edaravone

1 INDICATIONS AND USAGE Edaravone injection is indicated for the treatment of amyotrophic lateral sclerosis (ALS). Edaravone injection is indicated for the treatment of amyotrophic lateral sclerosis (ALS). ( 1 )

2 DOSAGE AND ADMINISTRATION Edaravone injection: The recommended dosage is 60 mg administered as an intravenous infusion over 60 minutes ( 2.1 ) Initial treatment cycle: daily dosing for 14 days followed by a 14- day drug-free period ( 2.1 ) Subsequent treatment cycles: daily dosing for 10 days out of 14- day periods, followed by 14-day drug-free periods ( 2.1 ) 2.1 Dosage Information The recommended dosage of edaravone injection is as follows: an intravenous infusion of 60 mg administered over a 60-minute period. Administer edaravone injection according to the following schedule: An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods 2.2 Preparation and Administration Information for Edaravone Injection Edaravone injection is for intravenous infusion only. Preparation Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Vial may be inverted for use with a medical infusion set. Prepare the dose for administration by inserting a vented intravenous set through the septum of the 100 mL vial. Examine the container contents before dose preparation or administering. DO NOT USE if particulate matter or discoloration is observed, or if the flip off seal is not intact. Administration 30 mg/100 mL single-dose vials: Administer each 60 mg dose of edaravone injection as two consecutive 30 mg intravenous infusion single-dose vials over a total of 60 minutes (infusion rate approximately 1 mg per minute [3.33 mL per minute]). 60 mg/100 mL single-dose vials: Administer a 60 mg dose of edaravone injection as an intravenous infusion single-dose vial over a total of 60 minutes (infusion rate approximately 1 mg per minute [1.67 mL per minute]). Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS ( 5.1 , 5.2 )] . Other medications should not be injected into the single-dose vial or mixed with edaravone injection. 2.4 Switching from Edaravone Injection to RADICAVA ORS® Patients treated with 60 mg of edaravone intravenous infusion may be switched to 105 mg (5 mL) RADICAVA ORS® using the same dosing frequency.

3 DOSAGE FORMS AND STRENGTHS Edaravone injection is supplied for intravenous infusion in a • Single-dose polypropylene bag containing 60 mg of edaravone in 100 mL of clear, colorless aqueous solution. • Single-dose polypropylene bag containing 30 mg of edaravone in 100 mL of clear, colorless aqueous solution. Injection: 60 mg/100 mL in a single-dose polypropylene bag and 30 mg/100 mL in a single-dose polypropylene bag ( 3 )

4 CONTRAINDICATIONS Edaravone injection is contraindicated in patients with a history of hypersensitivity to edaravone or any of the inactive ingredients in this product. Hypersensitivity reactions and anaphylactic reactions have occurred [see WARNINGS AND PRECAUTIONS ( 5.1 , 5.2 )] . Patients with a history of hypersensitivity to edaravone or any of the inactive ingredients in edaravone injection ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] • Sulfite Allergic Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (at least 10% of patients treated with edaravone injection and greater than placebo) are contusion, gait disturbance, and headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Piramal Crtical Care, Inc. at 1-800-414-1901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 patients with ALS were administered edaravone injection 60 mg in treatment cycles for 6 months. The population consisted of Japanese patients who had a median age of 60 years (range 29 to ­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 2 lists the adverse reactions that occurred in ≥ 2% of patients in the edaravone injection-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 injection-treated patients were contusion, gait disturbance, and headache. Table 2: Adverse Reactions from Pooled Placebo-Controlled Trials a that Occurred in ≥ 2% of Edaravone Injection-Treated Patients and ≥ 2% More Frequently than in Placebo Patients Adverse Reaction Edaravone Injection (N=184) % Placebo (N=184) % Contusion 15 9 Gait disturbance 13 9 Headache 10 6 Dermatitis 8 5 Eczema 7 4 Respiratory failure, respiratory disorder, hypoxia 6 4 Glycosuria 4 2 Tinea infection 4 2 a Pooled placebo-controlled studies include two additional studies with 231 additional patients, all using the same treatment regimen [see Clinical Studies (14) ]. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of edaravone injection. 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. [see Warnings and Precautions (5.1 , 5.2 )].

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 09/2023 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of edaravone injection 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 (see Animal Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk for major birth defects and miscarriage in patients with ALS is unknown. Data Animal Data 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 for edaravone injection, on a body surface area (mg/m 2 ) 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) for edaravone injection on a body surface area (mg/m 2 ) 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/m 2 basis. 8.2 Lactation 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 injection and any potential adverse effects on the breastfed infant from edaravone injection or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of edaravone injection in pediatric patients have not been established. 8.5 Geriatric Use Of the 184 patients with ALS who received edaravone injection 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.

12.1 Mechanism of Action The mechanism by which edaravone injection exerts its therapeutic effect in patients with ALS is unknown.

11 DESCRIPTION The active ingredient in edaravone injection is edaravone, which is a member of the substituted 2-pyrazolin-5-one class. The chemical name of edaravone is [3-methyl-1-phenyl-2-pyrazolin-5-one]. The molecular formula is C 10 H 10 N 2 O and the molecular weight is 174.20. The chemical structure is: Edaravone is a white crystalline powder with a melting point of 129.7°C. It is freely soluble in acetic acid, methanol, or ethanol and slightly soluble in water or diethyl ether. Edaravone injection is a clear, colorless liquid provided as a sterile solution. 30 mg/100 mL single-dose vials: Edaravone injection is supplied for intravenous infusion in a USP Type 1 Glass Vial containing 30 mg edaravone in 100 mL isotonic, sterile, aqueous solution. Individual vial will be placed in a carton (secondary packaging). Each single-dose vial contains the following inactive ingredients: L-cysteine hydrochloride hydrate (10 mg), sodium bisulfite (20 mg). Sodium chloride is added for isotonicity and phosphoric acid and sodium hydroxide are added to adjust to pH 4. 60 mg/100 mL single-dose vials: Edaravone injection is supplied for intravenous infusion in a USP Type 1 Glass Vial containing 60 mg edaravone in 100 mL isotonic, sterile, aqueous solution. Individual vial will be placed in a carton (secondary packaging). Each single-dose vial contains the following inactive ingredients: L-cysteine hydrochloride hydrate (20 mg), sodium bisulfite (40 mg). Sodium chloride is added for isotonicity and phosphoric acid and sodium hydroxide are added to adjust to pH 4. edrv-structure

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 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 USP Type 1 Glass Vial [see DOSAGE AND ADMINISTRATION (2.2) and HOW SUPPLIED/STORAGE AND HANDLING (16.2) ] . These are supplied in cartons as listed below. 30 mg/100 mL: NDC 39822-4500-1 single-dose glass vial, 2 vial per carton NDC 39822-4500-2 60 mg/100 mL: NDC 39822-4510-1 single-dose glass vial, 1 vial per carton NDC 39822-4510-1 16.2 Storage and Handling Store edaravone injection at up to 25°C (77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light.

16.1 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 USP Type 1 Glass Vial [see DOSAGE AND ADMINISTRATION (2.2) and HOW SUPPLIED/STORAGE AND HANDLING (16.2) ] . These are supplied in cartons as listed below. 30 mg/100 mL: NDC 39822-4500-1 single-dose glass vial, 2 vial per carton NDC 39822-4500-2 60 mg/100 mL: NDC 39822-4510-1 single-dose glass vial, 1 vial per carton NDC 39822-4510-1