SPL UNCLASSIFIED SECTION.

2.1 Dosage Information. The recommended dosage of RADICAVA and RADICAVA ORS is as follows:RADICAVA: an intravenous infusion of 60 mg administered over 60-minute periodRADICAVA ORS: 105 mg (5 mL) taken orally or via feeding tube in the morning after overnight fasting [see Dosage and Administration (2.3)] Administer RADICAVA or RADICAVA ORS according to the following schedule:An initial treatment cycle with daily dosing for 14 days, followed by 14-day drug-free periodSubsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods. RADICAVA: an intravenous infusion of 60 mg administered over 60-minute period. RADICAVA ORS: 105 mg (5 mL) taken orally or via feeding tube in the morning after overnight fasting [see Dosage and Administration (2.3)] An initial treatment cycle with daily dosing for 14 days, followed by 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.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. RADICAVAStore RADICAVA at up to 25C (77F). Excursions permitted from 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. 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.RADICAVA ORSPharmacyStore RADICAVA ORS refrigerated between 2C to 8C (36F to 46F) and protect from light. Do not freeze. Store upright.PatientStore RADICAVA ORS upright at room temperature between 20C to 25C (68F to 77F). Protect from light.Discard 15 days after opening bottle or if unopened 30 days from date of shipment indicated on the carton pharmacy label.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1). 8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with the use of RADICAVA or RADICAVA ORS 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 2-4% and 15-20%, respectively. The background risk for major birth defects and miscarriage in patients with ALS is unknown.DataAnimal DataIn 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. no-effect dose for embryofetal developmental toxicity was not identified; the low dose is less than the recommended human dose of 60 mg for RADICAVA on 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 times the recommended human dose (RHD) for RADICAVA on 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 mg/m2 basis.Reproductive and developmental toxicology studies of edaravone using the oral route have not been conducted.. 8.2 Lactation. Risk SummaryThere 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 mothers clinical need for RADICAVA and RADICAVA ORS and any potential adverse effects on the breastfed infant from RADICAVA and RADICAVA ORS or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness of RADICAVA or RADICAVA ORS in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 184 patients with ALS who received RADICAVA in placebo-controlled clinical trials, total of 53 patients were 65 years of age and older, including 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of RADICAVA ORS is based on bioavailability study comparing RADICAVA and RADICAVA ORS [see Clinical Pharmacology (12.3)].The efficacy of RADICAVA for the treatment of ALS was established in 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:1Functionality retained most activities of daily living (defined as scores of points or better on each individual text of the ALS Functional Rating Scale-Revised [ALSFRS-R; described below])2Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] >=80%)3Definite or Probable ALS based on El Escorial revised criteria4Disease duration of years or lessThe study enrolled 69 patients in the RADICAVA 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.RADICAVA was administered as an intravenous infusion of 60 mg given over 60-minute period according to the following schedule:An initial treatment cycle with daily dosing for 14 days, followed by 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 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 text 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 RADICAVA-treated patients as compared to placebo (see Table 3). The distribution of change in ALSFRS-R scores from baseline to Week 24 by percent of patients is shown in Figure 1.Table 3: Analysis of Change from Baseline to Week 24 in ALSFRS-R ScoresTreatmentChange from Baseline LS Mean +- SE (95% CI)Treatment Difference (RADICAVA placebo [95% CI])p-valueRADICAVA-5.01+-0.642.49 (0.99, 3.98)0.0013Placebo-7.50+-0.66Figure Distribution of Change from Baseline to Week 24 in ALSFRS-R Scores. 1Functionality retained most activities of daily living (defined as scores of points or better on each individual text of the ALS Functional Rating Scale-Revised [ALSFRS-R; described below]). 2Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] >=80%). 3Definite or Probable ALS based on El Escorial revised criteria. 4Disease duration of years or less. An initial treatment cycle with daily dosing for 14 days, followed by 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).. Figure 1.

ADVERSE REACTIONS SECTION.

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)] 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 RADICAVA and greater than placebo) are contusion, gait disturbance, and headache (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Shionogi Inc. at 1-888-292-0058 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 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 RADICAVA 60 mg in treatment cycles for months. The population consisted of Japanese patients who had 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 StudiesTable lists the adverse reactions that occurred in >=2% of patients in the RADICAVA-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 RADICAVA-treated patients were contusion, gait disturbance, and headache.Table 2: Adverse Reactions from Pooled Placebo-Controlled TrialsPooled placebo-controlled studies include two additional studies with 231 additional patients, all using the same treatment regimen [see Clinical Studies (14)]. that Occurred in >=2% of RADICAVA -Treated Patients and >=2% More Frequently than in Placebo PatientsAdverse ReactionRADICAVA (N=184) %Placebo (N=184) %Contusion159Gait disturbance139Headache106Dermatitis85Eczema74Respiratory failure, respiratory disorder, hypoxia64Glycosuria42Tinea infection42Additional Adverse Reactions with RADICAVA ORSIn an open-label study in patients with ALS (n=185) treated with RADICAVA ORS for months, fatigue was observed in 7.6% of patients.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of RADICAVA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Skin and subcutaneous tissue disorders: Hypersensitivity reactions and anaphylaxis [see Warnings and Precautions (5.1, 5.2)].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Oral administration of edaravone (0, 10, 30, 100, or 300 mg/kg/day) in dogs for 39 weeks resulted in neurotoxicity, characterized by white matter vacuolation in the spinal cord and vacuolation and nerve fiber atrophy in the sciatic nerve, at the two highest doses tested. The microscopic findings were accompanied by gait abnormalities, loss of patellar reflex, and inability to rise. Plasma edaravone exposures (Cmax and AUC) at the higher no-effect dose for neurotoxicity (30 mg/kg/day) were approximately times those in humans at the recommended human dose of RADICAVA ORS (105 mg).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 26-week carcinogenicity study in male and female transgenic (Tg rasH2) mice, oral administration of edaravone (0 [water control], [vehicle control], 100, 150, or 350 mg/kg) resulted in no increase in tumors.In 2-year carcinogenicity study in rats, oral administration of edaravone (0, 50, 100, or 200 mg/kg in males; 0, 50, 100, or 250 mg/kg in females) resulted in no increase in tumors.Carcinogenicity studies of edaravone using the intravenous route have not been conducted.MutagenesisEdaravone was negative in in vitro (bacterial reverse mutation and Chinese hamster lung chromosomal aberration) and in vivo (mouse micronucleus) assays.Impairment of FertilityIntravenous administration of edaravone (0, 3, 20, or 200 mg/kg) prior to and throughout mating in male and female rats and continuing in females to gestation day 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 approximately times the RHD for RADICAVA (60 mg) on body surface area (mg/m2) basis.Fertility studies of edaravone using the oral route have not been conducted.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism by which RADICAVA and RADICAVA ORS exert their therapeutic effect in patients with ALS is unknown.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt exposures at least times higher than that of the recommended doses of RADICAVA and RADICAVA ORS, edaravone does not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics. RADICAVA is administered by IV infusion. The maximum plasma concentration (Cmax) of edaravone was reached by the end of infusion. There was trend of more than dose-proportional increase in area under the concentration-time curve (AUC) and Cmax of edaravone. With multiple-dose administration, edaravone does not accumulate in plasma.RADICAVA ORS administered orally at the dose of 105 mg, under fasted conditions, was shown to demonstrate an equivalent AUC with RADICAVA (60 mg administered intravenously for 60 min) and Cmax not less than that of RADICAVA. RADICAVA ORS demonstrated similar pharmacokinetics following administration via feeding tubes and oral administration.In healthy subjects, RADICAVA ORS does not accumulate with once-daily administration, and the maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of edaravone is more than dose-proportional over the dose range of 30 to 300 mg (approximately 0.3 and times the recommended dosage, respectively).AbsorptionRADICAVA ORS has median time to maximum concentration (Tmax) occurring at approximately 0.5 hour (range, 0.25 to 0.75 hours) after fasted oral administration. The absolute oral bioavailability is about 57% because of first-pass effect when comparing RADICAVA ORS (105 mg oral suspension) and RADICAVA (60 mg intravenous formulation).Effect of FoodFollowing oral administration of RADICAVA ORS to healthy subjects hour before or hours after high-fat meals (800-1000 calories, 50% fat), hours after low-fat meals (400-500 calories, 25% fat), or hours after caloric supplement (250 calories, e.g., protein drink), the Cmax and AUC did not decrease significantly (less than 20% and 10% changes in Cmax and AUC, respectively) [see Dosage and Administration (2.3)].Following oral administration of RADICAVA ORS to healthy subjects, the Cmax decreased by 82%, and the AUC decreased by 61% with high-fat meal compared to fasted conditions. Following administration of RADICAVA ORS hours after high-fat meals, the Cmax and AUC decreased by 44% and 24%, respectively.Following administration of RADICAVA ORS hours after low-fat meals, the Cmax and AUC decreased by 45% and 21%, respectively.DistributionEdaravone is bound to human serum proteins (92%), mainly to albumin, with no concentration dependence in the range of 0.1 to 50 micromol/L. Edaravone has mean volume of distribution after intravenous administration of 63.1 L.EliminationThe mean terminal elimination half-life of edaravone is approximately 4.5 to hours. The half-lives of its metabolites are to hours. Following intravenous administration, the total clearance of edaravone is estimated to be 35.9 L/h.MetabolismEdaravone is metabolized to sulfate conjugate and glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17). In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases. RADICAVA ORS results in 1.3- and 1.7-fold higher exposures for both sulfate and glucuronide metabolites, respectively, when compared to RADICAVA because of first-pass metabolism.ExcretionIn Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate (60-80% of the dose up to 48 hours). Approximately 6-8% of the dose was recovered in the urine as the sulfate conjugate, and 1% of the dose was recovered in the urine as the unchanged drug. In vitro studies suggest that the sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the kidney before excretion into the urine.Specific PopulationsGeriatric PatientsNo age effect on edaravone pharmacokinetics has been found [see Use in Specific Populations (8.5)]. Patients with Renal ImpairmentFollowing single IV infusion of 30 mg edaravone (half the recommended dosage of RADICAVA) over 60 minutes, mean Cmax and AUC0- of unchanged edaravone were 1.15- and 1.20-fold greater in the subjects with mild renal impairment (eGFR 60-89 mL/min/1.73m2), and were 1.25- and 1.29-fold greater in the subjects with moderate renal impairment (eGFR 30-59 mL/min/1.73m2) when compared to subjects with normal renal function, respectively. These changes in exposures are not considered to be clinically significant and therefore no dosage adjustments are necessary in patients with mild to moderate renal impairment. The effects of severe renal impairment on the pharmacokinetics of edaravone have not been studied.Patients with Hepatic ImpairmentFollowing single IV infusion of 30 mg edaravone (half of the recommended dose of RADICAVA) over 60 minutes, mean Cmax and AUC0- of unchanged edaravone were 1.20- and 1.07-fold greater in the subjects with mild hepatic impairment (Child-Pugh score or 6), were 1.24- and 1.14-fold greater in the subjects with moderate hepatic impairment (Child-Pugh score to 9), and were 1.20- and 1.19-fold greater in the subjects with severe hepatic impairment (Child-Pugh score 10 to 14) when compared to subjects with normal hepatic function, respectively. These changes in exposures are not considered to be clinically significant and therefore no dosage adjustments are necessary in patients with hepatic impairment.Male and Female PatientsNo gender effect on edaravone pharmacokinetics has been found.Racial or Ethnic GroupsThere were no significant racial differences in Cmax and AUC of edaravone between Japanese and Caucasian subjects.Drug Interaction StudiesThe pharmacokinetics of edaravone is not expected to be significantly affected by inhibitors of cytochrome P450 (CYP) enzymes, UGTs, or major transporters. Concomitant oral administration of edaravone 120 mg (higher than the recommended dose of 105 mg for ORS) with sildenafil (CYP3A4 substrate), rosuvastatin (BCRP substrate), and furosemide (OAT3 substrate) did not produce any changes in Cmax and AUC of these drugs.In vitro studies demonstrated that, at the recommended dosage, edaravone and its metabolites are not expected to significantly inhibit CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A), conjugating enzymes UGT1A1 and UGT2B7, or other transporters (P-gp, OATP1B1, OATP1B3, OAT1, OCT2, MATE1, and MATE2-K) in humans. Edaravone and its metabolites are not expected to induce CYP1A2, or CYP2B6, at the recommended dosage of edaravone.In vitro data indicated that edaravone was not substrate of OATP1B1 or OATP1B3.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 RADICAVA 60 mg in treatment cycles for months. The population consisted of Japanese patients who had 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 StudiesTable lists the adverse reactions that occurred in >=2% of patients in the RADICAVA-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 RADICAVA-treated patients were contusion, gait disturbance, and headache.Table 2: Adverse Reactions from Pooled Placebo-Controlled TrialsPooled placebo-controlled studies include two additional studies with 231 additional patients, all using the same treatment regimen [see Clinical Studies (14)]. that Occurred in >=2% of RADICAVA -Treated Patients and >=2% More Frequently than in Placebo PatientsAdverse ReactionRADICAVA (N=184) %Placebo (N=184) %Contusion159Gait disturbance139Headache106Dermatitis85Eczema74Respiratory failure, respiratory disorder, hypoxia64Glycosuria42Tinea infection42Additional Adverse Reactions with RADICAVA ORSIn an open-label study in patients with ALS (n=185) treated with RADICAVA ORS for months, fatigue was observed in 7.6% of patients.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. RADICAVA and RADICAVA ORS are contraindicated in patients with 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 history of hypersensitivity to edaravone or any of the inactive ingredients in RADICAVA and/or RADICAVA ORS (4).

DESCRIPTION SECTION.

11 DESCRIPTION. The active ingredient in RADICAVA and RADICAVA ORS is edaravone, which is 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 C10H10N2O and the molecular weight is 174.20.The chemical structure is:Edaravone is white crystalline powder with melting point of 129.7C. It is freely soluble in acetic acid, methanol, or ethanol and slightly soluble in water or diethyl ether.RADICAVA injection is clear, colorless liquid provided as sterile solution.RADICAVA injection is supplied for intravenous infusion in polypropylene bag containing 30 mg edaravone in 100 mL isotonic, sterile, aqueous solution, which is further overwrapped with polyvinyl alcohol (PVA) secondary packaging. The overwrapped package also contains an oxygen absorber and oxygen indicator to minimize oxidation. Each bag 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.RADICAVA ORS (edaravone) oral suspension is white to off-white color, opaque, homogenous suspension containing 105 mg of edaravone per mL of suspension.RADICAVA ORS contains the following inactive ingredients: L-cysteine hydrochloride hydrate, polyvinyl alcohol, simethicone emulsion, sodium bisulfite, sorbitol, and xanthan gum. Phosphoric acid and sodium hydroxide are added to adjust to pH 4.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. RADICAVA: The recommended dosage is 60 mg administered as an intravenous infusion over 60 minutes (2.1)RADICAVA ORS: The recommended dosage is 105 mg (5 mL) taken orally or via feeding tube in the morning after overnight fasting. Food should not be consumed for hour after administration except water (2.1, 2.3)For RADICAVA and RADICAVA ORS: Initial treatment cycle: daily dosing for 14 days followed by 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) RADICAVA: The recommended dosage is 60 mg administered as an intravenous infusion over 60 minutes (2.1). RADICAVA ORS: The recommended dosage is 105 mg (5 mL) taken orally or via feeding tube in the morning after overnight fasting. Food should not be consumed for hour after administration except water (2.1, 2.3). For RADICAVA and RADICAVA ORS: Initial treatment cycle: daily dosing for 14 days followed by 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) Initial treatment cycle: daily dosing for 14 days followed by 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 RADICAVA and RADICAVA ORS is as follows:RADICAVA: an intravenous infusion of 60 mg administered over 60-minute periodRADICAVA ORS: 105 mg (5 mL) taken orally or via feeding tube in the morning after overnight fasting [see Dosage and Administration (2.3)] Administer RADICAVA or RADICAVA ORS according to the following schedule:An initial treatment cycle with daily dosing for 14 days, followed by 14-day drug-free periodSubsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods. RADICAVA: an intravenous infusion of 60 mg administered over 60-minute period. RADICAVA ORS: 105 mg (5 mL) taken orally or via feeding tube in the morning after overnight fasting [see Dosage and Administration (2.3)] An initial treatment cycle with daily dosing for 14 days, followed by 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 RADICAVA Injection. RADICAVA is for intravenous infusion only.PreparationDo 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 [see How Supplied/Storage and Handling (16.1, 16.2)]. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.AdministrationAdminister each 60 mg dose of RADICAVA injection as two consecutive 30 mg intravenous infusion bags over total of 60 minutes (infusion rate approximately mg per minute [3.33 mL per minute]).Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with hypersensitivity reaction [see Warnings and Precautions (5.1, 5.2)].Other medications should not be injected into the infusion bag or mixed with RADICAVA.. 2.3 Preparation and Administration Information for RADICAVA ORS Oral Suspension. See the Instruction for Use for further preparation and administration details.PreparationPrior to opening the bottle, turn it upside down (invert) and shake vigorously up and down for at least 30 seconds.AdministrationRADICAVA ORS can be administered by mouth or via feeding tube (see Feeding Tube Administration).RADICAVA ORS should be taken in the morning on an empty stomach after overnight fasting. Food should not be consumed for hour after administration except water [see Clinical Pharmacology (12.3)]. See Table for specific fasting conditions.Table 1: RADICAVA ORS Administration Relative to Type of Food ConsumptionType of food/caloric supplement consumedFasting time before and after RADICAVA ORS dose administration with regards to meal type High-fat meal (800-1,000 calories, 50% fat)8 hours before administration and one hour after administration Low-fat meal (400-500 calories, 25% fat)4 hours before administration and one hour after administration Caloric supplement (250 calories, e.g., protein drink)2 hours before administration and one hour after administrationAdminister RADICAVA ORS using 5 mL oral syringe that comes with the product. household teaspoon is not an adequate measuring device.Dispose of any RADICAVA ORS that is not used within 15 days after opening the bottle or within the 30 days from the date of shipment indicated on the carton pharmacy label, which ever happens first.Feeding Tube AdministrationNasogastric (NG) tubes or percutaneous endoscopic gastrostomy (PEG) tubes made of silicone, polyvinyl chloride (PVC), or polyurethane can be usedBefore and after administration, use catheter-tip syringe to flush the tube with at least ounce (30 mL) of water. Nasogastric (NG) tubes or percutaneous endoscopic gastrostomy (PEG) tubes made of silicone, polyvinyl chloride (PVC), or polyurethane can be used. Before and after administration, use catheter-tip syringe to flush the tube with at least ounce (30 mL) of water. 2.4 Switching from RADICAVA to RADICAVA ORS. Patients treated with 60 mg of RADICAVA intravenous infusion may be switched to 105 mg (5 mL) RADICAVA ORS using the same dosing frequency. Upon switching to RADICAVA ORS, patients should follow RADICAVA ORS dosing recommendations with regards to food consumption [see Dosage and Administration (2.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. RADICAVA is supplied for intravenous infusion in single-dose polypropylene bag containing 30 mg of edaravone in 100 mL of clear, colorless aqueous solution.RADICAVA ORS is supplied as an oral suspension in multi-dose amber glass bottle 105 mg/5 mL of white to off-white color.. Injection: 30 mg/100 mL in single-dose polypropylene bag (3)Oral suspension: 105 mg/5 mL in multi-dose amber glass bottle (3). Injection: 30 mg/100 mL in single-dose polypropylene bag (3). Oral suspension: 105 mg/5 mL in multi-dose amber glass bottle (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 184 patients with ALS who received RADICAVA in placebo-controlled clinical trials, total of 53 patients were 65 years of age and older, including 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. RADICAVARADICAVA is supplied as 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 [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16.2)]. These are supplied in cartons as listed below.NDC 70510-2171-130 mg/100 mL (0.3 mg/mL) single-dose bag NDC 70510-2171-22 bags per cartonRADICAVA ORSRADICAVA ORS is supplied in white to off-white suspension in multi-dose child resistant 60 mL amber glass bottle which is supplied as two configurations:RADICAVA ORS Starter Kit (14-day treatment cycle), including two (2) inner cartons, each containing one (1) bottle of 735 mg/35mL (105 mg/5 mL dose), two oral dosing syringes and one bottle adapter.RADICAVA ORS Kit (10-day treatment cycle), including one (1) bottle of 1050 mg/50 mL (105 mg/5 mL dose) with two oral dosing syringes and one bottle adapter.These are supplied in cartons as listed below:Unit of saleNDC numberPackage configurationRADICAVA ORS Starter KitNDC 70510-2321-1Carton of One (1) bottle of 35mL (105 mg/5 mL dose)NDC 70510-2321-2Carton of two (2) NDC 70510-2321-1RADICAVA ORS KitNDC 70510-2322-1Carton of One (1) bottle of 50 mL (105 mg/5 mL dose). RADICAVA ORS Starter Kit (14-day treatment cycle), including two (2) inner cartons, each containing one (1) bottle of 735 mg/35mL (105 mg/5 mL dose), two oral dosing syringes and one bottle adapter.. RADICAVA ORS Kit (10-day treatment cycle), including one (1) bottle of 1050 mg/50 mL (105 mg/5 mL dose) with two oral dosing syringes and one bottle adapter.. 16.2 Storage and Handling. RADICAVAStore RADICAVA at up to 25C (77F). Excursions permitted from 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. 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.RADICAVA ORSPharmacyStore RADICAVA ORS refrigerated between 2C to 8C (36F to 46F) and protect from light. Do not freeze. Store upright.PatientStore RADICAVA ORS upright at room temperature between 20C to 25C (68F to 77F). Protect from light.Discard 15 days after opening bottle or if unopened 30 days from date of shipment indicated on the carton pharmacy label.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. RADICAVA and RADICAVA ORS are indicated for the treatment of amyotrophic lateral sclerosis (ALS).. RADICAVA and RADICAVA ORS are indicated for the treatment of amyotrophic lateral sclerosis (ALS). (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Hypersensitivity ReactionsAdvise patients to seek immediate medical care if they experience signs or symptoms of hypersensitivity reaction [see Warnings and Precautions (5.1)]. Sulfite Allergic ReactionsAdvise patients about potential for sulfite sensitivity. Inform patients that RADICAVA and RADICAVA ORS contain 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 [see Warnings and Precautions (5.2)]. Pregnancy and BreastfeedingAdvise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during RADICAVA or RADICAVA ORS therapy [see Use in Specific Populations (8.1)].Advise patients to notify their healthcare provider if they intend to breastfeed or are breastfeeding an infant [see Use in Specific Populations (8.2)].RADICAVA ORS AdministrationAdvise patients to take RADICAVA ORS in the morning on an empty stomach. Instruct patients to fast hours before each dose if they consume high-fat meal, hours before each dose if they consume low-fat meal, or hours before each dose if they consume caloric supplement [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Also instruct patients to not to consume food for hour after each dose.Advise caregivers, if administering RADICAVA ORS via feeding tube, to use catheter-tip syringe and flush the feeding tube with approximately ounce (30 mL) of water before and after use (see Instructions for Use).

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USE RADICAVA (ra di ka vah) ORS (edaravone) oral suspensionRead this Instructions for Use before you take RADICAVA ORS(R) for the first time and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.Important information about measuring RADICAVA ORS: Always measure your prescribed dose of RADICAVA ORS using the oral syringe provided. Ask your healthcare provider or pharmacist who provided the medicine any questions you have about how to measure your prescribed dose. If you miss dose, do not take doses of RADICAVA ORS the next day. Do not take dose of RADICAVA ORS on days 15 through 28.How to prepare RADICAVA ORS: Keep this Instructions for Use handy when preparing the treatment.If your healthcare provider prescribes Starter Kit, you will receive bottles of RADICAVA ORS. Each bottle will contain 35 mL of RADICAVA ORS for total of 70 mL to be used for your first treatment cycle of 14 days. Only open the second bottle when you have finished the first bottle. If you were not prescribed the Starter Kit, for each treatment cycle you will receive bottle of RADICAVA ORS that contains total of 50 mL of RADICAVA ORS. After the first treatment cycle, RADICAVA ORS is to be used for 10 days out of 14-day periods.Only use the bottle adapter and the reusable mL oral syringes provided with the bottle. Do not use household teaspoon to measure your medicine.How to store RADICAVA ORS:Store RADICAVA ORS upright at room temperature between 68F to 77F (20C to 25C). Protect from light.Opening the bottle:When you open the bottle of RADICAVA ORS for the first use, write the date you open the bottle on the bottle label.After opening the bottle of RADICAVA ORS, use within 15 days.After bottle of Radicava ORS has been opened and used, white crust may form on the neck or on the side of the bottle. This is due to normal use and RADICAVA ORS can continue to be used as prescribed.Keep bottle tightly closed between each use.Throw away (discard) any RADICAVA ORS that is not used within 15 days after opening the bottle or within 30 days from the date of shipment shown on the carton pharmacy label, whichever happens first. Ask your pharmacist how to properly throw away (discard) RADICAVA ORS you are no longer able to use.Keep RADICAVA ORS and all medicines out of the reach of children.Each RADICAVA ORS carton contains:1 RADICAVA ORS bottle1 bottle adapter2 (5 mL) reusable oral syringesUse new mL oral syringe and bottle adapter when using new bottle of RADICAVA ORS (see Figure A).Figure AImportant information:Keep these instructions for future use.Do not share RADICAVA ORS with anyone else.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.People who have problems using their hands may need assistance to draw up and give the correct dose of RADICAVA ORS.How to take RADICAVA ORS:Take RADICAVA ORS as prescribed by your healthcare provider.Dosing information:RADICAVA ORS has different dosing schedules:For the first treatment cycle, you will take RADICAVA ORS every day for 14 days, followed by 14 days without the medicine.For the cycles after the first treatment cycle, you will take RADICAVA ORS daily for 10 out of 14 days, followed by 14 days without the medicine.How RADICAVA ORS will be provided:If your healthcare provider prescribes the Starter Kit, you will receive bottles of RADICAVA ORS. Each bottle contains 35 mL of RADICAVA ORS for total of 70 mL to deliver 14 doses. There may be some medicine that remains in each bottle after the dose on day and day 14 of the first treatment cycle. Throw away (discard) any medicine that remains. If you were not prescribed the Starter Kit, for each treatment cycle, you will receive bottle of RADICAVA ORS that contains total of 50 mL of RADICAVA ORS to deliver 10 doses. There may be some medicine that remains in each bottle after 10 doses. Throw away (discard) any medicine that remains. Fasting information:Do not eat or drink anything hours before each dose of RADICAVA ORS if you eat high-fat meal.Do not eat or drink anything hours before each dose of RADICAVA ORS if you eat low-fat meal.Do not eat or drink anything hours before each dose of RADICAVA ORS if you take calorie supplement.You should wait at least hour after taking your medicine before eating or drinking anything except water.Step 1: Before each use of RADICAVA ORS: Before opening the bottle, turn it upside down (invert) and shake vigorously up and down for at least 30 seconds (see Figure B). Look at the liquid medicine to make sure it is mixed well. If you see any small pieces at the bottom of the bottle, invert the bottle and shake it up and down for another 30 seconds or until you can no longer see the pieces at the bottom of the bottle (see Figure B). If the liquid medicine all looks the same, you can proceed to Step 2.Shake up and down for at least 30 seconds.Figure BStep 2: Open the bottle by firmly pressing down on the bottle cap and turning it counterclockwise (to the left). Place the open bottle upright on flat surface. Do not throw away the bottle cap; you will need to replace it after taking each dose.First-time use of bottle only. This must only be done time for each bottle. Insert the ribbed end of the bottle adapter into the bottle by firmly pressing it in as far as it will go (see Figure C). Do not remove the bottle adapter.Figure CStep 3: Remove the oral syringe from plastic wrap and make sure the plunger is inserted all the way into the barrel. Push the oral syringe plunger toward its tip to remove excess air (see Figure D). Insert the oral syringe into the opening of the bottle adapter until it is firmly in place (see Figure E). Turn the bottle upside down and slowly pull the plunger to remove small amount of liquid (see Figure F).Figure DFigure EFigure FStep 4: Keep the bottle upside down and pull the plunger until it goes up to the last line (5 mL) (see Figure G). While keeping the plunger in the same position, turn the bottle upright, and place it carefully on flat surface. Remove the oral syringe by gently twisting or pulling it out from the bottle (see Figure H). Check the amount of medicine again before moving on to the next step (see Figure I).Note: Do not remove the oral syringe while the bottle is upside down (medicine may leak out through the adapter).Note: If the dose is not correct, insert the oral syringe tip firmly into the bottle adapter. Push the plunger all the way in so that the medicine flows back into the bottle. Turn the bottle upside down. Repeat Step 4.Figure GFigure HFigure IStep 5: Place the tip of the oral syringe in the mouth and aim towards the inside of the cheek. Slowly press down on the plunger until the oral syringe is empty. Swallow all of the medicine (see Figure J). If needed, you can use up to ounces or cup of water to help swallow the medicine.Note: It is normal for small amount of medicine to remain in the tip of the syringe after taking.Figure JStep 6: Leave the bottle adapter inside the bottle. Place the bottle cap on the bottle and turn the cap clockwise (to the right). Keep bottle tightly closed between each use (see Figure K).Figure KStep 7: Remove the plunger from the oral syringe barrel by pulling the plunger and the barrel away from each other. Rinse the oral syringe (plunger and barrel) with water only. Allow it to air dry.Figure LStep 8: When the oral syringe (plunger and barrel) is dry, put the plunger back into the oral syringe barrel. Do not throw away the oral syringe. Store the syringe in clean, dry place.You must complete Steps through under How to take RADICAVA ORS before starting Step under How to take dose of RADICAVA ORS oral suspension through feeding tube.How to take dose of RADICAVA ORS oral suspension through feeding tube:Step 9: Using catheter-tip syringe, flush the feeding tube with ounce (30 mL) of water (see Figure M).Figure MStep 10: Place the oral syringe provided (containing the mL of RADICAVA ORS) into the feeding tube. Slowly push down the plunger until the oral syringe is empty (see Figure N).Figure NStep 11: Using catheter-tip syringe, flush the feeding tube with ounce (30 mL) of water after taking the dose of RADICAVA ORS (see Figure O).Figure OStep 12: Leave the adapter in the bottle. Place the bottle cap on the bottle and turn it clockwise (to the right) to close the bottle. Keep the bottle tightly closed between each use (see Figure P).Figure PStep 13: Remove the plunger from the oral syringe barrel by pulling the plunger and barrel away from each other. Rinse the oral syringe (plunger and barrel) with water only (see Figure Q). Allow it to air dry.Figure QStep 14: When the oral syringe (plunger and barrel) are dry, put the plunger back into the oral syringe barrel. Do not throw away the oral syringe. Store the oral syringe in clean, dry place.Manufactured for: Shionogi Inc. Florham Park, NJ 07932For more information, go to www.Radicava.com or call 1-888-292-0058.RADICAVA ORS is registered trademark of Shionogi Inc. (C) 2026 Shionogi Inc. All Rights Reserved.This Instructions for Use has been approved by the U.S. Food and Drug Administration.22022-4Issued: 05/2026. If your healthcare provider prescribes Starter Kit, you will receive bottles of RADICAVA ORS. Each bottle will contain 35 mL of RADICAVA ORS for total of 70 mL to be used for your first treatment cycle of 14 days. Only open the second bottle when you have finished the first bottle. If you were not prescribed the Starter Kit, for each treatment cycle you will receive bottle of RADICAVA ORS that contains total of 50 mL of RADICAVA ORS. After the first treatment cycle, RADICAVA ORS is to be used for 10 days out of 14-day periods.. Only use the bottle adapter and the reusable mL oral syringes provided with the bottle. Do not use household teaspoon to measure your medicine.. Store RADICAVA ORS upright at room temperature between 68F to 77F (20C to 25C). Protect from light.. Opening the bottle:When you open the bottle of RADICAVA ORS for the first use, write the date you open the bottle on the bottle label.After opening the bottle of RADICAVA ORS, use within 15 days.. When you open the bottle of RADICAVA ORS for the first use, write the date you open the bottle on the bottle label.. After opening the bottle of RADICAVA ORS, use within 15 days.. After bottle of Radicava ORS has been opened and used, white crust may form on the neck or on the side of the bottle. This is due to normal use and RADICAVA ORS can continue to be used as prescribed.. Keep bottle tightly closed between each use.. Throw away (discard) any RADICAVA ORS that is not used within 15 days after opening the bottle or within 30 days from the date of shipment shown on the carton pharmacy label, whichever happens first. Ask your pharmacist how to properly throw away (discard) RADICAVA ORS you are no longer able to use.. Keep RADICAVA ORS and all medicines out of the reach of children.. RADICAVA ORS bottle. bottle adapter. (5 mL) reusable oral syringes. Keep these instructions for future use.. Do not share RADICAVA ORS with anyone else.. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.. People who have problems using their hands may need assistance to draw up and give the correct dose of RADICAVA ORS.. For the first treatment cycle, you will take RADICAVA ORS every day for 14 days, followed by 14 days without the medicine.. For the cycles after the first treatment cycle, you will take RADICAVA ORS daily for 10 out of 14 days, followed by 14 days without the medicine.. If your healthcare provider prescribes the Starter Kit, you will receive bottles of RADICAVA ORS. Each bottle contains 35 mL of RADICAVA ORS for total of 70 mL to deliver 14 doses. There may be some medicine that remains in each bottle after the dose on day and day 14 of the first treatment cycle. Throw away (discard) any medicine that remains. There may be some medicine that remains in each bottle after the dose on day and day 14 of the first treatment cycle. Throw away (discard) any medicine that remains.. If you were not prescribed the Starter Kit, for each treatment cycle, you will receive bottle of RADICAVA ORS that contains total of 50 mL of RADICAVA ORS to deliver 10 doses. There may be some medicine that remains in each bottle after 10 doses. Throw away (discard) any medicine that remains. There may be some medicine that remains in each bottle after 10 doses. Throw away (discard) any medicine that remains.. Do not eat or drink anything hours before each dose of RADICAVA ORS if you eat high-fat meal.. Do not eat or drink anything hours before each dose of RADICAVA ORS if you eat low-fat meal.. Do not eat or drink anything hours before each dose of RADICAVA ORS if you take calorie supplement.. You should wait at least hour after taking your medicine before eating or drinking anything except water.. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L. Figure M. Figure N. Figure O. Figure P. Figure Q.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for RADICAVA and RADICAVA ORS and any potential adverse effects on the breastfed infant from RADICAVA and RADICAVA ORS or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The mechanism by which RADICAVA and RADICAVA ORS exert their therapeutic effect in patients with ALS is unknown.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 26-week carcinogenicity study in male and female transgenic (Tg rasH2) mice, oral administration of edaravone (0 [water control], [vehicle control], 100, 150, or 350 mg/kg) resulted in no increase in tumors.In 2-year carcinogenicity study in rats, oral administration of edaravone (0, 50, 100, or 200 mg/kg in males; 0, 50, 100, or 250 mg/kg in females) resulted in no increase in tumors.Carcinogenicity studies of edaravone using the intravenous route have not been conducted.MutagenesisEdaravone was negative in in vitro (bacterial reverse mutation and Chinese hamster lung chromosomal aberration) and in vivo (mouse micronucleus) assays.Impairment of FertilityIntravenous administration of edaravone (0, 3, 20, or 200 mg/kg) prior to and throughout mating in male and female rats and continuing in females to gestation day 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 approximately times the RHD for RADICAVA (60 mg) on body surface area (mg/m2) basis.Fertility studies of edaravone using the oral route have not been conducted.. 13.2 Animal Toxicology and/or Pharmacology. Oral administration of edaravone (0, 10, 30, 100, or 300 mg/kg/day) in dogs for 39 weeks resulted in neurotoxicity, characterized by white matter vacuolation in the spinal cord and vacuolation and nerve fiber atrophy in the sciatic nerve, at the two highest doses tested. The microscopic findings were accompanied by gait abnormalities, loss of patellar reflex, and inability to rise. Plasma edaravone exposures (Cmax and AUC) at the higher no-effect dose for neurotoxicity (30 mg/kg/day) were approximately times those in humans at the recommended human dose of RADICAVA ORS (105 mg).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL . radicava-soft-bag.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of RADICAVA or RADICAVA ORS in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt exposures at least times higher than that of the recommended doses of RADICAVA and RADICAVA ORS, edaravone does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. RADICAVA is administered by IV infusion. The maximum plasma concentration (Cmax) of edaravone was reached by the end of infusion. There was trend of more than dose-proportional increase in area under the concentration-time curve (AUC) and Cmax of edaravone. With multiple-dose administration, edaravone does not accumulate in plasma.RADICAVA ORS administered orally at the dose of 105 mg, under fasted conditions, was shown to demonstrate an equivalent AUC with RADICAVA (60 mg administered intravenously for 60 min) and Cmax not less than that of RADICAVA. RADICAVA ORS demonstrated similar pharmacokinetics following administration via feeding tubes and oral administration.In healthy subjects, RADICAVA ORS does not accumulate with once-daily administration, and the maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of edaravone is more than dose-proportional over the dose range of 30 to 300 mg (approximately 0.3 and times the recommended dosage, respectively).AbsorptionRADICAVA ORS has median time to maximum concentration (Tmax) occurring at approximately 0.5 hour (range, 0.25 to 0.75 hours) after fasted oral administration. The absolute oral bioavailability is about 57% because of first-pass effect when comparing RADICAVA ORS (105 mg oral suspension) and RADICAVA (60 mg intravenous formulation).Effect of FoodFollowing oral administration of RADICAVA ORS to healthy subjects hour before or hours after high-fat meals (800-1000 calories, 50% fat), hours after low-fat meals (400-500 calories, 25% fat), or hours after caloric supplement (250 calories, e.g., protein drink), the Cmax and AUC did not decrease significantly (less than 20% and 10% changes in Cmax and AUC, respectively) [see Dosage and Administration (2.3)].Following oral administration of RADICAVA ORS to healthy subjects, the Cmax decreased by 82%, and the AUC decreased by 61% with high-fat meal compared to fasted conditions. Following administration of RADICAVA ORS hours after high-fat meals, the Cmax and AUC decreased by 44% and 24%, respectively.Following administration of RADICAVA ORS hours after low-fat meals, the Cmax and AUC decreased by 45% and 21%, respectively.DistributionEdaravone is bound to human serum proteins (92%), mainly to albumin, with no concentration dependence in the range of 0.1 to 50 micromol/L. Edaravone has mean volume of distribution after intravenous administration of 63.1 L.EliminationThe mean terminal elimination half-life of edaravone is approximately 4.5 to hours. The half-lives of its metabolites are to hours. Following intravenous administration, the total clearance of edaravone is estimated to be 35.9 L/h.MetabolismEdaravone is metabolized to sulfate conjugate and glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17). In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases. RADICAVA ORS results in 1.3- and 1.7-fold higher exposures for both sulfate and glucuronide metabolites, respectively, when compared to RADICAVA because of first-pass metabolism.ExcretionIn Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate (60-80% of the dose up to 48 hours). Approximately 6-8% of the dose was recovered in the urine as the sulfate conjugate, and 1% of the dose was recovered in the urine as the unchanged drug. In vitro studies suggest that the sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the kidney before excretion into the urine.Specific PopulationsGeriatric PatientsNo age effect on edaravone pharmacokinetics has been found [see Use in Specific Populations (8.5)]. Patients with Renal ImpairmentFollowing single IV infusion of 30 mg edaravone (half the recommended dosage of RADICAVA) over 60 minutes, mean Cmax and AUC0- of unchanged edaravone were 1.15- and 1.20-fold greater in the subjects with mild renal impairment (eGFR 60-89 mL/min/1.73m2), and were 1.25- and 1.29-fold greater in the subjects with moderate renal impairment (eGFR 30-59 mL/min/1.73m2) when compared to subjects with normal renal function, respectively. These changes in exposures are not considered to be clinically significant and therefore no dosage adjustments are necessary in patients with mild to moderate renal impairment. The effects of severe renal impairment on the pharmacokinetics of edaravone have not been studied.Patients with Hepatic ImpairmentFollowing single IV infusion of 30 mg edaravone (half of the recommended dose of RADICAVA) over 60 minutes, mean Cmax and AUC0- of unchanged edaravone were 1.20- and 1.07-fold greater in the subjects with mild hepatic impairment (Child-Pugh score or 6), were 1.24- and 1.14-fold greater in the subjects with moderate hepatic impairment (Child-Pugh score to 9), and were 1.20- and 1.19-fold greater in the subjects with severe hepatic impairment (Child-Pugh score 10 to 14) when compared to subjects with normal hepatic function, respectively. These changes in exposures are not considered to be clinically significant and therefore no dosage adjustments are necessary in patients with hepatic impairment.Male and Female PatientsNo gender effect on edaravone pharmacokinetics has been found.Racial or Ethnic GroupsThere were no significant racial differences in Cmax and AUC of edaravone between Japanese and Caucasian subjects.Drug Interaction StudiesThe pharmacokinetics of edaravone is not expected to be significantly affected by inhibitors of cytochrome P450 (CYP) enzymes, UGTs, or major transporters. Concomitant oral administration of edaravone 120 mg (higher than the recommended dose of 105 mg for ORS) with sildenafil (CYP3A4 substrate), rosuvastatin (BCRP substrate), and furosemide (OAT3 substrate) did not produce any changes in Cmax and AUC of these drugs.In vitro studies demonstrated that, at the recommended dosage, edaravone and its metabolites are not expected to significantly inhibit CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A), conjugating enzymes UGT1A1 and UGT2B7, or other transporters (P-gp, OATP1B1, OATP1B3, OAT1, OCT2, MATE1, and MATE2-K) in humans. Edaravone and its metabolites are not expected to induce CYP1A2, or CYP2B6, at the recommended dosage of edaravone.In vitro data indicated that edaravone was not substrate of OATP1B1 or OATP1B3.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of RADICAVA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Skin and subcutaneous tissue disorders: Hypersensitivity reactions and anaphylaxis [see Warnings and Precautions (5.1, 5.2)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with the use of RADICAVA or RADICAVA ORS 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 2-4% and 15-20%, respectively. The background risk for major birth defects and miscarriage in patients with ALS is unknown.DataAnimal DataIn 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. no-effect dose for embryofetal developmental toxicity was not identified; the low dose is less than the recommended human dose of 60 mg for RADICAVA on 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 times the recommended human dose (RHD) for RADICAVA on 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 mg/m2 basis.Reproductive and developmental toxicology studies of edaravone using the oral route have not been conducted.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration22022-4Issued: 05/2026PATIENT INFORMATION RADICAVA (ra di ka vah) (edaravone) injection for intravenous use RADICAVA ORS (ra di ka vah r s) (edaravone) oral suspensionWhat are RADICAVA(R) and RADICAVA ORS(R) RADICAVA and RADICAVA ORS are prescription medicines used to treat people with amyotrophic lateral sclerosis (ALS). It is not known if RADICAVA or RADICAVA ORS are safe and effective in children.Do not receive RADICAVA or RADICAVA ORS if you are allergic to edaravone or any of the ingredients in RADICAVA and RADICAVA ORS. See the end of this leaflet for complete list of ingredients in RADICAVA and RADICAVA ORS.Before you take RADICAVA or RADICAVA ORS, tell your healthcare provider about all of your medical conditions, including if you:have asthma.are allergic to other medicines.are pregnant or plan to become pregnant. It is not known if RADICAVA or RADICAVA ORS will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if RADICAVA or RADICAVA ORS passes into your breastmilk.You and your healthcare provider should decide if you will receive RADICAVA or RADICAVA ORS or breastfeed. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive RADICAVAYou will be prescribed RADICAVA by healthcare provider and told how often you will receive RADICAVA.RADICAVA will be given by intravenous (IV) infusion into your vein.It takes about hour to receive the full dose of RADICAVA.Your healthcare provider will monitor you closely during your treatment with RADICAVA.How will take RADICAVA ORSSee the detailed Instructions for Use on how to take RADICAVA ORS at the end of this Patient Information leaflet.You will be prescribed RADICAVA ORS by healthcare provider and told how often you will take RADICAVA ORS.RADICAVA ORS is to be taken by mouth or by using feeding tube.RADICAVA ORS should be taken in the morning on an empty stomach. You should stop eating at bedtime. Do not eat or drink anything hours before each dose of RADICAVA ORS if you eat high-fat meal. Do not eat or drink anything hours before each dose of RADICAVA ORS if you eat low-fat meal.Do not eat or drink anything hours before each dose of RADICAVA ORS if you take calorie supplement. You should wait at least hour after taking your medicine before eating or drinking anything except water.What are the possible side effects of RADICAVA and RADICAVA ORS RADICAVA and RADICAVA ORS may cause serious side effects including:1. Hypersensitivity (allergic) reactions. Hypersensitivity reactions have happened in people receiving RADICAVA or taking RADICAVA ORS and can happen after your medicine has been given. Tell your healthcare provider right away or go to the nearest emergency room if you have any of the following symptoms:hivesbreathing problemsitchingswelling of the lips, tongue, facedizzinesswheezingfainting2. Sulfite allergic reactions. RADICAVA and RADICAVA ORS contain sodium bisulfite, sulfite that may cause type of allergic reaction that can be serious and life-threatening. Sodium bisulfite can also cause less severe allergic reactions, for example, asthma episodes, in certain people. Sulfite sensitivity can happen more often in people who have asthma than in people who do not have asthma. Tell your healthcare provider right away or go to the nearest emergency room if you have any of the following symptoms:hivestrouble breathing or swallowingitchingswelling of the lips, tongue, facedizzinessasthma attack (in people with asthma)wheezingfaintingYour healthcare provider will monitor you during treatment to watch for signs and symptoms of all the serious side effects and allergic reactions. The most common side effects of RADICAVA and RADICAVA ORS include bruising (contusion), problems walking (gait disturbance), and headache. These are not all the possible side effects of RADICAVA and RADICAVA ORS. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to www.fda.gov/medwatch or Shionogi Inc. at 1-888-292-0058. What are the ingredients in RADICAVA and RADICAVA ORSActive ingredient: edaravone RADICAVA Inactive ingredients: L-cysteine hydrochloride hydrate, sodium bisulfite, sodium chloride, phosphoric acid, and sodium hydroxide. RADICAVA ORS Inactive ingredients: L-cysteine hydrochloride hydrate, polyvinyl alcohol, simethicone emulsion, sodium bisulfite, sorbitol, and xanthan gum. Phosphoric acid and sodium hydroxide are added to adjust to pH 4. Manufactured for: Shionogi Inc. Florham Park, NJ 07932 For more information, go to www.Radicava.com or call 1-888-292-0058. RADICAVA and RADICAVA ORS are registered trademarks of Shionogi Inc. (C) 2026 Shionogi Inc. All Rights Reserved.. have asthma.. are allergic to other medicines.. are pregnant or plan to become pregnant. It is not known if RADICAVA or RADICAVA ORS will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if RADICAVA or RADICAVA ORS passes into your breastmilk.. You will be prescribed RADICAVA by healthcare provider and told how often you will receive RADICAVA.. RADICAVA will be given by intravenous (IV) infusion into your vein.. It takes about hour to receive the full dose of RADICAVA.. Your healthcare provider will monitor you closely during your treatment with RADICAVA.. See the detailed Instructions for Use on how to take RADICAVA ORS at the end of this Patient Information leaflet.. You will be prescribed RADICAVA ORS by healthcare provider and told how often you will take RADICAVA ORS.. RADICAVA ORS is to be taken by mouth or by using feeding tube.. RADICAVA ORS should be taken in the morning on an empty stomach. You should stop eating at bedtime. Do not eat or drink anything hours before each dose of RADICAVA ORS if you eat high-fat meal. Do not eat or drink anything hours before each dose of RADICAVA ORS if you eat low-fat meal.Do not eat or drink anything hours before each dose of RADICAVA ORS if you take calorie supplement. Do not eat or drink anything hours before each dose of RADICAVA ORS if you eat high-fat meal. Do not eat or drink anything hours before each dose of RADICAVA ORS if you eat low-fat meal.. Do not eat or drink anything hours before each dose of RADICAVA ORS if you take calorie supplement.. You should wait at least hour after taking your medicine before eating or drinking anything except water.. hives. breathing problems. itching. swelling of the lips, tongue, face. dizziness. wheezing. fainting. hives. trouble breathing or swallowing. itching. swelling of the lips, tongue, face. dizziness. asthma attack (in people with asthma). wheezing. fainting.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity Reactions: Advise patients to seek immediate medical care (5.1)Sulfite Allergic Reactions: RADICAVA and RADICAVA ORS contain sodium bisulfite, which may cause allergic type reactions, including anaphylactic symptoms and asthmatic episodes in susceptible people (5.2). Hypersensitivity Reactions: Advise patients to seek immediate medical care (5.1). Sulfite Allergic Reactions: RADICAVA and RADICAVA ORS contain sodium bisulfite, which may cause allergic type reactions, including anaphylactic symptoms and asthmatic episodes in susceptible people (5.2). 5.1Hypersensitivity 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 RADICAVA.Patients should be monitored carefully for hypersensitivity reactions. If hypersensitivity reactions occur, discontinue RADICAVA and/or RADICAVA ORS, treat per standard of care, and monitor until the condition resolves [see Contraindications (4)]. 5.2Sulfite Allergic Reactions. RADICAVA and RADICAVA ORS contain sodium bisulfite, 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 than non-asthmatic people.