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:

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

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

Contraindications

The drug is contraindicated in patients with a history of hypersensitivity to edaravone or any of the inactive ingredients of this product.

Goals and duration of treatment

Reported results of extensions of clinical trials of edaravone in the United States are up to 15 months as of the end of 2016. Results indicate that in patients with greater baseline functionality, longer-term therapy with edaravone may provide a durable and meaningful advantage over placebo. When given at an early stage of rapidly evolving amyotrophic lateral sclerosis, it may halt the progression of disease by neuroprotective effect.

In a 24-week phase 3 edaravone versus placebo study, amyotrophic lateral sclerosis patients treated with edaravone showed significantly less physical functional decline, and in the follow-up phase of switching of placebo group to edaravone, treatment resulted in beneficial effects that were maintained for 1 year (17).

Dosing

The dose of edaravone is 60 mg in 2 consecutive 30 mg intravenous infusions/100 cc over 60 minutes. The dosage schedule in clinical trials was in cycles of 10 to 14 days with 2-week breaks in between. The administration involves the establishment of a permanent intravenous line.

Special considerations

Pregnancy. There are no adequate data on the developmental risk associated with the use of edaravone in pregnant women. In animal studies, administration of edaravone to pregnant rats and rabbits resulted in adverse developmental effects (increased mortality, decreased growth, delayed sexual development, and altered behavior) at clinically relevant doses. Most of these effects occurred at doses that were also associated with maternal toxicity.

There are no data on the presence of edaravone in human milk, the effects on the breastfed infant, or the effects on milk production.

Pediatric. The safety and effectiveness of edaravone in pediatric patients has not been established.

Geriatric. No overall differences in the safety or effectiveness of edaravone were observed between elderly patients and younger patients in clinical trials.

Renal impairment. An open-label, single-dose study showed that mild to moderate renal impairment had no clinically significant effects on the pharmacokinetic profile of edaravone in Japanese subjects, relative to individuals with normal renal function, and there were no significant safety concerns (08). No dose adjustment is needed in these patients.

Hepatic impairment. Open-label, single-dose studies of the pharmacokinetics of edaravone in subjects with hepatic impairment compared to subjects with normal hepatic functioning showed no safety concerns and no dose adjustment is needed (09).

Interactions

At clinical doses, edaravone and its metabolites do not significantly inhibit cytochrome P450 enzymes and are unlikely to be involved in drug interactions.

Adverse effects

Hypersensitivity and allergic reactions. Hypersensitivity reactions and anaphylaxis have been listed in spontaneous postmarketing reports of edaravone. Patients should be monitored carefully for hypersensitivity reactions, and, if they occur, the drug should be discontinued and treatment given per standard of care.

Edaravone injection contains sodium bisulfite, which may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in susceptible persons.

The most common adverse reactions that occurred in 10% or more of edaravone-treated patients in clinical trials were contusion, gait disturbance, and headache.