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Edaravone

Class: Central Nervous System Agents, Miscellaneous
Chemical Name: 3-methyl-1-phenyl-2-pyrazolin-5-one
Molecular Formula: C10H10N2O
CAS Number: 89-25-8
Brands: Radicava

Introduction

Free radical scavenger.3 4 6 7 8 13

Uses for Edaravone

Amyotrophic Lateral Sclerosis

Treatment of amyotrophic lateral sclerosis (ALS; Lou Gehrig disease, Charcot's sclerosis);1 3 4 designated an orphan drug by FDA for this use.2

Has been shown to slow decline in functioning (e.g., fine motor, gross motor, bulbar, and respiratory function) as assessed by a standard rating scale (ALSFRS-R) used in patients with ALS.1 3 4

Long-term efficacy and effects on survival remain to be established.3 4 Some evidence indicates that benefits may be decreased in patients with more advanced disease.3 4

Edaravone Dosage and Administration

Administration

IV Administration

Administer by IV infusion.1

Commercially available in polypropylene infusion bags overwrapped with secondary packaging containing an oxygen absorber and indicator; designed to protect the drug from oxidation.1 Indicator should be pink when acceptable oxygen levels present; do not use if indicator has turned blue or purple prior to opening the package.1 (See Storage under Stability.)

Monitor for hypersensitivity reactions during administration; immediately discontinue infusion at first sign or symptom of such a reaction.1

Do not mix with other drugs.1

Rate of Administration

Administer over 60 minutes (approximately 1 mg/minute).1

Dosage

Adults

ALS
IV

60 mg (given as 2 consecutive 30-mg infusions over a total of 60 minutes) in 28-day treatment cycles according to the following schedule:1

Initial treatment cycle: Administer on days 1–14, followed by 14-day drug-free period.1

Subsequent treatment cycles: Administer for 10 out of the first 14 days, followed by 14-day drug-free period.1 16

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustments not needed.1 (See Hepatic Impairment under Cautions.)

Severe hepatic impairment: Manufacturer makes no specific dosage recommendation.1

Renal Impairment

Dosage adjustments not needed.1 (See Renal Impairment under Cautions.)

Cautions for Edaravone

Contraindications

  • History of hypersensitivity to edaravone or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., redness, wheals, erythema multiforme), including cases of anaphylaxis (e.g., urticaria, hypotension, dyspnea), reported during postmarketing experience.1

Monitor patients carefully.1 If a hypersensitivity reaction occurs, discontinue drug and initiate appropriate treatment; monitor patient until condition resolves.1

Sulfite Sensitivity

Contains sodium bisulfite; may cause allergic-type reactions (e.g., anaphylactic symptoms, life-threatening or less severe asthmatic episodes) in susceptible individuals.1

Overall prevalence of sulfite sensitivity in general population unknown.1 Sulfite sensitivity occurs more frequently in asthmatic individuals.1

Specific Populations

Pregnancy

No adequate data on developmental risk in pregnant women.1 In animal studies, adverse developmental effects (e.g., increased mortality, decreased growth, delayed sexual development, altered behavior) and maternal toxicity observed at clinically relevant doses.1

Lactation

Not known whether edaravone is distributed into human milk or if the drug has any effects on the breastfed infant or milk production.1 Distributed into milk in rats.1

Consider known benefits of breast-feeding along with the woman's clinical need for edaravone and any potential adverse effects of the drug or disease on the infant.1

Pediatric Use

Efficacy and safety not established in pediatric patients.1

Geriatric Use

No overall differences in efficacy or safety compared with younger adults.1 However, increased sensitivity cannot be ruled out.1

Hepatic Impairment

Pharmacokinetics not evaluated in patients with hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Pharmacokinetics not evaluated in patients with renal impairment; however, not expected to substantially affect edaravone exposure.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Contusion,1 4 gait disturbance,1 headache,1 dermatitis,1 4 eczema,1 4 upper respiratory tract inflammation,4 respiratory failure,1 respiratory disorder/hypoxia,1 back pain,4 myalgia,4 glycosuria,1 tinea infection.1

Interactions for Edaravone

Metabolized by multiple uridine diphosphate-glucuronosyltransferase (UGT) enzymes (i.e., UGT 1A6, 1A9, 2B7, and 2B17).1 15 Not expected to substantially inhibit UGT 1A1 or 2B7.1 3

Not expected to substantially inhibit major CYP isoenzymes (i.e., CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4) nor induce CYP isoenzymes 1A2, 2B6, or 3A4 at clinically relevant concentrations.1

Not expected to substantially inhibit major transporters (i.e., P-glycoprotein [P-gp], breast cancer resistance protein [BCRP], organic anion transporting polypeptide [OATP] 1B1, OATP1B3, organic anion transporter [OAT] 1, OAT3, organic cation transporter [OCT] 2).1 3 15

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely.1 15

Drugs Affecting or Metabolized by UGT Enzymes

Pharmacokinetic interactions unlikely.1 15

Drugs Affecting or Affected by Membrane Transporters

Pharmacokinetic interactions unlikely.1 3 15

Specific Drugs

Drug

Interaction

Comments

Riluzole

Pharmacokinetic interaction not expected; administered concomitantly with edaravone in most patients in clinical studies3 15

Edaravone Pharmacokinetics

Absorption

Plasma Concentrations

Following IV infusion over 60 minutes, peak plasma concentrations occur at the end of infusion.1

AUC and peak plasma concentrations appear to increase in a more than dose-proportional manner.1 No accumulation observed with repeated dosing.1

Distribution

Plasma Protein Binding

92%, primarily to albumin.1

Elimination

Metabolism

Metabolized to pharmacologically inactive sulfate and glucuronide conjugates by multiple UGT isoenzymes (i.e., UGT 1A6, 1A9, 2B7, and 2B17) in the liver and kidney and sulfotransferase.1

Elimination Route

In healthy individuals, 70–90% of a dose excreted in urine as the glucuronide conjugate, 5–10% excreted in urine as the sulfate conjugate, and ≤1% excreted in urine as unchanged drug.1

Half-life

Edaravone: 4.5–6 hours.1

Metabolites: 2–2.8 hours.1

Special Populations

Hepatic impairment: No data available.1

Renal impairment: No data available.1

Geriatric patients: No age effect on pharmacokinetics observed.1

Gender: No gender effect on pharmacokinetics observed.1

Race: No substantial differences in peak plasma concentrations or AUC between Japanese and Caucasian individuals.1

Stability

Storage

Parenteral

Injection, for IV Infusion

25°C (may be exposed to 15–30°C).1 Protect from light.1

Store in over-wrapped package until time of use to protect from oxidation.1 Once over-wrap package is opened, use within 24 hours.1 Oxygen indicator will turn blue or purple if oxygen exceeds acceptable levels.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Do not inject or mix with other drugs in infusion bag.1

Actions

  • Free radical scavenger.3 4 6 7 8 13

  • Exact mechanism in ALS not known, but presumed to involve its antioxidant effects in countering the oxidative damage that occurs in patients with ALS.3 4 6 7 8 13

  • Neuroprotective effects demonstrated in animal studies.4 7 8

Advice to Patients

  • Risk of hypersensitivity reactions, including anaphylaxis.1 Advise patients of the possible signs and symptoms of hypersensitivity reactions, and to seek immediate medical care if such manifestations occur.1

  • Risk of allergic reactions due to sulfite sensitivity.1 Advise patients that edaravone contains sodium bisulfite, which may cause allergic type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, and to seek immediate medical care if such manifestations occur.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Edaravone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV infusion

0.3 mg/mL (30 mg)

Radicava

Mitsubishi Tanabe

AHFS DI Essentials. © Copyright 2017, Selected Revisions November 20, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. MT Pharma America. Radicava (edaravone) injection, for intravenous use prescribing information. Jersey City, NJ; 2017 May.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2017 Jun 29.

3. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 209176Orig1s000: Summary Review. From FDA website.

4. Writing Group, Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017; 16:505-512. [PubMed 28522181]

5. 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; 15:610-7. [PubMed 25286015]

6. Nagase M, Yamamoto Y, Miyazaki Y et al. Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration. Redox Rep. 2016; 21:104-12. [PubMed 26191780]

7. 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:e0140316. [PubMed 26469273]

8. Dai B, Yan T, Shen YX et al. Edaravone protects against oxygen-glucose-serum deprivation/restoration-induced apoptosis in spinal cord astrocytes by inhibiting integrated stress response. Neural Regen Res. 2017; 12:283-289. [PubMed 28400812]

9. Bonafede R, Mariotti R. ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles. Front Cell Neurosci. 2017; 11:80. [PubMed 28377696]

10. Mathis S, Couratier P, Julian A et al. Current view and perspectives in amyotrophic lateral sclerosis. Neural Regen Res. 2017; 12:181-184. [PubMed 28400790]

11. Hogden A, Foley G, Henderson RD et al. Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach. J Multidiscip Healthc. 2017; 10:205-215. [PubMed ]

12. Covis. Rilutek (riluzole) tablets prescribing information. Cary, NC; 2016 April.

13. Sawada H. Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis. Expert Opin Pharmacother. 2017; 18:735-738. [PubMed 28406335]

14. Miller RG, Jackson CE, Kasarskis EJ et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009; 73:1218-26. [PubMed 19822872]

15. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 209176Orig1s000: Clinical Pharmacology and Biopharmaceutics review. From FDA website.

16. Mitsubishi Tanabe Pharma America. Jersey City, NJ: Personal communication.

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