1. Ｒｅ -evaluation and Safety/Efficacy for the Kampo Medicine In Japan 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

2. PMS Systems PMS System ： consists of three main systems Reevaluation Spontaneous ADR 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 1971 ～ 1980 ～ 1997 ～ 2001 ～ 1967 ～

3. Post-marketing surveillance （ PMS ） systems in Japan NDA New 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 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

4. Post-marketing Surveillance Reexamination New Drug Approval Reevaluation Drug Quality Reevaluation 4-6-10 years (5 years) Ad hoc reevaluation Reevaluation ADR Reporting System R&D Phase

5. 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 「肝臓機能障害 Lever functional disorder 」 1991 Finished re-evaluation 1995 Finished re-evaluation 1995 ( ２ ) 大黄甘草湯 daiokanzouto 「便秘症 Constipation 」 1991 Finished re-evaluation 1995 Finished re-evaluation 1995 (3) 小青竜湯 syoseiryuto 「通年性アレルギー性 鼻炎 Allergic rhinitis 」 1991 1991 Finished re-evaluation 1995 Finished re-evaluation 1995

6. Re-evaluation test by double blind test for the ethical Kampo medicines ( １ ) 小柴胡湯 syousaikoto 「慢性胃炎に伴う上腹部不定愁訴 general malaise with chronic gastritis 」 1994 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 These ethical Kampo medicines finished the re-evaluation test in 2004. Ministry will be reported the re-evaluation near future. Ministry will be reported the re-evaluation near future.

7. 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 ： (1)Effecacy ： Total improvement Score (2)Safety ： Grade of the safety (2)Safety ： Grade of the safety (3)Usefulness ： Grade of the usefulness (3)Usefulness ： Grade of the usefulness

8. Double blind test used the Syosaikoto 小柴胡湯 extract for the common cold Double blind test used the Syosaikoto 小柴胡湯 extract granule for the common cold 【 Main evaluation point 】

9. Double blind test used the Syosaikoto 小柴胡湯 extract for the common cold Double blind test used the Syosaikoto 小柴胡湯 extract granule for the common cold （ improvement Score in different symptom group ）

10. 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. 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 (1)Test style : double blind test (2) Period for the administration :test period is four week. Total weeks for administration is eight weeks. (2) Period for the administration :test period is four week. Total weeks for administration is eight weeks. 4.Main evaluation point (1) Efficacy ： (1) Efficacy ： Total improvement Score (2) Safety ： Grade of the safety (2) Safety ： Grade of the safety (3) Usefulness ： Grade of the usefulness (3) Usefulness ： Grade of the usefulness

11. Double blind test used the Orengedokuto 黄連解毒湯 for complication in hypertension

12. Safety for the ethical Kampo Medicines

13. ① A manufacturer will collect similar reports from now on. now on. ② Revision of relevant information in the precautions of the package insert. 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. recall. ⑥ Apply for partial change approval, such as changes of indications, dosage and administration. Actions to ensure safety (manufacturers)

14. 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

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

16. The ADR which does the origin in the crude drugs 1 ItemDescriptionCase CONTRAINDICATIONCONTRAINDICATIONS ① Patients with aldosteronism ② Patients with myopathy ③ Patients 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 Important Precautions ① Since 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. ② When 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. Glycyrrhizae Radix 〔 1 〕 Notification Literature

17. The ADR which does the origin in the crude drugs 2 ItemDescriptionCase Drug Interactions (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. Glycyrrhizae Radix 〔 2 〕Drugs Signs, Symptoms, and Treatment Mechanism and Risk Factors (1)Preparations containing Glycyrrhiza (2)Preparations containing glycyrrhizinic acid or glycyrrhizinates (3)Loop iuretics Furosemide Furosemide Etacrynic acid Etacrynic acid (4)Thiazide diuretics Trichlormethiazide 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. Notification

18. The ADR which does the origin in the crude drugs 3 The Case of shakuyakukanzoto contains Glycyrrhizae Radix ItemDescription Clinically significant adverse reactions Clinically significant adverse reactions (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. 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): (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. 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 : (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. 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.

19. Cinnamomum cassia

20. Panax ginseng ( Cult. Japan )

21. The ADR which does the origin in the crude drugs 4 ItemDescriptionCase PRECAU TIONS Hypersensitivity: Rash, redness, pruritus, etc. may occur.If such symptoms are observed, administration should be discontinued. Mention it in all of the cinnamon containing prescriptions. ItemDescriptionCase PRECAU TIONS Hypersensitivity: Rash, urticaria, etc. may occur. If such symptoms are observed, administration should be discontinued. Mention it in all of the Ginseng containing prescriptions. ItemDescriptionCase Use during Pregnancy, Delivery or Lactation 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.] Mention it in all of the Moutan containing prescriptions. JP Cinnamon Bark JP Ginseng JP Moutan Bark Literature

22. Post-marketing surveillance （ PMS ） systems in Japan 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 every 5 years report EPPV : Early Post-Marketing Phase Vigilance

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