1. 1 RIFINAH 用於 BCG 膀胱灌 注的感染 義大醫院 藥劑部 主講人 : 張逸芃 藥師 指導藥師 : 黃佳真 藥師 報告日期 ： 99/9/30

2. 2 Question

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4. 4 Patient History 47 歲，男性 Past history Urothelial carcinoma in situ of bladder Renal transplantation Hypertension Previous operation history End stage renal disease s/p cadarveric renal transplantation on 97/10/17 Transurethral resection of bladder tumor (TURBT) on 2010-04-27

5. 5 巴斯德 BCG 免疫治療劑 (BCG Immunotherapeutic)

6. 6 DESCRIPTION ImmuCyst – 是由 Bacillus Calmette- Guerin(BCG) 之 Connaught 菌株 ( 一種牛結 核桿菌 Mycobacterium bovis 的活減毒菌株 ) 製成的凍晶乾燥製劑

7. 7 INDICATIONS 治療及預防膀胱原發或復發性原位癌 (CIS) 或經尿道切除術 (TUR) 後之表淺性乳頭瘤 （Ｔ a 及Ｔ 1 ）

8. 8 PHARMACOLOGY BCG promotes a local acute inflammatory and sub-acute granulomatous reaction with macrophage and leukocyte infiltration in the urothelium and lamina propria of the urinary bladder. The local inflammatory effects are associated with an elimination or reduction of non-muscle invasive cancerous lesions of the urinary bladder. The exact mechanism of action is unknown, but the anti-tumour effect appears to be T-lymphocyte dependent. → 其治療機轉可能是經由 BCG 刺激免疫系統 活躍進而攻擊癌細胞的免疫反應

9. 9 Contraindications Bacillus of Calmette and Guerin Vaccine, Live 1) immunocompromised status 2) urinary tract infection or hematuria 3) acute febrile illness 4) 7 to 14 days following biopsy, transurethral resection, or traumatic catheterization; increased risk for systemic BCG infection 5) active tuberculosis 6) hypersensitivity to BCG products

10. 10 DOSAGE AND ADMINISTRATION 經膀胱內投藥治療應在組織切片或經尿道切除術 (TUR) 後 7 至 14 日開始，包括誘導期與維持期  誘導期包括每週經膀胱內灌注一次共 6 週。暫停 6 週後，再每週灌注一次為期 1 至 3 週  維持期為在誘導治療開始後的第 6 、 12 、 18 、 24 、 30 及 36 個月接受每週一次共 1 至 3 週的灌注

11. 11 Adverse Reaction

12. 12 ImmuCyst ® 相關不良反應之建議治療 症狀，徵候或症候群治療 刺激性膀胱症狀 < 48 小時 症狀療法，例如 pyridium ， propantheline ， bromide ， oxybutynin chloride ， acetaminophen 刺激性膀胱症狀≧ 48 小時 症狀療法；暫停下一次 ImmuCyst ® 療程直到症狀完 全消除。若一週內症狀未完全消除，投予 isoniazid (INH) 300 mg/day ，為期 15 day 。 伴隨細菌性尿路感染 (UTI) 暫停下一次 ImmuCyst ® 療程直到完成抗微生物治療， 且尿液培養呈陰性反應為止。 其它生殖泌尿系統不良反應：症狀性 肉芽腫性前列腺炎、副睾睾丸炎、輸 尿管阻塞或腎膿瘍 停用 ImmuCyst ® 。 投予 isoniazid (INH) 300mg/day + rifampin 600mg/day 為期 3-6 個月。 發燒 <38.5 ℃持續不到 48 小時 Acetaminophen 症狀療法 皮膚發疹、關節痛或遷移性關節炎 Antihistamine 或 NSAID ；若無效則停止使用 ImmuCyst ® 並投予 isoniazid (INH) 300mg/day 為期 3 個月。 無敗血性休克症狀的全身性 BCG 反應 停用 ImmuCyst ® ，尋求傳染病諮詢。投予三重抗結 核菌藥物治療 6 個月。 有敗血性休克症狀的全身性 BCG 反應同上，考慮加上短期高劑量全身性皮質類固醇治療。

13. 13 Question

14. 14 05/21 05/28 06/0406/1106/01807/2107/2808/0408/11 amlodipine yyyyyyyyy terazosin yyyyyyyyy Mycophenolate sodium 180mg/tab yyyyyyyyy Tacrolimus 1mg/cap yyyyyyyyy Prednisolone 5mg/tab yyyyyyyyy nifedipine yyyy Bacillus Calmette- Guerin (BCG)81mg/vail yyyyyyyy Rifampin 300mg+Isoniazid 150mg/tab yyyyyyyy Tranexamic acid yyy Diphenidol yy 1#BID 0.5#Q12H 2#Q12H 3#Q12H 1#QD 1#QD SL 1 vial IVCT 1#QD

15. 15 RIFINAH 用於 BCG 膀胱灌注的感染 1.Rifinah 預防性投與的合理性 ?? 2. 如何給予劑量 ?300mg 150mg 3. 注意事項 ?

16. 16 INTRAVESICAL BACILLUS CALMETTE-GUERIN FOR THE TREATMENT OF SUPERFICIAL BLADDER CANCER IN RENAL TRANSPLANT PATIENTS

17. 17 INTRAVESICAL BACILLUS CALMETTE-GUERIN FOR THE TREATMENT OF SUPERFICIAL BLADDER CANCER IN RENAL TRANSPLANT PATIENTS

18. 18 Conclusion Because there was no experience with renal transplant patients and BCG, we decided to treat the patients prophylactically with isoniazid and rifampin, because this is the, treatment recommended for patients with severe symptoms local or systemic side effects secondary to BCG 用於預防的合理性證據佐證仍不足 Rifampicin induces cytochromeP450 3A4 and so increases the metabolism of cyclosporine and tacrolimus, necessitating dose adjustment to maintain stable levels of immunosuppression and avoid rejection. 需要藥量調整維護免疫抑制反應的穩定

19. 19 Drug-Drug Interactions Severity Documentati on Summary ISONIAZID -- RIFAMPINMajorGood Concurrent use of RIFAMPIN and ISONIAZID may result in hepatotoxicity RIFAMPIN -- TACROLIMUS MajorGood Concurrent use of RIFAMPIN and TACROLIMUS may result in decreased tacrolimus efficacy.

20. 20 Reference 1. BCG intravesical instillations: recommendations for side-effects management.Rischmann P, Desgrandchamps F, Malavaud B, Chopin DK.Eur Urol. 2000;37 Suppl 1:33-6. 2. Practice guidelines inoncology-v.1.2009 3. TheOncologist,Vol.10,No.10,792-798,November2005; doi:10.1634/theoncologist.10-10-792 4. GarimaldiS,Farina LA, Cabezas CA, et al. Afectacio’n difusa y progresio’nra’pidadeuncarcinomatransicionaldealtogradoenunpacientetra splantadorenal.ActasUrolEsp2000;24:179–181. 5. 7.KhalifaMA,ElfvingP,Ma ‥ nsonW,etal.TheeffectofisoniazidonBCG Inducedtoxicityinpatientswithsuperficialbladd ercancer.EurUrol2000;37(suppl1):26–30 6. VegtPDJ,MeijdenAPM,SylvesterR,etal.Doesisoniazidreducesideeffectsofi ntravesicalbacillusCalmette-Gue’rintherapyinsuperfi- cialbladdercancer?InterimresultsofEuropeanorganizationforresearchandtr eatmentofcancerprotocol30911.JUrol1997;1571246–1249. 7 Impaired immune response by isoniazid treatment during intravesical BCG administration in the guinea pig. J Urol. 1992 Nov;148(5):1577-82. 8 http://www.rxlist.com/theracys-drug.htm#

21. 21 Thank you for your attention

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23. 23 Contraindications immunocompromised status including HIV infection (percutaneous and intravesical) urinary tract infection or hematuria (intravesical) acute febrile illness (intravesical) 7 to 14 days following biopsy, transurethral resection, or traumatic catheterization; increased risk for systemic BCG infection (intravesical) active tuberculosis (intravesical) hypersensitivity to BCG products

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25. 25 Prevention No measures have been demonstrated to be effective in preventing the occurrence of disseminated BCG infection.

26. 26 Intravesical BCG instillations for the treatment of superficial bladder tumours in renal transplant recipients Superficial urothelial tumours of the bladder are more frequent and more often at higher risk of progression and recurrence in renal transplant recipients. When conservative treatment of these tumours is indicated, BCG instillations are recommended. However, immunosuppression of renal transplant recipients constitutes a classical contraindication to BCG therapy. Some authors have nevertheless used BCG instillations in renal transplant recipients. The authors reviewed the use of BCG in renal transplant recipients by studying the effects of immunosuppression on the mechanisms of action of BCG and the various clinical experiences reported in the international literature

27. 27 Contraindication immunocompromised status including HIV infection (percutaneous and intravesical) urinary tract infection or hematuria (intravesical) acute febrile illness (intravesical) 7 to 14 days following biopsy, transurethral resection, or traumatic catheterization; increased risk for systemic BCG infection (intravesical) active tuberculosis (intravesical) hypersensitivity to BCG products 因有全身性 BCG 感染之風險 禁用於免疫抑制或有先天或後天性免疫系統缺損病患 目前或過去曾有全身性 BCG 反應徵狀病人 活動性肺結核病人 發燒、尿道感染或血尿應待緩解後再行治療 組織切片、尿道切除術或創傷性插管應間隔 7-14 天再使用