Methimazole was suspected to have caused agranulocytosis in a 22-year-old male being treated for Graves' disease. He developed fever and sore throat and was found to have a very low absolute neutrophil count of 26/uL. He was hospitalized and treated with antibiotics, granulocyte colony-stimulating factor, and discontinuation of methimazole. His white blood cell count and symptoms improved after treatment. Methimazole has been known to cause agranulocytosis, especially within the first 3 months of use, and is the most likely causative agent given the patient's clinical course and timeline of methimazole therapy.

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