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S:\NW March 29, 2007 FDA Announces Voluntary Withdrawal of Pergolide Products Agency Working with Product Manufacturers The U.S. Food and Drug Administration (FDA) today announced that manufacturers pergolide drug products, which are used to treat Parkinson’s disease will voluntarily remove these drugs from the market because of the risk of serious damage to patients’ heart valves. The products being withdrawn are Permax, the trade name for pergolide marketed by Valeant Pharmaceuticals, and two generic versions of pergolide manufactured by Par and Teva. Pergolide is in a class of medications called dopamine agonists and is used with levodopa and carbidopa to manage the symptoms (tremors and slowness of movement) of Parkinson’s disease. 10/02/03 - There have been rare reports of pleuritis, pleural effusion, pleural fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves, or retroperitoneal fibrosis in patients taking pergolide. Since Permax was first launched in the United States in 1989, a very limited number of cases have been reported to Lilly and to the FDA. Of the estimated $500,000 people who have been treated with pergolide since 1989, valvulopathy has been reported in less than 0.005%. Since Permax was first launched in the United States in 1989, a very limited number of cases have been reported to Lilly and to the FDA. Of the estimated $500,000 people who have been treated with pergolide since 1989, valvulopathy has been reported in less than 0.005%. There have been rare reports of pleuritis, pleural effusion, pleural fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves, or retroperitoneal fibrosis in patients taking pergolide. Results: 89% of pergolide-treated patients had some degree of valvular insufficiency. For each of the 3 valves for which there are control data, we found an approximately 2- to 3-fold increased risk of abnormal valves in the pergolide patients and an estimated 14fold increased risk of concerning tricuspid regurgitation. Here, we report a high prevalence of PAVHD; potentially serious valve disease was present in 44% of our patients taking pergolide who had echocardiograms. However, as the most common concerning valvular abnormality in our series was mild to moderate aortic insufficiency, which often carries a benign prognosis, it is unclear what percentage of these patients would progress to develop disabling heart disease. The ORs demonstrate that pergolide may damage heart valves, and the high prevalence of valvular disease in our pergolide-treated patients suggests that this may be a common problem. Based on this finding, we have recommended that all remaining patients come off pergolide, and we do not plan to initiate therapy with this drug in new patients unless its safety with respect to valvular heart disease can be demonstrated. Restrictive valvular heart disease is not a rare finding in patients treated with pergolide. The use of pergolide has been shown to increase the risk of cardiac valvular disease involving one or more valves. Some patients have required valve replacement, and deaths have been reported. Cases have been reported after exposures to pergolide ranging from several months to several years. The histopathology of explanted valves is similar to that of other drug-induced valvulopathies. Precise risk estimates of pergolide induced cardiac valvular disease are not available. 2007 PDR - Serous Inflammation and Fibrosis There have been rare reports of pulmonary fibrosis, pleurtits, pleural effusion, pleural fibrosis, pericarditis, pericardial: effusion, cardiac valvulopathy, involving one or more valves, or retroperitoneal fibrosis in patients taking pergolide. Fibrosis/Valvulopathy: As with other ergot derivatives, pleural effusion/pulmonary fibrosis and valvulopathy have been reported following long-term administration of cabergoline. Some reports were in patients previously treated with ergotinic dopamine agonists. Therefore, DOSTINEX should be used with caution in patients with a history of, or current signs and/or clinical symptoms of, respiratory or cardiac disorders linked to fibrotic tissue. Following diagnosis of pleural effusion/pulmonary fibrosis or valvulopathy, the discontinuance of cabergoline has been reported to result in improvement of signs and symptoms. “…findings should lead doctors to discontinue using the drugs and to tell patients to get echocardiograms to make sure they don’t have damage.” “…findings should lead doctors to discontinue using the drugs and to tell patients to get echocardiograms to make sure they don’t have damage.” “The incidence is kind of mind-blowing…” “It’s so prevalent in people taking these medications, you kind of wonder why it was missed.” Results Clinically important regurgitation (moderate to severe, grade 3 to 4) in any valve was found with significantly greater frequency in patients taking pergolide (23.4%) or cabergoline (28.6%) but not in patients taking non-ergotderived dopamine agonists (0%), a s compared with control subjects (5.6%). The relative risk for moderate or severe valve regurgitation in the pergolide group was 6.3 for mitral regurgitation (P=0.16); corresponding relative risks in the cabergoline group were 4.6 (P=0.09), 7.3 (P<0.001), and 5.5 (P=0.12). In 2000, we and others reported that norfenfluramine is a potent agonist at 5-HT2B receptors. These receptors are plentiful in human cardiac valves and appear to be essential for normal cardiac development. In 2000, we and others reported that norfenfluramine is a potent agonist at 5-HT2B receptors. These receptors are plentiful in human cardiac valves and appear to be essential for normal cardiac development. Taken together, these findings implicated activation of 5-HT2B receptors as a key step in initiating druginduced valvular heart disease. On the basis of these findings, my colleagues and I have urged pharmaceutical companies and regulatory agencies to screen candidate drugs and their major metabolites at 5-HT2B receptors comprehensively before launching clinical trials, in order to prevent "fen–phen"-type disasters.