 120 minutes) in patients with life-threatening bleeding or need for emergent invasive procedures.⁴⁴ Use of prothrombin complex concentrates (PCCs), activated prothrombin complex concentrate (aPCC), or recombinant factor VIIa may be considered for reversal; however clinical outcomes studies have not been conducted.^{1 9 34} Protamine sulfate, vitamin K, and tranexamic acid are not expected to be effective.¹ In addition, the drug is not appreciably removed by dialysis.^{1 35}

Patients with Prosthetic Heart Valves or Mitral Stenosis

Efficacy and safety not established; use not recommended.¹

Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

Risk of recurrent thrombotic events in patients with triple-positive antiphospholipid syndrome (APS) (i.e., positive for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies); use not recommended in these patients.¹

Specific Populations

Pregnancy

No adequate or well-controlled studies in pregnant women; use not recommended.^{1 38 1007} Not teratogenic, but fetotoxic effects observed in animals.¹

Use during labor and delivery in women receiving neuraxial anesthesia may result in epidural or spinal hematomas.¹ (See Spinal/Epidural Hematoma under Cautions.)

Consider use of a shorter-acting anticoagulant as delivery approaches.¹ Monitor for increased bleeding in the fetus or neonate.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Discontinue nursing or the drug.¹

Females of Reproductive Potential

Assess for increased risk of bleeding potentially requiring surgical intervention in females of reproductive potential and those with abnormal uterine bleeding.¹ (See Advice to Patients.)

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

No substantial differences in efficacy and safety relative to younger adults.¹

Hepatic Impairment

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment does not appear to affect pharmacokinetics or pharmacodynamics of edoxaban.¹ No clinical experience in patients with severe hepatic impairment (Child-Pugh class C).¹ (See Hepatic Impairment under Dosage and Administration.)

Do not use in patients with moderate or severe hepatic impairment because of possibility of intrinsic coagulation abnormalities.¹

Renal Impairment

Eliminated renally.¹ Clearance is decreased, and consequently, plasma concentrations are increased in patients with renal impairment.^{1 24}

Evaluate renal function prior to initiating therapy and periodically thereafter when clinically indicated.^{1 80} Calculate estimated Cl_cr using the Cockcroft-Gault method.^{1 83} Recommendations regarding use and dosage of edoxaban are based on Cl_cr.¹ (See Dosage and Administration.)

As renal function improves, plasma edoxaban concentrations may decrease and potentially decrease efficacy of the drug.¹ (See Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Cl_cr >95 mL/minute under Cautions.)

Hemodialysis does not substantially contribute to clearance of edoxaban.^{1 23}

Common Adverse Effects

Patients with nonvalvular atrial fibrillation: Bleeding, anemia.¹

Patients with acute VTE: Bleeding, rash, abnormal liver function tests, anemia.¹

Drug Interactions

Minimally metabolized by CYP3A4.¹ Does not inhibit CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, or 3A4; does not induce CYP1A2 or CYP3A4.¹

Substrate of P-glycoprotein (P-gp),^{1 22 30 31} but does not appear to be a substrate of other major uptake transporters such as organic anion transporters OAT1 and OAT3, organic cation transporter OCT2, or organic anion transporting polypeptide OATP1B1.²² Does not induce P-gp nor inhibit P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3.^{1 22}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP3A4: Pharmacokinetic interactions unlikely.¹

Substrates of major CYP isoenzymes (e.g., CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, 3A4): Pharmacokinetic interactions unlikely.¹

Drugs Affecting Efflux Transport Systems

Inhibitors of P-gp: Potential pharmacokinetic interaction (increased edoxaban exposure); potential for clinically important effects depends on degree of P-gp inhibition.^{1 22 24 30 31} Reduce edoxaban dosage in patients with acute VTE receiving certain P-gp inhibitors based on clinical studies.¹ (See Dosage under Dosage and Administration.) In patients with nonvalvular atrial fibrillation, no dosage adjustment necessary for concomitant P-gp inhibitor use.¹

Inducers of P-gp: Potential pharmacokinetic interaction (decreased edoxaban exposure).¹

Drugs Affecting Hemostasis

Potential increased risk of hemorrhage.^{1 8} Promptly evaluate any manifestations of bleeding.¹

Specific Drugs

Edoxaban Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations occur within 1–3 hours.^{1 26 27 28 31} Absolute bioavailability approximately 62%.^{1 24}

Bioavailability is unchanged when 60-mg tablets are crushed and mixed in either applesauce or suspended in water and given orally or through a nasogastric tube.¹

Food

Food delays absorption, but does not substantially affect systemic exposure.^{1 27}

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

Approximately 55%.^{1 9 28}

Elimination

Metabolism

Undergoes minimal metabolism by hydrolysis, conjugation, and CYP3A4 oxidation.¹ Main metabolite is formed by hydrolysis.¹

Elimination Route

Approximately 50% excreted unchanged in urine; remainder is metabolized and eliminated through biliary and intestinal routes.^{1 22}

No substantial accumulation with multiple dosing.¹

Not appreciably removed by dialysis.¹

Half-life

Approximately 10–14 hours.¹

Special Populations

Systemic exposure increased by 32, 74, and 72% in patients with Cl_cr of 51–79 mL/minute, 30–50 mL/minute, and <30 mL/minute, respectively, compared with those with normal renal function (Cl_cr ≥80 mL/minute).¹ Systemic exposure increased by 93% in patients undergoing peritoneal dialysis.¹

Systemic exposure also increased in patients with low body weight (e.g., ≤60 kg), but not influenced by age, gender, or race/ethnicity.¹

Stability

Storage

Oral

Tablet

20–25°C (may be exposed to 15–30°C).¹

Actions

• Binds directly and selectively to factor Xa; inhibits both free and prothrombinase-bound factor Xa and thrombin-induced platelet aggregation.^{1 3 8 23}

• Inhibition of coagulation factor Xa prevents prothrombin to thrombin conversion and subsequent thrombus formation.^{1 3 8}

• Does not require a cofactor (antithrombin III) to exert anticoagulant activity.¹

• Inhibits factor Xa activity and prolongs PT, aPTT, and INR in a dose-dependent manner.^{1 23 28}

Advice to Patients

• Importance of taking the drug exactly as prescribed and not discontinuing therapy without first consulting clinician.¹

• Importance of advising patients who cannot swallow edoxaban tablets whole to crush the tablets and combine with 2–3 ounces of water or applesauce and ingest immediately.¹

• Importance of advising patients with a gastric tube to crush edoxaban tablets and mix with 2–3 ounces of water and administer immediately via gastric tube.¹

• Importance of informing patients that they may bruise and/or bleed more easily and that a longer than normal time may be required to stop bleeding when taking edoxaban.¹ Importance of patient informing clinicians about any unusual bleeding or bruising during therapy.¹

• Importance of advising patients that if a dose is missed, it should be taken as soon as possible on the same day; the regular dosing schedule should be resumed the following day.¹ A dose should not be doubled to make up for a missed dose.¹

• Importance of advising patients undergoing neuraxial anesthesia or spinal puncture procedures to immediately report manifestations of spinal or epidural hematoma (e.g., tingling or numbness in lower limbs, muscle weakness, back pain, stool or urine incontinence) to clinician.¹

• Importance of patients informing clinicians that they are receiving edoxaban therapy before scheduling any medical, surgical, or invasive procedure, including dental procedures.¹

• Importance of women immediately informing clinicians if they are or plan to become pregnant.¹ Importance of informing patients not to breast-feed while taking edoxaban.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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