Approval Date.
Edaravone Injection Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Edaravone Injection
Trade name: RADICUT®, RADICUT®
English name: Edaravone Injection
Hanyu Pinyin: Yidalafeng Zhusheye
Ingredients
Active ingredient: Edaravone
Chemical name: 3-methyl-1-phenyl-2-pyrazolin-5-one
Chemical structure formula
Molecular Formula: C10H10N2O
Molecular weight: 174.20
Excipients: sodium bisulfite, L-cysteine hydrochloride monohydrate, sodium chloride, sodium hydroxide, phosphoric acid.
【Properties】.
This product is a colorless clear liquid.
Indications
Inhibiting the progression of dysfunction caused by amyotrophic lateral sclerosis (ALS).
Specification
100ml: 30mg
Dosage]
Normally, adults should take 60 mg (2 sachets) once daily by intravenous drip over 60 minutes.
Usually, the dosing and withdrawal periods of this product are combined to form a course of 28 days, which is repeated. The first course of treatment is stopped after 14 days of continuous daily dosing period of 14 days, and the second course is stopped after 14 days of 10 days of 14 days of dosing period.
[Adverse reactions].
Amyotrophic lateral sclerosis (ALS)
Japanese clinical trial
There were 37 cases (11.7%) of 46 adverse reactions reported out of a total of 317 cases. The main adverse reactions were 4 cases (1.3%) of skin rash, 4 cases (1.3%) of liver dysfunction, 3 cases (0.9%) of hypertension, 3 cases (0.9%) of elevated γ-GTP, and 3 cases (0.9%) of positive urine glucose.
(1) Serious adverse reactions
(1) *Acute renal insufficiency (0.26%), nephrotic syndrome (0.02%): Acute renal insufficiency and nephrotic syndrome may occur, and frequent renal function tests should be performed and adequately observed. If symptoms such as decreased renal function or oliguria are detected, discontinue administration and dispose of the drug appropriately. (See “2. Important basic precautions in [Precautions]”)
2) *Acute severe hepatitis (incidence unknown), liver dysfunction (0.24%), jaundice (incidence unknown): Severe hepatitis such as acute severe hepatitis, liver dysfunction with significant increases in AST (GOT), ALT (GPT), ALP, γ-GTP, LDH, bilirubin, etc., and jaundice may occur, and liver function tests should be performed frequently and observed adequately. If abnormalities are found, discontinue administration and dispose of the drug appropriately. (See “2. Important basic precautions in [Precautions]”)
(3) Thrombocytopenia (0.08%) and granulocytopenia (incidence unknown): Thrombocytopenia and granulocytopenia may occur, and frequent blood tests should be performed and adequately observed. When abnormalities are detected, discontinue administration and dispose of them appropriately. (See “2. Important basic precautions of [Precautions]”)
(4) Disseminated intravascular coagulation syndrome (DIC) (0.08%): Disseminated intravascular coagulation syndrome may occur, and periodic hematological examination should be performed. When hematologic manifestations of diffuse intravascular coagulation syndrome are suspected, drug administration should be discontinued and appropriate disposition should be made.
(5) Acute lung injury (incidence unknown): Acute lung injury with fever, cough, dyspnea, and abnormal chest X-ray may occur. The patient’s status should be fully observed, and when the above symptoms appear, the drug administration should be discontinued and proper treatment such as adrenocorticotropic hormone drugs should be given.
(6) Rhabdomyolysis (incidence unknown): rhabdomyolysis can occur and should be fully observed. When myalgia, weakness, elevated CK (CPK), elevated myoglobin in blood and urine are found, drug administration should be discontinued and proper disposition should be made.
(7) Shock and anaphylactic reactions (incidence unknown): Shock and anaphylactic reactions (urticaria, decreased blood pressure, dyspnea, etc.) may occur and should be fully observed.
(2) Other adverse reactions
Incidence
(Type 0.1 to <5%<0.1% incidence unknown allergy note) * rash flushing, swelling.
herpes, pruritus erythema (polymorphous exudative erythema, etc.) Blood erythrocytopenia, leukocytosis, leukopenia, decreased erythrocyte pressure product value, decreased hemoglobin, increased platelets, decreased platelets Injection site* Injection site rash, injection site redness, swelling Liver* Elevated total bilirubin, positive urobilinogen, elevated AST (GOT), elevated ALT (GPT), elevated LDH elevated ALP, elevated gamma-GTP bilirubinuria Renal* elevated BUN, elevated serum uric acid, proteinuria, hematuria, elevated creatinine lowered serum uric acid polyuria Digestive* nausea, vomiting Other* fever, elevated serum cholesterol, elevated triglycerides, decreased serum total protein, elevated CK (CPK), decreased CK (CPK), decreased serum potassium, elevated serum potassium, positive urine glucose Heat sensation, elevated blood pressure, decreased serum cholesterol, decreased serum calcium, headache *Incidence is based on clinical trials in patients with acute cerebral infarction, post-approval findings and clinical trials in patients with amyotrophic lateral sclerosis (ALS).
(Note) This condition should be handled appropriately by measures such as discontinuation of drug administration.
[Contraindicated].
(1) Patients with severe renal dysfunction [Risk of worsening renal dysfunction. See [Precautions] in 2-(3) for patient use].
(2) Patients with a previous history of hypersensitivity to the ingredients of this product.
Precautions]
1. Use with caution (this product should be used with caution in the following patients)
(1) Patients with renal dysfunction and dehydration [May cause acute renal insufficiency or worsening of renal dysfunction. In particular, several fatal events have been reported in patients with high BUN/creatinine ratios prior to administration. (See “2
. Important Basic Precautions”)]
(2) Infected patients [Deterioration of systemic status may lead to worsening acute renal insufficiency or renal dysfunction. (See “2. Important Basic Precautions”)]
(3) Patients with liver dysfunction [There is a risk of worsening liver dysfunction. (See “2. Important Basic Precautions”)]
(4) Patients with heart disease [Risk of worsening heart disease and risk of renal dysfunction]
(5) Patients with severe disorders of consciousness (Japan Coma Scale 100 or higher: unable to wake up after stimulation) [There have been more reports of fatal events. (See “2. Important Basic Precautions”)]
(6) Elderly [More fatal events have been reported. (See “2. Important Basic Precautions”)]
2. Important Basic Precautions
(1) The drug should be administered under the supervision of a physician who has adequate knowledge of the product and experience in the treatment of the indication.
(2) Information such as adverse reactions to this product should be fully explained to the patient or patient’s representative at the time of administration.
(3) Acute renal insufficiency or worsening renal dysfunction, severe hepatic dysfunction, and disseminated intravascular coagulation (DIC) can occur, resulting in fatal consequences. There are reports of critical cases of simultaneous renal dysfunction, hepatic dysfunction, and hematologic disorders in these cases.
(1) Since the rapid deterioration of test values is mostly seen at the beginning of dosing, renal function tests such as BUN, creatinine, AST (GOT), ALT (GPT), LDH, CK (CPK), red blood cells, platelets, etc., liver function tests and hematological tests should be performed before or as soon as possible after the start of dosing. Renal function tests, liver function tests and hematological tests should also be performed frequently during the administration of this product. If abnormal test values or manifestations such as oliguria are detected, the drug administration should be discontinued immediately and proper disposal should be carried out. Adequate observation should also be continued after drug administration.
2) In patients with a dehydrated state with a high BUN/creatinine ratio prior to drug administration, more fatal events have been reported, and systemic management should be carried out thoroughly at the time of drug administration.
3) In patients with amyotrophic lateral sclerosis (ALS), myasthenia gravis may be accompanied by a decrease in serum creatinine values as the disease progresses, so serum creatinine values at individual time points should not be compared to baseline values, but rather the passage of changes in serum creatinine values should be determined to confirm the presence of a worsening trend. In addition, since the BUN value may change according to the water content in the body and other factors, the BUN value at a single time point should not be compared with the baseline value, but the change in the BUN value should be confirmed and the tendency of deterioration should be confirmed.
4)
In patients with myasthenia gravis, tests such as estimation of glomerular filtration rate by serum cystatin C and calculation of creatinine clearance by cisternuria should be added to the measurement of serum creatinine value/BUN value before and periodically during the administration of the drug, and evaluation of renal function that is not easily affected by muscle mass should be performed.
(5) If renal dysfunction occurs during drug administration, discontinue drug administration immediately and dispose of it appropriately under the guidance of a physician with extensive knowledge and experience in treatment.
6) If complications such as infection occur during the course of administration and require the combination of antibiotics, careful consideration should be given to whether the administration can be continued, and special attention should be paid to conducting frequent examinations when the administration is continued. In addition, frequent check-ups should be performed after the end of drug administration for adequate observation. (See [Drug Interactions])
7) There have been many reports of fatal events in patients with co-infections and severe disorders of consciousness (Japan Coma Scale 100 or higher), so risks and benefits should be fully considered when administering the drug.
8) More fatalities have been reported, especially in the elderly, and care should be taken.
3. Precautions for care and use
(1) In order to maintain the stability of the preparation, the packaging system is equipped with oxygen absorbers, do not open the secondary packaging of plastic bags before use. If the secondary package is opened, it should be used within 24 hours.
(2) Do not use when the color of the oxygen indicator configured in the secondary package turns to a color other than pink.
(3) Avoid mixing with high energy infusions, amino acid preparations or dripping via the same route (mixing may result in a decrease in edaravone concentration).
(4) Avoid mixing with antitussive injections (diazepam, phenytoin sodium, etc.) (white turbidity can be produced).
(5) Avoid mixing with potassium canrenoate (can produce white turbidity).
4. Other precautions
In a 28-day toxicity test of 24-hour continuous intravenous infusion in dogs, signs of limited limb movement, abnormal gait, and degeneration of peripheral nerves and spinal cord (dorsal cord) nerve fibers seen on histopathological examination were observed at a dose of >60 mg/kg/day.
Pregnant women and nursing mothers
(1) Do not use this product during pregnancy or in women with the possibility of pregnancy (the safety of use during pregnancy is not known).
(2) Women who are breastfeeding should not breastfeed during the use of this product (the distribution of this product to breast milk has been reported in animal studies (rats)).
[Pediatric use].
The safety of the drug in children has not been established (ALS: no experience with the drug).
Geriatric use]
In general, the physiological functions of the elderly are reduced, and when adverse reactions occur, the administration of the drug should be discontinued and appropriate treatment should be carried out. In particular, a large number of fatalities have been reported in the elderly and should be noted. (See “2. Important Basic Precautions” in “Precautions”)
Drug interactions]
Precautions for combined use of drugs
Drug name and other clinical symptoms, measures and methods mechanism, risk factors Antibiotics
(Cefazolin sodium, cefotiam hydrochloride, piperacillin sodium, etc.) There is a risk of worsening renal dysfunction, and frequent renal function tests should be performed when combining drugs for adequate observation. (See “2. Important basic precautions in [Precautions]”.) The mechanism is not clear, but since this product is mainly excreted by the kidneys, there is a possibility of increasing the renal burden when combined with renal excretory antibiotics. [Drug overdose].
It is not clear.
Clinical trials
No trial has been conducted to confirm the effect of this product on survival.
1. Placebo-controlled double-blind comparative trial (2nd validation trial)
Patients with ALS (“definite” or “likely” according to El Escorial’s revised Airlie House diagnostic criteria, ALS severity class 1 or 2, 80% or more forceful spirometry (%FVC) and duration of disease <2 years) were given 60 mg of this product or placebo intravenously for 6 courses*, and the main evaluation items were The amount of change in the revised ALS Functional Rating Scale (ALSFRS-R) is shown in Table 1, with statistically significant differences between the dosing groups.
Table 1 Amount of change in ALSFRS-R scores
Number of cases evaluated in the dosing groupa) ALSFRS-R scoreb) Amount of change d) e) Comparison with the placebo groupe) Course 1
At final evaluation before starting dosing c) Difference between groups [95% confidence interval] p-value Placebo group 6641.9±2.235.0±5.6-7.50±0.662.49
[0.99, 3.98]0.0013 The present group 6841.9±2.537.5±5.3-5.01±0.64a) End of course 3 cases (cases arriving 81 days after the start of dosing) were evaluated
b) Mean ± standard deviation
c) 2 weeks after the end of the 6th course of administration or at discontinuation (LOCF)
d) Adjusted mean ± standard error
e) Based on an ANOVA model with the dosing group, the amount of change in ALSFRS-R score during the previous observation period, El Escorial revised Airlie House diagnostic criteria and age as factors
2. Placebo-controlled double-blind comparative trial (1st validation trial)
Patients with ALS (“definite”, “likely” or “likely-laboratory-supported” according to the El Escorial Revised Airlie House diagnostic criteria, ALS severity class 1 or 2, %FVC of 70% or more, duration of disease <3 years) were given 60 mg of this product or placebo intravenously for 6 courses of treatment*. The amount of change in the main evaluation item ALSFRS-R is shown in Table 2, and no statistically significant differences were seen between the administration groups.
Table 2 Amount of change in ALSFRS-R scores
Number of cases evaluated in the drug administration groupa) ALSFRS-R scoresb) Amount of changed) e) Comparison with placebo groupe) Course 1
Before starting dosing Final
At evaluation c) Difference between groups [95% confidence interval] p-value Placebo group 9941.1±2.935.1±7.4 -6.35±0.840.65
[-0.90, 2.19]0.4108 This product group 10040.5±3.535.3±7.1-5.70±0.85a) End of course 3 cases (cases arriving 81 days after the start of dosing) were evaluated
b) Mean ± standard deviation
c) 2 weeks after the end of the 6th course of administration or at discontinuation (LOCF)
d) Adjusted mean ± standard error
e) ANOVA model based on the amount of change in ALSFRS-R scores, initial symptoms (bulbar symptoms/extremity symptoms), and the combination of riluzole as factors for the drug administration group, the previous observation period
3. A placebo-controlled double-blind comparison trial in patients with ALS severity class 3
The amount of change in ALSFRS-R, the main evaluation item, is shown in Table 3.
Table 3 Amount of change in ALSFRS-R scores
Number of cases evaluated in the drug administration groupa) ALSFRS-R scoreb) Amount of change d) e) Comparison with the placebo groupe) Course 1
At final evaluation before starting dosing c) Difference between groups [95% confidence interval] p value Placebo group 1234.6±3.329.2±4.9 -6.00±1.83-0.52
[-5.62, 4.58] 0.8347 This product group 1332.5±5.526.6±9.9-6.52±1.78 a) End of course 3 cases (cases arriving 81 days after the start of dosing) were evaluated
b) Mean ± standard deviation
c) 2 weeks after the end of the 6th course of administration or at discontinuation (LOCF)
d) Adjusted mean ± standard error
e) Analysis of variance model based on the amount of change in ALSFRS-R scores as a factor in the dosing group and the previous observation period
※
Once-daily administration for 14 consecutive days and its subsequent 14-day discontinuation period were used as course 1, and after course 1, the course consisting of once-daily administration for a total of 10 days out of 14 days and its subsequent 14-day discontinuation period was repeated five times (courses 2 to 6).
Pharmacology and Toxicology
Pharmacological effects
The mechanism of action of edaravone in the treatment of amyotrophic lateral sclerosis (ALS) is unclear.
Toxicological studies
Genotoxicity
The results of Ames test, in vitro Chinese hamster lung cell chromosome aberration test and in vivo bone marrow micronucleus test of edaravone were negative.
Reproductive toxicity
No effect on fertility was observed in male rats given edaravone 3, 20 and 200 mg/kg intravenously from pre-mating to mating period and in female rats from pre-mating to day 7 of gestation, but prolonged estrous cycle and reduced mating rate were observed in the higher dose group. The no-effect dose for reproductive function was 20 mg/kg, which is 3 times the recommended human dose (RHD) of 60 mg based on body surface area (mg/m2).
Edaravone 3, 30 and 300 mg/kg were given intravenously to pregnant rats during the organogenesis period, and all doses resulted in reduced fetal litter weight, with maternal toxicity and reduced offspring weight seen in the high-dose group, and no effect on offspring reproductive function was seen. No effect dose was determined for embryo-fetal developmental toxicity. On a mg/m2 basis, the low dose of 3 mg/kg was lower than the RHD of 60 mg.
In pregnant rabbits given edaravone 3, 20, and 100 mg/kg intravenously during the organogenesis period, embryo/fetal death associated with maternal toxicity was seen in the high dose group. On a mg/m2 basis, the no-effect dose of 20 mg/kg for embryo-fetal developmental toxicity was approximately 6 times the RHD.
In two trials, pregnant rats were given edaravone 3, 20, and 200 mg/kg intravenously from day 17 of gestation to lactation to assess effects on the offspring. In the first trial, offspring mortality was observed at high doses and increased activity at high and medium doses. In the second trial, stillbirths, increased offspring mortality and delayed physical development (vaginal opening) were seen in the group at high doses. In both trials, no effects on offspring reproductive function were seen, and significant maternal toxicity was seen in the high and medium dose groups. The no-effect dose of 3 mg/kg/day for developmental toxicity was lower than RHD on a mg/m2 basis.
[Pharmacokinetics].
Refer to the pharmacokinetics of RADICUT Injection 30 mg
1. Blood concentration
In healthy adult males (5 cases) and healthy elderly people over 65 years of age (5 cases), this product was infused intravenously at a dose of 0.5 mg/kg over 30 minutes twice daily for 2 days. The parameters calculated from the changes in plasma concentrations of the prototype drug and the changes in plasma concentrations of the prototype drug at the time of the first administration are shown below.
(Mean ± S.D.)
Pharmacokinetic parameters Healthy adult males
(5 cases) Healthy elderly
(5 cases) Cmax (ng/ml) 888±1711041±106t1/2α (h) 0.27±0.110.17±0.03t1/2β (h) 2.27±0.801.84±0.17 Plasma concentrations of the prototype were eliminated in the same manner in both healthy adult males and healthy elderly people, and no accumulation was observed.
2. serum protein binding rate
The binding rates of edaravone (5 μM and 10 μM) to human serum protein and human serum albumin were 92% and 89-91%, respectively (in vitro).
3. Metabolism
The major metabolites in the plasma of healthy adult males and healthy elderly were sulfate conjugates, and glucuronide conjugates were also detected. In addition, the major metabolite in urine is glucuronide conjugate, and sulfate conjugate is also seen.
4. Excretion
When administered intravenously (0.5 mg/kg/30 min x 2 doses/day) twice daily for 2 consecutive days to healthy adult males and healthy elderly persons, urinary excretion of the prototype drug was 0.7-0.9% and metabolites were 71.0-79.9% within 12 hours after each dose.
Storage
Store under 25℃ under shade.
Package】
Primary package is polypropylene bag, secondary package is polyvinyl alcohol blister containing oxygen absorber and oxygen indicator; 100ml/bag, 10 bags/box.
Expiration date
36 months
【Execution standard
【Imported drug registration certificate number
【Manufacturer
Licensee’s name: Mitsubishi Tanabe Pharma Corporation
Licensee’s address: 3-2-10, Dosho-machi, Chuo-ku, Osaka 541-8505, Japan
Manufacturer’s name: Terumo Corporation, Kofu Factory
Manufacturer’s address: 1727-1, Tsuijiarai, Showa-cho, Nakakoma-gun, Yamanashi 409-3853, Japan