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Follow-Up to the August 2008 Early Communication About an Ongoing Safety Review of Ezetimibe/Simvastatin (marketed as Vytorin), Simvastatin (marketed as Zocor) and Ezetimibe (marketed as Zetia) - FDA Investigates a Report from the SEAS Trial

ROCKVILLE, Md., Dec. 22, 2009--In August 2008, the U.S. Food and Drug Administration (FDA) issued an Early Communication describing a possible association between the use of Vytorin – a combination of simvastatin ( Zocor) and ezetimibe ( Zetia) – and an increased risk of cancer and cancer-related death compared to placebo. The Early Communication was based on preliminary results from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial1.

FDA has now completed its review of the data from the SEAS trial as well as a review of interim data2 from two large-scale ongoing cardiovascular trials with Vytorin - the SHARP3 and IMPROVE-IT4 trials. Based on the currently available information, FDA believes it is unlikely that Vytorin or Zetia increase the risk of cancer or cancer-related death, but at this time an association cannot be definitively ruled out.

FDA is not advising healthcare professionals or consumers to stop using these medications, but to continue to evaluate the clinical benefits and potential risks of Vytorin or Zetia compared to other FDA-approved cholesterol lowering medications. Consumers should talk to their healthcare professional if they have any questions about Vytorin, Zetia, Zocor or the SEAS trial.

FDA weighed the following factors when evaluating the association between use of Vytorin or Zetia and cancer development:

  • Preclinical (animal) studies did not find that ezetimibe was associated with an increased incidence of cancer.
  • A large body of long-term clinical data indicates that simvastatin is not associated with an increased risk of cancer, but long-term clinical data on ezetimibe is insufficient to definitely rule out a cancer risk at this time.
  • Risk of cancer in the SEAS trial did not increase consistently over time with longer use of Vytorin, as would be expected if a drug caused cancer or promoted the growth of pre-existing cancers.
  • The reported increase in cancer and cancer-related deaths in the SEAS trial was the result of combining a wide variety of cancer types together. It is biologically less likely that a single drug increases the risk of a wide variety of cancer types.
  • When the cancer findings from the SEAS trial were compared with those from the SHARP and IMPROVE-IT trials, there was no consistent pattern of increased cancer risk among those being treated with Vytorin.
  • The SEAS trial was not designed to evaluate cancer risk and the analysis of the cancer findings was not pre-specified, but rather was performed after the fact and without statistical correction to account for multiple comparisons. Therefore, the true statistical significance of the cancer imbalance is unknown.

The SEAS trial consisted of 1,873 patients with aortic stenosis (narrowing of the aorta, the main blood vessel leaving the heart) who were given Vytorin (ezetimibe 10 mg plus simvastatin 40 mg, or 10/40 mg) or placebo and followed for 4 years to determine if lowering LDL-cholesterol with Vytorin would reduce the number of major cardiovascular adverse events. A lower overall cardiovascular risk was not found with Vytorin.

During the trial, investigators reported an increased number of cancers and cancer-related deaths in patients using Vytorin compared to placebo. Cancer was reported in 105 patients (11.1%) in the Vytorin group and in 70 patients (7.5%) in the placebo group. The number of deaths from cancer was also higher in the Vytorin group, with 39 deaths compared to 23 deaths in the placebo group.

The SHARP trial is placebo-controlled, but uses a lower dose of Vytorin (10/20 mg) than was used in the SEAS trial. The IMPROVE-IT trial compares Vytorin 10/40 mg to simvastatin 40 mg. An interim analysis of the cancer data from these two trials, which includes a total of 20,617 patients, did not show an increased risk of cancer with Vytorin. There was an increase in the number of cancer-related deaths, with 97 deaths in the Vytorin groups compared to 72 deaths in the control groups, but this finding was not statistically significant.

When completed, the SHARP and IMPROVE-IT trials will provide additional data to further assess cancer risk with simvastatin and ezetimibe. The SHARP trial is expected to be completed in 2010 and IMPROVE-IT in 2012.

FDA urges both healthcare professionals and consumers to report side effects from the use of Vytorin, Zocor, or Zetia to FDA's MedWatch Adverse Event Reporting program using the information at the bottom of the page.

References:

1. Rossebø AB, Pedersen TR, Boman K, Brudi P, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008 Sep 25;359(13):1343-56.

2. Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008 Sep 25;359(13):1357-66.

3. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int. 2003;63:Suppl 84:S207-S210.

4. Cannon CP, Giugliano RP, Blazing MA, et al. Rationale and design of IMPROVE IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndrome. Am Heart J. 2008 Nov;156(5):826-32.

Posted: December 2009


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