Edaravone is an oral and intravenous antioxidant indicated for the treatment of amyotrophic lateral sclerosis (ALS). Edaravone is not curative; however, it may slow the decline of functional abilities that occurs with ALS. In a 6-month, randomized, placebo-controlled, double-blind clinical trial, edaravone was associated with a significantly smaller decline in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) mean score from baseline compared to placebo (-5.01 +/- 0.64 vs. -7.5 +/- 0.66; p = 0.0013). Higher ALSFRS-R scores represent greater functional ability. Hypersensitivity reactions, including serious reactions such as anaphylaxis, have been reported with edaravone use.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer orally or via feeding tube in the morning on an empty stomach after overnight fasting.
-Administration relative to type of food consumption:
--High fat meal (800 to 1,000 calories, 50% fat): Fast 8 hours before and 1 hour after administration.
-Low fat meal (400 to 500 calories, 25% fat): Fast 4 hours before and 1 hour after administration.
-Calorie supplement (250 calories, e.g., protein drink): Fast 2 hours before and 1 hour after administration.
-Only water may be consumed in the 1 hour after administration.
-Nasogastric (NG) tubes or percutaneous endoscopic gastrostomy (PEG) tubes made of silicone, polyvinyl chloride (PVC), or polyurethane can be used.
-Missed dose: Do not administer 2 doses the next day. Do not administer a dose on days 15 through 28.
-Storage: Prior to dispensing, refrigerate suspension in an upright position. After opening, store suspension in an upright position at room temperature. Protect from light. Discard unused suspension 15 days after opening the bottle or within 30 days from the date of shipment indicted on the carton pharmacy label, whichever is first.
Oral Liquid Formulations
-Invert the suspension bottle and shake vigorously up and down for at least 30 seconds prior to use.
-Administer using the 5 mL oral syringe provided with the product.
-Feeding tube administration: Flush the tube with at least 30 mL of water using a catheter-tip syringe before and after administration.
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Do not use if the oxygen indicator has turned blue or purple before opening the package. The indicator will appear pink to reflect appropriate oxygen concentrations.
-Storage: Once the overwrap package is open, use within 24 hours.
Intravenous Administration
-Do not inject other medications into the infusion bag or mix with edaravone.
-Administer each 60 mg dose as 2 consecutive 30 mg IV infusion bags over a total of 60 minutes (i.e., at a rate of approximately 1 mg/minute).
Anaphylactoid reactions, including urticaria, hypotension, and dyspnea, and hypersensitivity reactions, including redness, wheals, and erythema multiforme, have been reported in postmarketing experience with edaravone. Monitor patients closely during treatment for hypersensitivity reactions. If hypersensitivity reactions occur, discontinue edaravone, treat per standard of care, and monitor until the reaction resolves. During randomized, placebo-controlled trials, dermatologic adverse reactions that occurred in edaravone-treated patients (n = 184) and at a rate of at least 2% more frequently than in placebo-treated patients (n = 184) included dermatitis (8% vs. 5%) and eczema (7% vs. 4%).
During randomized, placebo-controlled trials, common adverse reactions that occurred in edaravone-treated patients (n = 184) and at a rate of at least 2% more frequently than in placebo-treated patients (n = 184) included contusion (15% vs. 9%), gait disturbance (13% vs. 9%), and headache (10% vs. 6%).
During randomized, placebo-controlled trials, respiratory disorder, including respiratory failure and hypoxia, occurred in 6% of edaravone-treated patients (n = 184) vs. 4% of placebo-treated patients (n = 184).
During randomized, placebo-controlled trials, glycosuria occurred in 4% of edaravone-treated patients (n = 184) vs. 2% of placebo-treated patients (n = 184).
During randomized, placebo-controlled trials, tinea infection occurred in 4% of edaravone-treated patients (n = 184) vs. 2% of placebo-treated patients (n = 184).
In an open-label study, fatigue was observed in 7.6% of edaravone-treated patients (n = 185).
Edaravone is contraindicated for use in patients with a history of a hypersensitivity to edaravone or any of the inactive ingredients, including sulfite hypersensitivity. Hypersensitivity reactions, including anaphylactic reactions, have occurred with edaravone. Edaravone products contain sodium bisulfite, which may cause hypersensitivity reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible patients. Sulfite sensitivity occurs more frequently in persons with asthma. Monitor patients closely during treatment for hypersensitivity reactions. If hypersensitivity reactions occur, discontinue edaravone, treat per standard of care, and monitor until the reaction resolves.
There are no adequate human data on the developmental risk associated with edaravone use during pregnancy. Increased mortality and other adverse developmental effects were observed during reproductive animal studies with edaravone at clinically relevant doses. Reduced fetal weight was observed in rats given edaravone (0, 3, 30, or 300 mg/kg/day) throughout organogenesis; reduced offspring weight and maternal toxicity were observed at the highest dose. The low dose is less than the recommended human dose (RHD) of 60 mg on a body surface area (BSA, mg/m2) basis. In rats given edaravone (0, 3, 20, or 200 mg/kg/day) from gestational day 17 throughout lactation, offspring mortality and increased activity were observed at the high dose and mid to high doses, respectively. There was an increase in stillbirths, offspring mortality, and physical development delay (vaginal opening) at the highest dose tested. Maternal toxicity was observed at all but the lowest dose. Offspring reproductive function was not affected. The no-effect dose for developmental toxicity (3 mg/kg/day) is less than the RHD on a BSA basis. Edaravone (0, 3, 20, or 100 mg/kg/day) administration to rabbits throughout organogenesis resulted in embryofetal death at the highest dose, which was also associated with maternal toxicity. The higher no-effect dose for embryofetal developmental toxicity is approximately 6 times the RHD on a BSA basis.
There are no data on the presence of edaravone in human milk, the effects of edaravone on the breast-fed infant, or the effects of the drug on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for edaravone and any potential adverse effects on the breast-fed infant from edaravone or the underlying maternal condition.
For the treatment of amyotrophic lateral sclerosis (ALS):
NOTE: Persons treated with intravenous edaravone may be switched to oral edaravone using the same dosing frequency.
Oral dosage:
Adults: 105 mg PO once daily for 14 days followed by a 14-day drug-free period for an initial treatment cycle. For subsequent treatment cycles, administer for 10 days out of 14-day periods followed by 14-day drug-free periods.
Intravenous dosage:
Adults: 60 mg IV once daily for 14 days followed by a 14-day drug-free period for an initial treatment cycle. For subsequent treatment cycles, administer for 10 days out of 14-day periods followed by 14-day drug-free periods.
Maximum Dosage Limits:
-Adults
105 mg/dose PO; 60 mg/dose IV.
-Geriatric
105 mg/dose PO; 60 mg/dose IV.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed in patients with hepatic impairment.
Patients with Renal Impairment Dosing
No dosage adjustments are needed in patients with mild or moderate renal impairment (eGFR 30 to 89 mL/minute/1.73 m2). Edaravone has not been studied for use in patients with severe renal impairment.
*non-FDA-approved indication
There are no drug interactions associated with Edaravone products.
Edaravone is a potent free radical scavenger and antioxidant that may provide neuroprotection against oxidative stress. In motor neurons, oxidative stress may contribute to neurodegeneration and the development of amyotrophic lateral sclerosis (ALS). Antioxidant properties of edaravone include enhancement of prostacyclin production, hydroxyl radical trapping, and quenching of active oxygen.
Edaravone is administered orally and intravenously. Edaravone is bound to human serum proteins (92%), mainly albumin. Mean Vd after IV administration is 63.1 L. Metabolism to an inactive glucuronide conjugate occurs in the liver and kidney via glucuronide conjugation with multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17). An inactive sulfate conjugate is also formed by sulfotransferases. Metabolism of edaravone oral suspension results in 1.3- and 1.7-fold higher exposures for sulfate and glucuronide metabolites, respectively, compared to metabolism of IV edaravone because of first pass metabolism. Excretion of edaravone mostly occurs in the urine as the glucuronide form (60% to 80% of the dose up to 48 hours). Approximately 6% to 8% of the dose is recovered in the urine as the sulfate conjugate, and less than 1% of the dose is excreted in the urine as unchanged drug. Total clearance of edaravone is estimated to be 35.9 L/hour after IV administration. The mean terminal half-life of edaravone is 4.5 to 9 hours.
Affected cytochrome P450 isoenzymes and drug transporters: UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, UGT2B17
Edaravone is a substrate of UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17. The pharmacokinetics of edaravone are not expected to be significantly affected by inhibitors of cytochrome enzymes, UGTs, or major transporters.
-Route-Specific Pharmacokinetics
Oral Route
Oral administration of edaravone 105 mg under fasted conditions demonstrated an equivalent area under the concentration-time curve (AUC) with edaravone 60 mg IV administered over 60 minutes and maximum concentration (Cmax) not less than that of intravenous edaravone. Similar pharmacokinetics occurred with oral administration and administration via feeding tube. The Cmax and AUC of edaravone are more than dose-proportional over the dose range of 30 to 300 mg. Edaravone does not accumulate with once daily administration. Median time to maximum concentration (Tmax) occurs approximately 0.5 hour (range 0.25 to 0.75 hour) after fasted oral administration. Due to first pass effect, absolute oral bioavailability is about 57% when comparing edaravone 105 mg oral suspension to 60 mg IV. Significant decreases in Cmax (less than 20%) and AUC (less than 10%) did not occur after administration of edaravone 1 hour before or 8 hours after high fat meals (800 to 1,000 calories, 50% fat), 4 hours after low fat meals (400 to 500 calories, 25% fat), or 2 hours after caloric supplement (250 calories, e.g., protein drink). Cmax and AUC decreased by 82% and 61%, respectively, after coadministration of edaravone with a high fat meal and 44% and 24%, respectively, after edaravone administration 4 hours after high fat meals compared to fasting conditions. Cmax and AUC decreased by 45% and 21%, respectively, after edaravone administration 2 hours after low fat meals.
Intravenous Route
The maximum concentration (Cmax) of edaravone is reached by the end of the infusion (at 60 minutes). There is a more than dose-proportional increase in AUC and Cmax. Edaravone does not accumulate in plasma with multiple-dose administration.
-Special Populations
Hepatic Impairment
After a single edaravone 30 mg IV infusion, mean Cmax and AUC of unchanged edaravone were 1.2 and 1.07-fold greater in subjects with mild hepatic impairment (Child-Pugh score 5 or 6), 1.24 and 1.14-fold greater in subjects with moderate hepatic impairment (Child-Pugh score 7 to 9), and 1.2 and 1.19-fold greater in subjects with severe hepatic impairment (Child-Pugh score 10 to 14), respectively, compared to subjects with normal hepatic function; these changes in exposures are not considered to be clinically significant.
Renal Impairment
After a single edaravone 30 mg IV infusion, mean Cmax and AUC of unchanged edaravone were 1.15 and 1.2-fold greater in subjects with mild renal impairment (eGFR 60 to 89 mL/minute/1.73 m2) and 1.25 and 1.29-fold greater in subjects with moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m2), respectively, compared to subjects with normal renal function; these changes in exposures are not considered to be clinically significant. The pharmacokinetics of edaravone have not been studied in patients with severe renal impairment.
Geriatric
No age effect on the pharmacokinetics of edaravone has been found.
Gender Differences
No gender effect on the pharmacokinetics of edaravone has been found.
Ethnic Differences
No significant differences in the AUC and Cmax of edaravone were found between Japanese and Caucasian subjects.