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25 de jul de 2015

Bula do RADICUT (Edaravona) atualizada para o tratamento da ELA

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 
1)  Yokota S. et al.: Jpn. J. Clin. Pharmacol. Ther. 1997; 28(3): 693-702 
2)  Yamamoto M. et al.: Jpn. Pharmacol. Ther. 1997; 25(Suppl. 7): 1755-1763 ]
3)  Otomo E. et al.: Ther. Res. 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
5)  Otomo E. et al.: Cerebrovasc.Dis. 2003;15: 222-229
6)  Houkin K. et al.: J. Stroke Cerebrovasc. Dis. 1998;7(5): 315-322
7)  Mitsumori K. et al.: Ther. Res. 1998;19(4): 1333-1345
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 
14)  Takamatsu Y. et al.: Jpn. Pharmacol. Ther. 1997; 25(Suppl. 7): 1785-1791 
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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