Edoxaban

Edoxaban is used to prevent serious blood clots from forming due to a certain irregular heartbeat (atrial fibrillation). It is also used to treat certain blood clots (such as in deep vein thrombosis-DVT or pulmonary embolus-PE). Edoxaban is an anticoagulant that works by blocking certain clotting proteins in your blood.

Edoxaban is available under the following different brand names: Savaysa.

Dosage Forms and Strengths

Tablets

• 15 mg
• 30 mg
• 60 mg

The safety and efficacy of edoxaban have not been established in pediatric patients.

Dosage Considerations – Should be Given as Follows:

Stroke Prophylaxis with Atrial Fibrillation

• Indicated to reduce risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation (NVAF)
• 60 mg orally once daily
• Limitation of use
• CrCL greater than 95 mL/min: Do not use; increased risk of ischemic stroke compared with warfarin in NVAF trial

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
• Greater than 60 kg: 60 mg orally once daily
• Up to 60 kg: 30 mg orally once daily

Dosage Modifications

• Treatment of DVT/PE: Decrease dose to 30 mg orally once daily when coadministered with certain P-gp inhibitors
• Renal impairment (NVAF)
• CrCl greater than 95 mL/min: Do not use; increased ischemic stroke compared with warfarin (see Black Box Warnings)
• CrCl greater than 50 to 95 mL/min: No dosage adjustment required
• CrCl 15-50 mL/min: 30 mg orally once daily

Renal impairment (DVT/PE)

• Greater than 50 mL/min: No dosage adjustment required
• 15-50 mL/min: 30 mg orally once daily

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 is less than or equal to 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 hours 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 of greater than or equal to 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 of greater than or equal to 2.0 is achieved, discontinue the parenteral anticoagulant and continue warfarin

Side effects of Edoxaban may include:

• Abnormal liver function tests
• Rash
• Anemia
• Interstitial lung disease
• Major bleeding: gastrointestinal, intracranial, stroke, critical organs, other
• Other bleeding: vaginal, soft tissue, nosebleed, gastrointestinal, mouth or nose, blood in the urine, puncture site

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

• Severe interactions of edoxaban include:
  • defibrotide
• Edoxaban has serious interactions with at least 82 different drugs.
• Edoxaban has moderate interactions with at least 53 different drugs.
• Edoxaban has mild interactions with at least 104 different drugs.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

Warnings

This medication contains edoxaban. Do not take Savaysa if you are allergic to edoxaban or any ingredients contained in this drug.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Black Box Warnings

Reduced efficacy with CrCl greater than 95 mL/min

• Do not use with CrCL greater than 95 mL/min
• In the ENGAGE AF-TIMI 48 study, patients with NVAF with CrCL greater than 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

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 (e.g., NSAIDs, platelet inhibitors, other anticoagulants, antithrombotic agents, fibrinolytic therapy, norepinephrine reuptake inhibitors)
  • 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

Effects of Drug Abuse

• No information available.

Short-Term Effects

• See "What Are Side Effects Associated with Using Edoxaban?"

Long-Term Effects

• See "What Are Side Effects Associated with Using Edoxaban?"

Cautions

• Efficacy reduced in patients with nonvalvular atrial fibrillation (NVAF) with CrCl greater than 95 mL/min
• Increased risk of stroke with discontinuation in patients with NVAF
• 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
• 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 (e.g., 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

Reversal of anticoagulant effects

• There is not established way to reverse anticoagulant effects of edoxaban
• Effects may persist for 24 hours after the last dose
• Anticoagulant effects cannot be reliably monitored with standard laboratory testing
• Agent for edoxaban is not available; hemodialysis does not significantly contribute to edoxaban clearance
• Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of edoxaban; the use of prothrombin complex concentrates, or other procoagulant reversal agents such as activated prothrombin complex concentrate or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical outcome studies; when PCCs are used, monitoring for anticoagulation effect of edoxaban using clotting test or anti-FXa activity is not useful and not recommended

Pregnancy and Lactation

Available data about use of edoxaban in pregnant women are insufficient to determine whether there are drug-associated risks for adverse developmental outcomes; in animal developmental studies, no adverse developmental effects were seen when administered orally to pregnant rats and rabbits during organogenesis at up to 16-times and 8-times, respectively, the human exposure, when based on body surface area and AUC, respectively.

Pregnancy confers an increased risk of thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions; published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy.

Use of edoxaban during pregnancy may increase the risk of bleeding in a fetus and neonate; monitor neonates for bleeding.

Labor or delivery

• All patients receiving anticoagulants, including pregnant women, are at risk for bleeding; use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas; consider use of a shorter acting anticoagulant as delivery approaches

There are no data on the presence of edoxaban in human milk, or its effects on breastfeeding infant or on milk production; the drug was present in rat milk; because of the potential for serious adverse reactions in nursing infants, including hemorrhage, patients are advised that breastfeeding is not recommended during treatment with edoxaban.