Edaravone

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 )

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 1 hour after administration except water ( 2.1 , 2.3 ) For RADICAVA and RADICAVA ORS: 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 RADICAVA and RADICAVA ORS is as follows: RADICAVA: an intravenous infusion of 60 mg administered over a 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) ] Administer RADICAVA or RADICAVA ORS 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 RADICAVA Injection RADICAVA 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 [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. Administration Administer each 60 mg dose of RADICAVA 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 [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. Preparation Prior to opening the bottle, turn it upside down (invert) and shake vigorously up and down for at least 30 seconds. Administration RADICAVA 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 1 hour after administration except water [see Clinical Pharmacology (12.3) ] . See Table 1 for specific fasting conditions. Table 1: RADICAVA ORS Administration Relative to Type of Food Consumption Type of food/caloric supplement consumed Fasting 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 administration Administer RADICAVA ORS using a 5 mL oral syringe that comes with the product. A 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 Administration 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 a catheter-tip syringe to flush the tube with at least 1 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) ] .

RADICAVA is supplied for intravenous infusion in a 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 a multi-dose amber glass bottle 105 mg/5 mL of white to off-white color. Injection: 30 mg/100 mL in a single-dose polypropylene bag ( 3 ) Oral suspension: 105 mg/5 mL in a multi-dose amber glass bottle ( 3 )

RADICAVA and RADICAVA ORS are 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 RADICAVA and/or RADICAVA ORS ( 4 )

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 )

5.1 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 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) ].

5.2 Sulfite Allergic Reactions RADICAVA and RADICAVA ORS contain 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 than non-asthmatic people.

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 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 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 RADICAVA 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 2 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 Trials Pooled 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 Patients Adverse Reaction RADICAVA (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 Additional Adverse Reactions with RADICAVA ORS In an open-label study in patients with ALS (n=185) treated with RADICAVA ORS for 6 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 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) ].

Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 )

8.1 Pregnancy Risk Summary There 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. 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 RADICAVA 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 RADICAVA 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. Reproductive and developmental toxicology studies of edaravone using the oral route have not been conducted.

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 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 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.

Risk Summary There 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. 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 RADICAVA 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 RADICAVA 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. Reproductive and developmental toxicology studies of edaravone using the oral route have not been conducted.

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

Of the 184 patients with ALS who received RADICAVA 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.

The active ingredient in RADICAVA and RADICAVA ORS 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. RADICAVA injection is a clear, colorless liquid provided as a sterile solution. RADICAVA injection is supplied for intravenous infusion in a 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 a white to off-white color, opaque, homogenous suspension containing 105 mg of edaravone per 5 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

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

Cardiac Electrophysiology At exposures at least 5 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.

, Mutagenesis, Impairment of Fertility Carcinogenesis In a 26-week carcinogenicity study in male and female transgenic (Tg rasH2) mice, oral administration of edaravone (0 [water control], 0 [vehicle control], 100, 150, or 350 mg/kg) resulted in no increase in tumors. In a 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. 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 male and female rats 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 approximately 3 times the RHD for RADICAVA (60 mg) on a body surface area (mg/m 2 ) basis. Fertility studies of edaravone using the oral route have not been conducted.

17 PATIENT COUNSELING INFORMATION Advise the patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Hypersensitivity Reactions Advise patients to seek immediate medical care if they experience signs or symptoms of a hypersensitivity reaction [see Warnings and Precautions (5.1) ]. Sulfite Allergic Reactions Advise 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 Breastfeeding Advise 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 Administration Advise patients to take RADICAVA ORS in the morning on an empty stomach. Instruct patients to fast 8 hours before each dose if they consume a high-fat meal, 4 hours before each dose if they consume a low-fat meal, or 2 hours before each dose if they consume a caloric supplement [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . Also instruct patients to not to consume food for 1 hour after each dose. Advise caregivers, if administering RADICAVA ORS via feeding tube, to use a catheter-tip syringe and flush the feeding tube with approximately 1 ounce (30 mL) of water before and after use (see Instructions for Use ) .

RADICAVA Store RADICAVA 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. 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 ORS Pharmacy Store RADICAVA ORS refrigerated between 2°C to 8°C (36°F to 46°F) and protect from light. Do not freeze. Store upright. Patient Store RADICAVA ORS upright at room temperature between 20°C to 25°C (68°F to 77°F). Protect from light. Discard 15 days after opening bottle or if unopened 30 days from date of shipment indicated on the carton pharmacy label.