Edoxaban

Oral
Deep vein thrombosis, Pulmonary embolism

Oral
Prophylaxis of stroke in non-valvular atrial fibrillation, Prophylaxis of systemic embolism in non-valvular atrial fibrillation

Patients taking P-gp inhibitors (e.g. ciclosporin, dronedarone, erythromycin, ketoconazole): 30 mg once daily.

Patients on dialysis: Not recommended.

Prophylaxis of stroke and systemic embolism in non-valvular atrial fibrillation:

CrCl (mL/min)	Dosage
<15	Not recommended.
15-50	30 mg once daily.
51-80	60 mg once daily.

Deep vein thrombosis; Pulmonary embolism:

CrCl (mL/min)	Dosage
<15	Not recommended.
15-50	30 mg once daily.
51-80	60 mg once daily.

Moderate to severe: Not recommended.

Edoxaban May be taken with or without food. May crush tab & administer mixt orally or via feeding tubes. Consult product literature for specific instructions.

Active pathological bleeding, lesions, or conditions with significant risk for major bleeding (e.g. current or recent gastrointestinal ulceration, 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. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Pregnancy and lactation. Concomitant use with other anticoagulants (e.g. enoxaparin, dalteparin, heparin derivatives, oral anticoagulants), except under specific circumstances of switching anticoagulant therapy; other drugs that affect haemostasis (e.g. NSAIDs, SSRIs, SNRIs); rifampicin.

Patient with increased risk of bleeding, ALT/AST >2x ULN or total bilirubin ≥1.5x ULN, body weight ≤60 kg. Patients who are receiving neuraxial anaesthesia or those undergoing spinal, invasive or surgical procedures, or cardioversion. Not recommended for use in patients with moderate to severe mitral stenosis, mechanical heart valves, or during the 1st 3 months after implantation of a bioprosthetic heart valve; history of thrombosis who are diagnosed with triple-positive antiphospholipid syndrome. Not recommended to be used as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy. If edoxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, coverage with another anticoagulant should be considered (refer to detailed product information for the transition guidelines). Renal and hepatic impairment. Patients taking P-gp inhibitors (e.g. ciclosporin, dronedarone, erythromycin, ketoconazole). For patients with non-valvular atrial fibrillation (NVAF) and high CrCl, edoxaban use should only be considered after careful evaluation of individual thromboembolic and bleeding risk. In some countries, edoxaban is not recommended for the prophylaxis of stroke and systemic embolism in NVAF patients with a CrCl of >95 mL/min due to reduced efficacy and increased risk of ischaemic stroke; the use of alternative anticoagulant is suggested. Recommendations may vary between countries and individual products (refer to specific product information or local guidelines).

Blood and lymphatic system disorders: Anaemia.
Gastrointestinal disorders: Abdominal pain, nausea, gastrointestinal or oropharyngeal haemorrhage.
General disorders and administration site conditions: Puncture site haemorrhage.
Investigations: Increased bilirubin, GGT; abnormal LFT.
Nervous system disorders: Dizziness, headache.
Renal and urinary disorders: Macroscopic haematuria or urethral haemorrhage.
Reproductive system and breast disorders: Vaginal haemorrhage.
Respiratory, thoracic and mediastinal disorders: Epistaxis.
Skin and subcutaneous tissue disorders: Rash, pruritus, cutaneous soft tissue haemorrhage.
Potentially Fatal: Bleeding.

PO: C

Assess renal and liver functions prior to initiation of treatment and as clinically indicated. Monitor for signs and symptoms of blood loss.

Symptom: Haemorrhage. Management: Individualised according to the severity and location of the haemorrhage. Early administration of activated charcoal may be considered to reduce absorption. Symptomatic treatment could be used as appropriate, e.g. mechanical compression 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. Administer a 4-factor prothrombin complex concentrate (PCC) at 50 international units/kg for life-threatening bleeding that cannot be controlled by transfusion or haemostasis. Recombinant factor VIIa (r-FVIIa) may also be considered.

Increased plasma concentration with P-gp inhibitors (e.g. ciclosporin, dronedarone, erythromycin, ketoconazole, quinidine, verapamil). P-gp inducers, excluding rifampicin (e.g. phenytoin, carbamazepine, phenobarbital) may reduce the plasma concentration of edoxaban.
Potentially Fatal: Increased risk of bleeding with other anticoagulants (e.g. enoxaparin, warfarin), antiplatelets (e.g. aspirin), thrombolytics, NSAIDs (e.g. naproxen), SSRIs, SNRIs. Rifampicin significantly reduces the systemic exposure of edoxaban.

St. John's wort may reduce the plasma concentration of edoxaban.

Prolongs standard clotting tests (e.g. prothrombin time, INR, aPTT).

Description:
Mechanism of Action: Edoxaban is a highly selective, reversible and direct inhibitor of activated factor X (Xa). Factor Xa plays a central role in the blood coagulation cascade by serving as the convergence point for the intrinsic and extrinsic pathways. Inhibition of free factor Xa reduces thrombin generation, prolongs clotting time and decreases the risk of thrombus formation.
Pharmacokinetics:
Absorption: Absorbed from gastrointestinal tract. Bioavailability: Approx 62%. Time to peak plasma concentration: Within 1-2 hours.
Distribution: Volume of distribution: 107 L. Plasma protein binding: Approx 55%.
Metabolism: Minimally metabolised via hydrolysis by carboxylesterase 1 to the active metabolite M-4, conjugation, and oxidation by CYP3A4/5 enzyme.
Excretion: Via urine (approx 35%, mainly as unchanged drug); remainder via biliary and intestinal excretion. Elimination half-life: 10-14 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 10280735, Edoxaban. https://pubchem.ncbi.nlm.nih.gov/compound/Edoxaban. Accessed Nov. 25, 2022.

Store between 20-25°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AF03 - edoxaban ; Belongs to the class of direct factor Xa inhibitors. Used in the treatment of thrombosis.

Bohula EA, Giugliano RP, Ruff CT et al. Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation. 2016 Jul;134(1):24-36. doi: 10.1161/CIRCULATIONAHA.116.022361. Accessed 02/07/2024. PMID: 27358434

Corrochano M, Acosta-Isaac R, Plaza M et al. Impact of Increased Kidney Function on Clinical and Biological Outcomes in Real-World Patients Treated with Direct Oral Anticoagulants. PLoS One. 2022 Dec;17(12). doi: 10.1371/journal.pone.0278693. Accessed 02/07/2024. PMID: 36490245

Wang Y, Li L, Wei Z et al. Efficacy and Safety of Renal Function on Edoxaban Versus Warfarin for Atrial Fibrillation: A Systemic Review and Meta-Analysis. Medicines (Basel). 2023 Jan;10(1). doi: 10.13390/medicines10010013. Accessed 03/07/2024. PMID: 36662497

Yin O, Kakkar T, Duggal A et al. Edoxaban Exposure in Patients With Atrial Fibrillation and Estimated Creatinine Clearance Exceeding 100 mL/min. Clinical Pharmacology in Drug Development. 2022 May;11(5):666-674. doi: 10.1002/cpdd.1050. Accessed 03/07/2024. PMID: 34877813

Yu HT, Yang PS, Kim TH et al. Impact of Renal Function on Outcomes With Edoxaban in Real-World Patients With Atrial Fibrillation. Stroke. 2018 Oct;49(10):2421-2429. doi: 10.1161/STROKEAHA.118.021387. Accessed 02/07/2024. PMID: 30355093

Anon. Edoxaban Tosylate. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 27/06/2024.

Brayfield A, Cadart C (eds). Edoxaban. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 27/06/2024.

Edoxaban. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 27/06/2024.

Joint Formulary Committee. Edoxaban. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 27/06/2024.

Lixiana 15 mg, 30 mg, 60 mg Film-coated Tablets (A. Menarini Singapore Pte. Ltd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 27/06/2024.

Lixiana 15 mg, 30 mg, 60 mg Film-coated Tablets (Daiichi Sankyo Europe GmbH). European Medicines Agency [online]. Accessed 16/07/2024.

Lixiana 30 mg Film-coated Tablets (Daiichi Sankyo UK Ltd). MHRA. https://products.mhra.gov.uk. Accessed 27/06/2024.

Savaysa Tablet, Film Coated (Daiichi Sankyo Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 27/06/2024.