2 Savaysa™ - Edoxaban Clinical Application Indications:To reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation.Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.Place in therapy:Edoxban is the third factor Xa inhibitor approved for NVAFNoninferior to warfarin, with significant lower risk of bleedingImpaired renal function
3 Savaysa™ - Edoxaban Clinical Application Contraindications:Active pathological bleedingBlack Box Warnings:Reduced efficacy in nonvalvular atrial fibrillation patients with CrCl >95 mL/minute – Edoxaban should not be used in patients with CrCL >95 mL/minute.Premature discontinuation of edoxaban increases the risk of ischemic eventsSpinal/Epidural hematomas – Epidural or spinal hematomas may occur in patients treated with edoxaban who are receiving neuraxial anesthesia or undergoing spinal puncture.
4 Savaysa™ - Edoxaban Clinical Application Warnings / Precautions:May increase the risk of bleeding; serious, potentially fatal bleeding may occur.Not recommended for use in patients with mechanical heart valves or moderate to severe mitral stenosis; safety and efficacy have not been established.Patients with DVT and/or PE and body weight ≤60 kg, reduce dose to 30mgDiscontinue edoxaban at least 24 hours prior to elective surgery or invasive procedures.
5 Savaysa™ - Edoxaban Clinical Application Pregnancy:Category CLactation:Excretion in breast milk unknown/not recommended.Due to the potential for serious adverse reactions in the nursing infant, the decision to discontinue nursing or to discontinue the drug should be made taking into account the importance of treatment to the mother.
6 Savaysa™ - Edoxaban Drug Facts 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.
7 Savaysa™ - Edoxaban Drug Facts Pharmacokinetics:ABioavailability: 62%DVd: 107 L with ~55% protein bindingMNot significantly metabolizedEUrine (primarily unchanged); renal clearance: ~50% of total clearance.T1/2: 10 to 14 hours
8 Savaysa™ - Edoxaban Drug Interactions Drug Interactions – Object Drugs:Anticoagulants, Antiplatelets, and Thrombolytics – Co-administration may increase the risk of bleeding (anticoagulants, aspirin, other platelet aggregation inhibitors, and/or NSAIDs)
9 Savaysa™ - Edoxaban Drug Interactions Drug Interactions – Precipitant Drugs:P-glycoprotein Inducers: ↓concentration of EdoxabanRifampin P-glycoprotein Inhibitors: concentration of EdoxabanVerapamil, quinidine or the short-term use of azithromycin, clarithromycin, erythromycin, oral itraconazole or oral ketoconazole.NVAF: No dosage adjustmentDVT/PE: May need to dose reduce Edoxaban
11 Savaysa™ - Edoxaban Monitoring Parameters Efficacy Monitoring:Routine monitoring of coagulation tests not requiredToxicity Monitoring:Monitor for signs and symptoms of bleeding including neurological impairment.
12 Savaysa™ - Edoxaban Prescription Information Dosing:DVT/PE: Oral: 60 mg once daily after 5 to 10 days of initial therapy with a parenteral anticoagulant.Patient weight ≤60 kg: 30 mg once dailyConcomitant therapy with specific P-gp inhibitors: 30 mg once dailyNonvalvular atrial fibrillation: Oral: 60 mg once dailyCost: – Uptodate (03/01/2015)Brand – GenericDose$ 30 daySavaysa – edoxaban15 mg, 30mg, 60mg tablets (30)$333
13 Savaysa™ - Edoxaban Literature Review Edoxaban versus Warfarin in Patients with Atrial FibrillationSavaysa™ - Edoxaban Literature ReviewGiugliano RP, et al. NEJM 2013; 369:
14 Savaysa™ - Edoxaban Literature Review Phase 3, randomized, double-blind, double- dummy, non-inferiorityPrimary Endpoint: time to the first adjudicated stroke (ischemic or hemorrhagic) or systemic embolic eventPrincipal safety end point – adjudicated major bleedingSecondary composite end points: stroke, systemic embolic event, or death from cardiovascular causes (including bleeding)Treatment: 1:1:1 ratio, warfarin, high-dose (60mg) or low-dose (30mg) edoxabanGiugliano RP, et al. NEJM 2013; 369:
15 Savaysa™ - Edoxaban Literature Review Inclusion CriteriaAge ≥21 years oldHistory of AF of any duration within the prior 12 monthsCHADS2 index score ≥2Exclusion CriteriaAF due to a reversible disorderSevere renal dysfunction (CrCl < 30 mL/min)Condition associated with a high risk of bleedingModerate or severe mitral stenosisGiugliano RP, et al. NEJM 2013; 369:
16 Savaysa™ - Edoxaban Literature Review Patient Characteristic (n=21,105)Warfarin (N=7036)High-Dose Edoxaban (N=7035)Low-Dose Edoxaban (N=7034)Age (yr) – Median72Female37.5%37.9%38.8%CHADS2 score≤377.4%77.1%77.8%4-622.6%22.9%22.2%Dose reduction at randomizationCrCl ≤50 ml/min19.3%19.6%19.0%Weight ≤60 kg10.0%9.7%9.9%Use of verapamil or quinidine3.5%3.7%Giugliano RP, et al. NEJM 2013; 369:
17 Savaysa™ - Edoxaban Literature Review Results: (Median follow-up 2.8yrs)The annualized rate of the primary end point of stroke or systemic embolism1.50% with warfarin1.18% with high-dose edoxaban (P<0.001 for noninferiority)1.61% with low-dose edoxaban (P=0.005 for noninferiority)The annualized rate of major bleeding3.43% with warfarin2.75% with high-dose edoxaban (P<0.001)1.61% with low-dose edoxaban (P<0.001).Giugliano RP, et al. NEJM 2013; 369:
18 Savaysa™ - Edoxaban Literature Review ConclusionBoth once-daily regimens of edoxaban were noninferior to warfarinEdoxaban was associated with significantly lower rates of bleeding and death from cardiovascular causes.Giugliano RP, et al. NEJM 2013; 369:
19 Savaysa™ - Edoxaban Summary Savaysa™ (Edoxaban) is a factor Xa inhibitor, indicated to prevent stroke and systemic embolism in non-valvular atrial fibrillation and to treat DVT and PE. When used in the treatment of DVT/PE edoxaban requires 5 to 10 days of initial therapy with a parenteral anticoagulant.Edoxaban is typically given as a once daily 60mg dose, but should be administered at lower doses for patients with impaired renal or hepatic function or if the patient weights ≤60 kg.Edoxaban should not be used in NVAF patients with CrCL >95 mL/minute.The most common side effects of edoxaban include; vaginal, cutaneous soft tissue, nose, and GI bleeding.
20 Savaysa™ - Edoxaban References Savaysa package insert. Daiichi Sankyo. JanuaryEdoxaban: Drug information. Lexicomp Drug Information. Accessed through UpToDate on March 2, 2015.Giugliano RP, et al. NEJM 2013; 369: