日本の再評価制度と漢方薬の安全性・有効性

Ｒｅ-evaluation and
Safety/Efficacy for the Kampo
Medicine In Japan
日本の再評価制度と
漢方薬の安全性・有効性
Prof. Motoyoshi Satake
Ochanomizu University
Post-marketing surveillance (PMS) System in Japan
PMS System： consists of three main systems
Early Post-Marketing Phase Vigilance (6 mths)EPPV
Spontaneous
ADR Reporting
PMS Systems
Pharmaceuticals and Medical Devices Agency
PMDA
Reexamination
Periodic Safety Update Reports
Reevaluation
MHLW
The Ministry of Health , Labor and Welfare
Post-marketing surveillance（PMS）systems in Japan
Early Post-Marketing Phase Vigilance
Launch of new products
6months after launch
EPPV
NDA
New
Drug
Adverse Drug Reaction and
Infectious Disease Reporting
System
consists of three main systems
every 5 years
6years in Principle (4～10years)
Reevaluation
Reexamination system
system
Approval
report
Periodic Safety Reports
Initial 2 years : every 6 months
Thereafter
: every year
report
PMDA
Pharmaceuticals and Medical Devices Agency
MHLW
The Ministry of Health , Labor and Welfare
Reevaluation
New Drug
Approval
Reexamination
4-6-10 years
Reevaluation
(5 years)
Drug Quality
Reevaluation
(5 years)
Ad hoc reevaluation
R&D Phase
Post-marketing Surveillance
ADR Reporting System
Re-evaluation test by double blind test for
the ethical Kampo medicines
（1）小柴胡湯 syousaikoto
「肝臓機能障害 Lever functional disorder」
1991
Finished re-evaluation 1995
(２)大黄甘草湯 daiokanzouto 「便秘症Constipation」
1991
Finished re-evaluation 1995
(3)小青竜湯 syoseiryuto
「通年性アレルギー性鼻
炎Allergic rhinitis」
1991
Finished re-evaluation 1995
Re-evaluation test by double blind test for
the ethical Kampo medicines
「慢性胃炎に伴う上腹部不定愁訴
general malaise with chronic gastritis」
1994
(２)小柴胡湯 syousaikoto
「感冒Common cold」
1995
(３)芍薬甘草湯 syakuyakukanzoutou 「肝硬変に伴う筋痙攣Muscle cramo in Liver cirrhosis」
1993
(４)小青竜湯 syouseiryuto
「気管支炎Bronchitis」
1994
(５)桂枝加芍薬湯 keihikasyakuyakuto 「過敏性腸症候群Irritable bowel syndrome」
1993
(６)黄連解毒湯 orengedokuto 「高血圧症随伴症状complication in Hypertension」
1994
(７)芍薬甘草湯 syakuyakukanzoto 「月経痛menstration cramps
1994
(８)白虎加人参湯 byakokaninjinto 「薬剤性口渇Drug induced thirst」
1994
(９)白虎加人参湯
byakokaninjinto 「アトピー性皮膚炎の熱感・口渇Atopic dermatitis heatness and thirst」
1995
(１０)六君子湯 rikunshito 「上部消化管機能異常upper gastritic dysfunction」
1994
(１)小柴胡湯 syousaikoto
These ethical Kampo medicines finished the re-evaluation test in 2004.
Ministry will be reported the re-evaluation near future.
Double blind test used the Syosaikoto小柴胡湯 for the
common cold
1.Patient category
The patient been taken ill before 5 days who being
the cough and bad feeling inside the mouth or the
cough with appetite
2.Test medicines
(1) the ethical Syosaikoto extract granule（TJ-9）
(2) placebo granule
3.Method for the test
(1)Test style : double blind test
(2)Period for the administration：test period is one
week. When the patient has been recover, the
medical doctor stops to administration.
4.Main evaluation point
(1)Effecacy：Total improvement Score
(2)Safety：Grade of the safety
(3)Usefulness：Grade of the usefulness
Double blind test used the Syosaikoto小柴胡湯
extract granule for the common cold
【 Main evaluation point 】
Total Improvement Score
under the
more than
moderate
improvem
improvem
ent
ent
84
47
Group
distinct
improvement
moderate
no
change
worse
Syosaikoto
18
66
31
14
2
13.7%
50.4%
23.7%
10.7%
1.5%
64.1%
35.9%
9
43
42
23
2
52
67
7.6%
36.1%
35.3%
19.3%
1.7%
43.7%
56.3%
Placebo
total
Certification
131
p=0.001
Wilcoxon
119
p=0.001
Fisher
Double blind test used
the Syosaikoto小柴胡湯extract granule for the
common cold
（improvement Score in different symptom group ）
improvement Score in different symptom group
Item
more under
modethan
the
Group distinct
impro-vement
no change worse
rate
improv moder
ement
ate
TJ-9
31
35
8
20
3
66
31
Cough out phlegm
pracebo
32.0% 36.1%
10
33
8.2%
20.6%
3.1%
8
19
4
13.5% 44.6% 10.8% 25.7%
TJ-9
appetile
Joint
pain・
muscle
pain
9
44
12.7% 62.0%
pracebo
TJ-9
6
9
3
8.5%
12.7%
4.2%
3
39
6
15
4
4.5%
58.2%
9.0%
22.4%
6.0%
12
22
2
5
0
4.9%
12.2%
0.0%
3
7
1
29.3% 53.7%
pracebo
5.4%
4
19
total
Certification
97
p=0.021
Wilcoxon
74
p=0.201
Fisher
71
p=0.047
Wilcoxon
67
p=0.145
Fisher
41
p=0.035
Wilcoxon
34
p=0.175
68.0% 32.0%
43
31
58.1% 41.9%
53
18
74.6% 25.4%
42
25
62.7% 37.3%
34
7
82.9% 17.1%
23
11
Double blind test used the Orengedokuto黄連解毒湯
for complication in hypertension
1.Patient category
The complication in hypertension is (1)exitement (irritate)
(2)mild spirit (3)sleep difficulty (4) rush of blood the head
(5)flush. Test patient is one of them.
2.Test medicines
(1) the ethical Orengedokuto extract granule(TJ-15),
6 capsules per day
(2) placebo granule
3.Method for the test
(1)Test style : double blind test
(2) Period for the administration :test period is four week.
Total weeks for administration is eight weeks.
4.Main evaluation point
(1) Efficacy：Total improvement Score
(2) Safety：Grade of the safety
(3) Usefulness：Grade of the usefulness
Double blind test used the Orengedokuto黄連解毒湯for
complication in hypertension
Item
rush of blood to the head
flush
elecitement (irritate)
mild sprit
sleep dificulty
clasification
TJ-15
Placebo
minimum
-2
-2
center
1
0
maximam
3
3
average
0.7
0.5
minimum
-1
-2
center
1
0
maximam
3
2
average
0.7
0.4
minimum
-1
-2
center
0
0
maximam
3
2
average
0.6
0.5
minimum
-1
-1
center
0
0
maximam
2
2
average
0.4
0.3
minimum
-1
-2
center
0
0
maximam
2
3
average
0.7
0.5
Certification
（Wilcoxon）
p=0.035
p=0.022
p=0.523
p=0.437
p=0.354
Safety for the ethical Kampo
Medicines
Actions to ensure safety (manufacturers)
① A manufacturer will collect similar reports from
now on.
② Revision of relevant information in the precautions
of the package insert.
③ Distribution of a notice revised precautions.
④ Recall of defective products .
⑤ Suspension of manufacture and selling and product
recall.
⑥ Apply for partial change approval, such as changes of
indications, dosage and administration.
The mention of ADR which does
the origin in the crude drugs , on
the package insert
Glycyrrhizae Radix
Gypsum Fibrosum
Aconiti Tuber
Cinnamomi Corex
Cnidii Rhizoma
Natril Sulfus
Carthami Flos
Rhei Rhizoma
Ephedrae Herba
Achyranhis Radix
Angelicae Radix
Seami Semen
Persicae Semen
Gardeniae Fructus
Ginseng Radix
Zizyphi Spinosi Semen Moutan Cortex
Rehmanniae Radix
Coicis Semen
Glycyrhiza glabra L.
(Cult. Japan)
The ADR which does the origin in the crude drugs 1
Glycyrrhizae Radix 〔1〕
Notification
Item
Description
Case
CONTRAINDICATION
CONTRAINDICATIONS
①Patients with aldosteronism
② Patients with myopathy
③Patients with hypokalemia
[①– ③: These diseases or symptoms may be
aggravated.]
①②③
When a licorice is
contained as a
quantity for 1 day
more than 2.5g.
Important
Precautions
①Since this product contains Glycyrrhiza, careful
attention should be paid to the serum potassium
level, blood pressure, etc., and if any abnormality
is
observed,
administration
should
be
discontinued.
②When this product is coadministered with other
Kampo-preparations(Japanese traditional herbal
medicines), etc., attention should be paid to the
duplication of the contained crude drugs.
Mention it in all of
the licorice
containing
prescriptions.
Notification
Literature
The ADR which does the origin in the crude drugs 2
Glycyrrhizae Radix 〔2〕
Item
Drug
Notification
Case
Description
Drugs
Signs, Symptoms,
and Treatment
Mechanism
and Risk
Factors
(1)Preparations
containing
Glycyrrhiza
(2)Preparations
containing
glycyrrhizinic acid
or glycyrrhizinates
(3)Loop iuretics
Furosemide
Etacrynic acid
(4)Thiazide
diuretics
Pseudoaldosteronism
is likely to occur.
Besides, myopathy is
likely to occur as a
result
of
hypokalemia.
(Refer to the section
“Clinically significant
adverse reactions”.)
Since
glycyrrhizinic acid
and diuretics
have an
accelerating
action on the
potassium
excretion at the
renal tubules, an
acceleration of
decrease in the
serum potassium
level has been
suggested.
Interactions
Trichlormethiazide
(1)(2)(3)(4)
When a licorice
is contained as
a quantity for 1
day more than
2.5g.
(1)(2)
When a licorice
is contained as
a quantity for 1
day under 2.5g.
The ADR which does the origin in the crude drugs 3
The Case of shakuyakukanzoto contains Glycyrrhizae Radix
Item
Clinically
significant
adverse
reactions
Description
(1)Pseudoaldosteronism:
Pseudoaldosteronism such
as hypokalemia, increased blood pressure,
retention of sodium/body fluid, edema, increased body weight, etc. may occur. The
patient should be carefully monitored (measurement of serum potassium level, etc.),
and if any abnormality is observed, administration should be discontinued and
appropriate measures such as administration of potassium preparations should be
taken.
(2)Congestive heart failure, ventricular fibrillation, ventricular tachycardia
(including Torsades de Pointes):
The possibility that congestive heart failure, ventricular fibrillation, ventricular
tachycardia (including Torsades de Pointes) may occur cannot be ruled out, and the
patient should be carefully monitored (measurement of serum potassium levels,
etc.). If any abnormal findings such as palpitations, breathlessness, malaise,
dizziness, syncope, etc. are observed, administration of the drug should be
discontinued and appropriate therapeutic measures taken.
(3)Myopathy :
As a result of hypokalemia, myopathy/ rhabdomyolysis may occur. If weakness,
muscle weakness, myalgia, convulsion/paralysis of limbs, increased CK(CPK),
increased blood/urinary myoglobin are observed, administration should be
discontinued and appropriate measures such as an administration of a potassium
preparation taken.
Cinnamomum
cassia
Panax ginseng
(Cult. Japan)
The ADR which does the origin in the crude drugs 4
Literature
JP Cinnamon Bark
Item
Description
Case
PRECAU Hypersensitivity: Rash, redness, pruritus, etc. may occur.If
such symptoms are observed, administration should be
TIONS
discontinued.
JP Ginseng
Item
Literature
Description
Case
PRECAU Hypersensitivity: Rash, urticaria, etc. may occur. If such
symptoms are observed, administration should be
TIONS
discontinued.
JP Moutan Bark
Item
Use during
Pregnancy,
Delivery or
Lactation
Mention it in all of
the cinnamon
containing
prescriptions.
Mention it in all of
the Ginseng
containing
prescriptions.
Literature
Description
Use of this product in pregnant women, women who may
possibly be pregnant is not recommended. [Moutan Bark
contained in this product may cause premature birth or
abortion.]
Case
Mention it in all of
the Moutan
containing
prescriptions.
Post-marketing surveillance（PMS）systems in Japan
6 months after launch
EPPV
Kampo
Medicines
Adverse Drug Reaction and Infectious
Disease Reporting System
every 5 years
6 years as a rule (4～10years)
Reexamination system
Reevaluation
system
Periodic Safety Reports
Initial 2 years : every 6 months
Thereafter
report
report
: every year
MHLW
EPPV :Early Post-Marketing Phase Vigilance
PMDA
Thank you for your attention

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