Dosing and uses of Savaysa (edoxaban)
Adult dosage forms and strengths
tablet
- 15mg
- 30mg
- 60mg
Stroke Prophylaxis with Atrial Fibrillation
Indicated to reduce risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation (NVAF)
60 mg PO qDay
Limitation of use
- CrCL >95 mL/min: Do not use; increased risk of ischemic stroke compared with warfarin in NVAF trial (see Black box warnings)
DVT or PE Treatment
Indicated for treatment of deep vein thrombosis (DVT) and pulmonary embolus (PE) in patients who have been initially treated with a parenteral anticoagulant for 5-10 days
>60 kg: 60 mg PO qDay
≤60 kg: 30 mg PO qDay
Dosage modifications
Treatment of DVT/PE: Decrease dose to 30 mg PO qDay when coadministered with certain P-gp inhibitors (see Drug Interactions)
Renal impairment (NVAF)
- CrCl >95 mL/min: Do not use; increased ischemic stroke compared with warfarin (see Black box warnings)
- CrCl >50 to 95 mL/min: No dosage adjustment required
- CrCl 15-50 mL/min: 30 mg PO qDay
Renal impairment (DVT/PE)
- >50 mL/min: No dosage adjustment required
- 15-50 mL/min: 30 mg PO qDay
Hepatic impairment
- Mild (Child-Pugh A): No dose adjustment required
- Moderate-to-severe (Child-Pugh B/C): Not recommended; these patients have intrinsic coagulation abnormalities
Transition dosing to or from edoxaban
Transition to edoxaban
- From warfarin or other vitamin K antagonists (VKAs): Discontinue warfarin and start edoxaban when INR ≤2.5
- From oral anticoagulants other than warfarin or other VKAs: Discontinue current oral anticoagulant and initiate edoxaban at the time of the next scheduled dose of the previous oral anticoagulant
- From low molecular weight heparin (LMWH): Discontinue LMWH and initiate edoxaban at the time of the next scheduled administration of LMWH
- From unfractionated heparin: Discontinue heparin infusion and initiate edoxaban 4 hr later
Transition from edoxaban
- To non-vitamin-K-dependent oral anticoagulants: Discontinue edoxaban and start the other oral anticoagulant at the time of the next dose of edoxaban
- To parenteral anticoagulants: Discontinue edoxaban and start the parenteral anticoagulant at the time of the next dose of edoxaban
- To warfarin (oral option)
- If taking edoxaban 60 mg/day, reduce dose to 30 mg/day and begin warfarin concomitantly
- If taking edoxaban 30 mg/day, reduce dose to 15 mg/day and begin warfarin concomitantly
- INR must be measured at least weekly and just prior to the daily dose of edoxaban to minimize the influence on INR measurements
- Once a stable INR ≥2.0 is achieved, discontinue edoxaban and continue warfarin
- To warfarin (parenteral option)
- Discontinue edoxaban and administer a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose
- Once a stable INR ≥2.0 is achieved, discontinue the parenteral anticoagulant and continue warfarin
Pediatric dosage forms and strengths
Safety and efficacy not established
Savaysa (edoxaban) adverse (side) effects
1-10% (ENGAGE AF-TIMI-48 study)
Abnormal LFTs (4.8%)
Rash (4.2%)
1-10% (Hokusai VTE study)
Abnormal LFTs (7.8%)
Rash (3.6%)
Anemia (1.7%)
<1% (ENGAGE AF-TIMI-48 study)
Interstitial lung disease (0.2%)
Bleeding (ENGAGE AF-TIMI-48 study)
Clinically relevant nonmajor bleeding (9.4%); warfarin (10.9%)
Anemia-related adverse events (9.6%); warfarin (6.8%)
Gastrointestinal bleeding
- Major GI bleed (1.8%); warfarin (1.3%)
- Upper GI (1.06%); warfarin (0.74%)
- Lower GI (0.73%); warfarin (0.54%)
- Severe, caused hemodynamic compromise requiring intervention (0.14%); warfarin (0.14%)
- Fatal (<0.1%); warfarin (<0.1%)
Major bleeding
- Major (3.1%); warfarin (3.7%)
- Intracranial (0.5%); warfarin (1%)
- Type of intracranial bleeding
- Hemorrhagic stroke (0.3%); warfarin (0.6%)
- Other ICH (0.2%); warfarin (0.5%)
Fatal bleeding
- Fatal (1.8%); warfarin (0.4%)
- ICH (0.2%); warfarin (0.4%)
- Non-intracranial (<0.1%); warfarin (<0.1%)
Bleeding (Hokusai VTE study)
Any bleed (21.7%); warfarin (25.6%)
Clinically relevant major bleeding (8.5%); warfarin (10.3%)
Clinically relevant nonmajor bleeding (7.2%); warfarin (8.9%)
Nonfatal, noncritical organ bleeding (1%); warfarin (0.8%)
Decreased Hgb ≥2 g/dL (1%); warfarin (0.8%)
Transfusion ≥2 units of RBC (0.7%); warfarin (0.5%)
Major bleeding
- Major (1.4%); warfarin (1.6%)
- Fatal bleeding (<0.1%); warfarin (0.2%)
- Intracranial, fatal (none); warfarin 0.1%)
Critical organ bleeding
- Nonfatal (0.3%); warfarin (0.6%)
- Intracranial (0.1%); warfarin (0.3%)
Bleeding ADRs
- Vaginal (9%); warfarin (7.2%)
- Cutaneous soft tissue (5.9%); warfarin (10%)
- Epistaxis (4.7%); warfarin (5.7%)
- GI bleed (4.2%); warfarin 3.6%)
- Lower GI bleed (3.4%); warfarin (3.1%)
- Oral/pharyngeal (3.4%); warfarin (3.9%)
- Macroscopic hematuria/urethral (2.2%); warfarin (2.8%)
- Puncture site (1.4%); warfarin (2.4%)
Warnings
Black box warnings
Reduced efficacy with CrCl >95 mL/min
- Do not use with CrCL >95 mL/min
- In the ENGAGE AF-TIMI 48 study, patients with NVAF with CrCL >95 mL/min had an increased rate of ischemic stroke with edoxaban 60 mg/day compared with patients treated with warfarin
- In these patients, another anticoagulant should be used
Premature discontinuation increases risk for ischemic events
- Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events
- If 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 (see Adult Dosing)
Spinal/epidural hematoma
- 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
- Monitor patients frequently for signs and symptoms of neurological impairment; if neurological compromise is noted, urgent treatment is necessary
- 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 (eg, NSAIDs, platelet inhibitors, other anticoagulants, antithrombotic agents, fibrinolytic therapy)
- history of traumatic or repeated epidural or spinal punctures
- history of spinal deformity or spinal surgery
- optimal timing between the administration of edoxaban and neuraxial procedures is not known
Contraindications
Active pathological bleeding
Cautions
Efficacy reduced in patients with nonvalvular atrial fibrillation (NVAF) with CrCl >95 mL/min (see Black box warnings)
Increased risk of stroke with discontinuation in patients with NVAF (see Black box warnings)
Do not use neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture; patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis (see Black box warnings)
Increases the risk of bleeding and can cause serious and potentially fatal bleeding; promptly evaluate any signs or symptoms of blood loss; discontinue if patient experiences active pathological bleeding; concomitant drugs that affect coagulation can increase this risk
Not recommended for patients with mechanical heart valves or moderate-to-severe mitral stenosis; safety and efficacy have not been established
Coadministration with P-gp inhibitors
- Edoxaban is a P-gp substrate; avoid coadministration with P-gp inducers (eg, rifampin)
- NVAF: No dose reduction recommended when coadministered with P-gp inhibitors; based on clinical experience from the ENGAGE AF-TIMI 48 study, dose reduction in patients concomitantly receiving P-gp inhibitors resulted in edoxaban blood levels that were lower than in patients who were given the full dose
- DVT/PE treatment: Dose reduction recommended when coadministered with P-gp inhibitors
Pregnancy and lactation
Pregnancy category: C
Lactation: Unknown if distributed in human breast milk; because of the potential for adverse reactions in nursing infants, a decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Savaysa (edoxaban)
Mechanism of action
Factor Xa (FXa) inhibitor; inhibits platelet activation by selectively and reversibly blocking the active site of FXa without requiring a cofactor (eg, antithrombin III) for activity
Inhibits free FXa, prothrombinase activity, and thrombin-induced platelet aggregation
Inhibition of FXa in the coagulation cascade reduces thrombin generation and reduces thrombus formation
Absorption
Bioavailability: 62%
Peak plasma concentration: 1-2 hr
Food does not affect total systemic exposure
Substrate of P-gp transporter
Distribution
Disposition is biphasic
Steady-state reached: 3 days
Vd (steady-state): 107 L
Protein bound: 55%
Metabolism
Unchanged edoxaban is the predominant form in plasma
Minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4
<10% is hydrolyzed to the predominant metabolite M-4
Exposure to other metabolites is <5%
Elimination
Half-life: 10-14 hr
Renal clearance: 11 L/hr
Total clearance: 22 L/hr
Excretion: Primarily as unchanged drug in urine; metabolism and biliary/intestinal excretion account for the remaining clearance
Hemodialysis: 4 hr hemodialysis session reduced total edoxaban exposure by <7%
Administration
Instructions
May take with or without food
No data are available regarding the bioavailability upon crushing and/or mixing of edoxaban tablets into food, liquids, or administration through feeding tubes
Discontinuation before surgery/interventions and then restarting
- Discontinue at least 24 hr before invasive or surgical procedures because of the risk of bleeding
- If surgery cannot be delayed, there is an increased risk of bleeding; risk of bleeding should be weighed against the urgency of intervention
- Can be restarted after the surgical or other procedure as soon as adequate hemostasis has been established, noting that the time to onset of pharmacodynamic effect is 1-2 hr
- Administer a parenteral anticoagulant and then switch to oral edoxaban, if oral medication cannot be taken during or after surgical intervention
Missed dose
- Take as soon as possible on the same day; resume normal dosing schedule on the next day
- Do not double the dose to make up for a missed dose
