Simvastatin 635659 225612440 2008-07-14T15:36:21Z Chuckwatson 2154414 /* Sales */ {{drugbox | |width=171 |IUPAC_name = [(1''S'',3''R'',7''R'',8''S'',8''aR'')-8-[2-[(2''R'',4''R'')-4-hydroxy-6-<br />oxo-oxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8''a''<br />-hexahydronaphthalen-1-yl]2,2-dimethylbutanoate | image=Simvastatin.png | CAS_number = 79902-63-9 | ATC_prefix=C10 | ATC_suffix=AA01 | PubChem=54454 | DrugBank=APRD00104 | C=25 | H=38 | O=5 | molecular_weight = 418.566 g/mol | smiles = CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(= O)O3)[C@@H]12 | bioavailability = 5% | protein_bound = 95% | metabolism = [[Hepatic]] ([[CYP3A4]]) | elimination_half-life = 3 hours | excretion = [[Renal]] 13%, [[feces|faecal]] 60% | pregnancy_AU = D | pregnancy_US = X | pregnancy_category = | legal_AU = S4 | legal_UK = P | legal_US = Rx-only | legal_status = | routes_of_administration = Oral }} '''Simvastatin''' ([[International Nonproprietary Name|INN]]) ({{pronEng|ˈsɪmvəstætɨn}}), (marketed under the trade names '''Zocor''', Simvastatin, Simlup, Simcard and others) is a [[hypolipidemic agent|hypolipidemic drug]] belonging to the class of pharmaceuticals called "[[statin]]s". It is used to control [[hypercholesterolemia]] (elevated [[cholesterol]] levels) and to prevent [[cardiovascular disease]]. Simvastatin is a synthetic derivate of a fermentation product of ''[[Aspergillus terreus]]''. ==History== The development of simvastatin was closely linked with the research and development of [[Mevacor]]. Biochemist Jesse Huff and his colleagues at [[Merck & Co.|Merck]] began researching the biosynthesis of cholesterol in the early 1950s. In 1956, [[mevalonic acid]] was isolated from a yeast extract by [[Karl Folkers]], Carl Hoffman, and others at Merck; while Huff and his associates confirmed that mevalonic acid was an intermediate in cholesterol biosynthesis. In 1959, the [[HMG-CoA reductase]] enzyme (a major contributor of internal cholesterol production) was discovered by researchers at the [[Max Planck Institute]]. This discovery encouraged scientists worldwide to find an effective inhibitor of this enzyme. By 1976, [[Akira Endo (biochemist)|Akira Endo]] had isolated the first inhibitor ([[Compactin]], ML-236B) from the [[fungus]], ''[[Penicillium|Penicillium citrinium]]'' in [[Sankyo]], [[Japan]].<ref>Liao and Laufs. Pleiotropic Effects of Statins.(2005) Annu. Rev. Pharmacol. Toxicol:45:89-118</ref> In 1979, Hoffman and colleagues isolated lovastatin from a strain of the fungus ''[[Aspergillus|Aspergillus terreus]]''. While developing and researching lovastatin, Merck scientists synthetically derived a more potent HMG-CoA reductase inhibitor from a fermentation product of ''Aspergillus terreus'', which was designated MK-733 (later to be named simvastatin).<!-- --><ref name = "preview">{{cite book | title=Innovation Management - Strategies, Implementation, and Profits | url=http://www-personal.umich.edu/~afuah/ | editor=Ed. Allan Afuah | year=1998 | publisher=Oxford University Press | author= Olivia Williams, Anne-Marie Jacks, Jim Davis, Sabrina Martinez |chapter=Case 10: Merck(A): Mevacor* | chapterurl=http://www-personal.umich.edu/~afuah/cases/case10.html | accessdate=2006-07-19}}</ref> ==Uses== Simvastatin is a powerful lipid-lowering drug that can decrease [[low density lipoprotein]] (LDL) levels by up to 50%. It is used in doses of 5 [[milligram|mg]] up to 80 mg. Higher doses (160 mg) have been found to be too toxic, while giving only minimal benefit in terms of lipid lowering. There is no real effect on [[High density lipoprotein|HDL]] and [[triglyceride]] levels. From recent research it has become apparent that simvastatin and other statins inhibit the progression of [[atherosclerosis]] beyond their effects on LDL. Many explanations have been proposed, for example its inhibitory effect on [[macrophage]]s in the [[atherosclerotic plaque]] lesions. In one non-randomized study, simvastatin halved the risk of developing [[dementia]] or [[Parkinson's disease]].<ref>{{cite journal | last =Wolozin | first =B | coauthors =Wang SW, Li NC, Lee A, Lee TA, Kazis LE | title =Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease | journal =BMC Medicine | volume =5 | pages =20 | date =[[July 19]] [[2007]] | doi =10.1186/1741-7015-5-20 | pmid =17640385 | accessdate =2007-09-24}}</ref> == Rationing == Since its introduction, there has been a large debate surrounding the price for lipid-lowering treatment and its benefits on atherosclerosis. Although this has affected the other [[statin]]s as well, simvastatin was the first statin drug to be used extensively in clinical practice. A number of large [[epidemiology|epidemiological]] studies were conducted to discover which patients would benefit most from statin drugs; most studies involve simvastatin as the study drug. The most influential studies were the [[Scandinavian Simvastatin Survival Study]] (4S) and the [[Heart protection study]] (HPS). It has now become apparent that patients with one or more risk factors for [[cardiovascular disease]] (such as [[diabetes mellitus]], [[hypertension]] or a positive family history) can benefit from statins&mdash;even if they do not have substantially elevated cholesterol levels. Simvastatin was introduced in the late 1980s, and in many countries it is now available as a generic preparation. This has led to a decrease of the price of most statin drugs, and a reappraisal of the health economics of preventive statin treatment. In the UK, simvastatin (in a dose of 10 mg) has recently become available to purchase from pharmacies without prescription. == Pharmacology == {{main|Statin}} All statins act by inhibiting HMG-CoA reductase, the rate-limiting enzyme of the [[HMG-CoA reductase pathway]], the [[metabolic pathway]] responsible for the endogenous production of [[cholesterol]]. The drug is in the form of an inactive lactone that is hydrolized after ingestion to produce the active agent. It is a white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. === Interactions === [[Grapefruit]] contains the flavanones [[naringenin]] and [[bergamottin]], which inhibit the liver [[CYP3A4|cytochrome P450 3A4]]. This in turn slows metabolization of simvastatin and a large number of other drugs. Therefore, patients taking simvastatin should restrict their intake of grapefruit and grapefruit-containing products. == Side effects == Common side effects (>1% incidence) may include abdominal pain, diarrhea, indigestion, and a general feeling of weakness. Rare side effects include joint pain, memory loss, and muscle cramps.<ref>{{cite web |url=http://chealth.canoe.ca/drug_info_details.asp?channel_id=0&relation_id=0&brand_name_id=3499&page_no= |title=Gen-Simvastatin - Drug Factsheets - C-Health |accessdate=2007-08-15 |format= |work=}}</ref><ref>{{cite web |url=http://www.healthyontario.com/Drugs/S_-_Drugs/Simvastatin.htm |title=Simvastatin |accessdate=2007-08-15 |format= |work=}}</ref> == Marketing == [[Image:zocor.gif|frame|Zocor Logo]] Reference: Drug Discovery Today editorial, 2005.<!-- --><ref name = "sales">Maggon, Krishan. "Best-selling human medicines 2002-2004 (editorial)". 2005. Drug Discovery Today, 10(11):739-742</ref> Simvastatin was initially marketed by [[Merck & Co]] under the trade name '''Zocor''', but is now also available generically in most countries following the patent expiry. A combination of Simvastatin along with [[Ezetimibe]] is currently sold under the brand name [[Vytorin]] and is jointly marketed by Merck and [[Schering-Plough]]. Brand names: Zocor, Zocor Heart Pro, marketed by the [[pharmaceutical company]] [[Merck & Co.]] Simlup,Simvotin, Simcard [India] Denan (Germany), Liponorm, Sinvacor, Sivastin (Italy), Lipovas (Japan), Lodales (France), Zocord (Austria and Sweden), Zimstat, Simvahexal (Australia), Lipex (Australia and New Zealand), Simvastatin-Teva, Simvacor, Simvaxon, Simovil (Israel)and others. The primary US patent for Zocor expired on [[June 23]], [[2006]]; [[Ranbaxy Laboratories]] (at the 80-mg strength) and [[Teva Pharmaceutical Industries]] through its Ivax Pharmaceuticals unit (at all other strengths) were given approval by the FDA to manufacture and sell simvastatin as a [[generic drug]] with 180-day exclusivity. [[Dr. Reddy's Laboratories]] also has a license from Merck & Co. to sell simvastatin as an authorized generic drug. [[Ezetimibe/simvastatin]] is a combination product to lower lipids and marketed as Vytorin. == Sales == Prior to losing U.S. patent protection, simvastatin was Merck & Co.’s largest selling drug and second largest selling cholesterol lowering drug in the world; it recorded 4.3 billion dollars of sales in 2005.<!-- --><ref name = "sales" /> Zocor had an original patent expiration date of January 2006 but was extended by the United States Food and Drug Administration (FDA) to expire on [[June 23]], [[2006]]. The FDA granted the patent extension after Merck & Co, Inc. submitted data from studies of the drug’s positive effect on children, a move typically used by drug companies to lengthen exclusivity.<!-- --><ref name = "sales" /> Ordinarily, Merck & Co. would have expected a sharp decrease in sales after the generic versions of simvastatin entered the market; however, Merck has slashed the price of Zocor dramatically in an effort to claim sales that would have otherwise gone to the generic versions. At least two major U.S. health insurers, [[UnitedHealth Group|UnitedHealthcare]] and [[WellPoint]], are now offering Zocor to their members at generic copays.<!-- --><ref name = "pricewar">{{cite news | url=http://biz.yahoo.com/ap/060622/generic_drugs_zocor.html?.v=1 | title=Zocor Patent Expiring Means Bidding War | last=Brin | first=Dinah Wisenberg | publisher=Associated Press | date = [[2006-06-22]] | accessdate = 2006-07-09}}</ref> In addition, since Merck & Co. itself manufactures at least some versions of [[Dr. Reddy's Laboratories|Dr. Reddy's]] authorized generic simvastatin. Merck & Co. is also poised to profit from the Dr. Reddy's version. An 80 mg, 30-count bottle of Dr. Reddy's simvastatin obtained [[July 6]], [[2006]], states it is made by Merck Sharp & Dohme (Merck & Co.'s name outside the US to avoid conflicts with [[Merck KGaA]]) in the UK, just like 80 mg Zocor, and has a Merck & Co. logo on the bottom; except for omitting the "80" on one side, the tablets are visually identical to 80 mg Zocor, including "543" on the other side which is the key part of the [[National Drug Code]] for 80 mg Zocor. ==References== {{Reflist|2}} ==See also== * [[List of drugs affected by grapefruit]] ==External links== *[http://www.rxlist.com/cgi/generic/simva.htm RxList.com] - Simvastatin {{Statins}} {{Merck&Co}} [[Category:Merck]] [[Category:Statins]] [[es:Simvastatina]] [[fr:Simvastatine]] [[hu:Szimvasztatin]] [[nl:Simvastatine]] [[no:Simvastatin]] [[fi:Simvastatiini]] [[th:ซิมวาสแตติน]] [[zh:辛伐他汀]]