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
| image_class = skin-invert-image
| width = 180
| alt =
| image2 = Deferasirox ball-and-stick model.png
| width2 =
| alt2 =
| caption =
| 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 = By mouth
| class =
| ATC_prefix = V03
| ATC_suffix = AC03
| ATC_supplemental =
| legal_AU = S4
| legal_AU_comment =
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| legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment =
| legal_EU = Rx-only
| legal_EU_comment = {{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}}
| legal_UN =
| legal_UN_comment =
| legal_status = Rx-only
| 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%)
| 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
| 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 = {{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 }}
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Deferasirox, sold under the brand name Exjade among others, is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias.{{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 }}{{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 }} It is the first oral medication approved in the United States for this purpose.{{cite press release | url = https://www.fda.gov/bbs/topics/news/2005/NEW01258.html | archive-url = https://web.archive.org/web/20051126045009/http://www.fda.gov/bbs/topics/news/2005/NEW01258.html | url-status = dead | archive-date = 26 November 2005 | 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}}
It was approved by the US Food and Drug Administration (FDA) in November 2005.
According to the FDA (May 2007), kidney failure and cytopenias 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.{{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 }}{{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 }}{{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 }} It is on the World Health Organization's List of Essential Medicines.{{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 }}
In July 2020, Teva decided to discontinue deferasirox.{{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 | archive-url=https://web.archive.org/web/20200721035002/https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Deferasirox+Tablets&st=d&tab=tabs-4&panels=0 | url-status=dead | archive-date=21 July 2020 | access-date=20 July 2020}} It is available as a generic medication.{{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}}
Properties
Image:Deferasirox–iron(III) complex.png
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
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(4H)-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).{{cite journal | vauthors = Steinhauser S, Heinz U, Bartholomä M, Weyhermüller T, Nick H, Hegetschweiler K |title=Complex Formation of ICL670 and Related Ligands with FeIII and FeII |journal=European Journal of Inorganic Chemistry |volume=2004 |issue=21 |pages=4177–4192 |year=2004 |doi=10.1002/ejic.200400363}}]
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.{{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}} A boxed warning was added in the same year with regard to kidney failure, liver failure and gastrointestinal bleeding.{{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}} It is suspected that the main driver of this spike in suspected deaths relates to the re-analysis of adverse event data by Novartis.
References
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{{Chelating agents}}
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Category:Chelating agents used as drugs
Category:Drugs developed by Novartis