Edaravone
Radicava, Radicava ORS
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Amyotrophic lateral sclerosis (ALS) | Adults | Disease-modifying (may be used alongside riluzole) | FDA Approved |
Edaravone is one of a limited number of agents approved specifically for ALS. The pivotal trial (Study 19) enrolled patients with early-stage disease — those who were functionally independent, had definite or probable ALS per the revised El Escorial criteria, forced vital capacity of at least 80% predicted, and disease duration under two years. The drug slowed the decline in daily functioning over a 24-week period as measured by the ALSFRS-R. It does not reverse existing motor neuron damage and has not been shown to extend survival.
Acute ischaemic stroke (Japan, South Korea, other Asian markets): Edaravone has been approved for stroke recovery in Japan since 2001. It is not approved for stroke in the US or EU. Evidence quality: Moderate (post-marketing data and retrospective studies, no large Western RCTs).
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| ALS — initial treatment cycle (IV) | 60 mg IV daily × 14 days | 60 mg IV daily (10 of 14 days) | 60 mg/day | Infuse over 60 min as two consecutive 30 mg bags (~1 mg/min). Each cycle: 14 days on, 14 days off (cycle 1); then 10 of 14 days on, 14 days off (subsequent). Brand IV (Radicava) discontinued in US April 2025; IV generics remain available. |
| ALS — initial treatment cycle (Oral) | 105 mg PO daily × 14 days | 105 mg PO daily (10 of 14 days) | 105 mg/day | Take in morning after overnight fast. No food for 1 h after dose (water permitted). 5 mL via provided oral syringe or feeding tube. See fasting table below for meal-specific intervals. |
| Switch from IV to oral formulation | 105 mg PO daily | 105 mg PO daily | 105 mg/day | Maintain the same dosing frequency and cycle timing. Oral 105 mg provides equivalent AUC to IV 60 mg. Can switch at any point within a cycle. |
| ALS — mild-moderate renal impairment | No dose adjustment required | Exposure increases are clinically non-significant (~20–29% AUC rise with moderate renal impairment). Severe impairment not studied. Monitor renal function at baseline. | ||
| ALS — hepatic impairment (any severity) | No dose adjustment required | Exposure changes across mild, moderate, and severe hepatic impairment are not clinically significant (FDA PI). | ||
Oral Fasting Requirements
| Meal Type | Fast Before Dose | Fast After Dose |
|---|---|---|
| High-fat meal (800–1,000 kcal, 50% fat) | 8 hours | 1 hour |
| Low-fat meal (400–500 kcal, 25% fat) | 4 hours | 1 hour |
| Caloric supplement (~250 kcal, e.g., protein drink) | 2 hours | 1 hour |
Edaravone uses an unusual cyclic regimen. The first cycle is 14 consecutive daily doses followed by a 14-day drug-free period. All subsequent cycles consist of 10 dosing days within a 14-day period (typically weekdays for two weeks, omitting weekends), followed by a 14-day drug-free period. Patients and caregivers benefit from a written calendar marking “on” and “off” days to maintain adherence.
Pharmacology
Mechanism of Action
The precise mechanism by which edaravone slows functional decline in ALS has not been established. Edaravone is a synthetic free radical scavenger belonging to the substituted 2-pyrazolin-5-one class. Under physiological conditions, the molecule partially exists as an anion capable of donating electrons to reactive oxygen and nitrogen species, including hydroxyl radicals and peroxynitrite. By neutralising these species, edaravone is thought to reduce oxidative stress — a process broadly implicated in motor neuron degeneration. Preclinical work in SOD1-mutant mouse models showed that edaravone administration attenuated motor neuron loss and delayed symptom progression. However, the clinical benefit may not be fully explained by antioxidant activity alone, and the drug has not been shown to affect survival or reverse existing neuronal damage in humans.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral Tmax ~0.5 h (fasted); absolute bioavailability ~57% due to first-pass effect; high-fat meal reduces Cmax by 82% and AUC by 61% | Strict fasting requirements are essential for consistent drug exposure; non-adherence to fasting substantially reduces absorption |
| Distribution | Vd = 63.1 L (IV); 92% protein bound (albumin); no concentration-dependent binding | Moderate tissue distribution; protein-binding displacement interactions unlikely at therapeutic concentrations |
| Metabolism | Sulfate conjugate (sulfotransferases) and glucuronide conjugate (UGT1A1, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, 2B17); both metabolites inactive | Non-CYP metabolism means minimal risk of CYP-based drug interactions; multiple redundant UGT pathways reduce pharmacogenomic variability |
| Elimination | t½ = 4.5–9 h; CL = 35.9 L/h (IV); urinary excretion 60–80% as glucuronide, 6–8% as sulfate, <1% unchanged | Once-daily dosing is sufficient; no accumulation with repeated daily administration; renal elimination predominates |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Contusion (bruising) | 15% (vs 9% placebo) | Most commonly reported adverse effect; may reflect disease-related falls rather than a direct pharmacological effect; counsel patients on fall prevention |
| Gait disturbance | 13% (vs 9% placebo) | Likely multifactorial — overlaps with ALS progression; assess new or worsening gait changes to distinguish drug effect from disease course |
| Headache | 10% (vs 6% placebo) | Usually mild and self-limiting; routine analgesics may be used as needed |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dermatitis | 8% (vs 5% placebo) | Non-specific; monitor for progression to more severe skin reactions |
| Eczema | 7% (vs 4% placebo) | Manage with emollients and topical corticosteroids if needed |
| Fatigue | 7.6% (oral formulation, open-label) | Observed in the RADICAVA ORS open-label study; overlaps significantly with ALS-related fatigue |
| Respiratory failure / disorder / hypoxia | 6% (vs 4% placebo) | Difficult to separate from ALS disease progression; monitor respiratory function routinely |
| Glycosuria | 4% (vs 2% placebo) | Clinical significance unclear; not associated with hyperglycaemia in trials |
| Tinea infection | 4% (vs 2% placebo) | Superficial fungal infections; treat with standard topical antifungals |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Anaphylaxis | Rare | During or shortly after infusion/dose | Immediate discontinuation; emergency care (epinephrine, airway management); permanent discontinuation of edaravone |
| Hypersensitivity reactions (urticaria, erythema multiforme, decreased BP, dyspnoea) | Rare | Any time during treatment | Discontinue edaravone; treat per standard of care and monitor until resolution; do not rechallenge |
| Sulfite allergic reaction (asthmatic episodes) | Rare (higher risk in asthmatics) | After any dose (contains sodium bisulfite) | Discontinue; manage bronchospasm; assess sulfite allergy history before initiation |
| Neurotoxicity (spinal cord white matter vacuolation) | Not observed in humans at approved doses | Seen in 39-week dog study at supratherapeutic doses | No clinical action required at current doses; safety margin is approximately 2-fold above human exposure at approved dose. Report any unexplained neurological symptoms |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Dysphagia | 1.4% (edaravone) | Likely disease progression rather than drug effect |
| Respiratory disorder | 0% (edaravone) vs 1.5% (placebo) | No respiratory-related discontinuations in active arm |
Both formulations contain sodium bisulfite. Before starting edaravone, screen for asthma history and known sulfite sensitivity. During IV infusions, keep the patient under direct observation for the duration of the 60-minute infusion and have emergency medications available. For oral administration, instruct patients to recognise early signs of allergic reactions (hives, swelling, breathing difficulty) and seek immediate care.
Drug Interactions
Edaravone has a notably clean interaction profile. It is metabolised by sulfotransferases and multiple UGT isoforms rather than CYP450 enzymes. In vitro and clinical studies confirm that edaravone does not significantly inhibit or induce CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A), UGTs, or major drug transporters (P-gp, OATP1B1/1B3, OAT1, OCT2, MATE1/2-K). No known clinically significant drug-drug interactions have been identified. In clinical studies, co-administration with sildenafil (CYP3A4 substrate), rosuvastatin (BCRP substrate), and furosemide (OAT3 substrate) produced no meaningful pharmacokinetic changes.
Edaravone is one of the few ALS therapeutics with no known clinically significant drug-drug interactions. This is advantageous in ALS patients who frequently receive concomitant riluzole, baclofen, and other symptomatic medications. The non-CYP metabolism (sulfotransferases and UGTs) provides a wide therapeutic compatibility window.
Monitoring
-
Hypersensitivity Signs
Every infusion / dose
Routine Monitor for urticaria, erythema, wheals, dyspnoea, or hypotension during and immediately after IV infusions. For oral dosing, educate the patient and caregiver to recognise allergic signs. -
Respiratory Function (FVC)
Baseline, then every 3 months
Routine Forced vital capacity should be tracked as part of standard ALS care. Decline guides decisions about non-invasive ventilation and overall disease trajectory. The pivotal trial enrolled patients with FVC ≥80% predicted. -
ALSFRS-R Score
Baseline, then every 1–3 months
Routine The primary efficacy measure in the pivotal trial. Serial scores help clinicians assess treatment response and guide shared decision-making about continuing therapy. -
Renal Function
Baseline
Routine Assess creatinine and eGFR before initiation. No dose adjustment needed for mild-moderate impairment. Effects of severe renal impairment have not been studied. -
Sulfite Allergy / Asthma Status
Before first dose
Trigger-based Screen for asthma and known sulfite sensitivity. Both formulations contain sodium bisulfite. Sulfite sensitivity is more common in asthmatic individuals. -
Pregnancy Status
Before initiation, then as indicated
Trigger-based Animal studies showed developmental toxicity at clinically relevant doses. Advise patients of reproductive potential to use contraception and notify prescriber if pregnancy occurs. -
Skin Reactions
Each visit
Trigger-based Dermatitis and eczema occur more frequently with edaravone. Evaluate new rashes for early signs of erythema multiforme or more serious hypersensitivity.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to edaravone or any inactive ingredient in either formulation (including sodium bisulfite, L-cysteine hydrochloride hydrate, sorbitol). Prior anaphylaxis or erythema multiforme to edaravone is a permanent contraindication.
Relative Contraindications (Specialist Input Recommended)
- Asthma or known sulfite sensitivity: Both RADICAVA and RADICAVA ORS contain sodium bisulfite. Sulfite-sensitive asthmatics are at elevated risk for bronchospasm and anaphylaxis. A risk-benefit discussion with allergy or pulmonology input is warranted before initiation.
- Pregnancy: Animal reproductive studies demonstrated fetal harm (increased mortality, reduced growth, delayed development) at clinically relevant doses. No human data exist. Prescribing requires documented risk-benefit discussion with the patient.
- Severe renal impairment: Not studied. Although mild-moderate impairment does not meaningfully alter exposure, the effects of severe impairment on edaravone and its metabolites are unknown. Specialist nephrology input is advisable.
Use with Caution
- Breastfeeding: Edaravone and its metabolites are excreted in rat milk. No human data. Consider the risk-benefit balance.
- Patients with swallowing difficulty: Oral suspension can be administered via NG tube or PEG tube (silicone, PVC, or polyurethane). Flush with 30 mL water before and after administration.
- Paediatric patients: Safety and effectiveness have not been established in children.
Edaravone does not carry an FDA Boxed Warning. However, the FDA label includes prominent Warnings and Precautions for hypersensitivity reactions (including anaphylaxis reported in post-marketing surveillance) and sulfite allergic reactions. Both formulations contain sodium bisulfite, which may cause severe or life-threatening allergic-type reactions, particularly in asthmatic individuals. Clinicians should have emergency medications available during IV infusions and educate patients on oral formulation about recognising allergic symptoms.
Patient Counselling
Purpose of Therapy
Edaravone is a disease-modifying treatment for ALS that aims to slow the rate of functional decline. It does not cure ALS, reverse existing damage, or restore lost motor function. In the pivotal clinical trial, patients who received edaravone experienced a slower decline in daily activities (such as writing, eating, walking, and breathing) compared to those receiving placebo over a six-month period. Patients should understand that the treatment works alongside other ALS management strategies including riluzole, physical therapy, and nutritional support.
How to Take (Oral Formulation)
RADICAVA ORS is taken once daily in the morning on an empty stomach. Patients should shake the bottle vigorously upside-down for at least 30 seconds before each use. The dose is 5 mL (105 mg) drawn up with the provided oral syringe — household teaspoons must not be used. Patients must not eat food for at least 1 hour after taking the dose (water is permitted). Opened bottles must be discarded after 15 days, regardless of remaining volume.
Sources
- RADICAVA and RADICAVA ORS (edaravone) Prescribing Information. Mitsubishi Tanabe Pharma America, Inc. Jersey City, NJ; Revised 05/2022. FDA Label Primary source for all dosing, pharmacokinetic, safety, and contraindication data in this monograph.
- RADICAVA (edaravone injection) Prescribing Information. Initial approval 2017. FDA Label (2017) Original IV-only prescribing information; source for early PK data and IV-specific administration details.
- FDA Drug Approval Package: RADICAVA ORS (NDA 215446). U.S. Food and Drug Administration. Approved May 2022. FDA Approval Regulatory approval documentation for the oral suspension formulation including bioequivalence data.
- 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(7):505–512. doi:10.1016/S1474-4422(17)30115-1 Pivotal phase III trial (Study 19) that demonstrated a 2.49-point ALSFRS-R benefit vs placebo at 24 weeks and formed the basis for FDA approval.
- 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. doi:10.3109/21678421.2014.959024 Earlier phase III trial (Study 16) that did not reach its primary endpoint in the full ALS population; post-hoc analysis informed Study 19 design.
- Writing Group on Behalf of the Edaravone (MCI-186) 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. doi:10.1080/21678421.2017.1364269 24-week open-label extension of Study 19 providing longer-term safety and efficacy follow-up data through 48 weeks total treatment.
- Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review). Neurology. 2009;73(15):1227–1233. doi:10.1212/WNL.0b013e3181bc01a4 AAN guideline for ALS care; predates edaravone approval but remains the foundational ALS management framework referenced by most US centres.
- Leigh PN, Swash M, Iwasaki Y, et al. Amyotrophic lateral sclerosis: a consensus viewpoint on designing and implementing a clinical trial. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5(2):84–98. doi:10.1080/14660820410020187 Consensus document on ALS trial design that informed the methodology of the edaravone development programme.
- Hardiman O, van den Berg LH. Edaravone: a new treatment for ALS on the horizon? Lancet Neurol. 2017;16(7):490–491. doi:10.1016/S1474-4422(17)30163-1 Expert commentary on Study 19 results, discussing the clinical significance and limitations of the trial findings.
- Takei K, Watanabe K, Yuki S, Akimoto M, Sakata T, Palumbo J. Edaravone and its clinical development for amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(sup1):5–10. doi:10.1080/21678421.2017.1353101 Review of the edaravone clinical development programme from preclinical free radical scavenging data through pivotal trial results.
- Ali ZK, Baker DE. Formulary drug review: edaravone. Hosp Pharm. 2017;52(11):732–736. doi:10.1177/0018578717734877 Comprehensive formulary review covering pharmacokinetics, efficacy data, and cost considerations for hospital formulary committees.
- Nakamaru Y, Kinoshita S, Kawaguchi A, Takei K, Palumbo J, Suzuki M. Pharmacokinetic profile of edaravone: a comparison between Japanese and Caucasian populations. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(sup1):80–87. doi:10.1080/21678421.2017.1353100 Population PK analysis demonstrating no clinically significant racial differences in edaravone exposure between Japanese and Caucasian subjects.
- Turnbull J. Reappraisal of an ALS trial: unaccounted procedural risk. Lancet Neurol. 2020;19(9):717–718. doi:10.1016/S1474-4422(20)30265-9 Critical appraisal of Study 19 methodology, raising questions about procedural risk factors that may have influenced trial outcomes.