作者：Deborah Flapan
出處：WebMD醫學新聞
December 5, 2009 — 美國食品藥物管理局（FDA）與Endo、Novartis藥廠昨晚宣布，所有含有diclofenacsodium的產品治療，包括Voltaren凝膠，可能導致肝功能異常，造成嚴重的肝臟反應，甚至是肝臟移植或死亡。
曾有使用diclofenac後一個月內造成藥物引起肝臟毒性的病例被報導出來，但這實際上可能發生在治療期間的任何時候。
根據昨晚由FDA安全資訊與不良反應通報系統MedWatch發出的警訊，上市後監視報告發現已有許多嚴重肝臟反應的病例，包括肝臟壞死、黃疸、猛爆性肝炎，合併或未合併黃疸，以及肝臟衰竭。部份報告病例死亡或是需要肝臟移植。
根據Endo與Novartis藥廠給健康照護專業人員的信件，如果病患持續有肝臟功能檢驗異常，或肝臟功能惡化、發生肝臟疾病症狀、或是發生全身性表徵，例如嗜伊紅性球數目過高、皮疹、腹痛、腹瀉或是尿液顏色變深，臨床醫師們應該立即停止diclofenac治療。
這些公司也建議臨床醫師們應該提醒正在服用diclofenac的病患有關於肝臟毒性的病徵與症狀，包括噁心、倦怠、無力、腹瀉、搔癢、黃疸、右上腹壓痛、類流感症狀，以及發生這些病徵與症狀時該怎麼辦。
為了降低使用diclofenac sodium病患們發生肝臟毒性的風險，應使用最低有效劑量，且使用最短的治療時程。
【上市後研究數據】
在給醫療專業人員的一封信中，Endo與Novartis藥廠建議臨床醫師們針對長期接受diclofenac治療病患常規地監測轉胺酶濃度，因為嚴重的肝毒性可能發生在沒有可分辨症狀的情況下。監測轉胺酶最佳的時機與之後監測的時程目前仍然未知。
臨床研究數據與上市後經驗顯示，在開始以diclofenac治療4到8週後，應該監測轉胺酶濃度。然而，嚴重的肝臟反應仍然可能發生在治療期間的任何時間。
該公司在給健康照護專業人員的信中表示，約有15%接受diclofenac治療病患轉胺酶濃度些微上升或較高。他們指出，血清谷氨酸丙酮酸轉氨酶（ALT）（血清麩氨酸-焦葡萄酸轉胺酶）是監測肝臟損傷建議的肝臟功能指標。
然而，在臨床研究中，5,700位接受diclofenac治療的病患中，大約有2%發生臨床上重要的濃度上升（天門冬酸轉胺酶[AST]或稱血清麩胺酸－草醋酸轉胺酶上升超過正常值上限[ULN]三倍）。在一項較小型的開放標記研究中，針對3,700位病患進行研究發現大約有4%病患發生類似的ALT以及/或是AST濃度上升，而約有1%病患發生顯著上升（上升超過ULN的8倍）。該公司指出，在這項開放標記研究中，相較於其他NSAIDs（非固醇抗發炎藥物），使用diclofenac的病患們，肝臟指標些微上升（<3倍ULN）、中度上升（3~8倍ULN）、與顯著上升（>8倍ULN）的比例較高。
除此之外，相較於風濕性關節炎患者，接受骨關節炎治療患者，更常見轉胺酶濃度上升的情形。
Diclofenac是一種適用於緩解風濕性關節炎疼痛、骨關節炎與僵直性脊椎炎的非類固醇抗發炎藥物。
更多資訊請造訪FDA的MedWatch網站。
任何與diclofenac相關不良反應都應該通報到FDA的MedWatch通報系統，以電話1-800-FDA-1088或傳真至1-800-FDA-0178，線上通報
http://www.fda.gov/medwatch或郵寄到5600 Fishers Lane, Rockville, Maryland 20852-9787。
Diclofenac Linked to Liver Failure, Death
By Deborah Flapan
Medscape Medical News
December 5, 2009 — Treatment with all products containing diclofenac sodium, including Voltaren Gel, may increase liver dysfunction, resulting in severe hepatic reactions and liver transplantation or death, the US Food and Drug Administration (FDA), Endo, and Novartis announced late last night.
Cases of drug-induced hepatotoxicity have been reported within the first month of treatment with diclofenac but can occur at any time during treatment.
"Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure," according to an alert sent last night by MedWatch, the FDA's safety information and adverse event reporting program. "Some of these reported cases resulted in fatalities or liver transplantation."
Physicians should discontinue diclofenac treatment immediately if patients continue to have abnormal or worsening liver test results, if liver disease symptoms develop, or if systemic manifestations occur, such as eosinophilia, rash, abdominal pain, diarrhea, or dark urine, according to a letter from Endo and Novartis to healthcare professionals.
The companies also recommend that physicians advise their patients receiving diclofenac of the signs and symptoms of hepatotoxicity, including nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and flulike symptoms, and what to do if these signs and symptoms appear.
To reduce the risk for hepatotoxicity in patients receiving diclofenac sodium, the lowest effective dose should be used for the shortest time possible.
Postmarketing Data
In their letter to healthcare professionals, Endo and Novartis advise physicians to measure transaminase levels regularly in patients receiving long-term therapy with diclofenac "because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known."
Clinical trial data and postmarketing experiences suggest that transaminase levels should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. "However, severe hepatic reactions can occur at any time during treatment with diclofenac," they note.
Transaminase levels have been elevated at borderline or higher levels in about 15% of diclofenac-treated patients, the companies say in the letter to healthcare professionals. Alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase) is the recommended hepatic function marker for monitoring liver injury, they say.
However, in clinical trials, clinically important elevations (>3 times the upper limit of normal range [ULN]) of aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase) occurred in approximately 2% of about 5700 patients during diclofenac treatment (ALT was not measured in all patients). In a smaller open-label study of 3700 patients, similar elevations of ALT and/or AST levels were seen in approximately 4% of patients and "marked" elevations (>8 times the ULN) occurred in about 1% of patients. In this open-label study, "a higher incidence of borderline (<3 times the ULN), moderate (3-8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs [nonsteroidal anti-inflammatory drugs]," the companies point out.
In addition, elevated transaminase levels were more common in patients being treated for osteoarthritis than in those with rheumatoid arthritis.
Diclofenac is a nonsteroidal anti-inflammatory drug indicated for the relief of the pain of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.
More information is available on the FDA's MedWatch Web site.
Adverse events related to the use of diclofenac should be communicated to MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at
http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.
