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Edoxaban

Pronunciation

(e DOX a ban)

Index Terms

  • Edoxaban Tosylate

Dosage Forms

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

Tablet, Oral:

Savaysa: 15 mg, 30 mg, 60 mg

Brand Names: U.S.

  • Savaysa

Pharmacologic Category

  • Anticoagulant
  • Anticoagulant, Factor Xa Inhibitor
  • Direct Oral Anticoagulant (DOAC)

Pharmacology

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

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%

Special Populations: Renal Function Impairment

Systemic exposure increased by 32% (CrCl >50 to <80 mL/minute), 74% (CrCl 30 to 50 mL/minute), and 93% (CrCl <30 mL/minute) compared with patients with CrCl ≥80 mL/minute.

Special Populations Note

Body weight: Total exposure in patients with low body weight (55 kg) was increased by 13% compared with patients with high body weight (84 kg).

Use: Labeled Indications

Deep vein thrombosis and pulmonary embolism: Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.

Nonvalvular atrial fibrillation: To reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF)

Limitations of use: Edoxaban should not be used in NVAF patients with CrCl >95 mL/minute because of an increased risk of ischemic stroke compared to warfarin

Contraindications

Active pathological bleeding

Dosing: Adult

Note: Prior to initiation of edoxaban, assess creatinine clearance (CrCl) using the Cockcroft-Gault equation. For patients with nonvalvular atrial fibrillation, do not use edoxaban if CrCl is >95 mL/minute. Dosage reduction necessary in all patients with CrCl 15 to 50 mL/minute.

Deep vein thrombosis and pulmonary embolism: Oral: 60 mg once daily after 5 to 10 days of initial therapy with a parenteral anticoagulant.

Patient weight ≤60 kg: 30 mg once daily

Concomitant therapy with specific P-gp inhibitors (ie, verapamil, quinidine; the short-term use of azithromycin, clarithromycin, erythromycin, oral itraconazole, oral ketoconazole): 30 mg once daily

Nonvalvular atrial fibrillation (NVAF) (to prevent stroke and systemic embolism): Oral: 60 mg once daily

Conversion:

Conversion from continuous infusion unfractionated heparin: Discontinue heparin infusion and initiate edoxaban 4 hours later.

Conversion from low molecular weight heparin (LMWH): Discontinue LMWH and initiate edoxaban at the time of the next scheduled administration of LMWH.

Conversion from oral anticoagulants (other than warfarin and vitamin K antagonists): Discontinue current oral anticoagulant and initiate edoxaban at the time of the next scheduled dose of the other oral anticoagulant.

Conversion from warfarin or other vitamin K antagonists: Discontinue warfarin and initiate edoxaban as soon as INR falls to ≤2.5.

Conversion to a non-vitamin-K dependent oral anticoagulant: Discontinue edoxaban and initiate the other oral anticoagulant at the time the next dose of edoxaban would have been taken.

Conversion to a parenteral anticoagulant: Discontinue edoxaban and initiate the parenteral anticoagulant at the time the next dose of edoxaban would have been taken.

Conversion 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.

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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Manufacturer's labeling: Adults: Note: Calculate CrCl using the Cockcroft-Gault equation.

Deep vein thrombosis and pulmonary embolism:

CrCl ≥51 mL/minute: No dosage adjustment recommended.

CrCl 15 to 50 mL/minute: 30 mg once daily

CrCl <15 mL/minute: Use is not recommended.

Nonvalvular atrial fibrillation:

CrCl >95 mL/minute: Use is not recommended.

CrCl 51 to 95 mL/minute: No dosage adjustment recommended.

CrCl 15 to 50 mL/minute: 30 mg once daily

CrCl <15 mL/minute: Use is not recommended.

Hemodialysis: Total edoxaban exposure reduced by <7% during a 4-hour dialysis session.

Alternate recommendations: Geriatric patients ≥65 years (Beers Criteria [AGS 2015]):

CrCl 30 to 50 mL/minute: Dose should be reduced (specific dosage adjustment not provided although the manufacturer's labeling recommends 30 mg once daily for adults).

CrCl <30 mL/minute: Avoid use due to increased risk of bleeding.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B and C): Use is not recommended.

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

Administer without regard to food. If dose is missed, the dose should be taken as soon as possible on the same day. Dosing should resume the next day according to the normal dosing schedule. Dose should not be doubled.

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

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

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

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

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. Consider therapy modification

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

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

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

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

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

NSAID (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

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

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). 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 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

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

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. 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

Adverse Reactions

>10%:

Hematologic and oncologic: Hemorrhage (22%)

1% to 10%:

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

Gastrointestinal: Gastrointestinal hemorrhage (4%), lower GI bleeding (3%)

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

Hematologic and oncologic: Major hemorrhage, non-life-threatening (7% to 9%; non-critical organ: 1%; critical organ: <1%), major hemorrhage (1%), oral hemorrhage (≤3%), anemia (2%), decreased hemoglobin (≥ 2 g/dL: 1%), puncture site bleeding (1%)

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

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

<1% (Limited to important or life-threatening): Hemorrhagic stroke, interstitial pulmonary disease (confounded by concomitant amiodarone therapy and infectious pneumonia), intracranial hemorrhage (includes epidural hematoma, nonhemorrhagic stroke with major hemorrhagic conversion, primary hemorrhagic stroke, subarachnoid hemorrhage, subdural hematoma)

ALERT: U.S. Boxed Warning

Reduced efficacy in nonvalvular atrial fibrillation patients with CrCl >95 mL/minute:

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 edoxaban increases the risk of ischemic events:

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.

Spinal/Epidural hematomas:

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.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: May increase the risk of bleeding; serious, potentially fatal bleeding may occur. Concomitant use of drugs that affect hemostasis (eg, aspirin, other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, chronic NSAID use) may increase the risk of bleeding. Monitor for signs and symptoms of bleeding. Discontinue therapy with active pathological hemorrhage and promptly evaluate for bleeding source. No specific antidote exists for edoxaban reversal; hemodialysis does not have a substantial impact on edoxaban clearance. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant effect of edoxaban.

• Thromboembolic events: [U.S. 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.

Disease-related concerns:

• 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: [U.S. 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).

• Valvular disease: Safety and efficacy have not been established in patients with mechanical heart valves or moderate to severe mitral stenosis; use is not recommended. Nonvalvular atrial fibrillation is defined as atrial fibrillation that occurs in the absence of rheumatic mitral valve disease, mitral valve repair, or prosthetic heart valve (AHA/ACC/HRS [January, 2014]).

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: [U.S. 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 benefit versus risk prior to neuraxial intervention in patients who are anticoagulated or scheduled to be anticoagulated for thromboprophylaxis. Monitor frequently for signs and symptoms of neurologic impairment (eg, numbness/weakness of legs, bowel/bladder dysfunction). If neurologic impairment is noted, prompt 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.

• Surgery and invasive procedures: Discontinue edoxaban at least 24 hours prior to elective surgery or invasive procedures. If surgery cannot be delayed, the risk of bleeding should be weighed against the urgency of intervention. Reinitiate edoxaban when adequate hemostasis has been achieved unless oral therapy cannot be administered, then consider administration of a parenteral anticoagulant.

Monitoring Parameters

Routine monitoring of coagulation tests not required; however, edoxaban prolongs the PT and aPTT. Monitor for signs and symptoms of bleeding including neurological impairment.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Ten pregnancies were reported in a study using edoxaban for the treatment of DVT or PE. Estimated exposure occurred during the first trimester with duration of exposure ~6 weeks; outcomes included six live births (two preterm), one first-trimester spontaneous abortion, and three elective terminations of pregnancy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of bleeding (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 bleeding that is very bad or that you cannot stop), signs of stroke (strength differences from one side to another, difficulty speaking or thinking, change in balance, or blurred vision), pale skin, severe headache, or loss of strength or energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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