Deferasirox

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.[2][3] It is the first oral medication approved in the United States for this purpose.[4]

Deferasirox
Clinical data
Pronunciationde FER a sir ox
Trade namesExjade, Jadenu
Other namesCGP-72670, ICL-670A, IC L670
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability70%
Protein binding99%
MetabolismHepatic glucuronidation
Elimination half-life8 to 16 hours
ExcretionFecal (84%) and renal (8%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.211.077
Chemical and physical data
FormulaC21H15N3O4
Molar mass373.368 g·mol−1
3D model (JSmol)
Density1.4±0.1 g/cm3 [1]
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It was approved by the U.S.Food and Drug Administration (FDA) in November 2005.[2][4] According to the FDA (May 2007), kidney failure and cytopenias have been reported in patients receiving deferasirox oral suspension tablets. 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.[5][6][7]

In July 2020, Teva decided to discontinue deferasirox.[8] It is available as a generic medication.[9]

Properties
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:

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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).[10]

Risks

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.[11]

References
  1. "Material Safety Data Sheet (MSDS): Deferasirox". ChemSrc. 2018.
  2. Choudhry VP, Naithani R (August 2007). "Current status of iron overload and chelation with deferasirox". Indian Journal of Pediatrics. 74 (8): 759–64. doi:10.1007/s12098-007-0134-7. PMID 17785900. S2CID 19930076. Free full text Archived 2014-04-29 at the Wayback Machine
  3. Yang LP, Keam SJ, Keating GM (2007). "Deferasirox : a review of its use in the management of transfusional chronic iron overload". Drugs. 67 (15): 2211–30. doi:10.2165/00003495-200767150-00007. PMID 17927285.
  4. "FDA Approves First Oral Drug for Chronic Iron Overload" (Press release). United States Food and Drug Administration. November 9, 2005. Retrieved 2007-10-31.
  5. "Exjade – deferasirox" (PDF). European Medicines Agency. 2018.
  6. Kontoghiorghes GJ (April 2013). "Turning a blind eye to deferasirox's toxicity?". Lancet. 381 (9873): 1183–4. doi:10.1016/S0140-6736(13)60799-0. PMID 23561999. S2CID 27794849.
  7. "Review: Exjade side effects".
  8. "Deferasirox Discontinuation". U.S. Food and Drug Administration (FDA). Retrieved 20 July 2020.
  9. "Drugs@FDA: FDA-Approved Drugs". U.S. Food and Drug Administration. Retrieved 15 August 2020.
  10. Steinhauser S, Heinz U, Bartholomä M, Weyhermüller T, Nick H, Hegetschweiler K (2004). "Complex Formation of ICL670 and Related Ligands with FeIII and FeII". European Journal of Inorganic Chemistry. 2004 (21): 4177–4192. doi:10.1002/ejic.200400363.]
  11. ISMP (2010). "ISMP QuarterWatch(TM)". 15 (12). ISMP Medication Safety Alert. pp. 1–3.
  • "Deferasirox". Drug Information Portal. U.S. National Library of Medicine.
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