~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter 2004. June Vol.6...2 1. Desyrel (Trazodone)...2 2. Zyprexa (Olanzapine)...2 3. VIRAMUNE (nevirapine)...2 4. cisapride...3 5. benzbromarone...3 ADR!...3 Zelmac (Tegaserod Maleate)...4 ADR -...7...11...16...20 Taiwan Relief Foundation National Reporting Center of Adverse Reactions in Taiwan 1 Safety Newsletter 2004 June Vol.6
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ by 1. Desyrel (Trazodone) (FDA) (Bristol-Myers Squibb) trazodone(desyrel ) CYP3A4 Trazodone CYP3A4 ketoconazole ritonavir indinavir trazodone trazodone CYP3A4 trazodone carbamazepine trazodone trazodone http://www.fda.gov/medwatch/safety/2004/safety04.htm#desyrel 2. Zyprexa (Olanzapine) Eli Lilly Zyprexa (Olanzapine) (FDA) Lilly Zyprexa http://www.fda.gov/medwatch/safety/2004/safety04.htm#zyprexa 3. VIRAMUNE nevirapine VIRAMUNE HIV-1 苷 酶 Boehringer Ingelheim Pharmaceutical Inc. BIPI VIRAMUNE Boxed Warning 1. HIV CD4+ 250 cells/mm3 12 2. VIRAMUNE 3. VIRAMUNE Safety Newsletter 2003 Dec. Vol. 4 2
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ VIRAMUNE http://www.fda.gov/medwatch/safety/2004/viramune_deardoc_feb04.pdf 4. cisapride cisapride cisapride http://adr.doh.gov.tw/manage/data/b01/35.pdf 5. benzbromarone benzbromarone http://adr.doh.gov.tw/manage/data/b01/30.pdf ADR! by ADR! http://adr.doh.gov.tw/manage/data/b01/35.pdf http://adr.doh.gov.tw/manage/data/b01/33.pdf ADR E-mail E-mail adr@tdrf.org.tw Safety Newsletter 2003 Dec. Vol. 4 3
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ Zelmac (Tegaserod Maleate) Zelmac ( Tegaserod maleate 6 Irritable Bowel Syndrome, IBS Zelnorm Zelmac 2001 (EMEA Zelmac Zelmac 2 5-HT-4 5-HT-4 Zelmac IBS 2002 7 24 1, 5 (constipation-predominant Irritable Bowel Syndrome C-IBS) FDA risk/benefit 6 Zelnorm Epidemiological Zelmac Study ZEST) 2002 2000 9 Tegaserod 2005 Safety Newsletter 2004 June Vol.6 4
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 3 Zelmac 2003 7 2 2004 3 21 20 2003 11 3 (prospective, observational study) FDA 2004 4 28 Zelnorm (Zelmac in Asia-Pacific-Major Assessment of Safety, Tolerability & (Precautions) Effectiveness results) 500 6mg Zelnorm Warnings Safety Newsletter 2004 June Vol.6 5
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ Zelmac Zelnorm Zelmac 5 1. Zelmac Information for the patient 2. Zelnorm 3. 4. Zelnorm Oddi 4 1. Wagstaff AJ, Frampton JE, Croom KF ADR Tegaserod: a review of its use in the management of irritable bowel syndrome with 2000 12 constipation inwomen. s 2003; 63(11): 1101-20. Zelnorm 2. Ann I. Graul. A historical and research perspective on the 36 new products that Zelmac reached their first markets in 2001. The Year s New s News Perspect 2002; 15(1): 29-43. 3. Zelnorm approval letter (dated July 24 /2004) Available from: http://www.accessdata.fda.gov/scripts/cder/dru 2003 7 gsatfda/index.cfm?fuseaction=search.det ails 4. 2004 Safety Alerts for s Zelnorm (tegaserod maleate) FDA MedWatch. Available from: http://www.fda.gov/medwatch/safety/2004/ safety04.htm#zelnorm 5. Zelmac Package insert, Chinese version. 6. Zelmac, 2004 PDR (Physician's Desk Reference, USA). 5, 6 Safety Newsletter 2004 June Vol.6 6
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ ADR - 1 1 2, 3 1 2 3 1 2 ( 1 2 ) (contrast) X X 1200~2400 mosm/kg H 2 O 87 92 290~860 mosm/kg H 2 O 91 Safety Newsletter 2004 June Vol.6 7
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 46 36 39.6 WHO 30 causality 33.0 2 2.2% 23 25.3% 2 COSTART [] 1 A (%) 36 39.6 90 30 33.0 23 25.3 B 2 2.2 51 56.0 10 11.0 30 33.0 20 6 6.6 21 ~ 40 23 25.3 41 ~ 60 39 42.9 61 ~ 80 18 19.8 > 80 1 1.1 46 ADR 2 2.2 2 2.2 6 6.6 66 72.5 15 16.5 42 46.2% 1 1.1% COSTART 64 91 22 56 11 18 61.5 35 38.5 1 6 34 48 98.9% 78.0% 15 16.5% 4 4.4% WHO causality 24 26.4% 24 26.4% Safety Newsletter 2004 Mar. Vol.5 8
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ (%) 15 16.5 71 78.0 5 5.5 24 26.4 24 26.4 42 46.2 1 1.1 (%) 65 58.0 52 46.4 7 6.3 4 3.6 98.9 1 0.9 1 0.9 20 17.9 15 13.4 4 3.6 1 0.9 17 15.2 4 3.6 4 3.6 3 2.7 52.8 2 1.8 1 0.9 1 0.9 1 0.9 1 0.9 / H 1 9 8.0 6 2.7 2 1.8 1 0.9 1 0.9 1 0.9 Safety Newsletter 2004 Mar. Vol.5 9
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ Katayama mg/dl 0.04% 0.22% 169,284 168,363 4 2 [] COSTART: Coding Symbols for Thesaurus of Adverse Reaction Terms 5 th 12.1% 1. Robert BH. Intravascular Radiographic 87.9% Contrast Media: Issues for Family Physicians. J Am Board Fam Pract 1999; 12(1): 32-42. 2. Davies's Textbook of Adverse 13.4 Reactions, 5 th ed.1998; 834-856. 3. Meyler's Side Effects of, 14 th ed. 2000; 1596-1630. 4. Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology 1990; 175: 621-8. 5. Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospital-acquired renal 5 insufficiency: a prospective study. Am J Med 1983; 74: 243-8. 1.5 Safety Newsletter 2004 Mar. Vol.5 10
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 1 2 1 2 (selective serotonin reuptake inhibitors, SSRIs) citalopram fluoxetine fluvoxamine paroxetine sertraline Edwards JG 3 (norepinephrine NE) ( 1 (serotonin) ) ( ) fluoxetine (antidepressants) SSRIs NE (tricyclic antidepressants) paroxetine SSRIs fluvoxamine serotonin SSRIs citalopram 2 SSRIs (aspirin) 50% Safety Newsletter 2004 Mar. Vol.5 11
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ SSRIs 1. fluoxetine HCl (1996 4 21 2002 7 7 : Eli Lilly, labeling change) (Non-Steroidal Antiinflammatory s, NSAIDs) (phenytoin or carbamazapine) 4 benzodiazepines: diazepam, alprazolam(haloperidol, (risks/benefits) clozapine, pimozide) paroxetine SSRIs (warfarin) 18 ( ) 2. citalopram (2002 11 19 Forest Lab., labeling venlafaxine nefazodone change) 酶 QT nefazodone prolonged 3. sertraline HCl (2002 Bristol-Myers Squibb 9 18 20 Pfizer, labeling change) ( ) 2003 10 pimozide 酶 nefazodone 2003 (monoamine oxidase inhibitors, 11 27 MAOIs) FDA cisapride ( cisapride 35% FDA 4 ) 4. nefazodone (2002 12 9 Bristol-Myers Squibb, FDA labeling change): nefazodone Serzone Seroquel( ) (dispensing error) (MedWatch, FDA) 5 (Health Canada) Safety Newsletter 2004 Mar. Vol.5 12
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 2003 Depressive Disorder, MDD) FDA 10 27 Public Health Advisory 5 5. paroxetine (2003 6 2004 3 22 FDA 10 (bupropion citalopram, 19 GlaxoSmithKline, labeling escitalopram, fluoxetine, fluvoxamine, change) paroxetine 18 mirtazapine, nefazodone, paroxetine, sertraline and venlafaxine) 6 FDA Talk Paper paroxetine 18 ) (MAOIs) 酶 ( :guanethidine monosulfate) (TCAs) TCAs /( :epinephrine) Fluoxetine HCl MAOIs warfarin sodium, haloperidol, clozapine, alprazolam, triazolam, carbamazepine, beta blockers, cyclobenzaprine HCl, lithium, serotonergic drugs Sertraline HCl MAOIs TCAs, warfarin sodium, haloperidol, cimetidine, diazepam, tolbutamide, lithium, serotonergic drugs Paroxetine HCl MAOIs warfarin sodium, haloperidol, lithium, digoxin, procyclidine, phenobarbital, cimetidine, theophylline, phenytoin, serotonergic drugs Citalopram HBr MAOIs TCAs, metoprolol, cimetidine, lithium, serotonergic drugs Fluvoxamine MAOIs, cisapride warfarin, alprazolam, midazolam HCl, triazolam, maleate theophylline, lithium, serotonergic drugs Bupropion HCl MAOIs, levodopa bupropion ( : zyban) Venlafaxine MAOIs cimetidine, serotonergic drugs Nefazodone HCl MAOIs, cisapride digoxin, haloperidol, propranolol, serotonergic drugs Mirtazapine MAOIs serotonergic drugs,, alpha1-adrenergic antagonists( doxazosin mesylate), Roger JC. Antidepressant drug interactions in elderly. 7 Safety Newsletter 2004 Mar. Vol.5 13
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ FDA bupropion 10 10 77 7 fluoxetine (Prozac ) bupropion ( 2009.05.06 ) mirtazapine ( 2008.09.13 ) nefazodone 2008.03.19 ( ) venlafaxine 2005.11.04 ( ) escitalopram ( 2011.04.13 ) nefazodone ( 1998 2004.03 ) 8 FDA 10 (accident injury) venlafaxine 93.05.10 Safety Newsletter 2004 Mar. Vol.5 14
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 1998 2004/3 / Fluoxetine/28 26 Aspirin Citalopram/10 5 Fluvoxamine/4 (urticaria) 1 2.FDA Mirtazapine/4 5 (2008.09.13) Paroxetine/5 PT prolong( 8 ) Sertraline/5 21 Venlafaxine/10 19 (2005.11.04) Bupropion/3 0 (2009.05.06) Nefazodone/4 0 1.Bristol-Myers Squibb Canada nefazodone 2003 11 27 Escitalopram/4 (2011.04.13) 2004/4/13 /77 1. 6. Paxil-Seroxat News, available from URL: http://www.prozactruth.com/clinical_trials.htm 1999:119-65. 2. http://www.prozactruth.com/paxilnews.htmhttp: ( ) 2003: 365~374. //www.ahrp.org/risks/paxilwarning2a.jpg 3. Edwards JG, Anderson I, Systematic review and http://www.ahrp.org/risks/paxilwarning2b.jpg guide to selection of selective serotonin http://www.number-10.gov.uk/output/page3851. reuptake inhibitors. University of Southampton, asp Faculty of Medicine, Health and Biological 7. Roger JC. Antidepressant drug interactions in Sciences, Department of Psychiatry, Royal elderly. Postgraduate Medicine on line. 1999; South Hants Hospital, England. s. 1999; 57 106 (6). (4): 507-33. 4. BBC news, Health, 3 March, 2004, available 8. from URL: available from URL: http://adr.doh.gov.tw http://news.bbc.co.uk/1/hi/health/3526703.stm 9. bupropion, citalopram, http://medicines.mhra.gov.uk/aboutagency/regfr fluoxetine, fluvoxamine, mirtazapine, amework/csm/csmhomemain.htm nefazodone, paroxetine, sertraline, and 5. MedWatch, FDA, U.S.A.,safety information, venlafaxine available from URL: http://www.fda.gov/cder/drug/advisory/mdd.ht m Safety Newsletter 2004 Mar. Vol.5 15
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 1 1,2 1 1 2 ( ) 95 39 25 26 6 1 32 10 53 1 52 43 49.6 22.1 10 6.3 70 20.0 34 10 1 23 36 10 Safety Newsletter 2004 Mar. Vol.5 16
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 7 - (%) 2 1 39 40.5 25 26.3 1 26 26.9 6 6.3 52 54.7 23 43 45.3 92% 21 32 33.7 10 10.5 1 53 55.8 1 10 6 6.3 61 10~19 5 5.3 20~29 5 5.3 20 30~39 12 12.6 40~49 19 20.0 50~59 11 11.6 3 60~69 18 18.9 5 70~79 12 12.6 80 7 7.4 1 Mean ± SD 49.6±22.1 値 13 19 ( ) (n 34) 15,267,492 10 12,900,000 1 1,800,000 23 567,492 (n 61) 载 22 9 30 Safety Newsletter 2004 Mar. Vol.5 17
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ - (%) 28 13 21.3 82.4 65 3 4.9 73.0 1 1.6 19 31.2 2, 6 5 8.2 20 32.8 (%) n=89 Carbamazepine 29 32.6 Phenytoin 10 11.2 Allopurinol 9 10.1 Anti-TB drugs 4 4.5 Cefazolin 3 3.4 278 n=34 265 Phenytoin 12 35.3 Carbamazepine 7 20.6 244 NSAIDs 5 14.7 223 Anti-TB drugs 3 8.8 Allopurinol 2 5.9 89 40 25 4 60 61 38 62.3 carbamazepine 13 allopurinol 8 phenytoin carbamazepine sulindac mefenamic - acid naproxen cephalexin tetracycline 27 44.3 sulfamethoxazole trimethoprim Safety Newsletter 2004 Mar. Vol.5 18
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 载 72 75.8 55 76.4 Skin and subcutaneous disorders 65 Immune system disorders 11 Hepato-biliary disorders 4 Blood and lymphatic system disorders 4 Nervous system disorders 2 General disorders and administration site conditions 2 Respiratory, thoracic and mediastinal disorders 1 Skin and subcutaneous disorders 28 Immune system disorders 3 Hepato-biliary disorders 2 Renal disorders 1 1. 2003;1:8-11. 2. Allopurinol 2003 (%) :16-18. n=34 3. Phe Phenytoin 12 35.3 2003;1:16-20. Carbamazepine 7 20.6 4. NSAIDs 5 14.7 2003;2:16-21. Anti-TB drugs 3 8.8 5. Allopurinol 2 5.9 Carbamazepine n=38 2003;3:16-20. 6. Carbamazepine 13 34.2 Antimicrobial Agents Allopurinol 8 21.1 2003;5:18-28. NSAIDs 4 10.5 Anti-TB drugs 1 2.6 Phenytoin 1 2.6 allopurinol carbamazepine Safety Newsletter 2004 Mar. Vol.5 19
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 1 1,2 1 2 (pharmaco- vigilance) (hypothesis genera- ting step) (pharmacovigilance) (hypothesis testing step) (case- control studies) (cohort studies) (randomized controlled trials) 1 (registries) (surveys) Safety Newsletter 2004 Mar. Vol.5 20
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 4 1968 ADR 2 ADR 5 ADR 3 FDA MedWatch 20 European Agency for the Evaluation ADR of Medicinal Products ( EMEA) (signal) ( ) ADR Safety Newsletter 2004 Mar. Vol.5 21
5, 9 / / ADR / /1978 ( ) /1986 (drug bulletin) /1969 ADR (drug bulletin) /1980 /1963 5 /1992 2-4 18 /1983 /1964 4 /1966 ADR /1975 31
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ FDA 1960 FDA 80 6. 7 ( Pharmacovigilance Technical ADR Committee) ADR FDA FDA (advisory committee Pharmacovigilance Commission) EMEA 1999 FDA 11 FDA 8 ADR 1997 ADR FDA Reporting System of Safety Information on s etc. ( ) ADR ( 30 ) ADR 15 ADR Central Pharmaceutical Affairs Council ADR Investigation Committee FDA (risk assessment) 10 FDA Safety Newsletter 2004 June Vol.6 23
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ (safety signals) series) mining) FDA PUDFA III ( FDA CDER CBER ) 2004 (draft guidance) (1) FDA (Premarketing Risk Assessment) (2) (Good Pharmacovigiliance Practice & Phar- macoepidemiologic Assessment) (3) - (benefit-risk assess- ment) (Development and Use of Risk FDA Minimization Action Plans) (2) (3) 12 FDA (1) FDA (2) (Good (3) Reporting Practice) (pharmacovigilance plan) 13 Safety Newsletter 2004 Mar. Vol.5 24
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ (performance-linked access systems) FDA FDA FDA ( FDA ) European Union, EU EU ICH guideline (case by case) (1) (2)(3) 14 (1) (ADR reports PSUR (2) PMS) / (3) Safety Newsletter 2004 Mar. Vol.5 25
~~~~~~~~~~~~~~~~~~~~~~~~~~ Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ Safety post-market surveillance (PMS) 2000 2001 15 1. (the reexamination system) EMEA (the Pharmacovigilance Working GMPSP Party PhVWP) the Agency s scientific committee ( (1)(post-marke CPMP) surveillance) (2) (3) (use-results surveillance) 1980 (reexamination) (reevaluation) 1993 (special surveillance) Good Post-marketing ( Surveillance Practice (GPMSP ) 1997 (5) MHW Ordinance No. 10) ( Post-marketing clinical studies) ( ADR 10 PSUR 6 Safety Newsletter 2004 Mar. Vol.5 26
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 4 ) ( 6 ) 3 ( OPSR) GPMSP PSUR (Pharmaceuticals and Medical Devices PSUR Evaluation Center) (PAFSC) 2. 16 Safety Newsletter 2004 Mar. Vol.5 27
~~~~~~~~~~~~~~~~~~~~~~~~~~ Safety Newsletter~~~~~~~~~~~~~~~~~~~~~~~~~ 1. Clark JA, Klincewicz SL, Stang PE, eds. Overview-Spontaneous Signalling. In Mann RD, Andrews EB. Pharmacovigilance. John Wiley & Sons Press;2002: 247-271. 2. WHO Collaborating Centre for International Monitoring, National Pharmacovigilance Systems, 1997. 3. Bégaud B, Moride Y, Haramburu F. Quality improvement and statistical calculations made on spontaneous reports. Inf J 1994; 28: 1187-95. 4. Graham DJ, Ahmad SR, Piazza-hepp T,eds. Spontaneous Reporting USA. In: Mann RD and Andrews EB. Pharmacovigilance. John Wiley & Sons Press; 2002: 219-228. 5. Moore N, Bégaud B, eds. Pharmacovigilance Centres. In: Stephens MDB, Talbot JCC, Routledge PA. Detection of New Adverse Reactions. 4 th edition. Macmillan Reference Press, London: 1999; 319-28. 6. Edwards IR, Lindquist M, Wiholm B-E, Napke E. Quality criteria for early signals of possible adverse drug reactions. Lancet 1990; 336: 156-8. 7. Meyboom RH, Egberts AC, Edwards IR, Hekster YA, De Koning FH, Gribnau FW. Principles of signal detection in pharmacovigilance. Safety 1997; 16: 355-65. 8. Edward IR. safety monitoring: an international perspective. Ann Acad Med Singapore 1993; 22: 107-10. 9. Olsson S, ed. National Pharmacovigilance Systems. Uppsala: WHO Collaborating Centre for International Monitoring. 1999. 10. Pricing and Reimbursement for Pharmaceuticals, Japan. Available from: http://pharmacos.eudra.org/f3/g10/docs/tse/jap an.pdf 11. Managing the Risks From Medical Product Use & Creating a Risk Management Framework May 1999. Food and Administration, US. Available from: http://www.fda.gov/oc/tfrm/1999report.html 12. Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. Food And Administration, US. Available from: http://www.fda.gov/cder/guidance/5767dft.pdf 13. Development & Use of Risk Minimization Action Plans. Food And Administration, US. Available from: http://www.fda.gov/cder/guidance/5766dft.pdf 14. Position Paper on Compliance with Pharmacovigilance Regulatory Obligations (Adopted November 2001) Available form: http://www.emea.eu.int/pdfs/human/phvwp/161 801en.pdf 15. Pharmaceutical Administration and Regulation in Japan 2004. Japanese Pharmaceutical Manufacturers Association. Available from: http://www.jpma.or.jp/12english/parj/index.htm l 16. Annual Reports on Health and Welfare 1998-1999 Social Security and National Life. Ministry of Health, Labor and Welfare, Japan. Available from: http://www.mhlw.go.jp/english/wp/wp-hw/vol2 /p2c5.html 湶 19-1 1 02 2358-7343 02 2396-0100 02 2358-4100 http://www.tdrf.org.tw http://adr.doh.gov.tw 2281 Safety Newsletter 2004 June Vol.6 28