AHFS Class:

• Amyotrophic Lateral Sclerosis (ALS) Agents 28:44

Generic Name(s):

• Edaravone

Edaravone is a free radical scavenger.3,4,6,7,8,13

Amyotrophic Lateral Sclerosis

Edaravone is used for the treatment of amyotrophic lateral sclerosis (ALS)1 and has been designated an orphan drug by FDA for use in this condition.2

Clinical Experience

The current indication for edaravone (as the IV formulation) is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study in Japanese patients with ALS.1,3,4 The study was conducted after a previous phase 3 study failed to demonstrate a clinical benefit with edaravone after 24 weeks of treatment in a broad population of patients with ALS (i.e., those with definite, probable, or probable laboratory-supported ALS, a disease duration of 3 years or less, and forced vital capacity [FVC] of at least 70% at baseline).3,4,5 Based on a post hoc analysis of this study suggesting that edaravone may be effective in a subgroup of patients who were in an earlier stage of the disease, a second phase 3 study was subsequently conducted to evaluate efficacy and safety of the drug in this population.3,4 Response to treatment was evaluated in terms of the revised ALS Functional Rating Scale (ALSFRS-R), a standard 48-point questionnaire-based scale used to assess fine motor, gross motor, bulbar, and respiratory function in patients with ALS (maximum score of 0-4 points for each item with higher scores representing greater functional ability).

The study included adults with definite or probable ALS (excluding those with probable laboratory-supported ALS) who had a disease duration of 2 years or less, normal respiratory function (i.e., baseline FVC of at least 80%), and preserved functionality in most activities of daily living (defined as a score of 2 or higher on all items of the ALSFRS-R); additional eligibility criteria included a decline in the patient's ALSFRS-R score of 1-4 points during a 12-week observation period.1,3,4 After completion of the observation period, 137 patients were randomized in a 1:1 ratio to receive edaravone or placebo.1,3,4 Baseline characteristics were balanced between groups (58% male, mean age 60-61 years, 40% with definite ALS, 60% with probable ALS, 91% receiving concomitant riluzole, mean disease duration 1.1 years, mean baseline ALSFRS-R score before observation 43.5-43.6, mean ALSFRS-R score at baseline 41.8-41.9).1,3,4 Edaravone was administered at a dosage of 60 mg by IV infusion over 60 minutes for six 28-day treatment cycles.1 The initial treatment cycle consisted of daily dosing for the first 14 days, followed by 14 drug-free days; in subsequent cycles, the drug was administered for 10 out of 14 days, followed by 14 drug-free days.1,3,4 The primary efficacy end point was the change in ALSFRS-R score from baseline to 24 weeks.1,3,4 The decline in ALSFRS-R scores was substantially less in patients receiving edaravone compared with those receiving placebo (mean decrease of 5.01 and 7.5 points, respectively, corresponding to a statistically significant and clinically meaningful difference of 2.5 points).1,3,4 More patients who received edaravone had stable ALSFRS-R scores over time, while more patients who received placebo experienced marked declines in their scores.1,3 No substantial difference was observed between the treatment groups with respect to FVC, grip or pinch strength, and time to death or certain disease progression.3,4

In a multicenter, propensity score-matched, cohort study, long-term outcomes of patients with ALS who received at least 4 treatment cycles of IV edaravone were compared with patients who received standard therapy only.20 After a median of 13.9 months of treatment, disease progression in patients who received IV edaravone did not differ from patients who received standard therapy for a median of 11.2 months; in addition, no significant differences were observed between the groups in secondary outcomes including probability of survival, time to ventilation, and change in disease progression.20

Use of oral edaravone suspension is based on efficacy and safety results from the IV formulation in addition to pharmacokinetic studies demonstrating bioequivalence to IV edaravone.17,18,19

Clinical Perspective

ALS (i.e., Lou Gehrig disease, Charcot's sclerosis) is a fatal, progressive neurodegenerative disease affecting both upper and lower motor neurons; manifestations include gradual weakness and atrophy in limb, thoracic, abdominal, and bulbar muscles with related deficits in activities of daily living.3,9,10,13,14 Typically, the disease is fatal within 2-5 years of clinical onset, often as a result of respiratory failure.3,9,10,11,13 There is no cure for ALS and the limited treatment options available (e.g., riluzole, noninvasive ventilation, percutaneous endoscopic gastrotomy [PEG]) have shown only modest benefits in delaying disease progression and death.3,9,10,11,12,14 Disease management requires a multidisciplinary approach to address patients' physical deficits (e.g., loss of mobility, respiratory failure, dysarthria, dysphagia) as well as their social and psychological needs.11,14

The American Academy of Neurology published an evidence-based review of treatments for ALS in 2009; however, the only disease-modifying drug available at that time was riluzole.14 The availability of edaravone offers another option; however, both drugs provide limited improvement in survival.21 Currently, there is no treatment that provides substantial clinical benefit for patients with ALS.21 The mainstay of treatment is timely interventions to manage symptoms.21

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.1

Administration

Edaravone is administered orally (as an oral suspension) or by IV infusion.1

IV Administration

Edaravone injection is intended for IV infusion only; the drug is administered as an IV infusion over 60 minutes.1

Commercially available edaravone injection should be stored at 25°C with excursions between 15-30°C permitted; the drug should be protected from light.1 Edaravone solution for IV infusion is supplied in polypropylene infusion bags overwrapped with secondary packaging containing an oxygen absorber, designed to protect the drug from oxidation, and an oxygen indicator.1 The indicator should be pink when acceptable oxygen levels are present; the drug should not be used if the indicator has turned blue or purple prior to opening the package.1 The infusion bags should be stored in their overwrap packaging until time of use; once the overwrap package is opened, the drug must be used within 24 hours.1

Inspect the infusion solution visually for particulate matter and discoloration prior to administration.1 Do not inject other drugs into the infusion bag or mix with edaravone.1

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]).1

Oral Administration

Edaravone oral suspension may be administered by mouth or via feeding tube.1 The drug should be taken in the morning on an empty stomach after overnight fasting.1 (See Table 1 for specific fasting conditions.) Food should not be consumed for 1 hour after administration except water.1

Administer the oral suspension using the supplied 5-mL oral syrin a household teaspoon is not an adequate measuring device.1

Pharmacies should store edaravone oral suspension refrigerated at 2-8°C and protected from light; do not freeze and store upright.1 Patients should store the oral suspension upright at room temperature (20-25°C) and protected from light.1 The container should be inverted and vigorously shaken for at least 30 seconds before each use.1 The drug should be discarded 15 days after opening the bottle, or if unopened, 30 days from the date of shipment indicated on the carton pharmacy label.1

Administration via Feeding Tube

Edaravone oral suspension may be administered via nasogastric tubes or percutaneous endoscopic gastrostomy (PEG) tubes made of silicone, polyvinyl chloride (PVC), or polyurethane.1 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.1

Dosage

IV Dosage

The recommended adult IV dosage of edaravone for the treatment of amyotrophic lateral sclerosis (ALS) is 60 mg (2 consecutive 30-mg IV infusions over a total of 60 minutes) daily, administered in 28-day treatment cycles.1 In the initial treatment cycle, patients should receive edaravone for the first 14 days, followed by a 14-day drug-free period.1 In subsequent treatment cycles, patients should receive the drug for 10 out of the first 14 days, followed by a 14-day drug-free period.1,16

Oral Dosage

The recommended adult oral dosage of edaravone for the treatment of ALS is 105 mg (5 mL) administered orally or via feeding tube in the morning after overnight fasting.1 In the initial treatment cycle, patients should receive edaravone for the first 14 days, followed by a 14-day drug-free period.1 In subsequent treatment cycles, patients should receive the drug for 10 out of the first 14 days, followed by a 14-day drug-free period.1

Switching from IV Edaravone to Oral Edaravone

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.1 Upon switching to oral therapy, patients should follow the dosing recommendations for the oral suspension with regards to food consumption.1

Special Populations

Hepatic Impairment

Dosage adjustments of edaravone are not needed in patients with hepatic impairment.1

Renal Impairment

Dosage adjustments are not needed in patients with mild or moderate renal impairment.1

Geriatric Use

Dosage adjustments are not needed in geriatric patients; however, greater sensitivity to the drug for some older individuals cannot be ruled out.1

Contraindications

• Patients with a history of hypersensitivity to the drug or any other 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), have been reported during postmarketing experience with edaravone.1

Patients should be monitored carefully for hypersensitivity reactions.1 If a hypersensitivity reaction occurs, the drug should be discontinued and appropriate treatment initiated; the patient should be monitored until the condition resolves.1

Sulfite Sensitivity

Both formulations of edaravone contain sodium bisulfite, a sulfite that may cause allergic-type reactions (e.g., anaphylactic symptoms, life-threatening or less severe asthmatic episodes) in susceptible individuals.1 The overall prevalence of sulfite sensitivity in the general population is unknown.1 Sulfite sensitivity occurs more frequently in individuals with asthma than in individuals without asthma.1

Specific Populations

Pregnancy

There are no adequate data to determine whether edaravone is associated with a risk of developmental abnormalities when used during pregnancy.1 In animal studies, administration of edaravone to pregnant rats and rabbits resulted in adverse developmental effects (e.g., increased mortality, decreased growth, delayed sexual development, altered behavior) at clinically relevant doses.1 Most of these effects occurred at doses that were also associated with maternal toxicity.1

Lactation

It is not known whether edaravone is distributed into human milk or if the drug has any effects on milk production or the nursing infant.1 Edaravone and its metabolites are distributed into milk of lactating rats.1

The known benefits of breast-feeding should be considered 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 of edaravone have not been established in pediatric patients.1

Geriatric Use

No overall differences in efficacy or safety of edaravone have been observed in geriatric patients compared with younger adults.1 However, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out.1

Hepatic Impairment

Changes in exposures observed in patients with mild, moderate, or severe hepatic impairment are not considered clinically significant; therefore, dosage adjustments are not necessary in patients with hepatic impairment.1

Renal Impairment

Changes observed in mean peak plasma concentration and AUC in patients with mild to moderate renal impairment are not considered clinically significant; therefore, dosage adjustments are not necessary in such patients.1 The effects of severe renal impairment have not been studied.1

Common Adverse Effects

Most common adverse reactions (≥10%) include contusion, gait disturbance, and headache.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Edaravone and its metabolites are not expected to inhibit major cytochrome P-450 (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 doses.1,3,15

The pharmacokinetics of edaravone are not expected to be substantially affected by CYP inhibitors or inducers.1,3,15

Concomitant oral administration of edaravone suspension at a dose higher than the recommended dose of 105 mg with sildenafil (a CYP3A4 substrate) did not produce any changes in peak plasma concentration and AUC of sildenafil.1

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferase Enzymes

Edaravone is metabolized by multiple uridine diphosphate-glucuronosyltransferase (UGT) enzymes (i.e., UGT 1A1, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B17); therefore, the pharmacokinetics of the drug are not expected to be substantially affected by UGT inhibitors.1,15

Edaravone and its metabolites are not expected to substantially inhibit UGT 1A1 or 2B7 at clinically relevant doses.1

Drugs Affecting or Affected by Membrane Transporters

Edaravone and its metabolites are not expected to substantially inhibit major transporters (e.g., P-glycoprotein [P-gp], breast cancer resistance protein [BCRP], organic anion transporting polypeptide [OATP] 1B1, OATP1B3, organic anion transporter [OAT] 1, OAT3, MATE1, MATE2-K, and organic cation transporter [OCT] 2).1,15

Since edaravone has a high ability to permeate membranes, transporters play a limited role in the overall disposition of the drug.15 The pharmacokinetics of edaravone are not expected to be substantially affected by inhibitors of major transporters.1,3,15

Concomitant oral administration of edaravone suspension at a dose higher than the recommended dose of 105 mg with rosuvastatin (a BCRP substrate) or furosemide (an OAT3 substrate) did not produce any changes in peak plasma concentration and AUC of the substrate drugs.1

Riluzole

Edaravone is not expected to affect the pharmacokinetics of riluzole.3 In clinical studies, most patients received riluzole and edaravone concomitantly.15

Description

Edaravone is a free radical scavenger.3,4,6,7,8,13 The pathophysiology of amyotrophic lateral sclerosis (ALS) is poorly understood, but is likely to be multifactorial; one mechanism that has been proposed is an increase in oxidative stress.3,9,10,13 Biomarkers of oxidative stress (e.g., coenzyme Q10, 3-nitrotyrosine) are increased in patients with ALS.4,5,6,9 The exact mechanism of action of edaravone in patients with ALS has not been fully elucidated,1 but is presumed to involve its antioxidant effects; as a free radical scavenger, the drug is thought to counter the oxidative damage that occurs in the nervous system of a patient with ALS.3,4,6,7,8,13 Edaravone has shown neuroprotective effects in animal models of ALS.4,7,8

Following IV infusion of edaravone over 60 minutes, peak plasma concentrations occur at the end of the infusion.1 Following oral administration of the suspension, median time to peak plasma concentration occurred in approximately 0.5 hours under fasting conditions.1 Absolute bioavailability of the oral suspension is about 57% compared with IV administration.1 Equivalent exposure was demonstrated between the 105-mg dose of the oral suspension and the 60-mg dose of the IV formulation.1,17,18 Similar pharmacokinetics were observed following administration of the oral suspension via feeding tubes and by mouth.1 Peak plasma concentrations and systemic exposure of edaravone appear to increase in a more than dose-proportional manner.1 Following multiple doses of edaravone, no accumulation has been observed.1

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, were observed.1 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.1 Following oral administration of the suspension 4 hours after high-fat meals, peak plasma concentrations and AUC decreased by 44% and 24%, respectively.1 Following oral administration of the suspension 2 hours after low-fat meals, peak plasma concentrations and AUC decreased by 45% and 21%, respectively.1

Edaravone is 92% bound to serum proteins, primarily to albumin.1 The drug is metabolized to a sulfate conjugate presumed to be formed by sulfotransferases and to a glucuronide conjugate formed by multiple uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes (i.e., UGT 1A1, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B17) in the liver and kidney;1 both metabolites are pharmacologically inactive.1 In healthy individuals, 60-80% of a dose of edaravone is excreted in urine as the glucuronide conjugate, 6-8% is excreted in urine as the sulfate conjugate, and less than 1% is excreted in urine as unchanged drug.1 The mean terminal half-life of edaravone is 4.5-9 hours; the half-life of its metabolites ranges from 3 to 6 hours.1 Pharmacokinetics of edaravone are not affected by age, race (i.e., between Japanese and Caucasian individuals), or gender.1

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
• Advise the patients and caregivers to read the manufacturer's patient information and instructions for use for the oral suspension.1
• Advise patients to take edaravone oral suspension in the morning on an empty stomach.1 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.1 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.1
• 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.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

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.

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

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

17. Shimizu H, Nishimura Y, Shiide Y et al. Evaluation of Pharmacokinetics, Safety, and Drug-Drug Interactions of an Oral Suspension of Edaravone in Healthy Adults. Clin Pharmacol Drug Dev. 2021 Oct;10(10):1174-1187. Epub 2021 Mar 11. [PubMed 33704925]

18. Shimizu H, Nishimura Y, Shiide Y et al. Bioequivalence Study of Oral Suspension and Intravenous Formulation of Edaravone in Healthy Adult Subjects. Clin Pharmacol Drug Dev. 2021 Oct;10(10):1188-1197. Epub 2021 May 6. [PubMed 33955162]

19. FDA Center for Drug Evaluation and Research. Application number 215446Orig1s000 summary review. From the FDA website. [Web]

20. Witzel S, Maier A, Steinbach R et al. Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2022 Feb 1;79(2):121-130. Erratum in: JAMA Neurol. 2022 Jun 13;:null. [PubMed 35006266]

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