Edaravone (Radicava) for ALS

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease.¹ As progressive degeneration of motor neurons occurs, the ability of the brain to initiate and control muscle movement is lost. With voluntary muscle action progressively affected, patients may lose the ability to speak, eat, move, or breathe over time.

Although the exact pathogenesis of ALS is unknown, oxidative stress is an important contributing factor.² The FDA approved edaravone (Radicava) by Mitsubishi Tanabe Pharma Corporation in May 2017 for treatment of patients with ALS. The exact mechanism by which edaravone exerts its therapeutic effect in patients with ALS is not known1; however, it is predicted to be an excellent oxygen free-radical scavenger.³

Efficacy

A phase II open-label clinical trial suggested that edaravone is safe and effective in ALS, resulting in markedly reduced 3-nitrotyrosine levels in the cerebrospinal fluid.2 3-nitrotryosine acts as a laboratory marker of oxidative stress. Only one of the two phase III randomized placebo-controlled trials showed beneficial effects in the revised ALS functional rating scale (ALSFRS-R), although differences were not shown to be statistically significant.2 In the most recent trial, involving 69 patients, edaravone provided significant efficacy in ALSFRS-R scores over a 24-week period, where concomitant use of riluzole (an NMDA receptor antagonist) was permitted. Eligibility in this trial was restricted to patients with a relatively short disease duration and preserved vital capacity, significantly limiting interpretation of its broad applicability.^1,4

Safety

Common adverse effects with edaravone include gait disturbances, bruising, headache, dermatitis, and eczema as well as respiratory dysfunction and hypoxia.1 Less common but serious adverse effects include hypersensitivity reactions or sulfite allergic reactions. Before prescribing edaravone it is important to determine if the patient has asthma, is allergic to other medications, or is pregnant/nursing or planning to be.¹ It is unknown if edaravone is present in breastmilk or if it is safe or effective in children.

The use of edaravone in renal and hepatic dysfunction has not been formally studied; however, no dosing adjustment is needed with mild-to-moderate hepatic impairment and renal impairment is not expected to significantly affect the exposure to the drug.¹ The pharmacokinetic profile of edaravone is not shown to be significantly affected by inhibitors of CYP enzymes, UGTs, or major drug transporters. Edaravone is not expected to affect other drugs through inhibition or induction of CYP enzymes.¹

Dosing and Storage

The recommended dose of edaravone is 60 mg given as an IV infusion over 60 minutes. It is administered as two consecutive 30 mg/100 ml IV infusions at a rate approximately 1 mg/min or 3.33 ml/min.¹ During the initial cycle, edaravone should be dosed daily for 14 days followed by a 14-day drug free period. For all subsequent cycles, the drug should be dosed daily for 10 days within a 14-day period, followed by a 14-day drug free period.¹ Edaravone is indicated for IV use only and should not be mixed or compounded with other medications.¹   

Edaravone can be stored at up to 25°C and should be protected from light.1 The drug is stored in overlapped packaging to protect from oxygen degradation and is equipped with an oxygen indicator that will change color if oxygen has exceeded acceptable levels. Once the packaging is removed, edaravone should be used within 24 hours.  

References

1. Radicava [package insert]. Jersey City, NJ: Mitsubishi Tanabe Pharma Corporation; May, 2017.
2. Sawada H. Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis. Exp Opin Pharmacother. 2017; 18(7):735-738.
3. Pérez-González A, Galano A. OH Radical scavenging activity of edaravone: Mechanism and kinetics. J Phys Chem B. 2011; 115(5):1306-1314.
4. 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):610-617.