Pharmacology Update

Ezetimibe and Simvastatin Tablets (Vytorin)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA has approved the combination of ezetimibe and simvastatin for the treatment of hypercholesterolemia. This combination product provides different mechanisms of action for lowering cholesterol. Simvastatin is a widely used HMG-CoA reductase inhibitor and ezetimibe inhibits the absorption of cholesterol. The product is marketed by Merck/Schering-Plough as Vytorin.

Indications

Ezetimibe/simvastatin is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL-C, Apo B, triglycerides and non-HDL-C and to increase HDL-C in patients with primary hypercholesterolemia or mixed hyperlipidemia. It is also indicated for the reduction of elevated total and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid lowering treatments.1

Dosage

The usual recommended starting dose is 10 mg ezetimibe and 20 mg of simvastatin. The dose may range from 10 mg/10 mg to 10 mg/80 mg depending on the level of cholesterol reduction needed. No dosage adjustment is necessary in patients with mild or moderate renal dysfunction or mild hepatic dysfunction.1

Ezetimibe/simvastatin is supplied in 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, and 10 mg/80 mg tablets.

Potential Advantages

The combination product provides dual and complementary mechanisms for reducing cholesterol levels. Ezetimibe inhibits cholesterol absorption while simvastatin inhibits cholesterol synthesis. This combination is more effective than simvastatin alone.2 Statin-associated myopathy is dose related, and the combination achieves LDL reduction goals with a lower statin dose, thus reducing the risk of myopathy. The combination of ezetimibe/simvastatin produced greater LDL-C reduction and HDL-C increase than atorvastatin.3

Potential Disadvantages

The frequency of elevated ALT/AST (3 x upper limit of normal) appears to be higher with ezetimibe/simvastatin compared to simvastatin monotherapy.2,4 The experience of ezetimibe in non-Caucasians is limited.1 The long-term safety and effectiveness of ezetimibe has not been established.

Comments

The combination of ezetimibe and simvastatin provides dual complementary mechanisms for lowering cholesterol. The reduction in LDL-C change from untreated baseline ranged from -45% to -60% for the 10 mg/10 mg to 10 mg/80 mg.1 The addition of ezetimibe to statin monotherapy results in about an additional 25% reduction in LDL-C.4 In clinical studies, patients who received ezetimibe/simvastatin overall achieved significantly lower decrease in LDL-C, total cholesterol, ApoB, triglyceride, and non HDL-C. The combination also resulted in incremental decrease in high-sensitivity C-reactive protein.5 Ezetimibe does not appear to add to the increase in HDL-C.1 At maximum dose ezetimibe/simvastatin (10 mg/80 mg) reduced LDL-C by 59.4% compared to 52.5% for atorvastatin 80 mg (P < 0.001). HDL-C was increased by 12.3% compared to 6.5% respectively (P < 0.001).3 The combination is well tolerated and does not appear to result in increase risk of myopathy/rhabdomyolysis. However the combination may lead to a higher incidence of elevation of ALT/AST at 3 x upper limit of normal. The wholesale cost for ezetimibe/simvastatin is $2.34 per day for all strengths. The cost for atorvastatin (20 mg to 80 mg ) is $3 per day.

Clinical Implications

The combination of ezetimibe and simvastatin provides another option for lowering of LDL-C and non HDL-C. This is particularly valuable for patients who cannot tolerate high dose statin therapy. Given the finding from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) and the new LDL goals for patients at high risk for cardiovascular events, combination with complementary mechanisms may be useful in selected patients.

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.

References

1. Vytorin Product Information. Merck/Schering Plough Pharmaceuticals. July 2004.

2. Goldberg, AC et al. Mayo Clin Proc. 2004;79:620-629.

3. Ballantyne CM et al. Am J Cardiol. 2004;93(12):1487-1494.

4. Gagne C et al. Am J Cardiol. 2002;90:1084-1091.

5. Sager PT et al. Am J Cardiol. 2003;92(12):1414-1418.