simvastatin (Zocor)
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Introduction
Tradename: Zocor.
Indications
- primary hypercholesterolemia
- prevention of cardiovascular disease
- treatment of venous stasis ulcers ?[23]
Contraindications
- active liver disease
- concommitant therapy with bepridil (Ca+2-channel blocker)
- unexplained persistent elevations in serum transaminases
- hypersensitivity to simvastatin
- women with potential to become pregnant
- concurrent HIV protease inhibitor[19]; use atorvastatin
- disease-modifying agent for Parkinson's disease[27]
Dosage
- starting dose 20 mg QD with evening meal[11]
- adjust doses at intervals of 4 weeks or more
- maintenance: 5-80 mg/day
- average dose for LDL control is 40 mg/day
- maximum dose for patients with creatinine clearance < 30 mL/min is 20 mg/day Tabs 5, 10, 20, 40 & 80 mg.
Pharmacokinetics
- extensive 1st pass metabolism
- 95% of drug is bound to plasma proteins
- lipophilic in nature & crosses blood-brain barrier
- metabolized by the liver (activation & deactivation)
- lactone hydrolysis required for activation
- metabolized by cyt P450 3A4[7]
- 1/2 life of 1.9-3 hours for active metabolite
- 13% of drug is eliminated by the kidneys
- check fasting lipid profile after 12 weeks of initial therapy
elimination via liver
1/2life = 1.9-3 hours
protein binding = 95 %
Monitor
- see HMG CoA reductase inhibitor
- SLCO1B1 genotyping
- allelic variants of SLCO1B1 may be associated with statin-induced myopathy
Adverse effects
- 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]
- uncommon (< 1%)
- taste disturbance, lenticular opacities, blurred vision
- other
- hepatitis - increased serum transaminases
- myopathy & myositis (0.9% 80 mg vs 0.02% 20 mg)[15]
- potentially teratogenic
- increased risk of diabetes mellitus
- reversible cognitive dysfunction[24]
- arthralgia, arthritis, eosinophilia, vertigo, headache, angioedema, eczema, flatulence[28]
- erectile dysfunction[28]
- interstitial lung disease[28]
- drug adverse effects of HMG CoA reductase inhibitors
- drug adverse effects of anti-hyperlipidemic agents
Drug interactions
- bile acid sequestrants decrease oral bioavailability of simvastatin
- cyclosporin, erythromycin (& other macrolides?), gemfibrozil:
- severe myopathy or rhabdomyolysis may occur when used in combination
- coumadin: increased anticoagulant effect
- 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
- ritonavir-boosted HIV protease inhibitors may slow metabolism of simvastatin[6][9]; use atorvastatin or rosuvastatin[19]
- any drug which inhibits cyt P450 3A4 can increase simvastatin levels
- ritonavir ...
- any drug which induces cyt P450 3A4 can diminish simvastatin levels
- do NOT to exceed 10 mg/day in patients taking verapamil or diltiazem[16][25] (previously 20 mg/day[9][14])
- do NOT to exceed 20 mg/day in patients taking amiodarone, amlodipine & ranozoline[16][25]
- concurrent use of amlodipine increases risk of rhabomyolysis
- do NOT to exceed 20 mg/day in patients taking ticrgrelor[25]
- drugs contraindicated for use with simvastatin[16]
- close monitoring for myalgia when used in combination with colchicine[25]
- drug interaction(s) anticonvulsants with statins
- drug interaction(s) of statins with vitamin D
- drug interaction(s) of statins with SSRIs
- drug interaction(s) of statins with influenza virus vaccines
- drug interaction(s) of statins with macrolide
- drug interaction(s) of statins with antiviral protease inhibitors
- drug interaction(s) of statins with fibrates
- drug interaction(s) of simvastatin with amiodarone
- drug interaction(s) of simvastatin, verapamil & grapefruit
Laboratory
- SLCO1B1 genotyping may be indicated
Mechanism of action
- competitive inhibition of 3-hydroxymethyl glutaryl coenzyme A reductase (HMG CoA reductase)
- an increase in LDL receptor formation
- a decrease in LDL synthesis (30-40%)
- maximal effect (80 mg/day)
- total cholesterol: decrease of 30%
- LDL cholesterol: decrease of 48% (35% at 20 mg QD)[10]
- HDL cholesterol: increase of 8%
- triglycerides: decrease of 10-45%
- activates protein kinase Akt[12]
Clinical trials
- 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]
More general terms
Additional terms
Component of
- simvastatin/sitagliptin (Juvisync)
- ezetimibe/simvastatin (Vytorin)
- nicotinic acid/simvastatin (Simcor)
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1990. pg 882
- ↑ Merck & Company
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Jump up to: 6.0 6.1 Prescriber's Letter 7(8):45 2000
- ↑ Jump up to: 7.0 7.1 Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
- ↑ Jump up to: 9.0 9.1 9.2 Prescriber's Letter 9(8):44 2002
- ↑ Jump up to: 10.0 10.1 Prescriber's Letter 10(3):14 2003
- ↑ Jump up to: 11.0 11.1 Do All Statins Need to be Taken in the Evening? Prescriber's Letter 10(12):70 2003 Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=191206&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Jump up to: 12.0 12.1 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: https://www.ncbi.nlm.nih.gov/pubmed/10973320
- ↑ Jump up to: 13.0 13.1 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: https://www.ncbi.nlm.nih.gov/pubmed/15910950
- ↑ Jump up to: 14.0 14.1 Prescriber's Letter 15(10): 2008 Rhabdomyolysis with Combined Use of Amiodarone and Simvastatin Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=241002&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Jump up to: 15.0 15.1 15.2 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#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260409&pb=PRL (subscription needed) http://www.prescribersletter.com - ↑ Jump up to: 16.0 16.1 16.2 16.3 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 - ↑ Prescriber's Letter 18(9): 2011 COMMENTARY: New Restrictions, Contraindications, and Dose Limitations for Zocor (Simvastatin) Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=270902&pb=PRL (subscription needed) http://www.prescribersletter.com
Prescriber's Letter 18(11): 2011 - ↑ Jump up to: 18.0 18.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22115874 <Internet> 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: https://www.ncbi.nlm.nih.gov/pubmed/22115875 The Lancet, Early Online Publication, 22 November 2011 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61544-4/fulltext - ↑ Jump up to: 19.0 19.1 19.2 Medical Knowledge Self Assessment Program (MKSAP) 16, American College of Physicians, Philadelphia 2012
- ↑ Jump up to: 20.0 20.1 Carter AA et al. Risk of incident diabetes among patients treated with statins: Population based study. BMJ 2013 May 23; 346:f2610. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23704171
Huupponen R and Viikari J. Statins and the risk of developing diabetes. BMJ 2013 May 23; 346:f3156 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23709567 - ↑ Jump up to: 21.0 21.1 21.2 Deprecated Reference
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/21675881
- ↑ Jump up to: 23.0 23.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24506834 <Internet> http://onlinelibrary.wiley.com/doi/10.1111/bjd.12883/abstract;jsessionid=C488DE8C1D402816D9BD8A4E59150390.f03t0
- ↑ Jump up to: 24.0 24.1 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: https://www.ncbi.nlm.nih.gov/pubmed/27048383 Free PMC Article
- ↑ Jump up to: 25.0 25.1 25.2 25.3 25.4 25.5 25.6 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27754879 <Internet> http://circ.ahajournals.org/content/circulationaha/early/2016/10/17/CIR.0000000000000456.full.pdf
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/19206087
- ↑ Jump up to: 27.0 27.1 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: https://www.ncbi.nlm.nih.gov/pubmed/36315128 https://jamanetwork.com/journals/jamaneurology/fullarticle/2797508
- ↑ Jump up to: 28.0 28.1 28.2 28.3 28.4 28.5 Windle ML Rapid Rx Quiz: Statin Intolerance and Related Concerns Medscape. September 01, 2022 https://reference.medscape.com/viewarticle/979515
- ↑ HIGHLIGHTS OF PRESCRIBING INFORMATION ZOCOR(simvastatin) Tablets https://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf