Edoxaban: Difference between revisions

{{Short description|Anticoagulant medication}}

{{Use dmy dates|date=March 2022}}

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 415900881

| image = Edoxaban.svg

| width = 275

| alt =

| caption =

<!-- Clinical data -->

| pronounce =

| tradename = Savaysa, Lixiana, Roteas, others

| Drugs.com = {{drugs.com|monograph|edoxaban-tosylate}}

| MedlinePlus = a614055

| DailyMedID = Edoxaban

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_AU_comment =

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]]

| class =

| ATC_prefix = B01

| ATC_suffix = AF03

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=Health Canada | date=February 2024 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=24 March 2024}}</ref><ref>{{cite web | title=Health Canada New Drug Authorizations: 2016 Highlights | website=[[Health Canada]] | date=14 March 2017 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-canada-new-drug-authorizations-2016-highlights.html | access-date=7 April 2024}}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref name="Savaysa FDA label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Lixiana EPAR" /><ref name="Roteas EPAR">{{cite web | title=Roteas EPAR | website=[[European Medicines Agency]] (EMA) | url=https://www.ema.europa.eu/en/medicines/human/EPAR/roteas | access-date=25 September 2020}}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability = 62%; T_max 1–2 hours<ref name=a/>

| protein_bound = 55%<ref name=a/>

| metabolism = minimal [[CES1]], [[CYP3A4]]/[[CYP3A5|5]], hydrolysis, [[glucuronidation]]<ref name=a/>

| elimination_half-life = 10–14 hours<ref name=a/>

| excretion = 62% [[feces]], 35% [[urine]]

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 480449-70-5

| PubChem = 10280735

| IUPHAR_ligand = 7575

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB09075

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 8456212

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = NDU3J18APO

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = D09710

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 85973

| ChEMBL_Ref =

| ChEMBL =

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = DU-176b

<!-- Chemical and physical data -->

| IUPAC_name = ''N'''-(5-chloropyridin-2-yl)-''N''-[(1''S'',2''R'',4''S'')-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4''H''-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide

| C=24 | H=30 | Cl=1 | N=7 | O=4 | S=1

| smiles = CN1CCC2=C(C1)SC(=N2)C(=O)N[C@@H]3C[C@H](CC[C@@H]3NC(=O)C(=O)NC4=NC=C(C=C4)Cl)C(=O)N(C)C

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C24H30ClN7O4S/c1-31(2)24(36)13-4-6-15(27-20(33)21(34)30-19-7-5-14(25)11-26-19)17(10-13)28-22(35)23-29-16-8-9-32(3)12-18(16)37-23/h5,7,11,13,15,17H,4,6,8-10,12H2,1-3H3,(H,27,33)(H,28,35)(H,26,30,34)/t13-,15-,17+/m0/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = HGVDHZBSSITLCT-JLJPHGGASA-N

<!-- Definition and medical uses -->

'''Edoxaban''', sold under the brand name '''Lixiana''' among others, is an [[anticoagulant]] medication and a [[direct factor Xa inhibitor]].<ref name="Savaysa FDA label">{{cite web | title=Savaysa- edoxaban tosylate tablet, film coated | website=DailyMed | date=24 April 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e77d3400-56ad-11e3-949a-0800200c9a66 | access-date=23 July 2020}}</ref> It is taken [[Oral administration|by mouth]].<ref name="Savaysa FDA label" />

Compared with [[warfarin]] it has fewer [[drug interaction]]s.<ref name=a>{{cite journal | vauthors = Parasrampuria DA, Truitt KE | title = Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting FactorXa | journal = Clinical Pharmacokinetics | volume = 55 | issue = 6 | pages = 641–55 | date = June 2016 | pmid = 26620048 | pmc = 4875962 | doi = 10.1007/s40262-015-0342-7 }}</ref>

<!-- History and culture -->

It was developed by [[Daiichi Sankyo]] and approved in July 2011, in Japan for prevention of [[venous thromboembolism]]s following lower-limb [[orthopedic surgery]].<ref name="url_Daiichi_Sankyo_Europe_GmbH">{{cite press release |url=http://www.daiichi-sankyo.eu/media/press-news-in-english/news-detail/article/first-market-approval-in-japan-for-lixianaR-edoxaban.html |title=First market approval in Japan for Lixiana (Edoxaban) |date=22 April 2011 |work=Daiichi Sankyo Europe GmbH |url-status=dead |archive-url=https://web.archive.org/web/20131106002948/http://www.daiichi-sankyo.eu/media/press-news-in-english/news-detail/article/first-market-approval-in-japan-for-lixianaR-edoxaban.html |archive-date=6 November 2013 }}</ref> It was also approved in the United States by the [[Food and Drug Administration]] (FDA) in January 2015, for the prevention of stroke and non–central-nervous-system systemic [[embolism]].<ref>{{cite web | url=http://www.medscape.com/viewarticle/837837 | title=FDA Approves Edoxaban for Stroke Prevention in AF and DVT/PE Prevention | work=Medscape | date=9 January 2015 | access-date=10 January 2015 | last = O'Riordan | first = Michael | name-list-style = vanc }}</ref><ref>{{cite web | title=Drug Approval Package: Savaysa (edoxaban tosylate) Tablets NDA #206316 | website=U.S. [[Food and Drug Administration]] (FDA) | date=13 February 2015 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s000TOC.cfm | access-date=23 July 2020}}</ref> It was approved for use in the European Union in June 2015.<ref name="Lixiana EPAR" /> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>

==Medical uses==

In the United States, edoxaban is [[indicated]] to treat [[deep vein thrombosis]] and [[pulmonary embolism]] following five to ten days of initial therapy with a [[parenteral]] anticoagulant.<ref name="Savaysa FDA label" /> It is also indicated to reduce the risk of blood clots in people with [[nonvalvular atrial fibrillation]].<ref name="Savaysa FDA label" /><ref>{{cite journal | vauthors = Lowenstern A, Al-Khatib SM, Sharan L, Chatterjee R, Allen LaPointe NM, Shah B, Borre ED, Raitz G, Goode A, Yapa R, Davis JK, Lallinger K, Schmidt R, Kosinski AS, Sanders GD | display-authors = 6 | title = Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review | journal = Annals of Internal Medicine | volume = 169 | issue = 11 | pages = 774–787 | date = December 2018 | pmid = 30383133 | pmc = 6825839 | doi = 10.7326/M18-1523 | doi-access = free | title-link = doi }}</ref>

In the European Union, edoxaban is indicated for preventing blood clots in people with nonvalvular atrial fibrillation who also have at least one risk factor, such as having had a previous [[stroke]], [[high blood pressure]] (hypertension), [[diabetes mellitus]], [[congestive heart failure]] or being 75 years of age or older. It is also used to treat deep vein thrombosis and pulmonary embolism and to prevent either of these from reoccurring.<ref name="Lixiana EPAR">{{cite web | title=Lixiana EPAR | website=[[European Medicines Agency]] (EMA) | url=https://www.ema.europa.eu/en/medicines/human/EPAR/lixiana | access-date=23 July 2020}}</ref>

==Contraindications and notes==

Edoxaban is often contraindicated in people (incomplete list):

*with active pathological bleeding<ref name="Lixiana EMA PI"/>

*who are [[pregnant]] or [[breastfeeding]]<ref name="Lixiana EMA PI"/>

*who have conditions that increase bleeding risks. Examples: [[liver disease]] associated with [[coagulopathy]] and relevant bleeding risk, current or recent gastrointestinal ulceration, malignant [[neoplasm]]s at high risk of bleeding, recent [[brain injury]] or [[spinal injury]], recent brain, spinal or ophthalmic surgery, known or suspected [[esophageal varices]], [[arteriovenous malformation]]s, [[aneurysm]]s or major intraspinal or intracerebral vascular abnormalities<ref name="Lixiana EMA PI"/>

*who have uncontrolled and severe [[high blood pressure]]<ref name="Lixiana EMA PI"/>

*who use any other [[anticoagulant]]s<ref name="Lixiana EMA PI"/>

Edoxaban (incomplete list):

*is enhanced by the following strong [[P-glycoprotein]] (P-gp) inhibitors: [[ciclosporin]], [[dronedarone]], [[erythromycin]] or [[ketoconazole]]. Concomitant use of these and edoxaban may require 30&nbsp;mg doses of edoxaban (instead of 60&nbsp;mg). The efficacy of edoxaban may decrease when it is used with strong P-gp inducers such as [[phenytoin]], [[carbamazepine]], [[phenobarbital]] or [[St. John's Wort]]. If these medications are used with edoxaban, caution is advised.<ref name="Lixiana EMA PI"/>

*interacts with [[antiplatelets]], [[NSAIDs]], [[SSRIs]] and [[SNRIs]].<ref name="Lixiana EMA PI"/>

*inferior to [[warfarin]] in nonvalvular [[atrial fibrillation]] with a [[creatinine clearance]] (CrCl) greater than 95&nbsp;ml/min.<ref name="Savaysa FDA label" />

==Adverse effects==

May affect up to 1 in 10 people:<ref name="Lixiana EMA PI">{{Cite web|url=https://www.ema.europa.eu/en/documents/product-information/lixiana-epar-product-information_en.pdf|title=Lixiana, INN-edoxaban|url-status=live|archive-url=https://web.archive.org/web/20191106140905/https://www.ema.europa.eu/en/documents/product-information/lixiana-epar-product-information_en.pdf|archive-date=6 November 2019|access-date=6 November 2019}}</ref>

*stomach ache

*abnormal results of blood tests that measure liver function

*[[anemia]]

*bleeding from the skin, nose, vagina, bowel, mouth, throat or stomach

*rash

*[[bloody urine]]

*dizziness

*feeling sick

*headache

*itching

May affect up to 1 in 100 people:<ref name="Lixiana EMA PI"/>

*bleeding in the eyes, brain, after a surgical operation or other types of bleeding

*blood in the spit when coughing

*reduced number of [[Platelet|platelets]] in blood

*[[allergic reaction]]

*[[hives]]

May affect up to 1 in 1000 people: bleeding in the muscles, joints, abdomen, heart or inside the skull.<ref name="Lixiana EMA PI"/>

==Overdose==

Edoxaban overdose can cause serious bleeding.<ref name="Lixiana EPAR" /> No approved antidotes for edoxaban overdose exist {{as of|2021|04|lc=on}}.<ref name="Lixiana EPAR" /> [[Hemodialysis]] does not significantly contribute to edoxaban clearance.<ref name="Savaysa FDA label" /><ref name="Lixiana EMA PI"/> [[Andexanet alfa]] has been studied as an antidote for edoxaban overdose, but has only been approved for reversing [[rivaroxaban]] and [[apixaban]] effects by the FDA and the EMA as of 2019.<ref>{{Cite web |url= https://www.fda.gov/media/113954/download |title=Summary basis for regulatory action - ANDEXXA |last=Ovanesov |first=Mikhail |website=[[Food and Drug Administration]] | name-list-style = vanc |date=3 August 2017|access-date=6 November 2019}}</ref><ref>{{Cite web|url=https://www.ema.europa.eu/en/medicines/human/EPAR/ondexxya|title=Ondexxya|date=27 February 2019|website=European Medicines Agency|url-status=live|access-date=6 November 2019|archive-url=https://web.archive.org/web/20190716153654/https://www.ema.europa.eu/en/medicines/human/EPAR/ondexxya |archive-date=16 July 2019 }}</ref>

==Mechanism of action==

Edoxaban is a direct, [[Chemical specificity|selective]], reversible and competitive [[Enzyme inhibitor|inhibitor]] of human [[factor Xa]], with an [[inhibitory constant]] (K_i) value of&nbsp;0.561 [[Nanomolar|nM]]. In [[coagulation]], uninhibited factor Xa forms a [[prothrombinase]] complex with [[factor Va]] on [[platelet]] surfaces. Prothrombinases turn prothrombins to [[Thrombin|thrombins]]. Thrombins turn blood-soluble [[Fibrinogen|fibrinogens]] to insoluble [[Fibrin|fibrins]], which are the main components of blood clots.<ref name=a/>

==Pharmacokinetics==

In human, 15–150&nbsp;mg oral doses of edoxaban reach their maximum concentrations in blood 1–2&nbsp;hours after ingestion. With 60&nbsp;mg doses of [[Isotopic labeling|isotope labeled]] edoxaban, 97% of the total radiation was detected after oral administration, with 62% from feces and 35% from urine. 49% of the total radiation from the feces and 24% from the urine were from edoxaban, the rest from its metabolites.<ref name=a/>

Metabolism occurs mostly via [[CES1]], [[CYP3A4]], [[CYP3A5]] and enzymatic [[hydrolysis]]. CES1 oxidizes the [[tertiary amide]] [[carbonyl]] carbons of edoxabans to [[carboxylic acid]] groups. CYP3A4 and CYP3A5 oxidize edoxabans via [[hydroxylation]] or [[demethylation]]. In hydrolysis, [[2-amino-5-chloropyridine]] moiety of edoxaban is removed. [[Glucuronidation]] occurs to a lesser extent via [[glucuronosyltransferases]].<ref name=a/>

== References ==

{{Portal bar | Medicine}}

[[Category:Direct Xa inhibitors]]

[[Category:Chloroarenes]]

[[Category:Daiichi Sankyo]]