Edaravone (Monograph)

Brand name: Radicava; Radicava ORS
Drug class: Amyotrophic Lateral Sclerosis (ALS) Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Free radical scavenger.

Uses for Edaravone

Amyotrophic Lateral Sclerosis

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

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.

There is no cure for ALS and limited treatment options are available that have shown only modest benefits in delaying disease progression and death.

The American Academy of Neurology published an evidence-based guideline for ALS in 2009; however, the only disease-modifying drug available at that time was riluzole. Additional agents are currrently available (e.g., edaravone, tofersen); however, these drugs have not been shown to provide much, if any, improvement in survival.

Edaravone Dosage and Administration

General

Patient Monitoring

• Monitor patients for hypersensitivity reactions during administration of edaravone; promptly discontinue the drug at the first sign or symptom of such a reaction.

Administration

Administer orally (as an oral suspension) or by IV infusion.

IV Administration

Administer by IV infusion.

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

Do not mix with other drugs.

Rate of Administration

Administer each 60-mg dose as 2 consecutive 30-mg IV infusion bags over a total of 60 minutes (infusion rate of approximately 1 mg per minute [3.33 mL per minute]).

Oral Administration

Administer by mouth or via feeding tube.

Administer in the morning on an empty stomach after overnight fasting. (See Table 1 for specific fasting conditions.) Do not consume food for 1 hour after administration except water.

Before each use, invert the container and vigorously shake ≥30 seconds. Administer oral suspension using the supplied 5-mL oral syringe; a household teaspoon is not an adequate measuring device.

Administration via Feeding Tube

Oral suspension may be administered via nasogastric tubes or percutaneous endoscopic gastrostomy (PEG) tubes made of silicone, polyvinyl chloride (PVC), or polyurethane. Use a catheter-tip syringe to flush the tube with at least 1 ounce (30 mL) of water before and after administration of the drug.

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:

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

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

Oral

105 mg (5 mL) by mouth or via feeding tube using the oral suspension in 28-day treatment cycles according to the following schedule:

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

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

Switching from IV to Oral

Patients receiving IV edaravone 60 mg may be switched to oral edaravone 105 mg (5 mL of the oral suspension) using the same dosing frequency.

Upon switching to oral therapy, follow dosing recommendations for the oral suspension with regards to food consumption.

Special Populations

Hepatic Impairment

Dosage adjustments not needed.

Renal Impairment

Mild or moderate renal impairment: Dosage adjustments not needed. No data on severe renal impairment.

Geriatric Use

Dosage adjustments not needed; some older individuals may exhibit greater sensitivity.

Cautions for Edaravone

Contraindications

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

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.

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

Sulfite Sensitivity

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

Overall prevalence of sulfite sensitivity in general population unknown. Sulfite sensitivity occurs more frequently in individuals with asthma.

Specific Populations

Pregnancy

No adequate data on developmental risk when used in pregnant women. 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.

Lactation

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

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.

Pediatric Use

Efficacy and safety not established.

Geriatric Use

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

Hepatic Impairment

Changes in exposures observed in patients with mild, moderate, or severe hepatic impairment not considered clinically significant; therefore, dosage adjustments not necessary in patients with hepatic impairment.

Renal Impairment

Changes observed in mean peak plasma concentration and AUC in patients with mild to moderate renal impairment not considered clinically important; dosage adjustments therefore not necessary in such patients. The effects of severe renal impairment not studied.

Common Adverse Effects

Most common adverse reactions (≥10%): contusion, gait disturbance, headache.

Drug Interactions

Metabolized by multiple uridine diphosphate-glucuronosyltransferase (UGT) enzymes (i.e., UGT 1A1, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B17). Not expected to substantially inhibit UGT 1A1 or 2B7.

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.

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, MATE1, MATE2-K).

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely.

Drugs Affecting or Metabolized by UGT Enzymes

Pharmacokinetic interactions unlikely.

Drugs Affecting or Affected by Membrane Transporters

Pharmacokinetic interactions unlikely.

Specific Drugs

Edaravone Pharmacokinetics

Absorption

Plasma Concentrations

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

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

Well absorbed following oral administration of the suspension; median time to peak plasma concentration occurred in approximately 0.5 hours under fasting conditions. Absolute bioavailability is about 57%.

Equivalent exposure of the 105-mg dose of the oral suspension to the 60-mg dose of the IV formulation demonstrated. Similar pharmacokinetics observed following administration of the oral suspension via feeding tube and by mouth.

Following oral administration of the suspension to healthy subjects 1 hour before or 8 hours after high-fat meals (800–1000 calories, 50% fat), 4 hours after low-fat meals (400–500 calories, 25% fat), or 2 hours after caloric supplement (250 calories, e.g., protein drink), less than 20% and 10% changes in peak plasma concentrations and AUC, respectively, observed.

Following oral administration of the suspension to healthy subjects, peak plasma concentration decreased by 82%, and AUC decreased by 61% with a high-fat meal compared to fasted conditions.

Following oral administration of the suspension 4 hours after high-fat meals, peak plasma concentrations and AUC decreased by 44% and 24%, respectively.

Following oral administration of the suspension 2 hours after low-fat meals, peak plasma concentrations and AUC decreased by 45% and 21%, respectively.

Distribution

Plasma Protein Binding

92%, primarily to albumin.

Elimination

Metabolism

Metabolized to pharmacologically inactive sulfate conjugate, presumably by sulfotransferases, and to glucuronide conjugates by multiple UGT isoenzymes (i.e., UGT 1A1, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B17) in the liver and kidney.

Elimination Route

In healthy individuals, 60–80% of a dose excreted in urine as the glucuronide conjugate, approximately 6–8% excreted in urine as the sulfate conjugate, and ≤1% excreted in urine as unchanged drug.

Half-life

Edaravone: 4.5–9 hours.

Metabolites: 3–6 hours.

Special Populations

Hepatic impairment: Changes in exposures observed in patients with mild, moderate, or severe hepatic impairment not considered clinically significant.

Renal impairment: Changes observed in mean peak plasma concentration and AUC in patients with mild to moderate renal impairment not considered clinically significant. The effects of severe renal impairment not studied.

Geriatric patients: No age effect on pharmacokinetics observed.

Gender: No gender effect on pharmacokinetics observed.

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

Stability

Storage

Oral

Oral Suspension

Pharmacies: store at 2–8°C upright and protect from light; do not freeze.

Patients: store upright at room temperature (20–25°C) and protect from light.

Discard 15 days after opening bottle, or if unopened, 30 days from the date of shipment indicated on the carton pharmacy label.

Parenteral

Injection, for IV Infusion

25°C (excursions permitted to 15–30°C). Protect from light.

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

Actions

• Free radical scavenger.

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

• Neuroprotective effects demonstrated in animal studies.

Advice to Patients

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

• Risk of allergic reactions due to sulfite sensitivity. 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.

• Advise the patients and caregivers to read the manufacturer's patient information and instructions for use for the oral suspension.

• Advise patients to take edaravone oral suspension in the morning on an empty stomach. Instruct patients to fast 8 hours before each dose if they consume a high-fat meal, 4 hours before each dose if they consume a low-fat meal, or 2 hours before each dose if they consume a caloric supplement. Also, instruct patients to not consume food for 1 hour after each dose; if needed, up to 240 mL (8 ounces) of water may be consumed to assist with swallowing the suspension..

• Advise caregivers, if administering edaravone oral suspension via feeding tube, to use a catheter-tip syringe and flush the feeding tube with approximately 1 ounce (30 mL) of water before and after use.

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

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

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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