RADICAVA- edaravone_injection

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. RADICAVA is administered by IV infusion. The maximum plasma concentration (C max max 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 C max In healthy subjects, RADICAVA ORS does not accumulate with once-daily administration, and the maximum plasma concentration (C max Absorption RADICAVA ORS has a median time to maximum concentration (T max Effect of Food Following oral administration RADICAVA ORS to healthy subjects 1 hour before or 8 hours after high-fat meals (800-1000 calories, 50% fat), 4 hours after low-fat meals (400-500 calories, 25% fat), or 2 hours after caloric supplement (250 calories, e. , protein drink), the C max max [see Dosage and Administration (2. 3) Following oral administration of RADICAVA ORS to healthy subjects, the C max max max Distribution Edaravone 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 a mean volume of distribution after intravenous administration of 63. Elimination The mean terminal elimination half-life of edaravone is approximately 4. 5 to 9 hours. The half-lives of its metabolites are 3 to 6 hours. Following intravenous administration, the total clearance of edaravone is estimated to be 35. Metabolism Edaravone is metabolized to a sulfate conjugate and a 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. 7-fold higher exposures for both sulfate and glucuronide metabolites, respectively, when compared to RADICAVA because of first pass metabolism. Excretion In 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 Specific Populations Geriatric Patients No age effect on edaravone pharmacokinetics has been found [see Use in Specific Populations (8. 5) Patients with Renal Impairment Following single IV infusion of 30 mg edaravone (half the recommended dosage of RADICAVA) over 60 minutes, mean C max 0-infinity 2 2 Patients with Hepatic Impairment Following single IV infusion of 30 mg edaravone (half of the recommended dose of RADICAVA) over 60 minutes, mean C max 0-infinity Male and Female Patients No gender effect on edaravone pharmacokinetics has been found. Racial or Ethnic Groups There were no significant racial differences in C max Drug Interaction Studies The 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 C max In vitro In vitro.

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

DOSAGE AND ADMINISTRATION
3 2. 1 see Dosage and Administration (2. 3) RADICAVA is for intravenous infusion only. Preparation Do not use if the oxygen indicator has turned blue or purple before opening the package. [see How Supplied/Storage and Handling (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. 2) ] Other medications should not be injected into the infusion bag or mixed with RADICAVA. See the Instruction for Use 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) 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. , 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 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.
Instructions for Use
INSTRUCTIONS FOR USE RADICAVA (ra di ká vah) ORS (edaravone) oral suspension Important information about measuring RADICAVA ORS: do not Do not How to prepare RADICAVA ORS Only open the second bottle when you have finished the first bottle. Do not How to store RADICAVA ORS: Opening the bottle: 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. Keep RADICAVA ORS and all medicines out of the reach of children. Each RADICAVA ORS carton contains: Use a new 5 mL oral syringe and bottle adapter when using a new bottle of RADICAVA ORS (see Figure A) Figure A Important information: How to take RADICAVA ORS: Take RADICAVA ORS as prescribed by your healthcare provider. Dosing Information: How RADICAVA ORS will be provided: o o Fasting Information: Do not Do not Do not Step 1: Before each use of RADICAVA ORS: 30 seconds 30 seconds Shake up and down for at least 30 seconds Figure B Step 2: firmly pressing down Do not First time use of a bottle only. Do not Figure C Step 3: Remove the oral syringe from plastic wrap and make sure the plunger is inserted all the way into the barrel. Figure D Figure E Figure F Step 4: Note: Do not 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 G Figure H Figure I Step 5: Note: It is normal for a small amount of medicine to remain in the tip of the syringe after taking. Figure J Step 6: Figure K Step 7: Rinse the oral syringe (plunger and barrel) with water only Figure L Step 8: Do not throw away the oral syringe You must complete Steps 1 through 4 under "How to take RADICAVA ORS" before starting Step 9 under "How to take a dose of RADICAVA ORS oral suspension through a feeding tube. " How to take a dose of RADICAVA ORS oral suspension through a feeding tube: Step 9: Figure M Step 10: Figure N Step 11: Figure O Step 12: Leave the adapter in the bottle. Figure P Step 13: Figure Q Step 14: Do not throw away the oral syringe. Marketed and distributed by: Mitsubishi Tanabe Pharma America, Inc. , a US subsidiary of Mitsubishi Tanabe Pharma Corporation Jersey City, NJ 07310 For more information, go to www. com or call 1- 888-292-0058. RADICAVA ORS registered copyright 2021 Mitsubishi Tanabe Pharma Corporation. All rights reserved. This Instructions for Use has been approved by the U. Food and Drug Administration. 22022-1 Issued: 05/2022 ifu-figure-a ifu-figure-b ifu-figure-c ifu-figure-d ifu-figure-e ifu-figure-f ifu-figure-g ife-figure-h ifu-figure-i ifu-figure-j ifg-figure-k ifu-figure-l ifu-figure-m ifu-figure-n ifu-figure-o ifu-figure-p ifu-figure-q.

The following serious adverse reactions are described elsewhere in the labeling: [see Warnings and Precautions (5. 1) ] [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 Mitsubishi Tanabe Pharma America, Inc. at 1-888-292-0058 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 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 [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. 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.

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. 2 Patients with a history of hypersensitivity to edaravone or any of the inactive ingredients in RADICAVA and/or RADICAVA ORS ( 4.

Pregnancy: Based on animal data, may cause fetal harm. 1 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. 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 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 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 Reproductive and developmental toxicology studies of edaravone using the oral route have not been conducted. 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. 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.

NONCLINICAL TOXICOLOGY
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 in vivo 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 Fertility studies of edaravone using the oral route have not been conducted. 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 (C max.
CLINICAL STUDIES
The efficacy of RADICAVA ORS is based on a bioavailability study comparing RADICAVA and RADICAVA ORS [see Clinical Pharmacology (12. 3) ] The efficacy of RADICAVA for the treatment of ALS was established in a 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: 1. The 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 a 60-minute period according to the following schedule: The primary efficacy endpoint was a 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 item 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 Scores Treatment Change from Baseline LS Mean +/- SE (95% CI) Treatment Difference (RADICAVA en dash placebo [95% CI]) p RADICAVA IV −5. 0013 Placebo −7. 66 Figure 1 Distribution of Change from Baseline to Week 24 in ALSFRS-R Scores figure-1.

RADICAVA ORS- edaravone

RADICAVA- edaravone_injection Product manual source documgent