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Edoxaban Tosylate

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
Brands: Savaysa

Warning(s)

  • Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Clcr >95 mL/minute
  • Do not use in patients with Clcr>95 mL/minute; increased rate of ischemic stroke demonstrated in such patients.1 (See Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Clcr >95 mL/minute under Cautions.)

  • Use an alternative anticoagulant for stroke prevention in these patients.1

  • Risk of Thrombosis Following Premature Discontinuance of Anticoagulation
  • Premature discontinuance of any oral anticoagulant, including edoxaban, increases risk of thrombotic events.1

  • If edoxaban discontinued for reasons other than pathologic bleeding or completion of a course of therapy, consider coverage with an alternative anticoagulant.1 (See Risk of Thrombosis Following Premature Discontinuance of Therapy under Cautions.)

  • Spinal/Epidural Hematoma
  • Risk of epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, in anticoagulated patients also receiving neuraxial (spinal/epidural) anesthesia or spinal puncture.1

  • Risk increased by use of indwelling epidural catheters or by concomitant drugs affecting hemostasis (e.g., NSAIAs, platelet inhibitors, other anticoagulants).1

  • Risk also increased by history of traumatic or repeated epidural or spinal puncture, spinal deformity, or spinal surgery.1

  • Monitor frequently for manifestations of neurologic impairment and treat urgently if neurologic compromise noted.1

  • Consider potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for anticoagulant therapy.1 (See Spinal/Epidural Hematoma under Cautions.)

Introduction

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

Uses for Edoxaban Tosylate

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 Clcr >95 mL/minute.1 9 (See Boxed Warning.)

Noninferior to well-controlled (mean time in therapeutic INR range: 65%) warfarin therapy in preventing stroke and systemic embolism, and associated with lower rates of bleeding and cardiovascular death.1 2 7

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

Choice of antithrombotic therapy based on patient's risk for stroke and bleeding; in general, oral anticoagulant therapy recommended in patients who have a moderate to high risk for stroke and acceptably low risk of bleeding; consider aspirin or no antithrombotic therapy in patients at low risk.80 81 82 1007 Patients at increased risk of stroke generally include those with prior ischemic stroke or TIA, advanced age (e.g., ≥75 years), history of hypertension, diabetes mellitus, or CHF.80 81 82 1007 In addition, female sex considered an important risk factor for stroke in patients with atrial fibrillation, particularly in patients ≥75 years of age.1017

Although warfarin traditionally has been used for oral anticoagulation in patients with atrial fibrillation at increased risk of stroke, non-vitamin K antagonist oral anticoagulants such as edoxaban may be useful alternatives in selected patients at moderate to high risk of stroke who are unable to comply with warfarin monitoring requirements or in whom a consistent therapeutic response to warfarin cannot be achieved; warfarin may still be preferred in patients who are optimally managed and have well-controlled INRs.6 8 70 73 80 84 86

Relative efficacy and safety of the non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran, edoxaban, rivaroxaban) remain to be fully elucidated.9 15 84 85

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

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 DVT and/or PE

Treatment of 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 venous thromboembolism; associated with substantially reduced rates of clinically important bleeding.1 16

Edoxaban Tosylate Dosage and Administration

General

  • Prior to initiating therapy, assess renal function.1 Calculate Clcr using the Cockcroft-Gault method; dosage recommendations are based on estimated Clcr.1

  • 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

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 Clcr of 51–95 mL/minute: 60 mg once daily.1

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

Patients with Clcr >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 Clcr 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 a vitamin K antagonist (e.g., warfarin) to edoxaban: Discontinue vitamin K antagonist 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 an 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 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

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 Clcr of 15–50 mL/minute.1 24 Not recommended in patients with a Clcr <15 mL/minute.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.1

Body Weight

Manufacturer makes no dosage adjustment recommendations based on weight in patients with nonvalvular atrial fibrillation.1

In patients with venous thromboembolism, reduce dosage to 30 mg once daily in patients ≤60 kg.1

Cautions for Edoxaban Tosylate

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 plasma concentrations are affected by renal function, patients with good renal function may have reduced response due to lower plasma concentrations.1

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

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

Risk of Thrombosis Following Premature Discontinuance of Therapy

Premature discontinuance of any oral anticoagulant, including edoxaban, increases risk of thromboembolic events in the absence of adequate alternative anticoagulation.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 discontinuing edoxaban 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.) However, should not readily discontinue anticoagulation for commonly occurring minor or “nuisance” bleeding.83 (See Risk of Thrombosis Following Premature Discontinuance of Therapy under Cautions.)

Risk of bleeding may be increased in patients with renal impairment, low body weight (e.g., ≤60 kg), or in those receiving concomitant drugs that affect hemostasis (e.g., aspirin or other antiplatelet drugs, other anticoagulants, chronic use of NSAIAs).1 10 32 33 (See Interactions.) Limited data suggest increased risk of bleeding in patients receiving 60-mg daily dosage in 2 divided doses (currently not an FDA-labeled dosage) versus once daily.14

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 Preliminary findings from a study in healthy individuals suggest that 4-factor prothrombin complex concentrate (PCC) may be an effective reversal agent for edoxaban.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

Specific Populations

Pregnancy

Category C.1

No adequate or well-controlled studies in pregnant women.1 Not teratogenic, but fetotoxic effects observed in animals.1 Use during pregnancy only if potential benefits justify potential risks to the fetus.1

Lactation

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

Pediatric Use

Safety and efficacy not established in pediatric patients.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 with the drug 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 in such patients.1

Renal Impairment

Edoxaban is 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 Clcr using the Cockcroft-Gault method.1 83 Recommendations regarding use and dosage of edoxaban are based on Clcr.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 Clcr >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 DVT and/or PE: Bleeding, rash, abnormal liver function tests, anemia.1

Interactions for Edoxaban Tosylate

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 the efflux transporter 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 the degree of P-gp inhibition.1 22 24 30 31 Reduce edoxaban dosage in patients with acute venous thromboembolism who are 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 since patients who received such dosage adjustment in clinical studies had lower plasma edoxaban concentrations than those who received the full dosage of the drug.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

Drug

Interaction

Comments

Antiarrhythmic agents, class III (amiodarone, dronedarone)

Amiodarone: Increased peak plasma concentrations and systemic exposure of edoxaban by 66 and 40%, respectively

Dronedarone: Increased peak plasma concentrations and systemic exposure of edoxaban by 46 and 85%, respectively

Anticoagulants, other

Potential increased risk of hemorrhage1

Enoxaparin: No substantial changes in pharmacokinetics of either drug29

Long-term concomitant anticoagulants not recommended; short-term concomitant therapy may be necessary in patients switching anticoagulants1

Promptly evaluate if bleeding manifestations occur1

Antifungals, azole (oral itraconazole, oral ketoconazole)

Potential for increased peak plasma concentrations and systemic exposure of edoxaban1

Oral itraconazole or ketoconazole: Reduce edoxaban dosage to 30 mg daily for DVT or PE1

Antiplatelet agents (e.g., aspirin)

Potential increased risk of hemorrhage1

Aspirin (100 or 325 mg): Increased bleeding time; higher aspirin dose increased peak plasma concentrations and systemic exposure of edoxaban, but pharmacodynamic indices not affected1 33

Carefully monitor for bleeding in patients requiring long-term concomitant aspirin1

Promptly evaluate if bleeding manifestations occur1

Atorvastatin

14.2% decrease in peak plasma edoxaban concentration; 1.7% increase in edoxaban systemic exposure1 31

Cyclosporine

Potential for substantially increased peak plasma concentrations and systemic exposure of edoxaban1

Digoxin

Peak plasma concentrations and systemic exposure of edoxaban not substantially altered1 30 31

Peak plasma concentrations of digoxin increased by 28%, but remained within established therapeutic range1 30

Clinically important changes in pharmacodynamics of either drug not observed30

Esomeprazole

Peak plasma concentrations of edoxaban decreased, but systemic exposure not substantially affected1

Fibrinolytics

Potential increased risk of hemorrhage1

Promptly evaluate if bleeding manifestations occur1

Macrolides (azithromycin, clarithromycin, erythromycin)

Potential for substantially increased peak plasma concentrations and systemic exposure of edoxaban1 31

Reduce edoxaban dosage to 30 mg daily when treating DVT or PE1

NSAIAs (e.g., naproxen)

Potential increased risk of hemorrhage1 32

Naproxen: Increased bleeding time;1 33 pharmacokinetics and pharmacodynamics of edoxaban not altered33

Carefully monitor for bleeding in patients requiring long-term concomitant treatment with an NSAIA1

Promptly evaluate if bleeding occurs1

Quinidine

Edoxaban peak plasma concentration and systemic exposure increased by approximately 85 and 77%, respectively; quinidine pharmacokinetics not affected1 31

Reduce edoxaban dosage to 30 mg daily when treating DVT or PE1

Rifampin

Potential for substantially reduced systemic exposure of edoxaban1

Avoid concomitant use1

Verapamil

Edoxaban peak plasma concentration and systemic exposure increased by approximately 53%; pharmacokinetics of verapamil slightly altered1 31

Reduce edoxaban dosage to 30 mg daily when treating DVT or PE1

Edoxaban Tosylate 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

Not known whether bioavailability is altered when edoxaban crushed and/or mixed with food, liquids, or administered through feeding tubes.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 Clcr of 51–79 mL/minute, 30–50 mL/minute, and <30 mL/minute, respectively, compared with those with normal renal function (Clcr ≥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 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 or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements.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.

Edoxaban Tosylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

15 mg (of edoxaban)

Savaysa

Daiichi Sankyo

30 mg (of edoxaban)

Savaysa

Daiichi Sankyo

60 mg (of edoxaban)

Savaysa

Daiichi Sankyo

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

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