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FDA Drug Safety Communication: Review update of Trilipix (fenofibric acid) and the ACCORD Lipid trial

Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary

Safety Announcement

[11-9-2011] The U.S. Food and Drug Administration (FDA) is informing the public that the cholesterol-lowering medicine Trilipix (fenofibric acid) may not lower a patient's risk of having a heart attack or stroke. This is based on data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial, which evaluated the efficacy and safety of fenofibrate plus simvastatin combination therapy versus simvastatin alone in patients with type 2 diabetes mellitus (see Data Summary below). FDA reviewed this trial as part of its ongoing investigation of the safety and efficacy of Trilipix. 

Facts about Trilipix (fenofibric acid)

  • A prescription medicine used to treat cholesterol in the blood by lowering low-density lipoprotein (LDL) cholesterol ("bad cholesterol"), and increasing the high-density lipoprotein (HDL) cholesterol ("good cholesterol").
  • Can be used to lower very high levels of fat (triglycerides) in the blood to help reduce the risk for pancreatitis.
  • Can be used in combination with other cholesterol-lowering medicines called statins in patients at high risk for cardiovascular disease.

Information from the trial has been added to the Important Limitations of Use and Warnings and Precautions sections of the Trilipix physician label and to the patient Medication Guide. 

Healthcare professionals should consider the benefits and risks of Trilipix when deciding to prescribe the drug to patients. Patients should contact their healthcare professional if they have any questions or concerns about Trilipix. 

In the ACCORD Lipid trial, there was no significant difference in the risk of experiencing a major adverse cardiac event between the group treated with fenofibrate plus simvastatin compared with simvastatin alone. In addition, a subgroup analysis showed that relative to treatment in men, there was an increase in the risk for major adverse cardiac events in women receiving the combination therapy versus simvastatin alone. The clinical significance of this subgroup finding is unclear, as this finding was not observed in a separate large randomized controlled clinical trial of fenofibrate versus placebo. 

Based on results from the ACCORD Lipid trial and other clinical trials of drugs similar to Trilipix, FDA is requiring the manufacturer of Trilipix to conduct a clinical trial to evaluate the cardiovascular effects of Trilipix in patients at high risk for cardiovascular disease who are already taking statins. 

FDA had previously communicated to the public about the ACCORD Lipid trial in a Statement to Healthcare Professionals on March 15, 2010. The results of this trial were later discussed at the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting, held on May 19, 2011.

Additional Information for Patients 

  • Trilipix has not been shown to lower patients' risk of having a heart attack or a stroke.
  • Patients should not stop taking their Trilipix medicine without first consulting with their healthcare professional.
  • Patients should discuss the benefits and risks of taking Trilipix with their healthcare professional.
  • Patients should read the Medication Guide that they get along with their Trilipix prescription.
  • Patients should talk to their healthcare professional if they have any questions or concerns about Trilipix.
  • Patients should report serious side effects from the use of Trilipix to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of this page.

Additional Information for Healthcare Professionals 

  • Fenofibrate at a dose equivalent to 135 mg of Trilipix was not shown to reduce coronary heart disease morbidity and mortality in patients in two large randomized controlled trials of patients with type 2 diabetes mellitus.
  • Healthcare professionals should consider the benefits and risks of Trilipix when deciding to prescribe the drug to patients, and counsel patients about those benefits and risks.
  • Healthcare professionals should encourage patients to read the Medication Guide they receive along with their Trilipix prescription.
  • Healthcare professionals should report adverse events involving Trilipix to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of this page.

Data Summary

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial was a randomized, double-blind, placebo-controlled add-on trial which evaluated the efficacy and safety of adding fenofibrate therapy to treatment with simvastatin in patients with type 2 diabetes mellitus. Patients were randomized to receive simvastatin plus fenofibrate (n=2765) or simvastatin plus placebo (n=2753). All patients received open-label simvastatin therapy for four weeks prior to initiation of blinded therapy with fenofibrate or placebo. The primary outcome was major adverse cardiovascular events (MACE), a composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular disease death.

The mean duration of follow-up was 4.7 years. The results showed that fenofibrate plus simvastatin combination therapy was associated with a non-significant 8% relative risk reduction in the primary outcome of MACE (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.79-1.08; p=0.32) as compared to simvastatin plus placebo. In a prespecified subgroup analysis of the primary efficacy outcome, the HR for MACE in men receiving combination therapy versus simvastatin monotherapy was 0.82 (95% CI 0.69-0.99), and the HR for MACE in women receiving combination therapy versus simvastatin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear, as this finding was not observed in a separate large randomized controlled clinical trial of fenofibrate versus placebo.

However, the study results also raised the hypothesis that a subgroup of patients with high triglycerides and low high-density lipoprotein (HDL) cholesterol may experience some reduction in the risk of MACE from the combination therapy versus simvastatin monotherapy. 

The results of the ACCORD Lipid trial were discussed at the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting, held on May 19, 2011 (for complete reviews and background information discussed at this meeting see: May 19, 2011 AC meeting). 

Based on the results from the ACCORD Lipid trial and other clinical trials of drugs similar to Trilipix, FDA is requiring the manufacturer of Trilipix to conduct a randomized, double-blind, placebo-controlled clinical trial to test the hypothesis that Trilipix in combination with a statin versus statin alone significantly reduces the incidence of major adverse cardiovascular events in high-risk men and women who are at their low-density lipoprotein (LDL) cholesterol goal on statin therapy, but have residually high triglycerides and low HDL cholesterol.

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