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  39. <title>Rosiglitazone</title>
  40. <ns>0</ns>
  41. <id>604046</id>
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  43. <id>550970772</id>
  44. <parentid>550883248</parentid>
  45. <timestamp>2013-04-18T13:09:33Z</timestamp>
  46. <contributor>
  47. <username>Jfdwolff</username>
  48. <id>46555</id>
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  51. <comment>[[Help:Reverting|Reverted]] edits by [[Special:Contributions/|]] ([[User talk:|talk]]) to last version by Lahaun</comment>
  52. <text xml:space="preserve" bytes="37741">{{Drugbox
  53. | Verifiedfields = changed
  54. | verifiedrevid = 458777178
  55. | IUPAC_name = (''RS'')-5-[4-(2-[methyl(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione
  56. | image = rosiglitazone.svg
  57. | width = 200
  58. | imagename = 1 : 1 mixture (racemate)
  59. | drug_name = Rosiglitazone
  61. &lt;!--Clinical data--&gt;
  62. | tradename = Avandia
  63. | = {{|monograph|avandia}}
  64. | MedlinePlus = a699023
  65. | licence_EU = Avandia
  66. | licence_US = Rosiglitazone
  67. | pregnancy_AU = B3
  68. | pregnancy_US = C
  69. | legal_UK = POM
  70. | legal_US = Rx-only
  71. | routes_of_administration = Oral
  73. &lt;!--Pharmacokinetic data--&gt;
  74. | bioavailability = 99%
  75. | protein_bound = 99.8%
  76. | metabolism = [[Liver|Hepatic]] ([[CYP2C8]]-mediated)
  77. | elimination_half-life = 3-4 hours
  78. | excretion = [[Kidney|Renal]] (64%) and fecal (23%)
  80. &lt;!--Identifiers--&gt;
  81. | CASNo_Ref = {{cascite|correct|CAS}}
  82. | CAS_number_Ref = {{cascite|correct|??}}
  83. | CAS_number = 122320-73-4
  84. | ATC_prefix = A10
  85. | ATC_suffix = BG02
  86. | PubChem = 77999
  87. | IUPHAR_ligand = 1056
  88. | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
  89. | DrugBank = DB00412
  90. | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
  91. | ChemSpiderID = 70383
  92. | UNII_Ref = {{fdacite|correct|FDA}}
  93. | UNII = 05V02F2KDG
  94. | KEGG_Ref = {{keggcite|changed|kegg}}
  95. | KEGG = D00596
  96. | ChEBI_Ref = {{ebicite|correct|EBI}}
  97. | ChEBI = 50122
  98. | ChEMBL_Ref = {{ebicite|changed|EBI}}
  99. | ChEMBL = 121
  101. &lt;!--Chemical data--&gt;
  102. | C=18 | H=19 | N=3 | O=3 | S=1
  103. | molecular_weight = 357.428 g/mol
  104. | smiles = O=C1NC(=O)SC1Cc3ccc(OCCN(c2ncccc2)C)cc3
  105. | InChI = 1/C18H19N3O3S/c1-21(16-4-2-3-9-19-16)10-11-24-14-7-5-13(6-8-14)12-15-17(22)20-18(23)25-15/h2-9,15H,10-12H2,1H3,(H,20,22,23)
  107. | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
  108. | StdInChI = 1S/C18H19N3O3S/c1-21(16-4-2-3-9-19-16)10-11-24-14-7-5-13(6-8-14)12-15-17(22)20-18(23)25-15/h2-9,15H,10-12H2,1H3,(H,20,22,23)
  109. | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
  111. }}
  113. '''Rosiglitazone''' (trade name '''Avandia''', [[GlaxoSmithKline]]) is an [[antidiabetic drug]] in the [[thiazolidinedione]] class of drugs. It works as an [[insulin]] sensitizer, by binding to the [[PPAR]] receptors in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or in combination with [[metformin]] (trade name Avandamet) or with [[glimepiride]] (trade name Avandaryl). First released in 1999, annual sales peaked at approximately $2.5bn in 2006, but declined after the drug was found to increase risk of [[Myocardial infarction|heart attacks]]. The drug's patent expired in 2012.&lt;ref&gt;{{cite patent|US|5002953}}&lt;/ref&gt;
  115. Concerns about rosiglitazone's adverse effects has reduced its use despite the benefits it offers in [[Diabetes management |treating diabetes]].&lt;ref name=Ajjan/&gt; Adverse effects caused by rosiglitazone are currently the subject of over 13,000 lawsuits against GSK.&lt;ref name=&quot;;&gt;;/ref&gt; As of July 2010, GSK has agreed to settlements on more than 11,500 of these suits.
  117. The drug is controversial and is estimated to have caused 83,000 heart attacks in the United States alone. Some reviewers have recommended rosiglitazone be taken off the market, but a [[Food and Drug Administration]] panel disagreed, and it remains available in the U.S., subject to significant restrictions.&lt;ref&gt;{{cite web | url = | title = Controversial Diabetes Drug Harms Heart, U.S. Concludes | author = Gardiner Harris | publisher = ''New York Times'' | date = February 19, 2010}}&lt;/ref&gt; From November 18, 2011, the federal government will not allow Avandia to be sold without a prescription from certified doctors. Patients will be required to be informed of the risks associated with its use, and the drug will be required to be purchased by mail order through specified pharmacies.&lt;ref&gt;{{cite news| url=;utm_source=feedburner&amp;utm_medium=feed&amp;utm_campaign=Feed%3A+usatoday-NewsTopStories+%28News+-+Top+Stories%29 | work=USA Today | title=Most Popular E-mail Newsletter | date=2011-05-24}}&lt;/ref&gt;
  119. In Europe, the [[European Medicines Agency]] (EMA) recommended in September 2010 that the drug be suspended from the European market. However, patients currently taking rosiglitazone are advised to discuss alternative options during their next physician appointment.&lt;ref name=&quot;ema_recommend_suspend&quot;&gt;[;murl=menus/news_and_events/news_and_events.jsp&amp;mid=WC0b01ac058004d5c1&amp;jsenabled=false European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim]&lt;/ref&gt;&lt;ref name=&quot;bbc_ema_suspension&quot;&gt;[ Call to 'suspend' diabetes drug]&lt;/ref&gt; In New Zealand, rosiglitazone was withdrawn from the market in April 2011.&lt;ref name=&quot;;&gt;{{cite news |url= |title=Diabetes drug withdrawn |date=17 February 2011 |agency=[[NZPA]] |work=[[]] |accessdate=5 November 2011}}&lt;/ref&gt;
  121. ==Pharmacology==
  122. Rosiglitazone is a member of the thiazolidinedione class of drugs. Thiazolidinediones act as insulin sensitizers. They reduce glucose, fatty acid, and insulin blood concentrations. They work by binding to the [[peroxisome proliferator-activated receptor]]s (PPARs). PPARs are [[receptor (proteomics)|receptors]] on the membrane of the cell nucleus. Thiazolidinediones enter the cell, bind to the nuclear receptors, and affect the expression of DNA. The several PPARs include PPARα, PPARβ/δ, and PPARγ. Thiazolidinediones bind to [[Peroxisome proliferator-activated receptor gamma|PPARγ]].
  123. [[File:Avandia 2mg oral tablet.jpg|left|thumb|Avandia 2-mg oral tablet]]
  124. PPARs are expressed in fat cells, cells of the liver, muscle, heart, and inner wall (endothelium) and smooth muscle of blood vessels. PPARγ is expressed mainly in fat tissue, where it regulates genes involved in fat cell (adipocyte) differentiation, fatty acid uptake and storage, and glucose uptake. It is also found in pancreatic beta cells, vascular endothelium, and macrophages.&lt;ref&gt;[ Thiazolidinediones], Hannele Yki-Järvinen, New Engl J Med 351:1106-1118 (September 9, 2004).&lt;/ref&gt; Rosiglitazone is a selective ligand of PPARγ and has no PPARα-binding action. Other drugs bind to PPARα.
  126. Rosiglitazone also appears to have an anti-[[inflammation|inflammatory]] effect in addition to its effect on [[insulin resistance]]. Nuclear factor kappa-B ([[NF-κB]]), a signaling molecule, stimulates the inflammatory pathways. NF-κB inhibitor (IκB) downregulates the inflammatory pathways. When patients take rosiglitazone, NF-κB levels fall and IκB levels increase.&lt;ref&gt;{{cite journal |author=Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P |title=Evidence for a potent antiinflammatory effect of rosiglitazone |journal=J Clin Endocrinol Metab |volume=89 |issue=6 |pages=2728–35 |year=2004 |pmid=15181049 |doi=10.1210/jc.2003-032103}}&lt;/ref&gt;
  128. Rosiglitazone may also benefit patients with [[Alzheimer's disease]] who do not express the [[Apolipoprotein E|ApoE4]] [[allele]].&lt;ref&gt;{{cite journal |author=Risner ME et al. |title=Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease |journal=The Pharmacogenomics Journal |volume=6 |pages=246–254 |year=2006 |pmid=16446752 |issue=4 |doi=10.1038/sj.tpj.6500369 |last2=Saunders |first2=A M |last3=Altman |first3=J F B |last4=Ormandy |first4=G C |last5=Craft |first5=S |last6=Foley |first6=I M |last7=Zvartau-Hind |first7=M E |last8=Hosford |first8=D A |last9=Roses |first9=A D}}&lt;/ref&gt; This is the subject of a clinical trial currently underway.&lt;ref&gt;;/ref&gt;
  130. Rosiglitazone may also treat mild to moderate [[ulcerative colitis]], due to its anti-inflammatory properties as a PPAR ligand.&lt;ref&gt;{{cite journal |author=Lewis JD, Lichtenstein GR, Deren JJ, et al.|title=Rosiglitazone for Active Ulcerative Colitis: A Randomized Placebo Controlled Trials|journal=Gastroenterology |volume=134|pages=688–695|year=2008 |doi=10.1053/j.gastro.2008.03.030 |pmid=18471502 |issue=5}}&lt;/ref&gt;
  132. A clinical trial has suggested these agents may be of use in treating malaria.&lt;ref&gt;{{cite journal |author=Boggild AK, Krudsood S, Patel SN, Serghides L, Tangpukdee N, Katz K, Wilairatana P, Liles WC, Looareesuwan S, Kain KC |title=Use of Peroxisome proliferator-activated receptor gamma agonists as adjunctive treatment for ''Plasmodium falciparum'' malaria: A randomized, double-blind, placebo-controlled trial |journal=Clin. Infect. Dis. |volume=49|pages=841–9|year=2009 |doi=10.1086/605431 |issue=6 |pmid=19673614}}&lt;/ref&gt;
  134. == Adverse effects ==
  135. ===Heart disease===
  137. Some studies concluded rosiglitazone increases fatalities from heart disease, but other studies do not.
  139. A study in 2007 has been widely cited as finding Avandia may increase the risk of heart attack by as much as 43% relatively (for example, someone with a background risk of 1% would have a risk of 1.43% on average if they took the drug).&lt;ref&gt;[ LA Times ''Avandia: When does a drug's harm outweigh its benefit?''] by David Lazarus. 1 July 2010. Access date: July 24, 2010&lt;/ref&gt;&lt;ref&gt;;srvc=home&amp;position=emailed&lt;/ref&gt;
  141. A [[meta-analysis]] in May 2007 reported the use of rosiglitazone was associated with a significantly increased risk of [[myocardial infarction|heart attack]] ([[odds ratio]] = 1.43, 95% [[confidence interval]], 1.03 to 1.98; P=0.03), and an even higher risk of death from all cardiovascular diseases (odds ratio = 1.64, 95% [[confidence interval]], 0.98 to 2.74; P=0.06).&lt;ref&gt;{{cite journal |author= [[Steven Nissen|Nissen SE]], Wolski K | title= Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes |journal= N Engl J Med |volume=356 |issue=24 |year=2007 |pmid=17517853 |doi=10.1056/NEJMoa072761 |pages=2457–71 |url= |laysummary= |laysource=Associated Press |laydate=2007-05-21}}&lt;/ref&gt;
  142. The U.S. [[Food and Drug Administration]] (FDA) issued an alert on May 21, 2007.&lt;ref&gt;{{cite news| url = | title = FDA Issues Safety Alert on Avandia | date = May 21, 2007 | author = U.S. Food and Drug Administration | authorlink = Food and Drug Administration }}&lt;/ref&gt; On July 30, 2007, an Advisory Committee of the [[Food and Drug Administration]] concluded the use of rosiglitazone for the treatment of [[type 2 diabetes]] was associated with a greater risk of [[ischemic heart disease|myocardial ischemic events]] (including heart attacks) than a placebo, but data from several long term, prospective clinical trials showed when rosiglitazone was compared to [[metformin]], or [[sulfonylurea]], there was no difference in the risk of heart attack. These data, coupled with the meta-analysis, prompted the FDA to state the data on the association between rosiglitazone and myocardial ischemia were inconclusive. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate this, and several other reports have failed to conclude the controversy. Graham argued rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor.
  144. At the same time, a report by the [[United States Senate Committee on Finance|Senate Finance Committee]] accused GlaxoSmithKline of knowing about the drug's risks well before they became public. The report also criticized the FDA for letting [[clinical trial]]s continue, despite 83,000 heart attacks from 1999 to 2007 that the FDA linked to rosiglitazone. This Senate Committee report from November 2007 is entitled &quot;The Intimidation of Dr. John Buse and the Diabetes Drug Avandia&quot;. The title refers to (temporarily successful) efforts made by GSK beginning in 1999 to intimidate an academic scientist from continuing to suggest Avandia had cardiovascular risk. The drug now bears a black box warning about exactly this risk. GlaxoSmithKline maintains the drug is safe and the Senate report did not consider scientific evidence or the company's efforts to make known its concerns to the parties involved. However, the FDA still recommends patients continue taking it unless their doctors tell them otherwise.&lt;ref&gt;{{cite news|url=|title=Diabetes Drug Avandia Targeted By Reviewers on Safety|work=[[ABC News]]|date=2010-02-23}}&lt;/ref&gt;&lt;ref name=fallout/&gt;
  146. The 2009 RECORD study, an open-label trial published in the ''Lancet'', found no increase in cardiovascular hospitalisation or death with rosiglitazone compared to [[metformin]] plus [[sulfonylurea]], but the rate of heart failure causing admission to a hospital or death was significantly increased.&lt;ref&gt;Home PD, [[Stuart Pocock|Pocock SJ]], Beck-Nielsen H ''et al.'' Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. The Lancet. In Press, Corrected Proof. Available at:;/ref&gt;
  148. In February 2010, [[David Graham (epidemiologist)|David Graham]], the FDA's associate director of drug safety, recommended rosiglitazone be taken off the market. In June 2010, Graham ''et al''., published a retrospective study of 227,571 elderly American patients, comparing roziglitazone to pioglitazone, the other thiazolidinedione marketed in the United States. The authors concluded rosiglitazone was associated with &quot;an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of AMI, stroke, heart failure, or all-cause mortality in patients 65 years or older&quot;.&lt;ref&gt;Graham, D.J. et al.: Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone. JAMA. 2010;304(4): {{doi|10.1001/jama.2010.920}} [ Full text]&lt;/ref&gt; The [[number needed to harm]] with roziglitazone was sixty.
  150. Both TZDs are contraindicated in patients with [[NYHA classification|NYHA Class]] III and IV heart failure.
  152. The controversy over adverse effects has dramatically reduced the use of rosiglitazone, despite its important and sustained effects on [[glycemic control]].&lt;ref name=Ajjan&gt;{{cite journal |author= Ajjan RA, Grant PJ |title= The cardiovascular safety of rosiglitazone |journal= Expert Opin Drug Saf |volume=7 |issue=4 |pages=367–76 |year=2008 |pmid=18613801 |doi=10.1517/14740338.7.4.367}}&lt;/ref&gt; No studies have shown that rosiglitazone reduces the risk of stroke, amputation, heart attack, blindness, neuropathy or renal failure.
  154. A meta-analysis of observational studies released in March, 2011, provides more evidence that rosiglitazone is associated with a higher risk of heart failure, [[myocardial infarction]] and death than a similar agent, pioglitazone. The meta-analysis had 16 observational studies involving 810 000 patients taking rosiglitazone or [[pioglitazone]].&lt;ref&gt;{{cite web|last=Hughes|first=Sue|title=More damning data on rosiglitazone|url=||accessdate=6 April 2011|date=27 March 2011}}&lt;/ref&gt;
  156. ===Stroke===
  157. Avandia has been linked to stroke. In a study led by FDA scientist David J. Graham, MD, MPH, by comparing the patient records of elderly patients using Avandia and alternative drug Actos, found Avandia increased the risk of stroke by over 27% relatively (for example, someone with a 1% risk of stroke taking Actos would have a 1.27% risk taking Avandia, on average).&lt;ref&gt;{{cite news| url= | work=CBS News | title=Diabetes Drug and Risk: Avandia Linked to Stroke, Heart Trouble, Deaths | first=David W | last=Freeman | date=2010-06-29}}&lt;/ref&gt;&lt;ref&gt;{{cite news |url= |title=Drug Safety: Diabetes Drug Found to Increase Risk of Stroke, Heart Attack and Death. Researchers question why Avandia has not been removed from the market |author=Elizabeth Agnvall | publisher= AARP Bulletin | date=2010-06-28 |accessdate=2011-11-03 }}&lt;/ref&gt;&lt;ref&gt;{{cite news |url= |title=New Study: Avandia Riskier Than Actos: More Deaths, Heart Failure, Strokes in Elderly Patients Taking Diabetes Drug Avandia vs. Actos |author=Daniel J. DeNoon |publisher=WebMD Health News |review= Laura J. Martin, MD |date=2010-06-28 }}&lt;/ref&gt;
  159. ===Bone fractures===
  160. GlaxoSmithKline reported a greater incidence of [[fracture]]s of the upper arms, hands and feet in female diabetics given rosiglitazone compared with those given metformin or [[glyburide]].&lt;ref&gt;Cobitz, Alexander R (February 2007). {{PDFlink|[ Clinical Trial Observation of an Increased Incidence of Fractures in Female Patients Who Received Long-Term Treatment with Avandia (rosiglitazone maleate) Tablets for Type 2 Diabetes Mellitus]|49.9&amp;nbsp;[[Kibibyte|KiB]]&lt;!-- application/pdf, 51185 bytes --&gt;}}. [[GlaxoSmithKline]]. Retrieved on 10 April 2007.&lt;/ref&gt;
  161. The information was based on data from the ADOPT trial.&lt;ref&gt;{{cite journal |author=Kahn S, Haffner S, Heise M, Herman W, Holman R, Jones N, Kravitz B, Lachin J, O'Neill M, Zinman B, Viberti G |title=Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy |journal=[[New England Journal of Medicine|N Engl J Med]] |volume=355 |issue=23 |pages=2427–43 |year=2006 |pmid=17145742 |doi=10.1056/NEJMoa066224}}&lt;/ref&gt; The same increase has been found with pioglitazone (Actos), another TZD.
  163. ===Eye damage===
  164. Both rosiglitazone and pioglitazone have been suspected of causing [[macular edema]], which damages the retina of the eye and causes partial blindness. Blindness is also a possible effect of diabetes, which rosiglitazone is intended to treat. One report&lt;ref&gt;[;keytype2=tf_ipsecsha#R3-17 CMAJ]&lt;/ref&gt; documented several occurrences and recommended discontinuation at the first sign of vision problems.
  166. ===Hepatotoxicity===
  167. Moderate to severe acute hepatitis has occurred in several adults who had been taking the drug at the recommended dose for two to four weeks. Plasma rosiglitazone concentrations may be significantly increased in patients with pre-existing hepatic impairment.&lt;ref&gt;R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1399-1400.&lt;/ref&gt;
  169. ==Society and culture==
  170. ===Sales===
  171. US sales of the drug were of $2.2 billion in 2006.&lt;ref&gt;;/ref&gt; Sales in 2Q 2007 down 22% compared to 2006.&lt;ref&gt;{{cite news| url= | work=USA Today | title=FDA panels to weigh Avandia heart risks | first=Rita | last=Rubin | date=2007-07-26 | accessdate=2010-05-22}}&lt;/ref&gt; 4Q 2007 sales down to $252 million.&lt;ref&gt;{{cite news| url=;sid=aHobgoX8jyfg&amp;refer=home | work=Bloomberg | title=Glaxo Fourth-Quarter Profit Fell 10% on Avandia Sales (Update6) | date=2008-02-07}}&lt;/ref&gt;
  173. Though sales have gone down since 2007 due to safety concerns, Avandia sales for 2009 totalled $1.2 billion worldwide.&lt;ref name=fallout&gt;{{cite news|url=|title=Avandia fallout could hit Triangle|last=Ranii|first=David|work=[[News &amp; Observer]]|date=2010-02-23|accessdate=2010-03-05}}&lt;/ref&gt;
  175. ===Lawsuits===
  176. ''[[The Guardian]]'' reported [[lawsuit]]s over the drug could total from $1 billion to $6 billion, based on research by analysts for [[UBS AG|UBS]], who say 13,000 suits have been filed.&lt;ref&gt;{{cite news|url=|title=Avandia could cost GSK billions|last=Ranii|first=David|work=[[News &amp; Observer]]|date=2010-03-05|accessdate=2010-03-05}}&lt;/ref&gt; Included among those suing: [[Santa Clara County, California]], which claims to have spent $2 million on rosiglitazone between 1999 and 2007 at its public hospital and is asking for &quot;triple damages&quot;.&lt;ref&gt;{{cite news|url=
  177. |title=California county sues Glaxo over diabetes drug|work=[[Boston Globe]]|date=2010-03-01|accessdate=2013-02-25}}&lt;/ref&gt;
  178. In May 2010, GlaxoSmithKline (GSK) reached settlement agreements for some of the cases against the company, agreeing to pay $60 million to resolve 700 suits.&lt;ref&gt;{{cite news| url= | work=Bloomberg | first1=Jef | last1=Feeley | first2=Trista | last2=Kelley | title=Glaxo Said to Pay About $60 Million in First Avandia Heart-Risk Settlement | date=2010-05-11}}&lt;/ref&gt; In July 2010, GSK reached settlement agreements to close another 10,000 of the lawsuits against it, agreeing to pay about $460 million to settle these suits.&lt;ref&gt;{{cite news| url=;sid=aP.inHBfGVcU | work=Bloomberg | first1=Jef | last1=Feeley | first2=Trista | last2=Kelley | title=Glaxo Said to Pay $460 Million to Settle Avandia Damage Suits | date=2010-07-13}}&lt;/ref&gt;&lt;ref&gt;{{cite news| url= | location=London | work=The Independent | title=GSK 'settles Avandia claims' on first day of safety hearing | first=Alistair | last=Dawber | date=2010-07-14}}&lt;/ref&gt; In a statement, Michael Miller, the attorney representing 1,500 patients in the suit, said about the settlement, &quot;It's a compromise that allows both sides to put this behind them and move on.&quot;&lt;ref&gt;;utm_source=internal&lt;/ref&gt;
  180. ===Government investigations===
  181. The drug has been under investigation in the US and in Europe. In September 2010, the U.S. [[Food and Drug Administration]] (FDA) decided rosiglitazone can remain available, but with certain restrictions. Also, the [[European Medicines Agency]] has decided to stop making all rosiglitazone-containing antidiabetes medication available in Europe.&lt;ref&gt;{{cite web|last=Wood|first=Shelley|title=FDA restricts rosiglitazone; EMA pulls the plug|url=|publisher=|accessdate=1 April 2011}}&lt;/ref&gt; The FDA has decided on revising its prescribing information and medication guides for all rosilitazone containing medicines. The US label for rosiglitazone ([[Avandia]], [[GlaxoSmithKline]]) and all rosiglitazone-containing medications ([[Avandamet]] and [[Avandaryl]]) now include the additional safety information and restrictions.&lt;ref&gt;{{cite web|last=O'Riordan|first=Michael|title=New rosiglitazone label includes restrictions on use|url=|publisher=|accessdate=1 April 2011}}&lt;/ref&gt; The revised labels restrict use to patients already taking a rosiglitazone-containing medicine or to new patients who are unable to achieve adequate glycemic control on other diabetes medications and to those, who in consultation with their healthcare provider, have decided not to take Actos ([[pioglitazone]]) or other pioglitazone-containing medicines for medical reasons.&lt;ref&gt;{{cite web|title=GSK revises US Avandia label to include new restrictions on use|url=|publisher=|accessdate=1 April 2011}}&lt;/ref&gt;
  183. ====United States investigations====
  184. The FDA began investigating the drug in 2007 after reports it likely caused an increased risk in heart attacks, but following a 2007 study, an FDA advisory panel agreed Avandia did not cause a statistically significant increase in heart attacks. The FDA voted to keep the drug on the market; a few months later, however, the agency added a [[black-box warning]] about potential heart risks of Avandia.&lt;ref&gt;;/ref&gt; A study was conducted evaluating the geographic variation in the use of rosiglitazone following the black box warning issued in 2007. Residual use varied by state, which may be explained by uncertainty regarding how to translate FDA warnings into practice, by differences in coverage policies among health plans and in formularies among states, and by regional differences in the distribution and influence of pharmaceutical marketing, specialists, and opinion leaders.&lt;ref name=shah&gt;{{cite journal|last=Shah|first=Nilay|coauthors=Victor M Montori, Harlan M Krumholz, Karen Tu, G Caleb Alexander and Cynthia A Jackevicius|title=Responding to an FDA Warning — Geographic Variation in the Use of Rosiglitazone|journal=New England Journal of Medicine|date=25|year=2010|month=November|volume=363|pages=2081–2084|pmid=21083379|doi=10.1056/NEJMp1011042|issue=22}}&lt;/ref&gt;
  186. In 2007, a panel of independent researchers reported Avandia could, in fact, increase patients' risks of heart attack, but they recommended it remain on the market. An FDA oversight committee voted in 2007, eight to seven, to accept that advice and keep it on the market.&lt;ref&gt;{{cite news| url= | work=The Los Angeles Times | title=Avandia: When does a drug's harm outweigh its benefit? | first=David | last=Lazarus | date=2010-07-01}}&lt;/ref&gt;
  188. GlaxoSmithKline is currently being investigated by the FDA and the US Congress regarding Avandia.
  190. Senators Democrat [[Max Baucus]] and Republican [[Charles Grassley]] filed a report urging GSK to withdraw Avandia in 2008 due to the side effects. The report noted the drug caused 500 avoidable heart attacks a month, and Glaxo officials sought to intimidate doctors who criticized the drug. It also said GSK continued to sell and promote the drug despite knowing the increased risk of heart attacks and stroke.&lt;ref&gt;;/ref&gt;
  192. The [[Senate Finance Committee]], in a panel investigation, revealed emails from GSK company officials that suggest the company downplayed scientific findings about safety risks dating back to 2000. It was also alleged by the committee that the company initiated a &quot;ghostwriting campaign&quot;, whereby GSK sought outside companies to write positive articles about Avandia to submit to medical journals.&lt;ref&gt;;/ref&gt;
  193. GSK defended itself by presenting data that its own tests found Avandia to be safe, although an FDA staff report showed the conclusions were flawed.&lt;ref&gt;;/ref&gt; Many studies have found the drug to have serious safety concerns.&lt;ref&gt;;/ref&gt;
  195. On July 14, 2010, after two days of extensive deliberations, the FDA panel investigating Avandia came to a mixed vote. Twelve members of the panel voted to take the drug off the market, 17 recommended to leave it on but with a more revised warning label, and three voted to keep it on the market with the current warning label.&lt;ref&gt;;/ref&gt;&lt;ref&gt;;utm_source=internal&lt;/ref&gt; The panel has come to some controversy, however; on July 20, 2010, one of the panelists was discovered to have been a paid speaker for GlaxoSmithKline, arrousing questions of a conflict of interest. This panel member was one of the three who voted to keep Avandia on the market with no additional warning labels.&lt;ref&gt;;/ref&gt;&lt;ref&gt;{{cite news| url= | work=The Wall Street Journal | title=Panelist Who Backed Avandia Gets Fees From Glaxo | first=Alicia | last=Mundy | date=2010-07-20}}&lt;/ref&gt;&lt;ref&gt;{{cite news| url= | first=James | last=Gallagher | title=Report: Avandia panelist paid by GSK | date=2010-07-20}}&lt;/ref&gt;
  196. The FDA is expected to vote soon on what to do next in regards to Avandia, though the FDA almost always agrees with its panel votes.
  198. In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007.&lt;ref&gt;{{cite news|title=Glaxo Agrees to Pay $3 Billion in Fraud Settlement|newspaper=The New York Times|date=July 2, 2012|url=}}&lt;/ref&gt;
  200. ====European investigations====
  201. According to a probe by the ''[[British Medical Journal]]'' in September 2010, the United Kingdom's Commission on Human Medicines recommended to the Medicines and Healthcare Products Regulatory Agency (MHRA) back in July 2010, to withdraw Avandia sale because its &quot;risks outweigh its benefits&quot;. Additionally, the probe revealed that in 2000, members of the European panel in charge of reviewing Avandia prior to its approval had concerns about the long-term risks of the drug.&lt;ref&gt;{{cite news| url= | work=The Wall Street Journal | title=U.K. Medical Journal Questions Avandia License | first=Jason | last=Douglas | date=2010-09-06}}&lt;/ref&gt;&lt;ref&gt;;utm_source=internal&lt;/ref&gt; The European Medicines Agency recommended on 23 September 2010 that Avandia be suspended from the European market.&lt;ref name=&quot;ema_recommend_suspend&quot;/&gt;&lt;ref name=&quot;bbc_ema_suspension&quot;/&gt;
  203. ====New Zealand ====
  204. Rosiglitazone was withdrawn from the New Zealand market April 2011 because [[Medsafe]] concluded the suspected cardiovascular risks of the medicine for patients with type 2 diabetes outweigh its benefits.&lt;ref&gt;{{cite news| url =;objectid=10706910 | title = Diabetes drug to be withdrawn over heart risk fears | date = Feb 17, 2011 | publisher = New Zealand Herald}}&lt;/ref&gt;
  206. ====South Africa====
  207. A notice issued by the Medicines Control Council of South Africa on July 5, 2011 stated that it had resolved on July 3, 2011 to withdraw all rosiglitazone-containing medicines from the South African market due to safety risks. It disallowed all new prescriptions of Avandia.&lt;ref name=MCC&gt;{{cite web|last=Medicines Control Council|title=Withdrawal of rosiglitazone-containing medicines from SA market|url=|publisher=Department of Health, Republic of South Africa|accessdate=25 November 2012}}&lt;/ref&gt;
  209. ===Controversy and response===
  210. Following the reports in 2007 that Avandia can significantly increase the risk of heart attacks, the drug has been controversial. A 2010 article in ''Time'' uses the Avandia case as evidence of a broken FDA regulatory system that &quot;may prove criminal as well as fatal&quot;. It details the disclosure failures, adding, &quot;Congressional reports revealed that GSK sat on early evidence of the heart risks of its drug, and that the FDA knew of the dangers months before it informed the public.&quot; It reports, &quot;the FDA is investigating whether GSK broke the law by failing to fully inform the agency of Avandia's heart risks&quot;, according to deputy FDA commissioner Dr. Joshua Sharfstein. GSK threatened academics who reported adverse research results, and received multiple warning letters from the FDA for deceptive marketing and failure to report clinical data.&lt;ref&gt;After Avandia: Does the FDA Have a Drug Problem? Time, Thursday, Aug. 12, 2010,,8599,2010028,00.html&lt;/ref&gt;
  212. The maker of the drug, GlaxoSmithKline, has dealt with serious backlash against the company for the drug's controversy.&lt;ref&gt;;/ref&gt; Sales on the drug dropped significantly after the story first broke in 2007, dropping from $2.5 billion in 2006 to less than $408 million in 2009 in the US.&lt;ref&gt;;/ref&gt;
  214. In response to the rise in risk of heart attacks, the Indian government ordered GSK to suspend its research study, called TIDE, in 2010.&lt;ref&gt;;/ref&gt;&lt;ref&gt;;/ref&gt; [[Takeda Pharmaceuticals]] responded to the controversy by running a large advertising campaign for its rival diabetes drug [[Actos]], first in 2007 and again in 2010.&lt;ref&gt;;utm_source=internal&lt;/ref&gt; The FDA also halted the TIDE study in the United States.&lt;ref name=&quot;;&gt;;/ref&gt;&lt;ref name=&quot;;/&gt;
  216. Three doctors' groups, the [[Endocrine Society]], the [[American Diabetes Association]] and the [[American Association of Clinical Endocrinologists]], urged patients to continue to take the drug as it would be much worse to stop all treatment, despite any associated risk, but that patients could consult their doctors and begin a switch to a different drug if they or their doctors find concern.&lt;ref&gt;{{cite news| url= | work=Reuters | title=Don't dump Avandia, diabetes groups urge patients | date=2010-07-15}}&lt;/ref&gt;&lt;ref&gt;{{cite news| url= | work=The Los Angeles Times | title=Patients taking Avandia should keep on doing so, doctor groups say | first=Thomas H. | last=Maugh II | date=2010-07-15}}&lt;/ref&gt;&lt;ref&gt;{{cite news| url= | work=CBS News | title=Avandia News: What You Need to Know | first=Neil | last=Katz | date=2010-07-16}}&lt;/ref&gt; The [[American Heart Association]] said in a statement in June 2010: &quot; ...the reports deserves serious consideration, and patients with diabetes who are 65 years of age or older and being treated with rosiglitazone should discuss the findings with their prescribing physician....&quot;.
  217. &quot;For patients with diabetes, the most serious consequences are heart disease and stroke, and the risk of suffering from them is significantly increased when diabetes is present. As in most situations, patients should not change or stop medications without consulting their healthcare provider.&quot;&lt;ref&gt;{{cite news| url= | work=The Los Angeles Times | title=Booster Shots | date=2010-06-29}}&lt;/ref&gt;&lt;ref&gt;;/ref&gt;
  219. ==References==
  220. {{Reflist|2}}
  222. == External links ==
  223. * Rosiglitazone bound to proteins in the [[Protein Data Bank|PDB]]: [ S-rosiglitazone], [ R-rosiglitazone]
  224. * [ Official website]
  225. * [ MedlinePlus] article
  226. * [ Medscape]
  227. * {{ClinicalTrialsGov|NCT00265148|Brain Imaging Study of Rosiglitazone Efficacy and Safety in Alzheimer's Disease}}
  228. * [ U.S. National Library of Medicine: Drug Information Portal - Rosiglitazone]
  230. {{GlaxoSmithKline}}
  231. {{Oral hypoglycemics}}
  232. {{Androgenics}}
  233. {{Estrogenics}}
  234. {{Glucocorticoids}}
  235. {{Mineralocorticoids}}
  236. {{Progestogenics}}
  238. [[Category:Thiazolidinediones]]
  239. [[Category:Pyridines]]
  240. [[Category:Phenol ethers]]</text>
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  242. <model>wikitext</model>
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  244. </revision>
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