Vytorins label gets makeover to include SHARP results

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The FDA has approved an updated label for Merck’s Vytorin (ezetimibe/simvastatin) that includes results from the SHARP trial.

In the SHARP (Study of Heart And Renal Protection) trial, Vytorin 10/20 mg lowered LDL-cholesterol in patients with moderate to severe chronic kidney disease (CKD), and major vascular events were reduced in the treatment group compared to placebo. Because SHARP studied the combination of simvastatin and ezetimibe compared with placebo, it was not designed to assess the independent contributions of each drug to the observed effect; for this reason, the FDA did not approve a new indication for Vytorin or for Zetia (ezetimibe) and the study's efficacy results have not been incorporated into the label for Zetia.

Vytorin currently is indicated as an adjunct therapy to diet for the reduction of total cholesterol, LDL-cholesterol, apolipoprotein B, triglycerides and non-HDL cholesterol and to increase HDL-cholesterol in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia when diet alone is not enough. No incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

Vytorin should not be taken with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors and nefazodone); with gemfibrozil, cyclosporine or danazol; by anyone with active liver disease, unexplained persistent elevations of hepatic transaminase levels or hypersensitivity to the product; or by women who are pregnant, nursing or may become pregnant.

SHARP was a randomized, controlled trial involving LDL-cholesterol lowering therapy to demonstrate a reduction in cardiovascular outcomes in patients with CKD. The trial was designed and conducted by the Clinical Trial Service Unit (CTSU) of Oxford University (the trial's regulatory sponsor), which presented the analyses for the FDA.

SHARP, published June 2011 in The Lancet, enrolled a total of 9,438 patients with CKD. Approximately one-third of the patients were undergoing dialysis therapy for end-stage renal disease at the time of entry, and the remaining patients were predialysis patients with advanced CKD with a median estimated glomerular filtration rate (GFR, a measure of kidney function) of 25.6 ml/min/1.73m2. Patients with a prior history of MI or a coronary revascularization procedure were excluded from the study.

Based on these results, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously voted Nov. 2, 2011, to recommend Vytorin for use in patients with pre-dialysis chronic kidney disease.

In patients with CKD and GFR <60 mL/min/1.73 m2, the dose of Vytorin is 10/20 mg/day in the evening, according to Merck. In such patients, higher doses should be used with caution and close monitoring. For other patients, including those with mild renal impairment, the usual dosage range remains 10/10 mg/day to 10/40 mg/day and the recommended usual starting dose is 10/10 mg/day or 10/20 mg/day.

In the absence of moderate to severe renal impairment, patients who require a larger reduction in LDL cholesterol (greater than 55 percent) may be started at 10/40 mg/day. No dosage adjustment is necessary in patients with mild renal impairment (GFR ?60 mL/min/1.73 m2), Merck said.