Edaravone (DB12243): A Comprehensive Monograph on its Pharmacology, Clinical Efficacy, and Therapeutic Applications

Executive Summary

Edaravone is a small molecule, pyrazolone-derivative compound that has emerged as a significant therapeutic agent in the management of select neurodegenerative and neurovascular conditions. Initially developed and approved for acute ischemic stroke in Japan, its therapeutic scope has expanded to include amyotrophic lateral sclerosis (ALS), a progressive and fatal motor neuron disease. This report provides an exhaustive analysis of Edaravone, cataloging its molecular characteristics, pharmacological profile, clinical development, and therapeutic applications.

The primary mechanism of action of Edaravone is its function as a potent free radical scavenger. It effectively neutralizes highly reactive oxygen species (ROS), such as hydroxyl radicals and peroxynitrite, which are key mediators of oxidative stress-induced cellular damage. This antioxidant activity is the mechanistic foundation for its neuroprotective effects, as it mitigates lipid peroxidation of cell membranes, suppresses downstream inflammatory cascades, and inhibits apoptotic pathways in neuronal and vascular endothelial cells.

Clinically, Edaravone holds a unique dual-indication status. In Japan, it has been used since 2001 for the treatment of acute ischemic stroke, where it is administered to limit the reperfusion injury that follows a cerebrovascular event. Its approval for ALS by the U.S. Food and Drug Administration (FDA) in 2017 marked a landmark development, making it the first new treatment for the disease in over two decades. This approval was based on the pivotal MCI186-19 clinical trial, which demonstrated a statistically significant 33% slowing in the rate of functional decline in a carefully selected subpopulation of ALS patients.

The development trajectory of Edaravone is a notable case study in modern pharmaceutical lifecycle management. The initial intravenous (IV) formulation (Radicava®), while effective, presented significant logistical burdens and administration-related risks for patients with chronic illness. This led to the strategic development and subsequent approval in 2022 of an oral suspension (Radicava ORS®), which was shown to be bioequivalent to the IV form and offers a major improvement in patient convenience.

Ongoing research continues to explore the full potential of Edaravone. Current investigations are focused on identifying biomarkers to predict treatment response, developing novel formulations such as sublingual tablets, and exploring its efficacy in combination with other agents like dexborneol. Furthermore, its potential application is being studied in other oxidative stress-related conditions, including post-stroke cognitive impairment. While its efficacy in ALS is considered modest and its benefits in stroke are still debated outside of Japan, Edaravone represents a tangible therapeutic advance in neurology and serves as a compelling example of mechanistic repurposing, strategic clinical trial design, and patient-centric pharmaceutical innovation.

Molecular Profile and Physicochemical Properties

A comprehensive understanding of Edaravone begins with its fundamental chemical and physical identity. These properties govern its biological activity, inform its formulation development, and dictate its behavior in both experimental and clinical settings.

Identification and Nomenclature

Edaravone is a well-characterized synthetic organic small molecule.[1] It is internationally recognized by its International Nonproprietary Name (INN), Edaravone.[1] For research, regulatory, and database purposes, it is cataloged under several key identifiers:

• DrugBank ID: DB12243 [1]
• CAS Number: 89-25-8 [1]
• PubChem CID: 4021 [1]

Throughout its development and commercialization, it has been referred to by various synonyms and proprietary names. Its primary development code was MCI-186.[1] Commercially, it is marketed under the brand names Radicava® in the United States and other regions, and Radicut® in Japan.[1]

The compound's chemical structure is precisely defined by systematic nomenclature. Its IUPAC name is 5-methyl-2-phenyl-4H-pyrazol-3-one.[1] Other common chemical names include 3-methyl-1-phenyl-2-pyrazolin-5-one, 2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one, and 1-phenyl-3-methyl-5-pyrazolone.[2]

Chemical Structure and Composition

Edaravone is structurally classified as a pyrazolone. It is specifically a 2,4-dihydro-3H-pyrazol-3-one molecule substituted at the 2-position by a phenyl group and at the 5-position by a methyl group.[8] An important feature of its structure is the existence of three tautomeric forms, which contributes to its chemical reactivity and antioxidant capacity.[2]

• Molecular Formula: C10​H10​N2​O [2]
• Molecular Weight: The average molecular weight is consistently reported as 174.20 g/mol or 174.2 Da. Its precise monoisotopic mass is 174.07931295 Da, a value critical for mass spectrometry analysis.[2]
• Structural Identifiers: For computational and database applications, its structure is represented by:
• Canonical SMILES: CC1=NN(C(=O)C1)C2=CC=CC=C2 [5]
• InChIKey: QELUYTUMUWHWMC-UHFFFAOYSA-N [1]

Physicochemical Characteristics

The physical and chemical properties of Edaravone are summarized in Table 1. These characteristics have had a profound influence on its clinical development pathway.

• Physical Description: Edaravone is a solid that appears as a white to off-white or light yellow, odorless crystalline powder.[6] When crystallized from water, it forms monoclinic prisms.[8]
• Solubility Profile: Its solubility is highly dependent on the solvent and pH. It is characterized as poorly soluble in water at physiological pH, with a measured solubility of 25.4 µg/mL at pH 7.4.[8] However, its solubility increases in hot water and hot alcohol.[8] For laboratory use, it is highly soluble in dimethyl sulfoxide (DMSO), reaching concentrations up to 100 mM.[4] It is only slightly soluble in benzene and is considered insoluble in petroleum ether.[8]
• Thermal Properties: The melting point of Edaravone is reported within a narrow range, typically from 127 °C to 129.7 °C (261 °F to 266 °F).[8] Its boiling point is pressure-dependent, recorded as 287 °C at 105 mmHg.[8]
• Lipophilicity: The partition coefficient (LogP) is approximately 1.12, with an XLogP value of 1.49.[1] These values indicate moderate lipophilicity, a property that facilitates its ability to cross biological membranes.
• Druglikeness: Edaravone exhibits favorable characteristics for a therapeutic agent. It possesses 3 hydrogen bond acceptors, 0 hydrogen bond donors, and only 1 rotatable bond.[1] Critically, it does not violate any of Lipinski's Rule-of-Five, suggesting good potential for oral bioavailability and membrane permeability.[1]

The physicochemical profile of Edaravone reveals a fundamental duality that has shaped its entire clinical lifecycle. Its poor aqueous solubility at neutral pH presented a significant formulation challenge, making it difficult to achieve therapeutic plasma concentrations with a simple oral solution. This necessitated the initial development of an intravenous formulation to ensure reliable and complete bioavailability, which became the first approved product (Radicava).[8] However, a deeper analysis of its molecular properties—a low molecular weight, moderate lipophilicity, and full compliance with Lipinski's rules—strongly suggested that the molecule was inherently "druglike" and possessed the fundamental characteristics required for oral absorption.[1] This latent potential for oral delivery drove the extensive research and development efforts by its manufacturer to overcome the solubility barrier. These efforts ultimately culminated in the successful creation of Radicava ORS, an oral suspension that provides a less invasive, more patient-friendly alternative.[11] This journey illustrates how a thorough understanding of a compound's basic chemical properties can guide its long-term development strategy, transforming a clinical limitation into an opportunity for innovation.

Table 1: Summary of Edaravone's Physicochemical Properties

Property	Value	Source(s)
Molecular Formula	C10​H10​N2​O	2
Molecular Weight	174.20 g/mol (Average)	2
CAS Number	89-25-8	1
IUPAC Name	5-methyl-2-phenyl-4H-pyrazol-3-one	1
Physical Form	White to light yellow crystalline powder/solid	6
Melting Point	127 °C - 129.7 °C	8
Boiling Point	287 °C at 105 mmHg	8
Solubility in Water (pH 7.4)	25.4 µg/mL	8
Solubility in DMSO	Soluble to 100 mM	4
LogP	1.12 - 1.49	1
Hydrogen Bond Acceptors	3	1
Hydrogen Bond Donors	0	1
Rotatable Bonds	1	1
Lipinski's Rules Broken	0	1

Comprehensive Pharmacological Profile

Mechanism of Action

The therapeutic effects of Edaravone are rooted in its well-defined role as a potent antioxidant and neuroprotective agent. While the precise mechanisms in complex diseases like ALS are not fully elucidated, its activity is primarily attributed to its ability to counteract oxidative stress, a key pathological process in many neurological disorders.[2]

Primary Mechanism: Free Radical Scavenging

Edaravone is a powerful free radical scavenger.[7] Its chemical structure allows it to efficiently neutralize reactive oxygen species (ROS) and reactive nitrogen species (RNS) that cause significant damage to cellular components. The core of its antioxidant action is the donation of an electron from its anionic form to break autocatalytic chain reactions.[7] It demonstrates high reactivity against some of the most cytotoxic free radicals:

• Hydroxyl Radicals (•OH): Edaravone effectively scavenges hydroxyl radicals, which are highly reactive and can indiscriminately damage proteins, lipids, and DNA.[2]
• Peroxynitrite (ONOO⁻): It is particularly effective at scavenging peroxynitrite, a powerful oxidant and nitrating agent formed from the reaction of superoxide and nitric oxide.[2] This action is critical, as peroxynitrite is implicated in motor neuron death in ALS.[14]
• Lipid Peroxyl Radicals (LOO•): By quenching these radicals, Edaravone inhibits the chain reaction of lipid peroxidation, thereby protecting the integrity of cellular and mitochondrial membranes from oxidative damage.[2]

Neuroprotective Effects

The primary scavenging activity of Edaravone translates into a cascade of downstream neuroprotective effects that contribute to its therapeutic potential.

• Inhibition of Oxidative Damage: By reducing the burden of ROS, Edaravone protects vulnerable cells, such as neurons and vascular endothelial cells, from oxidative injury. This has been shown to limit neuronal cell death and preserve the function of the cerebral vasculature in models of ischemia.[2]
• Anti-inflammatory Properties: Oxidative stress and inflammation are intrinsically linked. In animal models, Edaravone has been shown to possess anti-inflammatory properties. It ameliorates ROS-induced inflammatory stress, inhibits neutrophil activation, and suppresses the expression of pro-inflammatory enzymes like inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS).[2]
• Anti-apoptotic and Anti-necrotic Effects: Edaravone modulates programmed cell death pathways. Experimental studies have shown it can suppress the expression of pro-apoptotic proteins (e.g., Fas-associated death domain protein) and increase the expression of anti-apoptotic proteins (e.g., B-cell lymphoma 2), thereby protecting neurons from apoptosis in ischemic conditions.[7]
• Vasoprotective Effects: In the context of cerebrovascular disease, Edaravone helps maintain the integrity of the endothelium. It has been shown to suppress endothelial cell damage induced by lipid peroxides and may have beneficial effects against cerebral vasospasm.[2]

A crucial pharmacological detail is that the primary metabolites of Edaravone—the sulfate and glucuronide conjugates—are pharmacologically inactive. They do not possess any free radical scavenging activity.[2] This indicates that the therapeutic effect is derived solely from the parent drug before it undergoes metabolism.

The clear, well-defined mechanism of Edaravone as a free radical scavenger provides a strong and rational bridge to its therapeutic indications. This direct mechanistic link distinguishes it from many other central nervous system drugs whose modes of action are often more complex or less understood. The pathophysiology of acute ischemic stroke is defined by a massive burst of ROS during reperfusion, which causes severe, acute tissue damage.[2] Edaravone's approval in Japan for this indication is a direct application of its antioxidant mechanism to an acute neurovascular crisis.[8] Similarly, the pathology of ALS involves a chronic, relentless progression of motor neuron death, in which oxidative stress is a well-established and significant contributor.[2] The decision to investigate Edaravone in ALS was therefore a logical extension of its known mechanism, repurposing it from an acute condition to a chronic neurodegenerative disease with a shared underlying pathology.[13] This represents a successful example of "mechanistic repurposing" in drug development.

Pharmacokinetics (Absorption, Distribution, Metabolism, and Excretion)

The pharmacokinetic (PK) profile of Edaravone has been extensively characterized for both its intravenous (IV) and oral suspension formulations. These properties, summarized in Table 2, are critical for determining appropriate dosing, understanding potential interactions, and ensuring patient safety.

Absorption

• Intravenous (Radicava®): When administered as a 60-minute IV infusion, plasma concentrations of Edaravone peak (Cmax​) at the end of the infusion period. Exposure, measured by both Cmax​ and the area under the concentration-time curve (AUC), increases in a more than dose-proportional manner. The cyclical dosing schedule does not lead to drug accumulation in the plasma.[2]
• Oral Suspension (Radicava ORS®): The oral formulation is absorbed rapidly, with a median time to peak concentration (Tmax​) of approximately 0.5 hours when taken under fasting conditions.[2] However, its absolute oral bioavailability is only about 57% compared to the IV formulation, a reduction attributed to a significant first-pass metabolism effect in the liver and gut wall.[2]
• Food Effect: The absorption of the oral suspension is profoundly affected by the presence of food, a critical factor for clinical use.
• A high-fat meal (800-1000 calories, 50% fat) taken with the dose dramatically reduces exposure, decreasing Cmax​ by 82% and AUC by 61%.[12]
• A low-fat meal (400-500 calories, 25% fat) also causes substantial reductions in exposure (Cmax​ decreased by 45%, AUC by 21%).[12]
• To ensure adequate absorption, strict fasting guidelines are required. The medication must be taken after an overnight fast, and no food (except water) should be consumed for one hour after administration.[9] The required fasting period before administration varies with the type of meal consumed (e.g., 8 hours after a high-fat meal).[9]

The pronounced food effect on the oral formulation represents a significant clinical challenge. While the development of an oral suspension was a major step forward in reducing the burden of IV administration, its pharmacokinetic fragility introduces a new complexity. The bioavailability is already limited to 57% due to first-pass metabolism.[2] The additional, drastic reduction in absorption caused by food is not a minor interaction; it has the potential to render a dose sub-therapeutic, thereby undermining the drug's efficacy.[12] For patients with ALS, who often face challenges with fatigue, dysphagia, and complex daily care routines, adherence to the required strict and somewhat complicated fasting regimens can be difficult. This creates a potential gap between the efficacy observed under the controlled conditions of a clinical trial and the effectiveness achieved in real-world clinical practice, necessitating meticulous patient education and monitoring.

Distribution

Edaravone distributes beyond the plasma compartment into tissues. It is highly bound to human plasma proteins (92%), primarily albumin, in a manner that is not dependent on drug concentration.[12] The mean volume of distribution (

Vd​) following IV administration is 63.1 L.[9]

Metabolism

Edaravone is extensively metabolized in the liver and kidneys into two major conjugates: a sulfate conjugate and a glucuronide conjugate. As previously noted, these metabolites are pharmacologically inactive.[2]

• The glucuronidation process involves a wide array of uridine diphosphate glucuronosyltransferase (UGT) isoforms, including UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17.[2] This redundancy of metabolic pathways minimizes the risk of significant drug-drug interactions caused by the inhibition of a single UGT enzyme.
• In human plasma, the sulfate conjugate is the most prominently detected metabolite and is presumed to be formed by sulfotransferase enzymes.[2]

Excretion

The primary route of elimination for Edaravone and its metabolites is renal.

• Studies in healthy volunteers showed that 60-80% of an administered dose is excreted in the urine as the glucuronide conjugate within 48 hours.[12]
• A smaller portion is excreted as the sulfate conjugate (6-8% of the dose), and a negligible amount (<1%) is excreted as unchanged parent drug.[12]
• The mean terminal elimination half-life (t1/2​) of Edaravone is approximately 4.5 to 9 hours. Its inactive metabolites are cleared more rapidly, with half-lives ranging from 3 to 6 hours.[2]
• The total systemic clearance of Edaravone is estimated to be 35.9 L/h.[2]

Table 2: Summary of Key Pharmacokinetic (ADME) Parameters

Parameter	IV Formulation (Radicava®)	Oral Formulation (Radicava ORS®)	Clinical Significance/Notes
Bioavailability	100% (by definition)	~57%	Oral bioavailability is reduced by first-pass metabolism.2
Tmax​	End of 60-min infusion	~0.5 hours (fasting)	Rapid oral absorption on an empty stomach.2
Food Effect	Not applicable	Severe. High-fat meal reduces AUC by 61%.	Strict fasting rules are critical for oral efficacy.12
Protein Binding	92% (mainly albumin)	92% (mainly albumin)	High protein binding, not concentration-dependent.12
Volume of Distribution (Vd​)	63.1 L	Not directly measured, but expected to be similar	Indicates distribution into tissues beyond plasma.20
Half-life (t1/2​)	4.5 - 9 hours	4.5 - 9 hours	Supports the cyclical dosing regimen without accumulation.2
Metabolism	Sulfate & glucuronide conjugation (inactive metabolites)	Sulfate & glucuronide conjugation (inactive metabolites)	Multiple UGT pathways reduce DDI risk.2
Excretion	Primarily renal (urine); >70% as conjugates	Primarily renal (urine); >70% as conjugates	Very little unchanged drug is excreted.12

Clinical Efficacy and Approved Indications

Edaravone has secured regulatory approval for two distinct neurological conditions in different global markets, a testament to its underlying mechanism of action against oxidative stress. Its primary indications are Amyotrophic Lateral Sclerosis (ALS) in the United States and other countries, and Acute Ischemic Stroke in Japan.

Indication 1: Amyotrophic Lateral Sclerosis (ALS)

Regulatory Status

Edaravone is indicated for the treatment of ALS, with the therapeutic goal of slowing the progressive loss of physical function.[17] Its approval by the U.S. FDA on May 5, 2017, was a landmark event, as it was the first new therapy for ALS in 22 years.[17] The intravenous formulation (Radicava®) was approved first, followed by the oral suspension (Radicava ORS®) on May 12, 2022.[17] In addition to the U.S., it is approved for ALS in Japan (2015), South Korea (2015), Canada (2018), Switzerland (2019), and several other nations.[19]

The Pivotal Trial - MCI186-19 (NCT01492686)

The FDA approval was based on the results of a single pivotal Phase III clinical trial, known as MCI186-19, conducted in Japan.[17] The design and outcome of this study are critical to understanding Edaravone's established efficacy.

• Background and Study Design: The MCI186-19 trial was a 24-week, randomized, double-blind, placebo-controlled study.[17] Its design was not arbitrary; it was prospectively developed based on a post-hoc analysis of a previous, larger Phase III study (MCI186-16) that had failed to meet its primary endpoint.[17] The analysis of the failed trial suggested that a treatment effect might be detectable in a more specific, less heterogeneous patient subgroup.[19]
• Patient Population and Strategic Enrichment: The success of the MCI186-19 trial was heavily dependent on a "strategic enrichment" of the patient population, which aimed to reduce variability and select for patients who were likely to show measurable disease progression within the study's 24-week timeframe.[23] The key inclusion criteria were highly restrictive and will be detailed in Table 3. In essence, the trial enrolled patients with early-stage, actively progressing ALS and relatively preserved functional and respiratory status.[23] This approach was designed to exclude patients who were progressing very slowly ("minimal progressors") or those with very advanced disease, as the high variability in these groups in the previous trial may have masked a potential treatment effect.[29]
• Primary Endpoint and Results: The primary efficacy endpoint was the change from baseline to week 24 in the total score of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), a validated 48-point scale that measures daily functioning.[22] The trial met its primary endpoint with high statistical significance.
• The mean decline in the ALSFRS-R score was -5.01 points in the edaravone group (n=68).
• The mean decline was -7.50 points in the placebo group (n=66).
• This resulted in a between-group difference of 2.49 points in favor of edaravone, which corresponds to a 33% slowing in the rate of functional decline over the 6-month period (p=0.0013).[22]
• Secondary Endpoints: Several secondary endpoints, including quality of life as measured by the ALS Assessment Questionnaire (ALSAQ-40), also showed statistically significant benefits for the edaravone group.[32]

Regulatory and Clinical Significance

The FDA's approval of Edaravone based on this single foreign trial represented a paradigm shift in the regulatory landscape for rare diseases, demonstrating a willingness to accept robust foreign data to address an unmet medical need.[24] The subsequent approval of the oral suspension (Radicava ORS) was based on pharmacokinetic studies demonstrating that a 105 mg oral dose provided equivalent exposure to the 60 mg IV dose, not on new efficacy trials.[18] This provided a crucial, less burdensome option for patients.

The enrichment strategy employed in the pivotal trial is a double-edged sword. On one hand, it was a scientifically rational approach that successfully isolated a treatment effect that was otherwise obscured by population heterogeneity, ultimately leading to the drug's approval and availability for patients.[29] On the other hand, it means that the robust evidence for Edaravone's efficacy is technically confined to the specific, narrowly defined patient population that met the trial's strict inclusion criteria. This has led to an ongoing debate about the drug's generalizability and effectiveness in the broader, more diverse real-world ALS population, which includes patients with longer disease duration, lower respiratory function, or slower progression rates. This context helps explain why some observational studies conducted in less restricted patient populations, such as a cohort study from the German Motor Neuron Disease Network, have not replicated the positive findings of the pivotal trial, fueling uncertainty among clinicians treating patients who do not fit the MCI186-19 profile.[17]

Table 3: Design and Key Outcomes of the Pivotal MCI186-19 Trial in ALS

Feature	Description
Study Name / NCT ID	MCI186-19 / NCT01492686 32
Phase	Phase III 17
Design	24-week, randomized, double-blind, placebo-controlled, parallel-group 27
Patient Population	137 patients with ALS in Japan.27 Key inclusion criteria included:
Treatment Arms	• Edaravone 60 mg via IV infusion over 60 minutes 22
Dosing Regimen	Cyclical: Cycle 1 was daily dosing for 14 days, followed by 14 days off. Cycles 2-6 were dosing on 10 of 14 days, followed by 14 days off.27
Primary Endpoint	Change in total ALSFRS-R score from baseline to week 24.22
Primary Endpoint Result	• Edaravone Group: Mean decline of -5.01 points.22
Conclusion	In a specifically defined population of patients with ALS, edaravone treatment resulted in a significantly smaller decline in functional loss over 24 weeks compared to placebo.27

Indication 2: Acute Ischemic Stroke (Japan)

Regulatory Status

Long before its approval for ALS, Edaravone was first approved in Japan by the Pharmaceuticals and Medical Devices Agency (PMDA) in 2001.[7] The approved indication is for the "improvement of neurological symptoms, disability in activities of daily living, and functional impairment associated with acute ischemic stroke".[10] This indication is unique to Japan and a few other countries and is not approved in the United States or Europe.

Clinical Trial Evidence

The PMDA approval was based on the results of clinical trials conducted in Japan during the 1990s.[13] A pivotal Phase III, randomized, placebo-controlled, double-blind study demonstrated that edaravone initiated within 72 hours of stroke onset led to a statistically significant improvement in functional outcomes at 3 months, as measured by the modified Rankin Scale (mRS) (

p=0.0382).[13] A subsequent analysis of these data revealed that the therapeutic benefit was most pronounced in patients who received treatment within 24 hours of symptom onset.[33] Based on this evidence, Edaravone (as Radicut®) is included in the Japanese Guidelines for the Management of Stroke 2021 with a Grade B recommendation and is widely used in clinical practice for this indication in Japan.[16]

Dosing and Administration for Stroke

The approved regimen for acute ischemic stroke differs from the ALS regimen. It consists of 30 mg of Edaravone administered via intravenous infusion over 30 minutes, twice daily (total 60 mg/day). Treatment should be initiated within 24 hours of the stroke onset and may be continued for a maximum of 14 days.[10]

Dosage, Formulations, and Administration

Edaravone is available in two distinct formulations, intravenous and oral, each with specific dosing and administration requirements designed to ensure efficacy and patient safety.

Available Formulations

• Intravenous (Radicava®): This formulation is a sterile, clear, and colorless aqueous solution supplied in single-dose polypropylene bags. Each bag contains 30 mg of edaravone in 100 mL of solution.[9]
• Oral Suspension (Radicava ORS®): This formulation is a white to off-white suspension provided in a multi-dose amber glass bottle. The concentration is 105 mg of edaravone per 5 mL of suspension.[9]

Dosing Regimen for ALS

The dosing schedule for ALS is cyclical and is identical in its timing for both the intravenous and oral formulations, ensuring continuity of care for patients who may switch between them.[9]

• Initial Treatment Cycle (Cycle 1): Patients receive the drug once daily for 14 consecutive days, which is then followed by a 14-day drug-free period.
• Subsequent Treatment Cycles (Cycle 2 and onwards): The treatment period is shortened. Patients receive the drug once daily for 10 days within a 14-day period, followed by a 14-day drug-free period.

The recommended daily dose is formulation-specific but provides equivalent systemic exposure:

• Intravenous Dose: 60 mg [9]
• Oral Dose: 105 mg (5 mL) [9]

Patients being treated with the 60 mg IV infusion can be switched to the 105 mg oral suspension at the same dosing frequency. Upon switching, it is imperative that patients follow the specific administration guidelines for the oral formulation, particularly regarding food consumption.[9]

Administration Guidelines

Proper administration is crucial for the efficacy and safety of Edaravone, with distinct procedures for each formulation.

Intravenous (Radicava®)

• Preparation: The product is supplied in an overwrap package that contains an oxygen absorber and an oxygen indicator. The infusion should not be used if the indicator has turned blue or purple, as this signifies degradation.[9] Once the overwrap is opened, the bag should be used within 24 hours.
• Administration: Each 60 mg dose is administered as two consecutive 30 mg infusion bags over a total duration of 60 minutes. This corresponds to an infusion rate of approximately 1 mg/min.[9] Other medications should not be mixed with Edaravone in the infusion bag.[9] The infusion must be discontinued immediately at the first sign of a hypersensitivity reaction.[9]

Oral Suspension (Radicava ORS®)

• Preparation: Before each use, the bottle must be inverted and shaken vigorously up and down for at least 30 seconds to ensure the suspension is homogenous.[21] The dose must be measured accurately using the 5 mL oral syringe provided with the product; household spoons are not adequate measuring devices.[9]
• Administration: The oral suspension must be taken in the morning on an empty stomach after an overnight fast.[9]
• Critical Food Interaction: This is the most important administration rule for the oral form. No food should be consumed for 1 hour after taking the dose, although water is permitted.[9] The required fasting time before administration depends on the type of the last meal consumed:
• High-fat meal: Fast for at least 8 hours before taking the dose.
• Low-fat meal: Fast for at least 4 hours before taking the dose.
• Caloric supplement (e.g., protein drink): Fast for at least 2 hours before taking the dose.
• Feeding Tube Administration: Radicava ORS can be administered via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes. The tube must be flushed with at least 30 mL (1 ounce) of water both before and after administration of the medication.[9]

Storage Requirements

• Intravenous: Radicava® bags should be stored at room temperature (up to 25°C or 77°F) and protected from light. They must remain in the protective overwrap until time of use.[21]
• Oral Suspension: At the pharmacy, Radicava ORS® should be refrigerated at 2-8°C (36-46°F) and protected from light. Do not freeze. Once dispensed to the patient, the bottle should be stored upright at room temperature (20-25°C or 68-77°F). The bottle must be discarded 15 days after it is first opened.[21]

Table 4: Dosing and Administration Guidelines for Intravenous and Oral Formulations

Feature	Radicava® (Intravenous)	Radicava ORS® (Oral Suspension)
Recommended Dose	60 mg	105 mg (5 mL)
Dosing Cycle	Initial: 14 days on, 14 days off. Subsequent: 10 days on (within a 14-day period), 14 days off.	Initial: 14 days on, 14 days off. Subsequent: 10 days on (within a 14-day period), 14 days off.
Administration Method	IV infusion of two 30 mg bags over a total of 60 minutes.	Taken orally or via feeding tube.
Food/Fasting Rules	Not applicable.	Must be taken after an overnight fast. No food for 1 hour after dose. Fasting time before dose depends on last meal (e.g., 8 hrs for high-fat).
Preparation	Inspect oxygen indicator. Do not mix with other drugs.	Shake bottle vigorously for 30 seconds. Use provided oral syringe.
Storage (Patient)	Store at room temperature (up to 25°C), protected from light.	Store upright at room temperature (20-25°C). Discard 15 days after opening.

Safety, Tolerability, and Risk Management

The safety profile of Edaravone has been established through a program of clinical trials and extensive post-marketing surveillance. While generally considered to have a manageable safety profile, there are specific risks related to hypersensitivity, its formulation, and the logistics of its administration that require careful clinical management.

Adverse Event Profile from Clinical Trials

In the pivotal clinical trial for ALS (MCI186-19), the overall incidence of adverse events was similar between the edaravone and placebo groups.[27] The most common adverse reactions reported in patients treated with Edaravone at a rate of at least 10% and more frequently than placebo were:

• Contusion (bruising): 15% (vs. 9% in placebo) [23]
• Gait disturbance: 13% (vs. 9% in placebo) [23]
• Headache: 10% (vs. 6% in placebo) [23]

In an open-label study evaluating the oral suspension, fatigue was also observed as a common adverse reaction in 7.6% of patients.[31]

Serious Adverse Events and Post-Marketing Data

More serious risks have been identified, primarily through post-marketing experience and are highlighted in the drug's prescribing information.

• Hypersensitivity Reactions: Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported.[23] Symptoms can include hives, swelling of the lips, tongue, or face, breathing problems, and dizziness.[31] Consequently, Edaravone is strictly contraindicated in patients with a known history of hypersensitivity to the drug or any of its inactive ingredients.[23] The IV infusion must be discontinued immediately if any signs of a hypersensitivity reaction are observed.[9]
• Sulfite Allergic Reactions: Both the intravenous and oral formulations contain sodium bisulfite as an excipient.[12] Sodium bisulfite is a sulfite that can cause severe allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic episodes, in susceptible individuals.[12] The risk is known to be higher in people with a history of asthma.[31]
• Post-Marketing Surveillance: Analysis of data from the FDA Adverse Event Reporting System (FAERS) has provided further real-world safety information. While many reported events are consistent with the known progression of ALS (e.g., dyspnea, falls, muscular weakness), this surveillance has also identified potential new safety signals not listed in the original drug insert. These include reports of disseminated intravascular coagulation, abnormal hepatic function, cerebral hemorrhage, and issues related to IV administration such as catheter-site thrombosis and poor venous access.[36] The most frequently reported serious adverse events in the post-marketing setting often relate to the underlying disease and the complexities of long-term IV therapy in a vulnerable patient population, such as pneumonia, respiratory failure, and device-related infections.[38]

A critical analysis of this safety data reveals that many of the most significant risks associated with Edaravone are not due to the intrinsic toxicity of the molecule itself, but are rather consequences of its formulation and administration. The most severe warnings on the label relate to hypersensitivity and sulfite reactions; the latter is caused by an excipient, not the active pharmaceutical ingredient.[12] Furthermore, the high incidence of serious adverse events like infections in post-marketing reports is strongly linked to the logistical challenges and risks of maintaining long-term intravenous access in patients with advanced ALS, who are often immobilized and frail.[38] This context underscores the significant clinical value of the oral formulation, which was developed specifically to mitigate these administration-associated risks, thereby improving the overall safety profile of the therapy beyond mere convenience.

Drug-Drug and Disease Interactions

• Drug Interactions: Edaravone has a low potential for causing clinically significant pharmacokinetic drug-drug interactions. Its metabolism via multiple, redundant UGT pathways and its lack of substantial inhibition or induction of major cytochrome P450 (CYP) enzymes or drug transporters make it an unlikely perpetrator of such interactions.[9] Clinical studies confirmed no interaction with substrates for CYP3A4 (sildenafil), BCRP (rosuvastatin), or OAT3 (furosemide).[12] While most common concomitant medications are considered safe, some drug interaction databases list a number of potential moderate interactions (e.g., with teriflunomide, probenecid) that may warrant clinical monitoring.[39]
• Disease Interactions: Due to the presence of sodium bisulfite, caution is strongly advised for patients with a history of asthma or a known sulfite allergy.[35]

Use in Specific Populations

• Renal Impairment: No dosage adjustment is required for patients with mild-to-moderate renal impairment. The drug has not been studied in patients with severe renal impairment (eGFR <30 mL/min/1.73m²).[12]
• Hepatic Impairment: No dosage adjustment is necessary for patients with any degree of hepatic impairment (mild, moderate, or severe).[9]
• Pregnancy and Lactation: There are no adequate human data on the use of Edaravone during pregnancy. Animal studies have indicated a potential for fetal harm at clinically relevant doses.[12] It is not known if Edaravone is excreted in human milk.[12]

Table 5: Summary of Safety Profile and Common Adverse Reactions

Category	Details	Source(s)
Contraindications	History of hypersensitivity to edaravone or any inactive ingredients.	23
Warnings & Precautions	Hypersensitivity Reactions: Anaphylaxis and other serious allergic reactions can occur. Discontinue immediately if symptoms appear. Sulfite Allergic Reactions: Contains sodium bisulfite, which can cause severe, life-threatening reactions, especially in patients with asthma.	12
Common Adverse Reactions (≥10%)	• Contusion (15%) • Gait disturbance (13%) • Headache (10%) • Fatigue (7.6% with oral formulation)	23
Serious Adverse Reactions (Post-Marketing)	Pneumonia, respiratory failure, device-related infection (often linked to ALS progression and IV administration). New potential signals include DIC and abnormal hepatic function.	36
Key Drug Interactions	Low potential for pharmacokinetic interactions. Not an inhibitor/inducer of major CYP enzymes.	12
Key Disease Interactions	Use with caution in patients with a history of asthma or sulfite allergy.	35

Development History and Future Directions

The trajectory of Edaravone from its initial discovery to its current status as a globally recognized therapeutic agent is a compelling narrative of scientific persistence, strategic repositioning, and patient-focused lifecycle management. Developed by Mitsubishi Tanabe Pharma Corporation (MTPC), its story continues to evolve as new research explores its full therapeutic potential.

Historical Development by Mitsubishi Tanabe Pharma (MTPC)

• Origins in Stroke Research (1980s-1990s): Edaravone, then known by its development code MCI-186, was first synthesized and investigated during the 1980s and 1990s. The initial therapeutic target was acute ischemic stroke, based on the hypothesis that its potent free radical scavenging properties could mitigate the severe oxidative damage caused by ischemia-reperfusion injury.[13]
• First Approval in Japan (2001): Following a series of clinical trials in Japan that demonstrated its efficacy in improving functional outcomes, Edaravone (marketed as Radicut®) received its first regulatory approval from the PMDA in 2001 for the treatment of acute ischemic stroke.[7]
• Pivot to ALS (2001): Recognizing the shared pathological mechanism of oxidative stress in both acute stroke and chronic neurodegeneration, MTPC made the strategic decision to initiate a clinical development program for Edaravone in amyotrophic lateral sclerosis (ALS) in 2001.[13]
• The ALS Approval Journey (2001-2017): The path to an ALS indication was challenging. An initial Phase III trial (MCI186-16) failed to meet its primary endpoint, but a careful post-hoc analysis identified a specific patient subgroup that appeared to benefit.[28] This led to the design of a second, confirmatory Phase III trial (the pivotal MCI186-19) with enriched inclusion criteria targeting this subgroup. The success of this trial led to the approval of Edaravone for ALS in Japan and South Korea in 2015.[26] This was followed by a landmark approval from the U.S. FDA in 2017 and subsequent authorizations in Canada (2018), Switzerland (2019), and numerous other countries.[17]
• Lifecycle Management and the Oral Formulation (2019-2022): To address the significant patient burden and risks associated with long-term IV infusions, MTPC undertook the development of an oral formulation. After a series of clinical pharmacology studies established that a 105 mg oral dose was bioequivalent to the 60 mg IV dose, Radicava ORS® was approved by the FDA in 2022, followed by approvals in Canada, Japan, and Switzerland.[11]

Ongoing and Future Research

The development of Edaravone did not end with its approval for ALS. It is the subject of a robust and ongoing research program aimed at optimizing its use, understanding its mechanism more deeply, and expanding its therapeutic applications.

• Biomarker Identification: A major focus of current research is the identification of biomarkers to predict treatment response and monitor efficacy. The REFINE-ALS study (NCT04259255) is a large, prospective observational study collecting biological samples to measure markers of oxidative stress (e.g., 8-OHdG, 3-nitrotyrosine) and neurodegeneration (e.g., neurofilaments) in patients treated with Edaravone.[43] The goal is to elucidate its biological effects and potentially identify a patient profile most likely to benefit from therapy. Another study (NCT04097158) is specifically examining biomarkers across different clinical phenotypes of ALS.[44]
• New Formulations and Dosing Regimens: Research into alternative delivery methods and dosing schedules continues. The ADORE trial (NCT05178810) is a Phase III study investigating a different oral formulation of edaravone (FAB122) administered with a continuous daily dosing regimen, as opposed to the approved cyclical regimen.[45] Another Phase IIIb study evaluating a daily dosing regimen of Radicava ORS (NCT04569084) was discontinued after an interim analysis found it was not superior to the approved 2-weeks-on/2-weeks-off schedule.[11]
• Combination Therapies: A highly promising area of investigation is the combination of edaravone with dexborneol, an agent with complementary anti-inflammatory effects. This combination therapy is being actively studied in multiple clinical trials for acute ischemic stroke (e.g., NCT05644223, NCT06645522) and has been granted Breakthrough Therapy Designation by the FDA, signaling its potential to offer a substantial improvement over existing therapies.[47]
• Exploration of New Indications: The core mechanism of Edaravone lends itself to exploration in other diseases driven by oxidative stress. A notable example is the ongoing Phase II clinical trial (NCT06315231) evaluating an edaravone dexborneol sublingual tablet for the treatment of post-stroke cognitive impairment (PSCI). This represents a potential expansion into a new therapeutic area with significant unmet need.[51]

Exploratory and Off-Label Potential

Preclinical data and early-stage studies have suggested that Edaravone's neuroprotective effects could be beneficial in other conditions, although these are not approved indications and off-label use appears limited.[52]

• Other Neurodegenerative Diseases: Given the role of oxidative stress in diseases like Parkinson's Disease and Alzheimer's Disease, Edaravone has been investigated in animal models for these conditions, with some studies suggesting a neuroprotective effect on dopamine neurons or an ability to inhibit neurodegeneration.[53]
• Other Conditions: Its antioxidant properties have also been explored in diverse conditions such as septic myocardial dysfunction and chemotherapy-induced oral mucositis.[53]

The complete development arc of Edaravone demonstrates that it is more than a single drug for a single disease. It functions as a "platform molecule." Its core antioxidant mechanism has been successfully leveraged across different pathologies (acute stroke, chronic ALS), and it continues to be explored for new indications (post-stroke cognitive impairment). This expansion is occurring in parallel with innovations in its delivery (from IV to oral suspension to sublingual tablets) and composition (combination with dexborneol). This multi-pronged strategy to maximize the therapeutic value of a proven molecular scaffold is a sophisticated approach to drug development. The story of Edaravone is not finished; it is an evolving platform that may continue to yield new therapeutic options, serving as a model for how to realize the full potential of a valuable pharmacological asset.

Conclusion and Expert Synthesis

Edaravone (DrugBank ID: DB12243) stands as a significant, albeit specialized, therapeutic agent in the modern neurology armamentarium. Its journey from an acute stroke treatment in Japan to a globally recognized therapy for amyotrophic lateral sclerosis (ALS) is a testament to a development strategy rooted in a clear understanding of its core pharmacological mechanism: the potent scavenging of free radicals. This comprehensive analysis confirms that Edaravone's primary value lies in its capacity to mitigate the profound cellular damage wrought by oxidative stress, a common pathological denominator in a range of devastating neurological disorders.

The clinical efficacy of Edaravone must be viewed with a nuanced and critical perspective. For ALS, the evidence from the pivotal MCI186-19 trial demonstrates a statistically significant, yet functionally modest, slowing of disease progression. The 33% reduction in the rate of decline on the ALSFRS-R scale is a meaningful outcome for patients facing an inexorable disease. However, this result was achieved in a highly selected, "enriched" patient population, which raises valid questions about its generalizability to the broader, more heterogeneous community of individuals living with ALS. The conflicting data from some real-world observational studies underscore this uncertainty and highlight the persistent gap between clinical trial efficacy and real-world effectiveness. In the context of acute ischemic stroke, its established role in Japan is supported by clinical data, but its failure to gain traction for this indication in Western regulatory domains reflects an ongoing debate about the magnitude and consistency of its benefit.

Perhaps the most impactful innovation in the Edaravone story is the successful development of the oral suspension, Radicava ORS®. This transition from a burdensome intravenous infusion to a self-administered oral liquid represents a major advancement in patient-centric care. It not only enhances convenience and quality of life but also mitigates the significant risks associated with long-term IV access, such as catheter-related infections. However, the oral formulation's own pharmacokinetic limitations, particularly its severe susceptibility to food effects, present a new set of challenges for ensuring patient adherence and achieving therapeutic drug exposure in a real-world setting.

Ultimately, the legacy of Edaravone is likely to be twofold. First, it provides a tangible, disease-modifying therapeutic option for select patients with two of the most challenging conditions in neurology, offering a measure of hope where few alternatives exist. Second, and perhaps more enduringly, Edaravone serves as an influential and instructive case study in contemporary pharmaceutical development. Its history exemplifies the power of mechanistic repurposing, the strategic utility and inherent limitations of enrichment in clinical trial design, the potential for pragmatic and flexible regulatory pathways to address unmet needs, and the profound value of intelligent lifecycle management in maximizing the clinical utility of a foundational molecule. The ongoing research into new formulations, combinations, and indications suggests that the story of this antioxidant platform is far from complete.

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