FDA Issues Early Communication about an Ongoing Review of Merck/Schering Plough’s Vytorin

The U.S. Food and Drug Administration today issued an Early Communication regarding the agency’s ongoing review of Vytorin based on preliminary results from a recently completed study—the Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE)—on this cholesterol lowering drug. Vytorin contains both Zetia (ezetimibe) and Zocor (simvastatin) in one tablet.

The FDA is informing the public that the agency will conduct a review of Merck and Schering Plough’s recent trial once the FDA receives the final study results.

Merck/Schering Plough Pharmaceuticals issued a press release reporting preliminary results of the study and stated that the study demonstrated no significant differences between the combination product and Zocor on the build up of cholesterol plaque in the carotid (neck) arteries. The study was not designed to detect any difference in risk of having a heart attack or stroke between the two treatments. An ongoing trial called "Improved Reduction of Outcomes: Vytorin Efficacy International Trial" (IMPROVE IT) is underway which is designed to evaluate the effect of Vytorin versus Zocor on heart disease and stroke.

Text of FDA’s Early Communication About Vytorin:

Early Communication about an Ongoing Data Review for Ezetimibe/Simvastatin (marketed as Vytorin), Ezetimibe (marketed as Zetia), and Simvastatin (marketed as Zocor)

This communication is based on information that FDA has not yet fully evaluated. FDA is not advising health care professionals to discontinue prescribing these products. FDA is considering, but has not reached a conclusion about whether this information warrants any regulatory action. FDA intends to update this document when additional information or analyses become available.

On January 14, 2008, Merck/Schering Plough Pharmaceuticals issued a Press Release reporting preliminary results from the Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial. This trial was designed to evaluate the amount of atherosclerotic plaque in blood vessels located in the neck based on images obtained through ultrasound in patients treated with Vytorin (ezetimibe plus simvastatin) or simvastatin alone. Merck/Schering Plough Pharmaceuticals, the company that conducted the trial, stated that there was no significant difference between Vytorin and simvastatin in the amount of atherosclerotic plaque in the inner walls of the carotid (neck) arteries despite greater lowering of LDL-cholesterol (bad cholesterol) with Vytorin compared to simvastatin. FDA has not received a final study report and at this time it is not clear why the lower levels of LDL cholesterol in the patients who took Vytorin did not lead to lesser amounts of plaque compared to patients treated with simvastatin alone.

ENHANCE was a 2-year, multi-national, randomized, double-blind study conducted in 720 patients with heterozygous familial hypercholesterolemia (HeFH), a condition that is associated with very high cholesterol levels and affects approximately 0.2 percent of the population. Half of the patients were treated with 10 mg of ezetimibe combined with 80 mg of simvastatin and half with 80 mg of simvastatin alone.

An elevated LDL-cholesterol level is an established risk factor for heart disease and many studies have supported the conclusion that lowering cholesterol levels reduces the risk for heart attack and stroke. Ezetimibe inhibits the absorption of cholesterol in the intestine and is approved to lower LDL-cholesterol levels. Simvastatin (Zocor) is a lipid-lowering agent (“statin”) approved to reduce LDL and increase high-density lipoprotein (HDL) (good) cholesterol levels and reduce the risk of cardiovascular events such as heart attack and stroke. Vytorin is approved for reducing LDL and increasing HDL cholesterol levels.

There are no clinical studies available that demonstrate a reduction in risk of heart attack or stroke when ezetimibe is used alone or in combination with a statin, including the fixed-dosed combination drug of ezetimibe and simvastatin, Vytorin. While the overall incidence of cardiovascular events in ENHANCE was similar in both the ezetimibe/simvastatin and simvastatin-alone groups, there were not enough patients in this study to reliably test whether treatment with ezetimibe/simvastatin compared with simvastatin alone reduces the risk of cardiovascular events. An ongoing trial known as IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) is examining this question in 12,500 patients and will likely be completed in 2011. Physicians and patients should carefully consider the available data and current labeling for Zetia and Vytorin as they make individual treatment decisions.

This early communication is in keeping with FDA’s commitment to inform the public about ongoing postmarketing drug issues. Once Merck/Schering Plough Pharmaceuticals completes the analysis of the unblinded data from ENHANCE, it will submit a final study report to FDA. Once FDA receives the final study report, FDA estimates it will take approximately 6 months to fully evaluate the data. After reviewing the data from the ENHANCE study, and considering all other available information about the link between LDL lowering and reduction of cardiovascular events, FDA will determine whether any further regulatory action is warranted with regard to Zetia and Vytorin and also whether any changes to FDA’s current approach to drugs that lower LDL cholesterol are warranted.

Patients should talk to their doctors if they have any questions about the information from the ENHANCE trial.

The FDA urges both healthcare professionals and patients to report side effects from the use of ezetimibe to the FDA’s MedWatch Adverse Event Reporting program

Source: FDA, January 25, 2008

Test for Respiratory Viruses Cleared by FDA

The U.S. Food and Drug Administration today cleared for marketing a test that simultaneously detects and identifies 12 specific respiratory viruses.

The test, called the xTAG Respiratory Viral Panel, is the first test for the detection and differentiation of influenza A subtypes H1 and H3. Influenza A is the most severe form of influenza for humans, and has been the cause of major epidemics. The new panel is also the first test for human metapneumovirus (hMPV), newly identified in 2001.

The xTAG Respiratory Viral Panel amplifies viral genetic material found in secretions taken from the back of the throat in patients with possible respiratory tract infections. In the test, specific beads, or microspheres, bind to the amplified viral genetic material. The beads are then sorted so that the specific virus can be identified.

The xTAG panel is the first FDA-cleared test for infectious respiratory disease viruses that uses a multiplex platform, allowing several tests to be processed using the same sample.

"Nucleic acid tests such as the xTAG Respiratory Viral Panel utilize small amounts of genetic material, and then replicate it many times," said Daniel G. Schultz, M.D., director of FDA’s Center for Devices and Radiological Health.

"This speeds up the usual process of detecting and identifying respiratory viruses, which can take up to a week," said Schultz. "And, because this multiplex viral panel tests for 12 viruses at once, it uses less of a patient’s test specimen."

Other viruses identified by the xTAG Respiratory Viral Panel:

  • influenza B – one of three types of human influenza, less severe than influenza A
  • respiratory syncytial virus subtype A and B – both are leading causes of infant pneumonia and bronchiolitis (an infection of the airways leading to the lungs) and often contribute to the development of long-term pulmonary disease
  • parainfluenza 1, 2 and 3 – all are leading factors in the croup and the common cold
  • rhinovirus – the most common viral infective agent in humans and a cause of the common cold
  • adenovirus – a cause of respiratory tract infections often similar to strep throat or tonsilitis

While the test is faster than conventional tests, it is specific to the dozen viruses listed and should be used with other diagnostics such as patient data, bacterial or viral cultures and X-rays. Positive results do not rule out other infection or co-infection and the virus detected may not be the specific cause of the disease or patient symptoms.

The xTAG Respiratory Viral Panel is manufactured by Toronto-based Luminex Molecular Diagnostics.

Source: FDA, January 3, 2008

FDA Panels to Evaluate Avandia Heart Risks

Two Food and Drug Administration advisory panels will meet to discuss the results of a study done by Cleveland Clinic cardiovascular medicine chairman and a leading author, Steven Nissen, claiming that the popular diabetes drug "Avandia" may increase the risk of heart attack in patients.

Nissen’s study is based on 42 clinical trials. Results showed that people on Avandia were at 43% higher risk of having a heart attack.

Glaxo, the drug maker, reported a fall of 23% in Avandia sales after the study was published.
The advisory panel may recommend anything from no action to a black box label. However, Glaxo spokeswoman Mary Anne Rhyne maintains that these drugs are safe and the decline in sales is only in new prescriptions.

FDA Warning on Sleep Medications: Ambien, Lunesta, Restoril, Others

The FDA has issued stronger warnings on sleep medications, such as Ambien, Lunesta, and Restoril, and has asked the drugs manufacturers to place stronger warnings on the package labels.

The agency cites concerns such as allergic reactions, and sleep walking and "sleep driving" in its statement.

Source: Food and Drug Administration (FDA)
P07-45