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| {{drugbox | | | __NOTOC__ |
| |image=Rosuvastatin.png
| | {{Rosuvastatin}} |
| |width=166
| | {{CMG}}; {{AE}} |
| |IUPAC_name = 7-[4-(4-fluorophenyl) -6-(1-methylethyl)- 2-(methyl-methylsulfonyl-amino)- pyrimidin-
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| 5-yl]- 3,5-dihydroxy-hept-6-enoic acid
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| |CAS_number = 287714-41-4
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| | ATC_prefix=C10
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| | ATC_suffix=AA07
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| | PubChem=6439133
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| | DrugBank= APRD00546
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| | C=22 | H=28 | F=1 | N=3 | O=6 | S=1
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| |molecular_weight = 481.539
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| |bioavailability = 20%
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| |metabolism = [[Liver]]
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| |elimination_half-life = 19 hours
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| |excretion = Urine / Faeces
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| |pregnancy_AU = D
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| |pregnancy_US = X
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| |pregnancy_category =
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| |legal_AU = S4
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| |legal_UK = POM
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| |legal_US = Rx-only
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| |legal_status =
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| |routes_of_administration = oral
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| }} | |
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| {{SI}}
| | '''''For patient information about Rosuvastatin, click [[Rosuvastatin (patient information)|here]].''''' |
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| {{CMG}} | | {{SB}} CRESTOR<sup>®</sup> |
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| ==[[Rosuvastatin (patient information)|For patient information, click here]]==
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| ==Overview== | | ==Overview== |
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| '''Rosuvastatin''' is a member of the [[medication|drug]] class of [[statin]]s, used to treat [[hypercholesterolemia]] and related conditions, and to prevent [[cardiovascular disease]]. It is currently being marketed by the [[pharmaceutical company]] [[AstraZeneca]] as '''Crestor'''. | | '''Rosuvastatin''' is a member of the [[medication|drug]] class of [[statin]]s, used to treat [[hypercholesterolemia]] and related conditions, and to prevent [[cardiovascular disease]]. It is currently being marketed by the [[pharmaceutical company]] [[AstraZeneca]] as '''Crestor'''. |
| | ==Category== |
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| ==Dosing==
| | Statins,Diols,Carboxylic acids,Sulfonamides,Pyrimidines,Organofluorides,Cardiovasular drugs. |
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| Rosuvastatin is available as Crestor in tablet form (5, 10, 20, or 40 mg) for oral administration. Tablets are pink, round or oval (40 mg), biconvex, film-coated, and imprinted with "ZD4522" and tablet strength.<!--
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| --><ref name="pill">{{cite web | title=Core Data Sheet, Crestor Tablets | url=http://www.crestor.info/gUserFiles/CRESTOR_CDS_10_40_mg_FINAL_170603.pdf | format=PDF | year=2003 | month=June 17 | publisher=AstraZeneca PLC}} - NOTE: this is provider-oriented information and should not be used without the supervision of a physician.</ref>
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| Japanese approval is in the dose range of 2.5 mg to 20 mg; therefore, smaller dose tablet forms might also be available outside the United States. Note that 97% of worldwide sales have been at or below the 20 mg dose.
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| ==Mechanism of action==
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| {{further|[[Statin]]}}
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| Rosuvastatin is a [[competitive inhibitor]] of the enzyme [[HMG-CoA reductase]], having a mechanism of action similar, yet higher [[efficacy]], to other statins.<!--
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| --><ref name="ASTEROID">{{cite journal |author=Nissen SE, Nicholls SJ, Sipahi I, ''et al'' |title=Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial |journal=JAMA |volume=295 |issue=13 |pages=1556-65 |year=2006 |pmid=16533939 |doi=10.1001/jama.295.13.jpc60002 |url=http://jama.ama-assn.org/cgi/reprint/jama;295/13/1556.pdf?ijkey=Md42dlk7z9TzyL8&keytype=finite |format=PDF}}</ref>
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| ==Indications and regulation==
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| Rosuvastatin is approved for the treatment of elevated [[Low density lipoprotein|LDL cholesterol]] ([[dyslipidemia]]), total cholesterol ([[hypercholesterolemia]]) and/or [[triglycerides]] ([[hypertriglyceridemia]]).<!--
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| --><ref name="pill"/>
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| As of 2004, rosuvastatin had been approved in 154 countries and launched in 56. Approval in the United States by the [[Food and Drug Administration|FDA]] came on August 12, 2003.<!--
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| --><ref name="FDAapproval">{{cite news | title=FDA Approves New Drug for Lowering Cholesterol | url=http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01247.html | date=August 12, 2003 | publisher=The Food and Drug Administration}}</ref>
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| ===Effects on cholesterol levels===
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| The effects of rosuvastatin on LDL cholesterol are dose-related. At the 10mg dose, the average LDL cholesterol reduction was found to be 46% in one trial. Increasing the dose from 10 mg to 40 mg gave a modest increase of an additional 9% absolute reduction in LDL levels (55% below baseline levels).<ref name="Jones-2003">{{cite journal | author=Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW. | title=Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial) | journal=Am J Cardiol | year=2003 | volume=92 | issue=2 | pages=152-60 | id=PMID 12860216}}</ref>
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| ===Debate & criticisms===
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| Several months after its introduction in Europe, [[Richard Horton]], the editor of the [[medical journal]] ''[[The Lancet]]'', criticized the way Crestor had been introduced to the marketplace. "AstraZeneca's tactics in marketing its cholesterol-lowering drug, rosuvastatin, raise disturbing questions about how drugs enter clinical practice and what measures exist to protect patients from inadequately investigated medicines," according to his editorial. ''The Lancet's'' editorial position is that the data for Crestor’s superiority relies too much on extrapolation from the lipid profile data and too little on hard clinical endpoints, which are available for other statins which had been on the market longer. The manufacturer responded by stating that few drugs had been tested so successfully in so many patients. In correspondence published in ''The Lancet'', AstraZeneca's CEO [[Tom McKillop|Sir Tom McKillop]] called the editorial "flawed and incorrect" and criticized the journal for making "such an outrageous critique of a serious, well-studied medicine."<!--
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| --><ref name="lancetoped">{{cite journal | author =Horton, Richard | title = The statin wars: why AstraZeneca must retreat. | journal = Lancet | volume = 362 | issue = 9393 | pages = 1341 | year = 2003 | month=October 25 | id = PMID 14585629 | url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-49V58KN-1&_coverDate=10%2F25%2F2003&_alid=258485295&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4886&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=ce2d0b8bd4d33f68f98df533b594ebc2}} - No author is listed with the online abstract; full-text is not available free online. <BR><!--
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| -->{{cite journal | author = McKillop T | title = The statin wars. | journal = Lancet | volume = 362 | issue = 9394 | pages = 1498 | year = 2003 | month=November 1 | id = PMID 14602449 | url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-49WMK9W-11&_coverDate=11%2F01%2F2003&_alid=258487424&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4886&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c03c924e107b06c6e03c9ebf377bbc9e}} - Full-text is not available free online.</ref>
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| In 2004, the consumer interest organisation Public Citizen filed a Citizen's Petition with the FDA asking that Crestor be withdrawn from the US market. On March 11, 2005, the FDA issued a letter to Sidney M. Wolfe, M.D. of Public Citizen both (a) denying the petition and (b) providing an extensive detailed analysis of findings which demonstrated no basis for concerns about rosuvastatin compared with the other statins approved for marketing in the United States; the full text of the FDA letter is available on-line: http://www.fda.gov/cder/drug/infopage/rosuvastatin/crestor_CP.pdf<ref name="FDA ruling">{{cite journal | author =Food and Drug Administration | title = Docket No. 2004P-0113/CP1 | http://www.fda.gov/cder/drug/infopage/rosuvastatin/crestor_CP.pdf }}</ref>.
| | ==FDA Package Insert== |
| | ''' [[Rosuvastatin indications and usage|Indications and Usage]]''' |
| | '''| [[Rosuvastatin dosage and administration|Dosage and Administration]]''' |
| | '''| [[Rosuvastatin dosage forms and strengths|Dosage Forms and Strengths]]''' |
| | '''| [[Rosuvastatin contraindications|Contraindications]]''' |
| | '''| [[Rosuvastatin warnings and precautions|Warnings and Precautions]]''' |
| | '''| [[Rosuvastatin adverse reactions|Adverse Reactions]]''' |
| | '''| [[Rosuvastatin drug interactions|Drug Interactions]]''' |
| | '''| [[Rosuvastatin use in specific populations|Use in Specific Populations]]''' |
| | '''| [[Rosuvastatin overdosage|Overdosage]]''' |
| | '''| [[Rosuvastatin description|Description]]''' |
| | '''| [[Rosuvastatin clinical pharmacology|Clinical Pharmacology]]''' |
| | '''| [[Rosuvastatin nonclinical toxicology|Nonclinical Toxicology]]''' |
| | '''| [[Rosuvastatin clinical studies|Clinical Studies]]''' |
| | '''| [[Rosuvastatin how supplied storage and handling|How Supplied/Storage and Handling]]''' |
| | '''| [[Rosuvastatin patient counseling information|Patient Counseling Information]]''' |
| | '''| [[Rosuvastatin labels and packages|Labels and Packages]]''' |
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| ===Myopathy=== | | ==Mechanism of Action== |
| As with all statins, there is a concern of [[rhabdomyolysis]] (a severe undesired side effect). The FDA has indicated that "it does not appear that the risk [of rhabdomyolysis] is greater with Crestor than with other marketed statins", but has mandated that a warning about this side effect, as well as a kidney toxicity warning, be added to the product label.<!--
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| --><ref name="FDAlabel">{{cite web | title=FDA Alert (03/2005) - Rosuvastatin Calcium (marketed as Crestor) Information | url=http://www.fda.gov/cder/drug/infopage/rosuvastatin/default.htm | date=March 14, 2005 | publisher=The Food and Drug Administration}} - <small>This page is subject to change; the date reflects the last revision date.</small></ref>
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| However, more recent, larger and more thorough reviews have actually demonstrated both slightly lower rates of myopathy for rosuvastatin than any of the other statins available within the United States and improved kidney function with all statin use, including rosuvastatin, see below.
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| Regarding myopathy and potential rhabdomyolysis, recent reviews of published data on all statins marketed in the US, and reviewed by the FDA, both pre and post-approval, have found that marked rises in the serum levels of muscle CK enzymes to 10 times normal or greater, the hallmark of serious muscle problems, remain very rare, 1:10,000 to 1:20,000 individuals. (For comparison, this incidence is about identical with that for acetaminophen (paracetamol), commonly purchased as Tylenol, an OTC agent about which most people rarely worry; accept as safe)
| | CRESTOR is a selective and competitive inhibitor of [[HMG-CoA]] reductase, the rate-limiting enzyme that converts 3‑hydroxy‑3‑methylglutaryl coenzyme A to mevalonate, a precursor of [[cholesterol]]. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for [[cholesterol]] lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles. |
| | ==Interaction with Alcohol== |
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| [[Cerivastatin]], a statin recalled in 2001, was an exception; it had a higher myopathy response. For the statins still on the market in the US, reported toxicity levels has been highest for [[pravastatin]], [[simvastatin]] next, [[atorvastatin]] next and rosuvastatin the lowest at similar milligram doses. Yet the efficacy of these agents to change blood LDLipoproteins levels, at the same milligram doses, is the exact opposite. So, from the standpoint of the rare but serious muscle toxicity events, rosuvastatin, as of mid-2005 has turned out to have the best [[therapeutic index]] of the currently available statins.
| | CRESTOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease.Chronic alcohol liver disease is known to increase rosuvastatin exposure. |
| | | ==References== |
| ===Renal effects===
| | {{Reflist|2}} |
| Recent reviews of published trial data, focusing on renal function, on placebo vs. statin, and tracking renal function over time have shown a small but distinct effect of statins to lessen renal dysfunction, when added to treatment (compared to placebo), and to slow the progression of further renal function decline over time. All the statins have a somewhat dose related response to increase urine protein levels. Because increased urine protein has long been relied upon as a warning sign of renal glomerular dysfunction, this increase as a result of statin treatment had been feared to indicate a negative effect on renal function.
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| However, all current evidence, see reference 6 and others, is that the increase in urinary protein is from the renal tubular cells, not the glomeruli, and is due to cholesterol synthesis inhibition within the tubular cells and is not associated with any decline in renal function. Instead, as mentioned above, clinical experience is that renal function, especially in those with partial renal failure, actually improves slightly and the rate of further decline decreases compared with those in the same trials who were randomized to the placebo agent.
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| ===Clinical Trial Data===
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| More recent human controlled research trial data continues to be more promising. One of the most recent was a 2 year trial of rosuvastatin treatment, the ASTEROID trial, in reported in 2006 that when several hundred people were treated with Crestor at the highest currently approved dose of 40 mg a day, [[IVUS]] showed some reversal of [[atherosclerosis|atherosclerotic]] plaque within the coronary arteries.<!--
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| --><ref name="ASTEROID"/>
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| == References == | |
| * {{cite web | title=Annual Report and Form 20-F, Information 2004 | year=2005 | url=http://www.astrazeneca.com/sites/7/imagebank/typearticleparam511562/astrazeneca-2004-annual-report.pdf | format=PDF | publisher=AstraZeneca PLC}}
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| * {{cite web | title=Annual Report and Form 20-F, 2003 | year=2004 | url=http://www.astrazeneca.com/sites/7/imagebank/typearticleparam503063/AstraZeneca%20Annual%20Report%202003.pdf | format=PDF | publisher=AstraZeneca PLC}}
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| * {{cite journal | author = McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A, Schneck D, Smith G, Warwick M | title = Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. | journal = Am J Cardiol | volume = 87 | issue = 5A | pages = 28B-32B | year = 2001 | id = PMID 11256847}}
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| ==Notes==
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| <div class="references-small"><references/></div>
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| ==External links==
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| * [http://www.crestor.com/ Crestor web site], by [[AstraZeneca]], and their [http://www.rosuvastatininformation.com Rosuvastatin Information] site providing access to clinical trial information.
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| * {{cite web |title=Rosuvastatin (Crestor) Information |url=http://www.emedicinehealth.com/rosuvastatin_crestor/article_em.htm |publisher=eMedicineHealth |date=10/16/2005}}
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| ** {{cite web |title=What Are Some Possible Side Effects of Crestor? |url=http://www.emedicinehealth.com/rosuvastatin_crestor/page6_em.htm |publisher=eMedicineHealth |date=10/16/2005}}
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| ===FDA documents index===
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| ====2005====
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| * 11 March 2005: [http://www.fda.gov/cder/drug/infopage/rosuvastatin/crestor_CP.pdf Letter from FDA to Public Citizen] informing of the denial of Public Citizen's 4 March 2004 Citizen's Petition
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| * 8 March 2005: [http://www.fda.gov/cder/warn/2005/Crestor_letter.pdf Letter from FDA to AstraZeneca] regarding "false or misleading claims regarding the superiority of Crestor".
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| * 2 March 2005: [http://www.fda.gov/cder/drug/advisory/crestor_3_2005.htm FDA Public Health Advisory on Crestor (rosuvastatin)], patient and healthcare provider information updated
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| * 2 March 2005: [http://www.fda.gov/cder/foi/appletter/2005/21366s005ltr.pdf Letter from FDA to AstraZeneca] mandating changes to prescription labeling
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| ====2004====
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| * 21 December 2004: [http://www.fda.gov/cder/warn/2004/12779.pdf Letter from FDA to AstraZeneca] regarding "false or misleading safety claims" in a print ad
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| * 4 November 2004: [http://www.fda.gov/ohrms/dockets/dailys/04/nov04/110404/110404.htm#04P0113 FDA Docket listing 2004P-0113], regarding Public Citizen's Citizens' Petition of 4 March 2004
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| * 15 September 2004: [http://www.fda.gov/ohrms/dockets/dailys/04/sep04/091504/091504.htm#04P0113 FDA Docket listing 2004P-0113], regarding Public Citizen's Citizens' Petition of 4 March 2004
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| * 1 September 2004: [http://www.fda.gov/ohrms/dockets/dailys/04/sep04/091504/04p-0113-let00001-vol1.pdf Letter from FDA to Public Citizen] indicating that Public Citizen's 4 March 2004 Citizen's Petition is still under consideration.
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| * 4 June 2004: [http://www.fda.gov/ohrms/dockets/dailys/04/June04/060404/060404.htm#04P0113 FDA Docket listing 2004P-0113], regarding Public Citizen's Citizens' Petition of 4 March 2004
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| * 18 May 2004: [http://www.fda.gov/ohrms/dockets/dailys/04/June04/060404/04p-0113-c00001-vol1.pdf Letter from Public Citizen to FDA], update to Citizen's Petition of 4 March 2004
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| * 6 March 2004: [http://www.fda.gov/ohrms/dockets/dailys/04/mar04/030504/030504.htm#04P0113 FDA Docket listing 2004P-0113], regarding Public Citizen's Citizens' Petition of 4 March 2004
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| * 5 March 2004: [http://www.fda.gov/ohrms/dockets/dailys/04/mar04/030504/04p-0113-ack0001-vol1.pdf Letter from FDA to Public Citizen] acknowledging receipt of Citizen's Petition.
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| * 4 March 2004: [http://www.fda.gov/ohrms/dockets/dailys/04/mar04/030504/04p-0113-cp0001-vol1.pdf Letter from Public Citizen to FDA] petitioning for the immediate removal of Crestor from the market
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| ====2003====
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| * 12 August 2003: [http://www.fda.gov/cder/foi/appletter/2003/21366ltr.pdf Letter from FDA to AstraZeneca], approval letter
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| * 9 July 2003: [http://www.fda.gov/ohrms/dockets/ac/03/slides/3968s1.htm Presentations to the Endocrinologoc (sic) and Metabolic Drugs Advisory Committee]
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| {{Statins}} | | {{Statins}} |
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| [[Category:Statins]] | | [[Category:Statins]] |
| [[Category:AstraZeneca]] | | [[Category:AstraZeneca]] |
| | [[Category:Carboxylic acids]] |
| | [[Category:Sulfonamides]] |
| | [[Category:Pyrimidines]] |
| | [[Category:Organofluorides]] |
| | [[Category:Cardiovasular drugs]] |
| [[Category:Drugs]] | | [[Category:Drugs]] |
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