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Prevention of stroke and systemic embolism: The recommended dose is 60 mg edoxaban once daily. Therapy with edoxaban in NVAF patients should be continued long term.
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTE):
The recommended dose is 60 mg edoxaban once daily following initial use of parenteral anticoagulant for at least 5 days. Edoxaban and initial parenteral anticoagulant should not be administered simultaneously.
The duration of therapy for treatment of DVT and PE (venous thromboembolism (VTE)), and prevention of recurrent VTE should be individualised after careful assessment of the treatment benefit against the risk for bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.
For NVAF and VTE the recommended dose is 30 mg edoxaban once daily in patients with one or more of the following clinical factors:
Moderate or severe renal impairment (creatinine clearance (CrCl) 15 – 50 mL/min).
Low body weight ≤ 60 kg.
Concomitant use of the following P-glycoprotein (P-gp) inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole.
Elderly population: No dose reduction is required.
Renal impairment: Renal function should be assessed in all patients by calculating the CrCl prior to initiation of treatment with edoxaban.
The method used to estimate renal function (CrCl in mL/min) during the clinical development of edoxaban was the Cockcroft-Gault method.
In patients with mild renal impairment (CrCl > 50 – 80 mL/min), the recommended dose is 60 mg edoxaban once daily.
In patients with moderate or severe renal impairment (CrCl 15 – 50 mL/min), the recommended dose is 30 mg edoxaban once daily.
In patients with end stage renal disease (ESRD) (CrCl < 15 mL/min) or on dialysis, the use of edoxaban is not recommended. See prescribing information for full details.
Hepatic impairment: Edoxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
In patients with severe hepatic impairment edoxaban is not recommended.
In patients with mild to moderate hepatic impairment the recommended dose is 60 mg edoxaban once daily.
Edoxaban should be used with caution in patients with mild to moderate hepatic impairment.
Patients with elevated liver enzymes (alanine aminotransferase (ALT) or aspartate transaminase (AST)> 2 x upper limit of normal (ULN)) or total bilirubin ≥ 1.5 x ULN, were excluded in clinical studies.
Therefore edoxaban should be used with caution in this population. Prior to
initiating edoxaban, liver function testing should be performed.
Body weight: For patients with body weight ≤ 60 kg, the recommended dose is 30 mg edoxaban once daily.
Gender: No dose reduction is required.
Concomitant use with P-glycoprotein (P-gp) inhibitors:
In patients concomitantly taking edoxaban and the following P-gp inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole, the recommended dose is 30 mg once daily.
No dose reduction is required for concomitant use of amiodarone, quinidine or verapamil.
The use with other P-gp inhibitors including HIV protease inhibitors has not been studied.
Paediatric population: Edoxaban is not indicated for use in paediatric population.
The safety and efficacy of edoxaban in children and adolescents less than 18 years of age have not been established. No data are available.
Patients undergoing cardioversion:
Edoxaban can be initiated or continued in patients who may require cardioversion. For transoesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, edoxaban treatment should be started at least 2 hours before cardioversion to ensure adequate anticoagulation. Cardioversion should be performed no later than 12 hours after the dose of edoxaban on the day of the procedure.
For all patients undergoing cardioversion: Confirmation should be sought prior to cardioversion that the patient has taken edoxaban as prescribed. Decisions on initiation and duration of treatment should follow established guidelines for anticoagulant treatment in patients undergoing cardioversion.
See prescribing information for more details.

Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and
for the prevention of recurrent DVT and PE in adults.

-Hypersensitivity to the active substance or to any of the excipients.
-Clinically significant active bleeding.
-Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
-Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
-Uncontrolled severe hypertension.
-Concomitant treatment with any other anticoagulants e.g. UFH, LMWH (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, rivaroxaban, apixaban etc.) except under specific circumstances of switching oral anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.
-Pregnancy and breast-feeding.

Edoxaban 15 mg is not indicated as monotherapy, as it may result in decreased efficacy. It is only indicated in the process of switching from edoxaban 30 mg. See prescribing information for more details.
Haemorrhagic risk:
Edoxaban increases the risk of bleeding and can cause serious, potentially fatal bleeding. Edoxaban, like other anticoagulants, is recommended to be used with caution in patients with increased risk of bleeding. Edoxaban administration should be discontinued if severe haemorrhage occurs.
In the clinical studies mucosal bleedings (e.g. epistaxis, gastrointestinal, genitourinary) and anaemia were seen more frequently during long term edoxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate.
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment. Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
The anticoagulant effect of edoxaban cannot be reliably monitored with standard laboratory testing.
A specific anticoagulant reversal agent for edoxaban is not available.
Haemodialysis does not significantly contribute to edoxaban clearance.
Elderly:
The co-administration of edoxaban with acetylsalicylic acid (ASA) in elderly patients should be used cautiously because of a potentially higher bleeding risk.
Renal impairment:
The plasma area under the curve (AUC) for subjects with mild (CrCl > 50 – 80 mL/min), moderate (CrCl 30 – 50 mL/min) and severe (CrCl < 30 mL/min but not undergoing dialysis) renal impairment was increased by 32%, 74%, and 72%, respectively, relative to subjects with normal renal function. In patients with end stage renal disease or on dialysis, edoxaban is not recommended.
Renal function in NVAF: A trend towards decreasing efficacy with increasing CrCl was observed for edoxaban compared to well-managed warfarin.
Edoxaban should be used in patients with NVAF and high CrCl only after a careful evaluation of the individual thromboembolic and bleeding risk.
Assessment of renal function: CrCl should be monitored at the beginning of the treatment in all patients and afterwards when clinically indicated.
Hepatic impairment:
Edoxaban is not recommended in patients with severe hepatic impairment.
Edoxaban should be used with caution in patients with mild or moderate hepatic impairment. Patients with elevated liver enzymes (ALT/AST > 2 x ULN) or total bilirubin ≥ 1.5 x ULN were excluded in clinical studies. Therefore edoxaban should be used with caution in this population. Prior to initiating edoxaban, liver function testing should be performed.
Periodic hepatic monitoring is recommended for patients on edoxaban treatment beyond 1 year.
Discontinuation for surgery and other interventions:
If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, edoxaban should be stopped as soon as possible and preferably at least 24 hours before the procedure.
In deciding whether a procedure should be delayed until 24 hours after the last dose of edoxaban, the increased risk of bleeding should be weighed against the urgency of the intervention. Edoxaban should be restarted after the surgical or other procedures as soon as adequate haemostasis has been established, noting that the time to onset of the edoxaban anticoagulant therapeutic effect is 1 –2 hours. If oral medicinal products cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant and then switch to oral once daily edoxaban.
Interaction with other medicinal products affecting haemostasis:
Concomitant use of medicines affecting haemostasis may increase the risk of bleeding. These include ASA, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), and chronic nonsteroidal anti-inflammatory drugs (NSAIDs).
Prosthetic heart valves and moderate to severe mitral stenosis
Edoxaban has not been studied in patients with mechanical heart valves, in patients during the first 3 months after implantation of a bioprosthetic heart valve, with or without atrial fibrillation, or in patients with moderate to severe mitral stenosis. Therefore, use of edoxaban is not recommended in these patients.
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy:
Edoxaban is not recommended as an alternative to UFH in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of edoxaban have not been established in these clinical situations.
Patients with active cancer:
Efficacy and safety of edoxaban in the treatment and/or prevention of VTE in patients with active cancer have not been established.
Patients with antiphospholipid syndrome:
Direct acting oral anticoagulants (DOACs) including edoxaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
Laboratory coagulation parameters:
Although treatment with edoxaban does not require routine monitoring, the effect on anticoagulation can be estimated by a calibrated quantitative anti-Factor Xa (anti-FXa) assay which may help to inform clinical decisions in particular situations as, e.g. overdose and emergency surgery.
Edoxaban prolongs standard clotting tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT) as a result of Factor Xa (FXa) inhibition. Changes observed in these clotting tests at the expected therapeutic dose are, however, small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of edoxaban.

Common: Anaemia, dizziness, headache, epistaxis, abdominal pain, lower gi haemorrhage, upper gi haemorrhage, oral/pharyngeal haemorrhage, nausea, blood bilirubin increased, gammaglutamyltransferase increased, cutaneous soft tissue haemorrhage, rash, pruritus, macroscopic haematuria/urethral haemorrhage, vaginal haemorrhage, puncture site haemorrhage, liver function test abnormal.

Edoxaban is predominantly absorbed in the upper gastrointestinal (GI) tract. Thus, medicines or disease conditions that increase gastric emptying and gut motility have the possibility of reducing edoxaban dissolution and absorption.
P-gp inhibitors:
Edoxaban is a substrate for the efflux transporter P-gp. In pharmacokinetic (PK) studies, concomitant administration of edoxaban with the P-gp inhibitors (e.g. ciclosporin, dronedarone, erythromycin, ketoconazole, quinidine, or verapamil) resulted in increased plasma concentrations of edoxaban.
Concomitant use of edoxaban with ciclosporin, dronedarone, erythromycin, or ketoconazole requires dose reduction to 30 mg once daily. Concomitant use of edoxaban with quinidine, verapamil, or amiodarone does not require dose reduction based on clinical data.
The use of edoxaban with other P-gp inhibitors including human immunodeficiency virus (HIV) protease inhibitors has not been studied.
Edoxaban 30 mg once daily must be administered during concomitant use with the following P-gp inhibitors:
-Ciclosporin: Concurrent administration of a single dose of ciclosporin 500 mg with a single dose of edoxaban 60 mg increased edoxaban AUC and maximum serum concentration (Cmax) by 73% and 74%, respectively.
-Dronedarone: Dronedarone 400 mg twice daily for 7 days with a single concomitant dose of edoxaban 60 mg on day 5 increased edoxaban AUC and Cmax by 85% and 46%, respectively.
-Erythromycin: Erythromycin 500 mg four times daily for 8 days with a single concomitant dose of edoxaban 60 mg on day 7 increased the edoxaban AUC and Cmax by 85% and 68%, respectively.
– Ketoconazole: Ketoconazole 400 mg once daily for 7 days with a single concomitant dose of edoxaban 60 mg on day 4, increased edoxaban AUC and Cmax by 87% and 89%, respectively.
Edoxaban 60 mg once daily is recommended during concomitant use with the
following P-gp inhibitors:
-Quinidine: Quinidine 300 mg once daily on days 1 and 4 and three times daily on days 2 and 3, with a single concomitant dose of edoxaban 60 mg on day 3, increased edoxaban AUC over 24 hours by 77% and Cmax by 85%, respectively.
– Verapamil: Verapamil 240 mg once daily for 11 days with a single concomitant dose of edoxaban 60 mg on day 10 increased the edoxaban AUC and Cmax by approximately
53%.
-Amiodarone: Co-administration of amiodarone 400 mg once daily with edoxaban 60 mg once daily increased AUC by 40% and Cmax by 66%. This was not considered clinically significant. In ENGAGE AF-TIMI 48 study in NVAF, efficacy and safety results were similar for subjects with and without concomitant amiodarone use.
P-gp inducers:
Co-administration of edoxaban with the P-gp inducer rifampicin led to a decrease in mean edoxaban AUC and a shortened half-life, with possible decreases in its pharmacodynamic effects. The concomitant use of edoxaban with other P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may lead to reduced edoxaban plasma concentrations. Edoxaban should be used with caution when co-administered with P-gp inducers.
P-gp substrates:
Digoxin: Edoxaban 60 mg once daily on days 1 to 14 with coadministration of multiple daily doses of digoxin 0.25 mg twice daily (days 8 and 9) and 0.25 mg once daily (days 10 to 14) increased the Cmax of edoxaban by 17%, with no significant effect on AUC or renal clearance at steady state. When the effects of edoxaban on digoxin PK were also examined, the Cmax of digoxin increased by approximately 28% and AUC by 7%. This was not considered clinically relevant. No dose
modification is necessary when edoxaban is administered with digoxin.
Anticoagulants, antiplatelets, NSAIDs and SSRIs/SNRIs:
Anticoagulants: Co-administration of edoxaban with other anticoagulants is contraindicated due to increased risk of bleeding.
ASA: Co-administration of ASA (100 mg or 325 mg) and edoxaban increased bleeding time relative to either medicine alone. Co-administration of high dose ASA (325 mg) increased the steady state Cmax and AUC of edoxaban by 35% and 32%, respectively. The concomitant chronic use of high dose ASA (325 mg) with edoxaban is not recommended. Concomitant administration of higher doses than
100 mg ASA should only be performed under medical supervision.
In clinical studies concomitant use of ASA (low dose ≤ 100 mg/day), other antiplatelet agents, and thienopyridines was permitted and resulted in approximately a 2-fold increase in major bleeding in comparison with no concomitant use, although to a similar extent in the edoxaban and warfarin groups. Co-administration of low dose ASA (≤ 100 mg) did not affect the peak or total exposure of edoxaban either after single dose or at steady-state.
Edoxaban can be co-administered with low dose ASA (≤ 100 mg/day).
Platelet inhibitors: In ENGAGE AF-TIMI 48 concomitant use of thienopyridines (e.g. clopidogrel) monotherapy was permitted and resulted in increased clinically relevant bleeding although with a lower risk of bleeding on edoxaban compared to warfarin. There is very limited experience on the use of edoxaban with dual antiplatelet therapy or fibrinolytic agents.
NSAIDs: Co-administration of naproxen and edoxaban increased bleeding time relative to either medicine alone. Naproxen had no effect on the Cmax and AUC of edoxaban. In clinical studies, co-administration of NSAIDs resulted in increased clinically relevant bleeding. Chronic use of NSAIDs with edoxaban is not recommended.
SSRIs/SNRIs: As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets.
Effect of edoxaban on other medicinal products:
Edoxaban increased the Cmax of concomitantly administered digoxin by 28%; however, the AUC was not affected. Edoxaban had no effect on the Cmax and AUC of quinidine. Edoxaban decreased the Cmax and AUC of concomitantly administered verapamil by 14% and 16%, respectively.

Women of childbearing potential:
Women of childbearing potential should avoid becoming pregnant during treatment with edoxaban.
Pregnancy:
Safety and efficacy of edoxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity. Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that edoxaban passes the placenta, this medicinal product is contraindicated during pregnancy.
Breast-feeding:
Safety and efficacy of edoxaban have not been established in breast-feeding women. Data from animals indicate that edoxaban is secreted into breast milk. Therefore this medicinal product is contraindicated during breast-feeding. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy.
Fertility:
No specific studies with edoxaban in human beings have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen.

Overdose with edoxaban may lead to haemorrhage. Experience with overdose cases is very limited.
A specific antidote antagonising the pharmacodynamic effect of edoxaban is not available.
Early administration of activated charcoal may be considered in case of edoxaban overdose to reduce absorption. This recommendation is based on standard treatment of medicinal product overdose and data available with similar compounds, as the use of activated charcoal to reduce absorption of edoxaban has not been specifically studied in the edoxaban clinical programme.
Management of bleeding:
Should a bleeding complication arise in a patient receiving edoxaban, the next edoxaban administration should be delayed or treatment should be discontinued as appropriate. Edoxaban has a half-life of approximately 10 to 14 hours. Management should be individualized according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or
platelets.
For life-threatening bleeding that cannot be controlled with the measures such as transfusion or haemostasis, the administration of a 4-factor prothrombin complex concentrate (PCC) at 50 IU/kg has been shown to reverse the effects of edoxaban 30 minutes after completing the infusion.
Recombinant factor VIIa (r-FVIIa) can also be considered. However, there is limited clinical experience with the use of this product in individuals receiving edoxaban.
Depending on local availability, a consultation with a coagulation expert should be considered in case of major bleedings.
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of edoxaban.
There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving edoxaban. There is neither scientific rationale for benefit nor experience with the use of systemic haemostatics (desmopressin, aprotinin) in individuals receiving edoxaban. Due to the high
plasma protein binding edoxaban is not expected to be dialysable.