Deferasirox

Last updated

Deferasirox
Deferasirox.svg
Deferasirox ball-and-stick model.png
Clinical data
Pronunciationde FER a sir ox
Trade names Exjade, others
Other namesCGP-72670, ICL-670A, IC L670
AHFS/Drugs.com Monograph
MedlinePlus a606002
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: WARNING [1] Rx-only
  • EU:Rx-only [2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 70%
Protein binding 99%
Metabolism Liver glucuronidation
Elimination half-life 8 to 16 hours
Excretion Fecal (84%) and kidney (8%)
Identifiers
  • 4-(3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.211.077 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H15N3O4
Molar mass 373.368 g·mol−1
3D model (JSmol)
Density 1.4±0.1 g/cm3 [3]
  • OC(=O)c1ccc(cc1)n2nc(nc2c3ccccc3O)c4ccccc4O
  • InChI=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) Yes check.svgY
  • Key:BOFQWVMAQOTZIW-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [4] [5] It is the first oral medication approved in the United States for this purpose. [6]

Contents

It was approved by the US Food and Drug Administration (FDA) in November 2005. [4] [6] 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. [7] [8] [9] It is on the World Health Organization's List of Essential Medicines. [10]

In July 2020, Teva decided to discontinue deferasirox. [11] It is available as a generic medication. [12]

Properties

Two deferasirox molecules binding iron Deferasirox-iron(III) complex.png
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 to be added Deferasirox synthesis.png
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(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). [13]

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. [14] A boxed warning was added in the same year with regard to kidney failure, liver failure and gastrointestinal bleeding. [15] It is suspected that the main driver of this spike in suspected deaths relates to the re-analysis of adverse event data by Novartis. [14]

Related Research Articles

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<span class="mw-page-title-main">Thalassemia</span> Family of inherited blood disorders

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time. Older terms included Cooley's anemia and Mediterranean anemia for beta-thalassemia. These have been superseded by the terms Transfusion-Dependent Thalassemia (TDT) and non-Transfusion-Dependent Thalassemia (NTDT). Patients with TDT require regular transfusions, typically every two to five weeks. TDTs include Beta-thalassemia major, nondeletional HbH disease, survived Hb Bart's disease, and severe HbE/beta-thalassemia.

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References

  1. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  2. "Exjade EPAR". European Medicines Agency. 28 August 2006. Retrieved 21 June 2024.
  3. "Material Safety Data Sheet (MSDS): Deferasirox". ChemSrc. 2018.
  4. 1 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 29 April 2014 at the Wayback Machine
  5. 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. S2CID   195686285.
  6. 1 2 "FDA Approves First Oral Drug for Chronic Iron Overload" (Press release). United States Food and Drug Administration. 9 November 2005. Retrieved 31 October 2007.
  7. "Exjade – deferasirox" (PDF). European Medicines Agency. 2018. Archived from the original (PDF) on 29 December 2017. Retrieved 26 November 2012.
  8. 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.
  9. "Review: Exjade side effects". Archived from the original on 4 March 2016. Retrieved 20 April 2013.
  10. World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  11. "Deferasirox Discontinuation". U.S. Food and Drug Administration (FDA). Retrieved 20 July 2020.
  12. "Drugs@FDA: FDA-Approved Drugs". U.S. Food and Drug Administration. Retrieved 15 August 2020.
  13. 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.]
  14. 1 2 "QuarterWatch™ (Quarter 4 and 2009 totals): Reported Patient Deaths Increased by 14% in 2009". Institute For Safe Medication Practices. Retrieved 28 June 2021.
  15. Pediatrics AA (19 February 2010). "Black box warning added to Exjade". AAP News. doi:10.1542/aapnews.20100219-1 (inactive 31 January 2024). ISSN   1073-0397. Archived from the original on 28 June 2021. Retrieved 28 June 2021.{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)