Mitsubishi
Tanabe Pharma Corporation 1
Revised:
June 2015 (18th version) D15 Standard Commodity Classification No. of
Japan 87119
-
Free radical scavenger - RADICUT Injection 30mg < The Japanese
Pharmacopoeia Edaravone injection > Prescription drug*
*Caution
- Use under the prescription of a physician etc.
CONTRAINDICATIONS
(RADICUT is contraindicated in the following patients.) (1) Patients with severe renal impairment [The
renal im- pairment may be aggravated.
For use in patients with amy- otrophic lateral sclerosis (ALS), see
(3)-3),4) of “Important Precautions” section.] (2) Patients with a history of hypersensitivity
to any of the ingredients of this product
DESCRIPTION
Active ingredient [in each ampoule (20 mL)] Edaravone (JP) 30 mg
Inactive
ingredients [in each ampoule (20 mL)]
Sodium
bisulfite 20 mg L-cysteine hydrochloride
hydrate 10 mg Sodium chloride 135 mg Sodium hydroxide q.s. Phosphoric acid q.s.
Description/ Dosage form
Clear
and colorless / aqueous solution for injection
pH
3.0 – 4.5 Osmotic pressure ratio ca. 1 (ratio to physiological saline)
INDICATIONS
1. Improvement of neurological symptoms, disorder
of activities of daily living, and functional disorder associated with acute
ischaemic stroke
2. Inhibition
on progression of functional disorder in patients with amyotrophic lateral
sclerosis (ALS)
<Precautions
related to INDICATIONS> Use in patients with amyotrophic lateral sclerosis
(ALS)
1. When this
product is administered, the patient’s eligibility should be assessed after
investigating background such as Japan ALS severity classification, respiratory
function of patients included in clinical trials and the result of each
clinical trial and understanding the efficacy and safety of this product. (See
“Clinical Studies” section.)
2. The
efficacy and safety of this product in patients with Japan ALS severity
classification of grade 4 or above and patients with forced vital capacity less
than 70% of theoretical normal value have not been established, since there is
little clinical experience in such patients.
Administration of this product in such patients should be judged
carefully in consideration of risks and benefits.
DOSAGE
AND ADMINISTRATION
1.
Improvement of neurological symptoms, disorder of activities of daily living,
and functional disorder associated with acute ischaemic stroke The usual adult
dosage is one ampoule (30 mg of edaravone) diluted with an appropriate volume
of physiological saline, etc., which is administered intravenously over 30
minutes twice a day in the morning and the evening. Administration of this
product should be initiated within 24 hours after the onset of the disease, and
the duration of ad- ministration should be within 14 days.
2. Inhibition
on progression of functional disorder in patients with amyotrophic lateral
sclerosis (ALS) The usual adult dosage is two ampoules (60 mg of edaravone)
diluted with an appropriate volume of physiological saline, etc., which is
administered intravenously over 60 minutes once a day. Usually, the duration of
administration and cessation of this product are combined in one cycle of
treatment for 28 days and the cycle should be repeated. This product is consecu- tively infused for
14 days in the duration of administration followed by cessation for 14 days in
the 1st cycle, and from the 2nd cycle, this product is infused for 10 of 14
days in the duration of administration followed by cessation for 14 days.
<Precautions
related to DOSAGE AND ADMINISTRATION > Use in patients with acute ischaemic
stroke It should be considered that the duration of administration is
Storage
Store at room temperature.
Expiration
date Do not use after the expiration date in- dicated on the package and the
label.
Approval
No. 21300AMZ00377000 Date of listing in the NHI reimbursement price June 2001
Date of initial marketing in Japan June 2001 International birth date April
2001 Date of latest reexamination March 2011 Date of latest additional
indication June 2015
2
Mitsubishi Tanabe Pharma Corporation
reduced
according to the patient’s clinical condition.
PRECAUTIONS
1. Careful Administration (RADICUT should be
adminis- tered with care in the following patients) (1) Patients with renal impairment and/or
dehydration [Acute renal failure or renal impairment may be aggravated. Especially in the patients with high
BUN/creatinine ratio before administration, its fatal outcome has been
reported. (See “Important Precautions”
section.)] (2) Patients with infections
[Acute renal failure or renal im- pairment may be aggravated due to the
deterioration of systemic conditions. (See
“Important Precautions” sec- tion.)] (3)
Patients with hepatic impairment [Hepatic impairment may be
aggravated. (See “Important Precautions”
sec- tion.)] (4) Patients with cardiac
diseases [Cardiac diseases may be aggravated.
Renal impairment may occur as well.] (5)
Patients with severe disturbance of consciousness (i.e. with Japan Coma
Scale score of ≥ 100, in which state pa- tients do not awake to the external
stimulation) [Fatal outcome has been reported in these patients. (See “Im- portant Precautions” section.)] (6) Elderly patients [Fatal outcome has been
reported in these patients. (See
“Important Precautions” section.)]
2. Important Precautions (1)
This product should be administered in
liaison with a well-trained physician, who is well aware of this product and
has enough experience treating for the disease indi- cated. (2) Prior to the administration of this product,
enough ex- planation of the adverse reactions, etc. should be given to the
patient or their appropriate proxy consenter on behalf of the patient. (3) After administration, aggravation of acute renal
failure or renal impairment, severe liver disorder, and/or dissemi- nated
intravascular coagulation (DIC), which can be fatal, may be observed. Among these patients, serious cases
concurrently developing renal impairment, hepatic im- pairment, and/or
hematological disorders, etc., have been reported. 1)
Laboratory tests for renal, hepatic function and blood cell counts
should be performed in order to detect early changes in BUN, creatinine, AST
(GOT), ALT (GPT), LDH, CK (CPK), red blood cell count and platelet count,
before or immediately after administration, since the la- boratory data may
deteriorate at the early stage of admin- istration in most cases. During administration, the labor- atory tests
should be performed frequently. If
abnormal laboratory data and/or symptoms such as oliguria are found, this
product should be immediately discontinued and appropriate therapeutic measures
should be taken. Careful monitoring
should be continued after the discon- tinuation of this product as well. 2)
Patients with dehydration before administration, showing high
BUN/creatinine ratio or other signs, should be care-
fully
monitored systemically during administration, since fatal outcome has been
reported in these patients. 3) Decreased serum creatinine due to muscle atrophy
may occur in association with the disease progression in patients with
ALS. Therefore, time course of serum
creatinine level should be monitored to detect deteriorating tendency, instead
of comparing serum creatinine value at single point in time with reference
value. Since BUN level may fluctuate
according to water amount in the body, time course of BUN level should be
monitored to detect deteriorating tendency, instead of comparing BUN value at
single point in time with reference value.
4) In patients with muscle atrophy, renal function evaluation unlikely
to be affected by muscle mass should be performed periodically before and
during the treatment such as estimated glomerular filtration rate (eGFR) based
on serum cystatin C level, calculation of creatinine clearance by urine
collection, in addition to measurement of serum creatinine and BUN. 5)
This product should be immediately discontinued and appropriate
therapeutic measures should be taken, in li- aison with a physician with enough
knowledge and expe- rience treating for renal failure, when renal impairment
occurs during administration. 6) It should be carefully considered whether to
continue the administration of this product or not, when an antibiotic is
coadministered for the treatment of infections during the administration of
this product. If the administration is
continued, laboratory data should be monitored more frequently. After the administration the patient should
also be carefully monitored by the frequent laboratory data monitoring. (See “Drug Interactions” section.) 7) In
the patients with infections or with severe disturbance of consciousness (i.e.
with Japan Coma Scale score of ≥ 100) many fatal cases have been reported. Therefore the risk/benefit evaluation should
be carefully carried out for these patients.
8) The elderly patients should be
monitored carefully, since many fatal outcomes have been reported in the
patients.
3. Drug Interactions
Precautions for
coadministration (RADICUT should be administered with care when coadministered
with the following drugs) Drugs Signs, Symptoms, and Treatment Mechanism
and Risk Factors Antibiotics (Cefazolin
so- dium, cefotiam hydrochloride, piperacillin so- dium, etc.) The patients
should be carefully monitored and renal function tests should be performed
frequently in the con- comitant use of the an- tibiotics, since renal
impairment may be aggravated. (See
“Important Precau- tions” section.) Mechanism is un- known. As this product is mainly ex- creted by the
kidney, concomitant use of renally eliminated antibiotics may aug- ment the
loads of kidney.
Mitsubishi Tanabe Pharma Corporation 3
4. Adverse Reactions
Acute ischaemic stroke Clinical trials for
NDA conducted in Japan (Data available at the time of approval) Thirty adverse
reactions due to this product were reported in 26 of 569 patients (4.57%). The main adverse reactions were 16 events of
hepatic dysfunction (2.81%) and 4 events of rash (0.70%). Also, abnormal changes in laboratory test
values were reported in 122 of 569 patients (21.4%). The major abnormal changes were abnormal
liver function test with increased AST (GOT) in 43 of 558 patients (7.71%) and
increased ALT (GPT) in 46 of 559 patients (8.23%). Post-marketing surveys (Data
available at the end of reexamination
period) In the drug use-result survey, 709 adverse reactions due to this
product were reported in 431 of 3,882 patients (11.10%). The main adverse reactions were 160 events of
liver disorder/abnormal hepatic function (4.12%), 79 events of increased AST
(GOT) (2.04%), 59 events of in- creased ALT (GPT) (1.52%), 34 events of
increased LDH (0.88%), 33 events of increased γ-GTP (0.85%), 24 events of
increased ALP (0.62%), and 22 events of renal im- pairment (0.57%). In the
post-marketing clinical study, 30 adverse reac- tions due to this product were
reported in 20 of 194 patients (10.31%).
The main adverse reactions were 5 events of liver disorder/abnormal
hepatic function (2.58%), 2 events of insomnia (1.03%), and 2 events of pyrexia
(1.03%). Also, abnormal changes in
laboratory test values were re- ported in 52 of 194 patients (26.8%). The major abnormal changes were 17 events of
increased AST (GOT) (8.67%), 12 events of increased ALT (GPT) (6.19%), 10 events of increased serum uric
acid (5.15%) and 9 events of in- creased creatinine (4.64%). In the specified
drug use survey in pediatric patients with ischaemic stroke, 6 adverse
reactions due to this product were reported in 5 of 118 patients (4.24%). The
main adverse reactions were 4 events of liver disor- der/abnormal hepatic
function (3.39%). Amyotrophic lateral sclerosis (ALS) Clinical trials for NDA
conducted in Japan (Data available at the time of approval of additional
indica- tion) Forty six adverse reactions due to this product were re- ported
in 37 of 317 patients (11.7%). The main
adverse reactions were 4 events of rash (1.3%), 4 events of liver disorder
(1.3%), 3 events of hypertension (0.9%), 3 events of increased γ-GTP (0.9%),
and 3 events of glucose urine present (0.9%). (1)
Clinically significant adverse reactions
1)
Acute renal failure (0.26%), nephrotic syndrome (0.02%): Renal function tests
should be performed fre- quently and patients should be monitored carefully,
since acute renal failure or nephrotic syndrome may occur. This product should be discontinued and
appropriate therapeu- tic measures should be taken, when decreased renal func-
tion and/or the symptoms of oliguria, etc. are found. (See “Important Precautions”
section.)
2) Fulminant hepatitis (incidence unknown),
hepatic dysfunction (0.24%), jaundice (incidence unknown): Liver function tests
should be performed frequently, and patients should be monitored carefully,
since severe hep- atitis including fulminant hepatitis, hepatic dysfunction or
jaundice with significant increase in AST (GOT), ALT (GPT), Al-P, γ-GTP, LDH,
blood bilirubin, etc. may oc- cur. This product should be discontinued and
appropriate therapeutic measures should be taken when any abnor- malities are
found. (See “Important Precautions” section.)
3) Thrombocytopenia (0.08%), granulocytopenia
(inci- dence unknown): Hematological tests should be per- formed frequently and
patients should be monitored carefully, since thrombocytopenia or
granulocytopenia may occur. This product
should be discontinued and ap- propriate therapeutic measures should be taken,
when any abnormalities are found. (See “Important Precautions” section.)
4) Disseminated intravascular coagulation
(DIC) (0.08%): Hematological tests should be performed peri- odically, since
DIC may occur. This product should be
discontinued and appropriate therapeutic measures should be taken, when any
abnormalities in hematological tests or symptoms suspicious of DIC are found.
5) Acute lung injury (incidence unknown):
Patients should be monitored carefully, since acute lung injury with py- rexia,
cough, dyspnoea and chest X-ray abnormality may occur. This product should be discontinued and
appro- priate therapeutic measures, including administration of corticosteroids,
should be taken, when any signs of acute lung injury are found.
6) Rhabdomyolysis (incidence unknown):
Patients should be monitored carefully, since rhabdomyolysis may occur. This product should be discontinued and
appropriate therapeutic measures should be taken, when myalgia, weakness,
increased CK (CPK) and increased blood and/or urine myoglobin are found.
7) Shock, anaphylactoid reaction (incidence
unknown, each): Patients should be monitored carefully, since shock and
anaphylactoid reactions (urticaria, blood pressure decreased and dyspnoea,
etc.) may occur. This product should be
discontinued and appropriate therapeutic measures should be taken, when any
abnormalities are found. (2) Other adverse reactions Incidence Type 5%
> ≥0.1% 0.1% > Incidence unknown
Hypersen- sitivity note) Rash Redness, swelling, wheals, pru- ritus Erythema
(erythema multiforme exsuda- tivum, etc.) Hemato- logic Decreased red blood
cell count, increased white blood cell count , decreased white blood cell count
, decreased haematocrit, decreased hae- moglobin, increased platelet count,
decreased platelet count
4
Mitsubishi Tanabe Pharma Corporation
Injection
site
Injection site rash, injection site redness
and swelling Hepatic Increased total
bilirubin, urobilinogen appeared, in- creased AST (GOT), in- creased ALT (GPT),
in- creased LDH, increased Al-P, increased γ-GTP Bilirubinuria Renal Increased BUN, increased serum uric
acid, proteinuria, haematuria, increased creati- nine Decreased serum uric acid
Polyuria Gastroin- testinal Nausea ,
vomiting Others Pyrexia, increased serum
cholesterol, increased tri- glyceride, decreased serum total protein, increased
CK (CPK), decreased CK (CPK), decreased serum potassium, increased serum
potassium, glucose urine present Feeling hot, increased blood pres- sure, de-
creased serum cholesterol, decreased serum calci- um, headache The incidences were calculated based on the
results of clinical studies in patients with acute ischaemic stroke conducted
in Japan, post-marketing surveys, and clinical studies in patients with ALS
conducted in Japan (at the time of approval of additional indication). Note
Appropriate therapeutic measures such as discontinuation of this product should be taken, when these
symptoms listed above occur.
5. Use in the Elderly
In elderly patients, this
product should be discontinued and appropriate therapeutic measures taken when
any adverse reactions are found, since they often have reduced physio- logical
function. Special caution should be
exercised in the elderly patients, since many fatal cases have been reported in
these patients. (See “Important Precautions” section.)
6. Use during Pregnancy, Delivery or
Lactation (1)
RADICUT is not recommended
to be administered to pregnant women or women who may possibly be pregnant.
[The safety of the product in pregnant women has not been established.] (2) Lactation should be prohibited during
administration of this product. [Animal studies in rats have shown that edaravone
is excreted in breast milk.]
7.
Pediatric Use
The safety of RADICUT in children has not
been estab- lished (acute ischaemic stroke: little clinical experience,
amyotrophic lateral sclerosis [ALS]: no clinical experience).
8. Precautions concerning Use (1) Precautions when opening the
ampoule: This product is supplied in a
“one-point-cut ampoule”. Break the
ampoule while pulling its neck downward with the round mark frontal. To avoid contamination with for- eign
substances upon cutting ampoule, the cut point of the
ampoule
should be wiped with an alcohol swab before opening. (2) Precautions in preparation 1) As a general rule, this product should be
diluted with physiological saline (if the product is mixed with any infusion
fluids including various saccharides, the con- centration of edaravone may
decrease with time). 2) This product
should not be mixed with total parenteral nutrition preparations and/or
amino-acid infusions be- fore administration (if the product is mixed with
them, the concentration of edaravone may decrease with time). 3) This product should not be mixed with
infusions of an- ticonvulsants including diazepam, phenytoin sodium, etc. (the
solution may become cloudy). 4) This
product should not be mixed with potassium canrenoate (the solution may become
cloudy).
9. Other Precautions (1) It has been reported that cerebral
embolism reoccurred or cerebral haemorrhage occurred during or after
administra- tion of this product. (2) In
a 28-days continuous intravenous infusion study in dogs, symptomatic changes,
such as limited usage of limbs, ab- normal gait, etc., and pathological nerve
fibre degeneration in the peripheral nerves and spinal cord (dorsal funiculus)
were observed at the doses of edaravone of 60 mg/kg/day and above.
PHARMACOKINETICS
1. Plasma concentration1)
The profiles of plasma unchanged drug
concentration after multiple intravenous doses (0.5 mg/kg) over 30 minutes
twice a day for 2 days to 5 healthy male adults and 5 healthy elderly males
aged 65 years or more are illustrated in the following figures and
pharmacokinetic parameters calcu- lated from the profiles in plasma unchanged
drug concen- tration after the initial dose are provided in the following
table. (Note) The approved dose of this product is 30 mg per one time for use
in patients with acute ischaemic stroke and 60 mg per one time for use in
patients with amyotrophic lateral sclerosis (ALS).
(ng/mL)
Measured
value, –Calculated value mean±S.D. (n=5)
Administration
Healthy
male adults
Time
(h)
Plasma
unchanged drug concentration
Mitsubishi Tanabe Pharma Corporation 5
(ng/mL)
（Mean
± S.D.）
Pharmacokinetic parameter
Healthy
male adults (n=5)
Healthy
elderly males (n=5) Cmax (ng/mL) 888±171
1041±106 t1/2α (h) 0.27±0.11 0.17±0.03 t1/2β (h) 2.27±0.80 1.84±0.17
The plasma unchanged drug concentration
disappeared in both healthy adults and elderly males in the almost same way
without any signs of accumulation.
2. Serum protein binding rates2) 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. Metabolism1)
The major metabolite in healthy male adults and healthy elderly males
was sulfate conjugate in plasma, and glucu- ronide conjugate was also detected
in plasma. In urine, the major
metabolite of the product was glucuronide conjugate and sulfate conjugate was
also detected.
4. Excretion1)
After repeated intravenous administration of this product to healthy
male adults and healthy elderly males twice a day for 2 days (0.5 mg/kg/30
minutes X 2 times/day), 0.7-0.9% and 71.0-79.9% of the dose were recovered as
unchanged drug and metabolites in urine, respectively, up to 12 hours after
each dose. (Note) The approved dose of this product is 30 mg per one time for
use in patients with acute ischaemic stroke and 60 mg per one time for use in
patients with amyotrophic lateral sclerosis (ALS).
CLINICAL
STUDIES
1. Acute ischaemic stroke3-7) In a placebo-controlled, double-blind
study in patients with the acute ischaemic stroke within 72 hours after
onset*1, some improvement in neurological symptoms and impaired activi- ties of
daily living were reported in the edaravone group. A difference in the improvement rate for
final global im- provement rating was 32.8% (95% confidence interval:
20.3-45.3%), showing a significant difference between the edaravone group and
the placebo group by the rank-sum test.
In the subjects administered within 24 hours after onset, the difference
in the improvement rate for final global im- provement rating was 48.2% (95%
confidence interval: 26.6-69.7%). Final
global improvement rate (improved or higher) in all subjects and that in the
group administered within 24 hours after onset are shown in Table 1. Table 1:
Proportion of subjects assessed as improved or higher in final global
improvement rate Edaravone group Placebo
group All subjects adminis- tered within 72 hours after onset 64.8% (81/125
subjects) 32.0% (40/125 subjects) Subjects administered within 24 hours after
onset 73.8% (31/42 subjects) 25.6% (10/39 subjects)
Furthermore,
the rank-sum test showed a significant difference between the edaravone group
and the placebo group, in func- tional prognosis (modified Rankin Scale)
assessed in all subjects upon discharge from the hospital within 3 months
(after 3 months if hospitalized for 3 months or more) and the edaravone group
surpassed the placebo group in the rate of “no symptom” (edaravone group: 22.3%
(27/121 subjects), placebo group: 10.0% (12/120 subjects). In the subjects administered within 24 hours
after onset, “no symptom” accounted for 34.1% (14/41 subjects) in the edaravone
group and 2.9% (1/35 subjects) in the placebo group. In both groups,
concentrated glycerol and fructose were coad- ministered as basal therapy. All
clinical data generated before approval including the above results
demonstrated more pronounced effect in subjects ad- ministered within 24 hours
after onset. It was endorsed by the fact that the improvement rate (improved or
higher) on global improvement rating in subjects administered 30 mg of edara-
vone within 24 hours after onset was 70.3% (71/101 subjects), but that in the
subjects treated within 72 hours*1 was 65.9% (178/270 subjects). *1 The
clinical studies at the developmental stage were mainly conducted in patients
with acute ischaemic stroke who were hospitalized within 72 hours after
onset. Although the sta- tistical
analysis conducted in all the subjects showed effi- cacy, its stratified
analysis revealed a more pronounced ef- fect in patients treated within 24
hours after onset. Ac- cordingly, the
approved dosage and administration states “treatment should be initiated within
24 hours after onset”. (Note) Excerpts from the approved dosage and administra-
tion of this product: Administration of this product should be initiated within
24 hours after the onset of the disease, and the duration of administration
should be within 14 days.
2. Amyotrophic lateral sclerosis (ALS)
This product
has not been evaluated in a study which can clarify the effect of the drug on
survival. (1) A placebo-controlled
double-blind comparative study (the 2nd
confirmatory study) 8) When edaravone or placebo was intravenously administered
at 60 mg in patients with ALS (warranting “Definite” or “Probable” according to
the El Escorial and the revised
Measured
value, –Calculated value mean±S.D. (n=5)
Administration
Healthy
elderly males
Time
(h)
Plasma
unchanged drug concentration
6
Mitsubishi Tanabe Pharma Corporation
Airlie
House diagnostic criteria for ALS, rated as grade 1 or 2 in Japan ALS severity
classification, having forced vital capacity (%FVC) not less than 80% and
illness duration within 2 years) in 6 cycles of treatment*2, mean changes from
baseline in the revised ALS functional rating scale (ALSFRS-R) as primary
endpoint were shown in Table 2 and statistically significant difference was
observed between the treatment groups. Table 2: Mean changes from baseline in
ALSFRS-R score
No.
of cases evaluateda)
ALSFRS-R
scoresb)
Mean
change from baselined),e)
Comparison
with placebo groupe)
Before
the 1st cycle
At
the final evaluationc)
Difference
between groups [95% CI]
P
value
Placebo
group
66
41.9±2.2 35.0±5.6 -7.50±0.66
2.49
[0.99, 3.98] 0.0013 Edara vone group 68 41.9±2.5 37.5±5.3 -5.01±0.64 a) The
cases completed the 3rd cycle (reached Day 81 after treatment initiation) were evaluated. b) Mean ± SD c)
At the time of 2 weeks after the 6th cycle completion or discontinuation of treatment (LOCF) d) Adjusted mean change ±
SE e) Based on a model of analysis of variance with treatment groups, mean changes in ALSFRS-R scores in run-in period,
the El Escorial and the revised Airlie House diagnostic criteria for ALS, and
age as factors (2) A placebo-controlled
double-blind comparative study (the 1st
confirmatory study) 9) When edaravone or placebo was intravenously administered
at 60 mg in patients with ALS (warranting “Definite”, “Probable” or
“Probable-laboratory-supported” according to the El Escorial and the revised
Airlie House diagnostic criteria for ALS, rated as grade 1 or 2 in Japan ALS
severity classification, having forced vital capacity (%FVC) not less than 70%,
and illness duration within 3 years) in 6 cycles of treatment*2, mean changes
from baseline in the revised ALS functional rating scale (ALSFRS-R) as primary
endpoint were shown in Table 3 and statistically significant difference was not
observed between the treatment groups. Table 3: Mean changes from baseline in
ALSFRS-R score
No.
of cases evaluateda)
ALSFRS-R
scoresb)
Mean
change from baselined),e)
Comparison
with placebo groupe)
Before
the 1st cycle
At
the final evaluationc)
Difference
between groups [95% CI]
P
value
Placebo
group
99
41.1±2.9 35.1±7.4 -6.35±0.84
0.65
[-0.90, 2.19] 0.4108 Edara vone group 100 40.5±3.5 35.3±7.1 -5.70±0.85 a) The
cases completed the 3rd cycle (reached Day 81 after treatment initiation) were evaluated. b) Mean ± SD c)
At the time of 2 weeks after the 6th cycle completion or discontinuation of treatment (LOCF) d) Adjusted mean change
± SE e) Based on a model of analysis of variance with treatment groups, mean
changes in ALSFRS-R scores in run-in period,
initial symptoms (bulbar/limb symptom)
and concurrent treatment with Riluzole as factors (3) A placebo-controlled
double-blind comparative study in
patients with Japan ALS severity classification of grade 3 10) When
edaravone or placebo was intravenously administered at 60 mg in patients with
Japan ALS severity classification of grade 3 ALS in 6 cycles of treatment*2,
mean changes from baseline in the revised ALS functional rating scale
(ALSFRS-R) as primary endpoint were shown in Table 4 and statistically
significant difference was not observed between the treatment groups. Table 4:
Mean changes from baseline in ALSFRS-R score
No.
of cases evaluateda)
ALSFRS-R
scoresb)
Mean
change from baselined),e)
Comparison
with placebo groupe)
Before
the 1st cycle
At
the final evaluationc)
Difference
between groups [95% CI]
P
value
Placebo
group
12
34.6±3.3 29.2±4.9 -6.00±1.83
-0.52
[-5.62, 4.58] 0.8347 Edara vone group 13 32.5±5.5 26.6±9.9 -6.52±1.78 a) The
cases completed the 3rd cycle (reached Day 81 after treatment initiation) were evaluated. b) Mean ± SD c)
At the time of 2 weeks after the 6th cycle completion or discontinuation of treatment (LOCF) d) Adjusted mean change ±
SE e) Based on a model of analysis of variance with treatment groups and
mean changes in ALSFRS-R scores in
run-in period as factors
*2:
Once-daily consecutive administration for 14 days and subsequent cessation for
14 days of this product were combined in the 1st cycle of treatment. After completion of the 1st cycle, this
product was administered for 10 of 14 days followed by cessation for 14 days
from the second to sixth cycle (the treatment cycle was repeated 5 times).
PHARMACOLOGY
1. Mechanism of action There have been many reports describing that
free radicals such as hydroxyl radical (·OH) play a major causative role in the
development of cerebral vascular disorder resulting from ischaemia. During ischaemia or ischaemic reperfu- sion,
the hyperactivity of a metabolic system of arachidonic acid, etc. increases the
production of free radicals. These free
radicals peroxidize unsaturated fatty acid of cell mem- brane lipids, which
leads to cell membrane injury and ulti- mately to cerebral dysfunction. Although the etiology of development and
disease progress of amyotrophic lateral sclerosis (ALS) are unknown, a pos-
sible involvement of oxidative stress caused by free radicals is
suggested. This product scavenges free
radicals and inhibits lipid pe- roxidation, and thereby prevents oxidative
damage to brain cells (vascular endothelial cells/nerve cells).
Mitsubishi Tanabe Pharma Corporation 7
In other words, this product protects the
brain in case of acute ischaemic stroke by exerting its inhibitory effects
against the development and progression (exacerbation) of ischaemic cerebral
vascular disorder such as cerebral oe- dema, cerebral infarction, neurological
deficits, and delayed neuronal death. In
case of amyotrophic lateral sclerosis (ALS), this product suppresses the
disease progression by exerting its inhibitory effects against the development
of oxidative damage to nerve cells.
2. Effects against the acute ischaemic
stroke (1) Neuroprotective effect6) NAA (N-acetyl aspartate) is a specific
marker for viable neuronal cells that is reported to decrease immediately after
the onset of ischaemic stroke and be scarcely detected in the injured tissues
after 24 hours. When NAA was determined
by 1H-MRS (magnetic resonance spectroscopy) after ad- ministration of this
product to patients with acute ischaemic stroke, NAA in the center of the
infarct lesion was signifi- cantly retained on the 28th day after onset as
compared to the control group. (2)
Inhibitory effect against a reduction in regional blood flow in the ischaemic
penumbra7) When regional cerebral blood
flow was determined by 135Xe-SPECT (single photon emission computerized to-
mography) after administration of this product to patients (n=8) with acute
ischaemic stroke, the product exhibited its inhibitory effect against the reduction
in regional cerebral blood flow in the ischaemic penumbra in 5 patients who
improved in functional outcomes (modified Rankin Scale).
3. Cerebroprotecting effect in a cerebral
ischaemia mod- el11-16) (1) Effects of
inhibiting cerebral oedema and ischaemic stroke and of alleviating neurological
deficits In an ischaemic cerebral
vascular disorder model (rat), the intravenous administration of this product
(3 mg/kg) after the occurrence of ischaemia or ischaemic reperfusion sup-
pressed the progression of cerebral oedema and ischaemic stroke and remitted
the following neurological deficits. (2)
Inhibitory effect against delayed neuronal death In a forebrain ischaemic reperfused model
(rat), the intra- venous administration of this product (3 mg/kg) immedi- ately
after ischaemic reperfusion suppressed delayed neu- ronal death.
4. Free radical scavenging
effect11,12,17-19) (1) Free radical
scavenging effect and inhibitory effect against lipid peroxidation (in
vitro) Edaravone exhibited a hydroxyl
radical scavenging effect. It also
inhibited the peroxidation of linoleic acid and the li- pid peroxidation in the
brain homogenate caused by hy- droxyl radical dose-dependently. Furthermore, it inhibited the lipid
peroxidation of artificial phospholipid membrane liposome caused by water- and
fat- soluble peroxyl radicals. (2) Free
radical scavenging effect in a cerebral ischaemia model.
The intravenous administration of this
product at the dose (3 mg/kg) that exhibited a cerebroprotecting effect in a
cerebral ischaemia model (rat) inhibited an increase in hydroxyl radical in the
penumbra of the ischaemia and at the reper- fused region of ischaemia. (3) Inhibitory effect against vascular
endothelial cell injury caused by free radical (in vitro) 1µM or more of this product inhibited
cultured vascular endothelial cell injury in vitro caused by 15-HPETE (hy-
droperoxyeicosatetraenoic acid).
5.
Non-clinical studies related to disease conditions of amyotrophic lateral
sclerosis (ALS)20) In an animal study
using transgenic rats in which mutant superoxide dismutase (known as a
responsible gene for familial ALS), edaravone was intravenously administered at
3 mg/kg/hr over 1 hour for 2 days followed by cessation for 2 days as one-cycle
and the cycle was repeated until loss of righting reflex. The result showed a significant inhibitory
effect on reduction of angle in female rats in an inclined plane test to
evaluate motor function in extremities globally.
PHYSICOCHEMISTRY
Nonproprietary name: Edaravone Chemical name:
5-Methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one Molecular formula:
C10H10N2O Molecular weight: 174.20 Structural formula:
Description: Edaravone occurs as white to pale yellowish
white crystals or crystalline powder. It is freely soluble in ethanol (99.5)
and in acetic acid (100), and slightly soluble in water. Melting point: 127-131
°C
CONDITIONS
FOR APPROVAL A risk management plan
should be prepared and implemented appropriately.
PACKAGING
RADICUT Injection 30 mg: 20 mL × 10 ampoules
REFERENCES
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2)
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1998;19(4): 1311-1332
8
Mitsubishi Tanabe Pharma Corporation
4) MCI-186 Study Group on the Acute Stage of
Cerebral Infarct: J. Clin. Exp. Med. (IGAKU NO AYUMI) 1998;185(11): 841-863
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2003;15: 222-229
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7)
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8) Mitsubishi
Tanabe Pharma Corporation: The second confirmatory study (internal report) 9)
Abe, K. et al.: Amyotroph Lateral Scler Frontotemporal Degener. 2014;15(7-8):
610-617 10) Mitsubishi Tanabe Pharma Corporation: Exploratory studies in
patients with Japan ALS severity classifica- tion of grade 3 (internal report)
11) Mizuno A. et al.: Gen. Pharmacol.
1998;30(4): 575-578
12) Yamamoto T. et
al.: Brain Res. 1997;762: 240-242
13)
Abe K. et al.: Stroke 1988;19(4): 480-485
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15) Kawai
H. et al.: J. Pharmaco. Exp. Ther. 1997;281(2): 921-927
16) Nishi H. et al.: Stroke 1989;20(9): 1236-1240
17) Watanabe T. et al.: Jpn. Pharmacol.
Ther. 1997; 25(Suppl. 7): 1691-1698
18)
Yamamoto Y. et al.: Redox Rep. 1996;2(5): 333-338
19) Watanabe T. et al.: Prostaglandins Leukot.
Essent. Fatty Acids 1988;33(1): 81-87
20) Mitsubishi Tanabe Pharma Corporation:
Effects of MCI-186 in superoxide dismutase (SOD) transgenic rats (amyotrophic
lateral sclerosis model) (internal report)
REQUEST
FOR LITERATURE SHOULD BE MADE TO: Safety Information Department
Pharmacovigilance & Quality Assurance Division Mitsubishi Tanabe Pharma
Corporation 3-2-10, Dosho-machi, Chuo-ku, Osaka 541-8505, Japan
Manufactured
and Distributed by : Mitsubishi Tanabe Pharma Corporation 3-2-10, Dosho-machi,
Chuo-ku, Osaka 541-8505, Japan
This
document is an English translation of the Japanese package insert.
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