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atorvastatin (Lipitor)

Tradename: Lipitor (atorvastatin calcium) generic Nov 30, 2011 [12] Indications: 1) hypercholesterolemia, prevention of cardiovascular events a) homozygous familial hypercholesterolemia b) hyperlipoproteinemia type 3 2) may be of benefit for hypertension without hypercholesterolemia [4] 3) arteriosclerosis a) coronary artery disease b) myocardial infarction c) ischemic stroke d) transient ischemic attack e) prevention of cardiovascular disease 4) rheumatoid arthritis* (in combination with DMARDs) [6] * not effective in cardiovascular risk reduction in patients with systemic lupus erythematosus (SLE) [13] * benefits may be less for women [16] Contraindications: - pregnancy (potentially teratogenic, risk may be small) - of no benefit in diabetics undergoing hemodialysis [18] Dosage: 1) start 10 mg QHS 2) usual dose: 20-40 mg PO QHS 3) maximum: 80 mg/day Tabs: 10, 20 & 40 mg. Pharmacokinetics: 1) oral dose is rapidly absorbed (may take with food) - bioavailability is 14% [19] 2) time to peak plasma concentrations is 1-2 hour 3) protein binding is >98% 4) metabolized by cyt P450 3A4 - not a prodrug - active ortho & para-hydroxylated derivatives - substrate of p-glycoprotein [19] 5) 1/2 life is 14 hours 6) undergoes enterohepatic circulation 7) maximal effect on plasma cholesterol in 2 weeks 8) crosses blood brain barrier Monitor: - see HMG CoA reductase inhibitor Adverse effects: 1) gastrointestinal (most common) - increased serum transaminases - constipation, diarrhea - flatulence - dyspepsia, abdominal pain 2) musculoskeletal - myopathy - myalgias - increased serum creatine kinase - myositis - rhabdomyolysis with acute renal failure - arthritis 3) neurologic - CNS: headache, mild confusion - peripheral neuropathy (suggested to be fairly common) [5] - tremor [17] 4) increased risk of hemorrhagic stroke (RR=1.68) [7] 5) endocrine: increased risk of type 2 diabetes [9] - risk may be greater among women [16] 6) potentially teratogenic Drug interactions: 1) limit dose of atorvastatin to 10 mg/day with coadministration of cyclosporine, tacrolimus, everolimus, sirolimus 2) any drug which inhibits cyt P450 3A4 can increase atorvastatin levels: i.e. erythromycin 3) any drug which induces cyt P450 3A4 can diminish atorvastatin levels 4) risk of myopathy increased with concurrent administration of a) erythromycin, clarithromycin b) fibrates (gemfibrozil) c) niacin d) azole anti-fungal agents e) close monitoring for myalgia with coadministration of colchicine [19] 5) atorvastatin decreases digoxin levels (20%) 6) atorvastatin increases estrogen levels in women taking oral contraceptives 7 ) no dose limitation in combination with ticagrelor [19] Mechanism of action: 1) inhibition of HMG CoA reductase 2) maximal effect (80 mg/day) a) total cholesterol: decrease of 45% b) LDL cholesterol: decrease of 55% c) HDL cholesterol: increase of 5% d) triglycerides: decrease of 10-45% 3) high doses of rosuvastatin & atorvastatin result in similar atherosclerosis regression, despite greater reductions in LDL cholesterol with rosuvastatin [11] 4) does not seem to reduce inflammation in patients with SLE [13] Notes: - not inferior to rosuvastatin in reducing atherosclerosis [10] - differences between rosuvastatin & atorvastatin are relatively small, & may not reach clinical significance - 6 year mortality lower for rosuvastatin vs atorvastatin (2.57 vs 2.83 & 0.66 vs 0.90 per 100 person years in 2 different databases [23] - rosuvastatin associated lower risks for major adverse cardiovascular events & major adverse liver outcomes than atorvastatin - risk for type 2 diabetes mellitus is higher with rosuvastatin than atorvastatin [23]

Interactions

drug interactions drug adverse effects (more general classes) monitor with HMG CoA reductase inhibitors (statins)

Related

ASCOT LLA trial cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) fibrate

General

lipophilic statin

Properties

SIZE: MW = 1209 G/M INHIBITS: HMG CoA reductase MISC-INFO: elimination route LIVER 1/2life 14 HOURS protein-binding 98% pregnancy-category X safety in lactation -

Database Correlations

PUBCHEM correlations

References

  1. Parke Davis package insert
  2. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  3. Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
  4. Journal Watch 23(10):77, 2003 Sever PS et al, Lancet 361(Apr 5):1149, 2003 Lindhol LH & Samuelsson O, Lancet 361(Apr 5):1144, 2003
  5. Journal Watch 22(12):91, 2002 - Gaist D, Jeppesen U, Andersen M et al, Statins and risk of polyneuropathy: a case-control study. Neurology. 2002 May 14;58(9):1333-7. PMID: 12011277
  6. Journal Watch 24(15):119, 2004 McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004 Jun 19;363(9426):2015-21. PMID: 15207950
  7. Goldstein LB et al, SPARCL investigators Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Level Study. Neurology 2007 http://dx.doi.org/10.1212/01.wnl.0000296277.63350.77 PMID: 18077795)
  8. Prescriber's Letter 17(6): 2010 CHART: Characteristics of the Various Statins CHART: Clinically Significant Statin Drug Interactions Detail-Document#: 260611 (subscription needed) http://www.prescribersletter.com
  9. Waters DD et al Predictors of New-Onset Diabetes in Patients Treated With Atorvastatin J Am Coll Cardiol, 2011; 57:1535-1545 PMID: 21453832 http://content.onlinejacc.org/cgi/content/abstract/57/14/1535
  10. HealthDay News, Nov 29, 2011
  11. Nicholls SJ et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011 Nov 15 PMID: 22085316 http://www.nejm.org/doi/full/10.1056/NEJMoa1110874
  12. Press Release: Watson Launches Generic Lipitor Nov 30, 2011 http://ir.watson.com/phoenix.zhtml?c=65778&p=irol-newsArticle&ID=1634538&highlight= - FDA News Release: Nov. 30, 2011 FDA approves first generic version of cholesterol-lowering drug Lipitor http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm281817.htm
  13. Petri MA, Kiani AN, Post W, Christopher-Stine L, Magder LS. Lupus Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis. 2011 May;70(5):760-5 PMID: 21177297
  14. AstraZeneca announces top-line results from SATURN study http://www.astrazeneca.com/Media/Press-releases/Article/02092011-astrazeneca-saturn-study-results
  15. Deprecated Reference
  16. Herman AO Lipitor Lawsuits Among Women Soar in Past 5 Months. Physician's First Watch, Aug 11, 2014 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org
  17. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
  18. Wanner C, Krane V, Marz W et al Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005 Jul 21;353(3):238-48. PMID: 16034009 Free Article
  19. Wiggins BS, Saseen JJ, Page RL 2nd et al 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. Circulation. 2016;134:00-00 PMID: 27754879 http://circ.ahajournals.org/content/circulationaha/early/2016/10/17/CIR.0000000000000456.full.pdf
  20. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367(20):1891-1900 PMID: 23113833 Free Article
  21. Gupta A, Thompson D, Whitehouse A et al Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. May 2, 2017 PMID: 28476288 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31075-9/fulltext?elsca1=tlpr - Pedro-Botet J, Rubies-Prat J. Statin-associated muscle symptoms: Beware of the nocebo effect. Lancet 2017 May 2 PMID: 28476289 http://www.jwatch.org/na44073/2017/05/25/muscle-symptoms-statin-users-might-be-nocebo-effect
  22. Herrett E, Williamson E, Brack K et al Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials. BMJ. 2021 Feb 24;372:n135 PMID: 33627334
  23. Zhou S, Chen R, Liu J et al Comparative Effectiveness and Safety of Atorvastatin Versus Rosuvastatin: A Multi-database Cohort Study. Ann Intern Med. 2024 Oct 29. PMID: 39467290 https://www.acpjournals.org/doi/10.7326/M24-0178

Component-of

amlodipine/atorvastatin (Caduet) atorvastatin/ezetimibe (Liptruzet)