Pharmaceutical-Approval UpdateEzetimibe/Simvastatin (Vytorin tablet) Manufacturer: Merck & Co./Schering-Plough Corp.

Indication: To treat elevated levels of low-density lipoprotein-cholesterol (LDL-C) (the “bad” cholesterol) in patients with primary hypercholesterolemia or mixed hyperlipidemia as adjunctive therapy to diet when diet alone is not enough to reduce LDL-C levels.

Drug Classes: Ezetimibe (Zetia medication, Merck) selectively inhibits the absorption of cholesterol and related plant sterols through the small intestine. Simvastatin (Zocor canadian, Schering-Plough) is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor that inhibits cholesterol production in the liver.

Uniqueness of Drug: Vytorin™ is the first product that treats the two sources of cholesterol: it inhibits the production of cholesterol in the liver and blocks the absorption of cholesterol, including cholesterol from food. In head-to-head trials, generic ezetimibe/simvastatin provided greater reductions in LDL-C than generic atorvastatin (Lipitor drug, Pfizer) and simvastatin in all doses.

Warnings for Simvastatin

Myopathy and Rhabdomyolysis. Like other inhibitors of HMG-CoA reductase, simvastatin occasionally causes myopathy, which is manifested as muscle pain, tenderness, or weakness with creatine kinase (CK) above 10 times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis, with or without acute renal failure, secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high concentrations of HMG-CoA reductase inhibitory activity in plasma.

The risk of myopathy or rhabdomyolysis is increased by the concomitant use of simvastatin (particularly in higher doses) with potent inhibitors of cytochrome P450 (CYP3A4): cyclo-sporine, itraconazole, ketoconazole, erythromycin, cla-rithromycin, human immunodeficiency virus (HIV) protease inhibitors, nefazodone, and large quantities of grapefruit juice (more than one quart daily).

Precautions for Ezetimibe: The concurrent administration of ezetimibe with a specific HMG-CoA reductase inhibitor should be in accordance with its product labeling.

Liver Enzymes. In controlled clinical monotherapy studies, the incidence of consecutive elevations (more than three times the ULN) in serum transaminases was similar between ezetimibe (0.5%) and placebo (0.3%).

In controlled clinical combination studies of ezetimibe canadian that were initiated concurrently with an HMG-CoA reductase inhibitor, the incidence of consecutive elevations (more than three times the ULN) in serum transaminases was 1.3% for patients receiving ezetimibe administered with HMG-CoA reductase inhibitors and 0.4% for patients given HMG-CoA reductase inhibitors alone.

These elevations in transaminases were generally asymptomatic with ezetimibe and were not associated with cholesta-sis. Values returned to baseline after the patients discontinued therapy or continued treatment.

When ezetimibe is coadministered with an HMG-CoA reductase inhibitor, liver function tests should be performed when therapy is begun and according to the protocols for the HMG-CoA reductase inhibitor.

Skeletal Muscle. In clinical trials, no excess of myopathy or rhabdomyolysis was associated with ezetimibe, compared with the relevant control arm (patients taking placebo or an HMG-CoA reductase inhibitor alone). However, myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors and other lipid-lowering drugs.

In clinical trials, the incidence of creatine phosphokinase (CPK), when more than 10 times the ULN, was 0.2% for ezetimibe and 0.1% for placebo. When ezetimibe was administered with an HMG-CoA reductase inhibitor, the incidence of CPK was 0.1%. When HMG-CoA reductase inhibitors were given alone, the incidence of CPK was 0.4%.

Hepatic Insufficiency. Because of the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, the drug is not recommended in these cases.

Precautions for Ezetimibe/Simvastatin

Skeletal Muscle. Patients who experience muscle pain, tenderness, or weakness after taking Vytorin™ should inform their doctors promptly because these may be signs of a serious side effect. Therapy should be discontinued if myopathy is diagnosed or suspected. To help prevent serious side effects, doctors should advise patients about medications or foods to be avoided during therapy with this product.

Serum Transaminases. In three placebo-controlled, 12-week trials, the incidence of consecutive serum transaminase elevations (more than three times the ULN) was 1.7% overall for patients taking the drug and 2.6% for patients taking ezetimibe/simvastatin 10 mg/80 mg.

In controlled long-term (48-week) extensions that included both newly treated and previously treated patients, the incidence of consecutive elevations (more than three times the ULN) in serum transaminases was 1.8% overall and 3.6% for patients taking 10/80 mg. These elevations were generally asymptomatic and were not associated with cholestasis. Values returned to baseline after patients discontinued therapy or continued treatment.

Liver Enzymes. Doctors should perform blood tests before and periodically during treatment, when clinically indicated, to check for liver problems. Patients taking the 10/80-mg dose should receive an additional liver function test before and three months after titration and periodically during the first year.

Because of the unknown effects of increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, Vytorin™ is not recommended in these patients.

Drug-Drug Interactions. The safety and effectiveness of this drug, when taken with fibrates, have not been established; therefore, coadministration with fibrates is not recommended.

Caution should be exercised for patients being treated with cyclosporine generic when they begin ezetimibe/simvastatin therapy and for patients with severe renal insufficiency.

Dosage and Administration: Patients should follow a standard cholesterol-lowering diet before taking Vytorinrin™ and should continue this diet during treatment. The dosage should be individualized according to baseline LDL-C levels, the recommended goals of therapy, and patients’ responses.

Ezetimibe/simvastatin should be taken as a single daily dose in the evening, with or without food. The dosage ranges from 10/10 to 10/80 mg/day. The recommended usual starting dose is 10/20 mg/day.

For patients who require less aggressive reductions of LDL-C, therapy may be initiated with 10/10 mg/day. Patients who require a larger reduction in LDL-C levels (greater than 55%) may begin therapy at 10/40 mg/day. After initiation or titration of Vytorin, lipid levels may be analyzed after two or more weeks and the dosage may be adjusted if needed.

P&T Committee Considerations: Vytorin™ is the first of its kind to combine a popular statin (simvastatin generic) with a nonstatin drug (ezetimibe) in a single formulation. Physicians are enthusiastic about the new medication because of studies showing that it can lower LDL-C more effectively than a statin alone. However, some physicians urge caution because it has not been proven that the drug actually prevents more cardioascular events or deaths than do currently available drugs.

In one study of 788 adults, Vytorin™ reduced LDL-C concentrations by an average of 59%, whereas atorvastatin canadian reduced it by an average of 53%. Lowering cholesterol as much as possible with statins is believed to prevent repeated heart attacks and death in patients with heart disease.

P&T committees should consider recommending the inclusion of ezetimibe/simvastatin in the formulary because of its potent ability to lower LDL cholesterol. If the drug cost is too high, perhaps administering individual doses of simvastatin and ezetimibe might be more practical.

Category: Drugs / Tags: Botox, Levofloxacin Tablets, Simvastatin

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