EDARAVONE: 3,762 Adverse Event Reports & Safety Profile

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

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 )

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 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 <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling (16.1 , 16.2) ]</span>. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

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 <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling (16.1 , 16.2) ]</span>. 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

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 )

REACTIONS The following serious adverse reactions are described elsewhere in the labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1) ]
• Sulfite Allergic Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (at least 10% of patients treated with RADICAVA and greater than placebo) are contusion, gait disturbance, and headache ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Tanabe Pharma America, 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 a that Occurred in ≥2% of RADICAVA -Treated Patients and ≥2% More Frequently than in Placebo Patients Adverse Reaction RADICAVA IV (N=184) % Placebo (N=184) % Contusion 15 9 Gait disturbance 13 9 Headache 10 6 Dermatitis 8 5 Eczema 7 4 Respiratory failure, respiratory disorder, hypoxia 6 4 Glycosuria 4 2 Tinea infection 4 2 a Pooled placebo-controlled studies include two additional studies with 231 additional patients, all using the same treatment regimen [see Clinical Studies (14) ].

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.2) ]</span>.

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 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>.

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.