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Methimazole induced agranulocytosis

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  • 1. Suspected Methimazole-Induced Agranulocytosis 2013. 06. 05 臨床藥學與藥物科技研究所 陳秋縈 指導老師 高淑敏藥師、歐弘毅醫師 ADR Report 特別感謝 林景翰醫師、李欣學醫師、林文亮藥師
  • 2. Today’s outline 2  Case description  ADR evaluation  Disease-related or drug-related ?  Antithyroid drug-induced agranulocytosis  Overview  Possible mechanism  Management  Case discussion  Patient evaluation  Prevention  Recorder’s opinion  Take home message
  • 3. 成大藥物不良反應通報表 GCSF= Granulocyte-colony Stimulating Factor 3 病患基本資料 床號:10A** 病歷號:******** 姓名: ○○○ 性別:男 報告者:陳秋縈 電話:5693 科部:成大臨床藥學與藥物科技研究所 出生年月日(或年齡): 1990/09/21 (22歲) 報告日期: 2013/04/21 請簡述該不良反應:Agranulocytosis 懷疑引起該不良反應之藥品 處方日期 反應發生日期 停藥日期 Methimazole 2013/02/21 2013/04/17 2013/04/21 該不良反應於何處發現?  護理紀錄  病歷  訪視病人 其他:醫師告知 若已知該不良反應所造成的結果或處置,請簡述: 1. 導致病人發生急性扁桃腺炎及住院 2. 停用可疑藥品Methimazole,並投予抗生素及G-CSF治療
  • 4. II. 不良反應有關資料 11. 不良反應結果  A. 死亡,日期︰ 年 月 日,死亡原因︰  B. 危及生命  C. 導致病人住院  D. 造成永久性殘疾  E. 延長病人住院時間  F. 需作處置以防永久性傷害  G. 先天性畸形  H. 非嚴重不良反應(請敘述) 成大藥物不良反應通報表 4 1. 發生日期︰2013/04/17 2. 通報者獲知日期︰2013/04/21 4. 通報者資料 姓名︰陳秋縈 電話︰5693 屬性: 藥師 服務機構︰成大醫院 地址:台南市北區勝利路138號 職稱︰ 藥師 I. 病人基本資料 5.識別代號︰ (供通報者辨識用) 6. 性別︰ 男  女 7. 年齡︰22歲 8. 體重︰67.8 公斤 9. 身高︰175 公分
  • 5. 其他相關資料 5 Present illness • Graves’ disease with thyrotoxic periodic paralysis Medication Methimazole 10 mg BID PO Propranolol 10 mg BID PO Loratadine 10 mg QD PO Past History • Allergic rhinitis Drug Allergy Family History • Bronchodilator: 心跳變快 • Not contribution Social History • Smoking (-) • Betel nut (-) • Drinking (-) • Drug abuse (-)
  • 6. ER • Sudden onset limb & leg weakness Muscle power: R’t>L’t, distal>proximal • HR: 130 bpm, K: 2.0 mmol/L  Suspect thyrotoxic periodic paralysis • KCl 20mEq IVD STAT Propranolol 10mg PO STAT • Slow K 8.06mEq 2 tab QID x 3 day • Thyroid function test and OPD follow up NCKUH OPD • Hyperthyroidism (lab data on 12/31) TSH: <0.005 μIU/mL TT3: 320.9 ng/dL, FT4: 5.10 ng/dL  Diagnosis: Thyrotoxic periodic paralysis • Refillable prescription Methimazole 10mg BID Propranolol 10mg TID • Slow K 8.06mEq BID x 7 days CMUH-Taipei branch OPD • Pruritus • Shift Methimazole to Propylthiouracil 10mg BID NCKUH OPD • (Lab data report on 02/14) T3: 106.88 ng/dL, T4: 8.53 ug/dL TSH: 0.07 uU/mL Anti-TSH receptor antibody: 4.27 U/L  Graves’ disease • Refillable prescription Methimazole 10mg BID Loratadine 10mg QD Propranolol 10mg BID 通報事件之描述 (1) 102 2/21 2/06 1/03 12/30 6
  • 7. NCKUH OPD • Fever, sore throat since 04/17 • BT: 38.7℃ Injected tonsil with pus coating  Acute supportive tonsillitis  Suggested admission, patient refused • Augmentin 875/125mg BID x 5 days • Diclofenac 25mg QID x 5 days ER • Fever, sore throat • Augmentin 875/125mg BID x 2 days • Diclofenac 25mg QID x 2 days • Oxethazaine/ Polymigel 5/244 mg QID AC x 3 days ER • Fever, sore throat, chills • BT: 39.5℃ , CRP: 348.8 mg/L WBC: 1000/μL, ANC: 26/μL  Acute tonsillitis and agranulocytosis, highly suspect methimazole induced  Admission • Hold methimazole • Throat swab and blood culture • Cefepime 2000mg Q12H IVD • Acetaminophen 500mg Q6H PRN Lysine Acetylsalicylate 0.9g Q6H PRN IVD 通報事件之描述 (2) 4/21 4/20 4/18 ANC= Absolute Neutrophil Count Admission 7
  • 8. • Intermittent chills with fever • Rhinorrhea, cough with sputum • WBC: 900/μL, ANC: 0/μL • Vancomycin 1000 mg Q12H IVD • G-CSF 300mcg QD SC • Cough mixture 10 ml TID • Throat swab culture report (4/21): Klebsiella pneumonia • No other infection focus • Consult ENT Chlorhexidine gargle for oral hygiene • WBC: 1000/μL, ANC: 380/μL • Fever subside • WBC: 10700/μL, ANC: 1564/μL • Tonsil swelling and injective improving • Stop G-CSF use • Stable condition, No fever Normal thyroid function (Lab on 4/24) TSH 2.82 μIU/mL TT3: 127.5 ng/dL, FT4: 0.908 ng/dL  Discharge medication Cefuroxime 500mg Q12H PO Acetaminophen 500mg Q6H PRN 通報事件之描述 (3) 4/26 4/25 4/24 4/28 4/29 4/30 4/21 Admission 8 GCSF= Granulocyte-colony Stimulating Factor
  • 9. 相關檢查及檢驗數據 9 生化 12/30 4/21 4/29 CREA(mg/dL) 0.66 0.9 0.7 AST(U/L) 34 29 ALT(U/L) 35 33 NA(mmol/L) 143 143 141 K(mmol/L) 2 4 3.8 MG(mg/dL) 1.8 CRP(mg/L) 348.8 血液 12/30 4/21 4/24 4/26 4/29 WBC(10^3/μL) 11.5 1 0.9 1 10.7 Blast(%) 0 0 0 Pro(%) 0 0 0 Myelo(%) 0 0 6 Meta(%) 0 0 14 Band(%) 0 15 20 Seg(%) 82 2.6 0 4 32 Eos(%) 0.2 13.6 5 2 0 Baso(%) 0.1 0.9 0 0 0 Mono(%) 7.1 2 0 4 6 Lymph(%) 10.6 80.9 20 25 22 RBC(10^6/μL) 5.34 4.62 Hb(g/dL) 15.8 14.2 Plt(10^3/μL) 343 254 Thyroid 12/31 2/14 4/24 TSH(μIU/mL) <0.005 2.82 TT3(ng/dL) 320.9 127.5 FT4(ng/dL) 5.1 0.908 TSH(μIU/mL) 0.07 T3(ng/dL) 106.88 T4(μg/dL) 8.53 ATR(U/L) 4.27
  • 10. Case summary- before hospitalization 10 Slow K MMI 10mg BID PTU 10mg TID MMI 10mg BID Propranolol 10mg TID BID Loratadine 10mg QD 18 OPD Acute supportive tonsillitis 4/17 20 ER Thyrotoxic Periodic Paralysis WBC: 11500/μL ANC: 9430/μL OPD CMUH Pruritus OPD 12/30 1/03 2/06 2/21 21 Fever sore throat ER Admission Agranulocytosis WBC: 1000/μL ANC: 26/μL MMI=Methimazole PTU= Propylthiouracil ANC= Absolute Neutrophil Count Augmentin, dilcofenec 4 daysOnset55 days
  • 11. 35 36 37 38 39 40 41 4/21 22 23 24 25 26 27 28 29 30 Body Temperature (°C) Fever subside Case summary-after admission 1000 900 1000 10700 26 0 380 1564 0 200 400 600 800 1000 1200 0 1000 2000 3000 4000 5000 6000 4/21 22 23 24 25 26 27 28 29 30 9000 10000 11000 1400 1600 1800 WBC (count/μL) ANC (count/μL) Admission G-CSF 300mcg QD SC Discharge
  • 12. 12 ADR evaluation Disease or drug-related?
  • 13. Causes of agranulocytosis 13 Disease-related Congenital neutropenia Hematological disease Autoimmune disease Certain infection Bacterial: typhoid fever, Shigella enteritis, brucellosis, and tuberculosis Viral: EB virus, CMV, hepatitis virus, parvovirus B19 Parasitic: Kala azar, malaria …… Drug-related (70% of cases) Chemotherapy Non-chemotherapy drugs Disease- related Agranulocytosis Neutrophil count < 500/μl Drug- related Less likely Less likely Less likely ?
  • 14. Non-chemotherapy drugs associated with agranulocytosis 14 Class Drug Analgesics and NSAIDs NSAID, gold salts, penicillamine, phenylbutazone, dipyrone Antithyroid drugs Methimazole, carbimazole, propylthiouracil Antipsychotics, sedatives, Antidepressants Amoxapine, clomipramine, clozapine, diazepam, chlordiazepoxide, Fluoxetine haloperidol, imipramine, levopromazine, miaxetin, Olanzapine, phenothiazines Anticonvulsants Carbamazepine, phenytoin, ethosuximide, valproate Anti platelets Ticlopidine, dipyridamole Cardiovascular drugs Quinidine, digoxin, procainamide, propranolol, methyldopa Diuretics Thiazides, acetazolamide, furosemide, spironolactone Gastrointestinal drugs Sulfasalazine, histamine h2-receptor antagonists Anti-infective agents Β-lactams, cephalosporins, dapsone, flucytosine, macrolides, Trimethoprim/sulfomethoxasole, zidovudine Anti-malarials Quinine, chloroquinine Miscellaneous Calcium dobesilate, chlorpropamide, meprobamate, rituximab
  • 15. Which is causative Agents ? 15 4/171/03 2/06 2/21 21 Symptoms fever sore throat Admission Agranulocytosis ANC: 26/μL MMI PTU MMI Propranolol 55 4 108 • PTU ? Time to recovery after discontinuation: 1-2 weeks • Propranolol vs MMI ? MMI=Methimazole PTU= Propylthiouracil ANC= Absolute Neutrophil Count 1534 Relative risk (95% CI) Duration of drug use Our patient Methimazole 230.9 (120.4–453.5) Usually within the first 3 months use 55 days Propranolol 2.5 (1.1–6.1) Association for short-term use ( < 28 days) use 108 days Clin Pharmacol Ther. 1991 Mar;49(3):330-41. JAMA. 1973 Mar 19;223(12):1376-7. Ann Intern Med. 2007;146:657-665
  • 16. 懷疑藥品 (包括西藥及中藥) 16 學名/商品名 含量/劑型 給藥途徑 劑量頻率 起迄日期 用藥原因 可疑 藥品 Methimazole (Methimazole®) 5mg/tab PO 10 mg BID 102/02/21- 04/21 Hyperthyroidism Propranolol (Inderal®) 10mg/tab PO 10 mg BID 102/01/03- 04/21 Hyperthyroidism 併用 藥品 Loratadine (Minlife®) 10mg/tab PO 10 mg QD 102/02/21- 04/21 Pruritus 廠牌/批號 效期 26. 曾使用同類藥品之經驗  是  否  無法得知 藥品︰Methimazole (34 days) 不良反應︰無 藥品︰Propylthiouracil (15 days) 不良反應︰無 27. 停藥後不良反應是否減輕  是  否  無法得知 28. 再投藥是否出現同樣反應  是  否  無法得知 Johnson Unknown 29. 是否同時使用  中草藥  西藥  健康食品  其他: 若有同時使用,請填入併用藥品內
  • 17. 17 Antithyroid drug-induced agranulocytosis Focused on methimazole
  • 18. Antithyroid drugs N Engl J Med. 2005;352:905-917. 18 Thionamide  Methimazole (MMI), carbimazole, and propylthiouracil (PTU) Mechanism of action  Inhibits thyroid hormone synthesis by interfering with iodine incorporation  Inhibit peripheral deiodination of T4 to T3 (only PTU) Adverse reactions Minor Major Skin reactions 4–6% Polyarthritis 1–2% Arthralgias 1–5% ANCA-positive vasculitis Rare Gastrointestinal effects 1–5% Agranulocytosis 0.1–0.5% Abnormal sense of taste or smell Rare Immunoallergic hepatitis 0.1–1% Sialadenitis Very rare Cholestasis, hypoglycemia, pancreatitis, hypoprothrombinemia, thrombocytopenia, aplastic anemia Rare ANCA= Antineutrophil Cytoplasmic Antibody
  • 19. Skin reactions of antithyroid drugs N Engl J Med. 2005;352:905-917. Thyroid. 2011;21(6):593. 19 Incidence  Equal frequency for MMI and PTU, approximately 5%  Cross-reactivity between PTU and MMI are up to 50% Associated symptoms  Pruritus, rash, urticarial Management  Mild skin reactions can be treated with antihistamine therapy without stopping MMI or PTU  For serious allergic reactions, therapy should be discontinued and prescribing another thionamide is not recommended
  • 20. Choice of drug in long-term therapy Thyroid. 2009 Jul;19(7):673-4 J Clin Endocrinol Metab. 1987;65(4):719. Thyroid. 2004;14(7):525 Clin Endocrinol (Oxf). 2004;60(6):671. J Clin Endocrinol Metab. 2009;94(6):1881. ANCA= Antineutrophil Cytoplasmic Antibody ATA= American Thyroid Association FDA= Food and Drug Administration 20 ATA and FDA recommended MMI as a first-line drug More quickly reverse hyperthyroidism • Time to achieve euthyroidism MMI 10 mg TID: average 5.8 weeks, PTU 100 mg TID: average 16.8 weeks Once-daily dosing and better compliance • Half-life MMI 4-6 hrs, PTU 75 mins Less likely to be associated with failure of radioiodine therapy • Cured by a 10 mCi dose of subsequent radioiodine therapy pretreated with MMI: 78% of patients, pretreated with PTU: 32% of patients Less toxicity • ANCA-positive vasculitis and severe hepatotoxicity were more strongly associated with PTU than MMI
  • 21. Antithyroid drug-induced agranulocytosis Thyroid 2004;14:459-62. N Engl J Med. 2005;352:905-917. Clin Endocrinol (Oxf). 2004 Nov;61(5):589-94. ANC= absolute neutrophil count MMI=Methimazole PTU= Propylthiouracil 21 Definition  Severe reduction of granulocytes in the peripheral blood with ANC < 500/μL Incidence  MMI: 0.35 %, PTU: 0.37 %  May occur in any age group, without gender difference Outcome  Severe (mortality rate of untreated patients: 6% ) Associated symptoms  Most common: sudden onset of fever and sore throat  Others: chills, cough, rhinorrhea, malaise, gingivitis, oral ulcer, pharyngitis or tonsillitis, dysphagia Our patient ANC: 26/μL Our patient Fever, sore throat, chills, tonsillitis
  • 22. Onset of agranulocytosis Am J Med 1954;17:36-40. Thyroid 2004;14:459-62. N Engl J Med. 2005;352:905-917. Clin Endocrinol (Oxf). 2004 Nov;61(5):589-94. J Clin Endocrinol Metab. 2012 Jan;97(1):E49-53. Endocr Pract. 2012;18:e69-e72 22  Rarely appeared before the 10th day of treatment  Due to slow accumulation of enough drug to induce a reaction in bone marrow tissue  Usually occurs within the first 3 months after initiation  Can also be delayed onset eg. 6 years of MMI  May also occur after renewed exposure following previous course of treatment The cumulative incidence of agranulocytosis Average time to onset: 69 days (range 11-233 days) Our patient: second exposure of MMI 55 days
  • 23. Possible mechanism Expert Opin. Drug Saf. (2007) 6(3):323-335N Engl J Med 2005;352: 905-17. J Clin Endocrinol Metab 1984;58:868-72. 23  Immunological reaction  Appearance of antineutrophil antibodies in the serum of affected patients  Leading to rapid destruction of mature neutrophil granulocytes and their bone marrow precursors  Direct cytotoxic effect Major mechanism
  • 24. Possible risk factors (1) 24 Dose Ref. • Incidence with initial MMI dose of 30 mg (4.11%) significantly higher than 15 mg (0.36%) 1 • A retrospective review of 21,800 patients receiving antithyroid drugs (duration, 15.7 ± 8.4 months) 0 patient developed agranulocytosis with MMI dose < 20 mg/day (n=15,412) 5 patients developed agranulocytosis with MMI dose ≥ 20mg/day (n=5,428) 2 • MMI dose ≥ 40 mg/day were associated with 8.6-fold increased risk of agranulocytosis than dose < 40 mg/day (p <0.001) • The prevalence with PTU was dose-independent 3 1. Endocr J. 2007;54:39-43. 2. Int J Endocrinol Metab. 2006;4:210-215. 3. Ann Intern Med. 1983;98(1):26. 4. Chang Gung Med J 2007;30:242-8 MMI=Methimazole PTU= Propylthiouracil • A case series in Taiwan in 9 patients developed agranulcytosis MMI or carbimazole dose 15-30 mg/day (mean±SD: 22.78±7.12 mg/day) 4 Lower dose reported Our patient MMI 10 mg BID
  • 25. Possible risk factors (2) 25 Age Ref. • The relative risk of developing agranulocytosis in patients over age 40 was 6.4 times that among younger patients (p <0.001) 1 Genetic factor Ref. • A case-control study in Japanese people the HLA DRB1*08032 allele appears to be strongly associated with susceptibility to methimazole-induced agranulocytosis 2 • Case report Methimazole-induced agranulocytosis in a mother and her young daughter 3 1. Ann Intern Med. 1983;98(1):26. 2. Ann Intern Med. 1996;124(5):490. 3. Int J Endocrinol Metab 2006; 4: 113-116.
  • 26. Prognostic factors Ann Intern Med. 2007;146:657-665. Expert Opin Drug Saf. 2007;6(3):323–335. QJM 2001;94:423-8. 26 Poor prognostic criterion  Age > 65 years  Neutrophil count < 100 cells /mm3  Higher rate of localized infections (59 vs 39%, p < 0.001), sepsis (20 vs 6%, p < 0.001) and fatal complications (10 vs 3%, p < 0.001)  Severe clinical infection, such as sepsis or shock  Severe underlying disease or comorbidity  Bone marrow morphology  The speed of neutrophil recovery depends on the number of myeloid precursor cells that are present in the bone marrow  Severe depression of myeloid precursors suggests a prolonged recovery time and a failure to respond to G-CSF GCSF= Granulocyte-colony Stimulating Factor Our patient • 22 year-old • ANC: 26/μL • Acute supportive tonsillitis
  • 27. Management J Endocrinol Invest. 1994;17(1):29. Am J Hematol. 2009 Jul;84(7):428-34. Br J Haematol. 2010;150(1):3. 27  Withdrawal of the offending drug  Regardless of whether the patient is symptomatic  Recovery occurred within 1 to 2 weeks (ranges 7-56 days) without treatment  Antimicrobial therapy  Empirical broad-spectrum antibiotic in patients with fever or infection sign  Granulocyte colony-stimulating factor  Efficacy is not conclusively proven in non oncology setting  Shorten recovery times, length of hospitalization, and less antibiotic use in non-randomized studies  Recommend to administer in poor prognosis patient  Usual dose: 5 mcg/kg/day
  • 28. 28 Case discussion Back to our patient Can we prevent this ADR ?
  • 29. Patient evaluation 1. Ann Intern Med. 1983 Jan;98(1):26-9. 2. N Engl J Med. 2005;352:905-917. 3. J Clin Endocrinol Metab. 2012 Jan;97(1):E49-53. 4. Chang Gung Med J 2007;30:242-8 29 Literature review1,2 Japan (cohort)3 Taiwan (case series)4 Our patient Age (yr) 50.6±16 Higher risk in age> 40 41 (12–74) 39.6 (28-61) 22 Sex (M/F) No gender difference 3/47 3/10 M MMI daily dose (mg) 49.4 (30-60) Higher risk in dose> 40 30 (5–30) 22.78 (15-30) 20 mg Onset (day) Usually within 90 days ( May also occur after renewed exposure) 69 (11–233) 36.4 (12-66) 55 days (Second exposure) Symptoms Fever and sore throat are most common NM Fever (100%), sore throat (76.9%), chills (46.1%) Fever, sore throat, chills Initial WBC(/μL) NM 1300 (400–4500) 1050 (100-2300) 1000 Initial ANC (/μL) NM 18 (0–416) 125 (5-400) 26 Recovery 1-2 weeks (7-56 days) 7 (2-22) days 7.6 (2-13) days 9 days NM= Not mentioned
  • 30. 成大醫院藥物不良反應評估表(1) 30 病患基本資料 床號:10A** 病歷號:******** 姓名: ○○○ 性別:男 該不良反應報告日期與實際發生日期是否相同? ■否 □是 (報告日期:2013/04/21) 不良反應實際發生日期:2013/04/17 出生年月日: 1990/09/21 (22歲) 診斷:Acute tonsillitis and agranulocytosis 促成該不良反應的危險因素: ■否 □是,危險因素為: 是否與藥物交互作用相關:■ 否 □ 是,品項為: 該不良反應的臨床表徵:Agranulocytosis □ Anaphylactic □ GI □ Metabolic □ Cardiovascular ■ Hematologic □ Nephrotoxicity □ CNS □ Hepatic □ Other □ Dermatologic □ Infection  Higher dose,  Age > 40 y/o,  Genetic factor
  • 31. 藥物不良反應相關性評估 Naranjo Score Clin. Pharmacol. Ther. 1981;30 (2): 239–45. 31 Yes No Do not know 1. Are there previous conclusive reports on this reaction? 此不良反應是否有確定的研究報告? +1 0 0 2. Did the adverse events appear after the suspected drug was given? 此不良反應是否發生於服藥之後? Symptoms onset: 55 days, agranulocytosis detected: 59 days +2 -1 0 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given? 當停藥或使用此藥之解藥,不良反應是否減輕? Recovery time: 9 days after stop MMI and G-CSF use for 5 days +1 0 0 4. Did the adverse reaction appear when the drug was readministered? 再次服用此藥,同樣的不良反應是否再度發生? +2 -1 0 5. Are there alternative causes that could have caused the reaction? 有沒有其他原因(此藥以外)可以引起同樣之不良反應? Propranolol: lower risk than MMI, and usually occurred soon after initiation -1 +2 0
  • 32. 藥物不良反應相關性評估 Naranjo Score Clin. Pharmacol. Ther. 1981;30 (2): 239–45. 32 Yes No Do not know 6. Did the reaction reappear when a placebo was given? 當給予安慰劑時,此項不良反應是否也會再度發生? -1 +1 0 7. Was the drug detected in any body fluid in toxic concentrations? 此藥物的血中濃度是否達到中毒劑量? +1 0 0 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 對此病人而言,藥物劑量與不良反應的程度是否成正向關係? +1 0 0 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 病人過去對同樣或類似藥物是否也產生同樣的不良反應? MMI for 34 days, PTU for 15 days +1 0 0 10.Was the adverse event confirmed by any objective evidence? 此不良反應是否有任何客觀證據可證實? +1 0 0 總分 4 ;判斷屬於下列何者: □  9分,確定; □ 5-8分,極可能; ■ 1-4分,可能; □  0分,存疑
  • 33. 成大醫院藥物不良反應評估表(2) 33 可能性評估: □確定 ( 9分) □極可能(5-8分) ■可能(1-4分) □存疑(0分) 嚴重程度: □死亡 □危及生命 □永久性殘疾 □先天性畸形 ■需做處置以防永久性傷害 □導致住院 □增加住院日 □需額外的醫療處置 □自行緩解 藥物不良反應型態:□ Type A (Pharmacological) ■ Type B (Idiosyncratic) 報告來源: □ 經由藥師訪視、住院藥品調配單或病歷記錄 □ 經由其他的預警因素如:緊急處方、實驗數值、報表或電腦 查詢等 □ 其他醫事人員通告如:護士、醫師等 ■ 經由其他醫事人員填寫之藥物不良反應報告表
  • 34. Preventable ADR ? J. Clin. Gastroenterol. (1997) 24:180-183. N Engl J Med. 2005;352:905-917. thyroid. 2011;21(6):593.  Routine monitoring is controversial and not recommended by some authorities  Low incidence of agranulocytosis  Agranulocytosis can occur suddenly (within 1-2 day)  Transient, reversable mild granulocytopenia (granulocyte count < 1500/mm3) - Occasionally occurs as a manifestation thyrotoxicosis itself, and occasionally in patients treated with antithyroid drugs - Does not usually increase the risk of infection and herald the onset of agranulocytosis ATA guidelines do not recommend routine monitoring 34
  • 35. Prevention and screening Thyroid. 2011;21(6):593. 35 Recommendation  A baseline differential WBC count should be obtained before initiation of therapy  White cell count with differential should be obtained immediately and the drug discontinued at the earliest sign of a sore throat or other infection  Patient education  the most cost-effective method All patients should be educated to discontinue the antithyroid drug and contact a physician immediately if fever or sore throat develops, especially within the first 3 months of medication
  • 36. Alternative treatment options Thyroid. 2011;21(6):593. N Engl J Med. 2005;352:905-917. 36  Substitution with another thionamide is contraindicated  Carbimazole is identical to methimazole is rapidly metabolized to methimazole in the liver after absorption  50% chance of cross-sensitivity between propylthiouracil and methimazole  Agranulocytosis is a severe and possible fatal ADR  Radioiodine therapy or surgery may be better choices than the use of another type of antithyroid drug
  • 37. 紀錄者意見 37  There is a reasonable time relationship between drug intake and agranulocytosis developed  Propranolol can also cause agranulocytosis, but MMI has a higher risk and clinical features consistent with our patient  This is a severe and possible fatal ADR with significant cross sensitivity between MMI and PTU, so this patient should not rechallenge these drugs in future  Radioiodine therapy may be an alternative treatment option
  • 38. Take home message 38 Incidence Management • MMI: 0.35%, PTU: 0.37% • G-CSF therapy to patients results in a good prognosis • Recommend to administer in poor prognosis patient Onset • Most frequently in the first 3 months • But can be delayed onset Presentation Prevention and screening • Fever and sore throat are most common • Early detection is the key factor Educating patients about the common symptoms of agranulocytosis may contribute to an early diagnosis  The most cost-effective method Possible Risk factors • Higher dose • Age > 40 y/o • Genetic factor
  • 39. Thanks for your attention!!! Any questions and comments are welcome! 39
  • 40. Thyrotoxic periodic paralysis 40 Thyrotoxic periodic paralysis Diagnosis and associated features Paralytic attack that is associated with hypokalemia and hyperthyroidism (low TSH with high T4 or high T3) Mechanism Thyroid hormone increases tissue responsiveness to beta-adrenergic stimulation  Increases Na-K ATPase activity on the skeletal muscle membrane  Drive potassium into cells  Hyperpolarization of the muscle membrane  Paralyses Etiology Thyrotoxicosis Possible inherited predisposition Age at onset >20 years Attack duration Hours to days Epidemiology Highest incidence in Asians, men > women Precipitants Rest after strenuous exercise High-carbohydrate load Stress Preventive treatment Euthyroid state Propranolol
  • 41. 41 Hypokalemic Periodic Paralysis Thyrotoxic Periodic Paralysis Hyperkalemic Periodic Paralysis Andersen Syndr Age at onset First or second decade >20 years First decade First or second dec Attack frequency Infrequent (a few times a year) Infrequent Frequent (up to several a day) Monthly Attack duration Hours to days Hours to days Minutes to hours Days Precipitants Exercise Carbohydrate load Stress Exercise Carbohydrate load Stress Exercise Fasting Stress K-rich food Rest after exercise Potassium level during attack Low Low Normal or elevated Low, normal, or ele Associated features Later onset myopathy Symptoms of thyrotoxicosis Low TSH with high T4 or high T3 Myotonia on examination and/or EMG Later onset myopathy Dysmorphic featur Ventricular arrhyth Long QT interval Etiology Autosomal dominant inherited defect in calcium or sodium ion channel on muscle membrane Thyrotoxicosis Possible inherited predisposition Autosomal dominant inherited defect of sodium ion channel on muscle membrane Autosomal domina inherited defect of inward rectifying potassium channel Penetrance Nonpenetrance common, especially in women High Nonpenetrance an incomplete penetr common Epidemiology Clinical expression in men more frequent than women Highest incidence in Asians and in men more than women Sexes equally affected Marked intrafamili phenotypic variatio Preventive treatment Carbonic anhydrase inhibitors Potassium-sparing diuretics Euthyroid state Propranolol Carbonic anhydrase inhibitors Thiazide diuretics Inhaled beta-agonists as Carbonic anhydras inhibitors
  • 42. 42
  • 43. 健保給付規範-白血球生長激素 (G-CSF) 43 短效型注射劑 (如 filgrastim、lenograstim) : (85/10/1、93/4/1、96/1/1、101/6/1) 1. 限  用於造血幹細胞移植患者。  血液惡性疾病接受靜注化學治療後。  先天性或循環性中性白血球低下症者(當白血球數量少於1000/cumm,或中性白血球(ANC) 少於500/cumm)。  其他惡性疾病患者在接受化學治療後,曾經發生白血球少於1000/cumm,或中性白血球 (ANC)少於500/cumm者,即可使用。(96/1/1)  重度再生不良性貧血病人嚴重感染時使用,惟不得作為此類病人之預防性使用。  化學治療,併中性白血球缺乏之發燒,若中性白血球小於100/cumm、癌症不受控制、肺 炎、低血壓、多器官衰竭或侵犯性黴菌感染等危機程度高之感染。  對於骨髓造血功能不良症候群(MDS)的病人,若因嚴重性的中性白血球過低 (ANC<500/cumm)而併發感染時,可間歇性使用G-CSF,但不得作為長期且常規性使用。  週邊血液幹細胞的趨動─不論在自體或異體幹細胞的收集,應於收集前之4~5日開始皮下注 射G-CSF,其劑量為10μg /KG/day。 2. 患者如白血球超過4000/cumm,或中性白血球超過2000/cumm時,應即停藥。惟當預估其骨 髓功能不易恢復時,雖其血球已達上述標準,仍可給予半量之治療,若仍可維持血球數,則 可給予四分之一劑量,若仍可維持血球數,則停用。任何時候,若白血球或中性白血球數過 度增高,即應停藥。
  • 44. G-CSF 44 Mechanism of Action  Stimulates the production, maturation, and activation of neutrophils; filgrastim activates neutrophils to increase both their migration and cytotoxicity. Pharmacodynamics/Kinetics  Onset of action: ~24 hours; plateaus in 3-5 days  Duration: Neutrophil counts generally return to baseline within 4 days  Absorption: SubQ: 100%  Distribution: Vd: 150 mL/kg; no evidence of drug accumulation over a 11- to 20-day period  Metabolism: Systemically degraded  Half-life elimination: 1.8-3.5 hours  Time to peak, serum: SubQ: 2-8 hours
  • 45. A case of delayed onset of agranulocytosis Endocr Pract. 2012;18:e69-e72  A 53-year-old woman had been treated continuously with antithyroid drugs for 11 years– PTU for 5 years and MMI for 6 years—before the onset of agranulocytosis Case report Drug-induced agranulocytosis can occur after a very prolonged period of low-dose treatment with antithyroid medications 1998/02 PTU 100-150 mg/day 2003/07 2009/03 AgranulocytosisMMI 20-30 mg 2004/02 MMI 5-15 mg
  • 46. Risk factors- initial dose Endocr J. 2007;54:39-43. Results  514 patients with Graves’ disease in Japan  9 patients (1.75%) developed agranulocytosis due to MMI treatment Statistically significant difference in agranulocytosis incidence between patients receiving 30 mg MMI and those receiving 15 mg MMI
  • 47. Risk factors- dose Int J Endocrinol Metab. 2006;4:210-215. 21800 received antithyroid drugs MMI 20840 Low doses (<20mg/day) 15412 Agranulocytosis 0 High doses (≥20mg/day) 5428 Agranulocytosis 5 PTU 960 Agranulocytosis 2 No patients receiving a methimazole dose < 20 mg daily developed agranulocytosis • A retrospective review of 21,800 patients receiving ATDs (duration, 15.7 ± 8.4 months)
  • 48. Risk factors- dose Int J Endocrinol Metab. 2006;4:210-215. The majority of agranulocytosis occurred within the first few weeks of ATD therapy
  • 49. Risk factors- Age and Drug Dose Ann Intern Med. 1983;98(1):26. Objective  Investigated the role of patient age, dosage and type of thionamide used, on development of agranulocytosis Results  Higher doses of MMI (> 40 mg/day) were associated with 8.6-fold increased risk of agranulocytosis (p <0.001)  Age over 40 years caused higher risk of development of agranulocytosis  The prevalence with PTU was dose-independent Agranulocytosis Associated with Antithyroid Drugs: Effects of Patient Age and Drug Dose DAVID S. COOPER, M.D.; DAVID GOLDMINZ, B.S.; ANN A. LEVIN, M.S.; PAUL W. LADENSON, M.D.; GILBERT H. DANIELS, M.D.; MARK E. MOLITCH, M.D.; and E. CHESTER RIDGWAY, M.D.
  • 50. Risk factors- genetics Ann Intern Med. 1996;124(5):490.  A case-control study in japanese people Objective  To determine the possible role of genetic factors in the development of methimazole-associated agranulocytosis in patients with graves disease Results  Among japanese patients with graves' disease, the HLA DRB1*08032 allele appears to be strongly associated with susceptibility to methimazole-induced agranulocytosis Association between the DRB1*08032 Histocompatibility Antigen and Methimazole-Induced Agranulocytosis in Japanese Patients with Graves Disease Hajime Tamai, MD; Tohru Sudo, MD; Akinori Kimura, MD; Toshio Mukuta, MD; Sunao Matsubayashi, MD; Kanji Kuma, MD; Shigenobu Nagataki, MD; and Takehiko Sasazuki, MD
  • 51. Risk factors- genetics Ann Intern Med. 1996;124(5):490.  A case-control study in japanese people Objective  To determine the possible role of genetic factors in the development of methimazole-associated agranulocytosis in patients with graves disease Results  Among japanese patients with graves' disease, the HLA DRB1*08032 allele appears to be strongly associated with susceptibility to methimazole-induced agranulocytosis Association between the DRB1*08032 Histocompatibility Antigen and Methimazole-Induced Agranulocytosis in Japanese Patients with Graves Disease Hajime Tamai, MD; Tohru Sudo, MD; Akinori Kimura, MD; Toshio Mukuta, MD; Sunao Matsubayashi, MD; Kanji Kuma, MD; Shigenobu Nagataki, MD; and Takehiko Sasazuki, MD Limitation of clinical utility • HLA typing is impractical-time and cost • Result indicates susceptibility only in japanese people • Positive result for a specific allele does not imply that methimazole should be withheld in patients with Graves hyperthyroidism, because of sufficiently low frequency of agranulocytosis in patients with these alleles
  • 52. Risk factors- genetics Int J Endocrinol Metab 2006; 4: 113-116  It seems reasonable to avoid the use of thionamide derivates in hyperthyroid relatives of patients who have had thionamide- induced agranulocytosis
  • 53. Suggest PTU instead of MMI 53  In pregnant women during their first trimester  In patients with life-threatening thyrotoxicosis or thyroid storm  Because of PTU’s ability to inhibit peripheral conversion of T4 to T3  In patients with adverse reactions to MMI who are not candidates for radioiodine or surgery  Other than agranulocytosis
  • 54. Rate of prolonged remission 54  20-30 % of patients treated with a thionamide for one to two years  Increased likelihood of remission  Initially TSH-receptor antibody-negative (77% vs 36%)  Disappearance of tsh-receptor antibodies during thionamide therapy  Age > 40 y/o (48% vs 33%, p= 0.01)  Female sex (40% vs 20 %, p< 0.01)
  • 55. Which is causative Agents 55 MMI 10mg BID PTU 10mg TID MMI 10mg BID Propranolol 10mg TID BID 4/171/03 2/06 2/21 21 Fever, sore throat Admission Agranulocytosis ANC: 26/μL MMI=Methimazole PTU= Propylthiouracil ANC= absolute neutrophil count -4 day-59 day day 1
  • 56. Propranolol vs MMI ? Arch Intern Med. 1999;159:369-74. Clin Pharmacol Ther. 1991;49:330-41. JAMA. 1973 Mar 19;223(12):1376-7 56 Relative risk (95% CI) Duration of drug use Our patient Methimazole 230.9 (120.4–453.5) Usually within the first 3 months use 55 days Propranolol 2.5 (1.1–6.1) Risks appeared to be highest shortly after initiation 10 mg tid/bid for 108 days A case report A 64 year-old man with arrhythmia developed agranulocytosis after 6 days of propranolol 40 mg Q4H use A population-based case-control study in Europe Duration (days) Exoposed c (n=22) < 28 7 (32%) 28-89 6 (27%) ≥ 90 9 (41%) nolol, among a total of 22 exposed cases, 7 (32%) been exposed for less than 28 days, whereas the esponding data for the exposed control subjects e 1 of 26 (4%). Th
  • 57. Cases comparison 1. Q J Med 1999; 92:455-461 2. J Chin Med Assoc 2009; 72: 395-401. 3. Chang Gung Med J 1991;14:168-73 57 Taiwan1 Taiwan2 Taiwan3 Our Case Age/sex 27/M 53/F 50/F 22/M Disease Graves’ disease Graves’ disease Graves’ disease Grave’s disease MMI dose 30 mg/day 30 mg/day 30 mg/day 20 mg/day Treatment duration 61 days 46 days Second exposure 23 days Second exposure 59 days Symptoms Fever, sore throat, chills Fever, sore throat, diarrhea NM Fever, sore throat, chills Clinical diagnosis Acute tonsillitis NM NM Acute tonsillitis Initial WBC/ANC (/μL) 850/0 450/0 1700/34 1000/26 G-CSF use + + - + Recovery 9 days 7 days 12 days 10 days NM= Not mentioned

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