A fixed-dose combination of 10 mg of ezetimibe with four different doses of atorvastatin has been approved by the Food and Drug Administration, the manufacturer, Merck, announced on May 3.
Ezetimibe, a selective inhibitor of the absorption of intestinal cholesterol and related phytosterols, was approved in 2002 and is marketed by Merck as Zetia. Atorvastatin, an HMG-CoA reductase inhibitor approved in 2006, is marketed as Lipitor by Pfizer and is available in generic formulations.
The combination product will be marketed under the trade name Liptruzet, for the treatment of elevated low-density lipoprotein (LDL) cholesterol in patients with primary or mixed hyperlipidemia as adjunctive therapy to diet, when diet alone is not enough, according to the company statement announcing the approval.
The Limitations of Use section of the prescribing information includes the statement that "no incremental benefit of Liptruzet on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established." This section also states that Liptruzet has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.
The approval comes after two Complete Response Letters from the Food and Drug Administration, requesting more data from the company.
Liptruzet is available in tablets that contain 10 mg of ezetimibe with 10, 20, 40, or 80 mg of atorvastatin (as Liptruzet 10/10, 10/20, 10/40, or 10/80, according to the release). The dosage range is from 10/10 mg a day to 10/80 mg a day.
The company’s release and the prescribing information summarize the results of different trials, including a 12-week study comparing different Liptruzet doses (administered as ezetimibe and atorvastatin) to atorvastatin, in 628 patients with hyperlipidemia. The pooled results of the different doses indicated significant reductions in total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and non-HDL cholesterol, as well as significant increases in HDL cholesterol, compared with the results for all atorvastatin doses (10-80 mg), according to the labeling. The findings after another 48 weeks in those who continued treatment were consistent with the 12-week results.
Dr. Harlan M. Krumholz
The Merck press release also includes the statement that "the clinical impact of comparative differences in lipid changes between Liptruzet (ezetimibe and atorvastatin) and atorvastatin is not known."
Since the results of the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) study were released in 2008, the value of adding ezetimibe has been questioned. In that controversial study, the combination of simvastatin and ezetimibe (Vytorin) was more potent than simvastatin alone in reducing LDL cholesterol, but the combination showed no advantage over the statin alone in reducing the progression of carotid atherosclerosis over 2 years.
"We are increasingly recognizing that drugs that reduce LDL may not always reduce patient risk, and the effect of ezetimibe alone or in combination with other drugs on patient outcomes remains unknown," Dr. Harlan Krumholz, the Harold H. Hines Jr. professor of Medicine (Cardiology) at Yale University, New Haven, Conn., said in an interview. "As a result, the use of ezetimibe should be reserved for circumstances where the patient cannot tolerate statins, and only in cases where patients are fully informed that the effects of the drug on patient outcomes are not yet known," he added.
The Merck statement said that the product will be available to wholesalers during the week of May 6. The catalog price for one tablet, at all doses, is $5.50, according to a Merck spokesperson. Merck also markets a fixed-dose product combining ezetimibe with simvastatin as Vytorin.
The prescribing information is available here.
Dr. Krumholz had no disclosures.