Edoxaban (Savaysa)

Dosing

The presence of chronic kidney disease is an independent risk factor for increased bleeding events, including hemorrhagic stroke. Please carefully consider the risks and benefits of any oral anticoagulant prior to initiating therapy.

CrCl	FDA Recommended Dose for Treatment of DVT/PE	FDA Recommended dose for Stroke Prevention in AF	UWMedicine Restrictions	Change in Exposure (AUC and Cmax)	T 1/2
80-95 ml/min	60mg daily	60mg daily	Non-Formulary	—	10-14 hours
50-79 ml/min				35% increase	10-14 hours
30-49 ml/min	30mg daily	30 mg daily	Non-Formulary RESTRICTED Consider alternative therapy	74% increase	10-14 hours
15-29 ml/min				72% increase	Not Reported
< 15 ml/min	Not Recommended	Not Recommended		93% increase	Not Reported

 

Drug Interactions

Drug Class	Examples (based on human in vivo data1)	Known or Probable Effect	US PI Recommendation	Suggested Management Guidelines2
P-gp Inhibitors	alfentanil, amiodarone*, azithromycin, carvedilol, clarithromycin, cobicistat, conivaptan, cyclosporine*, diltiazem, dronedarone*, duloxetine, erythromycin*, fenofibrate, grapefruit, all HIV protease inhibitors, itraconazole, ivacaftor, ketoconazole*, lapatinib, lomitapide, mefloquine, nicardipine, nifedipine, posaconazole, progesterone, propafenone, quinidine*, quinine, ranolazine, sunitinib, tacrolimus, tamoxifen, telithromycin, ticagrelor, tolvaptan, vemuranfenib, verapamil* *cited as examples in US PI, with pharmacokinetic data cited	significant increase in edoxaban concentration (AUC and Cmax)	AF: Do not reduce dose of edoxaban VTE Treatment: reduce dose to 30mg	AVOID USE
P-gp inducers	carbamazepine, dexamethasone, pentobarbital, phenobarbital, rifampin*, St. John’s wort, tipranavir *cited as example in US PI, with pharmacokinetic data cited	significant reduction in edoxaban concentration (AUC and Cmax)	Avoid use with rifampin	AVOID USE

(1) based on human in vivo data, in Cytochrome P450 Enzymes and Transporters Table, from Hansten PD and Horn JR.  The Top 100 Drug Interactions: A Guide to Patient Management, 2014 ed, H&H Publications, Freeland WA

(2) based on probable effects of edoxaban, taking into consideration known characteristics of the precipitant drug according to human in vivo data

 

Indications

An oral direct Xa inhibitor approved for:

1) Stroke prevention in non-valvular atrial fibrillation, using the following dosing:

• 60 mg once daily (if CrCl is > 50-95 ml/min)
• 30 mg once daily (if CrCl is 15-50 ml/min)
• NOTE:  Contraindicated if CrCl is > 95ml/min, due to increased risk of stroke

2) Treatment of DVT/PE

• 60 mg once daily after initial 5-10 days of parenteral anticoagulant therapy (if CrCl is > 50ml/min)
• 30 mg once daily after initial 5-10 days of parenteral anticoagulant therapy if
• CrCl is 15-50 ml/min
• Patient’s weight is < 60kg
• Taking certain concomitant P-gp inhibitors

 

Converting to/from Edoxaban

Conversion	UW Medicine Recommendation
From warfarin to edoxaban	Stop warfarin and start edoxaban with INR < lower limit of therapeutic range (Manufacturer recommends when INR < 2.5)
From edoxaban to warfarin NOTE: edoxaban is not intended to be used as a short term “bridge” to warfarin. These recommendations refer to transitioning patients who are taking edoxaban on a long-term basis and are switching to warfarin instead	Start warfarin and stop edoxaban 3 days later Manufacturer recommends a) for patients taking 60mg, reduce edoxaban to 30mg and start warfarin concomitantly. Stop edoxaban when INR > 2 b) for patients taking 30mg, reduce edoxaban to 15mg and start warfarin concomitantly. Stop edoxaban when INR > 2 OR if continuous , uninterrupted anticoagulation is necessary a) stop edoxaban b) begin both a parenteral anticoagulant (LMWH/fondaparinux or UFH) and warfarin at the same time that the next dose of edoxaban would have been given) stop the parenteral anticoagulant when the INR is > 2
From LMWH/Fondaparinux to edoxaban	Stop LMWH/Fondaparinux and start edoxaban at the same time that the next dose of LMWH/fondaparinux would have been given
From IV heparin to edoxaban	Stop IV heparin and start edoxaban simultaneously (manufacturer recommends starting edoxaban 4 hrs after stopping IV heparin)
From edoxaban to parenteral anticoagulant	Stop edoxaban and start the parenteral anticoagulant at the same time that the next dose of edoxaban would have been given
From Edoxaban to apixaban, dabigatran or rivaroxaban	Stop edoxaban and start the other anticoagulant at the same time that the next scheduled dose of edoxaban would have been given

 

Peri-Procedural Management of Edoxaban

CrCl	T 1/2	Time of last dose of edoxaban prior to procedure (peri-procedural bridging is generally not required)
		Standard Risk of Bleeding	High Risk of Bleeding (major surgery, spinal puncture or placement of spinal/epidural catheter, and other situations in which complete hemostasis is required) ASRA 4th edition 2018: hold 72 hours for all patients prior to neuraxial procedures, without regard for influence of renal function on half-life and clearance
30-95 ml/min	10-14 hrs	at least 24 hours	at least 48 hours
15-29 ml/min	17 hrs	at least 48 hours	at least 72 hours
< 15 ml/min	unknown	edoxaban assay is currently unavailable at UWMedicine to determine absence of drug effect

 

Reversal and Management of Bleeding

There is NO REVERSAL AGENT OR ANTIDOTE for edoxaban. Very limited data, primarily non-human, are available to guide the management of bleeding.

Mild Bleeding

• Delay the next dose or discontinue therapy

Moderate to Severe Bleeding

• Symptomatic treatment
• Mechanical compression
• Surgical intervention
• Fluid replacement and hemodynamic support
• Blood product transfusion
• Oral charcoal may block the continued absorption from the gut even if charcoal is given 6 hours after ingestion of edoxaban.
• NOTE: Not dialyzable

Life Threatening Bleeding

• Measures above
• Last resort: PCC – Kcentra

 

Management Plan

Therapeutic Monitoring

Edoxaban is not intended to be monitored using routine coagulation testing. Its fixed dosing is not intended to be adjusted on the basis of any coagulation laboratory parameter.

As a result of FXa inhibition, edoxaban prolongs clotting tests such as prothrombin time (PT)/ INR and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose, however, are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of edoxaban.

 

Relevant Clinical Trials

Stroke Prevention in Atrial Fibrillation

• Giugliano RP, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369(22):2093-2104. (ENGAGE AF-TIMI 48)

Treatment of DVT/PE

• Hokusai-VTE Investigators, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369(15):1406-1415. (Hokusai-VTE)