Edaravone

Edaravone
Clinical data
Trade namesRadicava, Radicut, Xavron, others
Other namesMCI-186
AHFS/Drugs.comMonograph
MedlinePlusa617027
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Excretionla
Identifiers
IUPAC name
  • 5-methyl-2-phenyl-4H-pyrazol-3-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.001.719
Edit this at Wikidata
Chemical and physical data
FormulaC10H10N2O
Molar mass174.203 g·mol−1
3D model (JSmol)
SMILES
  • O=C1N(/N=C(\C1)C)c2ccccc2
InChI
  • InChI=1S/C10H10N2O/c1-8-7-10(13)12(11-8)9-5-3-2-4-6-9/h2-6H,7H2,1H3 checkY
  • Key:QELUYTUMUWHWMC-UHFFFAOYSA-N checkY
  (verify)

Edaravone, sold as under the brand names Radicava and Radicut among others, is an intravenous medication used to help with recovery following a stroke and to treat amyotrophic lateral sclerosis (ALS).[1][2]

The label carries a warning about the potential for hypersensitivity reactions to edaravone, and adverse effects include bruising, gait disturbances, headache, skin inflammation, eczema, problems breathing, excess sugar in urine, and fungal skin infections.[1]

The mechanism by which edaravone might be effective is unknown.[1] The drug is known to be an antioxidant, and oxidative stress has been hypothesized to be part of the process that kills neurons in people with ALS.[3]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[4]

Medical uses

Edaravone is used to help people recover from stroke in Japan,[5] and is used to treat ALS in the US and Japan.[1][3] It was approved for ALS in the US in 2017 based on a small randomized controlled clinical trial with people who had early-stage ALS in Japan, who were administered the drug for 6 months; it had failed two earlier trials in people with all stages of ALS.[1][3]

It is given by intravenous infusion.[1]

There is no data on whether it is safe for pregnant women to take, and it is unknown if edaravone is secreted in breast milk.[1]

Adverse effects

The label carries a warning about the potential for hypersensitivity reactions to edaravone.[1]

The following adverse effects in at least 2% more people given the drug than were given placebo: bruising, gait disturbances, headache, skin inflammation, eczema, problems breathing, excess sugar in urine, and fungal skin infections.[1]

Pharmacology

The mechanism by which edaravone might be effective in ALS is unknown.[1] The drug is known to be an antioxidant, and oxidative stress has been hypothesized to be part of the process that kills neurons in people with ALS.[3]

The half-life of edaravone is 4.5 to 6 hours and the half-lives of its metabolites are 2 to 3 hours. It is metabolized to a sulfate conjugate and a glucuronide conjugate, neither of which are active. It is primarily excreted in urine as the glucuronide conjugate form.[1]

History

Researchers first developed the free radical scavenger edaravone in late 1980s as a treatment for stroke. The approach, introduced by Koji Abe, now at Okayama University Hospital in Japan, aimed to prevent the swelling of the brain which may occur after a stroke.[6]

It has been marketed in Japan by Mitsubishi Pharma for stroke since 2001 and is now generic.[5][7]

Mitsubishi Tanabe started a phase III clinical trial in ALS in 2011 in Japan and by June 2015, it had been approved for that use in Japan. The company had received Orphan Drug Designation for edaravone from the FDA and EU by 2016.[8]

In May 2017, I.V. edaravone was approved by the FDA to treat people with amyotrophic lateral sclerosis (ALS) in the United States.[9] The FDA approval was conditioned on Mitsubishi Tanabe completing several additional studies to clarify the risks of cancer and liver disease, among other effects of the drug.[10] Formulation of edaravone by mouth called TW001 (mixture of the edaravone and SBE-HP-βCD [11]) has been under development by Treeway for ALS; as of 2015 it had successfully completed Phase I trial and had received orphan status in the US and in Europe.[12]

Society and culture

The price for the drug when it launched in Japan for stroke in 2001 was set by the Japanese government at 9,931 yen/ampule.[13]

When the drug launched in Japan for ALS in 2001, the price was $35,000; the price in Japan in 2017 was $5,000, the US price at launch was around $145,000.[7] In the US the drug was approved for all people with ALS but it was unclear at approval whether insurers would agree to pay for the drug for all people with ALS, or only people in the early stages of the disease.[7][14] There are three filed trials for edaravone, demonstrating it may work in less than 5% of all ALS population.

Brand names include Radicut, ラジカット, Radicava, Xavron.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 "Radicava- edaravone injection". DailyMed. 29 November 2018. Retrieved 17 October 2020.
  2. ↑ Bailly, Christian; Hecquet, Paul-Emile; Kouach, Mostafa; Thuru, Xavier; Goossens, Jean-François (2020). "Chemical reactivity and uses of 1-phenyl-3-methyl-5-pyrazolone (PMP), also known as edaravone". Bioorganic & Medicinal Chemistry. 28 (10): 115463. doi:10.1016/j.bmc.2020.115463. PMID 32241621. S2CID 214766793.
  3. 1 2 3 4 Petrov D, Mansfield C, Moussy A, Hermine O (2017). "ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?". Front Aging Neurosci. 9: 68. doi:10.3389/fnagi.2017.00068. PMC 5360725. PMID 28382000.
  4. ↑ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Retrieved 16 September 2020.
  5. 1 2 Miyaji Y, Yoshimura S, Sakai N, Yamagami H, Egashira Y, Shirakawa M, et al. (2015). "Effect of edaravone on favorable outcome in patients with acute cerebral large vessel occlusion: subanalysis of RESCUE-Japan Registry". Neurol. Med. Chir. (Tokyo). 55 (3): 241–7. doi:10.2176/nmc.ra.2014-0219. PMC 4533339. PMID 25739433.
  6. ↑ "FDA Approves Edaravone as a Treatment for ALS". Research ALS. Archived from the original on 2019-02-12. Retrieved 2017-05-10.
  7. 1 2 3 Herper, Matthew. "The First ALS Drug In 22 Years Is Approved -- And It Costs 4 Times What It Does In Japan". Forbes. Retrieved 2017-05-10.
  8. ↑ Lane, EJ (April 20, 2016). "Mitsubishi Tanabe says ALS drug meets PhIII endpoint". FiercePharma.
  9. ↑ Commissioner, Office of the. "Press Announcements - FDA approves drug to treat ALS". www.fda.gov. Retrieved 2017-05-07.
  10. ↑ "NDA 209176 Approval letter" (PDF). FDA. May 5, 2017.
  11. ↑ Rong WT, Lu YP, Tao Q, Guo M, Lu Y, Ren Y, Yu SQ (February 2014). "Hydroxypropyl-sulfobutyl-β-cyclodextrin improves the oral bioavailability of edaravone by modulating drug efflux pump of enterocytes". J Pharm Sci. 103 (2): 730–42. doi:10.1002/jps.23807. PMID 24311389.
  12. ↑ "Edaravone oral". AdisInsight. Retrieved 13 May 2017.
  13. ↑ "Press release:Launching of RADICUT Injection. 30 mg". Mitsubishi-Tokyo Pharmaceuticals via Evaluate. May 23, 2001.
  14. ↑ Grady, Denise (5 May 2017). "A Second Drug Is Approved to Treat A.L.S." The New York Times. Retrieved 8 May 2017.
  • "Edaravone". Drug Information Portal. U.S. National Library of Medicine.
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