View source for Deferasirox

{{Short description|Oral iron chelator}}
{{Use dmy dates|date=June 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 460774502
| image = Deferasirox.svg
| width = 180
| alt = 
| image2 = Deferasirox ball-and-stick model.png
| width2 = 
| alt2 = 
| caption =

<!-- Clinical data -->
| pronounce = de FER a sir ox
| tradename = Exjade, others
| Drugs.com = {{drugs.com|monograph|deferasirox}}
| MedlinePlus = a606002
| DailyMedID = Deferasirox
| pregnancy_AU = C
| pregnancy_AU_comment = 
| pregnancy_category= 
| routes_of_administration = [[Oral administration|By mouth]]
| class = 
| ATC_prefix = V03
| ATC_suffix = AC03 
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = S4
| 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 = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = 
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title=Exjade EPAR | website=European Medicines Agency | date=28 August 2006 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/exjade | access-date=21 June 2024}}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability = 70%
| protein_bound = 99%
| metabolism = [[Liver]] [[glucuronidation]]
| metabolites = 
| onset = 
| elimination_half-life = 8 to 16 hours
| duration_of_action = 
| excretion = Fecal (84%) and [[kidney]] (8%)

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 201530-41-8
| CAS_supplemental = 
| PubChem = 214348
| IUPHAR_ligand = 
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01609
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4591431
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = V8G4MOF2V9
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D03669
| ChEBI_Ref = 
| ChEBI = 49005
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 550348
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = CGP-72670, ICL-670A, IC L670

<!-- Chemical and physical data -->
| IUPAC_name = 4-(3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid
| C=21 | H=15 | N=3 | O=4
| SMILES = OC(=O)c1ccc(cc1)n2nc(nc2c3ccccc3O)c4ccccc4O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C21H15N3O4/c25-17-7-3-1-5-15(17)19-22-20(16-6-2-4-8-18(16)26)24(23-19)14-11-9-13(10-12-14)21(27)28/h1-12,25-26H,(H,27,28)
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = BOFQWVMAQOTZIW-UHFFFAOYSA-N
| density = 1.4±0.1
| density_notes = <ref name="chemsrc">{{Cite web | url=https://www.chemsrc.com/en/cas/201530-41-8_894718.html | title= Material Safety Data Sheet (MSDS): Deferasirox | work = ChemSrc | date = 2018 }}</ref>
| melting_point = 
| melting_high = 
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}

'''Deferasirox''', sold under the brand name '''Exjade''' among others, is an oral [[iron]] [[Chelation therapy|chelator]]. Its main use is to reduce [[Iron overload disorder|chronic iron overload]] in patients who are receiving long-term [[blood transfusion]]s for conditions such as beta-[[thalassemia]] and other chronic [[anemia]]s.<ref name=Choudhry>{{cite journal | vauthors = Choudhry VP, Naithani R | title = Current status of iron overload and chelation with deferasirox | journal = Indian Journal of Pediatrics | volume = 74 | issue = 8 | pages = 759–64 | date = August 2007 | pmid = 17785900 | doi = 10.1007/s12098-007-0134-7 | s2cid = 19930076 }} [http://www.ijppediatricsindia.org/text.asp?2007/74/8/759/34579 Free full text] {{Webarchive|url=https://web.archive.org/web/20140429202722/http://www.ijppediatricsindia.org/text.asp?2007%2F74%2F8%2F759%2F34579 |date=29 April 2014 }}</ref><ref>{{cite journal | vauthors = Yang LP, Keam SJ, Keating GM | title = Deferasirox : a review of its use in the management of transfusional chronic iron overload | journal = Drugs | volume = 67 | issue = 15 | pages = 2211–30 | year = 2007 | pmid = 17927285 | doi = 10.2165/00003495-200767150-00007 | s2cid = 195686285 }}</ref>  It is the first oral medication approved in the United States for this purpose.<ref name=FDA>{{cite press release | url = https://www.fda.gov/bbs/topics/news/2005/NEW01258.html | title = FDA Approves First Oral Drug for Chronic Iron Overload | date = 9 November 2005 | access-date = 31 October 2007 | publisher = United States [[Food and Drug Administration]]}}</ref>

It was approved by the US [[Food and Drug Administration]] (FDA) in November 2005.<ref name=Choudhry/><ref name=FDA/>
According to the FDA (May 2007), [[kidney failure]] and [[cytopenia]]s have been reported in patients receiving deferasirox tablets for oral suspension. It is approved in the European Union by the [[European Medicines Agency]] (EMA) for children six years and older for chronic iron overload from repeated blood transfusions.<ref>{{cite web | url = http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000670/WC500033927.pdf | title = Exjade – deferasirox | publisher = European Medicines Agency | date = 2018 | access-date = 26 November 2012 | archive-date = 29 December 2017 | archive-url = https://web.archive.org/web/20171229231528/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000670/WC500033927.pdf | url-status = dead }}</ref><ref name="Kontoghiorghes_2013">{{cite journal | vauthors = Kontoghiorghes GJ | title = Turning a blind eye to deferasirox's toxicity? | journal = Lancet | volume = 381 | issue = 9873 | pages = 1183–4 | date = April 2013 | pmid = 23561999 | doi = 10.1016/S0140-6736(13)60799-0 | s2cid = 27794849 | doi-access = free }}</ref><ref>{{cite web | url = http://www.ehealthme.com/q/exjade-side-effects-drug-interactions | title = Review: Exjade side effects | access-date = 20 April 2013 | archive-date = 4 March 2016 | archive-url = https://web.archive.org/web/20160304070427/http://www.ehealthme.com/q/exjade-side-effects-drug-interactions | url-status = dead }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref>

In July 2020, Teva decided to discontinue deferasirox.<ref>{{cite web | title=Deferasirox Discontinuation | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Deferasirox+Tablets&st=d&tab=tabs-4&panels=0 | access-date=20 July 2020}}</ref> It is available as a [[generic medication]].<ref>{{cite web | title=Drugs@FDA: FDA-Approved Drugs | website=U.S. Food and Drug Administration | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=213374 | access-date=15 August 2020}}</ref>

==Properties==
[[Image:Deferasirox–iron(III) complex.png|thumb|left|Two deferasirox molecules binding iron]]
The half-life of deferasirox is between 8 and 16 hours allowing once a day dosing. Two molecules of deferasirox are capable of binding to 1 atom of iron which are subsequently eliminated by fecal excretion. Its low molecular weight and high lipophilicity allows the drug to be taken orally unlike [[deferoxamine]] which has to be administered by IV route (intravenous infusion). Together with [[deferiprone]], deferasirox seems to be capable of removing iron from cells (cardiac myocytes and hepatocytes) as well as removing iron from the blood.

==Synthesis==
Deferasirox can be prepared from simple commercially available starting materials (salicylic acid, salicylamide and 4-hydrazinobenzoic acid) in the following two-step synthetic sequence:
[[Image:Deferasirox synthesis.png|center|Image to be added]]
The condensation of salicyloyl chloride (formed ''in situ'' from salicylic acid and thionyl chloride) with salicylamide under dehydrating reaction conditions results in formation of 2-(2-hydroxyphenyl)-1,3(4''H'')-benzoxazin-4-one. This intermediate is isolated and reacted with 4-hydrazinobenzoic acid in the presence of base to give 4-(3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl)benzoic acid (deferasirox).<ref name="Steinhauser">{{cite journal | vauthors = Steinhauser S, Heinz U, Bartholomä M, Weyhermüller T, Nick H, Hegetschweiler K |title=Complex Formation of ICL670 and Related Ligands with Fe<sup>III</sup> and Fe<sup>II</sup> |journal=European Journal of Inorganic Chemistry |volume=2004 |issue=21 |pages=4177–4192 |year=2004 |doi=10.1002/ejic.200400363}}]</ref>

==Risks==
Deferasirox ranked second on the list of drugs most frequently suspected in reported patient deaths compiled for 2019, by the [[Institute for Safe Medical Practices]], with 1320 suspected deaths.<ref name=":0">{{Cite web|title=QuarterWatch™ (Quarter 4 and 2009 totals): Reported Patient Deaths Increased by 14% in 2009|url=https://www.ismp.org/resources/quarterwatchtm-quarter-4-and-2009-totals-reported-patient-deaths-increased-14-2009|access-date=28 June 2021|website=Institute For Safe Medication Practices|language=en}}</ref> A [[boxed warning]] was added in the same year with regard to [[kidney failure]], [[liver failure]] and [[gastrointestinal bleeding]].<ref>{{Cite journal|last=Pediatrics|first=American Academy of|date=19 February 2010|title=Black box warning added to Exjade|url=https://www.aappublications.org/content/early/2010/02/19/aapnews.20100219-1|journal=AAP News|language=en|doi=10.1542/aapnews.20100219-1|doi-broken-date=1 November 2024|issn=1073-0397|access-date=28 June 2021|archive-date=28 June 2021|archive-url=https://web.archive.org/web/20210628023800/https://www.aappublications.org/content/early/2010/02/19/aapnews.20100219-1|url-status=dead}}</ref> It is suspected that the main driver of this spike in suspected deaths relates to the re-analysis of adverse event data by [[Novartis]].<ref name=":0" />

== References ==
{{Reflist}}

{{Chelating agents}}
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{{Authority control}}

[[Category:Chelating agents]]
[[Category:Chelating agents used as drugs]]
[[Category:Orphan drugs]]
[[Category:Drugs developed by Novartis]]
[[Category:Antidotes]]
[[Category:Triazoles]]
[[Category:Benzoic acids]]
[[Category:2-Hydroxyphenyl compounds]]
[[Category:World Health Organization essential medicines]]