The Food and Drug Administration approved a revised label for Vytorin that now includes data from a study showing a benefit of treatment in patients with moderate to severe kidney disease, but the agency did not approve a new indication that reflects these findings for Vytorin or for ezetemibe, one of the components of the combination product, according to Merck.
In a Jan. 25 press release, Merck, the manufacturer of ezetimibe (Zetia) and Vytorin – a combination of ezetimibe and simvastatin – said that the FDA had approved the new labeling that now includes data from the Study of Heart and Renal Protection (SHARP). Themultinational, randomized, double-blind placebo controlled study of almost 9,500 patients with moderate to severe chronic kidney disease who did not have a history of myocardial infarction or coronary revascularization found that the lipid-lowering treatment reduced the risk of major vascular events, compared with placebo.
However, the FDA did not approve a new indication to reflect these results, because SHARP compared the combination of the two drugs with placebo and "was not designed to assess the independent contributions of each drug to the observed effect," the Merck release said, adding: "For this reason, the FDA did not approve a new indication for Vytorin or for Zetia," and the SHARP results have not been added to the ezetimibe label.
This was despite the unanimous recommendation of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee in November to approve Vytorin for reducing major cardiovascular events in patients with CKD who are not on dialysis. The panel also voted 10-6 that the data did not support approval of the combination for the same indication in patients with end-stage renal disease who are on dialysis.
Merck had filed for approval of the claim that 10 mg of ezetimibe plus 20 mg of simvastatin (in the fixed-dose combination pill or taken separately) reduces the risk of major cardiovascular events in patients with chronic kidney disease on the basis of the SHARP results.
About two-thirds of the patients enrolled in SHARP were not on dialysis at baseline, and in these patients, there was a 23% reduction in the primary end point – the risk of a major vascular event (nonfatal MI or cardiac death, stroke, or a revascularization procedure that excluded dialysis access–related procedures) – compared with those on placebo over a mean of 5 years (Lancet 2011;377:2181-92).
Among the patients who were on dialysis at baseline, the risk reduction was less (about 6% over placebo).
The two drugs remain approved for lipid-lowering indications only: Ezetimibe, a selective inhibitor of the absorption of intestinal cholesterol and related phytosterol, was approved in 2002; Vytorin, a combination of ezetimibe and the HMG-CoA reductase inhibitor simvastatin was approved in 2004; simvastatin was approved in 1991.
In an interview, Dr. William Hiatt, one of the members of the FDA panel that reviewed the SHARP data, said that "by allowing Merck to add the information from the SHARP trial to the product label, physicians will be able to use that information to help guide their decisions to use this medication for their CKD patients." Dr. Hiatt is professor of medicine, division of cardiology, University of Colorado, Denver. Members of FDA advisory panels are cleared of potential conflicts related to the topic of the meeting.
The agency usually follows FDA panel recommendations, which are not binding. At press time, no statement was available from the FDA to explain the decision.
SHARP was funded by Merck and Schering-Plough, but was independently conducted by the Oxford (England) University Clinical Trials Service Unit.