ＲｅＲｅ -evaluation and Safety/Effic-evaluation and Safety/Efficacy for the Kampo Medicine In Jacy for the Kampo Medicine In J

apanapan日本の再評価制度と

漢方薬の安全性・有効性

Prof. Motoyoshi Satake Prof. Motoyoshi Satake

Ochanomizu UniversityOchanomizu University

PMS Systems

PMS System ： consists of three main systems

Reevaluation

SpontaneousADR Reporting

Reexamination

Early Post-Marketing Phase Vigilance (6 mths)EPPV

Post-marketing surveillance (PMS) System in Japan

The Ministry of Health , Labor and Welfare

PMDA

MHLW

Pharmaceuticals and Medical Devices Agency

Periodic Safety Update Reports

19711971～～

19801980～～ 19971997

～～

20012001～～19671967

～～

Post-marketing surveillance （ PMS ） systems in

Japan

NDANew

Drug

Approval

Adverse Drug Reaction and Infectious Disease Reporting System

Reexamination system Reevaluation

system

Periodic Safety Reports

6years in Principle (4 ～ 10years)

EPPV

Initial 2 years : every 6 months

Thereafter : every year PMDA

MHLW

6months after launch

report

report

every 5 years

report

Launch of new products Early Post-Marketing Phase Vigilance

Pharmaceuticals and Medical Devices Agency

The Ministry of Health , Labor and Welfare

consists of three main systems

Post-marketing Surveillance

ReexaminationNew Drug Approval

ReevaluationDrug QualityReevaluation

4-6-10 years (5 years) (5 years)

Ad hoc 　 reevaluation

Reevaluation

ADR Reporting System

R&D Phase

　 Re-evaluation test by double blind test for the ethical Kampo medicines

（（ 11 ）小柴胡湯 ）小柴胡湯 syousaikoto syousaikoto 「肝臓機能障害　「肝臓機能障害　 Lever functional disorderLever functional disorder 」 」

19911991　　　　　　　　　　　　　　　　　　　　 Finished re-evaluation 1995Finished re-evaluation 1995(( ２２ )) 大黄甘草湯 大黄甘草湯 daiokanzoutodaiokanzouto 「便秘症「便秘症 ConstipatiConstipati

onon 」　　　」　　　 19911991　　　　　　　　　　　　　　　　　　　　 Finished re-evaluation 1995Finished re-evaluation 1995(3)(3) 小青竜湯 小青竜湯 syoseiryuto syoseiryuto 「通年性アレルギー「通年性アレルギー

性鼻炎性鼻炎 Allergic rhinitisAllergic rhinitis 」」　　　　　　 19911991　　　　　　　　　　　　　　　　　　　　 Finished re-evaluation 1995Finished re-evaluation 1995

Re-evaluation test by double blind test for the ethical Kampo medicines

(( １１ )) 小柴胡湯 小柴胡湯 syousaikoto syousaikoto 「慢性胃炎に伴う上腹部不定愁訴「慢性胃炎に伴う上腹部不定愁訴 general malaise with chronic gastritisgeneral malaise with chronic gastritis 」 」 19941994(( ２２ )) 小柴胡湯 小柴胡湯 syousaikotosyousaikoto 「感冒「感冒 Common coldCommon cold 」」 　　 　　 19951995(( ３３ )) 芍薬甘草湯 芍薬甘草湯 syakuyakukanzoutou syakuyakukanzoutou 「肝硬変に伴う筋痙攣「肝硬変に伴う筋痙攣 Muscle cramo in Liver cirrhosisMuscle cramo in Liver cirrhosis 」 」

　 　 　 　 19931993

(( ４４ )) 小青竜湯 小青竜湯 syouseiryutosyouseiryuto 「気管支炎「気管支炎 BronchitisBronchitis 」」 　　 　　 19941994(( ５５ )) 桂枝加桂枝加芍芍薬湯 薬湯 keihikasyakuyakuto keihikasyakuyakuto 「過敏性腸症候群「過敏性腸症候群 Irritable bowel syndromeIrritable bowel syndrome 」 」 19931993(( ６６ )) 黄連解毒湯 黄連解毒湯 orengedokuto orengedokuto 「高血圧症随伴症状「高血圧症随伴症状 complication in Hypertensioncomplication in Hypertension 」 」 19941994(( ７７ )) 芍薬芍薬甘草湯 甘草湯 syakuyakukanzoto syakuyakukanzoto 「月経痛「月経痛 menstration crampsmenstration cramps 　 　 19941994(( ８８ )) 白虎加人参湯 白虎加人参湯 byakokaninjinto byakokaninjinto 「薬剤性口渇「薬剤性口渇 Drug induced thirstDrug induced thirst 」 　　 」 　　 19941994(( ９９ )) 白虎加人参湯白虎加人参湯 byakokaninjinto byakokaninjinto 「アトピー性皮膚炎の熱感・口渇「アトピー性皮膚炎の熱感・口渇 Atopic dermatitis heatness and thirsAtopic dermatitis heatness and thirs

tt 」 」 19951995(( １０１０ )) 六君子湯 六君子湯 rikunshito rikunshito 「上部消化管機能異常「上部消化管機能異常 upper gastritic dysfunctionupper gastritic dysfunction 」」 19941994

These ethical Kampo medicines finished the re-evaluation test in 200These ethical Kampo medicines finished the re-evaluation test in 2004. 4.

Ministry will be reported the re-evaluation near future. 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 t

he 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 granule3.Method for the test　　　 (1)Test style : double blind test 　　　　　　　 (2)Period for the administration ： test period is on

e week. When the patient has been recover, the medical doctor stops to administration.

4.Main evaluation point　　　　 (1)Effecacy(1)Effecacy ：： Total improvement Score

　　　　 (2)Safety(2)Safety ：： Grade of the safetyGrade of the safety　　　　 (3)Usefulness(3)Usefulness ：： Grade of the usefulnessGrade of the usefulness

Double blind test used the SyosaikotoDouble blind test used the Syosaikoto 小柴胡湯小柴胡湯 eextract xtract granule for the common cold for the common cold

【 【 Main evaluation pointMain evaluation point 】】

Total Improvement Score

Group distinctimpro-vement

mode-rate

nochange

worsemore thanimprovem

ent

under themoderateimprovem

ent

total Certification

Syosaikoto 18 66 31 14 2 84 47 131 p=0.001

13.7% 50.4% 23.7% 10.7% 1.5% 64.1% 35.9% Wilcoxon

Placebo 9 43 42 23 2 52 67 119 p=0.001

7.6% 36.1% 35.3% 19.3% 1.7% 43.7% 56.3% Fisher

Double blind test used Double blind test used the Syosaikotothe Syosaikoto 小柴胡湯小柴胡湯 extract extract granule for the for the comcom

mon coldmon cold（（ improvement Score in different symptom groupimprovement Score in different symptom group ））

improvement Score in different symptom group

Item Group distinctimpro-vementmode-rate

no change worse

morethan

improvement

underthe

moderate

total Certification

TJ-9 31 35 8 20 3 66 31 97 p=0.021

32.0% 36.1% 8.2% 20.6% 3.1% 68.0% 32.0% Wilcoxon

pracebo 10 33 8 19 4 43 31 74 p=0.201

13.5% 44.6% 10.8% 25.7% 5.4% 58.1% 41.9% Fisher

TJ-9 9 44 6 9 3 53 18 71 p=0.047

12.7% 62.0% 8.5% 12.7% 4.2% 74.6% 25.4% Wilcoxon

pracebo 3 39 6 15 4 42 25 67 p=0.145

4.5% 58.2% 9.0% 22.4% 6.0% 62.7% 37.3% Fisher

TJ-9 12 22 2 5 0 34 7 41 p=0.035

29.3% 53.7% 4.9% 12.2% 0.0% 82.9% 17.1% Wilcoxon

pracebo 4 19 3 7 1 23 11 34 p=0.175

Cough out phlegm

appetile

Jointpain・musclepain

Double blind test used the Double blind test used the OrengedokutoOrengedokuto 黄連解毒湯黄連解毒湯 ff

or complication inor complication in hypertensionhypertension1.Patient category1.Patient category　　 　　 The complication in hypertension is The complication in hypertension is (1)exitement (irritate) (1)exitement (irritate)

(2)mild spirit (3)sleep difficulty (4) rush of blood the head (2)mild spirit (3)sleep difficulty (4) rush of blood the head (5)flush. Test patient is one of them. (5)flush. Test patient is one of them.

2.Test medicines2.Test medicines　　　 (1) the ethical Orengedokuto extract granule(TJ-15), 6 capsules per day　　 (2) placebo granule3.Method for the test3.Method for the test　　　　 (1)Test style : double blind test(1)Test style : double blind test 　　　　　　　　　　　　　　 (2) Period for the administration :test period is four wee(2) Period for the administration :test period is four wee

k. Total weeks for administration is eight weeks.k. Total weeks for administration is eight weeks.4.Main evaluation point4.Main evaluation point　　　　 (1) Efficacy(1) Efficacy ：： Total improvement Score　　　　 (2) Safety(2) Safety ：： Grade of the safetyGrade of the safety　　　　 (3) Usefulness(3) Usefulness ：： Grade of the usefulnessGrade of the usefulness

Item clasification TJ-15 PlaceboCertification

（Wilcoxon）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

sleep dificulty

p=0.035

p=0.022

p=0.523

p=0.437

p=0.354

rush of blood to the head

flush

elecitement (irritate)

mild sprit

Double blind test used the Double blind test used the OrengedokutoOrengedokuto 黄連解毒湯黄連解毒湯 for for complicacomplication in hypertensiontion in hypertension

Safety for the ethical Kampo MediciSafety for the ethical Kampo Medicinesnes

①① A manufacturer will collect similar reports from A manufacturer will collect similar reports from

now on.now on.

②② Revision of relevant information in the precautionsRevision of relevant information in the precautions

of the package insert.of the package insert.

③ ③ Distribution of a notice revised precautions. Distribution of a notice revised precautions.

④ ④ Recall of defective products .Recall of defective products .

⑤⑤ Suspension of manufacture and selling and productSuspension of manufacture and selling and product

recall. recall.

⑥ ⑥ Apply for partial change approval, such as changes of Apply for partial change approval, such as changes of

indications, dosage and administration.indications, dosage and administration.

Actions to ensure safety (manufacturers)

The mention of ADR which does the origin in the crude drugs , on the package insert

Glycyrrhizae Radix

Cinnamomi Corex

Carthami Flos

Achyranhis Radix

Seami Semen

Gardeniae Fructus

Zizyphi Spinosi Semen

Rehmanniae Radix

Gypsum Fibrosum

Cnidii Rhizoma

Rhei Rhizoma

Angelicae Radix

Persicae Semen

Ginseng Radix

Moutan Cortex

Coicis Semen

Aconiti Tuber

Natril Sulfus

Ephedrae Herba

Glycyrhiza glabra LGlycyrhiza glabra L.. (Cult. Japan)

The ADR which does the origin in the crude drugs 1The ADR which does the origin in the crude drugs 1

ItemItem DescriptionDescription CaseCaseCONTRAINDICATIONCONTRAINDICATION CONTRAINDICATIONS CONTRAINDICATIONS

①①Patients with aldosteronismPatients with aldosteronism

② ② Patients with myopathyPatients with myopathy

③③Patients with hypokalemiaPatients with hypokalemia

[ – : These diseases or symptoms may be ag① ③[ – : These diseases or symptoms may be ag① ③gravated.]gravated.]

①②③①②③

When a licorice is When a licorice is contained as a contained as a quantity for 1 day quantity for 1 day more than 2.5g.more than 2.5g.

Important Important PrecautionsPrecautions

①①Since this product contains Glycyrrhiza, careful Since this product contains Glycyrrhiza, careful attention should be paid to the serum potassium lattention should be paid to the serum potassium level, blood pressure, etc., and if any abnormality ievel, blood pressure, etc., and if any abnormality is observed, administration should be discontinues observed, administration should be discontinued. d.

②②When this product is coadministered with other When this product is coadministered with other Kampo-preparationsKampo-preparations(Japanese traditional herbal medi(Japanese traditional herbal medi

cines)cines), etc., attention should be paid to the duplica, etc., attention should be paid to the duplication of the contained crude drugs. tion of the contained crude drugs.

Mention it in all of Mention it in all of the licorice the licorice containing containing prescriptions.prescriptions.

Glycyrrhizae Radix 〔 1 〕Notification

NotificationLiterature

The ADR which does the origin in the crude drugs 2The ADR which does the origin in the crude drugs 2

ItemItem DescriptionDescription CaseCase

Drug InteraDrug Intera

ctionsctions (1)(2)(3)(4)(1)(2)(3)(4)

When a licorice When a licorice is contained as is contained as a quantity for 1 a quantity for 1 day day more than more than 2.5g.2.5g.

(1)(2)(1)(2)

When a licorice When a licorice is contained as is contained as a quantity for 1 a quantity for 1 day day under under 2.5g.2.5g.

Glycyrrhizae Radix 〔 2 〕

DrugsDrugs Signs, Symptoms, Signs, Symptoms, and Treatmentand Treatment

Mechanism Mechanism and Risk and Risk FactorsFactors

(1)Preparations con(1)Preparations containing Glycyrrhizataining Glycyrrhiza

(2)Preparations con(2)Preparations containing glycyrrhizinitaining glycyrrhizinic acidc acid 　　 or glycyrrhor glycyrrhizinates izinates

(3)Loop iuretics(3)Loop iuretics

FurosemideFurosemide

Etacrynic acidEtacrynic acid

(4)Thiazide diuretic(4)Thiazide diuretics s TrichlormethiazideTrichlormethiazide

Pseudoaldosteronism Pseudoaldosteronism is likely to occur. Beis likely to occur. Besides, myopathy is liksides, myopathy is likely to occur as aely to occur as a 　　 rresultesult 　　 of hypokalemof hypokalemia.ia.

(Refer to the section (Refer to the section “Clinically significant “Clinically significant adverse reactions”.)adverse reactions”.)

Since glycyrrhizinSince glycyrrhizinic acid and diuretiic acid and diuretics have an accelcs have an accelerating action on erating action on the potassium exthe potassium excretion at the rencretion at the renal tubules, an accal tubules, an acceleration of decreeleration of decrease in the serum ase in the serum potassium level hpotassium level has been suggestas been suggested.ed.

Notification

The ADR which does the origin in the crude drugs 3The ADR which does the origin in the crude drugs 3The Case of shakuyakukanzoto contains Glycyrrhizae Radix

ItemItem DescriptionDescription Clinically Clinically significant significant adverse adverse reactionsreactions

(1)Pseudoaldosteronism(1)Pseudoaldosteronism: : 　　　　　　　　 Pseudoaldosteronism suchPseudoaldosteronism such 　　 as hypokalemia, increased blood pressure, retentias hypokalemia, increased blood pressure, retenti

on of sodium/body fluid, on of sodium/body fluid, edema,edema, increased body weight, etc. may occurincreased body weight, etc. may occur. The patie. The patient should be carefully monitored (measurement of serum potassium level, etc.), annt should be carefully monitored (measurement of serum potassium level, etc.), and if any abnormality is observed, administration should be discontinued and appropd if any abnormality is observed, administration should be discontinued and appropriate measures such as administration of potassium preparations should be taken.riate measures such as administration of potassium preparations should be taken.

(2)Congestive(2)Congestive heart failure, ventricular fibrillation, ventricular tachycardia (includ heart failure, ventricular fibrillation, ventricular tachycardia (including Torsades de Pointes)ing Torsades de Pointes): :

　　　　　　　　 The possibility that congestive heart failure, ventricular fibrillation, ventricular tacThe possibility that congestive heart failure, ventricular fibrillation, ventricular tachycardia (including Torsades de Pointes) may occur cannot be ruled out,hycardia (including Torsades de Pointes) may occur cannot be ruled out, and the p and the patient should be carefully monitored (measurement of serum potassium levels, etatient should be carefully monitored (measurement of serum potassium levels, etc.). Ifc.). If any abnormal findings such as palpitations, breathlessness, malaise, dizzine any abnormal findings such as palpitations, breathlessness, malaise, dizziness, syncope, etc. are observed, administration of the drug should be discontinued ass, syncope, etc. are observed, administration of the drug should be discontinued and appropriate therapeutic measures taken.nd appropriate therapeutic measures taken.

　　 (3)Myopathy(3)Myopathy : :

　　　　　　　　 As a result of hypokalemia, myopathy/ rhabdomyolysis may occur. If weakness, As a result of hypokalemia, myopathy/ rhabdomyolysis may occur. If weakness, muscle weakness, myalgia, convulsion/paralysis of limbs, increased CK(CPK), incrmuscle weakness, myalgia, convulsion/paralysis of limbs, increased CK(CPK), increased blood/urinary myoglobin are observed, administration should be discontinueeased blood/urinary myoglobin are observed, administration should be discontinued and appropriate measures such as an administration of a potassium preparation td and appropriate measures such as an administration of a potassium preparation taken.aken.

Cinnamomum cassiCinnamomum cassiaa

Panax ginsengPanax ginseng ((Cult. JapanCult. Japan))

The ADR which does the origin in the crude drugs 4The ADR which does the origin in the crude drugs 4

ItemItem DescriptionDescription CaseCase

PRECAUPRECAUTIONSTIONS

HypersensitivityHypersensitivity: Rash, redness, pruritus, etc. may occur.If : Rash, redness, pruritus, etc. may occur.If such symptoms are observed, administration should be discosuch symptoms are observed, administration should be discontinued.ntinued.

Mention it in all of Mention it in all of the cinnamon the cinnamon containing containing prescriptions.prescriptions.

ItemItem DescriptionDescription CaseCase

PRECAUPRECAUTIONSTIONS

HypersensitivityHypersensitivity: Rash, urticaria, etc. may occur. If such sy: Rash, urticaria, etc. may occur. If such symptoms are observed, administration should be discontinued.mptoms are observed, administration should be discontinued.

Mention it in all of Mention it in all of the Ginseng the Ginseng containing containing prescriptions.prescriptions.

ItemItem DescriptionDescription CaseCase

Use during Use during Pregnancy, Pregnancy, Delivery or Delivery or LactationLactation

Use of this product in pregnant women, women who may Use of this product in pregnant women, women who may possibly be pregnant is not recommended. [Moutan Bark possibly be pregnant is not recommended. [Moutan Bark contained in this product may cause premature contained in this product may cause premature birth or abirth or abortionbortion.].]

Mention it in all of tMention it in all of the Moutan containihe Moutan containing prescriptions.ng prescriptions.

JP Cinnamon Bark

JP Ginseng

JP Moutan Bark

Literature

Literature

Literature

Post-marketing surveillancePost-marketing surveillance （（ PMSPMS ）） systemssystems in in JapanJapan

Kampo Medicines

Adverse Drug Reaction and Infectious Disease Reporting System

Reexamination system Reevaluation

system

Periodic Safety Reports

6 years as a rule (4 ～ 10years)

EPPV

Initial 2 years : every 6 months

Thereafter : every year PMDA

MHLW

6 months after launch

report

report

every 5 years

report

EPPV :Early Post-Marketing Phase Vigilance

Thank you for your attentionThank you for your attention