New Drug Reviews
Ezetimibe/Simvastatin (Vytorin) for Hypercholesterolemia
Am Fam Physician. 2005 Nov 15;72(10):2081-2082.
Ezetimibe/simvastatin (Vytorin) is a combination of ezetimibe (Zetia), which inhibits the absorption of cholesterol by the small intestine, and simvastatin (Zocor), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, or statin. Ezetimibe/simvastatin, in conjunction with diet changes, is indicated for patients with hypercholesterolemia.1
|Name||Starting dosage||Dose form||Approximate monthly cost*|
10/20 mg daily
10/10-mg, 10/20-mg, 10/40-mg, and 10/80-mg tablets
*— Average wholesale cost, based on Red Book, Montvale, N.J.: Medical Economics Data, 2005.
Adverse reactions to ezetimibe/simvastatin include elevated transaminase levels, myopathy, and rhabdomyolysis; they are related to the dose of simvastatin and almost always are reversible.1 Myopathy and rhabdomyolysis are the most serious known adverse reactions to statins. In clinical trials of the combination, rhabdomyolysis did not occur1–6 and there was only one reported occurrence of myopathy,4 which resolved after discontinuation. The rate of myopathy was approximately one per 2,800 persons.2–6 Elevation of liver enzymes to more than three times the normal level occurred in 1.7 percent of patients receiving ezetimibe/simvastatin.1 The product labeling for simvastatin states that in clinical trials, elevated liver function occurred in 1 percent of patients.7
Simvastatin serum levels may be increased when simvastatin is given concomitantly with medications that affect the cytochrome P450 (CYP450) 3A4 enzyme system, increasing the risk of myopathy and rhabdomyolysis. To avoid this risk, physicians may consider temporarily discontinuing ezetimibe/simvastatin for the duration of therapy with macrolide antibiotics and azole antifungals. Ezetimibe does not interact with drugs metabolized by the CYP450 system. It is pregnancy category X and must not be given to women who may be pregnant.1
Ezetimibe/simvastatin generally is well tolerated. The addition of ezetimibe to simvastatin did not affect tolerability over 40 weeks’ administration; no study has assessed ezetimibe/simvastatin for a longer duration.5 Adverse effects of ezetimibe/ simvastatin are similar to those of statin monotherapy.1–5 Headache, upper respiratory infection, influenza, myalgia, and pain in extremities were the only adverse effects more common than with placebo, and these occurred in less than 4 percent of patients receiving ezetimibe/simvastatin.1
Two studies,3,5 with a total of 1,555 participants, demonstrated ezetimibe/simvastatin to be more effective in lowering low-density lipoprotein (LDL) cholesterol levels than simvastatin monotherapy, with a mean reduction of 51 to 53 percent compared with 37 to 39 percent with simvastatin alone. Another two studies,2,6 with a total of 2,690 participants, showed ezetimibe/simvastatin to be more effective than atorvastatin (Lipitor) in lowering LDL cholesterol, resulting in an average reduction of 52 to 53 percent compared with 45 percent in both studies with atorvastatin alone. No studies of ezetimibe alone or the combination of ezetimibe and simvastatin have examined cardiovascular morbidity or mortality or all-cause mortality.
The price of ezetimibe/simvastatin (approximately $80 per month for all doses) is generally lower than that of other statins. Generic lovastatin costs less ($30 to $60 per month). The ezetimibe/simvastatin combination is more cost-effective than taking ezetimibe and a statin separately.
The recommended starting dosage for ezetimibe/simvastatin is 10 mg ezetimibe and 20 mg simvastatin daily in the evening, taken with or without food. Patients who need a smaller reduction in LDL cholesterol levels can start with a dosage of 10/10 mg daily, and those requiring a larger reduction in LDL levels (greater than 55 percent) may start with a dosage of 10/40 mg daily. No dosage adjustments are necessary in older patients, those with mild hepatic insufficiency, or those with mild to moderate renal insufficiency.1
Low doses of ezetimibe/simvastatin provide greater improvements in lipid profile than simvastatin or atorvastatin monotherapy. Ezetimibe/simvastatin may be useful in patients who are unable to tolerate high-dose statin therapy. Combination ezetimibe-simvastatin is less expensive than adding ezetimibe to a statin and more convenient than taking two separate medicines. No trials have been performed to determine the effect of ezetimibe/simvastatin on stroke, myocardial infarction, or mortality rate.
1. Vytorin (ezetimibe/simvastatin). Package insert. North Wales, Pa. Merck/Schering-Plough Pharmaceuticals. March 2005. Accessed online August 22, 2005, at: http://www.vytorin.com/vytorin/shared/documents/vytorin_pi.pdf.
2. Ballantyne CM, Blazing MA, King TR, Brady WE, Palmisano J. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am J Cardiol. 2004;93:1487-94.
3. Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ LeBeaut AP, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002;40:2125–34.
4. Feldman T, Koren M, Insull W Jr, McKenney J, Schrott H, Lewin A, et al. Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. Am J Cardiol. 2004;93:1481-6.
5. Goldberg AC, Sapre A, Liu J, Capece R. Mitchel YB; Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2004;79:620-9.
6. Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. 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;149:464-73.
7. Zocor (simvastatin). Package insert. Whitehouse Station, N.J. Merck & Co, Inc. August 2005. Accessed online August 22, 2005, at: http://www.zocor.com/zocor/shared/documents/english/pi.pdf.
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The series coordinator is Allen F. Shaughnessy, Pharm.D., Tufts University Family Medicine Residency Program, Boston, Mass.
Copyright © 2005 by the American Academy of Family Physicians.
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