Editing Simvastatin

{{Short description|Lipid-lowering medication}}
{{Use dmy dates|date=January 2024}}
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{{Drugbox
| verifiedrevid = 464391842
| image = Simvastatin.svg
| image_class = skin-invert-image
| width = 200
| alt = 
| image2 = Simvastatin3Dan.gif
| image_class2 = bg-transparent
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<!--Clinical data-->
| pronounce = {{IPAc-en|ˈ|s|ɪ|m|v|ə|s|t|æ|t|ᵻ|n|audio=LL-Q1860 (eng)-Naomi Persephone Amethyst (NaomiAmethyst)-simvastatin.wav}}
| tradename = Zocor, other
| Drugs.com = {{drugs.com|monograph|simvastatin}}
| MedlinePlus = a692030
| DailyMedID = Simvastatin
| pregnancy_AU = D
| routes_of_administration = [[Oral administration|By mouth]]
| ATC_prefix = C10
| ATC_suffix = AA01

| legal_AU = S4
| legal_UK = POM
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = <ref name="Zocor FDA label" />
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title = Active substance: simvastatin | work = List of nationally authorised medicinal products | url = https://www.ema.europa.eu/documents/psusa/simvastatin-list-nationally-authorised-medicinal-products-psusa/00002709/202004_en.pdf | date = 26 November 2020 | publisher = European Medicines Agency }}</ref>

<!--Pharmacokinetic data-->
| bioavailability = 5%
| protein_bound = 95%
| metabolism = [[Liver]] ([[CYP3A4]])
| elimination_half-life = 2 hours for simvastatin and 1.9 hours for simvastatin acid
| excretion = [[Kidney]] 13%, [[feces|faecal]] 60%

<!--Identifiers-->
| IUPHAR_ligand = 2955
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 79902-63-9
| PubChem = 54454
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00641
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 49179
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = AGG2FN16EV
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00434
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9150
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1064

<!--Chemical data-->
| IUPAC_name = (1''S'',3''R'',7''S'',8''S'',8a''R'')-8-{2-[(2''R'',4''R'')-4-hydroxy-6-oxotetrahydro-2''H''-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate
| C=25 | H=38 | O=5
| smiles = O=C(O[C@@H]1[C@H]3C(=C/[C@H](C)C1)\C=C/[C@@H]([C@@H]3CC[C@H]2OC(=O)C[C@H](O)C2)C)C(C)(C)CC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C25H38O5/c1-6-25(4,5)24(28)30-21-12-15(2)11-17-8-7-16(3)20(23(17)21)10-9-19-13-18(26)14-22(27)29-19/h7-8,11,15-16,18-21,23,26H,6,9-10,12-14H2,1-5H3/t15-,16-,18+,19+,20-,21-,23-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RYMZZMVNJRMUDD-HGQWONQESA-N
}}

<!-- Definition and medical uses -->
'''Simvastatin''', sold under the brand name '''Zocor''' among others, is a [[statin]], a type of [[lipid-lowering medication]].<ref name=AHFS2015>{{cite web|title=Simvastatin|url=https://www.drugs.com/monograph/simvastatin.html|publisher=The American Society of Health-System Pharmacists|access-date=8 January 2015|url-status=live|archive-url=https://web.archive.org/web/20150110101755/http://www.drugs.com/monograph/simvastatin.html|archive-date=10 January 2015}}</ref> It is used along with exercise, diet, and weight loss to decrease [[hyperlipidemia|elevated lipid levels]].<ref name=AHFS2015/> It is also used to decrease the risk of [[Cardiovascular disease|heart problems]] in those at high risk.<ref name=AHFS2015/> It is taken by mouth.<ref name=AHFS2015/>

<!-- Side effects and mechanism -->
Common side effects include constipation, headaches, and nausea.<ref name=AHFS2015/> Serious side effects may include [[rhabdomyolysis|muscle breakdown]], liver problems, and increased blood sugar levels.<ref name=AHFS2015/> A lower dose may be needed in people with [[chronic kidney disease|kidney problems]].<ref name=AHFS2015/> There is evidence of harm to the developing baby when taken during [[pregnancy]]<ref name=AHFS2015/><ref>{{cite web|title=Prescribing medicines in pregnancy database|url=http://www.tga.gov.au/hp/medicines-pregnancy.htm#.U1Yw8Bc3tqw|work=Australian Government|access-date=22 April 2014|date=3 March 2014|url-status=live|archive-url=https://web.archive.org/web/20140408040902/http://www.tga.gov.au/hp/medicines-pregnancy.htm#.U1Yw8Bc3tqw|archive-date=8 April 2014}}</ref> and it should not be used by those who are [[breastfeeding]].<ref name=AHFS2015/> It is in the [[statin]] class of medications and works by decreasing the manufacture of cholesterol by the liver.<ref name=AHFS2015/>

<!--History, society and culture -->
Simvastatin is made from the fungus ''[[Aspergillus terreus]]''.<ref name=Cec2012/> It was patented by [[Merck and Co.|Merck]] in 1980, and came into medical use in 1992.<ref name=Cec2012>{{cite book| vauthors = Cechinel-Filho V |title=Plant bioactives and drug discovery : principles, practice, and perspectives|date=2012|publisher=John Wiley & Sons|location=Hoboken, N.J.|isbn=9780470582268|page=104|url=https://books.google.com/books?id=hhraBwhymOUC&pg=PA104|url-status=live|archive-url=https://web.archive.org/web/20160305085553/https://books.google.ca/books?id=hhraBwhymOUC&pg=PA104|archive-date=5 March 2016}}</ref><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=472 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA472 |language=en}}</ref> Simvastatin is available as a [[generic medication]],<ref name=AHFS2015/> and is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In 2022, it was the nineteenth most commonly prescribed medication in the United States, with more than 26{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Simvastatin Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Simvastatin | access-date = 30 August 2024 }}</ref>

==Medical uses==
The primary uses of simvastatin are to treat [[dyslipidemia]] and to prevent atherosclerosis-related complications such as stroke and heart attacks in those who are at high risk.<ref name="AHFS2015"/> It is recommended to be used as an addition to a low-cholesterol diet.<ref name="AHFS2015"/>

In heart protection studies, simvastatin showed the ability to lower LDL cholesterol by about 1·5 mmol/L, which resulted in substantial reductions in mortality rates. Simvastatin also reduced the numbers of other events like heart attacks, strokes, and revascularizations and MI significantly.<ref name="Pedersen_2004">{{cite journal | vauthors = Pedersen TR, Tobert JA | title = Simvastatin: a review | journal = Expert Opinion on Pharmacotherapy | volume = 5 | issue = 12 | pages = 2583–96 | date = December 2004 | pmid = 15571475 | doi = 10.1517/14656566.5.12.2583 | s2cid = 36911054 }}</ref>

The [[Heart Protection Study]] evaluated the effects of simvastatin in people with risk factors including existing cardiovascular disease, diabetes, or stroke, but having relatively low LDL cholesterol. In this trial, which lasted 5.4 years, overall mortality was reduced by 13% and cardiovascular mortality was reduced by 18%.  People receiving simvastatin experienced 38% fewer nonfatal heart attacks and 25% fewer strokes.<ref name="Zocor PI">{{cite web|title=Zocor Full Prescribing Information|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019766s093lbl.pdf|url-status=dead|archive-url=https://web.archive.org/web/20151208172832/http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019766s093lbl.pdf|archive-date=8 December 2015|publisher=U.S. [[Food and Drug Administration]] (FDA)}}</ref>

Statins in general have been proposed as beneficial in reducing the progression of Age-related Macular Degeneration (AMD).<ref name="pmid30469381">{{cite journal | vauthors = Roizenblatt M, Naranjit N, Maia M, Gehlbach PL | title = The Question of a Role for Statins in Age-Related Macular Degeneration | journal = International Journal of Molecular Sciences | volume = 19 | issue = 11 | date = November 2018 | page = 3688 | pmid = 30469381 | pmc = 6274767 | doi = 10.3390/ijms19113688 | url = | doi-access = free }}</ref> Multiple observational studies have been conducted<ref>{{cite journal | vauthors = Al-Holou SN, Tucker WR, Agrón E, Clemons TE, Cukras C, Ferris FL, Chew EY | title = The Association of Statin Use with Age-Related Macular Degeneration Progression: The Age-Related Eye Disease Study 2 Report Number 9 | journal = Ophthalmology | volume = 122 | issue = 12 | pages = 2490–6 | date = December 2015 | pmid = 26435335 | pmc = 4658271 | doi = 10.1016/j.ophtha.2015.08.028 }}</ref><ref>{{cite journal | vauthors = Barbosa DT, Mendes TS, Cíntron-Colon HR, Wang SY, Bhisitkul RB, Singh K, Lin SC | title = Age-related macular degeneration and protective effect of HMG Co-A reductase inhibitors (statins): results from the National Health and Nutrition Examination Survey 2005-2008 | journal = Eye | volume = 28 | issue = 4 | pages = 472–80 | date = April 2014 | pmid = 24503725 | pmc = 3983650 | doi = 10.1038/eye.2014.8 }}</ref> to analyse the benefits of statin use in delaying the progression of AMD but have resulted in conflicting outcomes. Given the current available information, simvastatin should not be recommended solely for the treatment of AMD.{{cn|date=January 2025}}

==Contraindications==
Simvastatin is [[Contraindication|contraindicated]] with pregnancy, breastfeeding, and liver disease.<ref name=Rxlist/> Pregnancy must be avoided while on simvastatin due to potentially severe birth defects. Patients cannot breastfeed while on simvastatin due to potentially disrupting the infant's lipid metabolism.<ref name=LactMed>{{cite web|title=Simvastatin|url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~5v9vCs:1|work=LactMed|publisher=U.S. National Library of Medicine|access-date=1 December 2012}}</ref> High doses of simvastatin are also contraindicated with the widely used antihypertensive [[amlodipine]].<ref name=FDAJun2011 /> A lower dose is also recommended in people taking the calcium channel blockers, [[verapamil]] and [[diltiazem]], as well as those taking [[amiodarone]].<ref name=MHRA>{{cite journal |title=Simvastatin: updated advice on drug interactions - updated contraindications | journal = Drug Safety Update | publisher = Government of the United Kingdom | date = August 2012 | volume = 6 | issue = 1 | page = S1 |url=https://www.gov.uk/drug-safety-update/simvastatin-updated-advice-on-drug-interactions|access-date=3 November 2015|url-status=live|archive-url=https://web.archive.org/web/20160127121710/https://www.gov.uk/drug-safety-update/simvastatin-updated-advice-on-drug-interactions|archive-date=27 January 2016}}</ref><ref>{{cite web | title=FDA Drug Safety Communication: Revised dose limitation for Zocor (simvastatin) when taken with amiodarone | website=U.S. [[Food and Drug Administration]] (FDA) | date=15 December 2011 | url=https://www.fda.gov/Drugs/DrugSafety/ucm283137.htm | archive-url=https://web.archive.org/web/20121126053459/https://www.fda.gov/Drugs/DrugSafety/ucm283137.htm | archive-date=26 November 2012 | url-status=dead | access-date=12 October 2019}}</ref>

==Adverse effects==
Common side effects (>1% incidence) may include indigestion and eczema. There is evidence to suggest that rare side effects such as joint pain, memory loss, and muscle cramps are more likely to occur in patients who take higher doses of simvastatin.<ref name="Zocor PI" /> Cholestatic hepatitis, hepatic cirrhosis, [[rhabdomyolysis]] (destruction of muscles and blockade of renal system), and myositis have been reported in patients receiving the drug chronically.<ref>{{cite book |vauthors=Baselt R |title=Disposition of Toxic Drugs and Chemicals in Man |edition=8th |publisher=Biomedical Publications |location=Foster City, CA |date=2008 |pages=1431–3 }}</ref> Serious allergic reactions to simvastatin are rare.<ref name=Rxlist>{{cite web |title=Zocor |url=http://www.rxlist.com/zocor-drug/consumer-side-effects-precautions.htm|publisher=RxList |access-date=1 December 2012 |date=14 November 2012 |url-status=dead |archive-url=https://web.archive.org/web/20121104105217/http://www.rxlist.com/zocor-drug/consumer-side-effects-precautions.htm |archive-date=4 November 2012}}</ref>

A type of [[DNA]] variant known as a [[single nucleotide polymorphism]] (SNP) may help predict individuals prone to developing [[myopathy]] when taking simvastatin; a study ultimately including 32,000 patients concluded the carriers of one or two risk [[allele]]s of a particular SNP, rs4149056,<ref>{{Cite web|url=https://www.snpedia.com/index.php?title=Rs4149056|archiveurl=https://web.archive.org/web/20090111132256/http://www.snpedia.com/index.php?title=Rs4149056|url-status=dead |title=rs4149056 - SNPedia|archivedate=11 January 2009|website=www.snpedia.com}}</ref> were at a five-fold or 16-fold increased risk, respectively.<ref>{{cite journal | vauthors = Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R | display-authors = 6 | title = SLCO1B1 variants and statin-induced myopathy--a genomewide study | journal = The New England Journal of Medicine | volume = 359 | issue = 8 | pages = 789–99 | date = August 2008 | pmid = 18650507 | doi = 10.1056/NEJMoa0801936 | doi-access = free }}</ref> In 2012, the Clinical Pharmacogenetics Implementation Consortium has released guidelines regarding the use of rs4149056 genotype in guiding dosing of simvastatin<ref>{{cite journal | vauthors = Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, Maxwell WD, McLeod HL, Krauss RM, Roden DM, Feng Q, Cooper-DeHoff RM, Gong L, Klein TE, Wadelius M, Niemi M | display-authors = 6 | title = The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update | journal = Clinical Pharmacology and Therapeutics | volume = 96 | issue = 4 | pages = 423–8 | date = October 2014 | pmid = 24918167 | pmc = 4169720 | doi = 10.1038/clpt.2014.125 }}</ref> and updated the guideline in 2014.<ref>{{cite journal | vauthors = Wilke RA, Ramsey LB, Johnson SG, Maxwell WD, McLeod HL, Voora D, Krauss RM, Roden DM, Feng Q, Cooper-Dehoff RM, Gong L, Klein TE, Wadelius M, Niemi M | display-authors = 6 | title = The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy | journal = Clinical Pharmacology and Therapeutics | volume = 92 | issue = 1 | pages = 112–7 | date = July 2012 | pmid = 22617227 | pmc = 3384438 | doi = 10.1038/clpt.2012.57 }}</ref>

In March 2012, the U.S. [[Food and Drug Administration]] (FDA) updated its guidance for statin users to address reports of memory loss, liver damage, increased blood sugar, development of [[type 2 diabetes]], and muscle injury.<ref>{{cite web|title=FDA Expands Advice on Statin Risks|url=https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm293330.htm|publisher=U.S. [[Food and Drug Administration]] (FDA)|access-date=12 July 2012|url-status=unfit|archive-url=https://web.archive.org/web/20120629162246/https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm293330.htm|archive-date=29 June 2012}}</ref> The new guidance indicates:
* FDA has found that liver injury associated with statin use is rare but can occur.{{cn|date=January 2025}}
* The reports about memory loss, forgetfulness, and confusion span all statin products and all age groups. The FDA says these experiences are rare, but that those affected often report feeling "fuzzy" or unfocused in their thinking.{{cn|date=January 2025}}
* A small increased risk of raised blood sugar levels and the development of type 2 diabetes have been reported with the use of statins.  A 2010 published meta-analysis found for every 255 patients taking a statin for 4 years, one additional case of diabetes would occur whilst preventing 5.4 major coronary events.<ref>{{cite journal | vauthors = Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I | display-authors = 6 | title = Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials | language = English | journal = Lancet | volume = 375 | issue = 9716 | pages = 735–42 | date = February 2010 | pmid = 20167359 | doi = 10.1016/S0140-6736(09)61965-6 | s2cid = 11544414 }}</ref>
* Some drugs interact with statins in a way that increases the risk of muscle injury called myopathy, characterized by unexplained muscle weakness or pain.{{cn|date=January 2025}}

On 19 March 2010, the FDA issued another statement regarding simvastatin, saying it increases the risk of muscle injury (myopathy) when taken at high doses or at lower doses in combination with other drugs.<ref name="fda.gov">{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm |title=FDA Drug Safety Communication: Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury|date=19 March 2010|access-date=21 March 2010 |url-status=dead |archive-url=https://web.archive.org/web/20100320111330/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm |archive-date=20 March 2010 |publisher=U.S. [[Food and Drug Administration]] (FDA)}}</ref> The highest dose rate causes muscle damage in 610 of every 10,000 people in contrast to a lower dose, which causes muscle damage in eight of 10,000 people.<ref name=twsJunI>{{cite news | vauthors = Sternberg S |title = Simvastatin can damage muscles in high doses |work = [[USA Today]] |quote = The cholesterol-lowering drug simvastatin can cause severe muscle damage and should not be prescribed in high doses to patients who have taken it for less than a year or in any dose to people taking certain drugs, health officials said Tuesday. . . . Research has shown that the highest dose of simvastatin, 80 milligrams, causes muscle damage in 61 of every 1,000 patients, far higher than the eight-per-10,000 rate in patients taking a 40-milligram dose, Rosenblatt says. |date = 9 June 2011 |url = http://yourlife.usatoday.com/health/medical/story/2011/06/Simvastatin-can-damage-muscles-in-high-doses/48208588/1 |access-date = 9 June 2011 |url-status = dead |archive-url = https://web.archive.org/web/20110611043816/http://yourlife.usatoday.com/health/medical/story/2011/06/Simvastatin-can-damage-muscles-in-high-doses/48208588/1 |archive-date = 11 June 2011 }}</ref> The FDA warning, released again on 8 June 2011, suggested that high-dose "simvastatin should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury" and that it "should not be started in new patients, including patients already taking lower doses of the drug."<ref name=FDAJun2011 />

== Interactions ==

Simvastatin has important interactions with [[grapefruit]] juice and other drugs, including some that are commonly used for the treatment of cardiovascular disease.  These interactions are clinically important because increasing simvastatin serum levels above those normally provided by the maximum recommended dose increases the risk of muscle damage, including the otherwise rare and potentially fatal side effect of [[rhabdomyolysis]].<ref name=FDAJun2011/>

Consuming large amounts of grapefruit juice increases serum levels of simvastatin by up to three-fold, increasing the risk of side effects.<ref>{{cite journal | vauthors = Lilja JJ, Kivistö KT, Neuvonen PJ | title = Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors | journal = Clinical Pharmacology and Therapeutics | volume = 64 | issue = 5 | pages = 477–83 | date = November 1998 | pmid = 9834039 | doi = 10.1016/S0009-9236(98)90130-8 | s2cid = 37013910 }}</ref><ref>{{cite journal | vauthors = Lilja JJ, Neuvonen M, Neuvonen PJ | title = Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin | journal = British Journal of Clinical Pharmacology | volume = 58 | issue = 1 | pages = 56–60 | date = July 2004 | pmid = 15206993 | pmc = 1884539 | doi = 10.1111/j.1365-2125.2004.02095.x }}</ref><ref>{{Cite web | url=http://www.nhs.uk/conditions/cholesterol-lowering-medicines-statins/pages/interactions---other-medicines.aspx | title=Cholesterol-lowering medicines, statins - Interactions | date=16 April 2012 | publisher=[[National Health Service (England)|NHS]] | access-date=25 September 2013 | url-status=live | archive-url=https://web.archive.org/web/20130928105646/http://www.nhs.uk/conditions/cholesterol-lowering-medicines-statins/pages/interactions---other-medicines.aspx | archive-date=28 September 2013 }}</ref><ref>{{cite journal | vauthors = Lilja JJ, Kivistö KT, Neuvonen PJ | title = Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin | journal = Clinical Pharmacology and Therapeutics | volume = 68 | issue = 4 | pages = 384–90 | date = October 2000 | pmid = 11061578 | doi = 10.1067/mcp.2000.110216 | s2cid = 29029956 }}</ref> The FDA recommends that people taking statins should avoid consuming more than a quart (946 ml) of grapefruit juice per day.<ref name=FDAJun2011>{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/ucm256581.htm |title=FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury |url-status=dead |archive-url=https://web.archive.org/web/20110611062703/https://www.fda.gov/Drugs/DrugSafety/ucm256581.htm |archive-date=11 June 2011 |publisher=U.S. [[Food and Drug Administration]] (FDA)|date=8 June 2011 }}</ref>

Simvastatin also interacts with other drugs, including some used to treat cardiovascular problems.  It should not be taken by people who are also taking the antifungal drugs [[fluconazole]], [[itraconazole]], or [[posaconazole]]; the antibiotics [[erythromycin]], [[clarithromycin]], or [[telithromycin]]; HIV protease inhibitors; the antidepressant [[nefazodone]]; the cardiovascular drug [[gemfibrozil]]; the immunosuppressant [[ciclosporin]], or the endometriosis drug [[danazol]].  Reduced maximum doses of simvastatin apply for patients taking certain other drugs, including the cardiovascular drugs [[verapamil]], [[diltiazem]], [[amiodarone]], [[amlodipine]], and [[ranolazine]].<ref name=FDAJun2011 /><ref name="urlInformation on Simvastatin/Amiodarone">{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm118869.htm |title=Information on Simvastatin/Amiodarone |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=8 August 2008 |access-date=21 September 2008 |url-status=dead |archive-url=https://web.archive.org/web/20090607013919/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm118869.htm |archive-date=7 June 2009 }}</ref>

==Pharmacology ==
{{Main|Statin}}

=== Pharmacodynamics ===
All statins act by inhibiting 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase. [[HMG-CoA reductase]], the [[Rate-determining step|rate-limiting]] [[enzyme]] of the [[HMG-CoA reductase pathway]], the [[metabolic pathway]] responsible for the endogenous production of [[cholesterol]]. Statins are more effective than other lipid-regulating drugs at lowering [[Low-density lipoprotein|LDL]]-cholesterol concentration, but they are less effective than the [[fibrate]]s in reducing triglyceride concentration. However, statins reduce cardiovascular disease events and total mortality irrespective of the initial cholesterol concentration. This is a major piece of evidence that statins work in another way than the lowering of cholesterol (called pleiotropic effects).<ref>{{cite journal | vauthors = Pedersen TR | title = Pleiotropic effects of statins: evidence against benefits beyond LDL-cholesterol lowering | journal = American Journal of Cardiovascular Drugs | volume = 10 | pages = 10–7 | year = 2010 | issue = Suppl 1 | pmid = 21391729 | doi = 10.2165/1158822-S0-000000000-00000 | s2cid = 23195784 }}</ref>

Simvastatin is an effective serum [[lipid]]-lowering drug that can decrease [[low density lipoprotein]] (LDL) levels by up to 50%.{{citation needed|date=June 2012}} Simvastatin had been shown to interact with lipid-lowering transcription factor PPAR-alpha<ref name="pmid26118928">{{cite journal | vauthors = Roy A, Jana M, Kundu M, Corbett GT, Rangaswamy SB, Mishra RK, Luan CH, Gonzalez FJ, Pahan K | display-authors = 6 | title = HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice | journal = Cell Metabolism | volume = 22 | issue = 2 | pages = 253–65 | date = August 2015 | pmid = 26118928 | pmc = 4526399 | doi = 10.1016/j.cmet.2015.05.022 }}</ref> and that interaction might control the neurotrophic action of the drug.

=== Pharmacokinetics ===
The drug is in the form of an inactive [[lactone]] that is [[hydrolysis|hydrolyzed]] after ingestion to produce the active β-hydroxyacid form. Simvastatin is primarily metabolized by [[CYP3A4]] yielding products which are also active HMG-CoA reductase inhibitors.<ref name="Zocor FDA label">{{cite web | title=Zocor- simvastatin tablet, film coated | website=DailyMed | date=9 August 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f55d5de-5a4f-4a39-8c84-c53976dd6af9 | access-date=17 January 2024}}</ref>

==History==
The development of simvastatin was closely linked with [[lovastatin]]. Biochemist Jesse Huff and his colleagues at Merck began researching the biosynthesis of cholesterol in the early 1950s.<ref>{{cite book | vauthors = Li JJ |title=Triumph of the Heart: The Story of Statins |pages=59 |year=2009 | isbn = 978-0198043515 | publisher=Oxford University Press}}</ref> 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.<ref>{{Cite journal |last=Endo |first=Akira |date=2010 |title=A historical perspective on the discovery of statins |url=http://www.jstage.jst.go.jp/article/pjab/86/5/86_5_484/_article |journal=Proceedings of the Japan Academy, Series B |language=en |volume=86 |issue=5 |pages=484–493 |doi=10.2183/pjab.86.484 |issn=0386-2208 |pmc=3108295 |pmid=20467214|bibcode=2010PJAB...86..484E }}</ref>

By 1976, [[Akira Endo (biochemist)|Akira Endo]] had isolated the first inhibitor, [[mevastatin]], from the [[fungus]] ''[[Penicillium|Penicillium citrinium]]'' while working at [[Daiichi Sankyo]] in Japan.<ref>{{cite journal | vauthors = Liao JK, Laufs U | title = Pleiotropic effects of statins | journal = Annual Review of Pharmacology and Toxicology | volume = 45 | pages = 89–118 | year = 2005 | pmid = 15822172 | pmc = 2694580 | doi = 10.1146/annurev.pharmtox.45.120403.095748 }}</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 ''A. terreus'', which was designated MK-733 (later to be named simvastatin).<ref name="preview">{{cite book |title=Innovation Management - Strategies, Implementation, and Profits |url=https://archive.org/details/innovationmanage00afua |editor=Allan Afuah |year=1998 |publisher=Oxford University Press | vauthors = Williams O, Jacks AM, Davis J, Martinez S |chapter=Case 10: Merck(A): Mevacor |chapter-url=http://www-personal.umich.edu/~afuah/cases/case10.html |isbn=978-0-19-511346-4 |access-date=19 July 2006 |url-access=registration }}</ref>

In 1994, publication of the results of the [[Scandinavian Simvastatin Survival Study]] (4S) provided the first unequivocal evidence that lowering LDL cholesterol via statin treatment reduces cardiovascular events and overall mortality.  A total of 4,444 people with coronary heart disease and blood cholesterol levels from 5.5 to 8.0&nbsp;mmol/L were randomized to simvastatin treatment or placebo and followed for an average of 5 years. Compared to the placebo group, those treated with simvastatin experienced a 30% decrease in overall mortality, a 42% reduction in coronary death, a 34% reduction in major coronary events, and a 37% reduction in revascularization procedures.<ref name=pmid12815379>{{cite journal | vauthors = Tobert JA | title = Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors | journal = Nature Reviews. Drug Discovery | volume = 2 | issue = 7 | pages = 517–26 | date = July 2003 | pmid = 12815379 | doi = 10.1038/nrd1112 | s2cid = 3344720 }}</ref><ref name=pmid7968073>{{cite journal | vauthors = ((Scandinavian Simvastatin Survival Study Group)) | title = Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) | journal = Lancet | volume = 344 | issue = 8934 | pages = 1383–9 | date = November 1994 | pmid = 7968073 | doi = 10.1016/S0140-6736(94)90566-5 | s2cid = 5965882 }}</ref>

==Society and culture==

=== Economics ===
Prior to losing US patent protection, simvastatin was Merck & Co.'s largest-selling drug.<ref name="NYT Patent">{{cite news| vauthors = Berenson A |title=Merck Loses Protection for Patent on Zocor|url=https://www.nytimes.com/2006/06/23/business/23statin.html|access-date=14 January 2015|work=[[The New York Times]]|date=23 June 2006|url-status=live|archive-url=https://web.archive.org/web/20150114212534/http://www.nytimes.com/2006/06/23/business/23statin.html |archive-date=14 January 2015 | name-list-style=vanc}}</ref>

Under provisions of the [[Patient Protection and Affordable Care Act]] (PPACA) in the United States, health plans may cover the costs of simvastatin 10&nbsp;mg, 20&nbsp;mg, and 40&nbsp;mg for adults aged 40–75 years based on [[United States Preventive Services Task Force]] (USPSTF) recommendations.<ref>{{cite web | url=https://www.cigna.com/assets/docs/about-cigna/no-cost-share-preventive-medications.pdf | title=PPACA no cost-share preventive medications | publisher=Cigna | access-date=30 March 2020}}</ref><ref>{{cite journal | title=Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Recommendation Statement | journal=American Family Physician | volume=95 | issue=2 | date=15 January 2017 | url=https://www.aafp.org/afp/2017/0115/od1.html | access-date=31 March 2020 }}</ref><ref>{{cite web | title=Recommendation: Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication | website=United States Preventive Services Taskforce | date=15 November 2016 | url=https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/statin-use-in-adults-preventive-medication | access-date=7 May 2022}}</ref>

Zocor had an original patent expiry date in December 2005, but was extended by the [[United States Patent and Trademark Office]] (USPTO) to expire in June 2006.<ref>{{cite web | title=Merck gets Zocor patent extension | website=The Pharma Letter | url=https://www.thepharmaletter.com/article/merck-gets-zocor-patent-extension | date=3 November 2002 |access-date=12 October 2019}}</ref>

=== Brand names ===

Simvastatin was initially marketed by [[Merck & Co]] under the brand name Zocor but is available generically in most countries following the patent expiry.{{cn|date=May 2022}} A combination of simvastatin along with [[ezetimibe]] is sold under the brand name [[Vytorin]] and is jointly marketed by Merck and [[Schering-Plough]].{{cn|date=May 2022}}

Brand names include 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), available in Thailand under the brand Bestatin manufactured by Berlin Pharmaceutical Industry Co Ltd and others.{{citation needed|date=June 2012}}

In July 2004, Zocor Heart Pro 10mg was made available [[Over-the-counter drug|over the counter]] in the UK.<ref>{{Cite web |date=2022-02-10 |title=About simvastatin |url=https://www.nhs.uk/medicines/simvastatin/about-simvastatin/ |access-date=2025-05-19 |website=nhs.uk |language=en}}</ref><ref>{{Cite journal |last=Mayor |first=Susan |date=2005-06-18 |title=Drug regulator criticised for error in reporting consultation results |journal=BMJ (Clinical Research Ed.) |volume=330 |issue=7505 |pages=1410 |doi=10.1136/bmj.330.7505.1410 |issn=1756-1833 |pmc=558369 |pmid=15961813}}</ref><ref>{{Cite journal |last=Meek |first=C. |date=2005-06-07 |title=UK decision to sell statins over the counter criticized |journal=Canadian Medical Association Journal |language=en |volume=172 |issue=12 |pages=1543 |doi=10.1503/cmaj.050532 |issn=0820-3946 |pmc=558157}}</ref>  

== References ==
{{Reflist}}

{{Statins}}
{{Xenobiotic-sensing receptor modulators}}
{{Merck&Co}}
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[[Category:17β-Hydroxysteroid dehydrogenase inhibitors]]
[[Category:Carboxylate esters]]
[[Category:Delta-lactones]]
[[Category:Drugs developed by Merck & Co.]]
[[Category:Neuroprotective agents]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Secondary alcohols]]
[[Category:Statins]]
[[Category:Tetrahydropyrans]]
[[Category:World Health Organization essential medicines]]