降血糖藥--梵蒂雅

文章由 **李誠民** » 週三 8月 11, 2010 2:32 pm

李先生您好！所傳郵件，業已收悉。有關第二型糖尿病治療藥品rosiglitazone（藥品名Avandia及其他學名藥品）可能增加缺血性心衰竭及心臟病發作的風險等風險，本署風險評估說明如下：一、本署曾經2次再評估其安全性，經評估認為該藥品對於某些病人之臨床效益仍高於風險，因此在侷限其使用條件下，應可繼續供病患治療用，惟需加註心血管方面警語，並監測病人心臟衰竭的徵兆或症狀，例如過度、快速的體重增加，呼吸困難，及水腫等。此外，並提醒有限行動力或臥床等狀況之嚴重心衰竭病患，應避免使用此類藥物，遂於96年9月11日公告包括rosiglitazone成分在內的TZD類藥品之仿單，均應以最醒目的方式（粗體字加框刊載於仿單起始處）刊載心臟風險相關警語，同時禁用於心臟衰竭第3級獲第4級的病人。二、本署再次蒐集國內、外有關案內藥品之資訊，於99年7月15日召開藥物安全評估委員會，第3次評估rosiglitazone成分藥品的安全性，決議對某些病人而言rosiglitazone成分藥品之臨床效益仍高於風險，該藥品仍可繼續供病人臨床治療選擇，但必須加強警語內容並限縮其使用時機及對象：包括（1）本藥品只有當病人對其他降血糖藥品治療均無法良好控制時之第二型糖尿病治療。（2）不建議使用於缺血性心臟病之病人。（3）不建議使用於心臟衰竭症狀之病人。（4）心臟衰竭狀態第3級或第4級（紐約心臟協會『NYHA』Class III或IV cardiac status）的病人禁止使用本藥品。有關rosiglitazone成分藥品之安全性，經本署3次再評估，將本藥品列為第二型糖尿病治療之最後一線（非第二線）用藥，加強藥品仿單之警語刊載，待本署完成公告程序後將副知中央健康保險局，以利其修訂本藥品之給付規定。感謝您的來信，祝您健康、快樂! 行政院衛生署敬復
2010/07/20 受理上周五(2010-7-16)蘋果日報A20版刊載"降血糖藥梵蒂雅暫不下架"一文,梵蒂雅(Avandia)是一種近年開發的降血糖藥,主要是增強組織對胰島素的敏感來降低血糖;首先我們需了解糖尿病治療藥物的發展,才能了解治療糖尿病藥物的使用口服降糖藥在沒有胰島素注射前即已開發出來,到1950年代從豬提煉出胰島素,醫界以為治療糖尿病的問題解決了,但不幸的二十年後,胰島素治療糖尿病不但未解決許多問題,反而衍生許多其他問題,例如最早是從豬提煉的,與人的胰島素氨基酸排列不同,而產生過敏與抗體(抗藥性),等科技發展能從基因工程製出與人體相同的胰島素後,仍有注射部位與時間,無法準確與進食後的血糖升高完全配合的困擾,同時我們了解糖尿病有兩種:1.胰島素依賴型(因感冒或其他因素破壞了胰臟的胰島,而造成胰島素分泌缺乏減少,以前稱為少年型糖尿病,占糖尿病發生<20%);;2.非胰島素依賴型(多為成年後因飲食缺乏運動或遺傳等原因,造成組織對胰島素作用變差,早期可能胰島素不但不缺乏,反而升高同時血糖升高,以前稱成年型糖尿病,占糖尿病的80%),所以提早使用糖尿病除了會造成血糖降低危險外,往往使用量超過身體產生的生理量--每日四十單位,胰島素本身就有微小血管增生的困擾,所以又回頭使用口服降糖藥--Sulfourea&Metaformin Metaformin早期為pheformin會造成乳酸代謝的酸血症,已於1970年代禁用,而使用Metaformin,而乳酸中毒事件也大幅減少,主要使用在英國與歐洲國家,逐漸知道會增加胰島素的敏感性,正好是治療第二型(非胰島素依賴型)的最大優點,美國則開發第二代Sulfonurea,但增敏作用不如Metaformin且易發低血糖反應,故美國接著開發胰島素增敏藥物共三種:一種因會造成肝損傷而停用,一種即為Avandia(rosiglitazone)為美國葛蘭素(Glaxo)藥廠生產,另一種為美國禮來(Lilly)藥廠與日本合產的Actos(pioglitazone),Metaformin是超過四五十年的老藥,價廉與負作用都了解透徹,而且還知道新的作用--治療非酒精性脂肪肝與卵巢囊腫等,美國直至1994年才核准上市,上市後追蹤發現Metaformin 的副作用_--乳酸中毒發生機率非常小,也不易發生低血糖,講到這裡,我們應該曉得一件事,新藥的開發牽涉到藥廠的巨大利益,甚至如美國FDA都會介入干預--如至1994年才讓Metaformin 上市 Avandia從上市就有水腫的負作用,所以會加重心衰竭,同時也會增加心血管疾病的發生(隱匿?),在1993年美國加州與德州有三十二位病患控告藥廠的訴訟案件,英國在2007年根據美國多篇報導(包括NEJM)禁用,而歐盟的藥品管理局(EUropean medicine agency)決議仿單(藥品說明書)應加重警語,這就牽涉國際藥廠重大利益與貿易等因素,個人非專家,也就不多說了直至一周前美國FDA聯合諮詢委員會開會(報載):三十三位與會專家有十二位認為應全面禁售,十七未要求增加販賣限制,一人棄權,此決議將代美國FDA於數周內定奪,台灣衛生署食品藥物管理局有必要在上周五決議暫不下架嗎?而成為唯一的第二線糖尿病治療藥物嗎(第二線或最後一線皆誤導一般民眾)?難道不怕一般民眾誤解因其價昂才會成為第二線治療藥物?不發布新聞,而等美國FDA官方決議出來後,再來發怖新聞不可嗎? 美國因保護藥廠的利益,並且接受藥廠資助作新藥的追蹤,近年來被主要醫學雜誌批露幫忙藥廠隱瞞負作用與仿單故意標示不明或不標示警語,連番質疑,甚至權威性備受挑戰,歐巴馬總統的健保改革法案也有整頓藥廠(Drug co.)的革新方案,台灣是不是也要學學,減少健保醫療資源的浪費呢?

1.糖尿病用藥無所謂第一線或第二線問題
2.FDA延緩TIDE臨床實驗計畫
3.這是美國與英國對梵蒂雅的爭論,也牽涉到臨床藥物實驗的倫理規範問題,我們衛生署似乎無此警覺
故轉載BMJ:2010,July 31文章如下:

FDA puts rosiglitazone post-marketing trial on hold
Deborah Cohen

1 BMJ

The US Food and Drugs Administration has suspended a post-marketing trial of the thiazolidinedione rosiglitazone while it looks at whether to withdraw the drug or keep it on the market.

The thiazolidinedione intervention with vitamin D evaluation (TIDE) trial was designed to compare the cardiovascular safety of rosiglitazone (marketed as Avandia) and pioglitazone (Actos) in patients with type 2 diabetes. It was set up at the FDA’s request in 2007.

The FDA has placed a "partial clinical hold" on the trial, which means that no new patients can be enrolled until further notice. Patients already enrolled in the trial will be allowed to continue.

This follows the suspension by India’s drug controller general of the trial at the 19 sites taking part in the country, after publication of a cohort observational study and a meta-analysis that raised further concerns about the safety of rosiglitazone (JAMA doi:10.1001/jama.2010.920; Archives of Internal Medicine doi:10.1001/archinternmed.2010.207).

At an FDA advisory meeting last week a panel voted 19 to 11, with three abstentions, to continue the trial if the drug remains on the market, after a heated debate over the ethics of continuing a trial to test a drug when there are known safety concerns.

A spokesperson for GlaxoSmithKline, the company that markets rosiglitazone, said that a head to head trial would prove that rosiglitazone does not increase the risk of myocardial infarction and that the evidence suggesting that it does was "not scientific."

The trial’s principal investigator, Hertzel Gerstein, chair in diabetes research at McMaster University, Hamilton, Ontario, said that many ethics committees have approved the trial. He also said that a large randomised controlled trial is the best way to solve concerns over benefits versus risks when there is "clinical equipoise."

However, others said that more evidence on rosiglitazone’s safety profile had built up since the trial was approved and that there was no longer equipoise.

David Graham, a drug safety reviewer in the FDA’s office of surveillance and epidemiology, told the hearing that the only way to argue for equipoise would be to dismiss observational data—and that means ignoring post-marketing surveillance data.

"The study is extrinsically exploitative," he said, arguing that it is "patients who get the harm and the FDA and the company who get the benefits."

He also claimed that the consent form for the TIDE trial had not provided the necessary information on the cardiovascular risk associated with rosiglitazone. The FDA said that new information must be developed for informed consent, to reflect the information discussed at its recent advisory meeting reviewing the safety of the drug.

Without commenting on the details of the TIDE trial, Ruth Faden, professor of bioethics at Johns Hopkins University, Baltimore, said that it is ethical to begin a trial to evaluate a risk only if there was not enough evidence available to assess that risk.

She also pointed out that once a trial is under way risks need to be reassessed if new evidence comes to light. She said that a trial with unacceptable risks cannot be defended by using informed consent.

Enrolment into the TIDE trial has been slow. So far it has recruited just over 1000 participants in the 18 months since it started, and it hoped to recruit another 15 000 over the next year and a half. Tom Fleming, professor of biostatistics at Washington University, St Louis, expressed concern that the investigators would be unable to recruit the planned numbers in enough time.

Cite this as: BMJ 2010;341:c4017