Edoxaban

Edoxaban is an anticoagulant agent belonging to Factor Xa (FXa) inhibitor.

Edoxaban is a novel oral anticoagulant used for reducing the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).

Following oral administration, peak plasma edoxaban concentrations are observed within 1-2 hours. Absolute bioavailability is 62%. Food does not affect total systemic exposure to Edoxaban. Disposition is biphasic. The steady-state volume of distribution (Vdss) is 107 (19.9) L. In vitro plasma protein binding is approximately 55%. Steady-state concentrations are achieved within 3 days. There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4. Edoxaban is eliminated primarily as an unchanged drug in urine. The terminal elimination half-life of Edoxaban following oral administration is 10 to 14 hours.

Edoxaban shows common side effects like rash, unusual tiredness or weakness, dizziness, and pale skin.

Edoxaban is available in the form of an Oral tablet.

Edoxaban is available in India, the US, the UK, Ireland, the Netherlands, Switzerland, Italy, Japan, Germany, Spain, and Australia.

Edoxaban belonging to the Factor Xa (FXa) inhibitor, acts as an anticoagulant agent.

Edoxaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Edoxaban inhibits free FXa, and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of FXa in the coagulation cascade reduces thrombin generation and reduces thrombus formation.

The data on the onset of action and duration of Action of Edoxaban is not available.

The Tmax was found within 1-2 hours following the administration of Edoxaban.

Edoxaban is available in the form of an Oral tablet.

Edoxaban Oral tablet is taken by mouth usually once a day.

Edoxaban is a novel oral anticoagulant used for reducing the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).

Edoxaban is an anticoagulant agent belonging to Factor Xa (FXa) inhibitor.

Edoxaban is a selective inhibitor of factor Xa, a serine endopeptidase of the clotting cascade required for the cleavage of prothrombin into thrombin.

Edoxaban is approved for use in the following clinical indications

• Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

Edoxaban is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). Edoxaban should not be used in patients with CrCL > 95 mL/min because of an increased risk of ischemic stroke compared to warfarin.

• Treatment of Deep Vein Thrombosis and Pulmonary Embolism

Edoxaban is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.

• Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism)

Oral: 60 mg once daily.

• Treatment of Deep Vein Thrombosis and Pulmonary Embolism

Oral: 60 mg orally once a day following 5 to 10 days of initial therapy with a parenteral anticoagulant.

Edoxaban is available in various strengths as 15mg, 30mg and 50mg.

Edoxaban is available in the form of an Oral Tablet.

Dosage Adjustment in Kidney Patient

• Deep vein thrombosis and/or pulmonary embolism, treatment

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 15 to 50 mL/minute: Oral: 30 mg once daily.

CrCl <15 mL/minute: Use is not recommended.

• Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism)

CrCl >95 mL/minute: Use is not recommended due to the increased risk of ischemic stroke compared to warfarin.

CrCl >50 to 95 mL/minute: No dosage adjustment necessary.

CrCl 15 to 50 mL/minute: Oral: 30 mg once daily.

CrCl <15 mL/minute: Avoid use

Dosage Adjustment in Hepatic impairment Patient

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B and C): Use is not recommended.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Additive anticoagulant activity may increase the risk of bleeding (eg. garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba).

Edoxaban is contraindicated in patients with

• Active pathological bleeding.

• Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with CrCL > 95 mL/min

Edoxaban should not be used in patients with CrCL > 95 mL/min. In the randomized ENGAGE AFTIMI 48 study, NVAF patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with Edoxaban 60 mg daily compared to patients treated with warfarin. In these patients another anticoagulant should be used.

• Increased Risk of Stroke with Discontinuation of Edoxaban in Patients with Nonvalvular Atrial Fibrillation

Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If Edoxaban is 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.

• Risk of Bleeding

Edoxaban increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue Edoxaban in patients with active pathological bleeding. Concomitant use of drugs affecting hemostasis may increase the risk of bleeding. These include aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, and chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs). There is no established way to reverse the anticoagulant effects of Edoxaban, which can be expected to persist for approximately 24 hours after the last dose. The anticoagulant effect of Edoxaban cannot be reliably monitored with standard laboratory testing. A specific reversal 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.

• Spinal/Epidural Anesthesia or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, 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. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 12 hours after the last administration of Edoxaban. The next dose of Edoxaban should not be administered earlier than 2 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.

• Patients with Mechanical Heart Valves or Moderate to Severe Mitral Stenosis

The safety and efficacy of Edoxaban has not been studied in patients with mechanical heart valves or moderate to severe mitral stenosis. The use of Edoxaban is not recommended in these patients.

It is not known if Edoxaban is excreted in human milk. Edoxaban was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Edoxaban, a decision should be made to discontinue nursing or the drug, considering the importance of the drug to the mother.

Use of direct-acting oral anticoagulants increases the risk of bleeding in all patients. When used in pregnancy, there is also the potential for fetal bleeding or subclinical placental bleeding, which may increase the risk of miscarriage, preterm delivery, fetal compromise, or stillbirth. The use of direct acting oral anticoagulants during pregnancy and use in pregnant patients is not recommended.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Additive anticoagulant activity may increase the risk of bleeding (eg. garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba).

• Common Adverse effects

Hemorrhage, dermal hemorrhage, skin rash, gastrointestinal hemorrhage, gross hematuria, urethral bleeding, vaginal hemorrhage, anemia, oral hemorrhage, puncture site bleeding, epistaxis, pharyngeal bleeding, intracranial hemorrhage, interstitial pulmonary disease.

• Rare Adverse effects

Ischemia, spinal hematoma, epidural intracranial hemorrhage, urticaria, abdominal pain, thrombocytopenia, angioedema, hypersensitivity reaction, dizziness, headache.

• Anticoagulants

Edoxaban may enhance the anticoagulant effect of Anticoagulants.

• Agents with Antiplatelet Properties

May enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased.

• Antiplatelet Agents (P2Y12 Inhibitors)

May enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider the anticipated risks and benefits of this combination. If combined, increased monitoring for bleeding is recommended.

• Apixaban

May enhance the anticoagulant effect of Anticoagulants.

• Aspirin

May enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Aspirin may increase the serum concentration of Edoxaban. Management: Carefully consider the anticipated risks and benefits of this combination. If combined, increased monitoring for bleeding is recommended.

• Azithromycin (Systemic)

May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30mg daily when combined with azithromycin. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined.

• Clarithromycin

May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce edoxaban dose to 30 mg daily when combined with clarithromycin. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined.

• Erythromycin (Systemic)

May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30 mg daily when combined with erythromycin. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined.

• Ketoconazole (Systemic)

May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30 mg daily when combined with oral ketoconazole. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding).

• Nonsteroidal Anti-Inflammatory Agents (Nonselective)

May enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of edoxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding.

• P-glycoprotein/ABCB1 Inducers

May decrease the serum concentration of Edoxaban. Management: Avoid coadministration of Edoxaban and P-glycoprotein (P-gp) inducers if possible. If concomitant use is required, be aware the Edoxaban efficacy may be decreased.

• P-glycoprotein/ABCB1 Inhibitors

May increase the serum concentration of Edoxaban.

• Verapamil

May increase the serum concentration of Edoxaban. Management: In patients treated for DVT/PE, reduce the edoxaban dose to 30 mg daily when combined with verapamil. No dose adjustment is recommended for patients treated for atrial fibrillation. Monitor for increased edoxaban toxicities (ie, bleeding) when combined.

The common side effects of Edoxaban include the following

• Common

Rash, unusual tiredness or weakness, dizziness, pale skin.

• Rare

Bleeding gums, nosebleeds, heavy vaginal bleeding, red, pink, or brown urine, red or black, tarry stools, coughing up or vomiting blood or material that looks like coffee grounds.

• Pregnancy

Pregnancy Category C

Available data about Edoxaban use 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 Edoxaban was 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. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

• Nursing Mothers

It is not known if Edoxaban is excreted in human milk. Edoxaban was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Edoxaban, a decision should be made to discontinue nursing or the drug, considering the importance of the drug to the mother.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Of the total patients in the ENGAGE AF-TIMI 48 study, 5182 (74%) were 65 years and older, while 2838 (41%) were 75 years and older. In Hokusai VTE, 1334 (32%) patients were 65 years and older, while 560 (14%) patients were 75 years and older. In clinical trials the efficacy and safety of Edoxaban in elderly (65 years or older) and younger patients were similar.

• A specific reversal agent for Edoxaban is not available. Overdose of Edoxaban increases the risk of bleeding. The following are not expected to reverse the anticoagulant effects of Edoxaban: protamine sulfate, vitamin K, and tranexamic acid. Hemodialysis does not significantly contribute to edoxaban clearance

Pharmacodynamic

As a result of FXa inhibition, Edoxaban prolongs clotting time tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT). Changes observed in PT, INR, and aPTT at the expected therapeutic dose, however, are small, subject to a high degree of variability and not useful in monitoring the anticoagulant effect of edoxaban. Following oral administration, peak pharmacodynamic effects are observed within 1-2 hours, which correspond with peak edoxaban concentrations (Cmax).

Pharmacokinetics

• Absorption

Following oral administration, peak plasma Edoxaban concentrations are observed within 1-2 hours. Absolute bioavailability is 62%. Food does not affect total systemic exposure to Edoxaban. No data are available regarding the bioavailability upon crushing and/or mixing of edoxaban tablets into food, liquids, or administration through feeding tubes.

• Distribution

Disposition is biphasic. The steady-state volume of distribution (Vdss) is 107 (19.9) L [mean (SD)]. In vitro plasma protein binding is approximately 55%. There is no clinically relevant accumulation of Edoxaban (accumulation ratio 1.14) with once daily dosing. Steady state concentrations are achieved within 3 days.

• Metabolism

Unchanged edoxaban is the predominant form in plasma. There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4. The predominant metabolite M-4, formed by hydrolysis, is human-specific and active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.

• Excretion

Edoxaban is eliminated primarily as unchanged drug in urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion account for the remaining clearance. The terminal elimination half-life of Edoxaban following oral administration is 10 to 14 hours.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf
• https://www.mims.com/philippines/drug/info/edoxaban?mtype=generic
• https://www.drugs.com/dosage/edoxaban.html
• https://go.drugbank.com/drugs/DB09075
• https://www.rxlist.com/savaysa-drug.htm#indications
• https://www.uptodate.com/contents/edoxaban-drug-information#F26964813