10 MRM (modified radical mastectomy) CMF (5FU+MTX+cyclophosphamide) C6-T2, T11-L5 T3-T zoledronic acid 4 mg zoledronic ac

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1 用藥安全 Drug Safety 雙磷酸鹽類藥物可能引發顎骨壞死不良反應 國泰綜合醫院藥劑科藥師洪嘉慧 鄭繼鳳 林惜燕 摘要 (biphosphonates; BPs) 2009 (osteonecrosis of the jaws; ONJ) 0.8~12% 0.01~0.04% 5~21 57 (zoledronic acid) 9 16 biphosphonates osteonecrosis of the jaws (ONJ) 壹 前言 (biphosphonates; BPs) Marx RE (bisphosphonate-associated osteonecrosis of the jaws; BONJ) 貳 病例報告 THE JOURNAL OF TAIWAN PHARMACY Vol.27 No.2 Jun

2 10 MRM (modified radical mastectomy) CMF (5FU+MTX+cyclophosphamide) C6-T2, T11-L5 T3-T zoledronic acid 4 mg zoledronic acid acetaminophen 500 mg 1# qid amoxicillin 500 mg 1# qid minocycline 100 mg 1# bid 1 (debridement) (NS+H 2 O 2 irrigation) acetaminophen 500 mg 1# qid amoxicillin 500 mg 1# qid acetaminophen 500 mg 1# qid amoxicillin 500 mg 1# qid (cefazolin 1g q6h + hydrocortisone 100 mg q6h) X 3 ( ~) 表一病人用藥 / Dexamethasone 0.5 mg 8#Q12H Zoledronic acid 4 mg 1vial QM Medicon A 1#QID Iwell 1#Q12H Acarbose 50 mg 1#TID 1#BIDAC Metformin 500 mg 1#TID 1#BID Acetaminophen 500 mg 1#QID 1#Q6H Tramadol 50 mg 1#Q6H Morphine HCl 10 mg 1#Q6H 1#Q6HPRN Morphine sulfate 30 mg 1#Q12H Furosemide 40 mg Tab 1#QD 1#QDPRN ZA 272 Jun 藥學雜誌第 107 冊 127

3 用藥安全 Drug Safety 表二治療期間的各項檢驗值 / 01/09 04/17 08/18 Na 135~145 mmol/l Hb / 14~18 g/dl 01/09 04/17 08/ K 3.5~5.3 mmol/l Ht 42~52 % BUN 8~25 mg/dl RBC 4.7~6.1 *10^6/cmm Creatinine 0.5~1.5 mg/dl WBC 4~10 *1000/cmm Ca 8.5~10 mg/dl Neut. Seg 40~74 % P 2.5~4.5 mg/dl 4.6 Lympho 19~48 % GOT 5~35 IU/L Mono. 3.4~11 % GPT 5~35 IU/L Eos. 0~7 % D-Bili. 0.1~0.5 mg/dl Baso. 0~1.7 % T-Bili. 0.2~1.5 mg/dl MCV 80~94 fl LDH 95~215 IU/L MCH 26~34 Pg CRP 0.01~0.5 mg/dl MCHC 33~37 g/dl Glucose AC 70~ PLT 130~400 *1000/cmm BPS 9 16 參 討論 BPs 9 American Academy of Oral and Maxillofacial Surgeons (AAOMS) (2009) BONJ 31. BPs Naranjo Algorithm 3 () vinorebline ONJ ONJ (MTX 5FU) ONJ 2~8 2~8 2~5,7-8 2,4~6 BPs BONJ 表三 Naranjo Algorithm 評量表 Naranjo Algorithm (1) (2) (3) (4) (5) (6) (7) THE JOURNAL OF TAIWAN PHARMACY Vol.27 No.2 Jun

4 Naranjo Algorithm (8) (9) (10) 3 0 () 1-4 () 5-8 () 9 () BPs ( ) R2 nitrogen 2,9 BPs ONJ 2,5,7,8 BONJ BPs (0.8~12%) 2 BPs (0.01~0.04%) 2 BONJ 5~21 2 圖一 BPs 結構 : 骨架中之 P-C-P 基圖使得 BP 不易被水解,R2 側鏈含 Nitrogen 者效價較強 2,9 表四各種 BPs 藥效比較 Generic name Brand name Dosage Forms Nitrogen Containing Relative potency Etidronate Didronel 200- and 400-mg tab No 1 Alendronate Fosamax 70-mg and 2800-U cholecalciferol tab Yes 1000 Risedronate Actonel 5-, 30-, and 35-mg tab Yes 1000 Ibandronate Bonviva 2.5-,150-mg tablet 3 mg/3 ml Yes 1000 Pamidronate Aredia 30-, 60-, 90-mg vials Yes Zoledronic acid Zometa 4-mg vial Yes >10,000 Clodronate Bonefos 400-,800-mg tablets 60 mg/ml amp No NA BPs ( 2~3 ) BPs 7 BPs ,10 BPs 2~4,7,10 4~6 3 BPs BPs BPs 7,8,10 ONJ (~ ) 2 rh-pth(1-34) 272 Jun 藥學雜誌第 107 冊 129

5 用藥安全 Drug Safety [Teriparatide] 8 2 表五美國口腔顎顏面外科學會依據壞死情形的分期 IV BPs () 2 表六美國口腔顎顏面外科學會依各分期的處置 0 1 (0.12% chlorhexidine) 3 BPs 2 3. BONJ zoledronic acid 55% 200 3,11 zoledronic acid 2,3,8,10 BPs BPs BONJ BONJ 7 肆 結論 BONJ BPs BONJ BONJ 參考資料 : 1. Marx RE.Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws:a growing epidemic.j Oral Maxillofac Surg.2003;61: American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw-2009 Update. The Board of Trustees January Ibrahim T, Barbanti F, Giorgio-Marrano G, et al: Osteonecrosis of the Jaw in Patients with Bone Metastases Treated with Biphosphonate: A Retrospective Study. Oncologist ;13: Wilkinson GS, Kuo YF, Freeman JL, et al: Intravenous Bisphosphonate Therapy and Inflammatory Conditions or Surgery of the Jaw: A Population-Based Analysis. J Natl Cancer Inst 2007;99: Aguiar Bujanda D, Bohn Sarmiento U, Cabrera Suárez MA, et al: Assessment of renal toxicity and osteonecrosis of the jaws in patients receiving zoledronic acid for bone metastasis. Oncology 2007;18: Stuart L. Silverman, Regina Landesberg. Osteonecrosis of the Jaw and the Role of Biphosphonate: A Critical Review. Medicine, 2009;122(2A): S (163): ,et al J Taiwan Periodontol 130 THE JOURNAL OF TAIWAN PHARMACY Vol.27 No.2 Jun

6 ;13(3): Sook-Bin Woo; John W. Hellstein; and John R. Kalmar. Systematic Review: Biphosphonate and Osteonecrosis of the Jaws. Ann Intern Med. 2006;144: J.Family Dent 2009;3(4): Merigo E, Manfredi M, Meleti M, et al: Bone necrosis of the jaws associated with bisphosphonate treatment: a report of twenty-nine cases Acta Biomed. 2006;77(2): Biphosphonate Associated Osteonecrosis of the Jaw Chia-Hui Hung, Chi-Feng Cheng, Hsi-Yen Lin Department of Pharmacy, Cathay General Hospital, Taipei, Taiwan Abstract Biphosphonates are frequently used in osteoporosis, hypercalcemia, and cancer patients with bone metastases. In 2009, the American Association of Oral and Maxillofacial Surgeons had reported that the incidence rate of biphosphonate-associated osteonecrosis of the jaw was about 0.8 to 12% in injection form, and that of oral form biphosphonate was much lower in about 0.01 to 0.04%. During the medication period, the incidence might increase 5 to 21 times if extra invasive dental procedure is implemented concomitantly. We are going to report a patient suspected suffering from the adverse reaction after the use of biphosphonate. A 57 year-old female with breast cancer and bone metastases, after 9 months of zoledronic acid injections, chronic osteomyelitis and jaw bone necrosis were diagnosed. The patient then received continued treatments up to 16 months, including debridement, resections and long-term antibiotic treatment, After 16 months of treatment, the damaged bone stabilized and new bone grew. After reviewing the patient's medical history and medication history, we excluded the possibility of other medications taken by the patient during the suffered period, though there were some other risk factors of diseases left, we still think it would be biphosphonate-related. We hope that this case we report may remind the patients, caregivers and medical staff to reconize this severe but rare adverse reaction.physicians should evaluate and adjust the risk factors and the benefit of treatment before prescription of biphosphonate, and take actions to protect and ensure the safety of medication use. 272 Jun 藥學雜誌第 107 冊 131