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Drug Safety Evaluation

The safety of ezetimibe and simvastatin combination for the treatment of hypercholesterolemia

, &
Pages 559-569 | Received 30 Dec 2015, Accepted 18 Feb 2016, Published online: 16 Mar 2016

References

  • Barkas F, Liberopoulos EN, Kostapanos MS, et al. Lipid target achievement among patients with very high and high cardiovascular risk in a lipid clinic. Angiology. 2015;66:346–353.
  • Rizos CV, Barkas F, Elisaf MS. Reaching low density lipoprotein cholesterol targets. Curr Med Res Opin. 2014;30:1967–1969.
  • Toth PP, Davidson MH. Simvastatin plus ezetimibe: combination therapy for the management of dyslipidaemia. Expert Opin Pharmacother. 2005;6:131–139.
  • Agouridis AP, Filippatos TD, Katsiki N. Current lipid-modifying agents. Expert Opin Pharmacother. 2015;16:1117–1118.
  • Pedersen TR, Tobert JA. Simvastatin: a review. Expert Opin Pharmacother. 2004;5:2583–2596.
  • Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet. 1993;24:195–202.
  • Vickers S, Duncan CA, Vyas KP, et al. In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metab Dispos. 1990;18:476–483.
  • Vickers S, Duncan CA, Chen IW, et al. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab Dispos. 1990;18:138–145.
  • Desai CS, Martin SS, Blumenthal RS. Non-cardiovascular effects associated with statins. BMJ. 2014;349:g3743.
  • Davis HR, Veltri EP. Zetia: inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to reduce intestinal cholesterol absorption and treat hyperlipidemia. J Atheroscler Thromb. 2007;14:99–108.
  • van Heek M, Farley C, Compton DS, et al. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol. 2000;129:1748–1754.
  • Jia L, Betters JL, Yu L. Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu Rev Physiol. 2011;73:239–259.
  • Kosoglou T, Statkevich P, Johnson-Levonas AO, et al. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44:467–494.
  • Migoya EM, Bergman A, Hreniuk D, et al. Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects. Int J Clin Pharmacol Ther. 2006;44:83–92.
  • Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the scandinavian simvastatin survival study (4S). Lancet. 1994;344:1383–1389.
  • Athyros VG, Kakafika AI, Tziomalos K, et al. Pleiotropic effects of statins–clinical evidence. Curr Pharm Des. 2009;15:479–489.
  • Filippatos TD, Mikhailidis DP. Statins and heart failure. Angiology. 2008;59:58S–61S.
  • Filippatos TD, Elisaf MS. Fenofibrate plus simvastatin (fixed-dose combination) for the treatment of dyslipidaemia. Expert Opin Pharmacother. 2011;12:1945–1958.
  • Collins R, Armitage J, Parish S, et al. MRC/BHF heart protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005–2016.
  • Mikhailidis DP, Sibbring GC, Ballantyne CM, et al. Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy. Curr Med Res Opin. 2007;23:2009–2026.
  • Morrone D, Weintraub WS, Toth PP, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis. 2012;223:251–261.
  • Kalogirou M, Tsimihodimos V, Gazi I, et al. Effect of ezetimibe monotherapy on the concentration of lipoprotein subfractions in patients with primary dyslipidaemia. Curr Med Res Opin. 2007;23:1169–1176.
  • Tremblay AJ, Lamarche B, Hogue JC, et al. Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia. J Lipid Res. 2009;50:1463–1471.
  • Telford DE, Sutherland BG, Edwards JY, et al. The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin. J Lipid Res. 2007;48:699–708.
  • Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am J Cardiol. 1997;80:106–107.
  • Nicholls SJ, Brandrup-Wognsen G, Palmer M, et al. Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol. 2010;105:69–76.
  • Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation. 2000;101:207–213.
  • Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002;40:2125–2134.
  • Ohbu-Murayama K, Adachi H, Hirai Y, et al. Ezetimibe combined with standard diet and exercise therapy improves insulin resistance and atherosclerotic markers in patients with metabolic syndrome. J Diabetes Investig. 2015;6:325–333.
  • Chang E, Kim L, Choi JM, et al. Ezetimibe stimulates intestinal glucagon-like peptide 1 secretion via the MEK/ERK pathway rather than dipeptidyl peptidase 4 inhibition. Metabolism. 2015;64:633–641.
  • Kalogirou M, Tsimihodimos V, Elisaf M. Pleiotropic effects of ezetimibe: do they really exist? Eur J Pharmacol. 2010;633:62–70.
  • Nakou ES, Filippatos TD, Kiortsis DN, et al. The effects of ezetimibe and orlistat, alone or in combination, on high-density lipoprotein (HDL) subclasses and HDL-associated enzyme activities in overweight and obese patients with hyperlipidaemia. Expert Opin Pharmacother. 2008;9:3151–3158.
  • Nakou ES, Filippatos TD, Agouridis AP, et al. The effects of ezetimibe and/or orlistat on triglyceride-rich lipoprotein metabolism in obese hypercholesterolemic patients. Lipids. 2010;45:445–450.
  • Nakou ES, Filippatos TD, Georgoula M, et al. The effect of orlistat and ezetimibe, alone or in combination, on serum LDL and small dense LDL cholesterol levels in overweight and obese patients with hypercholesterolaemia. Curr Med Res Opin. 2008;24:1919–1929.
  • Takeshita Y, Takamura T, Honda M, et al. The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia. 2014;57:878–890.
  • Derdemezis C, Filippatos T, Tselepis A, et al. Effects of ezetimibe, either alone or in combination with atorvastatin, on serum visfatin levels: a pilot study. Expert Opin Pharmacother. 2008;9:1829–1837.
  • Filippatos TD, Elisaf MS. Statin-ezetimibe combination therapy in diabetic individuals. Angiology. 2015. doi:10.1177/0003319715598887. [Epub ahead of print]
  • Filippatos TD, Elisaf MS. Effects of ezetimibe/simvastatin combination on metabolic parameters. Int J Cardiol. 2016;202:273–274.
  • Florentin M, Liberopoulos EN, Moutzouri E, et al. The effect of simvastatin alone versus simvastatin plus ezetimibe on the concentration of small dense low-density lipoprotein cholesterol in subjects with primary hypercholesterolemia. Curr Med Res Opin. 2011;27:685–692.
  • Kostapanos MS, Elisaf MS, Mikhailidis DP. Effect of atorvastatin monotherapy and low-dose atorvastatin/ezetimibe combination on fasting and postprandial triglycerides in combined hyperlipidemia. J Cardiovasc Pharmacol Ther. 2012;17:427.
  • Moutzouri E, Liberopoulos EN, Florentin M, et al. Effects of statin monotherapy versus statin plus ezetimibe combination on serum uric acid levels. J Cardiovasc Pharmacol Ther. 2013;18:13–18.
  • Moutzouri E, Liberopoulos EN, Tellis CC, et al. Comparison of the effect of simvastatin versus simvastatin/ezetimibe versus rosuvastatin on markers of inflammation and oxidative stress in subjects with hypercholesterolemia. Atherosclerosis. 2013;231:8–14.
  • Moutzouri E, Tellis CC, Rousouli K, et al. Effect of simvastatin or its combination with ezetimibe on toll-like receptor expression and lipopolysaccharide - induced cytokine production in monocytes of hypercholesterolemic patients. Atherosclerosis. 2012;225:381–387.
  • Agouridis AP, Filippatos TD, Tsimihodimos V, et al. Combinations of ezetimibe with nonstatin drug regimens affecting lipid metabolism. Expert Rev Cardiovasc Ther. 2011;9:355–366.
  • Baigent C, Landray MJ, Reith C, et al. 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. Lancet. 2011;377:2181–2192.
  • Cannon CP, Blazing MA, Braunwald E, Ezetimibe plus a statin after acute coronary syndromes. N Engl J Med. 2015;373:1476–1477.
  • Filippatos TD, Elisaf MS. Are lower levels of LDL-cholesterol really better? Looking at the results of IMPROVE-IT: opinions of three experts - III. Hellenic J Cardiol. 2015;56:7–9.
  • [cited 2016 Feb 9]. Available from: https://www.escardio.org/The-ESC/Press-Office/Press-releases/Last-5-years/ezetimibe-reduces-cardiovascular-events-in-diabetics-with-recent-acute-coronary-syndrome
  • European Society Congress 2015 press releases [Internet]. 2015 [cited 2016 Feb 10]. Available from: http://www.medpagetoday.com/Cardiology/CardioBrief/55256
  • Food and Drug Administration [Internet]. [cited 2016 Feb 9]. Available from: http://www.fda.gov/safety/medwatch/safetyinformation/ucm208609.htm
  • Ip CK, Jin DM, Gao JJ, et al. Effects of add-on lipid-modifying therapy on top of background statin treatment on major cardiovascular events: a meta-analysis of randomized controlled trials. Int J Cardiol. 2015;191:138–148.
  • Fernandez G, Spatz ES, Jablecki C, et al. Statin myopathy: a common dilemma not reflected in clinical trials. Cleve Clin J Med. 2011;78:393–403.
  • Filippatos TD, Elisaf MS. Safety considerations with fenofibrate/simvastatin combination. Expert Opin Drug Saf. 2015;14:1481–1493.
  • Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;289:1681–1690.
  • Agouridis AP, Nair DR, Mikhailidis DP. Strategies to overcome statin intolerance. Expert Opin Drug Metab Toxicol. 2015;11:851–855.
  • Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European atherosclerosis society consensus panel statement on assessment, aetiology and management. Eur Heart J. 2015;36:1012–1022.
  • Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–1681.
  • Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376:1658–1669.
  • FDA drug safety communication: new restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. [cited 2016 Feb 10]. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm
  • Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63:157–181.
  • Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158:693–705.
  • Davidson MH, Maccubbin D, Stepanavage M, et al. Striated muscle safety of ezetimibe/simvastatin (Vytorin). Am J Cardiol. 2006;97:223–228.
  • de Denus S, Spinler SA, Miller K, et al. Statins and liver toxicity: a meta-analysis. Pharmacotherapy. 2004;24:584–591.
  • Stone NJ, Robinson JG, Lichtenstein AH, et al. ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2013;2014(63):2889–2934.
  • Liu Q, Tobias H, Petrovic LM. Drug-induced liver injury associated with ezetimibe therapy. Dig Dis Sci. 2007;52:602–605.
  • Stolk MF, Becx MC, Kuypers KC, et al. Severe hepatic side effects of ezetimibe. Clin Gastroenterol Hepatol. 2006;4:908–911.
  • Mombellia G, Calabresib L, Sirtoria C. Asymptomatic EBV infection may uncover ezetimibe liver alterations in a hypercholesterolemic child. J Med Cases. 2013;4:66–68.
  • Ballantyne CM, Abate N, Yuan Z, et al. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the vytorin versus atorvastatin (VYVA) study. Am Heart J. 2005;149:464–473.
  • McKenney JM, Jones PH, Bays HE, et al. Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Atherosclerosis. 2007;192:432–437.
  • Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592–1609.
  • Filippatos TD, Elisaf MS. Role of ezetimibe in non-alcoholic fatty liver disease. World J Hepatol. 2011;3:265–267.
  • Filippatos TD, Elisaf MS. Combination drug treatment in patients with non-alcoholic fatty liver disease. World J Hepatol. 2010;2:139–142.
  • Averna M. The effect of ezetimibe on NAFLD. Atheroscler Suppl. 2015;17:27–34.
  • Nelson A, Torres DM, Morgan AE, et al. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol. 2009;43:990–994.
  • Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207.
  • Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–742.
  • Koh KK, Quon MJ, Han SH, et al. Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients. Atherosclerosis. 2009;204:483–490.
  • Navarese EP, Szczesniak A, Kolodziejczak M, et al. Statins and risk of new-onset diabetes mellitus: is there a rationale for individualized statin therapy? Am J Cardiovasc Drugs. 2014;14:79–87.
  • Yada T, Nakata M, Shiraishi T, et al. Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet beta-cells. Br J Pharmacol. 1999;126:1205–1213.
  • Nakata M, Nagasaka S, Kusaka I, et al. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control. Diabetologia. 2006;49:1881–1892.
  • Koh KK, Quon MJ, Han SH, et al. Simvastatin improves flow-mediated dilation but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients. Diabetes Care. 2008;31:776–782.
  • Navarese EP, Buffon A, Andreotti F, et al. Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. Am J Cardiol. 2013;111:1123–1130.
  • Kohli P, Waters DD, Nemr R, et al. Risk of new-onset diabetes and cardiovascular risk reduction from high-dose statin therapy in pre-diabetics and non-pre-diabetics: an analysis from TNT and IDEAL. J Am Coll Cardiol. 2015;65:402–404.
  • Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2015;385:351–361.
  • Agouridis AP, Kostapanos MS, Elisaf MS. Statins and their increased risk of inducing diabetes. Expert Opin Drug Saf. 2015;14:1835–1844.
  • Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380:565–571.
  • Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011;305:2556–2564.
  • Cholesterol Treatment Trialists Collaborators, Mihaylova B, Emberson J, et al.. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–590.
  • Moutzouri E, Liberopoulos E, Mikhailidis DP, et al. Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance. Int J Clin Pract. 2011;65:1141–1148.
  • Barkas F, Elisaf M, Liberopoulos E, et al. Statin therapy with or without ezetimibe and the progression to diabetes. J Clin Lipidology. doi:10.1016/j.jacl.2015.11.015. [Epub ahead of print]
  • Koh KK, Oh PC, Sakuma I, et al. Vascular and metabolic effects of ezetimibe combined with simvastatin in patients with hypercholesterolemia. Int J Cardiol. 2015;199:126–131.
  • Kater AL, Batista MC, Ferreira SR. Improved endothelial function with simvastatin but unchanged insulin sensitivity with simvastatin or ezetimibe. Metabolism. 2010;59:921–926.
  • Blazing M. Incidence of new-onset diabetes in the IMPROVE-IT trial: does adding ezetimibe to simvastatin increase risk compared to simvastatin alone? Presented at: European Society of Cardiology Congress; 2015 Sep 1; London, England. Available from: https://www.acc.org/latest-in-cardiology/articles/2015/11/20/14/20/incidence-of-new-onset-diabetes-in-the-improve-it-trial?w_nav=Tab
  • Qamar A, Alexander KM. [cited 2016 Feb 9]. Available from: http://www.acc.org/latest-in-cardiology/articles/2015/11/20/14/20/incidence-of-new-onset-diabetes-in-the-improve-it-trial
  • Pattis P, Wiedermann CJ. Ezetimibe-associated immune thrombocytopenia. Ann Pharmacother. 2008;42:430–433.
  • Almquist T, Jacobson SH, Lins PE, et al. Effects of lipid-lowering treatment on platelet reactivity and platelet-leukocyte aggregation in diabetic patients without and with chronic kidney disease: a randomized trial. Nephrol Dial Transplant. 2012;27:3540–3546.
  • Haynes R, Lewis D, Emberson J, et al. Effects of lowering LDL cholesterol on progression of kidney disease. J Am Soc Nephrol. 2014;25:1825–1833.
  • Kiortsis DN, Filippatos TD, Mikhailidis DP, et al. Statin-associated adverse effects beyond muscle and liver toxicity. Atherosclerosis. 2007;195:7–16.
  • Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ. 2010;340:c2197.
  • Klein BE, Klein R, Lee KE, et al. Statin use and incident nuclear cataract. JAMA. 2006;295:2752–2758.
  • Erie JC, Pueringer MR, Brue SM, et al. Statin use and incident cataract surgery: a case-control study. Ophthalmic Epidemiol. 2016;23:40–45.
  • Wise SJ, Nathoo NA, Etminan M, et al. Statin use and risk for cataract: a nested case-control study of 2 populations in Canada and the United States. Can J Cardiol. 2014;30:1613–1619.
  • Leuschen J, Mortensen EM, Frei CR, et al. Association of statin use with cataracts: a propensity score-matched analysis. JAMA Ophthalmol. 2013;131:1427–1434.
  • Spence JD. Statins and cataracts: reverse causality? Can J Cardiol. 2015;31:691 e11.
  • Harris ML, Bron AJ, Brown NA, et al. Absence of effect of simvastatin on the progression of lens opacities in a randomised placebo controlled study. Oxford cholesterol study group. Br J Ophthalmol. 1995;79:996–1002.
  • Kostis JB, Dobrzynski JM. Prevention of cataracts by statins: a meta-analysis. J Cardiovasc Pharmacol Ther. 2014;19:191–200.
  • Bang CN, Greve AM, La Cour M, et al. Effect of randomized lipid lowering with simvastatin and ezetimibe on cataract development (from the Simvastatin and Ezetimibe in Aortic Stenosis Study). Am J Cardiol. 2015;116:1840–1844.
  • Adams AE, Bobrove AM, Gilliam AC. Statins and “chameleon-like” cutaneous eruptions: simvastatin-induced acral cutaneous vesiculobullous and pustular eruption in a 70-year-old man. J Cutan Med Surg. 2010;14:207–211.
  • Peramiquel L, Serra E, Dalmau J, et al. Occupational contact dermatitis from simvastatin. Contact Dermatitis. 2005;52:286–287.
  • Oskay T, Kutluay L. Acute generalized exanthematous pustulosis induced by simvastatin. Clin Exp Dermatol. 2003;28:558–559.
  • Granados MT, de la Torre C, Cruces MJ, et al. Chronic actinic dermatitis due to simvastatin. Contact Dermatitis. 1998;38:294–295.
  • Morimoto K, Kawada A, Hiruma M, et al. Photosensitivity to simvastatin with an unusual response to photopatch and photo tests. Contact Dermatitis. 1995;33:274.
  • Roger D, Rolle F, Labrousse F, et al. Simvastatin-induced lichenoid drug eruption. Clin Exp Dermatol. 1994;19:88–89.
  • Ruger RD, Simon JC, Treudler R. Subacute-cutaneous lupus erythematosus induced by simvastatin. J Dtsch Dermatol Ges. 2011;9:54–55.
  • Bellini V, Assalve D, Lisi P. Urticarial vasculitis from simvastatin: what is the alternative drug? Dermatitis. 2010;21:223–224.
  • Fauchais AL, J IB, Maurage P, et al. [Polymyositis induced or associated with lipid-lowering drugs: five cases]. Rev Med Interne. 2004;25:294–298.
  • De Groot RE, Willems LN, Dijkman JH. Interstitial lung disease with pleural effusion caused by simvastin. J Intern Med. 1996;239:361–363.
  • Lantuejoul S, Brambilla E, Brambilla C, et al. Statin-induced fibrotic nonspecific interstitial pneumonia. Eur Respir J. 2002;19:577–580.
  • Keech AC, Armitage JM, Wallendszus KR, et al. Absence of effects of prolonged simvastatin therapy on nocturnal sleep in a large randomized placebo-controlled study. Oxford cholesterol study group. Br J Clin Pharmacol. 1996;42:483–490.
  • Eckernas SA, Roos BE, Kvidal P, et al. The effects of simvastatin and pravastatin on objective and subjective measures of nocturnal sleep: a comparison of two structurally different HMG CoA reductase inhibitors in patients with primary moderate hypercholesterolaemia. Br J Clin Pharmacol. 1993;35:284–289.
  • Law MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum cholesterol. BMJ. 1994;308:373–379.
  • Davison KM, Kaplan BJ. Lipophilic statin use and suicidal ideation in a sample of adults with mood disorders. Crisis. 2014;35:278–282.
  • Haukka J, Niskanen L, Partonen T, et al. Statin usage and all-cause and disease-specific mortality in a nationwide study. Pharmacoepidemiol Drug Saf. 2012;21:61–69.
  • Callreus T, Agerskov Andersen U, Hallas J, et al. Cardiovascular drugs and the risk of suicide: a nested case-control study. Eur J Clin Pharmacol. 2007;63:591–596.
  • Yang CC, Jick SS, Jick H. Lipid-lowering drugs and the risk of depression and suicidal behavior. Arch Intern Med. 2003;163:1926–1932.
  • Huffman JC, Stern TA. Neuropsychiatric consequences of cardiovascular medications. Dialogues Clin Neurosci. 2007;9:29–45.
  • Lv HL, Jin DM, Liu M, et al. Long-term efficacy and safety of statin treatment beyond six years: a meta-analysis of randomized controlled trials with extended follow-up. Pharmacol Res. 2014;81:64–73.
  • Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–1356.
  • Green A, Ramey DR, Emneus M, et al. Incidence of cancer and mortality in patients from the simvastatin and ezetimibe in aortic stenosis (SEAS) trial. Am J Cardiol. 2014;114:1518–1522.
  • Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008;359:1357–1366.
  • Luo L, Yuan X, Huang W, et al. Safety of coadministration of ezetimibe and statins in patients with hypercholesterolaemia: a meta-analysis. Intern Med J. 2015;45:546–557.
  • Florentin M, Elisaf MS. Simvastatin interactions with other drugs. Expert Opin Drug Saf. 2012;11:439–444.
  • Watkins JL, Atkinson BJ, Pagliaro LC. Rhabdomyolysis in a prostate cancer patient taking ketoconazole and simvastatin: case report and review of the literature. Ann Pharmacother. 2011;45:e9.
  • Molden E, Skovlund E, Braathen P. Risk management of simvastatin or atorvastatin interactions with CYP3A4 inhibitors. Drug Saf. 2008;31:587–596.
  • Itakura H, Vaughn D, Haller DG, et al. Rhabdomyolysis from cytochrome p-450 interaction of ketoconazole and simvastatin in prostate cancer. J Urol. 2003;169:613.
  • McKelvie PA, Dennett X. Myopathy associated with HMG-CoA reductase inhibitors (statins): a series of 10 patients and review of the literature. J Clin Neuromuscul Dis. 2002;3:143–148.
  • Gilad R, Lampl Y. Rhabdomyolysis induced by simvastatin and ketoconazole treatment. Clin Neuropharmacol. 1999;22:295–297.
  • Roques S, Lytrivi M, Rusu D, et al. Rhabdomyolysis-induced acute renal failure due to itraconazole and simvastatin association. Drug Metabol Drug Interact. 2011;26:79–80.
  • Saliba WR, Elias M. Severe myopathy induced by the co-administration of simvastatin and itraconazole. Eur J Intern Med. 2005;16:305.
  • Krishna G, Ma L, Prasad P, et al. Effect of posaconazole on the pharmacokinetics of simvastatin and midazolam in healthy volunteers. Expert Opin Drug Metab Toxicol. 2012;8:1–10.
  • Page SR, Yee KC. Rhabdomyolysis in association with simvastatin and dosage increment in clarithromycin. Intern Med J. 2014;44:690–693.
  • Wagner J, Suessmair C, Pfister HW. Rhabdomyolysis caused by co-medication with simvastatin and clarithromycin. J Neurol. 2009;256:1182–1183.
  • Molden E, Andersson KS. Simvastatin-associated rhabdomyolysis after coadministration of macrolide antibiotics in two patients. Pharmacotherapy. 2007;27:603–607.
  • Fallah A, Deep M, Smallwood D, et al. Life-threatening rhabdomyolysis following the interaction of two commonly prescribed medications. Australas Med J. 2013;6:112–114.
  • Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 1998;64:177–182.
  • Chauvin B, Drouot S, Barrail-Tran A, et al. Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. Clin Pharmacokinet. 2013;52:815–831.
  • Karnik NS, Maldonado JR. Antidepressant and statin interactions: a review and case report of simvastatin and nefazodone-induced rhabdomyolysis and transaminitis. Psychosomatics. 2005;46:565–568.
  • Scarfia RV, Clementi A, Granata A. Rhabdomyolysis and acute kidney injury secondary to interaction between simvastatin and cyclosporine. Ren Fail. 2013;35:1056–1057.
  • Yang WH, Zeng ZS, Ren XW, et al. Simvastatin-induced myopathy with concomitant use of cyclosporine: case report. Int J Clin Pharmacol Ther. 2011;49:772–777.
  • Tong J, Laport G, Lowsky R. Rhabdomyolysis after concomitant use of cyclosporine and simvastatin in a patient transplanted for multiple myeloma. Bone Marrow Transplant. 2005;36:739–740.
  • Hsu WC, Chen WH, Chang MT, et al. Colchicine-induced acute myopathy in a patient with concomitant use of simvastatin. Clin Neuropharmacol. 2002;25:266–268.
  • Herring R, Caldwell G, Wade S. Rhabdomyolysis caused by an interaction of simvastatin and fusidic acid. BMJ Case Rep. 2009;2009:pii: bcr03.2009.1722. doi:10.1136/bcr.03.2009.1722.
  • Yuen SL, McGarity B. Rhabdomyolysis secondary to interaction of fusidic acid and simvastatin. Med J Aust. 2003;179:172.
  • Oh DH, Chan SQ, Wilson AM. Myopathy and possible intestinal dysfunction in a patient treated with colchicine and simvastatin. Med J Aust. 2012;197:332–333.
  • Justiniano M, Dold S, Espinoza LR. Rapid onset of muscle weakness (rhabdomyolysis) associated with the combined use of simvastatin and colchicine. J Clin Rheumatol. 2007;13:266–268.
  • Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol. 2004;58:56–60.
  • Kyrklund C, Backman JT, Kivisto KT, et al. Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 2000;68:592–597.
  • FDA drug safety communication. 2011 [cited 2015 Mar 30]. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm
  • Ezetrol® (ezetimibe) package insert. [cited 2015 Dec 27]. Available from: http://www.old.health.gov.il/units/pharmacy/trufot/alonim/1149.PDF
  • Robinson JG, Davidson MH. Combination therapy with ezetimibe and simvastatin to achieve aggressive LDL reduction. Expert Rev Cardiovasc Ther. 2006;4:461–476.

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