Physicians and their patients have a new weapon in the war against hypercholesterolemia. Last month, the FDA approved ezetimibe (Zetia, Merck/Schering-Plough) for the treatment of primary hypercholesterolemia. Ezetimibe is also indicated for the treatment of homozygous familial hypercholesterolemia and homozygous sitosterolemia. The drug can be administered either as monotherapy or in combination with a statin as an adjunctive therapy to diet.
Physicians and patients have a new weapon in the war against hypercholesterolemia. Last month, the Food & Drug Administration approved ezetimibe (Zetia, Merck/Schering-Plough) for the treatment of primary hypercholesterolemia. Ezetimibe is also indicated for the treatment of homozygous familial hypercholesterolemia and homozygous sitosterolemia. The drug can be administered either as monotherapy or in combination with a statin.
"Ezetimibe represents a new option to help physicians and their patients achieve the aggressive reduction in low-density lipoprotein (LDL) cholesterol levels recommended in recently published guidelines, such as those issued by the National Cholesterol Education Program Adult Treatment Panel III last year," said Christie Ballantyne, M.D., director, Center for Cardiovascular Disease Prevention, Methodist-DeBakey Heart Center, Baylor College of Medicine, Houston. Ezetimibe was slated to hit the shelves the second week in November.
This is the first in a new class of lipid-lowering agents to receive FDA approval since the statins were introduced 15 years ago. Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Instead, it appears to act at the brush border of the small intestine to inhibit the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.
The LDL-lowering effect of ezetimibe is additive to that of the statins, because their mechanisms of action are different, said Ballantyne. According to the manufacturer, the FDA based its approval of ezetimibe at least in part on the results of four coadministration studies in which combination therapy consisting of ezetimibe and a statin was initiated in previously untreated patients with hypercholesterolemia. The coadministration study of ezetimibe 10 mg and simvastatin (Zocor, Merck) 20 mg resulted in a 46% reduction in LDL cholesterola reduction similar to that seen with simvastatin 80-mg monotherapy, Ballantyne reported. Merck and Schering-Plough are currently testing a single drug that combines both ezetimibe and simvastatin, he continued. There are plans to file for approval of the combination drug in late 2003, with an anticipated approval in 2004.
The recommended dose of ezetimibe is one 10-mg tablet daily, taken without regard to food or time of day. Ballantyne recommends that his patients take their medication when it is most convenient. Dosing of ezetimibe should occur more than two hours before or more than four hours after administration of a bile acid sequestrant.
Ballantyne cautioned that ezetimibe is not recommended for use in those with moderate to severe hepatic insufficiency. In addition, ezetimibe should not be coadministered with a statin in persons with active liver disease or unexplained persistent elevations in serum transaminases.
The side-effect profile of ezetimibe is similar to that of a placebo, said Ballantyne. In clinical trials, the most frequently reported adverse events in patients treated with ezetimibe monotherapy were back pain and arthralgia, as listed in the package insert (PI). The most frequently reported adverse events in patients treated with the ezetimibe/statin combination were back pain and abdominal pain.
In persons given the ezetimibe/statin combination, the incidence of consecutive elevations in serum transaminases (more than three times the upper limit of normal) was slightly higher than in persons given statins alone, Ballantyne said. The PI states that these elevations in transaminases were generally asymptomatic and not associated with cholestasis, and that they returned to baseline values upon discontinuation of therapy or with continued treatment.
Ezetimibe, classified as a Pregnancy Category C, should be used in pregnant women only if the potential for therapeutic benefit outweighs any risk posed to the fetus, as stated in the PI. All statins are contraindicated for use during pregnancy and during breast-feeding, according to the PI, and if the ezetimibe/statin combination is administered to a woman of childbearing potential, the PI for the statin should be consulted.
Charlotte LoBuono. Lipid-lowering drug marks first new class in 15 years. Drug Topics 2002;22:19.