CLASSES
Agents for Amyotrophic Lateral Sclerosis (ALS)
DESCRIPTION
Oral and intravenous antioxidant
Used for treatment of amyotrophic lateral sclerosis (ALS)
Hypersensitivity reactions, including anaphylaxis, reported
COMMON BRAND NAMES
Radicava, Radicava ORS
HOW SUPPLIED
Edaravone Oral Susp: 5mL, 105mg
Radicava Intravenous Inj Sol: 0.3mg, 1mL
DOSAGE & INDICATIONS
For the treatment of amyotrophic lateral sclerosis (ALS).
NOTE: Patients treated with intravenous edaravone may be switched to oral edaravone using the same dosing frequency.
Oral dosage
Adults
105 mg PO once daily in the morning after overnight fasting 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
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.
DOSING CONSIDERATIONS
Hepatic Impairment
No dosage adjustments are needed in patients with hepatic impairment.
Renal Impairment
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.
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).
STORAGE
Radicava:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Protect from light
- See package insert for detailed storage information
- Store at 77 degrees F; excursions permitted to 59-86 degrees F
- Store in original package until time of use
Radicava ORS:
- Discard product that has been stored at room temperature for over 30 days
- Discard unused product 15 days after first opening
- Do not freeze
- Protect from light
- See package insert for detailed storage information
- Store between 68 to 77 degrees F
- Store in refrigerator at 2 to 8 degrees C (36 to 46 degrees F)
- Store upright
CONTRAINDICATIONS / PRECAUTIONS
Asthma, sulfite hypersensitivity
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.
Pregnancy
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.
Breast-feeding
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.
ADVERSE REACTIONS
Severe
anaphylactoid reactions / Rapid / Incidence not known
erythema multiforme / Delayed / Incidence not known
Moderate
hypoxia / Early / 6.0-6.0
glycosuria / Early / 4.0-4.0
hypotension / Rapid / Incidence not known
dyspnea / Early / Incidence not known
Mild
gait disturbance / Delayed / 13.0-13.0
headache / Early / 10.0-10.0
fatigue / Early / 7.6-7.6
infection / Delayed / 4.0-4.0
urticaria / Rapid / Incidence not known
DRUG INTERACTIONS
There are no drug interactions associated with Edaravone products.
PREGNANCY AND LACTATION
Pregnancy
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.
MECHANISM OF ACTION
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.
PHARMACOKINETICS
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.
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.