Array ( [0] => {{Short description|Cholesterol-lowering medication}} [1] => {{Use dmy dates|date=October 2022}} [2] => {{cs1 config |name-list-style=vanc |display-authors=6}} [3] => {{Infobox drug [4] => | Verifiedfields = [5] => | Watchedfields = changed [6] => | verifiedrevid = 477861573 [7] => | image = Atorvastatin.svg [8] => | width = 275 [9] => | alt = [10] => | image2 = Atorvastatin-from-xtal-3D-bs-17.png [11] => | width2 = 250 [12] => | alt2 = [13] => | caption = [14] => [15] => [16] => | pronounce = {{IPAc-en|ə|ˌ|t|ɔr|v|ə|ˈ|s|t|æ|t|ən}} [17] => | tradename = Lipitor, others [18] => | Drugs.com = {{drugs.com|monograph|lipitor}} [19] => | MedlinePlus = a600045 [20] => | DailyMedID = Atorvastatin [21] => | pregnancy_AU = D [22] => | pregnancy_AU_comment = {{cite web | title=Atorvastatin (Lipitor) Use During Pregnancy | website=Drugs.com | date=3 February 2020 | url=https://www.drugs.com/pregnancy/atorvastatin.html | access-date=26 February 2020 | archive-date=4 December 2019 | archive-url=https://web.archive.org/web/20191204214758/https://www.drugs.com/pregnancy/atorvastatin.html | url-status=live }} [23] => | pregnancy_category= Contraindicated [24] => | routes_of_administration = [[Oral administration|By mouth]] [25] => | class = [26] => | ATC_prefix = C10 [27] => | ATC_suffix = AA05 [28] => | ATC_supplemental = {{ATC|C10|BX08}} {{ATC|C10|BX03}} {{ATC|C10|BA05}} {{ATC|C10|BA08}} {{ATC|C10|BX15}} {{ATC|C10|BX12}} {{ATC|C10|BX06}} {{ATC|C10|BX11}} [29] => [30] => [31] => | legal_AU = S4 [32] => | legal_AU_comment = {{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}} [33] => | legal_BR = [34] => | legal_BR_comment = [35] => | legal_CA = [36] => | legal_CA_comment = [37] => | legal_DE = [38] => | legal_DE_comment = [39] => | legal_NZ = [40] => | legal_NZ_comment = [41] => | legal_UK = POM [42] => | legal_UK_comment = [43] => | legal_US = Rx-only [44] => | legal_US_comment = [45] => | legal_EU = Rx-only [46] => | legal_EU_comment = {{cite web | title=Lipitor | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/referrals/lipitor | access-date=26 February 2023}} [47] => | legal_UN = [48] => | legal_UN_comment = [49] => | legal_status = [50] => [51] => [52] => | bioavailability = 12% [53] => | protein_bound = [54] => | metabolism = [[Liver]] ([[CYP3A4]]) [55] => | metabolites = [56] => | onset = [57] => | elimination_half-life = 14 hours [58] => | duration_of_action = [59] => | excretion = [[Bile duct]] [60] => [61] => [62] => | CAS_number_Ref = {{cascite|correct|??}} [63] => | CAS_number = 134523-00-5 [64] => | CAS_supplemental = [65] => | PubChem = 60823 [66] => | IUPHAR_ligand = 2949 [67] => | DrugBank_Ref = {{drugbankcite|changed|drugbank}} [68] => | DrugBank = APRD00055 [69] => | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} [70] => | ChemSpiderID = 54810 [71] => | UNII_Ref = {{fdacite|changed|FDA}} [72] => | UNII = A0JWA85V8F [73] => | KEGG_Ref = {{keggcite|correct|kegg}} [74] => | KEGG = D07474 [75] => | ChEBI_Ref = {{ebicite|correct|EBI}} [76] => | ChEBI = 39548 [77] => | ChEMBL_Ref = {{ebicite|correct|EBI}} [78] => | ChEMBL = 1487 [79] => | NIAID_ChemDB = [80] => | PDB_ligand = 117 [81] => | synonyms = [82] => [83] => [84] => | IUPAC_name = (3''R'',5''R'')-7-[2-(4-Fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid [85] => | C=33 | H=35 | F=1 | N=2| O=5 [86] => | SMILES = O=C(O)C[C@H](O)C[C@H](O)CCn2c(c(c(c2c1ccc(F)cc1)c3ccccc3)C(=O)Nc4ccccc4)C(C)C [87] => | StdInChI_Ref = {{stdinchicite|correct|chemspider}} [88] => | StdInChI = 1S/C33H35FN2O5/c1-21(2)31-30(33(41)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-26(37)19-27(38)20-28(39)40/h3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40)/t26-,27-/m1/s1 [89] => | StdInChI_comment = [90] => | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} [91] => | StdInChIKey = XUKUURHRXDUEBC-KAYWLYCHSA-N [92] => | density = [93] => | density_notes = [94] => | melting_point = [95] => | melting_high = [96] => | melting_notes = [97] => | boiling_point = [98] => | boiling_notes = [99] => | solubility = [100] => | sol_units = [101] => | specific_rotation = [102] => }} [103] => [104] => '''Atorvastatin''' is a [[statin]] medication used to prevent [[cardiovascular disease]] in those at high risk and to treat [[dyslipidemia|abnormal lipid levels]]. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken [[by mouth]]. [105] => [106] => Common side effects include joint pain, diarrhea, heartburn, nausea, and muscle pains. Serious side effects may include [[rhabdomyolysis]], liver problems, and [[diabetes]]. Use during [[pregnancy]] may harm the fetus. Like all statins, atorvastatin works by inhibiting [[HMG-CoA reductase]], an [[enzyme]] found in the [[liver]] that plays a role in producing [[cholesterol]]. [107] => [108] => Atorvastatin was patented in 1986, and approved for medical use in the United States in 1996.{{cite web |title=Atorvastatin Calcium Monograph for Professionals |url=https://www.drugs.com/monograph/atorvastatin-calcium.html |website=Drugs.com |publisher=AHFS |access-date=23 December 2018 |archive-date=25 October 2010 |archive-url=https://web.archive.org/web/20101025140429/https://www.drugs.com/monograph/atorvastatin-calcium.html |url-status=live }}{{cite book |vauthors=Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=473 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA473 |access-date=10 May 2020 |archive-date=12 January 2023 |archive-url=https://web.archive.org/web/20230112030119/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA473 |url-status=live }} It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }} It is available as a [[generic medication]]. In 2021, it was the most commonly prescribed medication in the United States, with more than 116{{nbsp}}million prescriptions filled for over 28 million patients.{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | access-date=14 January 2024 | website=ClinCalc | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live}}{{cite web | title=Atorvastatin - Drug Usage Statistics | website=ClinCalc | url=https://clincalc.com/DrugStats/Drugs/Atorvastatin | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Drugs/Atorvastatin | url-status=live }} [109] => [110] => ==Medical uses== [111] => The primary uses of atorvastatin is for the treatment of [[dyslipidemia]] and the prevention of [[cardiovascular disease]]: [112] => [113] => ===Dyslipidemia=== [114] => * [[Hypercholesterolemia]] ([[Familial hypercholesterolemia#Heterozygous FH|heterozygous familial and nonfamilial]]) and mixed [[dyslipidemia]] ([[Fredrickson classification#Type IIa|Fredrickson types IIa]] and [[Fredrickson classification#Type IIb|IIb]]) to reduce total [[cholesterol]], [[Low-density lipoprotein|LDL-C]], [[Apolipoprotein B|apo-B]], [[triglyceride]]s levels, and [[C-reactive protein|CRP]] as well as increase [[High density lipoprotein|HDL]] levels. [115] => * [[Familial hypercholesterolemia#Heterozygous FH|Heterozygous familial hypercholesterolemia]] in [[pediatrics|children]] [116] => * [[Familial hypercholesterolemia#Homozygous FH|Homozygous familial hypercholesterolemia]] [117] => * Hypertriglyceridemia ([[Fredrickson classification#Hyperlipoproteinemia type IV|Fredrickson Type IV]]) [118] => * Primary dysbetalipoproteinemia ([[Fredrickson classification#Hyperlipoproteinemia type III|Fredrickson Type III]]) [119] => * [[Combined hyperlipidemia]] [120] => [121] => ===Cardiovascular disease=== [122] => * [[Primary prevention]] of heart attack, stroke, and need for revascularization procedures in people who have risk factors such as age, smoking, high blood pressure, low HDL-C, and a family history of early heart disease, but have not yet developed evidence of [[coronary artery disease]]. [123] => * [[Secondary prevention]] of [[myocardial infarction]], [[stroke]], [[unstable angina]], and [[revascularization]] in people with established coronary artery disease. [124] => * Myocardial infarction and stroke prevention in people with [[type 2 diabetes]] [125] => [126] => A 2014 meta-analysis showed high-dose [[statin]] therapy was significantly superior compared to moderate or low-intensity statin therapy in reducing plaque volume in patients with [[acute coronary syndrome]].{{cite journal | vauthors = Banach M, Serban C, Sahebkar A, Mikhailidis DP, Ursoniu S, Ray KK, Rysz J, Toth PP, Muntner P, Mosteoru S, García-García HM, Hovingh GK, Kastelein JJ, Serruys PW | title = Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies | journal = BMC Medicine | volume = 13 | issue = 1 | pages = 229 | date = September 2015 | pmid = 26385210 | pmc = 4575433 | doi = 10.1186/s12916-015-0459-4 | doi-access = free | title-link = doi }} The SATURN trial which compared the effects of high-dose atorvastatin and rosuvastatin also confirmed these findings.{{cite journal | vauthors = Nicholls SJ, Ballantyne CM, Barter PJ, Chapman MJ, Erbel RM, Libby P, Raichlen JS, Uno K, Borgman M, Wolski K, Nissen SE | title = Effect of two intensive statin regimens on progression of coronary disease | journal = The New England Journal of Medicine | volume = 365 | issue = 22 | pages = 2078–87 | date = December 2011 | pmid = 22085316 | doi = 10.1056/NEJMoa1110874 | doi-access = free | title-link = doi }} Despite the high dosage, the 40 mg pravastatin study arm in the REVERSAL trial failed to halt plaque progression, which suggests other factors such as which statin is used, duration and location of the plaque may also affect plaque volume reduction and thereby plaque-stabilization.{{cite journal | vauthors = Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN | title = Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial | journal = JAMA | volume = 291 | issue = 9 | pages = 1071–80 | date = March 2004 | pmid = 14996776 | doi = 10.1001/jama.291.9.1071 | doi-access = | title-link = doi }} Overall, plaque reduction should be considered as a surrogate endpoint and should not be directly used to determine clinical benefit of therapy. Increased risk of adverse events should also be taken into account when considering high-dose statin therapy. [127] => [128] => ===Kidney disease=== [129] => There is evidence from systematic review and meta-analyses that statins, particularly atorvastatin, reduce both decline in kidney function (eGFR) and the severity of protein excretion in urine,{{cite journal | vauthors = Su X, Zhang L, Lv J, Wang J, Hou W, Xie X, Zhang H | title = Effect of Statins on Kidney Disease Outcomes: A Systematic Review and Meta-analysis | journal = American Journal of Kidney Diseases | volume = 67 | issue = 6 | pages = 881–892 | date = June 2016 | pmid = 26905361 | doi = 10.1053/j.ajkd.2016.01.016 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Geng Q, Ren J, Song J, Li S, Chen H | title = Meta-analysis of the effect of statins on renal function | journal = The American Journal of Cardiology | volume = 114 | issue = 4 | pages = 562–570 | date = August 2014 | pmid = 25001155 | doi = 10.1016/j.amjcard.2014.05.033 }}{{cite journal | vauthors = Amarenco P, Callahan A, Campese VM, Goldstein LB, Hennerici MG, Messig M, Sillesen H, Welch KM, Wilson DJ, Zivin JA | title = Effect of high-dose atorvastatin on renal function in subjects with stroke or transient ischemic attack in the SPARCL trial | journal = Stroke | volume = 45 | issue = 10 | pages = 2974–2982 | date = October 2014 | pmid = 25147328 | doi = 10.1161/STROKEAHA.114.005832 | s2cid = 6575836 }} with higher doses having greater effect. Data are conflicting for whether statins reduce risk of kidney failure. Statins, including atorvastatin, before heart surgery do not prevent acute kidney injury.{{cite journal | vauthors = Xiong B, Nie D, Cao Y, Zou Y, Yao Y, Qian J, Rong S, Huang J | title = Preoperative Statin Treatment for the Prevention of Acute Kidney Injury in Patients Undergoing Cardiac Surgery: A Meta-Analysis of Randomised Controlled Trials | journal = Heart, Lung & Circulation | volume = 26 | issue = 11 | pages = 1200–1207 | date = November 2017 | pmid = 28242291 | doi = 10.1016/j.hlc.2016.11.024 }} [130] => [131] => Prior to contrast medium (CM) administration, pre-treatment with atorvastatin therapy can reduce the risk of contrast-induced acute kidney injury (CI-AKI) in patients with pre-existing chronic kidney disease (CKD) (eGFR < 60mL/min/1.73m2) who undergo interventional procedures such as cardiac catheterisation, coronary angiography (CAG) or percutaneous coronary intervention (PCI).{{cite journal | vauthors = Zhou X, Dai J, Xu X, Wang Z, Xu H, Chen J, Qiu Y, Mao W | title = Comparative Efficacy of Statins for Prevention of Contrast-Induced Acute Kidney Injury in Patients With Chronic Kidney Disease: A Network Meta-Analysis | journal = Angiology | volume = 70 | issue = 4 | pages = 305–316 | date = April 2019 | pmid = 30261736 | doi = 10.1177/0003319718801246 | s2cid = 52875826 }}{{cite journal | vauthors = Ma WQ, Zhao Y, Wang Y, Han XQ, Zhu Y, Liu NF | title = Comparative efficacy of pharmacological interventions for contrast-induced nephropathy prevention after coronary angiography: a network meta-analysis from randomized trials | journal = International Urology and Nephrology | volume = 50 | issue = 6 | pages = 1085–1095 | date = June 2018 | pmid = 29404930 | doi = 10.1007/s11255-018-1814-0 | s2cid = 3295220 | url = http://www.ijcem.com/files/ijcem0015476.pdf | access-date = 9 May 2020 | archive-date = 30 November 2020 | archive-url = https://web.archive.org/web/20201130175903/http://www.ijcem.com/files/ijcem0015476.pdf | url-status = live }}{{cite journal | vauthors = Cho A, Lee YK, Sohn SY | title = Beneficial effect of statin on preventing contrast-induced acute kidney injury in patients with renal insufficiency: A meta-analysis | journal = Medicine | volume = 99 | issue = 10 | pages = e19473 | date = March 2020 | pmid = 32150109 | doi = 10.1097/MD.0000000000019473 | pmc = 7478506 | doi-access = free | title-link = doi }} A meta-analysis of 21 RCTs confirmed that high dose (80 mg) atorvastatin therapy is more effective than regular dose or low dose statin therapy at preventing CI-AKI. Atorvastatin therapy can also help to prevent in-hospital dialysis post CM administration, however there is no evidence that it reduces all-cause mortality associated with CI-AKI. Overall, the evidence concludes that statin therapy, irrespective of the dose, is still more effective than no treatment or placebo at reducing the risk of CI-AKI.{{cite journal | vauthors = Zhang J, Guo Y, Jin Q, Bian L, Lin P | title = Meta-analysis of rosuvastatin efficacy in prevention of contrast-induced acute kidney injury | journal = Drug Design, Development and Therapy | volume = 12 | pages = 3685–3690 | date = October 2018 | pmid = 30464400 | doi = 10.2147/DDDT.S178020 | pmc = 6216974 | doi-access = free | title-link = doi }} [132] => [133] => ===Administration=== [134] => Statins (predominantly simvastatin) have been evaluated in [[Clinical trial|clinical trials]] in combination with [[Fibrate|fibrates]] to manage dyslipidemia in patients who also have type 2 diabetes, and a high cardiovascular disease risk, however, there is limited clinical benefit noted for most cardiovascular outcomes {{cite journal | vauthors = Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesäniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M | title = Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial | journal = Lancet | volume = 366 | issue = 9500 | pages = 1849–1861 | date = November 2005 | pmid = 16310551 | doi = 10.1016/S0140-6736(05)67667-2 | s2cid = 40744740 }}{{cite journal | vauthors = Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC, Cushman WC, Simons-Morton DG, Byington RP | title = Effects of combination lipid therapy in type 2 diabetes mellitus | journal = The New England Journal of Medicine | volume = 362 | issue = 17 | pages = 1563–1574 | date = April 2010 | pmid = 20228404 | pmc = 2879499 | doi = 10.1056/NEJMoa1001282 }} [135] => [136] => While many short half-lives statin medications should be taken in the evening for optimal effect, atorvastatin tablets can be taken at any time of day due to its long half-life profile, as long as it is taken at the same time every day. This also potentially ensures better patient compliance. Some studies found evening dose of both short and long half-life statins were significantly superior to morning dose for lowering LDL-C.{{cite journal | title = Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) | journal = JAMA | volume = 285 | issue = 19 | pages = 2486–2497 | date = May 2001 | pmid = 11368702 | doi = 10.1001/jama.285.19.2486 | last = ((Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) )) }}{{cite journal | vauthors = Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ | title = Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines | journal = Circulation | volume = 110 | issue = 2 | pages = 227–239 | date = July 2004 | pmid = 15249516 | doi = 10.1161/01.CIR.0000133317.49796.0E | title-link = doi | doi-access = free }}{{cite journal | vauthors = Maqsood MH, Messerli FH, Waters D, Skolnick AH, Maron DJ, Bangalore S | title = Timing of statin dose: a systematic review and meta-analysis of randomized clinical trials | journal = European Journal of Preventive Cardiology | volume = 29 | issue = 14 | pages = e319–e322 | date = October 2022 | pmid = 35512427 | doi = 10.1093/eurjpc/zwac085 }}{{cite journal | vauthors = Awad K, Serban MC, Penson P, Mikhailidis DP, Toth PP, Jones SR, Rizzo M, Howard G, Lip GY, Banach M | title = Effects of morning vs evening statin administration on lipid profile: A systematic review and meta-analysis | journal = Journal of Clinical Lipidology | volume = 11 | issue = 4 | pages = 972–985.e9 | date = July 2017 | pmid = 28826569 | doi = 10.1016/j.jacl.2017.06.001 | url = https://researchonline.ljmu.ac.uk/id/eprint/6701/1/Morning%20v%20Evening%20Statins%20Accepted%20Manuscript.pdf | access-date = 26 May 2023 | archive-date = 13 November 2023 | archive-url = https://web.archive.org/web/20231113023714/https://researchonline.ljmu.ac.uk/id/eprint/6701/1/Morning%20v%20Evening%20Statins%20Accepted%20Manuscript.pdf | url-status = live }} [137] => [138] => ===Specific populations=== [139] => * Geriatric: Plasma concentrations of atorvastatin in healthy elderly subjects are higher than those in young adults, and clinical data suggests a greater degree of LDL-lowering at any dose for people in the population as compared to young adults. [140] => * Pediatric: Pharmacokinetic data is not available for this population. [141] => * Gender: Plasma concentrations are generally higher in women than in men, but there is no clinically significant difference in the extent of LDL reduction between men and women. [142] => * Kidney impairment: Kidney disease has no statistically significant influence on plasma concentrations of atorvastatin and dose adjustment considerations should only be made in context of the patient's overall health.{{cite journal | vauthors = Lins RL, Matthys KE, Verpooten GA, Peeters PC, Dratwa M, Stolear JC, Lameire NH | title = Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients | journal = Nephrology, Dialysis, Transplantation | volume = 18 | issue = 5 | pages = 967–976 | date = May 2003 | pmid = 12686673 | doi = 10.1093/ndt/gfg048 | doi-access = free | title-link = doi }}{{Unreliable medical source|sure=y|date=May 2022}}{{cite journal | vauthors = Stern RH, Yang BB, Horton M, Moore S, Abel RB, Olson SC | title = Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol reduction of atorvastatin | journal = Journal of Clinical Pharmacology | volume = 37 | issue = 9 | pages = 816–819 | date = September 1997 | pmid = 9549635 | doi = 10.1002/j.1552-4604.1997.tb05629.x | s2cid = 752038 }}{{Unreliable medical source|sure=y|date=May 2022}} [143] => * Hemodialysis: Although there has been moderate-to-high quality of evidence to show the lack of clear and significant clinical benefits of statins (including atorvastatin at a dose of 20mg) minimizing non-fatal myocardial infarction, stroke, and cardiovascular mortality in adult patients on haemodialysis (including those with diabetes and/or pre-existing cardiovascular diseases) despite the clinically relevant reduction in total/LDL cholesterol levels,{{cite journal | vauthors = Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, Ritz E | title = Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis | journal = The New England Journal of Medicine | volume = 353 | issue = 3 | pages = 238–48 | date = July 2005 | pmid = 16034009 | doi = 10.1056/NEJMoa043545 | doi-access = free | title-link = doi }}{{Unreliable medical source|sure=y|date=May 2021}}{{cite journal | vauthors = Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Grönhagen-Riska C, De Lima JJ, Lins R, Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci D, Süleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wüthrich RP, Gottlow M, Johnsson E, Zannad F | title = Rosuvastatin and cardiovascular events in patients undergoing hemodialysis | journal = The New England Journal of Medicine | volume = 360 | issue = 14 | pages = 1395–407 | date = April 2009 | pmid = 19332456 | doi = 10.1056/NEJMoa0810177 | doi-access = free | title-link = doi }} there is evidence that haemodialysis patients who received moderate intensity statin therapy had a lower risk of all-cause mortality.{{cite journal | vauthors = Jung J, Bae GH, Kang M, Kim SW, Lee DH | title = Statins and All-Cause Mortality in Patients Undergoing Hemodialysis | journal = Journal of the American Heart Association | volume = 9 | issue = 5 | pages = e014840 | date = March 2020 | pmid = 32089045 | pmc = 7335561 | doi = 10.1161/JAHA.119.014840 }} [144] => * However, data ([[post hoc analysis]]) on atorvastatin has revealed that it may still be beneficial in reducing combined cardiac events, cardiac and all-cause mortality in those with a higher baseline LDL cholesterol >3.75 mmol/L.{{cite journal | vauthors = März W, Genser B, Drechsler C, Krane V, Grammer TB, Ritz E, Stojakovic T, Scharnagl H, Winkler K, Holme I, Holdaas H, Wanner C | title = Atorvastatin and low-density lipoprotein cholesterol in type 2 diabetes mellitus patients on hemodialysis | journal = Clinical Journal of the American Society of Nephrology | volume = 6 | issue = 6 | pages = 1316–25 | date = June 2011 | pmid = 21493741 | pmc = 3109927 | doi = 10.2215/CJN.09121010 }}{{Unreliable medical source|sure=y|date=May 2021}} While the SHARP study suggested that LDL cholesterol-lowering treatments (e.g. statin/ezetimibe combination) are effective in reducing the risks of major atherosclerotic events in the CKD patients including those on dialysis, the subgroup analysis of the haemodialysis patients had revealed no significant benefits.{{cite journal | vauthors = Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C, Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M, Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U, Ophascharoensuk V, Fellström B, Holdaas H, Tesar V, Wiecek A, Grobbee D, de Zeeuw D, Grönhagen-Riska C, Dasgupta T, Lewis D, Herrington W, Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P, Young A, Collins R | title = The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial | journal = Lancet | volume = 377 | issue = 9784 | pages = 2181–92 | date = June 2011 | pmid = 21663949 | pmc = 3145073 | doi = 10.1016/S0140-6736(11)60739-3 }}{{Unreliable medical source|sure=y|date=May 2021}} Whether or not haemodialysis had any impact on the statin levels was not specifically addressed in these major trials. [145] => *Hepatic Impairment: Increased drug levels can be seen in patients with advanced [[cirrhosis]]; specific precaution should be used in patients with chronic [[alcoholic liver disease]]. Despite these concerns, a 2017 systematic review and analysis of available evidence has shown that statins, such as atorvastatin, are relatively safe to use in stable, asymptomatic cirrhosis and may even reduce the risk of liver disease progression and death.{{cite journal | vauthors = Kim RG, Loomba R, Prokop LJ, Singh S | title = Statin Use and Risk of Cirrhosis and Related Complications in Patients With Chronic Liver Diseases: A Systematic Review and Meta-analysis | journal = Clinical Gastroenterology and Hepatology | volume = 15 | issue = 10 | pages = 1521–1530.e8 | date = October 2017 | pmid = 28479502 | pmc = 5605397 | doi = 10.1016/j.cgh.2017.04.039 }} [146] => [147] => ==Contraindications== [148] => * Active liver disease: [[cholestasis]], [[hepatic encephalopathy]], [[hepatitis]], and [[jaundice]] [149] => * [[Pregnancy]]: Atorvastatin is unlikely to cause fetal anomalies but may be associated with low birth weight and preterm labour.{{cite journal | vauthors = Chang JC, Chen YJ, Chen IC, Lin WS, Chen YM, Lin CH | title = Perinatal Outcomes After Statin Exposure During Pregnancy | journal = JAMA Network Open | volume = 4 | issue = 12 | pages = e2141321 | date = December 2021 | pmid = 34967881 | pmc = 8719244 | doi = 10.1001/jamanetworkopen.2021.41321 }} [150] => * [[Breastfeeding]]: Small amounts of other statin medications have been found to pass into breast milk, although atorvastatin has not been studied, specifically. Due to risk of disrupting a breastfeeding infant's metabolism of lipids, atorvastatin is not regarded as compatible with breastfeeding.{{cite web|title=TOXNET|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?.%2Ftemp%2F~r09l0q%3A1|website=toxnet.nlm.nih.gov|publisher=U.S. National Library of Medicine|access-date=29 May 2018|archive-date=12 June 2018|archive-url=https://web.archive.org/web/20180612113230/https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?.%2Ftemp%2F~r09l0q%3A1|url-status=live}} [151] => * Markedly elevated [[Creatine kinase|CPK]] levels or if a [[myopathy]] is suspected or diagnosed after dosing of atorvastatin has begun. Very rarely, atorvastatin may cause [[rhabdomyolysis]], and it may be very serious leading to [[acute kidney injury]] due to [[myoglobinuria]]. When rhabdomyolysis is suspected or diagnosed, atorvastatin therapy is discontinued immediately. The likelihood of developing a [[myopathy]] is increased by the co-administration of [[cyclosporine]], [[Fibrate|fibric acid derivatives]], [[erythromycin]], [[Niacin (nutrient)|niacin]], and [[azole]] [[antifungal medication|antifungals]]. [152] => [153] => ==Side effects== [154] => [155] => ===Major=== [156] => * [[Type 2 diabetes]] is observed in a small number of people, and is an uncommon class effect of all statins.{{cite journal | vauthors = Thakker D, Nair S, Pagada A, Jamdade V, Malik A | title = Statin use and the risk of developing diabetes: a network meta-analysis | journal = Pharmacoepidemiology and Drug Safety | volume = 25 | issue = 10 | pages = 1131–1149 | date = October 2016 | pmid = 27277934 | doi = 10.1002/pds.4020 | publisher = Wiley | s2cid = 22626629 }}{{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 | title = Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials | journal = Lancet | volume = 375 | issue = 9716 | pages = 735–742 | date = February 2010 | pmid = 20167359 | doi = 10.1016/s0140-6736(09)61965-6 | publisher = Elsevier BV | s2cid = 11544414 }}{{cite journal | vauthors = Shah RV, Goldfine AB | title = Statins and risk of new-onset diabetes mellitus | journal = Circulation | volume = 126 | issue = 18 | pages = e282–e284 | date = October 2012 | pmid = 23109518 | doi = 10.1161/CIRCULATIONAHA.112.122135 | title-link = doi | doi-access = free }} It appears it may be more likely in people who were already at a higher risk of developing diabetes before starting a statin due to multiple risk factors, for example raised fasting glucose levels.{{cite journal | vauthors = Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun CC, Kastelein JJ, Colhoun H, Barter P | title = Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials | journal = Journal of the American College of Cardiology | volume = 57 | issue = 14 | pages = 1535–1545 | date = April 2011 | pmid = 21453832 | doi = 10.1016/j.jacc.2010.10.047 | s2cid = 64660561 | doi-access = free | title-link = doi }} However, the benefits of statin therapy in preventing fatal and non-fatal stroke, fatal coronary heart disease, and non-fatal myocardial infarction are significant. For most people the benefits of statin therapy far outweigh the risk of developing diabetes.{{cite journal | vauthors = Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R | title = Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials | journal = Lancet | volume = 376 | issue = 9753 | pages = 1670–1681 | date = November 2010 | pmid = 21067804 | pmc = 2988224 | doi = 10.1016/S0140-6736(10)61350-5 }} A 2010 meta-analysis demonstrated that every 255 people treated with a statin for four years – produced a reduction of 5.4 major coronary events and induced only one new case of diabetes. [157] => * In some case and clinical studies mild muscle pain or weakness have been reported (around 3%), compared to a placebo.{{cite journal | vauthors = Reith C, Baigent C, Blackwell L, Emberson J, Spata E, Davies K, Halls H, Holland L, Wilson K, Armitage J, Harper C, Preiss D, Roddick A, Keech A, Simes J, Collins R, Barnes E, Fulcher J, Herrington WG, Kirby A, Mihaylova B, O'Connell R, Amarenco P, Barter P, Betteridge DJ, Blazing M, Bosch J, Bowman L, Braunwald E, Cannon CP | title = Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials | journal = Lancet | volume = 400 | issue = 10355 | pages = 832–845 | date = September 2022 | pmid = 36049498 | pmc = 7613583 | doi = 10.1016/s0140-6736(22)01545-8 }}{{cite journal | vauthors = LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK | title = Intensive lipid lowering with atorvastatin in patients with stable coronary disease | journal = The New England Journal of Medicine | volume = 352 | issue = 14 | pages = 1425–1435 | date = April 2005 | pmid = 15755765 | doi = 10.1056/NEJMoa050461 | doi-access = free | title-link = doi }} However, this increase was not related to statin therapy in 90% of cases in a large meta-analysis of randomized controlled trials. In patients taking higher statin doses, a similarly low increase in muscle pain and weakness was present (5%) with no clear evidence of a dose-response relationship. Duration of treatment with atorvastatin is unlikely to increase the risk of muscle-related side effects as most occur within the first year of treatment, after which the risk is not increased further. The known cardiovascular benefits of atorvastatin over time outweigh the low risk of muscle-related side effects.{{cite journal | vauthors = Macedo AF, Taylor FC, Casas JP, Adler A, Prieto-Merino D, Ebrahim S | title = Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis | journal = BMC Medicine | volume = 12 | issue = 1 | pages = 51 | date = March 2014 | pmid = 24655568 | pmc = 3998050 | doi = 10.1186/1741-7015-12-51 | doi-access = free | title-link = doi }} [158] => * There is also an increased risk of statin-induced [[rhabdomyolysis]] when statins are taken over the long term.{{cite journal | vauthors = Mendes P, Robles PG, Mathur S | title = Statin-induced rhabdomyolysis: a comprehensive review of case reports | journal = Physiotherapy Canada. Physiotherapie Canada | volume = 66 | issue = 2 | pages = 124–132 | date = April 2014 | pmid = 24799748 | pmc = 4006404 | doi = 10.3138/ptc.2012-65 }} [159] => * Persistent liver enzyme abnormalities (usually elevated in hepatic transaminases) have been documented.{{cite journal|vauthors=Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, Krumholz HM |date=December 2006|title=Risks associated with statin therapy: a systematic overview of randomized clinical trials|journal=Circulation|volume=114|issue=25|pages=2788–97|doi=10.1161/CIRCULATIONAHA.106.624890|pmid=17159064 | doi-access = free | title-link = doi }} Elevations threefold greater than normal were recorded in 0.5% of people treated with atorvastatin 10 mg-80 mg rather than placebo.{{cite journal|vauthors=Newman CB, Palmer G, Silbershatz H, Szarek M |date=September 2003 |title=Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients|journal=American Journal of Cardiology|volume=92|issue=6|pages=670–6|doi=10.1016/S0002-9149(03)00820-8|pmid=12972104 }} Usage instructions in package inserts for this statin define the requirement that [[liver function|hepatic function]] be assessed with laboratory tests before beginning atorvastatin treatment and repeated periodically as clinically indicated - usually a clinicians' judgement. Package inserts for this statin recommend actions should liver abnormalities be detected, ultimately, this is the judgment of the prescribing physician. [160] => [161] => ===Common=== [162] => The following have been shown to occur in 1–10% of people taking atorvastatin in clinical trials: [163] => * [[Arthralgia|Joint pain]] [164] => * [[Diarrhea|Loose stools]] [165] => * [[Dyspepsia|Indigestion]] [166] => * [[Myalgia|Muscle pain]] [167] => * [[Nausea]] [168] => * [[Hyperglycemia]] Atorvastatin may increase fasting plasma glucose and regular blood sugar monitoring may be advised. {{cite journal | vauthors = Sukhija R, Prayaga S, Marashdeh M, Bursac Z, Kakar P, Bansal D, Sachdeva R, Kesan SH, Mehta JL | title = Effect of statins on fasting plasma glucose in diabetic and nondiabetic patients | journal = Journal of Investigative Medicine | volume = 57 | issue = 3 | pages = 495–499 | date = March 2009 | pmid = 19188844 | doi = 10.2310/JIM.0b013e318197ec8b | s2cid = 2955398 }}{{cite journal | vauthors = Cui JY, Zhou RR, Han S, Wang TS, Wang LQ, Xie XH | title = Statin therapy on glycemic control in type 2 diabetic patients: A network meta-analysis | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 43 | issue = 4 | pages = 556–570 | date = August 2018 | pmid = 29733433 | doi = 10.1111/jcpt.12690 | s2cid = 19151464 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Livingstone SJ, Looker HC, Akbar T, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Fuller JH, Colhoun HM | title = Effect of atorvastatin on glycaemia progression in patients with diabetes: an analysis from the Collaborative Atorvastatin in Diabetes Trial (CARDS) | journal = Diabetologia | volume = 59 | issue = 2 | pages = 299–306 | date = February 2016 | pmid = 26577796 | pmc = 4705133 | doi = 10.1007/s00125-015-3802-6 }} [169] => [170] => ===Other=== [171] => ====Cognitive==== [172] => There have been rare reports of reversible memory loss and confusion with all statins, including atorvastatin; however, there has not been enough evidence to associate statin use with cognitive impairment, and the risks for cognition are likely outweighed by the beneficial effects of adherence to statin therapy on cardiovascular and cerebrovascular disease.{{cite journal | vauthors = Ott BR, Daiello LA, Dahabreh IJ, Springate BA, Bixby K, Murali M, Trikalinos TA | title = Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials | journal = Journal of General Internal Medicine | volume = 30 | issue = 3 | pages = 348–58 | date = March 2015 | pmid = 25575908 | doi = 10.1007/s11606-014-3115-3 | pmc = 4351273 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Chu CS, Tseng PT, Stubbs B, Chen TY, Tang CH, Li DJ, Yang WC, Chen YW, Wu CK, Veronese N, Carvalho AF, Fernandes BS, Herrmann N, Lin PY | title = Use of statins and the risk of dementia and mild cognitive impairment: A systematic review and meta-analysis | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 5804 | date = April 2018 | pmid = 29643479 | doi = 10.1038/s41598-018-24248-8 | pmc = 5895617 | bibcode = 2018NatSR...8.5804C | doi-access = free | title-link = doi }}{{cite journal | vauthors = Samaras K, Makkar SR, Crawford JD, Kochan NA, Slavin MJ, Wen W, Trollor JN, Brodaty H, Sachdev PS | title = Effects of Statins on Memory, Cognition, and Brain Volume in the Elderly | journal = Journal of the American College of Cardiology | volume = 74 | issue = 21 | pages = 2554–2568 | date = November 2019 | pmid = 31753200 | doi = 10.1016/j.jacc.2019.09.041 | doi-access = free | title-link = doi }}{{cite web|url=https://www.nhs.uk/medicines/atorvastatin/|title=Atorvastatin: A medicine used to lower cholesterol|date=3 January 2019|access-date=7 November 2021|archive-date=7 November 2021|archive-url=https://web.archive.org/web/20211107043716/https://www.nhs.uk/medicines/atorvastatin/|url-status=live}} [173] => [174] => ====Pancreatitis==== [175] => There is some evidence that atorvastatin use may increase the risk of acute pancreatitis, in people who are already at a higher risk.{{cite journal | vauthors = Lai SW, Lin CL, Liao KF | title = Atorvastatin Use Associated With Acute Pancreatitis: A Case-Control Study in Taiwan | language = en-US | journal = Medicine | volume = 95 | issue = 7 | pages = e2545 | date = February 2016 | pmid = 26886597 | pmc = 4998597 | doi = 10.1097/MD.0000000000002545 }}{{cite journal | vauthors = Preiss D, Tikkanen MJ, Welsh P, Ford I, Lovato LC, Elam MB, LaRosa JC, DeMicco DA, Colhoun HM, Goldenberg I, Murphy MJ, MacDonald TM, Pedersen TR, Keech AC, Ridker PM, Kjekshus J, Sattar N, McMurray JJ | title = Lipid-modifying therapies and risk of pancreatitis: a meta-analysis | journal = JAMA | volume = 308 | issue = 8 | pages = 804–811 | date = August 2012 | pmid = 22910758 | doi = 10.1001/jama.2012.8439 | url = http://eprints.gla.ac.uk/69063/3/69063.pdf | access-date = 23 January 2023 | archive-date = 23 January 2022 | archive-url = https://web.archive.org/web/20220123204919/http://eprints.gla.ac.uk/69063/3/69063.pdf | url-status = live }} However, there is also evidence that atorvastatin use decreases the risk of acute pancreatitis in people with mild to moderate hypertriglyceridemia, by lowering triglyceride levels. [176] => [177] => ====Erectile dysfunction==== [178] => Statins seem to have a positive effect on [[erectile dysfunction]].{{cite journal | vauthors = Kostis JB, Dobrzynski JM | title = The effect of statins on erectile dysfunction: a meta-analysis of randomized trials | journal = The Journal of Sexual Medicine | volume = 11 | issue = 7 | pages = 1626–35 | date = July 2014 | pmid = 24684744 | pmc = | doi = 10.1111/jsm.12521 }}{{cite journal | vauthors = Cui Y, Zong H, Yan H, Zhang Y | title = The effect of statins on erectile dysfunction: a systematic review and meta-analysis | journal = The Journal of Sexual Medicine | volume = 11 | issue = 6 | pages = 1367–75 | date = June 2014 | pmid = 24628781 | pmc = | doi = 10.1111/jsm.12497 }} [179] => [180] => === Interactions === [181] => Fibrates are a class of drugs that can be used for severe or refractory mixed [[Hyperlipidemia|hyperlipidaemia]] in combination with statins or as monotherapy. Several studies suggest that the concomitant therapy of atorvastatin with drugs from the fibrate drug class (such as [[gemfibrozil]], [[fenofibrate]]) can increase the risk of [[myopathy]] and [[rhabdomyolysis]],{{cite journal | vauthors = Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R | title = Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs | journal = JAMA | volume = 292 | issue = 21 | pages = 2585–2590 | date = December 2004 | pmid = 15572716 | doi = 10.1001/jama.292.21.2585 | title-link = doi | doi-access = | s2cid = 22429669 }}{{cite journal | vauthors = Iliadis EA, Rosenson RS | title = Long-term safety of pravastatin-gemfibrozil therapy in mixed hyperlipidemia | journal = Clinical Cardiology | volume = 22 | issue = 1 | pages = 25–28 | date = January 1999 | pmid = 9929751 | pmc = 6655916 | doi = 10.1002/clc.4960220110 }}{{cite journal | vauthors = Shek A, Ferrill MJ | title = Statin-fibrate combination therapy | journal = The Annals of Pharmacotherapy | volume = 35 | issue = 7–8 | pages = 908–917 | date = July 2001 | pmid = 11485144 | doi = 10.1345/aph.10315 | s2cid = 23785176 }}{{cite web|title=Independent, reliable, relevant and respected|url=https://www.tg.org.au/|access-date=9 May 2021|website=Therapeutic Guidelines|language=en-AU|archive-date=8 May 2021|archive-url=https://web.archive.org/web/20210508093109/https://www.tg.org.au/|url-status=live}} however other studies have found this to not be the case. {{cite journal | vauthors = Geng Q, Ren J, Chen H, Lee C, Liang W | title = Adverse events following statin-fenofibrate therapy versus statin alone: a meta-analysis of randomized controlled trials | journal = Clinical and Experimental Pharmacology & Physiology | volume = 40 | issue = 3 | pages = 219–226 | date = March 2013 | pmid = 23324122 | doi = 10.1111/1440-1681.12053 | s2cid = 9148062 }}{{cite journal | vauthors = Wägner AM, Jorba O, Bonet R, Ordóñez-Llanos J, Pérez A | title = Efficacy of atorvastatin and gemfibrozil, alone and in low dose combination, in the treatment of diabetic dyslipidemia | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 7 | pages = 3212–3217 | date = July 2003 | pmid = 12843167 | doi = 10.1210/jc.2003-030153 }} [182] => [183] => Co-administration of atorvastatin with one of [[CYP3A4]] inhibitors such as [[itraconazole]], [[telithromycin]], and [[voriconazole]], may increase serum concentrations of atorvastatin, which may lead to adverse reactions. This is less likely to happen with other CYP3A4 inhibitors such as [[diltiazem]], [[erythromycin]], [[fluconazole]], [[ketoconazole]], [[clarithromycin]], [[cyclosporine]], [[Protease inhibitor (pharmacology)|protease inhibitors]], or [[verapamil]], and only rarely with other CYP3A4 inhibitors, such as [[amiodarone]] and [[aprepitant]]. Often, [[bosentan]], [[fosphenytoin]], and [[phenytoin]], which are CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. Only rarely, though, [[barbiturate]]s, [[carbamazepine]], [[efavirenz]], [[nevirapine]], [[oxcarbazepine]], [[rifampicin|rifampin]], and [[rifamycin]], which are also CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. [[Oral contraceptive]]s increased AUC values for [[norethisterone]] and [[ethinylestradiol]]; these increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin. [184] => [185] => [[Antacid]]s can rarely decrease the plasma concentrations of statin medications, but do not affect the [[Low-density lipoprotein|LDL-C]]-lowering [[efficacy]].{{cite journal | vauthors = McKenney JM | title = Efficacy and safety of rosuvastatin in treatment of dyslipidemia | journal = American Journal of Health-System Pharmacy | volume = 62 | issue = 10 | pages = 1033–47 | date = May 2005 | pmid = 15901588 | doi = 10.1093/ajhp/62.10.1033 | doi-access = free | title-link = doi }} [186] => [187] => [[Niacin (nutrient)|Niacin]] also is proved to increase the risk of myopathy or rhabdomyolysis. [188] => [189] => Some statins may also alter the concentrations of other medications, such as [[warfarin]] or [[digoxin]], leading to alterations in effect or a requirement for clinical monitoring. The increase in digoxin levels due to atorvastatin is a 1.2 fold elevation in the [[Area under the curve (pharmacokinetics)|area under the curve (AUC)]], resulting in a minor drug-drug interaction. The [[American Heart Association]] states that the combination of digoxin and atorvastatin is reasonable.{{cite journal | vauthors = Wiggins BS, Saseen JJ, Page RL, Reed BN, Sneed K, Kostis JB, Lanfear D, Virani S, Morris PB | title = Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association | journal = Circulation | volume = 134 | issue = 21 | pages = e468–e495 | date = November 2016 | pmid = 27754879 | doi = 10.1161/CIR.0000000000000456 | s2cid = 19169932 | doi-access = free | title-link = doi }} In contrast to some other statins, atorvastatin does not interact with warfarin concentrations in a clinically meaningful way (similar to [[pitavastatin]]). [190] => [191] => [[Vitamin D]] supplementation lowers atorvastatin and active metabolite concentrations, yet [[synergy|synergistically]] reduces LDL and total [[cholesterol]] concentrations. [192] => [193] => [[Grapefruit juice]] components are known inhibitors of intestinal CYP3A4. Drinking grapefruit juice with atorvastatin may cause an increase in [[Cmax (pharmacology)|Cmax]] and [[Area under the curve (pharmacokinetics)|area under the curve]] (AUC). This finding initially gave rise to concerns of toxicity, and in 2000, it was recommended that people taking atorvastatin should not consume grapefruit juice "in an unsupervised manner."{{cite journal | vauthors = Kane GC, Lipsky JJ | title = Drug-grapefruit juice interactions | journal = Mayo Clinic Proceedings | volume = 75 | issue = 9 | pages = 933–42 | date = September 2000 | pmid = 10994829 | doi = 10.4065/75.9.933 | doi-access = free | title-link = doi }} Small studies (using mostly young participants) examining the effects of grapefruit juice consumption on mainly lower doses of atorvastatin have shown that grapefruit juice increases blood levels of atorvastatin, which could increase the risk of adverse effects.{{cite journal | vauthors = Ando H, Tsuruoka S, Yanagihara H, Sugimoto K, Miyata M, Yamazoe Y, Takamura T, Kaneko S, Fujimura A | title = Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin | journal = British Journal of Clinical Pharmacology | volume = 60 | issue = 5 | pages = 494–7 | date = November 2005 | pmid = 16236039 | pmc = 1884940 | doi = 10.1111/j.1365-2125.2005.02462.x }}{{cite journal | vauthors = Reddy P, Ellington D, Zhu Y, Zdrojewski I, Parent SJ, Harmatz JS, Derendorf H, Greenblatt DJ, Browne K | title = Serum concentrations and clinical effects of atorvastatin in patients taking grapefruit juice daily | journal = British Journal of Clinical Pharmacology | volume = 72 | issue = 3 | pages = 434–41 | date = September 2011 | pmid = 21501216 | pmc = 3175512 | doi = 10.1111/j.1365-2125.2011.03996.x }}{{cite journal | vauthors = Lilja JJ, Kivistö KT, Neuvonen PJ | title = Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin | journal = Clinical Pharmacology and Therapeutics | volume = 66 | issue = 2 | pages = 118–27 | date = August 1999 | pmid = 10460065 | doi = 10.1053/cp.1999.v66.100453001 | s2cid = 8103490 }} No studies assessing the impact of grapefruit juice consumption have included participants taking the highest dose of atorvastatin (80 mg daily), which is often prescribed for people with a history of [[cardiovascular disease]] (such as [[Myocardial infarction|heart attack]] or [[Stroke|ischaemic stroke]]) or in people at high risk of cardiovascular disease. People taking atorvastatin should consult with their doctor or pharmacist before consuming grapefruit juice, as the effects of grapefruit juice consumption on atorvastatin will vary according to factors such as the amount and frequency of juice consumption in addition to differences in juice components, quality and method of juice preparation between different batches or brands.{{cite journal|vauthors=McLachlan A, Ramzan I|date=1 April 2006|title=Meals and medicines|url=https://www.nps.org.au/australian-prescriber/magazine/29/2/40/2|journal=Australian Prescriber|volume=29|issue=2|pages=40–42|doi=10.18773/austprescr.2006.026| doi-access = free | title-link = doi |access-date=10 May 2020|archive-date=27 August 2021|archive-url=https://web.archive.org/web/20210827232212/https://www.nps.org.au/australian-prescriber/articles/meals-and-medicines|url-status=live}} [194] => [195] => A few cases of myopathy have been reported when atorvastatin is given with [[colchicine]]. [196] => [197] => ==Mechanism of action== [198] => {{Main|Statin}} [199] => [200] => As with other statins, atorvastatin is a competitive [[Enzyme inhibitor|inhibitor]] of [[HMG-CoA reductase]]. Unlike most others, however, it is a completely [[Chemical synthesis|synthetic]] compound. HMG-CoA reductase catalyzes the reduction of [[HMG-CoA reductase pathway|3-hydroxy-3-methylglutaryl-coenzyme A]] (HMG-CoA) to [[mevalonate]], which is the [[Rate-determining step|rate-limiting step]] in hepatic [[cholesterol]] biosynthesis. Inhibition of the enzyme decreases ''[[de novo synthesis|de novo]]'' cholesterol synthesis, increasing expression of low-density lipoprotein receptors ([[LDL receptor]]s) on [[hepatocyte]]s. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces blood levels of [[triglyceride]]s and slightly increases levels of [[High density lipoprotein|HDL-cholesterol]]. [201] => [202] => In people with [[acute coronary syndrome]], high-dose atorvastatin treatment may play a plaque-stabilizing role.{{cite journal | vauthors = Liberale L, Carbone F, Montecucco F, Sahebkar A | title = Statins reduce vascular inflammation in atherogenesis: A review of underlying molecular mechanisms | journal = The International Journal of Biochemistry & Cell Biology | volume = 122 | pages = 105735 | date = May 2020 | pmid = 32126319 | doi = 10.1016/j.biocel.2020.105735 | s2cid = 212408322 }}{{cite journal | vauthors = Rosa GM, Carbone F, Parodi A, Massimelli EA, Brunelli C, Mach F, Vuilleumier N, Montecucco F | title = Update on the efficacy of statin treatment in acute coronary syndromes | journal = European Journal of Clinical Investigation | volume = 44 | issue = 5 | pages = 501–515 | date = May 2014 | pmid = 24601937 | doi = 10.1111/eci.12255 | s2cid = 28738671 | doi-access = free | title-link = doi }} At high doses, statins have anti-inflammatory effects, incite reduction of the necrotic plaque core, and improve endothelial function, leading to plaque stabilization and, sometimes, plaque regression. There is a similar thought process with using high-dose atorvastatin as a form of secondary [[thrombotic stroke]] recurrence prevention.{{cite journal | vauthors = Furie KL | title = High-dose statins should only be used in atherosclerotic strokes | journal = Stroke | volume = 43 | issue = 7 | pages = 1994–1995 | date = July 2012 | pmid = 22581818 | doi = 10.1161/STROKEAHA.111.633339 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Amarenco P, Bogousslavsky J, Callahan A, Goldstein LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA | title = High-dose atorvastatin after stroke or transient ischemic attack | journal = The New England Journal of Medicine | volume = 355 | issue = 6 | pages = 549–559 | date = August 2006 | pmid = 16899775 | doi = 10.1056/NEJMoa061894 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Gaspardone A, Arca M | title = Atorvastatin: its clinical role in cerebrovascular prevention | journal = Drugs | volume = 67 | issue = 1 | pages = 55–62 | date = 1 November 2007 | pmid = 17910521 | doi = 10.2165/00003495-200767001-00006 | s2cid = 195685309 }} [203] => [204] => ===Pharmacodynamics=== [205] => The liver is the primary site of action of atorvastatin, as this is the principal site of both cholesterol synthesis and LDL clearance. It is the dosage of atorvastatin, rather than systemic medication concentration, which correlates with extent of LDL-C reduction. In a Cochrane systematic review the dose-related magnitude of atorvastatin on blood lipids was determined. Over the dose range of 10 to 80 mg/day total cholesterol was reduced by 27.0% to 37.9%, LDL cholesterol by 37.1% to 51.7% and triglycerides by 18.0% to 28.3%.{{cite journal | vauthors = Adams SP, Tsang M, Wright JM | title = Atorvastatin for lowering lipids | journal = Cochrane Database of Systematic Reviews | issue = 3 | pages = CD008226 | date = March 2015 | volume = 2015 | pmid = 25760954 | pmc = 6464917 | doi = 10.1002/14651858.cd008226.pub3 | doi-access = free | title-link = doi }} [206] => [207] => ==Pharmacokinetics== [208] => {{More citations needed section|date=December 2017}} [209] => [210] => ===Absorption=== [211] => Atorvastatin undergoes rapid absorption when taken orally, with an approximate time to maximum plasma concentration ([[Transport maximum|Tmax]]) of 1–2 h. The absolute [[bioavailability]] of the medication is about 14%, but the systemic availability for [[HMG-CoA reductase]] activity is approximately 30%. Atorvastatin undergoes high intestinal clearance and [[first-pass metabolism]], which is the main cause for the low systemic availability. Administration of atorvastatin with food produces a 25% reduction in [[Cmax (pharmacology)|Cmax]] (rate of absorption) and a 9% reduction in [[Area under the curve (pharmacokinetics)|AUC]] (extent of absorption), although food does not affect the plasma [[Low-density lipoprotein|LDL-C]]-lowering [[efficacy]] of atorvastatin. Evening dose administration is known to reduce the Cmax and AUC by 30% each. However, time of administration does not affect the plasma LDL-C-lowering efficacy of atorvastatin. [212] => [213] => ===Distribution=== [214] => The mean [[volume of distribution]] of atorvastatin is approximately 381 L. It is highly protein bound (≥98%), and studies have shown it is likely secreted into human breastmilk. [215] => [216] => ===Metabolism=== [217] => Atorvastatin [[metabolism]] is primarily through [[cytochrome P450]] [[CYP3A4|3A4]] [[hydroxylation]] to form active ortho- and parahydroxylated [[metabolites]], as well as various [[beta-oxidation]] metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic [[HMG-CoA reductase]] activity. The ortho-hydroxy metabolite undergoes further metabolism via [[glucuronidation]]. As a substrate for the CYP3A4 isozyme, it has shown susceptibility to inhibitors and inducers of CYP3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested ''in vitro'' with concurrent administration of [[erythromycin]], a known CYP3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. It is also an inhibitor of cytochrome 3A4. [218] => [219] => ===Excretion=== [220] => Atorvastatin is primarily eliminated via [[hepatic]] [[biliary]] excretion, with less than 2% recovered in the [[urine]]. [[Bile]] elimination follows hepatic and/or extrahepatic metabolism. There does not appear to be any [[enterohepatic circulation|entero-hepatic recirculation]]. Atorvastatin has an approximate elimination [[half-life]] of 14 hours. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20–30 hours, which is thought to be due to the active metabolites. Atorvastatin is also a substrate of the intestinal [[P-glycoprotein]] efflux transporter, which pumps the medication back into the intestinal lumen during medication absorption. [221] => [222] => In [[liver failure|hepatic insufficiency]], plasma concentrations of atorvastatin are significantly affected by concurrent liver disease. People with Child-Pugh Stage A liver disease show a four-fold increase in both Cmax and AUC. People with Child Pugh stage B liver disease show a 16-fold increase in Cmax and an 11-fold increase in AUC. [223] => [224] => [[Geriatrics|Geriatric]] people (>65{{nbsp}}years old) exhibit altered pharmacokinetics of atorvastatin compared to young adults, with mean AUC and Cmax values that are 40% and 30% higher, respectively. Additionally, healthy elderly people show a greater pharmacodynamic response to atorvastatin at any dose; therefore, this population may have lower effective doses. [225] => [226] => ==Pharmacogenetics== [227] => Several genetic [[genetic polymorphism|polymorphisms]] may be linked to an increase in statin-related side effects with single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene showing a 45 fold higher incidence of statin related myopathy{{cite journal | vauthors = Canestaro WJ, Austin MA, Thummel KE | title = Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review | journal = Genetics in Medicine | volume = 16 | issue = 11 | pages = 810–819 | date = November 2014 | pmid = 24810685 | pmc = 4676271 | doi = 10.1038/gim.2014.41 }} than people without the polymorphism. [228] => [229] => There are several studies showing genetic variants and variable response to atorvastatin.{{cite journal |vauthors=Thompson JF, Man M, Johnson KJ, Wood LS, Lira ME, Lloyd DB, Banerjee P, Milos PM, Myrand SP, Paulauskis J, Milad MA, Sasiela WJ |title=An association study of 43 SNPs in 16 candidate genes with atorvastatin response |journal=Pharmacogenomics Journal |year=2005 |volume=5 |issue=6 |pages=352–8 |doi=10.1038/sj.tpj.6500328 |pmid=16103896 |doi-access= | s2cid=5928092 }} The polymorphisms that showed genome wide significance in Caucasian population were the SNPs in the apoE region; rs445925, rs7412, rs429358 and rs4420638 which showed variable LDL-c response depending on the genotype when treated with atorvastatin. Another genetic variant that showed genome wide significance in Caucasians was the SNP rs10455872 in the LPA gene that lead to higher Lp(a) levels which cause an apparent lower LDL-c response to atorvastatin. These studies were in Caucasian population, more research with a large cohort need to be conducted in different ethnicities to identify more polymorphisms that can affect atorvastatin pharmacokinetics and treatment response. [230] => [231] => ==Chemical synthesis== [232] => [233] => [[File:Atorvastatin synthesis stereocenter commercial.png|thumb|right|600 px|Atorvastatin synthesis in commercial production (process) chemistry. The key step of establishing this medication's stereocenters, through initial use of an inexpensive natural product ([[chiral pool]] approach).]] [234] => [235] => [[File:Atorvastatin synthesis stereocenter firstdiscovery.png|thumb|right|600 px|Atorvastatin synthesis during discovery chemistry. The key step of establishing stereocenters, using of a chiral ester auxiliary approach.]] [236] => [237] => The first synthesis of atorvastatin at Parke-Davis that occurred during [[drug discovery]] was [[racemic mixture#Synthesis|racemic]] followed by [[chiral column chromatography|chiral chromatographic]] separation of the [[enantiomer]]s. An early [[enantioselective synthesis|enantioselective]] route to atorvastatin made use of an ester [[chiral auxiliary]] to set the stereochemistry of the first of the two alcohol functional groups via a diastereoselective [[aldol reaction]].{{cite journal |vauthors=Roth BD, Blankley CJ, Chucholowski AW, Ferguson E, Hoefle ML, Ortwine DF, Newton RS, Sekerke CS, Sliskovic DR, Wilson M | title = Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran 2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus | year = 1991 | journal = [[J. Med. Chem.]] | volume = 34 | issue = 1 | pages = 357–366 | doi = 10.1021/jm00105a056| pmid = 1992137 }} [238] => [239] => Once the compound entered [[pre-clinical development]], [[process chemistry]] developed a cost-effective and scalable synthesis. In atorvastatin's case, a key element of the overall synthesis was ensuring stereochemical purity in the final drug substance, and hence establishing the first stereocenter became a key aspect of the overall design. The final commercial production of atorvastatin relied on a [[chiral pool]] approach, where the stereochemistry of the first alcohol functional group was carried into the synthesis—through the choice of [[erythorbic acid|isoascorbic acid]], an inexpensive and easily sourced plant-derived natural product.{{cite book | vauthors = Li JJ, Johnson DS, Sliskovic DR, Roth BD |title=Contemporary Drug Synthesis |publisher=John Wiley & Sons, Inc. |year=2004 |pages=113–125 |chapter=Chapter 9. Atorvastatin Calcium (Lipitor) |isbn=978-0-471-21480-9}} [240] => [241] => The ''atorvastatin calcium'' [[coordination complex|complex]] involves two atorvastatin ions, one [[calcium]] ion and three water molecules.{{cite web|url=https://www.researchgate.net/figure/Chemical-structure-of-Atorvastatin-Calcium_fig1_317526111|title=Fig. 1. Chemical structure of Atorvastatin Calcium|website=Researchgate.net|access-date=25 May 2022|archive-date=21 August 2022|archive-url=https://web.archive.org/web/20220821165547/https://www.researchgate.net/figure/Chemical-structure-of-Atorvastatin-Calcium_fig1_317526111|url-status=live}} [242] => [243] => ==History== [244] => [[Bruce Roth]], who was hired by Warner-Lambert as a chemist in 1982, had synthesized an "experimental compound" codenamed CI 981 – later called atorvastatin.{{cite news | url=https://www.ft.com/content/d0f7af5c-d7e6-11de-b578-00144feabdc0 |archive-url=https://ghostarchive.org/archive/20221210/https://www.ft.com/content/d0f7af5c-d7e6-11de-b578-00144feabdc0 |archive-date=10 December 2022 |url-status=live | title=The fall of the world's best-selling drug | work=[[Financial Times]] | date=28 November 2009 | access-date=24 November 2015 | vauthors = Andrew J | url-access=subscription }} It was first made in August 1985.{{cite book | vauthors = Roth BD | title = The discovery and development of atorvastatin, a potent novel hypolipidemic agent | chapter = 1 the Discovery and Development of Atorvastatin, A Potent Novel Hypolipidemic Agent | volume = 40 | pages = 1–22 | year = 2002 | pmid = 12516521 | doi = 10.1016/S0079-6468(08)70080-8 | isbn = 978-0-444-51054-9 | series = Progress in Medicinal Chemistry | publisher = Elsevier }}{{cite web | url = https://archive.fortune.com/magazines/fortune/fortune_archive/2003/01/20/335643/index.htm | title = The $10 Billion Pill Hold the fries, please. Lipitor, the cholesterol-lowering medication, has become the bestselling pharmaceutical in history. Here's how Pfizer did it | work = [[Fortune (magazine)|Fortune]] | vauthors = Simons J | date = 20 January 2003 }}{{ cite patent | country = US | number = 4681893 | status = patent | title = Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis | gdate = 21 July 1987 | fdate = 30 May 1986 | inventor = Roth BD }}{{cite journal | vauthors = Hoefle ML | year = 2000 | title = The Early History of Parke-Davis and Company | journal = Bull. Hist. Chem. | volume = 25 | issue = 1 | pages = 28–34 | url = https://www.scs.illinois.edu/~mainzv/HIST/bulletin_open_access/v25-1/v25-1%20p28-34.pdf | access-date = 12 March 2020 | archive-date = 20 September 2018 | archive-url = https://web.archive.org/web/20180920162755/http://www.scs.illinois.edu/~mainzv/HIST/bulletin_open_access/v25-1/v25-1%20p28-34.pdf | url-status = live }}{{cite news | url = https://www.nytimes.com/2000/02/08/business/pfizer-gets-its-deal-to-buy-warner-lambert-for-90.2-billion.html | title = Pfizer Gets Its Deal to Buy Warner-Lambert for $90.2 Billion | work = [[The New York Times]] | date = 8 February 2000 | vauthors = Petersen M | access-date = 18 February 2017 | archive-date = 15 December 2018 | archive-url = https://web.archive.org/web/20181215134547/https://www.nytimes.com/2000/02/08/business/pfizer-gets-its-deal-to-buy-warner-lambert-for-90.2-billion.html | url-status = live }} Warner-Lambert management was concerned that atorvastatin was a [[Me-too compound|me-too]] version of rival [[Merck & Co.]]'s [[orphan drug]] lovastatin (brand name [[Mevacor]]). Mevacor, which was first marketed in 1987, was the industry's first statin and Merck's synthetic version – [[simvastatin]] – was in the advanced stages of development. Nevertheless, Bruce Roth and his bosses, Roger Newton and Ronald Cresswell, in 1985, convinced company executives to move the compound into expensive clinical trials. Early results comparing atorvastatin to simvastatin demonstrated that atorvastatin appeared more potent and with fewer side effects. [245] => [246] => In 1994, the findings of a Merck-funded study were published in ''[[The Lancet]]'' concluding the efficacy of statins in lowering cholesterol proving for the first time not only that a "statin reduced 'bad' LDL cholesterol but also that it led to a sharp drop in fatal heart attacks among people with heart disease."{{cite journal | 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 | vauthors = ((Scandinavian Simvastatin Survival Study Group)) | s2cid = 5965882 }} [247] => [248] => In 1996, Warner-Lambert entered into a co-marketing agreement with Pfizer to sell Lipitor, and in 2000, Pfizer acquired Warner-Lambert for $90.2{{nbsp}}billion.{{cite news | url = https://www.wsj.com/articles/SB948677773420632448 | title = The Birth of a Blockbuster: Lipitor's Route out of the Lab | vauthors = Winslow R | date = 24 January 2000 | work = [[The Wall Street Journal]] | access-date = 26 October 2011 | url-access = subscription | archive-date = 7 April 2019 | archive-url = https://web.archive.org/web/20190407204143/https://www.wsj.com/articles/SB948677773420632448 | url-status = live }} Lipitor was on the market by 1996.{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020702_s000.pdf |title=Approval Letter |publisher=U.S. [[Food and Drug Administration]] (FDA) |access-date=21 June 2019 |archive-date=24 September 2020 |archive-url=https://web.archive.org/web/20200924091139/https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020702_s000.pdf |url-status=live }} By 2003, Lipitor had become the best selling pharmaceutical in the United States. From 1996 to 2012, under the trade name Lipitor, atorvastatin became the world's best-selling medication of all time, with more than $125{{nbsp}}billion in sales over approximately 14.5{{nbsp}}years.{{cite web | url = https://www.crainsnewyork.com/article/20111228/HEALTH_CARE/111229902/lipitor-becomes-world-s-top-selling-drug | title = Lipitor becomes world's top-selling drug | date = 28 December 2011 | publisher = Crain's New York Business via Associated Press | access-date = 24 November 2011 | archive-date = 29 December 2011 | archive-url = https://web.archive.org/web/20111229032228/http://www.crainsnewyork.com/article/20111228/HEALTH_CARE/111229902 | url-status = live }} and $13 billion a year at its peak,{{cite web | url = https://annarborobserver.com/articles/the_vindication_of_roger_newton.html#.YfvQI_nMKUk | title = The Vindication of Roger Newton | date = April 2020 | publisher = Ann Arbor Observer | access-date = 19 August 2022 | archive-date = 17 September 2021 | archive-url = https://web.archive.org/web/20210917235712/https://annarborobserver.com/articles/the_vindication_of_roger_newton.html#.YfvQI_nMKUk | url-status = live }} Lipitor alone "provided up to a quarter of Pfizer Inc.'s annual revenue for years." [249] => [250] => Pfizer's patent on atorvastatin expired in November 2011.{{cite news | title = Lipitor loses patent, goes generic | url = https://edition.cnn.com/2011/11/30/health/lipitor-generic/index.html | publisher = [[CNN]] | date = 30 November 2011 | access-date = 18 November 2012 | archive-date = 18 January 2017 | archive-url = https://web.archive.org/web/20170118041132/http://edition.cnn.com/2011/11/30/health/lipitor-generic/index.html | url-status = live }} [251] => [252] => == Society and culture == [253] => === Economics === [254] => Atorvastatin is relatively inexpensive.{{cite book |vauthors=Hitchings A, Lonsdale D, Burrage D, Baker E |title=The Top 100 Drugs e-book: Clinical Pharmacology and Practical Prescribing |date=2014 |publisher=Elsevier Health Sciences |isbn=978-0-7020-5515-7 |page=197 |url=https://books.google.com/books?id=oeYjAwAAQBAJ&pg=PA197 |access-date=27 June 2022 |archive-date=26 February 2023 |archive-url=https://web.archive.org/web/20230226050503/https://www.google.com/books/edition/The_Top_100_Drugs_e_book/oeYjAwAAQBAJ?gbpv=1&pg=PA197 |url-status=live }} Under provisions of the [[Patient Protection and Affordable Care Act]] (PPACA) in the United States, health plans may cover the costs of atorvastatin 10 mg and 20 mg for adults aged 40–75 years based on [[United States Preventive Services Task Force]] (USPSTF) recommendations.{{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 | archive-date=2 December 2020 | archive-url=https://web.archive.org/web/20201202121432/https://www.cigna.com/assets/docs/about-cigna/no-cost-share-preventive-medications.pdf | url-status=live }}{{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 | archive-date=3 August 2020 | archive-url=https://web.archive.org/web/20200803014843/https://www.aafp.org/afp/2017/0115/od1.html | url-status=live }}{{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 | archive-date=9 May 2022 | archive-url=https://web.archive.org/web/20220509124640/http://uspreventiveservicestaskforce.org/uspstf/recommendation/statin-use-in-adults-preventive-medication | url-status=live }} Some plans only cover other statins.{{cite web|url=https://www.uhc.com/content/dam/uhcdotcom/en/Pharmacy/PDFs/UHC-SignatureValue-Formulary-PPACA-ZeroCost-Preventive-Meds-Eff-Sept-2021.pdf|date=September 2021|title=SignatureValue Zero Cost Share Preventive Medications PDL|website=Uhc.com|access-date=25 May 2022|archive-date=5 February 2022|archive-url=https://web.archive.org/web/20220205144210/https://www.uhc.com/content/dam/uhcdotcom/en/Pharmacy/PDFs/UHC-SignatureValue-Formulary-PPACA-ZeroCost-Preventive-Meds-Eff-Sept-2021.pdf|url-status=live}}{{cite web | title=Affordable Care Act Implementation FAQs - Set 12 | website=CMS | date=22 April 2013 | url=https://www.cms.gov/CCIIO/Resources/Fact-Sheets-and-FAQs/aca_implementation_faqs12 | access-date=7 May 2022 | archive-date=5 May 2022 | archive-url=https://web.archive.org/web/20220505071209/https://www.cms.gov/CCIIO/Resources/Fact-Sheets-and-FAQs/aca_implementation_faqs12 | url-status=live }} [255] => [256] => ===Brand names=== [257] => [[File:Atorvastatin40mg.jpg|right|thumb|Pack and tablet of atorvastatin (Lipitor) 40mg]] [258] => Atorvastatin calcium tablets are sold under the brand name Lipitor.{{cite web|author=Medical Product Reviews|title=Atorvastatin Calcium (Lipitor Tablets) – Uses, Dosage and Side Effects|url=http://www.medicalproductreviews.com/atorvastatin-calcium-lipitor.html|access-date=3 May 2012|archive-date=6 October 2013|archive-url=https://web.archive.org/web/20131006104235/http://www.medicalproductreviews.com/atorvastatin-calcium-lipitor.html|url-status=dead}} Pfizer also packages the medication in combination with other medications, such as [[atorvastatin/amlodipine]].{{cite web|author=News Medical|title=Lipitor – What is Lipitor?|url=http://www.news-medical.net/health/Lipitor-What-is-Lipitor.aspx|access-date=3 May 2012|date=March 2010|archive-date=8 March 2012|archive-url=https://web.archive.org/web/20120308124655/http://www.news-medical.net/health/Lipitor-What-is-Lipitor.aspx|url-status=dead}} [259] => [260] => Pfizer's U.S. patent on Lipitor expired on 30 November 2011.{{cite web | title=Pfizer's 180-Day War for Lipitor | website=PM360 | date=8 August 2013 | url=https://www.pm360online.com/pfizers-180-day-war-for-lipitor/ | access-date=12 April 2020 | archive-date=12 April 2020 | archive-url=https://web.archive.org/web/20200412215249/https://www.pm360online.com/pfizers-180-day-war-for-lipitor/ | url-status=live }} Initially, generic atorvastatin was manufactured only by [[Actavis|Watson Pharmaceuticals]] and India's [[Ranbaxy Laboratories]]. Prices for the generic version did not drop to the level of other generics—$10 or less for a month's supply—until other manufacturers began to supply the medication in May 2012.{{cite web | url = http://www.nelm.nhs.uk/en/NeLM-Area/News/2012---May/30/June-Drug-Tariff-Reduced-prices-for-atorvastatin/ | date = June 2012 | title = Price to UK for 28 tablets from £3.25 (10mg) to £10.00 (80mg) | publisher = [[National Health Service]] | access-date = 31 July 2012 | archive-url = https://web.archive.org/web/20120920054426/http://www.nelm.nhs.uk/en/NeLM-Area/News/2012---May/30/June-Drug-Tariff-Reduced-prices-for-atorvastatin/ | archive-date = 20 September 2012 | url-status = dead}} [261] => [262] => In other countries, atorvastatin calcium is made in tablet form by generic medication makers under various brand names including Atoris, Atorlip, Atorva, Atorvastatin Teva, Atorvastatina Parke-Davis, Avas, Cardyl, Liprimar, Litorva, Mactor, Orbeos, Prevencor, Sortis, Stator, Tahor, Torid, Torvacard, Torvast, Totalip, Tulip, Xarator, and Zarator.{{cite web | title=Atorvastatin international | website=Drugs.com | date=4 May 2020 | url=https://www.drugs.com/international/atorvastatin.html | access-date=10 May 2020 | archive-date=3 August 2020 | archive-url=https://web.archive.org/web/20200803213547/https://www.drugs.com/international/atorvastatin.html | url-status=live }}{{cite web | title=Lipitor referral | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/referrals/lipitor | access-date=10 May 2020 | archive-date=20 October 2020 | archive-url=https://web.archive.org/web/20201020011042/https://www.ema.europa.eu/en/medicines/human/referrals/lipitor | url-status=live }} Pfizer also makes its own generic version under the name Zarator.{{cite news | vauthors = Rapley L |date= 31 May 2012 |title= Atorvastatin sole funding announced |url= http://www.pharmacytoday.co.nz/news/2012/may-2012/31/atorvastatin-sole-funding-announced.aspx |archive-url= https://archive.today/20140717211539/http://www.pharmacytoday.co.nz/news/2012/may-2012/31/atorvastatin-sole-funding-announced.aspx |url-status= dead |archive-date= 17 July 2014 |publisher= PharmacyToday.co.nz |access-date= 16 July 2014}} [263] => [264] => ===Medication recalls=== [265] => On 9 November 2012, Indian drugmaker [[Ranbaxy Laboratories]] Ltd. voluntarily recalled 10-, 20- and 40-mg doses of its generic version of atorvastatin in the United States.{{cite news |vauthors=Loftus P, Weaver C |date=23 November 2012 |title=Ranbaxy Recalls Generic Lipitor Doses |url=https://www.wsj.com/articles/SB10001424127887324352004578137241552301304 |work=The Wall Street Journal |access-date=6 March 2021 |archive-date=17 May 2021 |archive-url=https://web.archive.org/web/20210517191148/https://www.wsj.com/articles/SB10001424127887324352004578137241552301304 |url-status=live }}{{cite news | vauthors=Johnson LA | title=Ranbaxy recalls generic Lipitor doses | work=[[The Boston Globe]] | date=24 November 2012 | url=https://www.bostonglobe.com/business/2012/11/24/ranbaxy-recalls-generic-lipitor-doses/iRsoUYfYzHStRzIe82LFCK/story.html | access-date=29 December 2017 | agency=[[Associated Press]] | archive-date=29 December 2017 | archive-url=https://web.archive.org/web/20171229171904/https://www.bostonglobe.com/business/2012/11/24/ranbaxy-recalls-generic-lipitor-doses/iRsoUYfYzHStRzIe82LFCK/story.html | url-status=live }} The lots of atorvastatin, packaged in bottles of 90 and 500 tablets, were recalled due to possible contamination with very small glass particles similar to the size of a grain of sand (less than 1{{nbsp}}mm in size). The FDA received no reports of injury from the contamination.{{cite web|title=FDA Statement on Ranbaxy Atorvastatin Recall|url=https://www.fda.gov/drugs/drugsafety/ucm329951.htm|publisher=U.S. [[Food and Drug Administration]] (FDA)|date=30 December 2012|access-date=19 April 2014|archive-date=19 April 2014|archive-url=https://web.archive.org/web/20140419234350/http://www.fda.gov/drugs/drugsafety/ucm329951.htm|url-status=live}} Ranbaxy also issued recalls of bottles of 10-milligram tablets in August 2012 and March 2014, due to concerns that the bottles might contain larger, 20-milligram tablets and thus cause potential dosing errors.{{cite news |vauthors=Loftus P |url=https://www.wsj.com/articles/ranbaxy-recalls-more-than-64-000-bottles-of-generic-lipitor-in-u-s-1394226119 |title=Ranbaxy Recalls More Than 64,000 Bottles of Generic Lipitor in U.S. |work=[[The Wall Street Journal]] |date=7 March 2014 |url-access=subscription |access-date=21 June 2019 |archive-date=21 June 2019 |archive-url=https://web.archive.org/web/20190621042502/https://www.wsj.com/articles/ranbaxy-recalls-more-than-64-000-bottles-of-generic-lipitor-in-u-s-1394226119 |url-status=live }}{{cite news | title=Indian drugmaker Ranbaxy recalls more than 64,000 bottles of its generic version of Lipitor | newspaper=[[The Washington Post]] | date=8 March 2014 | url=https://www.washingtonpost.com/politics/indian-drugmaker-ranbaxy-recalls-more-than-64000-bottles-of-its-generic-version-of-lipitor/2014/03/08/e36a41b4-a716-11e3-a5fa-55f0c77bf39c_story.html | access-date=29 December 2017 | vauthors=Siddiqui Z, Sikka K | archive-date=29 December 2017 | archive-url=https://web.archive.org/web/20171229171922/https://www.washingtonpost.com/politics/indian-drugmaker-ranbaxy-recalls-more-than-64000-bottles-of-its-generic-version-of-lipitor/2014/03/08/e36a41b4-a716-11e3-a5fa-55f0c77bf39c_story.html | url-status=live }} [266] => {{clear}} [267] => [268] => == References == [269] => {{Reflist|refs = [270] => [271] => {{cite web | title = Atorvastatin Calcium | url = https://www.drugs.com/monograph/atorvastatin-calcium.html | publisher = [[American Society of Health-System Pharmacists]] | access-date = 3 April 2011 | archive-date = 25 October 2010 | archive-url = https://web.archive.org/web/20101025140429/https://www.drugs.com/monograph/atorvastatin-calcium.html | url-status = live }} [272] => [273] => {{cite book | veditors = Rossi S | title = Australian medicines handbook 2006 | publisher = Australian Medicines Handbook Pty Ltd. | location = Adelaide, S. 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| pages = 128–33 | date = January 1996 | pmid = 8531308 | doi = 10.1001/jama.1996.03530260042029 }} [290] => [291] => {{cite journal | vauthors = Marais AD, Firth JC, Bateman ME, Byrnes P, Martens C, Mountney J | title = Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 17 | issue = 8 | pages = 1527–31 | date = August 1997 | pmid = 9301631 | doi = 10.1161/01.ATV.17.8.1527 }} [292] => [293] => {{cite journal | vauthors = Jones P, Kafonek S, Laurora I, Hunninghake D | title = Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study) | journal = The American Journal of Cardiology | volume = 81 | issue = 5 | pages = 582–7 | date = March 1998 | pmid = 9514454 | doi = 10.1016/S0002-9149(97)00965-X }} [294] => [295] => {{cite journal | vauthors = Mazzu AL, Lasseter KC, Shamblen EC, 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low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis | journal = BMJ | volume = 326 | issue = 7404 | pages = 1423–0 | date = June 2003 | pmid = 12829554 | pmc = 162260 | doi = 10.1136/bmj.326.7404.1423 }} [304] => [305] => {{cite journal | vauthors = McCrindle BW, Ose L, Marais AD | title = Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial | journal = The Journal of Pediatrics | volume = 143 | issue = 1 | pages = 74–80 | date = July 2003 | pmid = 12915827 | doi = 10.1016/S0022-3476(03)00186-0 }} [306] => [307] => {{cite journal | vauthors = Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH | title = Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial | journal = Lancet | volume = 364 | issue = 9435 | pages = 685–96 | year = 2004 | pmid = 15325833 | doi = 10.1016/S0140-6736(04)16895-5 | s2cid = 28885209 }} [308] => [309] => {{cite journal | vauthors = Backman JT, Luurila H, Neuvonen M, Neuvonen PJ | title = Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites | journal = Clinical Pharmacology and Therapeutics | volume = 78 | issue = 2 | pages = 154–67 | date = August 2005 | pmid = 16084850 | doi = 10.1016/j.clpt.2005.04.007 | s2cid = 8715786 }} [310] => [311] => {{cite journal | vauthors = Hermann M, Bogsrud MP, Molden E, Asberg A, Mohebi BU, Ose L, Retterstøl K | title = Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy | journal = Clinical Pharmacology and Therapeutics | volume = 79 | issue = 6 | pages = 532–9 | date = June 2006 | pmid = 16765141 | doi = 10.1016/j.clpt.2006.02.014 | s2cid = 12838555 | url = https://www.duo.uio.no/bitstream/10852/28920/1/Artikkelxatorvabelastningxjunix2006xLipidklinikken.pdf | access-date = 28 December 2020 | archive-date = 26 February 2023 | archive-url = https://web.archive.org/web/20230226050544/https://www.duo.uio.no/bitstream/handle/10852/28920/Artikkelxatorvabelastningxjunix2006xLipidklinikken.pdf?sequence=1 | url-status = live }} [312] => [313] => {{cite journal | vauthors = Ozaki K, Kubo T, Imaki R, Shinagawa H, Fukaya H, Ohtaki K, Ozaki S, Izumi T, Aizawa Y | title = The anti-atherosclerotic effects of lipid lowering with atorvastatin in patients with hypercholesterolemia | journal = Journal of Atherosclerosis and Thrombosis | volume = 13 | issue = 4 | pages = 216–9 | date = August 2006 | pmid = 16908955 | doi = 10.5551/jat.13.216 | doi-access = free | title-link = doi }} [314] => [315] => {{cite journal | vauthors = Neil HA, DeMicco DA, Luo D, Betteridge DJ, Colhoun HM, Durrington PN, Livingstone SJ, Fuller JH, Hitman GA | title = Analysis of efficacy and safety in patients aged 65–75 years at randomization: Collaborative Atorvastatin Diabetes Study (CARDS) | journal = Diabetes Care | volume = 29 | issue = 11 | pages = 2378–84 | date = November 2006 | pmid = 17065671 | doi = 10.2337/dc06-0872 | doi-access = free | title-link = doi }} [316] => [317] => {{cite journal | vauthors = Neuvonen PJ, Niemi M, Backman JT | title = Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance | journal = Clinical Pharmacology and Therapeutics | volume = 80 | issue = 6 | pages = 565–81 | date = December 2006 | pmid = 17178259 | doi = 10.1016/j.clpt.2006.09.003 | s2cid = 35917120 }} [318] => [319] => [320] => [321] => {{cite journal | vauthors = Schwartz JB | title = Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence | journal = Clinical Pharmacology and Therapeutics | volume = 85 | issue = 2 | pages = 198–203 | date = February 2009 | pmid = 18754003 | doi = 10.1038/clpt.2008.165 | s2cid = 23604512 }} [322] => [323] => {{cite journal | vauthors = Deshmukh HA, Colhoun HM, Johnson T, McKeigue PM, Betteridge DJ, Durrington PN, Fuller JH, Livingstone S, Charlton-Menys V, Neil A, Poulter N, Sever P, Shields DC, Stanton AV, Chatterjee A, Hyde C, Calle RA, Demicco DA, Trompet S, Postmus I, Ford I, Jukema JW, Caulfield M, Hitman GA | title = Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a) | journal = Journal of Lipid Research | volume = 53 | issue = 5 | pages = 1000–11 | date = May 2012 | pmid = 22368281 | pmc = 3329377 | doi = 10.1194/jlr.P021113 | doi-access = free | title-link = doi }} [324] => [325] => {{cite journal | vauthors = Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB | title = Prediction of coronary heart disease using risk factor categories | journal = Circulation | volume = 97 | issue = 18 | pages = 1837–47 | date = May 1998 | pmid = 9603539 | doi = 10.1161/01.CIR.97.18.1837 | doi-access = free | title-link = doi }} [326] => [327] => }} [328] => [329] => == Further reading == [330] => {{Refbegin}} [331] => * {{cite journal | vauthors = Maggon K | title = Best-selling human medicines 2002–2004 | journal = Drug Discovery Today | volume = 10 | issue = 11 | pages = 739–42 | date = June 2005 | pmid = 15922927 | doi = 10.1016/S1359-6446(05)03468-9 }} [332] => * {{cite web | url = https://archive.fortune.com/magazines/fortune/fortune_archive/2003/01/20/335643/index.htm | title = The $10 Billion Pill Hold the fries, please. Lipitor, the cholesterol-lowering medication, has become the bestselling pharmaceutical in history. Here's how Pfizer did it | work = [[Fortune (magazine)|Fortune]] | vauthors = Simons J | date = 20 January 2003 }} [333] => * {{cite news | url = https://www.wsj.com/articles/SB948677773420632448 | title = The Birth of a Blockbuster: Lipitor's Route out of the Lab | vauthors = Winslow R | date = 24 January 2000 | work = [[The Wall Street Journal]] | access-date = 26 October 2011 | url-access = subscription | archive-date = 7 April 2019 | archive-url = https://web.archive.org/web/20190407204143/https://www.wsj.com/articles/SB948677773420632448 | url-status = live }} [334] => {{Refend}} [335] => [336] => {{Statins}} [337] => {{Portal bar | Medicine}} [338] => {{Authority control}} [339] => [340] => [[Category:Anilides]] [341] => [[Category:Diols]] [342] => [[Category:Fluoroarenes]] [343] => [[Category:Isopropyl compounds]] [344] => [[Category:Drugs developed by Pfizer]] [345] => [[Category:Pyrroles]] [346] => [[Category:Statins]] [347] => [[Category:Wikipedia medicine articles ready to translate]] [] => )
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Atorvastatin

Atorvastatin, marketed under the brand name Lipitor, is a medication used to lower cholesterol levels and prevent cardiovascular diseases. It is classified as a statin, a type of drug that works by inhibiting the enzyme responsible for cholesterol production in the liver.

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It is classified as a statin, a type of drug that works by inhibiting the enzyme responsible for cholesterol production in the liver. Atorvastatin is highly effective in lowering both LDL (bad) cholesterol and triglycerides, while also increasing levels of HDL (good) cholesterol. This drug is commonly prescribed to individuals with high cholesterol or those at risk of developing heart disease, stroke, or other cardiovascular complications. Atorvastatin has been extensively studied and has shown significant benefits in reducing the risk of cardiovascular events, such as heart attacks and strokes, in both men and women. It is typically taken orally and its dosage varies depending on the patient's condition and response to treatment. Common side effects include muscle pain, digestive issues, and an increased risk of developing type 2 diabetes. It is important to take Atorvastatin as prescribed and to regularly monitor cholesterol levels to ensure its effectiveness. Overall, Atorvastatin has proven to be a valuable and widely used medication in the management of high cholesterol and cardiovascular health.

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Pediatrics is the branch of medicine that deals with the medical care of infants, children, and adolescents.

Rifampicin

Rifampicin is a medication primarily used to treat tuberculosis and leprosy.

Voriconazole

Voriconazole, sold under the brand name Vfend among others, is an antifungal medication used to treat a number of fungal infections.