3. 成大藥物不良反應通報表
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）
1. 發生日期︰2013/04/04 2. 通報者獲知日期︰2013/04/04
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︰34歲
8. 體重︰62.2 公斤
9. 身高︰168.5 公分
3
4. 其他相關資料
Past Medical History
• Rectal cancer, adenocarcinoma, KRAS mutation: G12D, with multiple liver
metastasis and possible R’t cardiac involvement, stage IV,
s/p FOLFIRI + Bevacizumab*3, in progression, s/p FOLFOX*4
• Alcoholic hepatitis
Drug Allergy Family History
• NKDA • Not contribution
Social History
• Smoking (+)
• Betel nut (+)
• Drinking (+)
• Drug abuse (-)
4
5. 通報事件之描述 (1)
NCKUH GI OPD
• Lower abdominal cramping pain and bloody stool for month
Colonscopy
• Rectal tumor mass at 10 cm above AV (anal verge)
• External hemorrhoid
Biopsy and pathologic finding
• Adenocarcinoma
Abdominal CT
• Rectal tumor with pre-sacral invasion
• Multiple liver metastasis and one nodular lesion at right cardiac ventricle
T4N2M1 stage IV
分子診斷檢驗報告: KRAS mutation: G12D
2012
11/20
11/05
10/26
10/01
5
6. 通報事件之描述 (2)
6
10/26
Diagnosis
Rectal cancer with liver
metastasis, T4N2M1 stage IV
11/29
2012
01/14
2012/11/1 12/14 2013/1/4 1/21
CEA.(ng/mL) 1739 2752 3373 3042
FOLFIRI + Bevacizumab (3 cylcles)
Premedication
Diphenhydramine, Dexamethasone,
Metoclopramide, Granisetron,
Atropine
C/T drug
Irinotecan, Leucovorin, 5FU,
Bevacizumab
CEA
abd CT: increased size of liver and
cardiac metastasis
02/01 05/06
mFOLFOX6 (7 cylcles)
Premedication
Diphenhydramine, Dexamethasone,
Metoclopramide, Granisetron,
C/T drug
Oxaliptin
Leucovorin
5FU
2013
765
ADR
7. 通報事件之描述 - 1st hypersensitivity
7
4/4 - 5th mFOLFOX6
• 168.5cm, 62.2kg, BSA: 1.71
• TPR: 36/85/19, BP: 116/86
ADR EVENT
15:10 Oxaliplatin (85mg/m2) 150mg in D5W 250ml IVD 2hr
15:44 (已滴注Oxaliplatin 38.4mg)
Dyspnea, erythema and generalized itching, 焦躁坐立不安, 流鼻水
TPR: 36.6/96/30, BP: 128/72, SpO2: 96%
MANAGEMENT
15:45 Hold oxaliplatin
Hydrocortisone 100mg IVD stat
15:46 Epinephrine 0.5mg IM stat
15:50 Diphenhydramine 30mg IVD stat
16:10 皮膚泛紅、流鼻水、呼吸喘情形皆有改善
TPR: 36.6/104/21, BP: 129/74, SpO2: 98%
4/5 5‐FU and leucovorin via infusor
8. 通報事件之描述 – 2nd hypersensitivity
8
4/19 - 6th mFOLFOX6
• 168.5cm, 63.1kg, BSA: 1.72
• TPR: 36.2/92/18, BP: 126/82
• Add ranitidine and prolong oxaliplatin infusion time
ADR EVENT
16:10 Ranitidine 50 mg IVD
17:15 Oxaliplatin (85mg/m2) 150mg in D5W 250ml IVD 6hr
18:00 (已滴注Oxaliplatin 19.2mg)
全身癢，前胸臉頰皆有紅疹情形，煩躁不安
TPR: 37.6/106/20, BP: 136/89
MANAGEMENT
18:00 Hold oxaliplatin
18:02 Epinephrine 0.3mg IM stat
Diphenhydramine 30mg IVD stat
18:09 Hydrocortisone 100mg IVD stat
20:00 主訴已無不適情形，TPR: 36.6/88/18, BP: 113/86
21:15 5‐FU and leucovorin via infusor
12. Outline
Oxaliplatin induced hypersensitivity reaction
Incidence and clinical features
Pathophysiology
Management
ADR evaluation
Case discussion
Take home message
Patient evaluation
Treatment strategies
13. Outline
Oxaliplatin induced hypersensitivity reaction
Incidence and clinical features
Pathophysiology
Management
ADR evaluation
Case discussion
Take home message
Patient evaluation
Treatment strategies
14. 14
Hypersensitivity Reaction (HSR)
Anticancer Drugs. 2009 Jan;20(1):1-6.
Met Based Drugs. 2010;2010. pii: 207084.
Type Mediators Symptoms related
I IgE
Early onset symptoms:
Itching, rash, angioedema, bronchospasm ,
anaphylactic reactions
II
(Cytotoxic)
IgG, IgM, Hemolysis, thrombocytopenia
III
(Immune complex)
IgG Chronic urticaria, joint pain, proteinuria
IV
(Delayed,
cell-mediated)
T-cells
Delayed reactions, hours or days after infusion:
Contact dermatitis, morbilliform eruptions
Definition
• Unexpected reactions with signs and symptoms inconsistent with known
toxicity of the drugs
(unpredictable, not related to the pharmacologic reactions)
Symptoms
1st HSR Dyspnea, erythema and generalized itching, 焦躁坐立不安, 流鼻水
2nd HSR 全身癢，前胸臉頰皆有紅疹情形，煩躁不安
3rd HSR 全身發紅起紅疹，雙手、雙腳及後背癢，大腿內側尤其明顯
15. Which is the culprit drug ?
15
1st
2nd
3rd
4th
5th
6th
7th
2/1 2/15 3/2 3/22 4/4 4/19 5/3 5/6
Antiemetics (IVD before C/T)
Diphenhydramine 30 mg D1
Dexamethasone 10mg D1 20 mg
Metoclopramide 10mg q8h D1,2
Granisetron 3mg D1
Ranitidine 50mg D1 Before oxaliplatin
Hydrocortisone 100mg Before bag 5
C/T drug
Oxaliplatin (85mg/m2
)
in D5W 250ml IVD 2hr
150 mg IVD 6hr Desensitization
Leucovorin (400mg/m2
)
in D5W 250ml IVD 2hr
700 mg 680 mg
5-FU (2400mg/m2
) in D5W
500ml IVD 46hr pump
4200
mg
4150
mg
4100
mg
Long-term medication
MgO 250mg tid
Bisacodyl 10mg hs
Morphine 5mg q4h
Naproxen 250mg bid
Estazolam 2mg hs
Chlorpromazine 50mg prn
1st HSR
16. 16
Which is the culprit drug ?
Diphenhydramine
Dexamethasone
Metoclopramide
Granisetron
Oxaliplatin
Leucovorin
5-FU
ADR
FOLFOX
s/p FOLFIRI + Bevacizumab
(11/29-01/14)
Premedication
Diphenhydramine
Dexamethasone
Metoclopramide
Granisetron
Atropine
C/T drug
Irinotecan
Leucovorin
5FU
Bevacizumab
18. Outline
Oxaliplatin induced hypersensitivity reaction
Incidence and clinical features
Pathophysiology
Management
ADR evaluation
Case discussion
Take home message
Patient evaluation
Treatment strategies
19. 19
Oxaliplatin
Pharmacological Properties
Third-generation platinum derivative, an alkylating agent
Covalently binds to DNA forming cross-links which inhibit DNA
replication and transcription, resulting in cell death
Cell-cycle nonspecific
Indication
Micromedex, Uptodate
Expert Opin Drug Saf. 2006 Sep;5(5):687-94.
[(1R,2R)-cyclohexane-1,2-diamine]
(ethanedioato-O,O')platinum(II)
FDA-labeled
In combination with 5-FU/leucovorin
• Stage III colon cancer, adjuvant
• Metastatic colorectal cancer, first-line
Unlabeled
Esophageal cancer, gastric cancer, hepatobiliary cancer, non-hodgkin's
lymphoma, ovarian cancer, pancreatic cancer, testicular cancer
20. 20
Oxaliplatin
Product Information: ELOXATIN ®. Sanofi-Aventis U.S. LLC, Bridgewater, NJ, 2011
Drugs 2000; 60(4):895-924.
Common Side Effects (>10%)
Hematologic Anemia, thrombocytopenia, leukopenia, lymphopenia
Immunologic Allergic reaction (skin rash, conjunctivitis, rhinitis)
Neurologic Peripheral neuropathy (dose limiting), dysgeusia, headache
Respiratory Dyspnea, cough
Gastrointestinal N/V, diarrhea, abdominal pain, constipation, anorexia, stomatitis
Musculoskeletal Back pain
Other Fatigue, fever, hepatic enzyme increase
Clinical trials & post marketing experience
Pharmacokinetics
Distribution Vd: 440 L
Protein binding: >90% (irreversible binding)
Metabolism Nonenzymatic biotransformation, rapid and extensive
Excretion Urine: 54%; feces: 2%
Elimination Half Life T1/2α: 0.43 h, T1/2β: 16.8 h, T1/2γ: 391 h
21. 21
Oxaliplatin-associated hypersensitivity reactions
Incidence
Rising incidence as a result of increasing clinical use
Usually are mild, but life-threatening anaphylactic reactions can occur
Expert Opin Drug Saf. 2006 Sep;5(5):687-94.
Met Based Drugs. 2010;2010. pii: 207084.
Semin Radiat Oncol. 2003 Jul;13(3):176-81.
CTCAE = Common Toxicity Criteria for Adverse Events
HSR = hypersensitivity reaction
Grading of Hypersensitivity Reactions (CTCAE, v3.0)
Grade 1 Transient flushing or rash, drug fever < 38°C
Grade 2 Rash, flushing, urticaria, dyspnea, drug fever > 38°C
Grade 3 Symptomatic bronchospasm, with or without urticaria; parenteral
medication indicated; allergy-related edema/angioedema; hypotension
Grade 4 Anaphylaxis
Grade 5 Death
Overall Grade 3-4
10-18.9% 1-2%
22. 22
Clinical features:
Retrospectively analyzed 308 cases of hypersensitivity reaction related
to oxaliplatin
76% patients with colorectal cancer (81% metastatic, 19% adjuvant)
Regimen: FOLFOX (Oxaliplatin 85-130 mg/m2 IVD 2hours)
Mild reaction (n = 195; 63%) Severe reaction (n = 113; 37%)
Symptoms Flush, localized skin rash and
itching (particularly on palms
and soles), fever, chills, nausea,
vomiting, abdominal pain,
malaise
severe erythema, angioedema,
bronchospasm, laryngospasm
tachycardia, hypotension
Initial onset Mostly after 6th course, median 9th (range 1-24)
Time of onset Either upon completion of
oxaliplatin infusion or during
the next few hours
Within 5–10 min of drug
infusion
Outcome
Reversible upon oxaliplatin withdrawal and symptomatic treatment
(within minutes or hours)
A 10-year experience in a single institute Oncology 2009;76:36–41
23. 23
Pathophysiology
Most oxaliplatin HSR seem to be IgE-mediated type I reactions
1. Expert Opin Drug Saf. 2006 Sep;5(5):687-94.
2. Met Based Drugs. 2010;2010. pii: 207084.
3. Ann Oncol. 2000 Apr;11(4):497.
4. Jpn J Clin Oncol. 2009 Sep;39(9):616-20.
5. Ann Oncol. 2001 Jan;12(1):132-3.
Reported possible mechanism of oxaliplatin allergic reactions
Type of reaction Onset Mediators Symptoms related Ref
I early IgE
Itching, rash, hypoxemia,
anaphylactic reactions
1,2
II
(Cytotoxic)
late IgG, IgM,
Hemolysis,
thrombocytopenia
3
III
(Immune complex)
late IgG
Chronic urticaria, joint pain,
proteinuria
4
Idiosyncratic
reaction
late
nonimmune-mediated
cytokine release
(IL-6, TNF-a)
Chills, fever, N/V, abdominal
cramps, diarrhea, chest
tightness, hypotension
5
Symptoms of
our patient
1st HSR Dyspnea, erythema and generalized itching, 焦躁坐立不安, 流鼻水
2nd HSR 全身癢，前胸臉頰皆有紅疹情形，煩躁不安
3rd HSR 全身發紅起紅疹，雙手、雙腳及後背癢，大腿內側尤其明顯
24. Type I hypersensitivity reaction
Trends Immunol. 2008 Dec;29(12):633-42.
Allergen re-exposed
Oxaliplatin associated type I HSR
• Need of multiple infusions for sensitization
• Rapid onset symptoms
• Positive intradermal skin tests in majority of patients with history of
oxaliplatin hypersensitivity
24
Sensitization
25. 25
Risk factors
Oncology 2009;76:231–238
USA, N=29/247 (11.7%)
Female sex
Female 17.2% p= 0.01
Male 6.4%
Younger mean age
With HSR 54.9±12.5 p= 0.02
Without HSR 60.4±12.4
Use of oxaliplatin as salvage therapy
Initial 9.1% p=0.01
2nd line or higher 23.9%
J Formos Med Assoc 2010;109(5):362–368
Taiwan, N=43/383 (12.7%)
Premedication with 5 mg dexamethasone
5 mg vs. ≥ 10mg HR 2.094 (1.141–3.843)
Higher oxaliplatin dose
3rd quartile vs.
1st quartile
HR 1.024 (1.007–1.040)
Oncology 2010;79:136–143
Japan, N=45/223 (20.1%)
Younger age
< 60 y vs. ≥ 60 y OR 3.5 (1.4–8.6)
Oxaliplatin-free interval in stop-and-go
FOLFOX
Yes vs. no OR 3.1 (1.2–7.7)
Stop-and-go strategy
• To reduce neurotoxicity
• Preplanned withdrawal of oxaliplatin after six
cycles and reintroduction of FOLFOX at the
time of disease progression
26. 26
Management of HSR
1. Stop oxaliplatin infusion immediately
2. Administer:
• I.V. Antihistamines
• Low-dose corticosteroids
3. In case of a more severe reaction (dyspnea, laryngospasm, bronchospasm)
• Oxygen, bronchodilators
• High dose steroids (hydrocortisone 100-1000 mg)
4. In case of hypotension or airway obstruction symptoms
• Epinephrine
5. Monitoring until symptoms resolve completely or for several hours later in
case of severe hypersensitivity
Expert Opin Drug Saf. 2006 Sep;5(5):687-94.
Met Based Drugs. 2010;2010. pii: 207084
27. Outline
Oxaliplatin induced hypersensitivity reaction
Incidence and clinical features
Pathophysiology
Management
ADR evaluation
Case discussion
Take home message
Patient evaluation
Treatment strategies
28. 28
Patient evaluation
Japan
21/125 (17%)
60 (42-78)
19% / 15%
-
9 (2-15)
-
-
Gr1-2 (76%)
1. Oncology 2009;76:231–238 2. Ann Oncol. 2006 Feb;17(2):259-61. 3. J Formos Med Assoc. 2010 May;109(5):362-8.
USA 1 Hong kong 2 Taiwan 3 Our patient
N (incidence) 29/247 (11.7%) 27/180 (15%) 47/383 (12.3%) -
Age (yr) 54.9 (42-67) - 61 (21-91) 34
Sex (F/M) 17.2% / 6.4% - - M
Line of
therapy
Salvage 24.9%
Initial 9%
Salvage 19.6%
Initial 10.2%
- Salvage
Cycles (median) 7 (1–11) 8.5 (1-18) 10 (2-19)
85% after 6th cycle
5
Onset (min) 70 (10-240) 55.6% pt < 60 40 (5-215)
88.7% pt < 120
1st : 34
2nd : 45
Most
common
symptoms
Flushing (52%)
Urticarial (52%)
Dyspnea (24%)
Rash (44%)
Itchiness (33%)
Fever/chills (29%)
Flushing (29%)
Chest tightness (18%)
Cutaneous (70%)
Respiratory (30%)
Fever (25%)
HTN (18%)
Chills (18%)
Erythema
Itching
Dyspnea
焦躁坐立不安
流鼻水
Severity Gr1-2 (86%) Gr1-2 (85%) Gr1-2 (90.7%)
1 pt died of
anaphylactic shock
Gr 2
29. 29
Treatment Strategies
Expert Opin Drug Saf. 2006 Sep;5(5):687-94.
Oncology 2009;76:36–41
Modereate-Severe reactions
Respiratory disturbance,
cardiovascular reaction,
skin reactions, angioedema
Life-threatening reactions
Anaphylactic shock,
cardiac arrest
No standardized protocol for reintroduction was established
• Infusion rate and premedication
• Desensitization protocols
• Alternative treatment options
Definitive drug
discontinuation
Mild-moderate reactions
Localized skin rash, itching,
fever, chills, N/V, abdominal
pain, malaise
Evaluate the risk and benefit of reintroduce
4/19 2nd HSR
5/06 3rd HSR
30. 30
Infusion rate and premedication
Patients with mild to moderate hypersensitivity reactions to
oxaliplatin may be able to tolerate rechallenge with
Premedication with antihistamine, steroids
Increase infusion duration
J Support Oncol 2008;6:373–378
Expert Opin Drug Saf. 2006 Sep;5(5):687-94.
30 pt with Gr1/2 HSR
A retrospective study in a single institute in Japan
Rechallenge with secondary prevention
• Premedication:
(30 min before oxaliplatin infusion)
Dexamethasone 20 mg IV
Diphenhydramine 50 mg PO
Famotidine 40 mg PO
• Prolong infusion (2 4hr)
Successful prevention ≥ 2 courses
19 (63.3%)
Failure
11 (36.7%)
Severity on 2nd HSR
• Equivalent: 9 (81.8%)
• Worse: 2 (18.2%)
Premedications cannot prevent all HSR, and
mild reactions may escalate to severe reactions
Our patient- 4/19 2nd HSR
Dexamethasone 10 mg
Diphenhydramine 30 mg
Ranitidine 50mg
Prolong infusion (2 6hr)
31. Reported desensitization protocols for oxaliplatin
1. Oncologist2004; 9:546–549
2. Clin Transl Oncol. 2013 Mar;15(3):219-25.
3. Clin Colorectal Cancer. 2009 Mar;8(2):106-9
4. Anticancer Drugs. 2004 Jul;15(6):605-7.
Ref n Premedication Steps Duration Success rate
1 1
(Gr3)
• Dexamethasone PO for 1 day
• Diphenhydramine IVD
Hydrocortisone 100 mg IVD
before oxaliplatin
5 steps
From 1 : 10000
to 1 : 1
8 h 100 %
2 53
(Gr1-3)
• Corticosteroids 1mg/kg/d
Ranitidine 300mg/d
Cetirizine 20mg/d
Montelukast 10mg/d
For 1 day and 30 min before oxaliplatin
13 steps
From 1: 10000
to 1 : 1
3-4 h 89 %
3 3
(Gr1-2)
• None 13 steps
From 1 : 100000
to 1 : 1
8 h 100 %
4 1
(Gr2)
• Diphenhydramine 50mg PO QID
for 1 day
• Diphenhydramine 30 mg IVD
Dexamethasone 5mg IVD
before oxaliplatin
Continuous fixed rate
(0.15 mg/ml)
24 h 100 %
Administer premedication Escalating concentrations Prolonged infusion
32. 5 steps desensitization protocols
32
Ref n Premedication Steps Duration Success rate
1 1
(Gr3)
• Dexamethasone PO for 1 day
• Diphenhydramine IVD
Hydrocortisone 100 mg IVD
before oxaliplatin
5 steps
From 1 : 10000
to 1 : 1
8 h 100 %
Our patient
Premedication (IVD before C/T)
Diphenhydramine 30 mg IVD
Dexamethasone 20 mg IVD
Ranitidine 50 mg IVD
Hydrocortisone 100 mg IVD 4hr (bag5 30min前給)
C/T drug Conc (mg/ml)
Oxaliplatin 0.014 mg in D5W 100ml IVD 1hr [bag 1] 0.00014
Oxaliplatin 0.14 mg in D5W 100ml IVD 1hr [bag 2] 0.0014
Oxaliplatin 1.4 mg in D5W 100ml IVD 1hr [bag 3] 0.014
Oxaliplatin 14 mg in D5W 100ml IVD 1hr [bag 4] 0.14
Oxaliplatin 126 mg in D5W 100ml IVD 4hr [bag 5] 1.26
HSR: 35ml
Oncologist2004; 9:546–549
33. 34
Desensitization protocols
Disadvantages
Time-consuming
Inconvenience of the patient
Burden of the oncology departments
Risks and benefits must be carefully weighed before offering
desensitization procedure
Patients should be informed of the danger as there is still risk
of anaphylaxis, or even death during the rechallenge
Indicated especially for patient who
Have been benefited by the drug
No alternative treatment options
Expert Opin Drug Saf. 2006 Sep;5(5):687-94.
Oncology 2009;76:36–41.
Met Based Drugs. 2010;2010. pii: 207084
35. Alternative treatment options ?
Treatment sequencing options for patients with metastatic colorectal
cancer who can tolerate intensive therapy
Initial therapy
FOLFIRI + bevacizumab
Therapy after 1st progression
• FOLFOX or CAPOX
• Irinotecan + cetuximab
(WT KRAS only)
• Cetuximab or panitumumab
(WT KRAS only)
Therapy after 2nd progression
• Irinotecan + cetuximab
(WT KRAS only)
• Cetuximab or panitumumab
(WT KRAS only)
• Regorafenib
Therapy after 3rd progression
• Regorafenib (if not given previously)
• Clinical trial
• Best supportive care
34 y/o, male
• T4N2M1 stage IV
• KRAS mutation: G12D
36
WT: wild-type
Approval
FDA 2012/09
TFDA 2013/10
36. 37
Regorafenib tab 40mg/tab (Stivarga)
Mechanism of Action
A multikinase inhibitor, involved with tumor angiogenesis, oncogenesis,
and maintenance of the tumor microenvironment
適應症
適用於治療先前曾接受下列療法的轉移性大腸直腸癌患者，療法包括
fluoropyrimidine-、oxaliplatin-、irinotecan-為基礎的化療，和anti-VEGF等療法
160 mg QD PO for the first 21 days of each 28-day cycle
Common side effect
Asthenia/fatigue, hand-foot skin reaction, diarrhea, decreased appetite,
hypertension, mucositis…
Micromedex, uptodate
NCKUH 專案藥品
Severe and sometimes fatal hepatotoxicity has been
observed in clinical trials
37. Our patient
39
1st HSR 2nd HSR 3rd HSR
Protocol Standard Rechallenge Desensitization
Premedication Diphenhydramine 30mg
Dexamethasone 10 mg
Diphenhydramine 30mg
Dexamethasone 10 mg
Ranitidine 50 mg
Diphenhydramine 30mg
Dexamethasone 20 mg
Ranitidine 50 mg
Infusion
duration
2 h 6 h 8 h
Onset 34 min 45 min 4 h 50 min
Dosage 38.4 mg 19.2 mg 50.6 mg
Symptoms Dyspnea, erythema and
generalized itching, 焦躁
坐立不安, 流鼻水
全身癢，前胸臉頰皆有
紅疹情形，煩躁不安
全身發紅起紅疹，雙手、
雙腳及後背癢，大腿內
側尤其明顯
41. 43
Take home message
Incidence Symptoms
• Overall 10-18.9%, Grade 3-4 1-2%
• Variable (Flush, skin rash, itching,
dyspnea, fever, nausea, tachycardia,
hypotension, anaphylaxis…)
Initial onset
• Mostly after 6th cycles
Time of onset Can it be reintroduced ?
• Minutes-hours
Yes (except life-threatening reactions)
• Premedication
• Prolong infusion time
• Desensitization protocol
Cannot prevent all HSR
Mild reactions may escalate into severe
reactions
Patients should be informed of the risk
Possible Risk factors
• Female sex
• Younger age
• Oxaliplatin as salvage therapy
• Lower dexamethasone dose
• Higher oxaliplatin dose
• Oxaliplatin-free interval
