FDA Finally Yanks Permax Off the US Market

Evelyn Pringle April 4, 2007

On March 29, 2006, the FDA withdrew Permax (pergolide) from the market because it increases the risk of valvular heart disease. Permax belongs to a class of drugs known as dopamine agonists that help regulate balance and movement in Parkinson’s patients who suffer from a lack of dopamine.

When Permax was FDA approved in 1988, Eli Lilly marketed the drug, but in the US today, the drug is manufactured by Valeant Pharmaceuticals and generic versions are sold by Par and Teva. According to IMS Health, a prescription drug tracking firm, more than 72,000 prescriptions for the drug were written in 2006.

The decision by the FDA to take Permax off the market came after 2 recent studies were published in the New England Journal of Medicine in January 2007, that confirmed previous studies that linked Permax, and another drug prescribed to treat Parkinson’s disease, Dostinex, to heart valve disease.

Dostinex is marketed by Pfizer, and is approved to treat Parkinson’s patients in other countries. However, the drug has only been approved to treat the hormonal disorder, hyperprolactinemiam in the US, which means any prescriptions for Dostinex written for Parkinson’s patients in this country were off-label, because the drug has never passed the required FDA approval process to demonstrate that it is safe and effective in treating patient’s with Parkinson’s disease.

The NEJM studies did not assess patients who were taking Dostinex for the hormonal disorder, and according to Dr Shlomo Melmed, an endocrinologist and a senior vice president of Cedars-Sinai Medical Center in Los Angeles, in the January 4, 2007, New York Times, tens of thousands of people in the US, mostly women, have taken the drug for hyperprolactinemiam.

Experts say the valve damage is not likely to be profound in patients treated for the hormone disorder because lower doses of Dostinex are used compared to Parkinson’s patients, but Dr Melmed told the Times that men can develop the condition and may need higher doses, so those men should be monitored for heart valve damage.

In 2003, Eli Lilly first added the risk of heart valve damage to the Permax label but by then an estimated half million people had already taken the drug. Although the warning stated: “Some patients have required valve replacement, and deaths have been reported,” Lilly said at the time that only 5 out of 100,000 patients developed valve damage.

The company also sent out a Dear Dr letter to prescribing doctors to warn about the increased risk in 2003, but the FDA did not add a black box warning about valve damage to the label on Permax until 2006. A “precaution” was also added to the label of Dostinex in December 2006.

Heart valve damage is a life-threatening condition that can lead to heart failure and sudden death. It cannot be treated with medication and open heart surgery for valve replacement is the only option available for patients with valve disease.

The surgery itself is complex, costly, and life-threatening. According to the Texas Heart Institute, for valve replacement surgery, the breastbone must be divided, the heart stopped, and blood must filtered through a heart-lung machine.

Following surgery, the Institute says, patients must be maintained in the Intensive Care Unit for one to 3 days, and patients typically remain hospitalized for about a week.

There are 2 types of valves used for replacement. Mechanical valves, which are made with plastic or metal, and biological valves which are made with animal tissue or human tissue from a donated heart.

Experts say, mechanical valves last longer than biological valves but blood tends to stick to devices, causing blood clots to form and patients often need to take a blood-thinning drug for life. Because blood thinners are known to increase the risk of bleeding within the body, patients taking the drugs must wear a medical alert bracelet at all times so medical professionals will know they are on the medication.

Patients with biological valves are usually not required to take blood-thinners but these valves are not as sturdy as the mechanical valves and often need to be replaced every 10 years.

According to FDA officials, to date the agency is aware of at least 14 cases where patients have required replacement surgery, but Dr Robert Temple of the FDA’s office of drug evaluation, said at a briefing that 14 is likely to be an underestimate.

The FDA has consistently acknowledged on may occasions that only between 1% and 10% of all adverse events associated with prescription drugs are reported through the agency’s data tracking system which means the actual number of patients with valve damage is bound to be much higher.

The FDA was made aware of the link between Permax and valve disease more than 5 years ago, when doctors at the Mayo Clinic reported in 2002, that 3 patients who had no history of heart disease had developed valve damage after taking Permax for several years and 2 had required replacement surgery to correct the problem.

This discovery led the doctors to review surgery records to determine whether any of the other 17 patients who had undergone valve replacement in the previous year had been taking pergolide and found that one other patient who required surgery had been on drug.

In 2004, as a follow-up to previous reports of valve disease, researchers led by Dr Richard Dewey Jr, an associate professor from the University of Texas Southwestern Medical Center, sent 200 letters to Parkinson’s patients who were known to be on Permax to determine whether the earlier reports of valve damage were isolated cases.

For this study, echocardiograms were performed on 46 patients, and then compared to the results of a similar-aged healthy comparison group. The researchers determined that 89% of the Permax patients had evidence of leaky heart valves, and were up to 18 times more likely to have significant leakage in at least one valve than patients in the control group.

After the study was released, on April 28, 2004, HealthDay News reported that Dr Dewey recommended that Permax should be taken off the market back then.

In the two new studies in the New England Journal of Medicine, researchers note that the number of patients who developed heart valve damage is higher than previously expected.

One study conducted in Milan, Italy, titled, “Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation,” led by Dr Renzo Zanettini, obtained records of echocardiograms for 155 patients taking the Parkinson’s drugs, and compared them to the records of 90 healthy patients in another group.

After analyzing the records, the researchers found moderate to severe valve damage in more than 23% of the Permax patients and 29% of Dostinex patients compared to less than 6% of the patients in the comparison group.

The second study, conducted by Dr Rene Schade and colleagues in Berlin and Montreal, analyzed records from more than 11,400 patients in Great Britain, between the ages of 40 to 80 who were prescribed the drugs between 1988 and 2005, and determined that Permax patients were 7 times more likely to have leaky heart valves and Dostinex patients were 5 times more likely to have valve damage, when compared to patients in the control group.

This second study also showed that Permax patients on the highest doses of the drug had a 37 times greater risk of developing valve disease, and at higher doses, Dostinex patients were over 50 times more likely to develop damage.

Dr Bryan Roth, a professor at the University of North Carolina School of Medicine and director of the psychoactive drug screening program at the National Institute of Mental Health, wrote an analysis that accompanied the studies in the NEJM, and said the drugs cause the same valve damage as Wyeth’s fen-phen diet drugs that were pulled off the market in 1997.

According to Dr Roth, the drugs cause cells in the valves to multiply and thicken until the valves can no longer open and close properly. “The incidence is kind of mind-blowing,” he told the Wall Street Journal on January 4, 2007.

“It’s so prevalent in people taking these medications,” he said, “you kind of wonder why it was missed.”

Medical experts are not advising all patients who have taken these drugs to undergo testing to determine whether they have developed heart valve disease.

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