Edaravone …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 04.23.2021
Released 05.15.2017
Expires For CME 04.23.2024

Edaravone

Author: K K Jain MD†

See Contributor Disclosures

Edaravone

In This Article

Quick Link

Introduction

Historical note and terminology

Edaravone, a free radical scavenger, was approved in Japan for the treatment of cerebral infarction in 2005 and was available in South Korea as well. It was approved for the treatment of amyotrophic lateral sclerosis in those countries in 2015. Edaravone was approved by the U.S. Food and Drug Administration (FDA) in 2017 and is available in the United States. This is the first approval of a new drug for amyotrophic lateral sclerosis since the approval of the only other drug for amyotrophic lateral sclerosis, riluzole, more than 2 decades ago (14). The drug will be sold under the brand name Radicava, and 1 year of treatment costs more than $145,000. The manufacturer will provide some copay assistance to patients with commercial insurance and other help to those who are uninsured or face delays in coverage. Those who qualify might even be treated for free.

Pharmacology

Edaravone is a member of the substituted 2-pyrazolin-5-one class with the chemical name 3-methyl-1-phenyl-2-pyrazolin-5-one.

Pharmacodynamics. The neuroprotective effect of edaravone in cerebral infarction was demonstrated in rat stroke models and attributed to its free radical scavenger effect. Similar neuroprotective effects of edaravone were reported in 3 rodent amyotrophic lateral sclerosis models (03). The mechanism by which edaravone exerts its therapeutic effect in patients with amyotrophic lateral sclerosis is not well understood, although oxidative stress is involved in the pathogenesis of neurodegenerative disorders such as amyotrophic lateral sclerosis as indicated by biomarker studies (10). Excessive amounts of free radicals, such as reactive oxygen species, have detrimental effects on neurons leading to cell damage via peroxidation of unsaturated fatty acids in the cell membrane. Comparative 2D gel electrophoresis-based proteomic analyses on neuroblastoma cells exposed to oxidative stress have shown that edaravone can reverse the cytotoxic effects of hydrogen peroxide at cellular as well as protein levels via induction of peroxiredoxin-2 (04).

Edaravone has been shown to suppress motor functional decline and nitration of tyrosine residues in the CSF in open phase 2 clinical trials in amyotrophic lateral sclerosis patients. Edaravone functions therapeutically as a scavenger of peroxynitrite as well as lipid peroxyl radicals, which is consistent with the finding that edaravone treatment reduces levels of 3-nitrotyrosine in the CSF of patients with amyotrophic lateral sclerosis (02).

Pharmacokinetics. Important points regarding the pharmacokinetics of edaravone include the following:

	• The maximum plasma concentration (Cmax) of edaravone is reached by the end of intravenous infusion, the usual method of administration. Edaravone does not accumulate in plasma following administration of multiple doses.
	• Edaravone is bound to human serum proteins (92%), mainly to albumin.
	• The mean terminal elimination half-life of edaravone is 4.5 to 6 hours. The half-lives of its metabolites are 2 to 2.8 hours.
	• Edaravone is metabolized to a sulfate conjugate and a glucuronide conjugate, which are pharmacologically inactive. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase isoforms in the liver and the kidney. In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases.
	• In healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate form (70% to 90% of the dose). Approximately 5% to 10% of the dose was recovered in the urine as sulfate conjugate, and only 1% of the dose or less was recovered in the urine in unchanged form. In vitro studies suggest that the sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the human kidney before excretion into the urine.

Routes of administration. Edaravone is used as an intravenous preparation because of poor oral availability. Oral liquid dosage form would be the preferred delivery method, and an oral delivery system is in development to enhance oral bioavailability (12).

Clinical trials

Clinical trials of edaravone are shown in Table 1.

Table 1. Clinical Trials of Edaravone in Amyotrophic Lateral Sclerosis

Type of trial	Results	References
In a phase 2, open-label trial, amyotrophic lateral sclerosis patients received either 30 or 60 mg of edaravone via IV drip once/day for 2 weeks followed by a 2-week observation period. This 4-week cycle was repeated 6 times. The primary endpoint was change in ALSFRS-R (amyotrophic lateral sclerosis functional rating scale - revised) score; the secondary endpoint was 3-nitrotyrosine (3NT) level in CSF.	During the 6-month treatment period, the decline in ALSFRS-R score in the 60-mg group was significantly less than that in the 6 months prior to edaravone administration. In almost all patients, CSF 3NT, a biomarker for oxidative stress, was markedly reduced to almost undetectable levels at the end of the 6-month treatment period. There was delay in the progression of amyotrophic lateral sclerosis by reduction of oxidative stress.	(20)
In a phase 3, double-blind, parallel group clinical trial of amyotrophic lateral sclerosis patients who received placebo or IV edaravone infusion over 60 min for the first 14 days in cycle 1, and for 10 of the first 14 days during cycles 2 to 6 during a 24-week treatment period, the primary endpoint was change in ALSFRS-R scale.	This study failed to demonstrate the efficacy of edaravone in delaying the progression of amyotrophic lateral sclerosis in patients with longstanding disease. Although the primary endpoint was not achieved, the results enabled the identification of a patient population in which edaravone could be expected to show efficacy in the phase 3 trial.	(01)
In a 48-week, placebo-controlled, randomized, double-blind, phase 3 study of edaravone, a 24-week double-blind period was followed by a 24-week open-label phase. Each cycle consisted of 10 days of treatment over 2 weeks followed by a 14-day drug-free period, for a total of 48 weeks. Main efficacy endpoints were changes in ALSFRS-R and ALSAQ40 scores (NCT01492686).	Patients initially randomized to edaravone (versus placebo), and who continued edaravone treatment for up to 48 weeks, showed a sustained efficacy advantage compared to those who began on placebo double-blind and switched to edaravone 24 weeks later. Early treatment with edaravone appears to improve efficacy and quality of life in this population of amyotrophic lateral sclerosis patients.	(11)

In the latest phase 3 trial, eligibility was restricted to patients with a relatively short disease duration and preserved vital capacity. Concomitant use of riluzole was permitted. Results demonstrated that edaravone provided significant efficacy as assessed by ALSFRS-R scores. Therefore, the combination of edaravone and riluzole should be started at an earlier stage of amyotrophic lateral sclerosis (15).

In a 24-week open label extension of the latest phase 3 double-blind trial, there was no deterioration of ALSFRS-R in the edaravone-treated patients, and no safety concerns related to edaravone were detected (19).

A metaanalysis of controlled clinical trials has shown that intravenous edaravone is effective and safe in patients with amyotrophic lateral sclerosis (05).

Indications

Off-label uses

	• Based on animal experimental studies, edaravone may be useful for treating retinal diseases associated with oxidative stress, eg, age-related macular degeneration and diabetic retinopathy (06).
	• Results of a randomized, double-blind, placebo-controlled study done to prospectively evaluate the effects of edaravone on acute diabetic stroke patients show that edaravone is a promising neuroprotectant against cerebral ischemic injury in diabetic patients (23).
	• Results of a retrospective study suggest that edaravone is a tolerable and feasible treatment for carbon monoxide poisoning with neurologic manifestations (07).
	• Edaravone prevents mitochondria oxidative damage caused by amyloid beta in SH-SY5Y cells, which suggests that it may have potential clinical application in Alzheimer disease therapy (21).
	• The protective effects of edaravone against oxidative damage due to activation of the Nrf2 (a protein that regulates the expression of antioxidant)/antioxidant response element signaling pathway improved cognitive deficits in a mouse model of Alzheimer disease (22).
	• In an open study on patients with acute cerebral infarction, edaravone significantly reduced neurologic impairment and improved function as well as quality of life compared to the placebo group (18).
	• Edaravone has been proposed as a treatment for cytokine release syndrome in COVID-19, a condition in which various cytokines are extremely elevated through excessive immune response to the virus infection (13).
	• Protocol of a randomized clinical trial to assess the effectiveness of edaravone for acute stroke has been published (16). The trial is based on the hypothesis that edaravone is an antioxidant that can inhibit lipid peroxidation during the scavenging of oxygen free radicals and also has antiinflammatory neuroprotective effects, increases cerebral blood flow, as well as improves neurologic functions.

References

01: Abe K, Itoyama Y, Sobue G, et al. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener 2014;15(7-8):610-7. PMID 25286015
02: Fujisawa A, Yamamoto Y. Edaravone, a potent free radical scavenger, reacts with peroxynitrite to produce predominantly 4-NO-edaravone. Redox Rep 2016;21(3):98-103. PMID 26196041
03: Ikeda K, Iwasaki Y. Edaravone, a free radical scavenger, delayed symptomatic and pathological progression of motor neuron disease in the wobbler mouse. PLoS One 2015;10(10):e0140316. PMID 26469273
04: Jami MS, Salehi-Najafabadi Z, Ahmadinejad F, et al. Edaravone leads to proteome changes indicative of neuronal cell protection in response to oxidative stress. Neurochem Int 2015;90:134-41. PMID 26232623
05: Luo L, Song Z, Li X, et al. Efficacy and safety of edaravone in treatment of amyotrophic lateral sclerosis-a systematic review and meta-analysis. Neurol Sci 2019;40(2):235-41. PMID 30483992
06: Masuda T, Shimazawa M, Hara H. Retinal diseases associated with oxidative stress and the effects of a free radical scavenger (edaravone). Oxid Med Cell Longev 2017;2017:9208489. PMID 28194256
07: Mori K, Beppu T, Fujisawa Y, et al. Effect of free radical scavenger, edaravone, for patients with carbon monoxide poisoning. Clin Neurol Neurosurg 2015;139:56-61. PMID 26368269
08: Nakamaru Y, Kakubari M, Yoshida K, Akimoto M, Kondo K. An open-label, single-dose study to evaluate the pharmacokinetic variables of edaravone in subjects with mild, moderate, or no renal impairment. Clin Ther 2020b;42(9):1699-714. PMID 32868037
09: Nakamaru Y, Kakubari M, Yoshida K, et al. Open-label, single-dose studies of the pharmacokinetics of edaravone in subjects with mild, moderate, or severe hepatic impairment compared to subjects with normal hepatic functioning. Clin Ther 2020a;42(8):1467-82.e4. PMID 32800532
10: Niedzielska E, Smaga I, Gawlik M, et al. Oxidative stress in neurodegenerative diseases. Mol Neurobiol 2016;53(6):4094-125. PMID 26198567
11: Palumbo J, Sakata T, Tanaka M, Akimoto M. Sustained efficacy for up to 12 months in an active extension of a phase III study of edaravone (MCI-186) for treatment of amyotrophic lateral sclerosis (ALS). Neurology 2016;86(16)Supplement:P3.190.
12: Parikh A, Kathawala K, Tan CC, Garg S, Zhou XF. Development of a novel oral delivery system of edaravone for enhancing bioavailability. Int J Pharm 2016;515(1-2):490-500. PMID 27789367
13: Reznik SE, Tiwari AK, Ashby CR Jr. Edaravone: a potential treatment for the COVID-19-induced inflammatory syndrome? Pharmacol Res 2020;160:105055. PMID 32619723
14: Rothstein JD. Edaravone: a new drug approved for ALS. Cell 2017;171(4):725. PMID 29100067
15: Sawada H. Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis. Expert Opin Pharmacother 2017;18(7):735-8.** PMID 28406335
16: Shan H, Jiao G, Cheng X, Dou Z. Safety and efficacy of edaravone for patients with acute stroke: a protocol for randomized clinical trial. Medicine (Baltimore) 2021;100(8):e24811.** PMID 33663100
17: Shefner J, Heiman-Patterson T, Pioro EP, et al. Long-term edaravone efficacy in amyotrophic lateral sclerosis: post-hoc analyses of study 19 (MCI186-19). Muscle Nerve 2020;61(2):218-21.** PMID 31621933
18: Sun Z, Xu Q, Gao G, Zhao M, Sun C. Clinical observation in edaravone treatment for acute cerebral infarction. Niger J Clin Pract 2019;22(10):1324-7. PMID 31607719
19: Writing group on behalf of the edaravone ALS 19 study group. Open-label 24-week extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2017;18(sup1):55-63. PMID 28872920
20: Yoshino H, Kimura A. Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study). Amyotroph Lateral Scler 2006;7(4):241-5. PMID 17127563
21: Zhang GL, Zhang L, Guo YY, et al. Protective effect of edaravone against Aβ25-35-induced mitochondrial oxidative damage in SH-SY5Y cells. Cell Mol Biol (Noisy-le-grand) 2017;63(5):36-42. PMID 28719344
22: Zhang L, Guo Y, Wang H, et al. Edaravone reduces Aβ-induced oxidative damage in SH-SY5Y cells by activating the Nrf2/ARE signaling pathway. Life Sci 2019;221:259-66. PMID 30769116
23: Zheng J, Chen X. Edaravone offers neuroprotection for acute diabetic stroke patients. Ir J Med Sci 2016;185(4):819-24. PMID 26597952

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Edaravone

Other Pertinent Drugs

Masitinib (under review by European authorities)
Riluzole

Also Relevant

Amyotrophic lateral sclerosis
Neuromuscular diseases: high cost of new treatments
Neuroprotection for CNS disorders

Edaravone …

Edaravone

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Edaravone in Amyotrophic Lateral Sclerosis

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Drug-induced myasthenic syndromes

Distal myopathies

Acupuncture

Amyotrophic lateral sclerosis

ALS-like disorders of the Western Pacific

Illicit drug use: neurologic complications

Paraspinal neuromuscular syndromes

Dementia associated with amyotrophic lateral sclerosis

Edaravone

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Edaravone in Amyotrophic Lateral Sclerosis

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Drug-induced myasthenic syndromes

Distal myopathies

Acupuncture

Amyotrophic lateral sclerosis

ALS-like disorders of the Western Pacific

Illicit drug use: neurologic complications

Paraspinal neuromuscular syndromes

Dementia associated with amyotrophic lateral sclerosis

This is an article preview.
Start a Free Account
to access the full version.