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{{Short description|Oral iron chelator}}
{{drugbox | Verifiedfields = changed
{{Use dmy dates|date=June 2024}}
| verifiedrevid = 401979549
{{cs1 config |name-list-style=vanc |display-authors=6}}
|
{{Infobox drug
| IUPAC_name = benzoic acid
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 460774502
| image = Deferasirox.svg | image = Deferasirox.svg
| width = 180 | 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 = ]
| 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 = ] ]
| metabolites =
| onset =
| elimination_half-life = 8 to 16 hours
| duration_of_action =
| excretion = Fecal (84%) and ] (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_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4591431 | ChemSpiderID = 4591431
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = V8G4MOF2V9 | UNII = V8G4MOF2V9
| ChEMBL_Ref = {{ebicite|changed|EBI}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D03669
| ChEMBL = <!-- blanked - oldvalue: 1201122 -->
| ChEBI_Ref =
| InChI = 1/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/h1-12,22-23H,(H,27,28)/b19-15-,20-16+
| ChEBI = 49005
| smiles = O=C4/C=C\C=C/C4=C2\N(N/C(=C1\C(=O)\C=C/C=C1)N2)c3ccc(C(=O)O)cc3
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| InChIKey = FMSOAWSKCWYLBB-VBGLAJCLBX
| ChEMBL = 550348
| CASNo_Ref = {{cascite|correct|CAS}}
| 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_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/h1-12,22-23H,(H,27,28)/b19-15-,20-16+ | 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_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FMSOAWSKCWYLBB-VBGLAJCLSA-N | StdInChIKey = BOFQWVMAQOTZIW-UHFFFAOYSA-N
| density = 1.4±0.1
| CAS_number_Ref = {{cascite|correct|??}}
| 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>
| CAS_number = 201530-41-8
| ATC_prefix = V03 | melting_point =
| ATC_suffix = AC03 | melting_high =
| melting_notes =
| PubChem = 5493381
| boiling_point =
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| boiling_notes =
| DrugBank = DB01609
| solubility =
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D03669 | sol_units =
| specific_rotation =
| C = 21| H = 15| N = 3 | O = 4
| molecular_weight = 373.362 g/mol
| bioavailability = 70%
| protein_bound = 99%
| metabolism = ] ]
| elimination_half-life = 8 to 16 hours
| excretion = Fecal (84%) and ] (8%)
| pregnancy_AU = C
| pregnancy_US = B
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = Oral
| licence_EU =Exjade
| license_US =Deferasirox
}} }}
'''Deferasirox''' (marketed as '''Exjade''') is a ]<ref name=Choudhry>{{cite journal |author=Choudhry VP, Naithani R |title=Current status of iron overload and chelation with deferasirox |journal=Indian J Pediatr |volume=74 |issue=8 |pages=759–64 |year=2007 |pmid=17785900 |doi=10.1007/s12098-007-0134-7}} </ref> oral ] ]. Its main use is to reduce ] in patients who are receiving long-term ]s for conditions such as beta-] and other chronic ]s.<ref name=Choudhry/><ref>{{cite journal |author=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=}}</ref> It is the first oral medication approved in the USA for this purpose.<ref name=FDA>{{cite press release | url = http://www.fda.gov/bbs/topics/news/2005/NEW01258.html | title = FDA Approves First Oral Drug for Chronic Iron Overload | date = November 9, 2005 | accessdate = 2007-10-31 | publisher = United States ]}}</ref>


'''Deferasirox''', sold under the brand name '''Exjade''' among others, is an oral ] ]. Its main use is to reduce ] in patients who are receiving long-term ]s for conditions such as beta-] and other chronic ]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 }} {{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 ]}}</ref>
It was approved by the ] ] (FDA) in November 2005.<ref name=Choudhry/><ref name=FDA/>
According to FDA (May 2007), ] and ]s have been reported in patients receiving deferasirox oral suspension tablets.


It was approved by the US ] (FDA) in November 2005.<ref name=Choudhry/><ref name=FDA/>
==Properties of deferasirox==
According to the FDA (May 2007), ] and ]s have been reported in patients receiving deferasirox tablets for oral suspension. It is approved in the European Union by the ] (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 ].<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. ] (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 ].<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==
] ]
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 desferoxamine which has to be administered by IV route (intravenous infusion). Together with ], deferasirox seems to be capable of removing iron from cells (cardiac myocytes and hepatocytes) as well as removing iron from the blood. 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 ] which has to be administered by IV route (intravenous infusion). Together with ], deferasirox seems to be capable of removing iron from cells (cardiac myocytes and hepatocytes) as well as removing iron from the blood.


==Synthesis== ==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: Deferasirox can be prepared from simple commercially available starting materials (salicylic acid, salicylamide and 4-hydrazinobenzoic acid) in the following two-step synthetic sequence:
] ]
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 |author=Stefan Steinhauser, Uwe Heinz, Mark Bartholomä, Thomas Weyhermüller, Hanspeter Nick, Kaspar Hegetschweiler |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> 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== ==Risks==
Deferasirox ranked second on the list of drugs most frequently suspected in reported patient deaths compiled for 2019, by the ], 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 ] was added in the same year with regard to ], ] and ].<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 ].<ref name=":0" />
Deferasirox was the #2 drug on the list of 'Most frequent suspected drugs in reported patient deaths' compiled by the Institute for Safe Medical Practices in 2009. There were 1320 deaths reported, perhaps explained by an update to the ADE data of Novartis, and a new boxed warning about gastrointestinal haemorrhage as well as kidney and liver failure.
<ref>{{cite news |author=ISMP |title=ISMP QuarterWatch(TM) |publisher=ISMP Medication Safety Alert |volume=15 |issue=12 |pages=1–3 |year=2010 }}</ref>


==References== == References ==
{{Reflist}} {{Reflist}}


{{Chelating agents}} {{Chelating agents}}
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