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March 2005 Issue

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FDA Warning Letters Fail to Improve Drug-Safety Monitoring

Published March 2005

Diabetes patients could be risking liver failure because they are not getting the liver function tests recommended with their medication.

UC College of Pharmacy researchers attribute the lack of testing to a failure of some people in "the system"--physicians, pharmacists and even the patients themselves--to heed U.S. Food and Drug Administration (FDA) warnings.

The problem came to light when Pamela Heaton, PhD, assistant professor of pharmacy practice, and Bob Cluxton, PharmD, associate professor of pharmacy practice and family medicine, studied 8,700 type 2 diabetes patients using the drug troglitazone (Rezulin), one of a class of pharmaceuticals called thiazolidinediones.

Their findings are published in the journal Pharmacoepidemiology and Drug Safety.

Because of the risk of liver failure with troglitazone, the FDA called for routine liver-function monitoring during therapy. Eventually, following the death of 90 people from liver failure, the FDA ordered troglitazone withdrawn.

Dr. Heaton and Dr. Cluxton's study showed that despite repeated FDA warnings, just 26 percent of patients were tested before they began taking the drug, and only 50 percent received at least one test while using it.

"These results," says Dr. Heaton, "are disconcerting in the face of such severe and repeated warnings for liver failure, a life-threatening, adverse drug event."

Although Rezulin is no longer available, the FDA has left in place the recommendation for liver enzyme testing for the two other widely used thiazolidinedione drugs--rosiglitazone (Avandia) and posiglitazone (Actos).

No deaths have been connected with either of these Rezulin-type drugs, but FDA recommendations calling for baseline liver testing, plus bimonthly testing while the drugs are being taken, apply to them, too.

Both Avandia and Actos were among the top 100 drugs dispensed in the United States in 2003. According to the Centers for Medicaid and Medicare Services, in 2004 Ohio Medicaid recipients used 45,409 prescriptions for Avandia, 60,662 for Actos.

Unfortunately, say Drs. Heaton and Cluxton, despite Rezulin's example of what could go wrong, in the case of Avandia liver-function testing hasn't improved. Their study showed that only 19.3 percent of Avandia patients received the baseline test. Actos was not included in the study because it was not FDA approved during the study period.

"Because there have been no reported cases of death due to liver failure during the several years Avandia has been on the market," says Dr. Heaton, "people are ignoring the FDA warnings."

"We don't know exactly why testing isn't being done," says Dr. Cluxton, "we just know that it isn't, and that reflects a problem with the system.

"It's probably a mixture of everything ... physicians not ordering the tests, patients not following up and pharmacists not providing information about appropriate use," he says.

For example, Dr. Cluxton points out, pharmacists should provide warnings about adverse effects of all drugs they dispense. They are supposed to remind patients to follow instructions to assure safe use of whatever drugs they are on--having liver function monitored regularly while using thiazolidinediones being one of them.

"We need changes in the system so the people involved know what needs to be done to ensure safe use of all drugs," says Dr. Cluxton.

"What is clear from our results is that the FDA's policy of sending out warning letters to doctors is not an effective method to improve monitoring for drug safety."

"We don't want to fix blame," says Dr. Cluxton, "we want to fix the problem.

"We need a safer medication management system, one that allows health-care providers and patients to know what safety measures are needed and if they are implemented or not."

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