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simvastatin (Zocor)

Tradename: Zocor. Indications: - primary hypercholesterolemia - reduction of total cholesterol & LDL cholesterol - homozygous familial hypercholesterolemia - hyperlipoproteinemia type 3 [21] - prevention of cardiovascular disease - transient ischemic attack [21] - coronary artery disease - post myocardial infarction - peripheral vascular disease - arteriosclerosis - treatment of venous stasis ulcers ? [23] cost-effective [13] Contraindications: 1) active liver disease 2) concommitant therapy with bepridil (Ca+2-channel blocker) 3) unexplained persistent elevations in serum transaminases 4) hypersensitivity to simvastatin 5) women with potential to become pregnant 6) concurrent HIV protease inhibitor [19]; use atorvastatin 7) disease-modifying agent for Parkinson's disease [27] Dosage: 1) starting dose 20 mg QD with evening meal [11] 2) adjust doses at intervals of 4 weeks or more 3) maintenance: 5-80 mg/day 4) average dose for LDL control is 40 mg/day 5) maximum dose for patients with creatinine clearance < 30 mL/min is 20 mg/day Tabs 5, 10, 20, 40 & 80 mg. Pharmacokinetics: 1) extensive 1st pass metabolism - 4 hours after oral dose to reach maximum plasma level [25] 2) 95% of drug is bound to plasma proteins 3) lipophilic in nature & crosses blood-brain barrier 4) metabolized by the liver (activation & deactivation) a) lactone hydrolysis required for activation b) metabolized by cyt P450 3A4 [7] 5) 1/2 life of 1.9-3 hours for active metabolite 6) 13% of drug is eliminated by the kidneys 3) check fasting lipid profile after 12 weeks of initial therapy Monitor: - see HMG CoA reductase inhibitor - SLCO1B1 genotyping - allelic variants of SLCO1B1 may be associated with statin-induced myopathy Adverse effects: 1) not common (1-10%) - headache, flatus, abdominal cramps, diarrhea, rash, constipation, nausea, dyspepsia, heartburn, dizziness, myalgia, elevated creatine kinase (CK), muscle injury (dose-related) [15], upper respiratory tract infection (9%) [28] 2) uncommon (< 1%) - taste disturbance, lenticular opacities, blurred vision 3) other - hepatitis - increased serum transaminases - myopathy & myositis (0.9% 80 mg vs 0.02% 20 mg) [15] - myalgias - increased serum creatine kinase - rhabdomyolysis - renal failure - potentially teratogenic - increased risk of diabetes mellitus - simvastatin diminishes insulin secretion [20] - reversible cognitive dysfunction [24] - amnesia, confusion, forgetfulness, memory impairment, memory loss [28] - arthralgia, arthritis, eosinophilia, vertigo, headache, angioedema, eczema, flatulence [28] - erectile dysfunction [28] - interstitial lung disease [28] Drug interactions: 1) bile acid sequestrants decrease oral bioavailability of simvastatin 2) cyclosporin, erythromycin (& other macrolides?), gemfibrozil: - severe myopathy or rhabdomyolysis may occur when used in combination 3) coumadin: increased anticoagulant effect 4) itraconazole, ketoconazole, fluconazole: increase in HMG CoA reductase inhibitor levels by 20-fold; hold HMG CoA reductase inhibitor therapy if azole antifungal therapy is needed 5) ritonavir-boosted HIV protease inhibitors may slow metabolism of simvastatin [6,9]; use atorvastatin or rosuvastatin [19] 6) any drug which inhibits cyt P450 3A4 can increase simvastatin levels - ritonavir ... 7) any drug which induces cyt P450 3A4 can diminish simvastatin levels 8) do NOT to exceed 10 mg/day in patients taking verapamil or diltiazem [16,25] (previously 20 mg/day [9,14]) 9) do NOT to exceed 20 mg/day in patients taking amiodarone, amlodipine & ranozoline [16,25] - concurrent use of amlodipine increases risk of rhabomyolysis 10) do NOT to exceed 20 mg/day in patients taking ticrgrelor [25] 11) drugs contraindicated for use with simvastatin [16] a) antifungal agents: itraconazole, ketoconazole, posaconazole b) antibiotics: erythromycin, clarithromycin, telithromycin c) antiretroviral protease inhibitors d) nefazodone (antidepressant) e) fibrates: gemfibrozil f) cyclosporine, tacrolimus, everolimus, sirolimus g) danazol h) niacin i) conivaptan [25] 12) close monitoring for myalgia when used in combination with colchicine [25] Laboratory: - SLCO1B1 genotyping may be indicated Mechanism of action: 1) competitive inhibition of 3-hydroxymethyl glutaryl coenzyme A reductase (HMG CoA reductase) 2) an increase in LDL receptor formation 3) a decrease in LDL synthesis (30-40%) 4) maximal effect (80 mg/day) a) total cholesterol: decrease of 30% b) LDL cholesterol: decrease of 48% (35% at 20 mg QD) [10] c) HDL cholesterol: increase of 8% d) triglycerides: decrease of 10-45% 5) activates protein kinase Akt [12] Clinical trials: 1) 11-year follow-up on 20,000 high-risk patients randomized to simvastatin or placebo for 5 yeard - cardiovascular risk reduction with simvastatin continued to year 11, 6 years after stopping simvastatin - no added risk for cancer-related death or death from other other causes, even among older patients [18]

Interactions

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

Related

cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

General

lipophilic statin

Properties

INHIBITS: HMG CoA reductase MISC-INFO: elimination route LIVER 1/2life 1.9-3 HOURS protein-binding 95% pregnancy-category X safety in lactation -

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1990. pg 882
  3. Merck & Company
  4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  5. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  6. Prescriber's Letter 7(8):45 2000
  7. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  8. Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
  9. Prescriber's Letter 9(8):44 2002
  10. Prescriber's Letter 10(3):14 2003
  11. Do All Statins Need to be Taken in the Evening? Prescriber's Letter 10(12):70 2003 Detail-Document#: 191206 (subscription needed) http://www.prescribersletter.com
  12. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000 Sep;6(9):1004-10. Erratum in: Nat Med 2001 Jan;7(1):129. PMID: 10973320
  13. Journal Watch 25(14):114, 2005 Mihaylova B, Briggs A, Armitage J, Parish S, Gray A, Collins R; Heart Protection Study Collaborative Group. Cost-effectiveness of simvastatin in people at different levels of vascular disease risk: economic analysis of a randomised trial in 20,536 individuals. Lancet. 2005 May;365(9473):1779-85. PMID: 15910950
  14. Prescriber's Letter 15(10): 2008 Rhabdomyolysis with Combined Use of Amiodarone and Simvastatin Detail-Document#: 241002 (subscription needed) http://www.prescribersletter.com
  15. FDA Medwatch Zocor (simvastatin): increased risk of muscle injury with high doses http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm205404.htm - Prescriber's Letter 17(4): 2010 Increased Risk of Muscle Injury with High-Dose Zocor (Simvastatin) COMMENTARY: Increased Risk of Muscle Injury with High-Dose Zocor (Simvastatin) CHART: Clinically Significant Statin Drug Interactions Detail-Document#: 260409 (subscription needed) http://www.prescribersletter.com
  16. Physician's First Watch for June 9, 2011 Journal Watch, Massachessetts Medical Society - FDA MedWatch Zocor (simvastatin): Label Change - New Restrictions, Contraindications, and Dose Limitations http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258384.htm
  17. Prescriber's Letter 18(9): 2011 COMMENTARY: New Restrictions, Contraindications, and Dose Limitations for Zocor (Simvastatin) Detail-Document#: 270902 (subscription needed) http://www.prescribersletter.com - Prescriber's Letter 18(11): 2011
  18. Heart Protection Study Collaborative Group Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial The Lancet, Early Online Publication, 22 November 2011 PMID: 22115874 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61125-2/abstract - Original Text - Kohli P and Cannon CP Statins and safety: can we finally be reassured? PMID: 22115875 The Lancet, Early Online Publication, 22 November 2011 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61544-4/fulltext
  19. Medical Knowledge Self Assessment Program (MKSAP) 16, American College of Physicians, Philadelphia 2012
  20. Carter AA et al. Risk of incident diabetes among patients treated with statins: Population based study. BMJ 2013 May 23; 346:f2610. PMID: 23704171 - Huupponen R and Viikari J. Statins and the risk of developing diabetes. BMJ 2013 May 23; 346:f3156 PMID: 23709567
  21. Deprecated Reference
  22. Egan A, Colman E. Weighing the benefits of high-dose simvastatin against the risk of myopathy. N Engl J Med. 2011 Jul 28;365(4):285-7 PMID: 21675881
  23. Evangelista MT et al. Simvastatin as a novel therapeutic agent for venous ulcers: A randomized, double-blind, placebo-controlled trial. Br J Dermatol 2014 Feb 7 PMID: 24506834 http://onlinelibrary.wiley.com/doi/10.1111/bjd.12883/abstract;jsessionid=C488DE8C1D402816D9BD8A4E59150390.f03t0
  24. Suraweera C, de Silva V, Hanwella R. Simvastatin-induced cognitive dysfunction: two case reports. J Med Case Rep. 2016 Apr 5;10(1):83. PMID: 27048383 Free PMC Article
  25. 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
  26. Rowan C, Brinker AD, Nourjah P et al Rhabdomyolysis reports show interaction between simvastatin and CYP3A4 inhibitors. Pharmacoepidemiol Drug Saf. 2009 Apr;18(4):301-9. PMID: 19206087
  27. Stevens KN, Creanor S, Jeffery A et al Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease. A Randomized Clinical Trial. JAMA Neurol. Published online October 31, 2022 PMID: 36315128 https://jamanetwork.com/journals/jamaneurology/fullarticle/2797508
  28. Windle ML Rapid Rx Quiz: Statin Intolerance and Related Concerns Medscape. September 01, 2022 https://reference.medscape.com/viewarticle/979515
  29. HIGHLIGHTS OF PRESCRIBING INFORMATION ZOCOR(simvastatin) Tablets https://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf

Component-of

ezetimibe/simvastatin (Vytorin) nicotinic acid/simvastatin (Simcor) simvastatin/sitagliptin (Juvisync)