Edaravone

Edaravone
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand

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Black Box Warning

Warning Title See full prescribing information for complete Boxed Warning. Condition Name: (Content)

Overview

Edaravone is a Acetylcholine release inhibitor, Adrenergic receptor agonist that is FDA approved for the (type of indication of drug) of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

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Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition 1

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

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Condition 2

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

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Non–Guideline-Supported Use

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Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition 1

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Condition 2

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Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition 1

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

• Dosing Information/Recommendation

• (Dosage)

Condition 2

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

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Non–Guideline-Supported Use

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Contraindications

• Edaravone is contraindicated in patients with a history of hypersensitivity to edaravone or any of the inactive ingredients of this product. Hypersensitivity reactions and anaphylactic reactions have occurred.

Warnings

Warning Title See full prescribing information for complete Boxed Warning. Condition Name: (Content)

Hypersensitivity Reactions

• Hypersensitivity reactions (redness, wheals, and erythema multiforme) and cases of anaphylaxis (urticaria, decreased blood pressure, and dyspnea) have been reported in spontaneous postmarketing reports with edaravone.
• Patients should be monitored carefully for hypersensitivity reactions. If hypersensitivity reactions occur, discontinue edaravone, treat per standard of care, and monitor until the condition resolves.

Sulfite Allergic Reactions

• Edaravone contains sodium bisulfite, a sulfite that may cause allergic type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity occurs more frequently in asthmatic people.

Adverse Reactions

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• In randomized, placebo-controlled trials, 184 ALS patients were administered edaravone 60 mg in treatment cycles for 6 months. The population consisted of Japanese patients who had a median age of 60 years (range 29-75) and were 59% male. Most (93%) of these patients were living independently at the time of screening.

Most Common Adverse Reactions Observed During Clinical Studies

• Table 1 lists the adverse reactions that occurred in ≥ 2% of patients in the edaravone-treated group and that occurred at least 2% more frequently than in the placebo-treated group in randomized placebo-controlled ALS trials. The most common adverse reactions that occurred in ≥10% of edaravone-treated patients were contusion, gait disturbance, and headache.

This image is provided by the National Library of Medicine.

• A Pooled placebo-controlled studies include two additional studies with 231 additional patients, all using the same treatment regimen

Postmarketing Experience

• The following adverse reactions have been identified during postapproval use of edaravone outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
• Skin and subcutaneous tissue disorders: Hypersensitivity reactions and anaphylaxis.

Drug Interactions

There is limited information regarding Edaravone Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Risk Summary

• There are no adequate data on the developmental risk associated with the use of edaravone in pregnant women. In animal studies, administration of edaravone to pregnant rats and rabbits resulted in adverse developmental effects (increased mortality, decreased growth, delayed sexual development, and altered behavior) at clinically relevant doses. Most of these effects occurred at doses that were also associated with maternal toxicity.
• In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk for major birth defects and miscarriage in patients with ALS is unknown.

Data (Animal)

• In rats, intravenous administration of edaravone (0, 3, 30, or 300 mg/kg/day) throughout the period of organogenesis resulted in reduced fetal weight at all doses. In dams allowed to deliver naturally, offspring weight was reduced at the highest dose tested. Maternal toxicity was also observed at the highest dose tested. There were no adverse effects on reproductive function in the offspring. A no-effect dose for embryofetal developmental toxicity was not identified; the low dose is less than the recommended human dose of 60 mg, on a body surface area (mg/m²) basis.
• In rabbits, intravenous administration of edaravone (0, 3, 20, or 100 mg/kg/day) throughout the period of organogenesis resulted in embryofetal death at the highest dose tested, which was associated with maternal toxicity. The higher no-effect dose for embryofetal developmental toxicity is approximately 6 times the recommended human dose (RHD) on a body surface area (mg/m²) basis.
• The effects on offspring of edaravone (0, 3, 20, or 200 mg/kg/day), administered by intravenous injection to rats from GD 17 throughout lactation, were assessed in two studies. In the first study, offspring mortality was observed at the high dose and increased activity was observed at the mid and high doses. In the second study, there was an increase in stillbirths, offspring mortality, and delayed physical development (vaginal opening) at the highest dose tested. Reproduction function in offspring was not affected in either study. Maternal toxicity was evident in both studies at all but the lowest dose tested. The no-effect dose for developmental toxicity (3 mg/kg/day) is less than the RHD on a mg/m² basis.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Edaravone in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Edaravone during labor and delivery.

Nursing Mothers

Risk Summary

• There are no data on the presence of edaravone in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Edaravone and its metabolites are excreted in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for edaravone and any potential adverse effects on the breastfed infant from edaravone or from the underlying maternal condition.

Pediatric Use

• Safety and effectiveness of edaravone in pediatric patients have not been established.

Geriatic Use

• Of the 184 patients with ALS who received edaravone in 3 placebo-controlled clinical trials, a total of 53 patients were 65 years of age and older, including 2 patients 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Gender

There is no FDA guidance on the use of Edaravone with respect to specific gender populations.

Race

There is no FDA guidance on the use of Edaravone with respect to specific racial populations.

Renal Impairment

• The effect of renal impairment on the pharmacokinetics of edaravone has not been studied. However, renal impairment is not expected to significantly affect the exposure to edaravone. No dose adjustment is needed in these patients.

Hepatic Impairment

• The effect of hepatic impairment on the pharmacokinetics of edaravone has not been studied. No dose adjustment is needed for patients with mild or moderate hepatic impairment. No specific dosing recommendation can be provided for patients with severe hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Edaravone in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Edaravone in patients who are immunocompromised.

Administration and Monitoring

Administration

Preparation and Administration Information

• Edaravone is for intravenous infusion only.

Preparation

• Do not use if the oxygen indicator has turned blue or purple before opening the package. Once the overwrap package is opened, use within 24 hours.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Administration

• Administer each 60 mg dose of edaravone injection as two consecutive 30 mg intravenous infusion bags over a total of 60 minutes (infusion rate approximately 1 mg per minute [3.33 mL per minute]).
• Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction.
• Other medications should not be injected into the infusion bag or mixed with edaravone.

Monitoring

• Lack of disability progression or maintained functional ability in amyotrophic lateral sclerosis indicates efficacy.
• Hypersensitivity reaction.

IV Compatibility

There is limited information regarding the compatibility of Edaravone and IV administrations.

Overdosage

There is limited information regarding Edaravone overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Mechanism of Action

• The mechanism by which edaravone exerts its therapeutic effect in patients with ALS is unknown.

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

(Description)

Pharmacokinetics

• Edaravone is administered by IV infusion. The maximum plasma concentration (C_max) of edaravone was reached by the end of infusion. There was a trend of more than dose-proportional increase in area under the concentration-time curve (AUC) and C_max of edaravone. With multiple-dose administration, edaravone does not accumulate in plasma.

Distribution

• Edaravone is bound to human serum proteins (92%), mainly to albumin, with no concentration dependence in the range of 0.1 to 50 micromol/L.

Elimination

• The mean terminal elimination half-life of edaravone is 4.5 to 6 hours. The half-lives of its metabolites are 2 to 2.8 hours.

Metabolism

• Edaravone is metabolized to a sulfate conjugate and a glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A6, UGT1A9, UGT2B7, and UGT2B17) in the liver and kidney. In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases.

Excretion

• In Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate form (70-90% of the dose). Approximately 5-10% of the dose was recovered in the urine as sulfate conjugate, and only 1% of the dose or less was recovered in the urine as unchanged form. In vitro studies suggest that sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the human kidney before excretion into the urine.

Specific Populations

Geriatric Patients

• No age effect on edaravone pharmacokinetics has been found.

Patients with Renal and Hepatic Impairment

• No pharmacokinetic data are available in patients with renal impairment or hepatic impairment.

Male and Female Patients

• No gender effect on edaravone pharmacokinetics has been found.

Racial or Ethnic Groups

• There were no significant racial differences in Cmax and AUC of edaravone between Japanese and Caucasian subjects.

Drug Interaction Studies

• The pharmacokinetics of edaravone is not expected to be significantly affected by inhibitors of CYP enzymes, UGTs, or major transporters.
• In vitro studies demonstrated that, at clinical dose, edaravone and its metabolites are not expected to significantly inhibit cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4), UGT1A1, UGT2B7, or transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2) in humans. Edaravone and its metabolites are not expected to induce CYP1A2, CYP2B6, or CYP3A4 at the clinical dose level of edaravone.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

• The carcinogenic potential of edaravone has not been adequately assessed.

Mutagenesis

• Edaravone was negative in in vitro (bacterial reverse mutation and Chinese hamster lung chromosomal aberration) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

• Intravenous administration of edaravone (0, 3, 20, or 200 mg/kg) prior to and throughout mating in males and females and continuing in females to gestation day 7 had no effect on fertility; however, disruption of the estrus cycle and mating behavior was observed at the highest dose tested. No effects on reproductive function were observed at the lower doses, which are up to 3 times the RHD of 60 mg, on a body surface area (mg/m²) basis.

Clinical Studies

• The efficacy of edaravone for the treatment of ALS was established in a 6-month, randomized, placebo-controlled, double-blind study conducted in Japanese patients with ALS who were living independently and met the following criteria at screening:

1. Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale – Revised [ALSFRS-R; described below])
2. Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] ≥ 80%)
3. Definite or Probable ALS based on El Escorial revised criteria
4. Disease duration of 2 years or less

• The study enrolled 69 patients in the edaravone arm and 68 in the placebo arm. Baseline characteristics were similar between these groups, with over 90% of patients in each group being treated with riluzole.
• Edaravone was administered as an intravenous infusion of 60 mg given over a 60 minute period according to the following schedule:

• An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period (Cycle 1)
• Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods (Cycles 2-6).

• The primary efficacy endpoint was a comparison of the change between treatment arms in the ALSFRS-R total scores from baseline to Week 24. The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency). Each item is scored from 0-4, with higher scores representing greater functional ability. The decline in ALSFRS-R scores from baseline was significantly less in the edaravone-treated patients as compared to placebo (see Table 2). The distribution of change in ALSFRS-R scores from baseline to Week 24 by percent of patients is shown in Figure 1.

This image is provided by the National Library of Medicine.

How Supplied

• Edaravone injection is supplied as a 30 mg/100 mL (0.3 mg/mL) clear, colorless, sterile solution for intravenous infusion in single-dose polypropylene bags, each overwrapped with polyvinyl alcohol (PVA) secondary packaging containing an oxygen absorber and oxygen indicator, which should be pink to reflect appropriate oxygen levels. These are supplied in cartons as listed below.

• NDC 70510-2171-1 30 mg/100 mL (0.3 mg/mL) single-dose bag
• NDC 70510-2171-2 2 bags per carton

Storage

• Store at up to 25°C (77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F). Protect from light. Store in overwrapped package to protect from oxygen degradation until time of use. The oxygen indicator will turn blue or purple if the oxygen has exceeded acceptable levels. Once the overwrap package is opened, use within 24 hours.

Images

Drug Images

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Package and Label Display Panel

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

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Patient Counseling Information

• Advise the patients to read the FDA-approved patient labeling.

Hypersensitivity Reactions

• Advise patients to seek immediate medical care if they experience signs or symptoms of a hypersensitivity reaction.

Sulfite Allergic Reactions

• Advise patients about potential for sulfite sensitivity. Inform 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 they experience these signs or symptoms.

Pregnancy and Breastfeeding

• Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during edaravone therapy.
• Advise patients to notify their healthcare provider if they intend to breastfeed or are breastfeeding an infant.

This image is provided by the National Library of Medicine.

Precautions with Alcohol

Alcohol-Edaravone interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

• Radicava

Look-Alike Drug Names

There is limited information regarding Edaravone Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.