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===Cost===
===Cost===
{{disputed-section}}
Simvastatin is relatively in expensive.<ref name=El2012>{{cite journal |last1=Elavarasu |first1=S |last2=Suthanthiran |first2=TK |last3=Naveen |first3=D |title=Statins: A new era in local drug delivery. |journal=Journal of pharmacy & bioallied sciences |date=August 2012 |volume=4 |issue=Suppl 2 |pages=S248-51 |doi=10.4103/0975-7406.100225 |pmid=23066263|quote=Simvastatin... is a universally accepted and relatively inexpensive drug.}}</ref><ref name=Kis2018/><!-- Given its lower cost and off-patent status --> The wholesale cost in some [[LMIC]] is around US$0.01 to 0.15 per 20 mg dose {{as of|2014|lc=y}}.<ref name=IDPI2014>{{cite web|title=Simvastatin|url=https://apps.who.int/medicinedocs/documents/s21982en/s21982en.pdf|website=International Drug Price Indicator Guide|accessdate=28 November 2015|url-status=live}}</ref> The [[defined daily dose]] is 30 mg per the World Health Organization.<ref name=IDPI2014/> The price decreased from roughly US$1,200 to $40 per year of medication following the patent expiring in 2006.<ref name=Kis2018>{{cite journal |last1=Kishore |first1=Sandeep P. |last2=Blank |first2=Evan |last3=Heller |first3=David J. |last4=Patel |first4=Amisha |last5=Peters |first5=Alexander |last6=Price |first6=Matthew |last7=Vidula |first7=Mahesh |last8=Fuster |first8=Valentin |last9=Onuma |first9=Oyere |last10=Huffman |first10=Mark D. |last11=Vedanthan |first11=Rajesh |title=Modernizing the World Health Organization List of Essential Medicines for Preventing and Controlling Cardiovascular Diseases |journal=Journal of the American College of Cardiology |date=February 2018 |volume=71 |issue=5 |pages=564–574 |doi=10.1016/j.jacc.2017.11.056}}</ref> In the United States, it costs about US$10 to 20 per month since patent protection ended.<ref>{{cite book |title=Understanding Health Care Reform: Bridging the Gap Between Myth and Reality |date=2011 |publisher=CRC Press |isbn=978-1-4665-1679-3 |page=142 |url=https://www.google.com/books/edition/Understanding_Health_Care_Reform/bjR1sAkp3gsC?hl=en&gbpv=1&dq=Simvastatin+cost&pg=PA142 |language=en}}</ref><ref>{{cite web |title=Simvastatin Prices, Coupons & Patient Assistance Programs |url=https://www.drugs.com/price-guide/simvastatin |website=Drugs.com |accessdate=30 March 2020 |language=en}}</ref> In the UK in 2008, the typical per-patient cost to the NHS of simvastatin was about £1.50 per month.<ref>{{cite news |url=http://news.bbc.co.uk/1/hi/programmes/politics_show/7192271.stm |title=NHS overspends on statins |date=Jan 2008 |url-status=live |archiveurl=https://web.archive.org/web/20090214163933/http://news.bbc.co.uk/1/hi/programmes/politics_show/7192271.stm |archivedate=2009-02-14 }}</ref><!-- Quote = A generic version of Simvastatin, which many doctors say will do the same job for the majority of patients, costs £1.39. --> (40&nbsp;mg/day costs UK NHS £1.37/month in 2012<ref>{{cite web |url=http://www.cks.nhs.uk/diabetes_type_2/drugs_in_this_topic/scenario_managing_lipids/simvastatin_40mg_tablets |title=Simvastatin 40mg tablets }}</ref>) The price in Canada is about $CAD 130 to 160 per year as of 2016.<ref>{{cite web |title=Common Drug Review Evolocumab|url=https://www.cadth.ca/sites/default/files/cdr/pharmacoeconomic/SR0441_Repatha_PE_Report.pdf |website=CADTH |accessdate=30 March 2020 |date=February 2016}}</ref>
Simvastatin is relatively in expensive.<ref name=El2012>{{cite journal |last1=Elavarasu |first1=S |last2=Suthanthiran |first2=TK |last3=Naveen |first3=D |title=Statins: A new era in local drug delivery. |journal=Journal of pharmacy & bioallied sciences |date=August 2012 |volume=4 |issue=Suppl 2 |pages=S248-51 |doi=10.4103/0975-7406.100225 |pmid=23066263|quote=Simvastatin... is a universally accepted and relatively inexpensive drug.}}</ref><ref name=Kis2018/><!-- Given its lower cost and off-patent status --> The wholesale cost in some [[LMIC]] is around US$0.01 to 0.15 per 20 mg dose {{as of|2014|lc=y}}.<ref name=IDPI2014>{{cite web|title=Simvastatin|url=https://apps.who.int/medicinedocs/documents/s21982en/s21982en.pdf|website=International Drug Price Indicator Guide|accessdate=28 November 2015|url-status=live}}</ref> The [[defined daily dose]] is 30 mg per the World Health Organization.<ref name=IDPI2014/> The price decreased from roughly US$1,200 to $40 per year of medication following the patent expiring in 2006.<ref name=Kis2018>{{cite journal |last1=Kishore |first1=Sandeep P. |last2=Blank |first2=Evan |last3=Heller |first3=David J. |last4=Patel |first4=Amisha |last5=Peters |first5=Alexander |last6=Price |first6=Matthew |last7=Vidula |first7=Mahesh |last8=Fuster |first8=Valentin |last9=Onuma |first9=Oyere |last10=Huffman |first10=Mark D. |last11=Vedanthan |first11=Rajesh |title=Modernizing the World Health Organization List of Essential Medicines for Preventing and Controlling Cardiovascular Diseases |journal=Journal of the American College of Cardiology |date=February 2018 |volume=71 |issue=5 |pages=564–574 |doi=10.1016/j.jacc.2017.11.056}}</ref> In the United States, it costs about US$10 to 20 per month since patent protection ended.<ref>{{cite book |title=Understanding Health Care Reform: Bridging the Gap Between Myth and Reality |date=2011 |publisher=CRC Press |isbn=978-1-4665-1679-3 |page=142 |url=https://www.google.com/books/edition/Understanding_Health_Care_Reform/bjR1sAkp3gsC?hl=en&gbpv=1&dq=Simvastatin+cost&pg=PA142 |language=en}}</ref><ref>{{cite web |title=Simvastatin Prices, Coupons & Patient Assistance Programs |url=https://www.drugs.com/price-guide/simvastatin |website=Drugs.com |accessdate=30 March 2020 |language=en}}</ref> In the UK in 2008, the typical per-patient cost to the NHS of simvastatin was about £1.50 per month.<ref>{{cite news |url=http://news.bbc.co.uk/1/hi/programmes/politics_show/7192271.stm |title=NHS overspends on statins |date=Jan 2008 |url-status=live |archiveurl=https://web.archive.org/web/20090214163933/http://news.bbc.co.uk/1/hi/programmes/politics_show/7192271.stm |archivedate=2009-02-14 }}</ref><!-- Quote = A generic version of Simvastatin, which many doctors say will do the same job for the majority of patients, costs £1.39. --> (40&nbsp;mg/day costs UK NHS £1.37/month in 2012<ref>{{cite web |url=http://www.cks.nhs.uk/diabetes_type_2/drugs_in_this_topic/scenario_managing_lipids/simvastatin_40mg_tablets |title=Simvastatin 40mg tablets }}</ref>) The price in Canada is about $CAD 130 to 160 per year as of 2016.<ref>{{cite web |title=Common Drug Review Evolocumab|url=https://www.cadth.ca/sites/default/files/cdr/pharmacoeconomic/SR0441_Repatha_PE_Report.pdf |website=CADTH |accessdate=30 March 2020 |date=February 2016}}</ref>


Revision as of 00:30, 31 March 2020

Simvastatin
Clinical data
Pronunciation/ˈsɪmvəstætɪn/
Trade namesZocor, other
AHFS/Drugs.comMonograph
MedlinePlusa692030
License data
Pregnancy
category
  • AU: D
Routes of
administration		by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability5%
Protein binding95%
MetabolismHepatic (CYP3A4)
Elimination half-life2 hours for simvastatin and 1.9 hours for simvastatin acid
ExcretionRenal 13%, faecal 60%
Identifiers
  • (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.115.749 Edit this at Wikidata
Chemical and physical data
FormulaC25H38O5
Molar mass418.566 g/mol g·mol−1
3D model (JSmol)
  • 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
  • InChI=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 checkY
  • Key:RYMZZMVNJRMUDD-HGQWONQESA-N checkY
  (verify)

Simvastatin, marketed under the trade name Zocor among others, is a lipid-lowering medication.[2] It is used along with exercise, diet, and weight loss to decrease elevated lipid levels.[2] It is also used to decrease the risk of heart problems in those at high risk.[2] It is taken by mouth.[2]

Common side effects include constipation, headaches, and nausea.[2] Serious side effects may include muscle breakdown, liver problems, and increased blood sugar levels.[2] A lower dose may be needed in people with kidney problems.[2] There is evidence of harm to the developing baby when taken during pregnancy[2][3] and it should not be used by those who are breastfeeding.[2] It is in the statin class of medications and works by decreasing the manufacture of cholesterol by the liver.[2]

Simvastatin was patented by Merck in 1980, and came into medical use in 1992.[4][5] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] It is available as a generic medication.[2] Simvastatin is made from the fungus Aspergillus terreus.[4] In 2016, it was the eighth most prescribed medication in the United States, with more than 65 million prescriptions.[7]

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.[2] It is recommended to be used as an addition to a low-cholesterol diet.[2]

In the Scandinavian Simvastatin Survival Study (a placebo-controlled, randomized clinical trial of five years' duration), simvastatin reduced overall mortality in people with existing cardiovascular disease and high LDL cholesterol by 30% and reduced cardiovascular mortality by 42%.[8][9] The risks of heart attack, stroke, or needing a coronary revascularization procedure were reduced by 37%, 28%, and 37%, respectively.[10]

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.[10]

Simvastatin has been used to explore whether statins have an effect on delaying on the onset and progression of age-related macular degeneration (AMD).[11] Results from one trial showed participants assigned to simvastatin had lower odds (0.51 OR) of having AMD progression at three years compared to those assigned to placebo, though the results were not significant.[12] Overall, evidence is insufficient to conclude that simvastatin has an effect in delaying the onset and progression of AMD.[11]

Contraindications

Simvastatin is contraindicated with pregnancy, breastfeeding, and liver disease.[13] 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.[14] High doses of simvastatin are also contraindicated with the widely used antihypertensive amlodipine.[15] A lower dose is also recommended in people taking the calcium channel blockers, verapamil and diltiazem, as well as those taking amiodarone.[16][17]

Adverse effects

Common side effects (>1% incidence) may include indigestion and eczema. Rare side effects include joint pain, memory loss, and muscle cramps.[10] Cholestatic hepatitis, hepatic cirrhosis, rhabdomyolysis (destruction of muscles and blockade of renal system), and myositis have been reported in patients receiving the drug chronically.[18] Serious allergic reactions to simvastatin are rare.[13] If the following signs of a serious allergic reaction occur, seek medical attention immediately: rash, hoarseness itching/swelling, dizziness, or difficulty swallowing/breathing.[13]

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 alleles of a particular SNP, rs4149056,[19] were at a five-fold or 16-fold increased risk, respectively.[20] In 2012, the Clinical Pharmacogenetics Implementation Consortium has released guidelines regarding the use of rs4149056 genotype in guiding dosing of simvastatin[21] and updated the guideline in 2014.[22]

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.[23] The new guidance indicates:

  • FDA has found that liver injury associated with statin use is rare but can occur.
  • 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.
  • A small increased risk of raised blood sugar levels and the development of type 2 diabetes have been reported with the use of statins.
  • Some drugs interact with statins in a way that increases the risk of muscle injury called myopathy, characterized by unexplained muscle weakness or pain.

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.[24] 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.[25] 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."[15]

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.[15]

Consuming large amounts of grapefruit juice increases serum levels of simvastatin by up to three-fold, increasing the risk of side effects.[26][27][28][29] The FDA recommends that people taking statins should avoid consuming more than a quart (946 ml) of grapefruit juice per day.[15]

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.[15][30]

Pharmacology

Main article: Statin

All statins act by inhibiting 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase. HMG-CoA reductase, the 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 LDL-cholesterol concentration, but they are less effective than the fibrates 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).[31]

The drug is in the form of an inactive lactone that is hydrolyzed 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.

Simvastatin is an effective serum lipid-lowering drug that can decrease low density lipoprotein (LDL) levels by up to 50%.[citation needed] Simvastatin had been shown to interact with lipid-lowering transcription factor PPAR-alpha [32] and that interaction might control the neurotrophic action of the drug.

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.[33] 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.[citation needed]

By 1976, Akira Endo had isolated the first inhibitor, mevastatin, from the fungus Penicillium citrinium while working at Daiichi Sankyo in Japan.[34] In 1979, Hoffman and colleagues isolated lovastatin from a strain of the fungus 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).[35]

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 5.5 to 8.0 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.[8][9]

Society and culture

Cost

Simvastatin is relatively in expensive.[36][37] The wholesale cost in some LMIC is around US$0.01 to 0.15 per 20 mg dose as of 2014.[38] The defined daily dose is 30 mg per the World Health Organization.[38] The price decreased from roughly US$1,200 to $40 per year of medication following the patent expiring in 2006.[37] In the United States, it costs about US$10 to 20 per month since patent protection ended.[39][40] In the UK in 2008, the typical per-patient cost to the NHS of simvastatin was about £1.50 per month.[41] (40 mg/day costs UK NHS £1.37/month in 2012[42]) The price in Canada is about $CAD 130 to 160 per year as of 2016.[43]

Economics

Simvastatin was introduced in the late 1980s, and since 2006 in many countries, it is 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.

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. In 2005, recorded US$3.1 billion of sales in the United States and US$4.4 billion worldwide.[44]

Zocor had an original patent expiry date of 24 December 2005, but was extended by the United States Patent and Trademark Office (USPTO) to expire on 23 June 2006.[45] The USPTO granted the patent extension after Merck submitted data from studies of the drug's positive effect on children. In the UK, the patent for simvastatin had expired by 2004.[citation needed]

In the UK, simvastatin was the most prescribed medication in the community in 2013, with 39.9 million items dispensed. This compares to 30.9 million items for aspirin, and 27.7 million for levothyroxine sodium, the second- and third-most prescribed drugs in the UK in 2013.[46]

Marketing

Simvastatin was initially marketed by Merck & Co under the trade name Zocor, but is available generically in most countries following the patent expiry. A combination of simvastatin along with ezetimibe is sold under the brand name Vytorin and is jointly marketed by Merck and Schering-Plough.

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]

The U.S. patent for Zocor expired on 23 June 2006.[44] 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.[47]

See also

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ a b c d e f g h i j k l m "Simvastatin". The American Society of Health-System Pharmacists. Archived from the original on 10 January 2015. Retrieved 8 January 2015.
  3. ^ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Archived from the original on 8 April 2014. Retrieved 22 April 2014.
  4. ^ a b Cechinel-Filho, Valdir (2012). Plant bioactives and drug discovery : principles, practice, and perspectives. Hoboken, N.J.: John Wiley & Sons. p. 104. ISBN 9780470582268. Archived from the original on 5 March 2016.
  5. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 472. ISBN 9783527607495.
  6. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ^ "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
  8. ^ a b Tobert JA (2003). "Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors". Nat Rev Drug Discov. 2 (7): 517–26. doi:10.1038/nrd1112. PMID 12815379.
  9. ^ a b Scandinavian Simvastatin Survival Study Group (November 1994). "Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)". Lancet. 344 (8934): 1383–89. doi:10.1016/S0140-6736(94)90566-5. PMID 7968073.
  10. ^ a b c "Zocor Full Prescribing Information" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on 8 December 2015.
  11. ^ a b Gelbach P, Li T, Hatef E (2016). "Statins for age-related macular degeneration". Cochrane Database Syst Rev (8): CD006927. doi:10.1002/14651858.CD006927.pub5. PMC 5029465. PMID 27490232.
  12. ^ Guymer RH, Baird PN, Varsamidis M, Busija L, Dimitrov PN, Aung KZ, Makeyeva GA, Richardson AJ, Lim L, Robman LD (2013). "Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration". PLOS ONE. 8 (12): e83759. Bibcode:2013PLoSO...883759G. doi:10.1371/journal.pone.0083759. PMC 3877099. PMID 24391822.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  14. ^ "Simvastatin". LactMed. U.S. National Library of Medicine. Retrieved 1 December 2012.
  15. ^ a b c d e "FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury". U.S. Food and Drug Administration (FDA). 8 June 2011. Archived from the original on 11 June 2011.
  16. ^ "Simvastatin: updated advice on drug interactions - updated contraindications". Archived from the original on 27 January 2016. Retrieved 3 November 2015.
  17. ^ "FDA Drug Safety Communication: Revised dose limitation for Zocor (simvastatin) when taken with amiodarone". U.S. Food and Drug Administration (FDA). 15 December 2011. Archived from the original on 26 November 2012. Retrieved 12 October 2019.
  18. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1431–3.
  19. ^ rs4149056 Archived 2009-01-11 at the Wayback Machine
  20. ^ SEARCH Collaborative Group, Group; Link E; Parish S; Armitage J; Bowman L; Heath S; Matsuda F; Gut I; Lathrop M; Collins R (2008). "SLCO1B1 variants and statin-induced myopathy--a genomewide study". N Engl J Med. 359 (8): 789–99. doi:10.1056/NEJMoa0801936. PMID 18650507. {{cite journal}}: |first1= has generic name (help)
  21. ^ 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 (October 2014). "The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update". Clinical Pharmacology and Therapeutics. 96 (4): 423–8. doi:10.1038/clpt.2014.125. PMC 4169720. PMID 24918167.
  22. ^ 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; Clinical Pharmacogenomics Implementation Consortium, (CPIC) (July 2012). "The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy". Clinical Pharmacology and Therapeutics. 92 (1): 112–7. doi:10.1038/clpt.2012.57. PMC 3384438. PMID 22617227.
  23. ^ "FDA Expands Advice on Statin Risks". U.S. Food and Drug Administration (FDA). Archived from the original on 29 June 2012. Retrieved 12 July 2012.{{cite web}}: CS1 maint: unfit URL (link)
  24. ^ "FDA Drug Safety Communication: Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury". U.S. Food and Drug Administration (FDA). 19 March 2010. Archived from the original on 20 March 2010. Retrieved 21 March 2010.
  25. ^ Steve Sternberg (9 June 2011). "Simvastatin can damage muscles in high doses". USA Today. Archived from the original on 11 June 2011. Retrieved 9 June 2011. 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.
  26. ^ Lilja JJ, Kivistö KT, Neuvonen PJ (November 1998). "Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors". Clin Pharmacol Ther. 64 (5): 477–83. doi:10.1016/S0009-9236(98)90130-8. PMID 9834039.
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