再論降血糖藥--梵第雅, 台灣下市了嗎? 政府偷偷摸摸幹事又一樁!!!

[李誠民]

去年7-16蘋果日報A20板刊出"梵蒂雅",台灣衛生署根據專家會議"暫不下架"文報導,個人屢次與衛生署投書請教,主要重點是美國FDA所召開的 專家會議雖議決暫不下市,但FDA正式宣佈卻在延遲中,台灣衛生署食品衛生處有甚麼好急的,引起本人好奇...
請先參考99-8-17本網站個人呈衛生署文--降血糖藥-梵蒂雅
由於衛生署連分類與用藥都似乎誤解本人意思,故再未答覆,以生誤解,因今天諾美婷事件,個人在此說名糖尿病為甚麼沒有第二線或最後一線用藥,當然與糖尿病分類有關,特說明如下:(也會呈衛生署參考)

糖尿病分類目前是胰島素依賴型(以前的第一型糖尿病)與非胰島素依賴型(第二型糖尿病),胰島素依賴型顧名思義就是血糖升高是身體胰島素缺乏所造成的,非胰島素依賴型指的是血糖升高釋胰島素作用變差了,也就是胰島素抗拒,早期臨床表現是高胰島素血症,飯前血糖升高與胰島素抗拒,所以才會從胰島素發明後,因胰島素對心血管會造成傷害,故又回頭使用與開發口服降糖藥:;,等糖尿病進入後期,普遍胰島分泌胰島素衰竭,成為胰島素缺乏,那就只有用胰島素控制了,所以沒報載第二線或貴署最後一線用藥.

其實在開發所謂胰島素增敏藥物時--梵蒂雅前,就知道胰島素會有刺激Catecholamin的作用--血管收縮與體液滯留問題

蒂帆雅就在1999年上市了,主要藥廠(Glaxo 美國公司)所作研究追蹤根據糖化血色素(HgbA1c)降低1%,當然也隱匿了雖然血糖控治好了,但心血管疾病發生風險上昇了(即可能美國FDA有幫助隱匿之嫌),2008年底對於到底嚴格控制血糖能否降低心血管疾病(?)有了大型研究計畫結果出爐(美國衛生研究院五年計畫,作了三年就停止了,因為結果已顯示致死性新肌梗塞增加了),當然糖化血色素(HgbA1c)是否是好的糖尿病控制指標的文章也在這些年紛紛出現,至少糖尿病控制指標--HgbA1c從6-6.5%放寬到7甚至7.5%

今年八月新英格蘭雜誌(NEJM:Revisiting Rosiglitazone Story--Lessons learned 2010:363.803-6)作者(Dr. Rosen C.J.)就是當初2007年七月美國FDA 專家會議主持人,文中提到自2007年專家會議後,到今年七月專家會議有十篇新的實驗計畫都顯示梵蒂雅會增加心肌梗塞風險(30-80%),文章作者結論為退出市場吧!

有關新藥上市後才來做藥物副作用的研究是否適當,成為討論的焦點,因為這是醫學倫理極嚴重與嚴肅的課題,梵蒂雅 諾美婷 與降血脂藥,藥廠當然不樂於見到,影響新藥上市至少十年;我們在SARS與H1N1流行期間,克流感(美國藥廠)都是相同問題,隱匿或刮大其效用

衛生署請小心,醫生是當醫生前需認同醫師誓言,與受道赫爾辛基與伊斯坦堡宣言所制約的,公衛專家或藥廠並沒這約束--當然如果是醫師還是要小心的

台灣健保許多制度的改變都可能違反了醫師誓言規範,尤其是不尊重(侵犯)醫師專業
P.S.:1.Rosiglitazone:a cautionary tale;Godlee F.:BMJ 2010341:c4896
2.Licensing drugs for diabetes;Lehman R.:BMJ2010;341:c4805
3. 我的前輩告訴我說:現代醫師不可沒有政治關與經濟關
4.有用過梵蒂雅的前輩們,還是先看一下病歷記載,台灣病人是習慣告醫師的--容易,美國是告藥廠與國家--賠償金額極大;;前輩們!同意嗎?ˋ
avandia對心血管的影響和血糖的的控制到底好還壞?如果不好，我相信actos也應該一樣，不可能兩個一樣的藥對心血管的影響不一樣，而且Nissan先生的研究贊助者與ACTOS藥廠有關，讓人有不同的聯想
摘錄自BMJ 2010:341:c4848 文 不知能否解答您的指正:
.....
Where next for diabetes drugs?
While the focus has been firmly on rosiglitazone, what about pioglitazone? Its manufacturer Takeda had benefited from the controversy of rosiglitazone. But like rosiglitazone, pioglitazone is associated with an increased risk of oedema, heart failure, and bone fracture.23

As Professor Van Belle said, he doesn’t want to be sitting at an FDA advisory meeting in three years’ time discussing pioglitazone. Professor Gale is also concerned. In a letter to the UK regulator in 2008 seen by the BMJ, he wrote that...... “there is an urgent need to determine the safety of pioglitazone”....

...“Pioglitazone may or may not prove to be safer than rosiglitazone. There is an urgent need for more and better data addressing this issue. On present evidence, its safety cannot and should not be assumed,” he wrote. Takeda say that they continuously monitor the safety and efficacy of their compounds. ....

Meanwhile other anti-diabetic drugs using a similar pathway are in development: the chequered history of the glitazones not having deterred manufacturers. According to reports, Dr Reddy’s Laboratories and Nordic Bioscience’s partial PPAR-gamma agonist balaglitazone met its primary endpoint in its first phase III trial in patients with type 2 diabetes (reduction in glycated haemoglobin). It was claimed to be “non-inferior” to pioglitazone. The companies are currently in discussions with regulators and hope to eventually file the drug in the European Union and the United States.24 And both Roche and Metabolex have drugs in phase two trials.25

Will regulators, industry, and the clinical community do a better job for patients next time?

....1997
Troglitazone withdrawn from UK market after six weeks because of hepatotoxicity.....

1999
April: American Diabetes Association declares that the drug’s properties are not shared by any others, offering new options to healthcare professionals

May: Rosiglitazone approved as monotherapy by FDA with label precautions for use in patients with heart failure

September: European Association for the study of Diabetes heard that rosiglitazone would be useful as a first line therapy

October: Rosiglitazone turned down by EMA by 14 of 25 votes

....2000
March: Troglitazone withdrawn in United States....

July: Rosiglitazone given market authorisation in Europe with restrictions and with warnings on heart failure. GlaxoSmithKline (GSK, then SmithKline Beecham) is asked to conduct two post-marketing trials: one study to look at effect on cardiovascular structure; the other to assess cardiovascular safety—the RECORD trial.

October: Pioglitazone approved in Europe

2001
February: FDA approve new warnings on potential for heart failure

2004
With an increasing number of people taking rosiglitazone, World Health Organization picks up safety signals and alerts GSK

June: GSK ordered to publish summaries of results of all its clinical trials on its website once a product has been launched in a settlement in New York

....2005
September: Internal GSK meta-analysis finds 29% non-significant increased risk of ischaemic cardiovascular events.....

2006
February: FDA approves Avandaryl (rosiglitazone maleate and glimepiride)

April: FDA approves new warnings on risks of cardiovascular events

....May: Internal GSK meta-analysis finds 31% increase in ischaemic events.....

June: EMA approves Avaglim (rosiglitazone maleate and glimepiride)

....2007
May: New England Journal of Medicine publishes meta-analysis reporting 43% increased risk of myocardial infarction ...

June: NEJM publishes interim analysis of the RECORD trial

....July: FDA advisory committee finds increased cardiac ischaemic risk but votes to keep drug on market....

October: European Medicines Evaluation Agency asserts positive benefit-risk profile, recommends new warnings for patients with ischaemic heart disease

....November: FDA approves new boxed warnings that drug may increase myocardial ischaemic events, including myocardial infarction, though evidence “inconclusive”...

December: UK Medicine and Healthcare products Regulatory Agency warns drug might be associated with small increased risk of cardiac ischaemia

2008
Updated internal GSK analysis finds no risk of myocardial infarction or other major cardiovascular events

2009
March: International Journal of Cardiology meta-analysis finds no risk of myocardial infarction

June: RECORD trial published in the Lancet. EMA add a statement to their scientific information document saying there was no difference in the number of adjudicated primary endpoints between the arms of the study.

....2010
February: US Senate finance committee releases report that includes internal FDA safety report calling for drug to be withdrawn...

February: GSK responds with 30 page document

June: David Graham’s study leaked to the Pharmalot blog. It is published in JAMA regardless. At the same time, another JAMA journal, Archives of Internal Medicine, publishes an updated meta-analysis by Steve Nissen

13-14 July: FDA advisory committee meeting held. FDA drug approver gives damning verdict on the RECORD trial. Majority of committee vote either to withdraw the drug or restrict it severely

....15 July MHRA meet. Commission on Human Medicines vote to withdraw rosiglitazone.....

....TIDE trial suspended by the FDA...

19-22 July: EMA meet to discuss rosiglitazone

26 July: the MHRA send out “dear doctor” letter advising doctors to consider alternative treatments where appropriate

September: EMA will finalise its review
x:EMA:European Medicines Agency
x:MHRA:Medicines and Healthcare prodoct Regulatory Agency (UK)
Rosglitazone 是Glaxo第二大暢銷藥,每年約有三十億美元銷售額
BMJ2010;341:c5333:inciders criticise FDA's decision not to withdraw rosiglitazone:
......
David Graham, associate director for science and medicine at the FDA’s Office of Surveillance and Epidemiology, was critical of the FDA’s response. “The FDA decision was disappointing, was not in the best interests of patient safety and public health, was not evidence based, and was inherently self contradictory
很抱歉!Actos(pioglitazone)是Lilly co.與武田共同生產的PPARG(TZD)降血糖藥,;控制血糖目的就是減少血管損害,減少心血管疾病與腦中風發生,就如同1970年代控制血壓的 Framgminham study 一樣,所以開發了 ACEI Ca. blockade B1 inhibitor...;
所以Rsoiglitazone會增加30-80%急性心肌梗塞風險,降血糖的目的就不知為何了?
況且ACCORD study顯示嚴格控制血糖,低血糖的機率增加了,致死性心血管疾病風險也增加了,HgbA1c指標值也放寬了--7-7.5%
p.s.:目前也有許多文章探討HgbA1c是否是血糖控制良好的指標?
請指正!

[李誠民]

台灣中化與日本藥廠生產 picoglitazone(Actos),在未專利權消失前,開始作post-marketing trial,被LillyCo.告侵權行為,網站可查,台灣法院三(二?)審都敗訴,可是個人在去年一次研討會中就教中化經理說:三審勝訴,...不關我事,也就沒討論了!
"北風北 安全下莊"......但是如果又無奈,輪道搬風怎麼辦???????......

[poki]

台灣中化與日本藥廠生產 picoglitazone(Actos),在未專利權消失前,開始作post-marketing trial,被LillyCo.告侵權行為,網站可查,台灣法院三(二?)審都敗訴,可是個人在去年一次研討會中就教中化經理說:三審勝訴,...不關我事,也就沒討論了!
"北風北 安全下莊"......但是如果又無奈,輪道搬風怎麼辦???????......

這件事我很清楚

actos是武田的, 所以是武田告中化, 不是Lilly
中化是被武田告仿單相同(台灣規定仿單有些部分必須跟原廠相同), 侵犯智慧財產權,
武田幾乎無勝訴可能, 但可利用假扣押阻礙中化出貨, 企業競爭常見的手法

[poki]

"偷偷摸摸幹事"是什麼意思?
看不太懂, 可否寫簡單扼要一些?

[李誠民]

Poki 醫師您好!謝謝指正,又增加了些常識

因為本網站有人對降糖藥有所發言,本人又不想隨便發言,只好亂扯一通,,如果屬實,我也不算雞婆,但政府欠我一個公道!!!.....
Poki 醫師前輩,我應是好國民吧?!

[poki]

Poki 醫師您好!謝謝指正,又增加了些常識

因為本網站有人對降糖藥有所發言,本人又不想隨便發言,只好亂扯一通,,如果屬實,我也不算雞婆,但政府欠我一個公道!!!.....
Poki 醫師前輩,我應是好國民吧?!

不要那麼客氣,

這個是安全問題, 你的發言很重要,
所以想要問清楚

[李誠民]

嗨!原諒我!我只是Intern程度,Intern 就可以胡扯一通,因為他是學生,您是老V只好去查資料或負責的回答我問題(玩笑一句,可別介意!!!)
再次謝謝Poki 前輩的指導!

[李誠民]

偷偷摸摸幹事就是不會光明磊落幹事,去年蘋果刊載是衛生署開記者會,說明暫不下架理由,如果本網站他人發言屬實,為甚麼衛生署沒開記者會---媒體(-文字或電子)沒有報導,謝謝Poki醫師指正

[poki]

我完全不怪衛生署,
判斷藥物對患者好或是不好, 不必全靠衛生署, 這就是醫生的價值

這類藥以前也有一個下市的藥叫Troglitazone, 因有肝毒性而下市,
結果有人DM 吃Troglitazone 血糖控制得很好, 也沒有發生肝毒性, 卻不能繼續用, 對這些人不就不公平嗎?
(當時, 糖尿病口服藥種類可沒今天那麼多, 胰島素種類也沒那麼多)

以下是推論, 未經證實 , 自己判斷:
2005年(或更早)就發現avandia 會增加LDL 30%, 而增加1 mg/dl的LDL 會增加 1% MI的機會,
大約可以解釋吃avandia增加30%MI的機會,
而actos不增加LDL, 會增加HDL, 所以actos不會像avandia 有MI的問題,
如果這個推斷成立, 有的患者 LDL 不高, 或是對降血脂藥效果很好的, 要服用avandia也不是不行,
我認為衛生署禁東禁西的反而綁手綁腳

我在2006年就幾乎完全不用avandia, 改用actos, 當醫生原本就要能判斷, 不必等衛生署禁用

[李誠民]

Poki醫師您好!謝謝指正
您的某些論點,我不能認同::Troglitazone在1997年先由英國下市,2000年自美國市場下市,不能說您使用上,沒有肝毒性與您個
人經驗中,就推論是適當的;
我同意您醫師有根據專業獨立判斷的能力,但其前提建立在您自我要求與不斷閱讀新知與判斷上,也建立在醫師基本信念--以病患權益為優先考量上,
美國FDA近十年來有許多抗癌與非類固醇止痛藥有隱瞞 包庇藥廠的記錄,其公信力備受考驗,(請參考本網站的"藥命危.機....."文),如果台灣衛生署FDA不搶先英國與美國FDA發佈暫不下架的記者會,也不會引起我的好奇,追蹤其原委,;個人非糖尿病專家,但對事情的邏輯判斷是自覺還可以,故為甚麼在本發言中,特別轉錄BMJ文章的目地所在;;
有關Actos的個人見解,主要中化是台灣藥廠又在追蹤期間,見網站中化被日本(或美國?)藥廠控告侵權行為,才引起興趣,同樣節錄本人發言的引用文章--"...Pioglitazone may or may not prove to be safer than rosiglitazone. There is an urgent need for more and better data addressing this issue...",只是有關pioglitazone-Actos的 post-marketing trial還不完全而已....
若仍有失誤處,不吝指正!

[yehmy]

BC24780100 AVANDIA F.C. TABLET 4MG "SPAIN" "西班牙"梵帝雅膜衣錠４毫克 ROSIGLITAZONE (MALEATE) 4 MG 單方 27.5 104.04.01 迄今,
BC24459100 AVANDAMET F.C.TABLETS 2MG/500MG "SPAIN" "西班牙"梵帝美錠2毫克/500毫克 METFORMIN HCL
ROSIGLITAZONE (MALEATE) 500 MG
2 MG 複方 14.2 104.02.01 迄今

[min]

感謝.

[olctw]

看起來蠻多相同成份的藥物，只是不知道差異

http://drugs.olc.tw/ingredients/view/54 ... 56d38a10d1

[yehmy]

看起來蠻多相同成份的藥物，只是不知道差異

http://drugs.olc.tw/ingredients/view/54 ... 56d38a10d1

有些是單方ROSIGLITAZONE
有些是複方 分別加上 METFORMIN or GLIMEPIRIDE ...

健保用藥品項查詢
http://www.nhi.gov.tw/Query/query1.aspx ... &WD_ID=831