Pergolide (Permax) Withdrawn Over Heart Valvulopathies

ROCKVILLE, Md., March 29 -- The FDA today withdrew the Parkinson's disease drug pergolide -- a dopamine agonist sold as Permax and as a generic -- because of an increased risk of valvular heart disease.

Robert Temple, M.D., associate director for medical policy at the Center for Drug Evaluation and Research, said pergolide associated with fivefold relative increase in regurgitation of the mitral, atrial, or tricuspid valves compared with the general population.

Dr. Temple said the drug, which was approved in 1988, is used by a minority of Parkinson's patients, an estimated 12,000 to 25,000 patients. Permax is manufactured by Valeant Pharmaceuticals and generic versions of the drug are made by Par and Teva.

The FDA has known about the link between pergolide and valve disease since 2002 and in 2003 a warning about valvulopathy was added to the drug's label and a "Dear Healthcare Provider" letter was sent to clinicians by Lilly, which then marketed Permax. In 2006, the warning was upgraded to a black box because of new data concerning risks of heart valve damage.

Dr. Temple said the FDA decided to ask makers of the drug to take it off the market following publication of two new studies, published in the New England Journal of Medicine in January, that confirmed the link between pergolide and valve disease. Those studies also reported that "this risk did not extend to other drugs in this class," said Dr. Temple.

"I would say there was general agreement that the time for this drug has run out," Dr. Temple said.

The FDA said clinicians who have patients taking pergolide should:

• Assess the patient's need for dopamine agonist therapy. If continued treatment with a dopamine agonist is necessary, another dopamine agonist should be substituted for pergolide. There are other dopamine agonists approved for the treatment of Parkinson's disease that are not associated with heart valve damage. Published transition regimens describe the conversion from one dopamine agonist to another.
• If treatment with a dopamine agonist is to be discontinued, pergolide should not be stopped abruptly, because rapid discontinuation of all dopamine agonist therapies can be dangerous. Instead, gradually decrease the dose of pergolide.
• Patients who will be taken off pergolide should be told that other effective options for treatment exist, including three other dopamine agonists that are not associated with damage to heart valves.

Although the companies have agreed to stop shipping pergolide for distribution, a limited supply of the drug will remain available in pharmacies. This delay will allow time for healthcare professionals and patients to discuss appropriate treatment options and to change treatments. Dr. Temple said the FDA is also discussing with manufacturers the possibility of continuing access to the drug through an IND.

Dostinex (cabergoline), another dopamine agonist, was also linked to valve disease in the NEJM papers. Dr. Temple said that drug was used in Europe for treatment of Parkinson's disease but in the U.S. it is only approved for the treatment of hyperprolactinemic disorders, which requires a much lower dose. At that lower dose, he said, there have been no reports of increased risk of valvulopathy.